Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.Br.Br.[NH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][C:11]([N:13]2[CH2:18][CH2:17][N:16]([CH:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)[CH2:15][CH2:14]2)=[O:12])[N:9]=1.[Cl:26][C:27]1[S:31][C:30]([C:32](O)=[O:33])=[CH:29][CH:28]=1>>[CH3:25][N:22]1[CH2:23][CH2:24][CH:19]([N:16]2[CH2:15][CH2:14][N:13]([C:11](=[O:12])[CH2:10][C:8]3[N:9]=[C:5]([NH:4][C:32]([C:30]4[S:31][C:27]([Cl:26])=[CH:28][CH:29]=4)=[O:33])[S:6][CH:7]=3)[CH2:18][CH2:17]2)[CH2:20][CH2:21]1
Reactant: O=C(O)c1ccc(Cl)s1
Reactant: CN1CCC(N2CCN(C(=O)Cc3csc(N)n3)CC2)CC1
Agent: Br
Product: CN1CCC(N2CCN(C(=O)Cc3csc(NC(=O)c4ccc(Cl)s4)n3)CC2)CC1

Procedure:
In analogy to example 47.3, 2-(2-amino-thiazol-4-yl)-1-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-ethanone trihydrobromide (example 47.2) was coupled with 5-chlorthiophene-2-carboxylic acid, using general method D, to give 5-chloro-thiophene-2-carboxylic acid (4-{2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-thiazol-2-yl)-amide. Light orange solid. MS 468.5 ([M+H]+)
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[CH:7][NH:6][C:5](=[O:9])[CH:4]=1.[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:10]([N:6]1[C:5](=[O:9])[CH:4]=[C:3]([NH:2][CH3:1])[N:8]=[CH:7]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CNc1cc(=O)[nH]cn1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CNc1cc(=O)n(Cc2ccccc2)cn1
Yield: 43.6 %

Procedure:
6-(Methylamino)pyrimidin-4(3H)-one (compound 1B; 3 g, 24 mmol, 1 eq), benzyl bromide (5.7 mL, 48 mmol, 2 eq) and potassium carbonate (6.96 g, 50.4 mmol, 2.1 eq) were stirred in ethanol (30 mL) at RT overnight. The solvent was removed in vacuo and the residue purified by silica chromatography to give 2.25 g of the title compound (43%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.64 (d, J=4.29 Hz, 3 H) 4.92-5.01 (m, 2 H) 6.96 (q, J=4.63 Hz, 1 H) 7.22-7.30 (m, 3 H) 7.30-7.37 (m, 2 H) 8.24 (s, 1 H). [M+H] calc'd for C12H13N3O, 216; found, 216.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:21])[C:9]=1[O:10][Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:5]=[O:6].O.[BH4-].[Na+].Cl>CO>[F:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:7]=[C:8]([F:21])[C:9]=1[O:10][Si:11]([CH:15]([CH3:17])[CH3:16])([CH:18]([CH3:20])[CH3:19])[CH:12]([CH3:13])[CH3:14]
Reactant: CC(C)[Si](Oc1c(F)cc(C=O)cc1F)(C(C)C)C(C)C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)[Si](Oc1c(F)cc(CO)cc1F)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
35.0 g (111 mmol) of 3,5-difluoro-4-triisopropylsilanyloxybenzaldehyde are introduced into 150 ml of water and 40 ml of methanol, cooled to 0° C. and, after addition of 8.42 g (222 mmol) of sodium borohydride in portions, stirred at RT overnight. The mixture is cautiously acidified with 1 N hydrochloric acid and extracted with ethyl acetate, and the combined organic phases are washed with saturated sodium chloride solution and dried over magnesium sulfate, and the solvent is distilled out in vacuo. Chromatography on silica gel 60 (mobile phase: cyclohexane/ethyl acetate 4:1) results in 29.5 g (93.2 mmol, 84% of theory) of the title compound.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[CH2:3][NH:4][C:5](=S)[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][S:14][CH2:15][CH2:16][N:17]2[C:21](=[O:22])[C:20]3=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]3[C:18]2=[O:27])[N:8]=1.[NH3:31]>CN(C)C=O>[F:1][C:2]([F:30])([F:29])[CH2:3][N:4]=[C:5]([NH2:31])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][S:14][CH2:15][CH2:16][N:17]2[C:21](=[O:22])[C:20]3=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]3[C:18]2=[O:27])[N:8]=1
Reactant: N
Reactant: O=C1c2ccccc2C(=O)N1CCSCc1nccc(NC(=S)NCC(F)(F)F)n1
Solvent: CN(C)C=O
Product: NC(=NCC(F)(F)F)Nc1ccnc(CSCCN2C(=O)c3ccccc3C2=O)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-[3-(2,2,2-trifluoroethyl)thioureido]-2-[(2-phthalimidoethyl)thiomethyl]pyrimidine (6.8 g.), dimethylformamide (30 ml.), saturated ethanolic ammonia (5 ml.) and yellow mercuric oxide (6.5 g.) was stirred at room temperature for 2 hours and then filtered. The filtrate was evaporated to dryness and the residue triturated with ether and filtered to give 4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[(2-phthalimidoethyl)thiomethyl]pyrimidine (5.6 g.), m.p. 167°-168° after crystallisation from ethanol.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[C:11](=[O:15])[NH:12][CH2:13][CH2:14][C:3]=12.[H-].[Na+].Cl[CH2:19][C:20]1[N:21]=[CH:22][N:23]([C:26]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:24]=1[CH3:25]>CN(C)C=O.O>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[C:11](=[O:15])[N:12]([CH2:19][C:20]3[N:21]=[CH:22][N:23]([C:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C:24]=3[CH3:25])[CH2:13][CH2:14][C:3]=12
Reactant: Cc1c2n(c3ccccc13)C(=O)NCC2
Reactant: Cc1c(CCl)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c2n(c3ccccc13)C(=O)N(Cc1ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c1C)CC2
Temperature: 5 °C
Reaction time: 0.67 h
Yield: 64.6 %

Procedure:
To a solution of 3,4-dihydro-5-methylpyrimido[1,6-a]-indol-1(2H)-one (0.67 g) in N,N-dimethylformamide (8 ml) at 5° C. was added sodium hydride (60% in mineral oil, 0.16 g). The mixture was stirred at 5° C. for 40 minutes and then at room temperature for 15 minutes and again cooled to 5° C. 4-Chloromethyl-5-methyl-1-trityl-1H-imidazole (1.50 g) was added to the solution in small portions over two minutes. After being stirred at 5° C. for 2 hours, the reaction mixture was diluted with chilled water to give precipitates. The precipitates collected were dissolved in dichloromethane. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. Column chromatography (silica, gel, 0.5% methanol in chloroform as an eluent) of the residue, followed by recrystallization from toluene-hexane, gave 3,4-dihydro-5-methyl-2-[(5-methyl-1-trityl-1H-imidazol-4-yl)methyl]pyrimido[1,6-a]indol-1 (2H)-one (1.16 g).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH3:12])[N:11]=1)[C:6]([NH2:8])=O)[CH3:2].N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl.O>[CH2:1]([C:3]1[CH:4]=[C:5]([C:6]#[N:8])[CH:9]=[C:10]([CH3:12])[N:11]=1)[CH3:2]
Reactant: CCc1cc(C(N)=O)cc(C)n1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCc1cc(C#N)cc(C)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 104.2 %

Procedure:
To a solution of 2-ethyl-6-methyl-isonicotinamide (2.85 g, 17.4 mmol) and pyridine (6.74 g, 85.2 mmol) in DCM (80 mL), trifluoroacetic anhydride (9.11 g, 43.4 mmol) is added dropwise at 0° C. The mixture is stirred at 0° C. for 1 h before it is carefully diluted with water and DCM. The mixture is washed with 4% aq. citric acid solution followed by sat. aq. NaHCO3-solution. The washings are extracted twice with DCM. The combined org. extracts are dried over MgSO4, filtered and concentrated and briefly dried under HV to give 2-ethyl-4-cyano-6-methyl-pyridine (2.65 g) as a colourless liquid; LC-MS: tR=0.58 min, [M+1]+=147.06; 1H NMR (CDCl3): δ 1.33 (t, J=7.5 Hz, 3H), 2.61 (s, 3H), 2.86 (q, J=7.8 Hz, 2H), 7.21 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:53]=[CH:52][C:6]([C:7]([O:20][CH2:21][C@@H:22]([C@H:49]([CH3:51])[OH:50])[NH:23][C:24](=[O:48])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][NH:30]C(OCC2C3C(=CC=CC=3)C3C2=CC=CC=3)=O)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.N1CCCCC1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([O:20][CH2:21][C@@H:22]([C@H:49]([CH3:51])[OH:50])[NH:23][C:24](=[O:48])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][NH2:30])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:52][CH:53]=1
Reactant: COc1ccc(C(OC[C@H](NC(=O)CCCCCNC(=O)OCC2c3ccccc3-c3ccccc32)[C@H](C)O)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: COc1ccc(C(OC[C@H](NC(=O)CCCCCN)[C@H](C)O)(c2ccccc2)c2ccccc2)cc1
Reaction time: 1 h
Yield: 71.2 %

Procedure:
14 (9.1 g, 12.77 mmol) was dissolved in DMF (100 ml) containing piperidine (10 ml) and the reaction mixture was kept at RT for about 1 hour. The solvents were removed in vacuo and the residue purified by silica gel column chromatography using 1-10% gradient of methanol in dichloromethane to afford 15 as a syrup (4.46 g, 71%). 1H-NMR 7.48-6.92 (m, 14H, aromatic), 6.16 (d, J=8.8, 1H, NH), 4.17 (m, 1H, H3 Thr), 4.02 (m, 1H, H2 Thr), 3.86 (s, 3H, OCH3), 3.50 (dd, J=9.7, J=4.4, 1H, H1 Thr), 3.37 (dd, J=9.7, J=3.4, 1H, H1′ Thr), 2.78 (t, J=6.8, 2H, CH2CO Acp), 2.33 (t, J=7.6, 2H, CH2NH Acp), 1.76 (m, 2H, CH2 Acp), 1.56 (m, 2H, CH2 Acp), 1.50 (m, 2H, CH2 Acp), 1.21 (d, J=6.4, 3H, CH3). MS/ESI+ m/z 491.5 (M+H)+.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:8]3[N:9]([C:13]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([NH:30][CH:31]5[CH2:35][CH2:34][CH2:33][CH2:32]5)[N:25]=4)=[C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([O:22]C)[CH:17]=4)[N:15]=3)[CH:10]=[CH:11][CH:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.B(Br)(Br)Br>ClCCl>[CH:1]1([NH:6][C:7]2[C:8]3[N:9]([C:13]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([NH:30][CH:31]5[CH2:35][CH2:34][CH2:33][CH2:32]5)[N:25]=4)=[C:14]([C:16]4[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=4)[N:15]=3)[CH:10]=[CH:11][CH:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cccc(-c2nc3c(NC4CCCC4)cccn3c2-c2ccnc(NC3CCCC3)n2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cccc(-c2nc3c(NC4CCCC4)cccn3c2-c2ccnc(NC3CCCC3)n2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.3 %

Procedure:
To a cold (−78° C.) solution of formed N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(3-methoxyphenyl)imidazo[1,2-α]pyridin-8-amine (42 mg, 0.09 mmol) in dichloromethane (5 mL) was added boron tribromide (0.5 mL, 1 M in dichloromethane, 0.5 mmol) dropwise. The solution was allowed to warm to room temperature over 4 hours and stirred for an additional 16 hours. The reaction was quenched by the addition of methanol followed by saturated aqueous sodium bicarbonate. Ether was added and the layers separated. The organic layer was washed with brine. The aqueous layer was extracted with ether and the combined organics were dried over magnesium sulfate. Filtration and concentration followed by flash chromatography (1:1 hexanes:ethyl acetate) provided 3-{8-(cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]imidazo[1,2-α]pyridin-2-yl}phenol (30 mg, 73%) as a yellow solid. 1H NMR (CDCl3): δ 8.90 (broad, 1H), 7.96 (d, 1H), 7.31 (s, 1H), 7.17 (t, 1H), 7.01 (d, 1H), 6.81–6.75 (m, 2H), 6.38 (d, 1H), 6.27 (d, 1H), 5.53 (d, 1H), 5.28 (d, 1H), 4.30 (m, 1H), 3.88 (m, 1H), 2.10–1.93 (m, 4H), 1.78–1.48 (m, 12H); MS m/z 455 (M+1).
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3](O)=[O:4].[CH3:7][NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)Cl>[F:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[N:8]([CH3:7])[C:3](=[O:4])[CH:2]([Br:1])[CH3:6]
Reactant: CC(Br)C(=O)O
Reactant: CNc1ccccc1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClC(Cl)Cl
Product: CC(Br)C(=O)N(C)c1ccccc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.4 %

Procedure:
2-Bromopropionic acid (3.4 g, 0.022 mol) and N-methyl-2-fluoroaniline(3 g. 0.024 mol) were dissolved in 50 ml of chloroform and cooled to 0° C. A solution of dicyclohexylcarbodiimide(5 g, 0.024 mol) in 10 ml of chloroform was slowly injected through a syringe. A temperature of the reaction mixture was raised to room temperature and it was stirred for 1 hour. Solid remained during the reaction was filtered out and washed twice with 20 ml of chloroform. The filtrate was concentrated under reduced pressure and the crude product was purified by column chromatography (eluent; ethyl acetate/n-hexane=⅓) to afford 5 g of the target product.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][NH2:15])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30](=O)[CH2:31][CH2:32][C:33](=O)[CH3:34])=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:16]([O:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[N:15]([CH2:14][CH2:13][CH2:12][C:9]3[CH:8]=[CH:7][C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:11][CH:10]=3)[C:33]([CH3:34])=[CH:32][CH:31]=2)=[CH:28][CH:29]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(=O)CCC(=O)c1ccc(OCc2ccccc2)cc1
Reactant: CCCCCc1ccc(CCCN)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCc1ccc(CCCn2c(C)ccc2-c2ccc(OCc3ccccc3)cc2)cc1
Yield: 75 %

Procedure:
A solution of 3-(4-pentylphenyl)propylamine (1.8 g, 8.8 mmol) and 1-(4-benzyloxyphenyl)-1,4-pentanedione (2.43 g, 8.7 mmol) and p-toluenesulfonic acid monohydrate (200 mg) in toluene (30 ml) was refluxed for 12 hours under heating and the solvent was removed under reduced pressure. The residue was silica gel chromatography (hexane:ethyl acetate=9:1) to give the object compound as an oily substance. 2.99 g, (yield 75%)
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[Br:13][CH2:14][CH2:15][CH2:16][CH2:17]Br.C([O-])([O-])=O.[K+].[K+]>CCO.O>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: BrCCCCBr
Reactant: O=c1ccc2ccc(O)cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=c1ccc2ccc(OCCCCBr)cc2[nH]1
Yield: 41.4 %

Procedure:
A mixture of intermediate 14 (193 mg, 1.2 mmol), 1,4-dibromobutane (0.43 mL, 3.6 mmol) and anhydrous K2CO3 (166 mg, 1.2 mmol) was dissolved in EtOH and the solution was heated to reflux overnight. The solution was diluted with water and extracted with EtOAc. The combined organic layers was washed with saturated aq NaHCO3, brine, dried over anhydrous Na2SO4, concentrated in vacuo and purified by flash chromatography on silica gel column (elution with PE/EtOAc=2:1) to give 7-(4-bromobutoxy)quinolin-2(1H)-one (intermediate 15) (147 mg, 41%) as a yellow solid.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12]OS(C)(=O)=O)=[CH:8][C:7]([C:18]3[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[CH:20][CH:19]=3)=[N:6]2)[CH2:3][CH2:2]1.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12][N:30]3[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]3)=[CH:8][C:7]([C:18]3[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[CH:20][CH:19]=3)=[N:6]2)[CH2:2][CH2:3]1
Reactant: CN1CCNCC1
Reactant: CSc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC3CC3)n2)cc1
Product: CSc1ccc(-c2cc(CN3CCN(C)CC3)c(=O)n(CC3CC3)n2)cc1
Yield: 85.7 %

Procedure:
Following the procedure of Example 1(10), 2-cyclopropylmethyl-4-methanesulfonyloxymethyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one and 1-methyl-piperazine were reacted to yield the title compound as a yellow oil (yield: 85.7%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9]C)=[O:8])=[CH:5][C:4]=1[CH2:13][N:14]1[CH2:19][CH2:18][N:17]([C:20](=[O:37])[C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:29])=[CH:23][CH:22]=2)[CH2:16][CH2:15]1.[OH-].[Li+].O>CO>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[CH2:13][N:14]1[CH2:19][CH2:18][N:17]([C:20](=[O:37])[C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:29])=[CH:23][CH:22]=2)[CH2:16][CH2:15]1
Reactant: COC(=O)c1ccc(OC)c(CN2CCN(C(=O)c3ccc(NC(=O)Nc4ccccc4)cc3)CC2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(C(=O)O)cc1CN1CCN(C(=O)c2ccc(NC(=O)Nc3ccccc3)cc2)CC1
Temperature: 45 °C
Reaction time: 8 h
Yield: 37.1 %

Procedure:
Methyl 4-methoxy-3-((4-(4-(3-phenylureido)benzoyl)piperazin-1-yl)methyl)benzoate (216 mg, 0.43 mmol) was dissolved in methanol (20 mL) at room temperature. Lithium hydroxide (51.5 mg, 2.15 mmol) was added, followed by water (1 mL). The mixture was stirred at 45° C. overnight and concentrated under vacuum. The residue was dissolved in water (15 mL) and brought to pH ˜3 with 1M aqueous hydrochloric acid. The mixture was extracted with ethyl acetate (×2) and with dichloromethane (×2). The combined organic phases were dried on magnesium sulfate, filtered and concentrated under vacuum. The residue was submitted to silica chromatography (0-10% methanol in dichloromethane as eluant) to give the title compound (78 mg). MS (ESI) m/z 489.1 [M+H]+
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:14]=[C:7]2[C:8]([O:10][C:11](=O)[NH:12][C:6]2=[CH:5][CH:4]=1)=[O:9].[NH:17]([CH2:19]C(O)=O)[CH3:18].O>CS(C)=O>[CH3:18][N:17]1[C:8](=[O:9])[C:7]2[CH:14]=[C:3]([C:2]([F:16])([F:15])[F:1])[CH:4]=[CH:5][C:6]=2[NH:12][C:11](=[O:10])[CH2:19]1
Reactant: CNCC(=O)O
Reactant: O=c1[nH]c2ccc(C(F)(F)F)cc2c(=O)o1
Solvent: CS(C)=O
Solvent: O
Product: CN1CC(=O)Nc2ccc(C(F)(F)F)cc2C1=O
Temperature: 110 °C
Reaction time: 4 h

Procedure:
A suspension of 5.76 g (24.9 mmol) of 5-(trifluoromethyl)isatoic acid anhydride and 2.44 g (27.4 mmol) of sarcosine in 8 ml of dimethyl sulphoxide is stirred at 110° C. for 4 hours, subsequently poured into 70 ml of water and evaporated to dryness in vacuo. After column chromatography on silica gel using ethyl acetate/n-hexane (9:1) for the elution and recrystallization of the product from ethanol, there is obtained 3,4-dihydro-4-methyl-7-(trifluoromethyl)-2H-1,4-benzodiazepine-2,5(1H)-dione of melting point 203°-206° C.
Reaction SMILES: [CH3:1][C:2]1O[CH:4]=[CH:5][C:6](=[O:25])[C:7]=1[O:8][CH2:9][C@:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[F:26][C:27]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:28]=1[CH2:29][NH2:30]>C(O)C>[F:26][C:27]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:28]=1[CH2:29][N:30]1[CH:4]=[CH:5][C:6](=[O:25])[C:7]([O:8][CH2:9][C@:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])([NH2:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:2]1[CH3:1]
Reactant: Cc1occc(=O)c1OC[C@@](N)(C(=O)OC(C)(C)C)c1ccccc1
Reactant: NCc1c(F)cccc1F
Solvent: CCO
Product: Cc1c(OC[C@@](N)(C(=O)OC(C)(C)C)c2ccccc2)c(=O)ccn1Cc1c(F)cccc1F
Temperature: 120 °C
Reaction time: 16 h

Procedure:
Crude 2-methyl-3-[(2R)-Boc-amino-2-phenylethoxy]-4H-pyran-4-one (1.00 g, ˜2.90 mmol), 2,6-difluorobenzyl amine (700 μL, 5.8 mmol) and ethanol (3 mL) were combined and heated to 120° C. in a pressure vessel. After 16 h, the volatiles were removed in vacuo and the residue purified by column chromatography, eluting with EtOAc. The product was isolated as a white foam (204 mg, 0.43 mmol, 15%, assuming pure starting material). 1H NMR (CDCl3-300 MHz) δ 7.42-7.19 (m, 7H); 6.98 (t, J=8.1 Hz, 2H); 6.43 (d, J=7.8 Hz, 1H); 5.06 (s, 2H); 4.87-4.83 (m, 1H); 4.06 (dd, J1=9.9 Hz, J2=4.2 Hz, 1H); 3.93 (dd, J=9.9 Hz, J2=6.8 Hz, 1H); 2.34 (s, 3H); 1.42 (s, 9H); LRMS m/z 471.1 (M++1), 371.0 (M+−boc+1).
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]([C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=1[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:6])[CH3:5].[OH-].[Li+].Cl.C(OCC)(=O)C>O1CCOCC1>[CH2:17]([O:16][C:8]1[CH:9]=[CH:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][C:7]=1[C:4]([CH3:6])([CH3:5])[C:3]([OH:24])=[O:2])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)C(C)(C)c1cc([N+](=O)[O-])ccc1OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C(=O)O)c1cc([N+](=O)[O-])ccc1OCc1ccccc1
Temperature: 100 °C
Yield: 91.9 %

Procedure:
To the compound (1.54 g) obtained in Example 562 in 1, 4-dioxane (20 ml) was added an aqueous lithium hydroxide solution (1.0M, 47 ml). The reaction mixture was heated under reflux at 100° C. for 12 h and then 2 N HCl and ethyl acetate were added. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was recrystallized from ethyl acetate to give 1.355 g of the titled compound (yield, 92%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([O:21]C4C(F)=C(F)C(F)=C(F)C=4F)(=[O:20])=O)=[CH:15][CH:16]=3)[CH:11]=[CH:10][C:9]2=[O:33])=[C:4]([O:34][CH3:35])[CH:3]=1.[N:36]1[CH:41]=[CH:40][CH:39]=[C:38]([NH2:42])[N:37]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([NH:42][C:38]4[N:37]=[N:36][CH:41]=[CH:40][CH:39]=4)(=[O:20])=[O:21])=[CH:15][CH:16]=3)[CH:11]=[CH:10][C:9]2=[O:33])=[C:4]([O:34][CH3:35])[CH:3]=1
Reactant: COc1cc(Br)ccc1-n1c(=O)ccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc21
Reactant: Nc1cccnn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(Br)ccc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3cccnn3)ccc21
Temperature: 0 °C
Yield: 120.4 %

Procedure:
A flask was charged with perfluorophenyl 1-(4-bromo-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (3.33 g, 5.78 mmol) and pyridazin-3-amine (0.659 g, 6.93 mmol). A septum was attached and THF (28.9 ml) was added. The mixture was cooled to 0° C. and a THF solution of lithium bis(trimethylsilyl)amide (12.13 ml, 12.13 mmol, 1 M) was added dropwise to give a brown solution. The solution was maintained at 0° C. for 20 min. The reaction mixture was partitioned between 1 N HCl (200 mL) and EtOAc (200 mL), the layers were separated and the aqueous layer was extracted with DCM (100 mL) and EtOAc (200 mL). The combined organic layers were dried (Na2SO4) and concentrated to provide 1-(4-bromo-2-methoxyphenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide (3.39 g, 6.96 mmol, 120% yield) as a light yellow foam. Although contaminated with solvent, the product was of sufficient purity for use in the next step. m/z (ESI) 485.1 (M−H)−.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:14][OH:15])[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[S:5][CH2:4]1.I([O-])(=O)(=O)=[O:17].[Na+]>CO.O>[OH:15][CH2:14][C:3]1([CH2:2][OH:1])[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[S:5](=[O:17])[CH2:4]1
Reactant: O=C1c2ccccc2SCC1(CO)CO
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C1c2ccccc2S(=O)CC1(CO)CO
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 3,3-bis(hydroxymethyl)thiochroman-4-one (200 mg, 0.9 mmol) in MeOH (5 ml) was admixed with a solution of sodium metaperiodate (206 mg, 0.96 mmol) in water (2 ml) and stirred at RT for 72 h. The reaction mixture was diluted with water (10 ml) and extracted with EtOAc (3×30 ml), the combined organic phases were dried over sodium sulfate and the solvent was removed under reduced pressure. After column chromatography purification of the residue (silica gel, EtOAc), the desired product was obtained as a white solid (113 mg, 52% of theory, m.p. 108-111° C.).
Reaction SMILES: [O:1]=[C:2]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[C:16]([Cl:19])[C:17]=1[Cl:18])[CH2:14][CH:13]([CH2:20][CH3:21])[CH2:12]2)[C:3]1[NH:7][N:6]=[N:5][N:4]=1.[BH4-].[K+]>O>[OH:1][CH:2]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[C:16]([Cl:19])[C:17]=1[Cl:18])[CH2:14][CH:13]([CH2:20][CH3:21])[CH2:12]2)[C:3]1[NH:7][N:6]=[N:5][N:4]=1
Reactant: CCC1Cc2cc(OC(=O)c3nnn[nH]3)c(Cl)c(Cl)c2C1
Agent: [BH4-]
Agent: [K+]
Solvent: O
Product: CCC1Cc2cc(OC(O)c3nnn[nH]3)c(Cl)c(Cl)c2C1

Procedure:
5-(1-Hydroxy-2-ethyl-6,7-dichloro-5-indanyloxymethyl)tetrazole is prepared following substantially the same procedure described in Example 1, using the following substances: 5-(1-oxo-2-ethyl-6,7-dichloro-5-indanyloxymethyl)tetrazole (6.54 g., 0.02 mole); potassium borohydride (2.0 g.); and water (200 ml.).