Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([CH:6]([Cl:15])[C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=2)=[CH:4][CH:3]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:37].Cl.Cl>C(OCC)(=O)C>[ClH:15].[ClH:37].[Br:1][C:2]1[CH:17]=[CH:16][C:5]([CH:6]([N:22]2[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]2)[C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=2)=[CH:4][CH:3]=1
Reactant: CN1CCNCC1
Reactant: COc1cccc(C(Cl)c2ccc(Br)cc2)c1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CCOC(C)=O
Product: COc1cccc(C(c2ccc(Br)cc2)N2CCN(C)CC2)c1
Temperature: 25 °C

Procedure:
The crude benzhydryl chloride from above (6.5 g, 21 mmole) was added to 8.3 g (83 mmole) of 1-methylpiperazine and the reaction was heated to reflux for four hours. After cooling to room temperature, the mixture was dissolved in 100 ml of ethyl acetate and washed with two 150 ml portions of 1.0 M sodium hydroxide, followed by two 150 ml portions of water and 100 ml of saturated aqueous sodium chloride. The solution was dried over magnesium sulfate and the solvent removed to give 6.5 g of crude product as an oil. The product was purified by chromatography on silica gel (Waters Prep 500) with dichloromethane:ethanol:triethylamine (100:0.2:0.1) to give a colorless oil. A portion was converted to the dihydrochloride salt with ethanolic hydrochloric acid and precipitated from ethanol with 1:1 hexane:diethyl ether to give 1-(α-(4-bromophenyl)-3-methoxybenzyl)-4-methylpiperazine dihydrochloride as a white powdery solid, mp. 195°-197° C. Calc. for C19H23BrN2O 2HCl: C, 50.91; H, 5.62; N, 6.25; Total halogen calc. as Cl, 23.73. Found: C, 51.00; H, 5.66; N, 6.23; Total halogen calc. as Cl, 23.78.
Reaction SMILES: CN1CCN([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[N:20]=[C:19]([C:21]4[C:22]([C:26]5[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=5)=[N:23][NH:24][CH:25]=4)[CH:18]=[CH:17][N:16]=3)=[CH:10][CH:9]=2)CC1.NC1C=CC([S:40]([NH2:43])(=[O:42])=[O:41])=CC=1>>[C:29]1([CH3:32])[CH:30]=[CH:31][C:26]([C:22]2[C:21]([C:19]3[CH:18]=[CH:17][N:16]=[C:15]([NH:14][C:11]4[CH:12]=[CH:13][C:8]([S:40]([NH2:43])(=[O:42])=[O:41])=[CH:9][CH:10]=4)[N:20]=3)=[CH:25][NH:24][N:23]=2)=[CH:27][CH:28]=1
Reactant: Cc1ccc(-c2n[nH]cc2-c2ccnc(Nc3ccc(N4CCN(C)CC4)cc3)n2)cc1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Product: Cc1ccc(-c2n[nH]cc2-c2ccnc(Nc3ccc(S(N)(=O)=O)cc3)n2)cc1

Procedure:
The title compound is prepared as described in Example 1 using ethyl-4-methylbenzoate (see Example 25) and 4-amino-benzenesulfonamide.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([Cl:20])=[C:12]([N+:17]([O-:19])=[O:18])[CH:13]=2)[NH:8][CH:7]=1)=[O:5])C.[OH-].[Na+].Cl>C(O)C>[Cl:20][C:11]1[CH:10]=[C:9]2[C:14]([C:15](=[O:16])[C:6]([C:4]([OH:5])=[O:3])=[CH:7][NH:8]2)=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18]
Reactant: CCOC(=O)c1c[nH]c2cc(Cl)c([N+](=O)[O-])cc2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1c[nH]c2cc(Cl)c([N+](=O)[O-])cc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.8 %

Procedure:
A mixture of 12.0 g (40.5 mmol) of 7-chloro-6-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (J. Med. Chem. 23, 1358 (1980)) and 60.0 mL of 2.5 N sodium hydroxide in 160.0 mL of ethanol is heated at reflux temperature for 1.5 hours. After allowing the reaction mixture to cool to room temperature, it is further cooled in an ice bath, brought to pH 4 with 4.0 N hydrochloric acid and stirred for 0.5 hour. The solid is collected by filtration, washed with water and dried in vacuo to yield 10.1 g of 7-chloro-6-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid as a tan solid, mp 294-297° C.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][C:13]1([CH3:26])[CH:22]([CH2:23][CH2:24][OH:25])[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[O:14]1>N1C=CC=CC=1>[CH3:12][C:13]1([CH3:26])[CH:22]([CH2:23][CH2:24][O:25][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[O:14]1
Reactant: CC1(C)Oc2ccccc2CC1CCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCC2Cc3ccccc3OC2(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
38 g (0.2 mol) of 4-toluenesulfonyl chloride are added at room temperature, while stirring, to a solution of 37.1 g (0.18 mol) of 2,2-dimethyl-3-(2-hydroxyethyl)-chroman in 150 ml of pyridine, the slightly exothermic reaction being maintained at room temperature with an ice bath. The mixture is then stirred for 4 hours at room temperature. The reaction mixture is then poured onto ice-water and extracted with diethyl ether. The combined ethereal phases are washed three times using 150 ml of citric acid solution (5%) each time and three times using 150 ml of water each time, then dried over sodium sulfate and concentrated by evaporation, yielding 59.1 g (89% of the theoretical yield) of 2,2-dimethyl-3-[2-(4-toluenesulfonyloxy)-ethyl]-chroman in the form of a yellow oil which is further used in that form.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].[H-].[Na+].[O:15]1[CH2:18][CH:17](O)[CH2:16]1>CN(C=O)C>[CH3:12][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[O:1][CH:17]1[CH2:18][O:15][CH2:16]1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(O)c(C)c1
Reactant: OC1COC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC2COC2)c(C)c1
Temperature: 80 °C

Procedure:
To methyl 4-hydroxy-3-methyl-benzoate (498 mg, 3 mmol) was added DMF (3 mL) and sodium hydride (240 mg, 6.0 mmol) followed by oxetan-3-ol (445 mg, 6 mmol) and the reaction mixture was heated at 80° C. for 4 hours. The reaction was cooled and quenched with brine solution and extracted with EtOAc (3×10 mL). The organic layer was separated and dried over sodium sulfate and evaporated to give methyl 3-methyl-4-(oxetan-3-yloxy)benzoate. To methyl 3-methyl-4-(oxetan-3-yloxy)benzoate was added sodium hydroxide (3 mL of 1 M NaOH, 3 mmol) solution and the reaction mixture was stirred for 1 hour. The reaction was acidified with 1 M HCl solution to pH 3 and extracted with EtOAc. The organics were separated and dried and concentrated in vacuo to give 3-methyl-4-(oxetan-3-yloxy)benzoic acid. ESI-MS m/z calc. 208.1. Found 209.3 (M+1)+; Retention time: 1.04 minutes (3 min run).
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[CH3:16][C:17]([C:20]1[CH:27]=[CH:26][C:23](C=O)=[CH:22][CH:21]=1)([CH3:19])[CH3:18]>CCCCCC.O1CCCC1>[CH3:16][C:17]([C:20]1[CH:27]=[CH:26][C:23]([CH:8]2[O:7][C:1](=[O:6])[CH:2]=[C:3]([OH:4])[CH2:5]2)=[CH:22][CH:21]=1)([CH3:19])[CH3:18]
Reactant: COC(=O)CC(C)=O
Reactant: CC(C)(C)c1ccc(C=O)cc1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(C2CC(O)=CC(=O)O2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
The title compound was prepared as described in General Method 1 using 5.0 mL of methyl acetoacetate, 2.0 g of NaH 60% dispersion in oil, 31.5 mL of 1.6M n-butyl lithium in hexane, 9.0 g of 4-(1,1-dimethylethyl)benzaldehyde and 100 mL of tetrahydrofuran. After addition of the aldehyde, the reaction was stirred for 15 minutes at 0° C. then allowed to warm to room temperature overnight. The crude product was triturated from diethyl ether to afford a solid (m.p. 164°-165° C.). 1 H NMR (CDCl3) δ 1.33 (s, 9 H), 2.94 (dd, 2 H), 3.59 (dd, 2 H), 5.69 (dd, 1 H), 7.31-7.47 (m, 4 H).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]([C:13]3[NH:14][C:15]4[C:20]([CH:21]=3)=[CH:19][C:18]([C:22]([N:24]3[CH2:29][CH2:28][N:27]([CH:30]([CH3:32])[CH3:31])[CH2:26][CH2:25]3)=[O:23])=[CH:17][CH:16]=4)=[O:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[H-].[Na+].[CH:35]1([CH2:38]Br)[CH2:37][CH2:36]1>CN(C)C=O>[CH:35]1([CH2:38][N:14]2[C:15]3[C:20](=[CH:19][C:18]([C:22]([N:24]4[CH2:25][CH2:26][N:27]([CH:30]([CH3:32])[CH3:31])[CH2:28][CH2:29]4)=[O:23])=[CH:17][CH:16]=3)[CH:21]=[C:13]2[C:11]([N:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)=[O:12])[CH2:37][CH2:36]1
Reactant: BrCC1CC1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC5(CC4)OCCO5)cc3c2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC4(CC2)OCCO4)n3CC2CC2)CC1
Yield: 76 %

Procedure:
The title compound was synthesized in analogy to example 51, from (1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 196), sodium hydride and cyclopropylmethyl bromide in N,N-dimethylformamide, to give the desired product as a colorless foam (76%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:19][CH2:20][CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:9][C:10]=2[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[N:5]=[CH:4][N:3]=1.[CH2:27]1[O:36][C:35]2[C:29](=[C:30]([CH:32]=[CH:33][CH:34]=2)[NH2:31])[O:28]1.[ClH:37]>C(O)(C)C>[ClH:1].[ClH:37].[ClH:1].[CH2:27]1[O:36][C:35]2[C:29](=[C:30]([CH:32]=[CH:33][CH:34]=2)[NH:31][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:19][CH2:20][CH2:21][N:22]4[CH2:23][CH2:24][CH2:25][CH2:26]4)=[CH:9][C:10]=3[N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[N:5]=[CH:4][N:3]=2)[O:28]1
Reactant: Nc1cccc2c1OCO2
Reactant: CN1CCN(c2cc(OCCN3CCCC3)cc3ncnc(Cl)c23)CC1
Agent: Cl
Solvent: CC(C)O
Product: CN1CCN(c2cc(OCCN3CCCC3)cc3ncnc(Nc4cccc5c4OCO5)c23)CC1

Procedure:
Using an analogous procedure to that described in Example 5, 4-chloro-5-(4-methylpiperazin-1-yl)-7-(2-pyrrolidin-1-ylethoxy)quinazoline (0.11 g) was reacted with 2,3-methylenedioxyaniline (0.045 g) in the presence of a 6M solution of hydrogen chloride in isopropanol to give the title compound, as a trihydrochloride salt (0.105 g), a portion of which was converted into the free base using an analogous procedure to that described in Example 3. The free base gave the following characterising data: NMR Spectrum: (CDCl3) 1.78 (br s, 4H), 2.3 (s, 3H), 2.5 (m, 2H), 2.6 (br s, 4H), 2.8 (d, 2H), 2.95 (m, 4H), 3.08 (d, 2H), 4.18 (m, 2H), 5.98 (s, 2H), 6.6 (d, 1H), 6.86 (m, 1H), 6.94 (s, 1H), 8.06 (d, 1H), 8.5 (s, 1H), 11.8 (s, 1H); Mass Spectrum: M+H+ 477.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=2)([CH3:14])[N:13]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[Br:28][C:29]1[CH:38]=[CH:37][C:32]2[C:33](Cl)=[N:34][S:35][C:31]=2[CH:30]=1>C1COCC1>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:33]3[C:32]4[CH:37]=[CH:38][C:29]([Br:28])=[CH:30][C:31]=4[S:35][N:34]=3)[CH:16]=2)([CH3:14])[N:13]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Clc1nsc2cc(Br)ccc12
Reactant: CC(C)(C)OC(=O)NC1=NC(C)(c2cccc(N)c2)COC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1=NC(C)(c2cccc(Nc3nsc4cc(Br)ccc34)c2)COC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of [5-(3-amino-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester (51 mg, 0.167 mmol) in THF (2 ml) was stirred at −78° C. under nitrogen. Butyllithium (1.6 M solution in hexanes, 0.26 ml, 0.418 mmol) was added at once. After 10 minutes a solution of 6-bromo-3-chloro-benzo[d]isothiazole (WO 2006091858, page 132; 52 mg, 0.209 mmol) in 0.4 ml THF was added rapidly. After stirring for 30 minutes the mixture was quenched with 5% aq. NH4Cl and warmed to rt. The mixture was extracted with EtOAc, and the organic phase was washed with brine, dried with Na2SO4 and evaporated under reduced pressure. The residue was purified by chromatography on silica gel (hexanes/20-35% EtOAc) to yield the title compound.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[CH2:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH:10]1[CH:18]=[O:19]>CS(C)=O>[CH2:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:9][CH:10]1[CH:18]1[CH2:4][O:19]1
Reactant: C[S+](C)(C)=O
Reactant: O=CC1Cc2ccccc2C1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: c1ccc2c(c1)CC(C1CO1)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.5 %

Procedure:
To a mixture containing NaH (9.8 mg, 0.2 mmol) and trimethylsulfoxoniumiodide (57.8 mg, 0.26 mmol) was added slowly DMSO (0.44 ml). After 30 minutes stirring at room temperature, a solution of indan-2-carbaldehyde (32 mg, 0.22 mmol) in DMSO (0.1 ml) was added. The reaction mixture was stirred 18 hours at room temperature and then quenched with H2O. The aqueous phase was extracted with ethylacetate, combined organic phases were dried over Na2SO4, filtered and concentrated. The residue was chromatographed over silica gel (hexane-ethylacetate 98:2) to provide (RS)-2-indan-2-yl-oxirane (9 mg, 26%) as a colorless oil, MS: m/e=160.0 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C([O-])([O-])=O.[Na+].[Na+].[CH2:17]([O:24][CH2:25][CH2:26][OH:27])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CS(C)=O.O>[CH2:17]([O:24][CH2:25][CH2:26][O:27][C:8]1[CH:7]=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([Br:1])[CH:9]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=Cc1ccc(F)cc1Br
Reactant: OCCOCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=Cc1ccc(OCCOCc2ccccc2)cc1Br
Temperature: 130 °C

Procedure:
A mixture of 2-bromo-4-fluoro-benzaldehyde (32.0 g, 157 mmol), Na2CO3 (85.5 g, 788 mmol), and 2-benzyloxy ethanol (24.0 g, 158 mmol) in anhydrous DMSO (300 mL) were heated under N2 at 130° C. (bath temp) for 18 h. The reaction mixture cooled to rt, diluted with H2O (100 mL), and extracted with EtOAc The organic layer was washed with H2O then brine, dried (MgSO4), and concentrated in vacuo The residue was purified by flash chromatography (hexane to 10% EtOAc in hexane) to give the title compound as a viscous liquid: yield 11.8 g (22%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6]1=[O:14].[C:15]1([CH:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C>O>[C:28]1([CH:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:22]2[CH2:23][CH2:24][N:25]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=4[NH:7][C:6]3=[O:14])[CH2:26][CH2:27]2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: O=c1[nH]c2ccccc2n1CCCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: O=c1[nH]c2ccccc2n1CCCN1CCN(C(c2ccccc2)c2ccccc2)CC1

Procedure:
A mixture of 5.3 parts of 1-(3-chloropropyl)-1,3-dihydro-2H-benzimidazol-2-one, 5-parts of 1-(diphenylmethyl)piperazine, 6.4 parts of sodium carbonate and 200 parts of 4-methyl-2-pentanone is stirred and refluxed overnight with water-separator. After cooling, water is added and the layers are separated. The 4-methyl-2-pentanone-phase is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 5% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The oily residue is crystallized from a mixture of 2,2'-oxybispropane and a small amount of 2-propanol. The product is filtered off and dried, yielding 1-{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one; mp. 153.6° C.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][C@H:12]([CH2:21][OH:22])[CH2:13][CH:14]([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17])=[C:4](Cl)[N:3]=1.[OH-].[K+].C(O)(=[O:28])C>O>[CH2:16]([O:15][CH:14]([O:18][CH2:19][CH3:20])[CH2:13][C@@H:12]([CH2:21][OH:22])[CH2:11][N:8]1[CH:7]=[N:6][C:5]2[C:4](=[O:28])[NH:3][C:2]([NH2:1])=[N:10][C:9]1=2)[CH3:17]
Reactant: CC(=O)O
Reactant: CCOC(C[C@@H](CO)Cn1cnc2c(Cl)nc(N)nc21)OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCOC(C[C@@H](CO)Cn1cnc2c(=O)[nH]c(N)nc21)OCC
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
To the product of Example 30, step a) (22.5 kg, 65.4 moles) was added an aqueous solution of KOH (prepared by dissolving 12.9 kg of KOH in 225 kg of water). This mixture was refluxed for 16 hours. The reaction was cooled to about room temperature and filtered into a larger reactor equipped with a pH electrode standardized to pH 7–10. The filtered solution was cooled to 5° C. and the product precipitated by slow addition of dilute acetic acid solution (prepared by mixing glacial acetic acid (12.6 kg, 210 moles) with 75 kg of water and cooling the mixture to 5° C.) until the pH is between 7.5 and 9.0 (target 8.5). The resulting slurry was immediately filtered and the filter cake was recharged back to the reactor. The reactor was charged with 225 kg of distilled water. The mixture was heated to not more than 50° C. for 30 minutes, then cooled to 15±10° C. and stirred for 30 minutes. The resulting precipitate was filtered by vacuum filtration, rinsed with 50 kg of distilled water and dried in a vacuum oven at not more than 45° C. for not less than 8 hours to provide the desired product as a tan solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4[CH:19]=[CH:20][NH:21][C:15]=4[CH:14]3[CH3:22])=[O:12])[CH:10]=2)[CH:7]=1.[NH:23]1[CH:27]=[N:26][N:25]=[N:24]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4[CH:19]=[CH:20][N:21]([C:27]5[NH:26][N:25]=[N:24][N:23]=5)[C:15]=4[CH:14]3[CH3:22])=[O:12])[CH:10]=2)[CH:7]=1
Reactant: c1nnn[nH]1
Reactant: CC1c2[nH]ccc2CCN1C(=O)c1cc2ncc(Br)cn2n1
Product: CC1c2c(ccn2-c2nnn[nH]2)CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 52, (6-bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(7-methyl-1,4,5,7-tetrahydro-pyrrolo[2,3-c]pyridin-6-yl)-methanone is reacted with 1H tetrazole to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:10]C)[CH:5]=[C:6]([O:8]C)[CH:7]=1.B(Br)(Br)Br>C(Cl)Cl.O>[Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([OH:10])[CH:3]=1
Reactant: COc1cc(Cl)cc(OC)c1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Oc1cc(O)cc(Cl)c1
Temperature: 25 °C

Procedure:
A solution of 5-chloro-1,3-dimethoxybenzene (5.41 g, 31.3 mM) in methylene chloride (75 mL) at −78° C. was stirred with a 1M solution of BBr3 in methylene chloride (63 mL) for 45 minutes. The reaction was allowed to warm to room temperature overnight and diluted with water (75 mL). The layers were separated and the aqueous layer washed two times with methylene chloride. The aqueous layer was acidified with 1N HCl and extracted 3 times with ethyl acetate. The combined organic layers were washed with 1N sodium thiosulfate (1×35 mL) and water (1×25 mL). The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure and purified by chromatography (methylene chloride/acetone) to provide the titled compound. MS ESI(−)) m/e 143 (M−H)+; 1H NMR (300 MHz, CDCl3) δ 6.45 (d, 2H), 6.25 (t, 1H), 5.41 (bs, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.[CH2:18]1[O:27][C:26]2[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][C:20]=2[O:19]1>>[CH2:18]1[O:27][C:26]2[CH:25]=[CH:24][C:22]([NH:23][C:2]3[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[N:3]=3)=[CH:21][C:20]=2[O:19]1
Reactant: Nc1ccc2c(c1)OCO2
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccccc2)n1
Product: FC(F)(F)c1cc(Nc2ccc3c(c2)OCO3)nc(-c2ccccc2)n1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-phenyl-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 3,4-methylenedioxyaniline (40 mg, 0.290 mmol) similar to Example 77 and isolated as a tan solid (16 mg, 23%). 1H NMR (CDCl3): 8.44–8.40 (m, 2H), 7.50–7.45 (m, 3H), 7.02 (s, 1H), 6.91 (s, 1H), 6.85 (d, J=8.1 Hz, 1H), 6.78 (dd, J=2.0, 8.3 Hz, 1H), 6.71 (s, 1H), 6.03 (s, 2H).
Reaction SMILES: CCCC[Sn]([O:14][Sn:15]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19])(CCCC)CCCC.[CH3:28][N:29]([CH3:34])[CH2:30][CH:31](O)[CH3:32].O>C1C=CC=CC=1>[CH2:24]([Sn:15]([O:14][CH:31]([CH3:32])[CH2:30][N:29]([CH3:34])[CH3:28])([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:25][CH2:26][CH3:27]
Reactant: CC(O)CN(C)C
Reactant: CCCC[Sn](CCCC)(CCCC)O[Sn](CCCC)(CCCC)CCCC
Solvent: O
Solvent: c1ccccc1
Product: CCCC[Sn](CCCC)(CCCC)OC(C)CN(C)C

Procedure:
1-Dimethylamino-2-Propyl Tributylstannyl Ether is prepared from 89.4 gm (0.15 mole) bis(tributyltin) oxide and 30.9 gm (0.3 mole) 1-dimethylamino-2-propanol in 200 ml benzene. This is stirred and heated to reflux in a system that contains a Dean-Starke tube. After refluxing 23 hours a total of 2.6 ml of water (theory 2.7 ml) had collected in the Dean-Starke tube. The solvent is stripped off on a rotating evaporator to provide 111.0 gm of yellow liquid. This is fractionated at reduced pressure with collection at 167°-175° C. at 0.5 mm of 63.4 gm of straw colored liquid. (Percent yield - 54). Infrared spectral analysis shows this liquid to be the desired ether.
Reaction SMILES: [CH2:1]1[O:3][CH:2]1[CH2:4][OH:5].[CH3:6][NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>C1(C)C=CC=CC=1>[CH3:6][N:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:1][CH:2]([OH:3])[CH2:4][OH:5]
Reactant: OCC1CO1
Reactant: CCCCCCCCCCCCCCCCCCNC
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCN(C)CC(O)CO
Reaction time: 3 h
Yield: 74.6 %

Procedure:
A mixture of glycidol (4 ml, 60 mmol) and N-methyl-octadecylamine (16 g, 60 mmol) in dry toluene (50 ml) was refluxed under stirring for 3 hours. After evaporation of the solvent, the residue was crystallized to yield 16 g (84%) of the title compound. m.p. 59° C. (Hexane).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH2:13]([OH:16])[C:14]#[CH:15]>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>[N:8]1([C:5]2[CH:6]=[CH:7][C:2]([C:15]#[C:14][CH2:13][OH:16])=[CH:3][CH:4]=2)[CH:12]=[CH:11][CH:10]=[N:9]1
Reactant: Brc1ccc(-n2cccn2)cc1
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Product: OCC#Cc1ccc(-n2cccn2)cc1
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 36.7 %

Procedure:
A mixture of 1-(4-bromophenyl)-1H-pyrazole (prepared as described in Bull. Soc. Chim. Fr. 1966, 2832) (2.24 g, 10.04 mmol), Pd(Ph3P)2Cl2 (180 mg, 0.26 mmol), and copper(I) iodide (95 mg, 0.50 mmol) in TEA (20 mL) was stirred for 5 min, propargyl alcohol (0.70 mL, 12.02 mmol) was added, and the mixture was heated to 80° C. for 48 h. The volatiles were evaporated, ethyl acetate (50 mL) and water (50 mL) were added to the residue, and the mixture was filtered through a pad of Celite. The organic layer from the filtrate was washed with brine (50 mL), dried (Na2SO4), and concentrated. Purification by chromatography (SiO2, 3:2 hexane/ethyl acetate) yielded 0.73 g (37%) of the title compound as a brown solid. MS 199 (M+H)+.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:16])([C:9]1C=CC(C)=CC=1)[CH2:7][OH:8].[Li+].[BH4-].CO>C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:16])([CH3:9])[CH2:7][OH:8]
Reactant: Cc1ccc(C(C)(CO)CCCCBr)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(CO)CCCCBr
Yield: 99 %

Procedure:
According to the procedure described for the synthesis of 206e (Ackerley, N. et al. J. Med. Chem. 1995, 38, 1608-1628; Manley, P. W. et al. J. Med. Chem. 1987, 30, 1812-1818), 205c (500.0 g, 2.0 mol) was reacted with LiBH4 (65.0 g, 3.0 mol) and methanol (95.0 g, 3.0 mol) in CH2Cl2 (6.0 L) to afford 206c (417.0 g, 99%) as an oil. 1H NMR (CDCl3): δ 3.38 (t, 2H, J=7.4), 3.50-3.40 (br. s, 1H, OH), 3.22 (d, 2H, J=5.6), 1.85 (qv, 2H, J=7.4), 1.50-1.35 (m, 2H), 1.30-1.20 (m, 2H), 0.85 (s, 6H). 13C NMR (CDCl3) δ 71.4, 37.5, 34.9, 33.9, 33.4, 23.7, 22.4.