Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:2]1=[O:15].C([O-])(=O)C.[Na+].[Br:21]Br>C(O)(=O)C>[Br:21][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][C:2](=[O:15])[C:3]12[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=C1Nc2ccccc2C12CCCCC2
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1Nc2ccc(Br)cc2C12CCCCC2
Reaction time: 0.5 h
Yield: 65.4 %

Procedure:
To a solution of spiro[cyclohexane-1,3′-[3H]indol]-2′ (1′H)-one (17.6 g, 0.09 mol) in acetic acid (300 cm3) was added sodium acetate (8.0 g, 0.1 mol) and bromine (14.6 g, 0.091 mol) with stirring. After 30 min. at room temperature, the reaction mixture was partitioned between water and EtOAc. The aqueous phase was extracted twice with EtOAc. The combined organic layers were washed with water, dried (MgSO4) and evaporated and the residue was triturated with hexane. The precipitate was collected, and dried in vacuo to obtain the subtitled compound (16.5 g, 67%) as off-white crystals: mp 196-199° C.; 1H NMR (DMSO-d6) δ 1.62 (m, 10H), 6.8 (d, 1H, J=6.8 Hz), 7.36 (d, 1H, J=8.2, 1.8 Hz), 7.58 (dd, 1H, J=8.2, 1.8 Hz), 10.44 (S, 1H).
Reaction SMILES: [Cl-].[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH3+:14])[CH2:12][CH3:13])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3].C([O:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[CH:33]=[CH:32][C:31]([CH2:34][N:35]2[C:43]3[C:38](=[CH:39][C:40]([C:44](O)=[O:45])=[CH:41][CH:42]=3)[C:37]([CH3:47])=[C:36]2[CH3:48])=[CH:30][CH:29]=1)=[O:21])(C)(C)C>>[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH:14][C:44]([C:40]2[CH:39]=[C:38]3[C:43](=[CH:42][CH:41]=2)[N:35]([CH2:34][C:31]2[CH:30]=[CH:29][C:28]([C:23]4[C:22]([C:20]([OH:21])=[O:19])=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:33][CH:32]=2)[C:36]([CH3:48])=[C:37]3[CH3:47])=[O:45])[CH2:12][CH3:13])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3]
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: CC[C@H]([NH3+])c1cccc(C(C)C)c1
Agent: [Cl-]
Product: CC[C@H](NC(=O)c1ccc2c(c1)c(C)c(C)n2Cc1ccc(-c2ccccc2C(=O)O)cc1)c1cccc(C(C)C)c1

Procedure:
The title compound was prepared following the same general synthetic procedure as described in Steps 3-4, Example 2, starting with (S)-1-(3-isopropylphenyl)propan-1-aminium chloride and 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of (S)-1-(4-(tert-butyl)phenyl)ethanaminium chloride and 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 558 [M+1]+.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH2:6][CH2:7][CH2:8]Cl)[CH3:5].[CH3:10][N:11]1[C:17]2=[CH:18][S:19][CH:20]=[C:16]2[C:15](=[O:21])[NH:14][C:13]2[CH:22]=[CH:23][CH:24]=[N:25][C:12]1=2.Cl([O-])(=O)(=O)=O>O.CN(C)C=O>[CH3:3][N:4]([CH3:5])[CH2:6][CH2:7][CH2:8][N:14]1[C:15](=[O:21])[C:16]2=[CH:20][S:19][CH:18]=[C:17]2[N:11]([CH3:10])[C:12]2[N:25]=[CH:24][CH:23]=[CH:22][C:13]1=2
Reactant: CN1c2cscc2C(=O)Nc2cccnc21
Reactant: CN(C)CCCCl
Agent: [H-]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCCN1C(=O)c2cscc2N(C)c2ncccc21
Reaction time: 18 h

Procedure:
A mixture of 0.69 g. of 55% sodium hydride-mineral oil dispersion and 0.9 ml. of dimethylaminopropylchloride in 30 ml. of dry dimethylformamide is stirred at room temperature for 0.5 hours. To the mixture is added 0.70 g. of 5,10-dihydro-10-methyl-6H-pyrido[3,2-b]thieno[3,4-e] [1,4]diazepin-6-one and stirring is continued for 18 hours. The reaction mixture is cooled, quenched with water and extracted with chloroform. The dried chloroform extracts are concentrated to an amber oil, which is purified by preparative thin layer chromatography (tlc) on silica gel with 10:1 benzene:methanol as eluent to give a semi-solid. The perchlorate salt is preparaed by standard procedures and is recyrstallized from water to give a white solid, m.p. 263°-265°C. (dec.).
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.[C:24]1([CH:30]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:31][C:32](O)=[O:33])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:32](=[O:33])[CH2:31][CH:30]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=2)(=[O:6])=[O:7])[CH2:3][CH2:2]1
Reactant: O=C(O)CC(c1ccccc1)c1ccccc1
Reactant: O=S(=O)(c1cccc(C(F)(F)F)c1)N(C1CCNCC1)C1CC1
Product: O=C(CC(c1ccccc1)c1ccccc1)N1CCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1

Procedure:
N-Cyclopropyl-N-[1-(3,3-diphenylpropanoyl)piperidin-4-yl]-3-trifluoromethylbenzenesulfonamide was prepared from N-cyclopropyl-N-(piperidin-4-yl)-3-trifluoromethylbenzenesulfonamide and 3,3-diphenylpropanoic acid. LC: 100%. MS: m/z=557 (M+H+). 1H NMR (CDCl3): δ 8.11 (1H, s), 8.02 (1H, d), 7.84 (1H, d), 7.70 (1H, t), 7.23 (10H, m), 4.64 (2H, m), 3.98 (1H, m), 3.85 (1H, d), 3.00 (2H, m), 2.82 (1H, t), 2.37 (1H, t), 1.86 (1H, m), 1.60 (4H, m), 0.91 (1H, m), 0.72 (3H, m);
Reaction SMILES: [C:1]([C:3]1[CH:15]=[CH:14][C:6]2[O:7][C:8]([CH3:13])([CH3:12])[CH:9]3[O:11][CH:10]3[C:5]=2[CH:4]=1)#[N:2].[OH-].[NH4+:17]>>[C:1]([C:3]1[CH:15]=[CH:14][C:6]2[O:7][C:8]([CH3:13])([CH3:12])[C@@H:9]([OH:11])[C@H:10]([NH2:17])[C:5]=2[CH:4]=1)#[N:2]
Reactant: [NH4+]
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Agent: [OH-]
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](N)[C@@H]1O

Procedure:
The title compound was prepared by stirring 6-cyano-3,4-dihydro-2,2-dimethyl-3,4-epoxy-2H-benzo-[b]pyran in ethanolic ammonium hydroxide solution at room temperature until thin layer chromatography showed consumption of the starting epoxide.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]([CH2:15][CH3:16])[C:7](=[O:14])[CH:8]([N:11]([CH3:13])[CH3:12])[CH2:9][CH2:10][C:4]=2[C:3]=1[O:19][CH3:20].Cl[C:22]1[N:27]=[C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[N:35]2[CH:39]=[CH:38][CH:37]=[N:36]2)[C:25]([Cl:40])=[CH:24][N:23]=1>>[Cl:40][C:25]1[C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[N:35]2[CH:39]=[CH:38][CH:37]=[N:36]2)=[N:27][C:22]([NH:1][C:2]2[CH:18]=[CH:17][C:5]3[N:6]([CH2:15][CH3:16])[C:7](=[O:14])[CH:8]([N:11]([CH3:12])[CH3:13])[CH2:9][CH2:10][C:4]=3[C:3]=2[O:19][CH3:20])=[N:23][CH:24]=1
Reactant: Clc1ncc(Cl)c(Nc2ccccc2-n2cccn2)n1
Reactant: CCN1C(=O)C(N(C)C)CCc2c1ccc(N)c2OC
Product: CCN1C(=O)C(N(C)C)CCc2c1ccc(Nc1ncc(Cl)c(Nc3ccccc3-n3cccn3)n1)c2OC
Yield: 9.3 %

Procedure:
Following a procedure analogous to Example 113, 7-Amino-3-dimethylamino-1-ethyl-6-methoxy-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (78 mgs) and (2,5-Dichloro-pyrimidin-4-yl)-(2-pyrazol-1-yl-phenyl)-amine (78 mgs) were converted to the title compound as a white foam (13 mgs). 1H-NMR (CDCl3): 1029 (s, 1H), 8.52 (d, J=8.3 Hz, 1H), 8.31 (d, J=7.5 Hz, 1H), 8.10 (s, 1H), 7.88 (s, 1H), 7.83 (s, 1H), 7.44-7.41 (m, 3H), 7.28-7.26 (m, 1H), 6.93 (d, J=8.4 Hz, 1H), 6.54 (s, 1H), 4.33-4.25 (m, 1H), 3.81 (s, 3H), 3.54-2.10 (complex series of m, 10H), 1.15 (t, J=7.1 Hz, 3H). LC/MS found (M+H)+=547.21
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.C[O-:12].[Na+].[CH3:14][C:15]1C=C[CH:18]=[CH:17][C:16]=1C>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:9]#[N:10])[CH2:18][CH2:17][C:16](=[O:12])[CH2:15][CH2:14]2)=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: Cc1ccccc1C
Reactant: N#CCc1ccc(F)cc1
Agent: [Na+]
Product: N#CC1(c2ccc(F)cc2)CCC(=O)CC1
Reaction time: 0.08 h

Procedure:
A mixture of 221 parts of 4-fluorobenzeneacetonitrile, 700 parts of sodium methoxide solution 30% and 900 parts of dimethylbenzene is stirred for 5 minutes. Then there are added dropwise 309 parts of methyl 2-propanoate (exothermic reaction: temperature rises to 65° C.). Upon completion, stirring is continued overnight at reflux temperature. The methanol is distilled off till an internal temperature of 110° C. is reached. After cooling, 1000 parts of a hydrochloric acid solution 6 N are added dropwise and the whole is stirred and refluxed for 5 minutes. Upon cooling, the layers are separated. The organic phase is dried, filtered and evaporated. The residue is stirred and refluxed for 4 hours together with 500 parts of acetic acid, 500 parts of water and 500 parts of a hydrochloric acid solution. After cooling, the product is extracted with trichloromethane. The extract is washed successively with water, with a diluted sodium hydroxide solution and again with water till neutralization, dried, filtered and evaporated. The residue is crystallized from 2-propanol, yielding 134.5 parts of 1-(4-fluorophenyl)-4-oxocyclohexanecarbonitrile; mp. 91.8° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:10]1.Cl.[NH:28]1[CH2:33][CH2:32][O:31][C@H:30]([CH2:34][OH:35])[CH2:29]1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][N:28]2[CH2:33][CH2:32][O:31][C@H:30]([CH2:34][OH:35])[CH2:29]2)[NH:12][C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:10]1
Reactant: OC[C@@H]1CNCCO1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCO[C@H](CO)C2)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Yield: 23.2 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (1 g, 2 mmol) was reacted with (S)-morpholin-2-ylmethanol hydrochloride (0.34 g, 2.2 mmol) according to the procedure as described in Example 25, Step B to give the title compound as a yellow solid (0.25 g, 23%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:11]3[C:19](=[O:20])[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]3=[O:21])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23].N12CCCN=C1CCCCC2>ClCCl.Cl>[Si:22]([O:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:11]3[C:19](=[O:20])[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]3=[O:21])=[N:7][NH:8]2)=[CH:4][CH:3]=1)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: O=C1c2ccccc2C(=O)N1c1n[nH]c2cc(O)ccc12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc2c(N3C(=O)c4ccccc4C3=O)n[nH]c2c1
Temperature: 50 °C
Yield: 71 %

Procedure:
To a suspension of 15.03 g (53.82 mmol) of 2-({6-hydroxy}-1H-indazol-3-yl)-1H-isoindole-1,3(2H)-dione in 150 ml of dichloromethane, a solution of 20.19 g (0.134 mol) of TBDMS chloride in 75 ml of dichloromethane was added. The resulting mixture was treated dropwise with 12.06 ml (80.73 mmol) of 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) at room temperature, obtaining a clear solution. After 3 hours the reaction mixture was poured in 250 ml of 0.5 N HCl. The aqueous layer was separated and extracted with 120 ml of dichloromethane. Organic extracts were dried over sodium sulfate and the solvent evaporated under vacuum. The moist raw product was stirred in 50 ml of ethyl acetate at 50° C. Then, about one half of the solvent was evaporated under vacuum and the mixture was treated dropwise with 100 ml of cyclohexane. The product was isolated by suction as light yellow solid (15.04 g). Yield=71.0%. mp=207-209° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH3:12].O.[CH2:14]([NH2:17])[CH2:15][NH2:16].C(N)CN.Cl>>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:16][CH2:15][CH2:14][NH2:17])=[C:3]([O:11][CH3:12])[CH:4]=1)([O-:10])=[O:9]
Reactant: NCCN
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Agent: Cl
Solvent: O
Product: COc1cc([N+](=O)[O-])ccc1NCCN
Yield: 86.1 %

Procedure:
31 g (0.165 mole) of 2-chloro-5-nitro-anisole is added to 130 cm3 (1.65 mole) ethylenediamine hydrate. The reaction mixture is heated at reflux for five hours, and the excess of ethylenediamine driven off under vacuum. The residue is treated with 200 cm3 of a 5N hydrochloric acid solution, and dried, yielding 30 g of 4-nitro-2-methoxy-N(β-aminoethyl) aniline, which is washed with acetone.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11](O)=[O:12])=[CH:4][C:3]=1[C:17](=[O:25])[NH:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1.[CH2:26]([NH:28][CH2:29][CH3:30])[CH3:27]>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:10]([C:11](=[O:12])[N:28]([CH2:29][CH3:30])[CH2:26][CH3:27])[CH:9]=2)=[CH:4][C:3]=1[C:17]([NH:18][C:19]1[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=1)=[O:25]
Reactant: Nc1ncc(-c2cccc(C(=O)O)c2)cc1C(=O)Nc1ccncc1
Reactant: CCNCC
Product: CCN(CC)C(=O)c1cccc(-c2cnc(N)c(C(=O)Nc3ccncc3)c2)c1

Procedure:
Reaction of 3-[6-amino-5-(pyridin-4-ylcarbamoyl)-pyridin-3-yl]-benzoic acid with diethyl amine gives “A98”; method 1: HPLC/MS: 1.37 min, [M+H]=390;
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.O[C:11]([CH3:34])([CH3:33])[CH2:12][CH:13]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][C:27]2=[O:32])[CH2:14]1.O>ClCCl>[F:7][C:11]([CH3:34])([CH3:33])[CH2:12][CH:13]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][C:27]2=[O:32])[CH2:14]1
Reactant: CC(C)(O)CC1CCN(CCc2ccccc2N2CCCCC2=O)C1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CC(C)(F)CC1CCN(CCc2ccccc2N2CCCCC2=O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
Diethylaminosulfur trifluoride (31 μl, 0.235 mmol, 1.5 eq) is added to 1-(2-{2-[3-(2-hydroxy-2-methyl propyl)pyrrolidin-1-yl]ethyl}phenyl)piperidin-2-one a13-2 (54 mg, 0.157 mmol, 1 eq) in dichloromethane (5 ml) dropwise and the reaction mixture stirred at room temperature overnight. The reaction mixture is poured into water and stirring is pursued for 1 hour. After phase separation, the aqueous phase is further extracted with dichloromethane (3 times). The combined organic phases are washed with brine (1 time), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue is purified by basic reverse phase chromatography (gradient: acetonitrile/H2O/ammonium formiate from 5% to 40% of acetonitrile in 8 minutes) to afford 6 mg of 1-(2-{2-[3-(2-fluoro-2-methylpropyl)pyrrolidin-1-yl]ethyl}phenyl)piperidin-2-one 85 as a yellow oil.
Reaction SMILES: [Si]([O:8][C@@H:9]([C@H:11]1[C:39](=[O:40])[N:13]2[C:14]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=3)=[O:27])=[C:15]([C:18]3[S:22][C:21]4=[CH:23][N:24]=[CH:25][N:20]4[CH:19]=3)[C@H:16]([CH3:17])[C@H:12]12)[CH3:10])(C(C)(C)C)(C)C.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>C1COCC1.C(OCC)(=O)C>[OH:8][C@@H:9]([C@H:11]1[C:39](=[O:40])[N:13]2[C:14]([C:26]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][C:33]([N+:36]([O-:38])=[O:37])=[CH:34][CH:35]=3)=[O:27])=[C:15]([C:18]3[S:22][C:21]4=[CH:23][N:24]=[CH:25][N:20]4[CH:19]=3)[C@H:16]([CH3:17])[C@H:12]12)[CH3:10]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cncc4s3)[C@H](C)[C@H]12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cncc4s3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 20 h
Yield: 64.2 %

Procedure:
To a solution of 111 mg of 4-nitrobenzyl (1S,5R,6S)-6-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate in 3 ml of anhydrous THF were added 0.164 ml of acetic acid and 0.954 ml of a 1 M solution of tetra-n-butylammonium fluoride/THF, and the mixture was stirred at room temperature under the atmosphere of argon at 20 hours. The reaction mixture was diluted with ethyl acetate, and washed with a mixed solvent of semi-saturated aqueous saline and saturated aqueous sodium hydrogen carbonate (pH 8.0), and semi-saturated aqueous saline in this sequence. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent was removed by distillation. The residue thus obtained was purified by column chromatography on Sephadex LH-20 (chloroform:methanol=1:1) to give 57.3 mg of 4-nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)[C:2]#[CH:3].[CH3:10][O:11][C:12](=[O:34])[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]#[C:24][C:25]2[CH:30]=[C:29]([Br:31])[CH:28]=[C:27](Br)[CH:26]=2)=[CH:17][C:16]=1[CH3:33]>CN(C=O)C.C(N(CC)CC)C.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>[CH3:10][O:11][C:12](=[O:34])[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]#[C:24][C:25]2[CH:26]=[C:27]([C:3]#[C:2][CH2:1][N:4]3[CH2:9][CH2:8][O:7][CH2:6][CH2:5]3)[CH:28]=[C:29]([Br:31])[CH:30]=2)=[CH:17][C:16]=1[CH3:33]
Reactant: C#CCN1CCOCC1
Reactant: COC(=O)COc1ccc(OCC#Cc2cc(Br)cc(Br)c2)cc1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(OCC#Cc2cc(Br)cc(C#CCN3CCOCC3)c2)cc1C
Temperature: 60 °C

Procedure:
A mixture of 4-prop-2-ynyl-morpholine (330 mg, 2.64 mmol), {4-[3-(3,5-dibromophenyl)-prop-2-ynyloxy]-2-methyl-phenoxy}-acetic acid methyl ester (206 mg, 0.44 mmol, intermediate 2), Pd(PPh3)2Cl2 (50 mg, 0.044 mmol), CuI (23 mg, 0.123 mmol) in dry DMF (2 ml) and triethylamine (2 ml) was heated in a microwave own for 30 min at 60° C. in a sealed tube. The reaction mixture was filtered through Decalite and the filtrate was evaporated. The residue was purified on column chromatography using methylene chloride/THF mixtures to give (4-{3-[3-bromo-5-(3-morpholin-4-yl-prop-1-ynyl)-phenyl]-prop-2-ynyloxy}-2-methylphenoxy)-acetic acid methyl ester in 130 mg (58%) yield.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6]3[CH2:7][CH2:8][CH2:9][N:10]([C:14]([NH:16]C(=O)CCl)=[O:15])[C:11]=3[CH2:12][CH2:13][C:4]=2[CH:3]=1.O.NN>C(O)C>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6]3[CH2:7][CH2:8][CH2:9][N:10]([C:14]([NH2:16])=[O:15])[C:11]=3[CH2:12][CH2:13][C:4]=2[CH:3]=1
Reactant: O=C(CCl)NC(=O)N1CCCC2=C1CCc1cc(Cl)ccc12
Agent: NN
Solvent: O
Solvent: CCO
Product: NC(=O)N1CCCC2=C1CCc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of 11.85 g (0.035 mol) of 8-chloro-N-(chloroacetyl)-2,3,5,6-tetrahydrobenzo[f]quinoline-4(1H)-carboxamide and 4.4 ml (0.091 mol) of hydrazine hydrate in 250 ml of ethanol is stirred at room temperature for 3 hours, concentrated in a vacuum and extracted with methylene chloride/water. Drying with magnesium sulfate and distillation of the solvent in a vacuum yields 8-chloro-2,3,5,6-tetrahydrobenzo[f]quinoline-4(1H)-carboxamide as white crystals which exhibit a melting point of 169°-171° after recrystallization from methylene chloride.
Reaction SMILES: ClC(C)C(NC1C(OC)=C(OC)C=CC=1C[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][N:10]=1)=O.C(N)CC>>[CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][N:10]=1
Reactant: COc1ccc(Cc2nccc3ccccc23)c(NC(=O)C(C)Cl)c1OC
Solvent: CCCN
Product: c1ccc2cnccc2c1

Procedure:
Following the procedure of Example 1, but reacting 1-(2-[2-chloro-propionyl] amino-3,4-dimethoxybenzyl) isoquinoline with n-propylamine, there is obtained 1-(2-[2-n-propylaminoprionyl] amino-3,4-dimethoxybenzyl) isoquinoline.
Reaction SMILES: C(OC([NH:6][C:7]1[CH2:11][CH2:10][CH2:9][C:8]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=O)C.C[O-].[Na+].CO>O>[NH2:6][C:7]1[CH2:11][CH2:10][CH2:9][C:8]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)NC1=C(C(=O)OCC)CCC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCOC(=O)C1=C(N)CCC1
Temperature: 25 °C
Yield: 88.2 %

Procedure:
A solution containing ethyl 2-[(ethoxycarbonyl)amino]-1-cyclopentene-1-carboxylate (72 g, 0.32 moles) and 25 wt % sodium methoxide in methanol (91.5 mL, 0.40 moles) was refluxed for about 18 hours. Methanol (200 mL) was added during the course of the reaction. The reaction mixture was allowed to cool to ambient temperature then diluted with water and extracted with diethyl ether (5×100 mL). The ether extracts were combined, treated with activated charcoal, dried over sodium sulfate then evaporated to provide 43.8 g of ethyl 2-amino-1-cyclopentene-1-carboxylate as an ivory solid, m.p. 90°-92° C.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][OH:14])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(OCC)(=O)C>[CH3:22][S:23]([O:14][CH2:13][CH2:12][CH2:11][C:8]1[CH:7]=[CH:6][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[CH:10][CH:9]=1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCc1ccc(CCCO)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCCc1ccc(CCCOS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 3-(4-butylphenyl)propanol (2.86 g, 14.9 mmol) and triethylamine (1.51 g, 14.9 mmol) in ethyl acetate (30 ml) was added methanesulfonyl chloride (1.70 g, 14.9 mmol) and the mixture was stirred at room temperature for 2 hours. The reaction solution was washed with water and saturated brine, dried over magnesium sulfate anhydride and concentrated under reduced pressure to give the object compound as an oily substance. 4.02 g (yield: 100%)
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].C[O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][C:13](=[O:17])[NH:14]2)=[CH:9][CH:8]=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCCl>[C:1]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:7]=1[OH:6])[NH:14][C:13](=[O:17])[CH2:12][CH2:11]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: COc1ccc2c(c1)NC(=O)CC2
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(=O)c1cc2c(cc1O)NC(=O)CC2
Temperature: 0 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
Acetyl chloride (2.0 mL, 28.1 mmoL) was added to a mixture of 3,4-dihydro-7-methoxy-2H-quinolin-2-one (1.99 g, 11.2 mmol) in 1,2-dichloroethane (30 mL). The mixture obtained was cooled to 0° C. and AlCl3 (6.0 g, 44.98 mmol) was added in portions. The mixture was heated to reflux for 2 hours. The reaction was cautiously poured over ice-H2O, stirred for a minimum of 1 hour (to overnight), and extracted with CH2Cl2. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated to give the title compound (1.89 g, 82%) as an off-white solid.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH2:16]=[O:17]>[OH-].[Na+]>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:13])[F:14])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[CH2:16][OH:17]
Reactant: Oc1ccnc2cc(C(F)(F)F)ccc12
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Product: OCc1cnc2cc(C(F)(F)F)ccc2c1O
Reaction time: 8 h

Procedure:
A mixture of 4-hydroxy-7-trifluoromethylquinoline (30.0 g.), 40% aqueous formaldehyde solution (36 ml.) and 1 M aqueous sodium hydroxide solution (250 ml.) was stirred at 40°-50° for 8 hours. The solid product was collected and dried to give the novel 4-hydroxy-3-hydroxymethyl-7-trifluoromethylquinoline, m.p. 302°-304°.