Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N:2]1([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([Cl:18])=[O:17])=[CH:14][CH:13]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH2:21]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[CH2:25][CH2:24][NH:23][CH2:22]1>>[ClH:18].[N:2]1([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([N:23]3[CH2:22][CH2:21][C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[CH2:25][CH2:24]3)=[O:17])=[CH:14][CH:13]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C(Cl)c1ccc(OCCCN2CCCCC2)cc1
Reactant: c1ccc2c(c1)CCNCC2
Agent: Cl
Product: O=C(c1ccc(OCCCN2CCCCC2)cc1)N1CCc2ccccc2CC1

Procedure:
The title compound was prepared from 4-(3-piperidin-1-ylpropoxy)benzoyl chloride hydrochloride (D3) (0.20 g) and 2,3,4,5-tetrahydro-1H-3-benzazepine (WO00/21951) (0.89 g) using the procedure described for Example 1 and isolated as a white solid (0.16 g). MS electrospray (+ion) 393 (MH+). 1H NMR δ (DMSO-d6): 9.68 (1H, s), 7.34 (2H, d, J=6.8 Hz), 7.14 (4H, m), 7.00 (2H, d, J=6.8 Hz), 4.10 (2H, t, J=5.9 Hz), 3.81-3.45 (6H, m), 3.17 (2H, m), 2.90 (6H, m), 2.17 (2H, m), 1.83-1.37 (6H, m).
Reaction SMILES: [C-]#N.[K+].Cl.O.COC([CH:10]1[C:14]2([C:24]3=[C:25]4[C:20](=[CH:21][CH:22]=[CH:23]3)[CH2:19][CH2:18][CH2:17][N:16]4[C:15]2=[O:26])[C:13](=[O:27])[NH:12][C:11]1=[O:28])=O>CO>[C:14]12([CH2:10][C:11](=[O:28])[NH:12][C:13]1=[O:27])[C:24]1=[C:25]3[C:20](=[CH:21][CH:22]=[CH:23]1)[CH2:19][CH2:18][CH2:17][N:16]3[C:15]2=[O:26]
Reactant: COC(=O)C1C(=O)NC(=O)C12C(=O)N1CCCc3cccc2c31
Agent: Cl
Agent: [C-]#N
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C1CC2(C(=O)N1)C(=O)N1CCCc3cccc2c31
Temperature: 25 °C
Reaction time: 3 h
Yield: 38 %

Procedure:
To a suspension of ethyl α-cyano-5,6-dihydro-2-oxo-Δ1,α -4H-pyrrolo[3,2,1-ij]quinolineacetate (8.47 g, 0.03 mole) in methanol (30 ml) was added potassium cyanide (2.93 g, 0.04 mole) and the mixture was stirred for 3 hours room temperature. The resultant solution was cooled to 0° C., saturated with hydrogen chloride gas and allowed to stand overnight. The mixture was warmed at 50° C. for an hour and refluxed for 4 hours. After cooling, an addition of water (30 ml) gave a viscous tar containing 4-methoxycarbonyl-5',6'-dihydrospiro[pyrrolidine-3,1'-[4H]pyrrolo[3,2,1-ij]quinoline]-2,2',5(1'H)-trione, which was extracted with benzene, washed with water and dried. Evaporation of the benzene afforded yellow oily residue, to which was added 40 ml of acetic acid and refluxed for 10 hours. After evaporation of the solvent, the residue was treated with benzene to give a fine solid. Recrystallization from ethanol yielded 2.92 g (38.0%) of 5',6'-dihydrospiro[pyrrolidine-3,1'-[4H]pyrrolo[3,2,1-ij]quinoline]-2,2',5(1'H)-trione, as colorless needles, mp. 253°-255° C.
Reaction SMILES: OC(C(F)(F)F)=O.[CH3:8][C:9]1[C:14]([N:15]2[CH2:19][CH:18]([C:20]([OH:22])=O)[N:17]([CH3:23])[C:16]2=[O:24])=[CH:13][CH:12]=[C:11]([CH3:25])[N:10]=1.C(N1CCOCC1)C.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Cl:57][C:58]1[C:63]([C:64]([F:67])([F:66])[F:65])=[CH:62][CH:61]=[CH:60][C:59]=1[CH2:68][NH2:69]>ClCCl>[Cl:57][C:58]1[C:63]([C:64]([F:66])([F:67])[F:65])=[CH:62][CH:61]=[CH:60][C:59]=1[CH2:68][NH:69][C:20]([CH:18]1[CH2:19][N:15]([C:14]2[C:9]([CH3:8])=[N:10][C:11]([CH3:25])=[CH:12][CH:13]=2)[C:16](=[O:24])[N:17]1[CH3:23])=[O:22]
Reactant: NCc1cccc(C(F)(F)F)c1Cl
Reactant: Cc1ccc(N2CC(C(=O)O)N(C)C2=O)c(C)n1
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(N2CC(C(=O)NCc3cccc(C(F)(F)F)c3Cl)N(C)C2=O)c(C)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 47.2 %

Procedure:
A mixture of crude 1-(2,6-dimethyl-3-pyridinyl)-3-methyl-2-oxo-4-imidazolidinecarboxylic acid TFA salt (10 ml of 0.05M solution in DCM, 0.5 mmol), N-ethylmorpholine (0.383 ml, 3.00 mmol), 1-hydroxybenzotriazole hydrate (92 mg, 0.600 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (115 mg, 0.600 mmol) was stirred at room temperature for 10 minutes. A solution of {[2-chloro-3-(trifluoromethyl)phenyl]methyl}amine (105 mg, 0.5 mmol) in dichloromethane (1 ml) was added and the reaction stirred at room temperature for 18 hours. The reaction mixture was diluted with dichloromethane and the solution was washed with saturated sodium hydrogen carbonate solution, water and brine, dried and evaporated. The residue was purified by silica gel chromatography eluting with 0-10% methanol in dichloromethane. The residue was triturated with ether and the resulting solid was collected and dried to give N-{[2-chloro-3-(trifluoromethyl)phenyl]methyl}-1-(2,6-dimethyl-3-pyridinyl)-3-methyl-2-oxo-4-imidazolidinecarboxamide (104 mg, 47%). LC/MS [M+H]+=441, retention time=1.86 minutes.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[CH:9][O:8][CH:7]=1)=[O:5])[CH3:2].BrBr.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.O.Cl.[C:41]([OH:44])(=[O:43])C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:41]([OH:44])=[O:43])[O:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccoc1
Reactant: CC(=O)O
Agent: [Pd+2]
Agent: BrBr
Agent: CC(=O)[O-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1coc(C(=O)O)c1
Reaction time: 8 h

Procedure:
3-Furancarboxylic acid ethyl ester (1.4 g, 10.0 mmol) was dissolved in acetic acid (10 mL), bromine (1.6 g, 10.0 mmol) was added, and the mixture was stirred overnight. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20). The obtained crude fraction was dissolved in N,N-dimethylformamide (15 mL), palladium acetate (0.18 g, 0.78 mmol), triphenylphosphine (0.41 g, 1.55 mmol), triethylamine (2.2 mL, 15.5 mmol), and water (0.7 mL, 38.8 mmol) were added, and the mixture was stirred at 80° C. overnight under a carbon monoxide atmosphere. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by high performance liquid chromatography to give the title compound (0.47 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23](Cl)(=[O:25])=[O:24])([O-])=O>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:23]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[NH2:14])(=[O:25])=[O:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccccc2N)CC1
Yield: 82 %

Procedure:
The title compound (2 g, 82%) was obtained as a white solid from piperazine-1-carboxylic acid tert-butyl ester and 2-nitrobenzenesulfonyl chloride following the same procedure as described in Preparation 2.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)=[C:5]([NH2:14])[NH:4][N:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]([C:22](=O)[CH2:23][C:24](OCC)=[O:25])[CH:19]=[CH:20][CH:21]=1>N1C=CC=CC=1>[Cl:13][C:10]1[CH:9]=[CH:8][C:7]([C:6]2[C:2]([CH3:1])=[N:3][N:4]3[C:22]([C:18]4[CH:19]=[CH:20][CH:21]=[C:16]([Cl:15])[CH:17]=4)=[CH:23][C:24](=[O:25])[NH:14][C:5]=23)=[CH:12][CH:11]=1
Reactant: CCOC(=O)CC(=O)c1cccc(Cl)c1
Reactant: Cc1n[nH]c(N)c1-c1ccc(Cl)cc1
Solvent: c1ccncc1
Product: Cc1nn2c(-c3cccc(Cl)c3)cc(=O)[nH]c2c1-c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 41.1 %

Procedure:
3-Methyl-4-(4-chlorophenyl)-1H-pyrazol-5-amine (578 mg) and ethyl 3-(3-chlorophenyl)-3-oxopropanoate (728 mg) are stirred overnight in a pyridine (30 mL) solvent at 95° C. After cooling to room temperature, the reaction solvent is removed by distillation under reduced pressure. The remainder is extracted with ethyl acetate and water. The extracted organic layer is washed with brine and dehydrated with anhydrous MgSO4. The dehydrated organic layer is distilled under reduced pressure and concentrated and then 424 mg of the target compound is yielded by column chromatography. 1H NMR (CDCl3, 300 MHz) δ 9.90 (br, 1H), 7.88 (m, 1H), 7.75 (m, 1H), 7.53 (m, 1H), 7.33 (m, 5H), 3.99 (br, 1H), 2.23 (s, 3H).
Reaction SMILES: C(C(=N[OH:14])C=C)CCCCCCCC.[CH2:15]([C:24](=[CH2:27])[C:25]#[N:26])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>CC1C=CC=CC=1C>[CH2:15]([C:24](=[CH2:27])[C:25]([NH2:26])=[O:14])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: C=C(C#N)CCCCCCCCC
Reactant: C=CC(CCCCCCCCC)=NO
Solvent: Cc1ccccc1C
Product: C=C(CCCCCCCCC)C(N)=O
Temperature: -20 °C
Reaction time: 1.5 h
Yield: 318.9 %

Procedure:
418.8 g of 94% pure α-nonylacrolein oxime, 1,030 g of o-xylene, 94.6 g of 95% pure α-nonylacrylonitrile and 13.9 g (2 mol %, based on oxime) of Cu(II) 2-ethylhexanoate were heated at 130° C. A vigorous exothermic reaction began; after this reaction had abated, stirring was continued for a further 1.5 hours at 110° C. Analysis by gas chromatography showed that 98.8% of the oxime used had been converted. 1.2 liters of petroleum ether were added to the reaction mixture, the latter was then cooled to -20° C., and the crude amide precipitated was filtered off under suction. Recrystallization from cyclohexane gave 332 g (84%) of α-nonylacrylamide as colorless crystals of melting point 80°-81° C.
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.Br[C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:35][CH2:36][CH2:37][OH:38])(=[O:34])=[O:33])=[CH:28][CH:27]=1>>[F:24][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:26]3[CH:31]=[CH:30][C:29]([S:32]([NH:35][CH2:36][CH2:37][OH:38])(=[O:34])=[O:33])=[CH:28][CH:27]=3)=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: O=S(=O)(NCCO)c1ccc(Br)cc1
Product: O=S(=O)(NCCO)c1ccc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cc1

Procedure:
The title compound was prepared from 7-difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (340 mg, 1.0 mmol) and 4-bromo-N-(2-hydroxy-ethyl)-benzenesulfonamide (example B.29) (276 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (360 mg, 66%). MS (ISP) 537.3 [(M+H)+]; mp 191-194° C.
Reaction SMILES: [CH3:1][S:2]([C:4]([S:19][CH3:20])=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=1)=O.N1C=CC=CC=1.S(Cl)([Cl:29])=O>C(Cl)Cl>[CH3:1][S:2][C:4]([S:19][CH3:20])=[C:5]([Cl:29])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: CSC(=Cc1cccc(Oc2ccccc2)c1)S(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CSC(SC)=C(Cl)c1cccc(Oc2ccccc2)c1
Yield: 70.4 %

Procedure:
1-Methylsulfinyl-1-methylthio-2-(m-phenoxyphenyl)ethylene (4.56 g) was dissolved in 40 ml of methylene chloride, and 2 ml of pyridine was added. With stirring under ice cooling, 10 ml of a methylene chloride solution of 2.15 g of thionyl chloride was added dropwise over the course of 5 minutes. The mixture was further stirred for 1 hour under ice cooling, and methylene chloride was added in an amount sufficient to adjust the total amount of the mixture to 80 ml. The mixture was then washed three times with 20 ml of water. The product was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was chromatographed on a Florisil column using hexane/benzene as an eluant to afford 3.403 g of 1,1-bis(methylthio)-2-chloro-2-(m-phenoxyphenyl)-ethylene as an oil in a yield of 70%. Samples for analysis were obtained by short-path distillation of this product [160°-180° C. (bath temperature)/0.01 mmHg].
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:23])([CH3:22])[O:6][CH:7]1[CH2:21][CH2:20][C:10]2([CH2:14][NH:13][CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11]2)[CH2:9][CH2:8]1)([CH3:4])[CH3:3].C(N(CC)CC)C.[CH:31]1[CH:36]=[CH:35][C:34]([CH2:37][O:38][C:39](Cl)=[O:40])=[CH:33][CH:32]=1>C(Cl)Cl>[CH3:1][C:2]([Si:5]([CH3:23])([CH3:22])[O:6][CH:7]1[CH2:21][CH2:20][C:10]2([CH2:14][N:13]([C:39]([O:38][CH2:37][C:34]3[CH:35]=[CH:36][CH:31]=[CH:32][CH:33]=3)=[O:40])[CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11]2)[CH2:9][CH2:8]1)([CH3:3])[CH3:4]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)C1CC2(CCC(O[Si](C)(C)C(C)(C)C)CC2)CN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1CC2(CCC(O[Si](C)(C)C(C)(C)C)CC2)CN1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 38.5 %

Procedure:
To a solution of ethyl 8-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-2-azaspiro[4.5]decane-3-carboxylate (110) (10.61 g, 31.3 mmol) dissolved in dry DCM, triethylamine was added (10.8 mL, 78 mmol), cooled to 0° C. followed by the addition of Cbz-Cl (6.2 mL, 43.5 mmol), and the reaction stirred at 0° C., for 5 min, rt for 1 h. Reaction diluted with DCM (700 mL), washed with 0.1N HCl (700 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 10-60% hexanes/EtOAc to afford the title compound as a yellow oil (5.73 g, 39% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([N:25]2[CH2:29][CH2:28][CH2:27][S:26]2(=[O:31])=[O:30])[CH:3]=1.[O:32]=[C:33]1[NH:37][C@H:36]([CH2:38][O:39][C:40](=[O:47])[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:35][O:34]1>>[C:40]([O:39][CH2:38][C@@H:36]1[CH2:35][O:34][C:33](=[O:32])[N:37]1[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([N:25]2[CH2:29][CH2:28][CH2:27][S:26]2(=[O:31])=[O:30])[CH:3]=1)(=[O:47])[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(Br)cc3N3CCCS3(=O)=O)CC2)c(C)c1
Reactant: O=C1N[C@H](COC(=O)c2ccccc2)CO1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4COC(=O)c4ccccc4)cc3N3CCCS3(=O)=O)CC2)c(C)c1
Yield: 90.7 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 91 and using [4-bromo-2-(1,1-dioxoisothiazolidin-2-yl)phenyl][4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (3.04 g) described in Preparation Example 180 and benzoic acid (R)-2-oxooxazolidin-4-ylmethyl ester (1.33 g), the title compound (3.52 g) was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.C([O:15][C:16](=O)[CH2:17][C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[N:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[CH:20]=1)(C)(C)C>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[NH:9][C:16](=[O:15])[CH2:17][C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]4[N:30]=[CH:29][CH:28]=[CH:27][N:26]=4)[CH:20]=3)=[N:10][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ncccn2)c1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Solvent: Cc1ccccc1C
Product: O=C1CC(c2cccc(-c3ncccn3)c2)=Nc2cc(Cl)c(Cl)cc2N1

Procedure:
The title compound was prepared from 4,5-dichlorophenylenediamine (89 mg 0.5 mmol) and 3-oxo-3-(3-pyrimidin-2-yl-phenyl)-propionic acid tert-butyl ester (Example K44) (164 mg, 0.55 mmol) by refluxing in xylene according to the general procedure M. Obtained as a light yellow solid (127 mg).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:12]#[N:13])[C:7](=O)[NH:8][C:9]=1[CH3:10])(=[O:3])[CH3:2].CN(C)C1C=CC=CC=1.O=P(Cl)(Cl)[Cl:25].[OH-].[Na+]>ClC1C=CC=CC=1>[C:1]([C:4]1[C:9]([CH3:10])=[N:8][C:7]([Cl:25])=[C:6]([C:12]#[N:13])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(C#N)c(=O)[nH]c1C
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Clc1ccccc1
Solvent: CN(C)c1ccccc1
Product: CC(=O)c1cc(C#N)c(Cl)nc1C
Temperature: 100 °C

Procedure:
35 g (0.2 mol) of 5-acetyl-3-cyano-6-methyl-2-pyridone* are suspended in 400 ml of chlorobenzene, 24.2 g (0.2 mol) of N,N-dimethylaniline are added, and 37 g (0.24 mol) of POCl3 are added dropwise. The mixture is then heated at 100° C. for three hours. After cooling, the mixture is cautiously poured onto water, neutralization with dilute sodium hydroxide solution is carried out, the organic phase is separated off, and the aqueous phase is again extracted with CHCl3. The combined extracts are dried with Na2SO4 and evaporated. The residue is purified by filtration through silica gel, using CH2Cl2 /ethyl acetate as eluent.
Reaction SMILES: Cl.N[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17])=[O:10].N([O-])=O.[Na+].[I:22]I>CC(O)=O.O.CCOC(C)=O>[Cl:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[I:22])=[O:10]
Reactant: Nc1ccccc1C(=O)c1ccccc1Cl
Reactant: II
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(c1ccccc1Cl)c1ccccc1I
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 116.3 %

Procedure:
Add concentrated HCl (0.5 mL) to a solution of (2-amino-phenyl)-(2-chloro-phenyl)-methanone (495 mg, 2.14 mmol) in glacial AcOH (1.1 mL). Cool solution to 10° C.; add a solution of sodium nitrite (156 mg, 2.26 mmol) in water (1 mL) dropwise over 30 min. After an additional 30 min., add water (4° C., 2 mL) and EtOAc (4° C., 4 mL). Add a solution of KI (425 mg, 2.56 mmol) and I2 (319 mg, 1.25 mmol) in water (2 mL) dropwise over 25 min. Stir at 5-15° C. for 2.5 hours under N2. Extract with EtOAc (×3), wash with 1N aqueous Na2S2O3 solution (×3), saturated aqueous NaHCO3 solution (×3) and brine. Dry the combined organic layers over Na2SO4 and concentrate. Purify the residue by flash chromatography on silica gel eluting with 0-10% EtOAc/hexanes to afford the title compound (498 mg, 68%): MS(IS) 343 (M+1); TLC (10% EtOAc/hexanes) Rf=0.39.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH2:15])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:40][C:41]1[C:49]([O:50][CH3:51])=[CH:48][CH:47]=[CH:46][C:42]=1[C:43](O)=[O:44].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1([NH:15][C:43](=[O:44])[C:42]2[CH:46]=[CH:47][CH:48]=[C:49]([O:50][CH3:51])[C:41]=2[CH3:40])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Reactant: COc1cccc(C(=O)O)c1C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C1(NC(=O)c2cccc(OC)c2C)Cc2ccccc2C1
Reaction time: 0.03 h
Yield: 85.3 %

Procedure:
A 100 mL round bottom flask is charged with 2-amino-indane-2-carboxylic acid ethyl ester (750 mg, 3.65 mmol) and dry DCM (10 mL). A stirring bar is added and stirring is initiated. The HBTU (1.38 g, 3.65 mmol) is added. After 2 min, the 2-methyl-3-methoxy-benzoic acid (0.61 g, 3.65 mmol) and DIPEA (1.5 mL, 8.6 mmol) are added. The reaction is allowed to stir for 36 h. Analysis by tlc of the reaction mixture (silica, 50% EtOAc/heptanes) indicates complete consumption of the starting amine. The contents of the reaction flask are diluted with EtOAc (50 mL) and transferred to a separatory funnel. This is washed consecutively with dilute aqueous NaHCO3 (25 mL) and brine (25 mL), dried over MgSO4, filtered and evaporated in vacuo to provide 1.1 g of thick brownish gum. This material is purified utilizing an ISCO Companion with a 40 g cartridge of silica. The gradient is 15% EtOAc in heptanes over 2 column volumes followed by a step gradient to 30% EtOAc then 50% and then 70% EtOAc for 3 column volumes each with ramp of 1 column volume. 35 mL fractions are collected. Fractions 15 through 21 are combined and evaporated in vacuo. Pumping to a constant weight gives a white solid (1.15 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]2[C:15]([CH:16]=[CH:17][CH:18]=1)=[C:14]([C:19]1[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=1[F:26])[C:13](=[O:27])[CH:12]=[CH:11]2.[Br:28]Br.C(Cl)Cl>C(Cl)Cl>[Br:28][C:12]1[C:13](=[O:27])[C:14]([C:19]2[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=2[F:26])=[C:15]2[N:10]([CH:11]=1)[C:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])=[CH:18][CH:17]=[CH:16]2
Reactant: BrBr
Reactant: O=c1ccn2c(-c3ccc(F)cc3F)cccc2c1-c1c(F)cccc1F
Solvent: ClCCl
Product: O=c1c(Br)cn2c(-c3ccc(F)cc3F)cccc2c1-c1c(F)cccc1F

Procedure:
To a solution of 6-(2,4-difluorophenyl)-1-(2,6-difluorophenyl)-2H-quinolizin-2-one (Example 11, 78 mg, 0.211 mmol) in CH2Cl2 was added a solution of Br2:CH2Cl2 (1:1) at room temperature. The reaction was stirred for a couple hours until complete by LCMS. The reaction mixture was concentrated in vacuo and the crude material was purified via silica gel chromatography (100% EtOAc).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([OH:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][C:13]1([CH3:40])[CH:17]([C:18]([O:20]CC2C=CC([N+]([O-])=O)=CC=2)=[O:19])[N:16]2[C:31](=[O:39])[CH:32]([NH:33][C:34]3[NH:35][CH:36]=[CH:37][N:38]=3)[C@H:15]2[S:14]1>C(O)C.C(Cl)Cl.[Pd]>[C:1]1([CH3:11])[CH:2]=[CH:3][C:4]([S:7]([OH:10])(=[O:8])=[O:9])=[CH:5][CH:6]=1.[CH3:12][C:13]1([CH3:40])[CH:17]([C:18]([OH:20])=[O:19])[N:16]2[C:31](=[O:39])[CH:32]([NH:33][C:34]3[NH:38][CH:37]=[CH:36][N:35]=3)[C@H:15]2[S:14]1
Reactant: CC1(C)S[C@@H]2C(Nc3ncc[nH]3)C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: ClCCl
Product: CC1(C)S[C@@H]2C(Nc3ncc[nH]3)C(=O)N2C1C(=O)O

Procedure:
A solution of p-nitrobenzyl 2,2-dimethyl-6-(imidazol-2-yl)aminopenam-3-carboxylate toluene-p-sulphonate (360 mg.) in a mixture of ethanol (18 ml.) and CH2Cl2 (5 ml.) was hydrogenated at atmospheric pressure for 3 hours in the presence of 10% w/w palladium-on-carbon (180 mg.). The mixture was filtered, the filtrate evaporated and the residual yellow gum triturated with ether to give 2,2-dimethyl-6-(imidazol-2-yl)aminopenam-3-carboxylic acid toluene-p-sulphonate as a yellow solid (258 mg.) having the following n.m.r. in d6DMSO: 1.5 (s, 3H); 1.6 (s, 3H); 2.30 (s, 3H); 4.35 (s, 1H); 5.46 (d, 1H); 5.66 (d, 1H); 6.97 (s, 2H); 7.10 (d, 2H); 7.50 (d, 2H); 8.7-9.0 (br, 1H). By integration the product was 50% pure and contained 2 moles of toluene-p-sulphonic acid per mole of β-lactam.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[C:18]([OH:25])[CH:19]=[CH:20][CH:21]=4)[N:16]=3)=[CH:13][N:14]=[C:8]2[CH:7]=1.Br[CH2:27][CH2:28][NH:29]C(=O)OC(C)(C)C.[I-].C([NH3+])(C)(C)C.O.[OH-].[Cs+].C(O)(C(F)(F)F)=O>CN(C=O)C.CCOC(C)=O.O.C(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[C:18]([O:25][CH2:27][CH2:28][NH2:29])[CH:19]=[CH:20][CH:21]=4)[N:16]=3)=[CH:13][N:14]=[C:8]2[CH:7]=1
Reactant: COCCOc1ccn2c(-c3ccc4cccc(O)c4n3)cnc2c1
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: CC(C)(C)[NH3+]
Agent: [Cs+]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COCCOc1ccn2c(-c3ccc4cccc(OCCN)c4n3)cnc2c1
Reaction time: 8 h
Yield: 35.2 %

Procedure:
To 2-(7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl)quinolin-8-ol (50 mg, 0.15 mmol) in DMF (3 mL) was added 4 angstrom molecular sieves (2 g), tert-butyl 2-bromoethylcarbamate (40 mg, 0.18 mmol), t-butylammonium iodide (3 mg) and cesium hydroxide hydrate (50 mg, 0.30 mmol). The reaction mixture was stirred overnight, then dilute with EtOAc/H2O (10 mL/10 mL). The aqueous layer was extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered, and concentrated to give crude, N-Boc-protected product, to which was added DCM (1 mL) and TFA (1 mL). This mixture was stirred for 30 minutes and then concentrated. The residue was purified by silica gel chromatography, eluting with DCM/MeOH/NH4OH (10:1:0.1) to provide the desired product (20 mg). APCI (+) m/z 379.2 (M+1) detected.