Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([SH:9])[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:18][C:19]1[C:20](F)=[CH:21][C:22]([F:45])=[C:23]([S:25]([N:28]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][C:36]=2[O:43][CH3:44])[C:29]2[S:30][CH:31]=[N:32][N:33]=2)(=[O:27])=[O:26])[CH:24]=1>CS(C)=O>[Cl:18][C:19]1[C:20]([S:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:10])[F:11])[CH:4]=2)=[CH:21][C:22]([F:45])=[C:23]([S:25]([N:28]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][C:36]=2[O:43][CH3:44])[C:29]2[S:30][CH:31]=[N:32][N:33]=2)(=[O:26])=[O:27])[CH:24]=1
Reactant: FC(F)(F)c1cccc(S)c1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Sc3cccc(C(F)(F)F)c3)cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.1 %

Procedure:
To 3-(trifluoromethyl)thiophenol (0.116 g, 0.649 mmol) in dimethylsulfoxide (5 mL) was added potassium carbonate (0.254 g, 1.62 mmol) followed by 5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide (Preparation 2, 0.250 g, 0.541 mmol). The reaction mixture was stirred at ambient temperature overnight. The mixture was partitioned between dichloromethane and water and the layers separated by phase separation cartridge. The organic layer was concentrated in vacuo and the resulting residue purified by silica gel flash column chromatography (10%-20% ethyl acetate in heptane gradient elution) to afford the title compound as a solid (0.215 g, 64%).
Reaction SMILES: [C:1]([CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[O:12])(OCC)=O.C(=O)([O-])[O-].[K+].[K+].BrC[C:21]1[S:22][CH:23]=[CH:24][CH:25]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[S:22]1[CH:23]=[CH:24][CH:25]=[C:21]1[CH2:1][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[O:12]
Reactant: CCOC(=O)C1CCCCC1=O
Reactant: BrCc1cccs1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Product: O=C1CCCCC1Cc1cccs1

Procedure:
2-carboethoxycyclohexanone, finely powdered potassium carbonate, 2-bromomethyl thiophene, and tetrabutylammonium iodide are reacted by the method of Example 38 to generate the title material.
Reaction SMILES: C([O:3][C:4](=[O:38])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:36])[C:20]([OH:35])([C:25]3[CH:26]=[N:27][C:28]4[C:33]([CH:34]=3)=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:21]([F:24])([F:23])[F:22])=[C:15]([Cl:37])[CH:14]=2)=[CH:7][CH:6]=1)C.[Li+].[OH-].Cl.O>O1CCCC1.C(O)C>[Cl:37][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][C:16]=1[CH:19]([CH3:36])[C:20]([OH:35])([C:25]1[CH:26]=[N:27][C:28]2[C:33]([CH:34]=1)=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:21]([F:24])([F:23])[F:22])[O:12][CH2:11][C:8]1[CH:9]=[CH:10][C:5]([C:4]([OH:38])=[O:3])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(COc2ccc(C(C)C(O)(c3cnc4ccccc4c3)C(F)(F)F)c(Cl)c2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CC(c1ccc(OCc2ccc(C(=O)O)cc2)cc1Cl)C(O)(c1cnc2ccccc2c1)C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h
Yield: 66.8 %

Procedure:
To a solution of 4-[3-chloro-4-(3,3,3-trifluoro-2-hydroxy-1-methyl-2-quinolin-3-yl-propyl)-phenoxymethyl]-benzoic acid ethyl ester (Example 140, 30 mg) in tetrahydrofuran (1 ml) and ethanol (1 ml) was added a 1 M aqueous LiOH solution (0.3 ml) at 0° C. The mixture was stirred at 0° C. for 2 h. More LiOH solution (0.23 ml) was added and the mixture was stirred overnight at room temperature. The mixture was cooled in an ice bath and acidified using 1 M aqueous HCl. After addition of water a precipitation was formed. The suspension was filtered and the solid was washed with diethyl ether and dried to give the title compound as a colorless solid (19 mg). MS (m/e)=515.9 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH3:15])=[N:8][C:7]([OH:16])=[CH:6]2.[OH-].[K+].Cl.Cl[CH2:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[N:28]=[CH:27][CH:26]=[CH:25]2.N1C2C(=CC(CO)=CC=2)C=CC=1>COCCOC.O=S(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH3:15])=[N:8][C:7]([OH:16])=[C:6]2[CH2:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[N:28]=[CH:27][CH:26]=[CH:25]2
Reactant: ClCc1ccc2ncccc2c1
Reactant: COc1cc2cc(O)nc(C)c2cc1OC
Agent: Cl
Agent: OCc1ccc2ncccc2c1
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: COCCOC
Product: COc1cc2c(C)nc(O)c(Cc3ccc4ncccc4c3)c2cc1OC
Temperature: 115 °C
Reaction time: 0.42 h

Procedure:
To a solution of 6,7-dimethoxy-1-methylisoquinolin-3-ol CCH 18060 (200 mg, 0.912 mmol) in DME (5 mL) in a 10 mL microwave vial equipped with a magnetic stirrer was added a 2 N aq. KOH solution (0.95 mL, 1.90 mmol) at RT followed by 6-(chloromethyl)quinoline hydrochloride (234 mg, 1.093 mmol, prepared by stirring quinolin-6-yl methanol (330 mg) in SOCl2 (1 mL) for 1 h at RT, then concentration under vacuum and repeated coevaporation with CH2Cl2 and the mixture was stirred at 115° C. for 25 min under microwave irradiation. After cooling to RT, the mixture was diluted with H2O (5 mL) before extraction with EtOAc (50 mL). The organic phase was washed with brine (10 mL) and the aqueous phase was further extracted with CH2Cl2 (50 mL). The dichloromethane phase was washed with brine (10 mL), combined with the first organic phase, dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 92:8) gave 37 mg of 6,7-dimethoxy-1-methyl-4-(quinolin-6-ylmethyl)isoquinolin-3-ol as a yellow solid. This free base was dissolved in MeOH (10 mL) in a 25 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.09 M HCl solution in MeOH (4.0 mL). The reaction mixture was stirred for 5 min at RT and concentrated at 40° C. under vacuum to afford 6,7-dimethoxy-1-methyl-4-(quinolin-6-ylmethyl)isoquinolin-3-ol dihydrochloride 24 as a brown solid (44 mg, 11% yield).
Reaction SMILES: S(Cl)([Cl:3])=O.[Br:5][C:6]1[CH:7]=[CH:8][C:9]2[C:13]([CH3:14])=[C:12]([CH2:15]O)[S:11][C:10]=2[CH:17]=1>N1C=CC=CC=1.C(Cl)(Cl)Cl>[Br:5][C:6]1[CH:7]=[CH:8][C:9]2[C:13]([CH3:14])=[C:12]([CH2:15][Cl:3])[S:11][C:10]=2[CH:17]=1
Reactant: Cc1c(CO)sc2cc(Br)ccc12
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: Cc1c(CCl)sc2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Thionyl chloride (2.0 ml) was added dropwise to a stirred solution of 6-bromo-2-hydroxymethyl-3-methylbenzo[b]thiophene (3.60 g) and pyridine (3 drops) in chloroform (80 ml). The solution was stirred at room temperature for 1 hour, then washed with water, sodium bicarbonate solution and dried (Na2SO4). Evaporation of the solvent gave a quantitative yield of 6-bromo-2-chloromethyl-3-methylbenzo[b]thiophene. A sample crystallised from petrol (b.p. 40°-60°) had m.p. 92°-93°.
Reaction SMILES: [CH2:1]([C:3]1(O)[CH:27]=[C:26]2[C@:21]([CH3:29])([CH2:22][CH2:23][C@H:24]([OH:28])[CH2:25]2)[C@@H:20]2[C@@H:4]1[C@H:5]1[C@:17]([CH3:30])([CH2:18][CH2:19]2)[C@@H:8]([C@H:9]([CH3:16])[CH2:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:7][CH2:6]1)[CH3:2].C(OC)(=O)CCC#C>[Pd]>[CH2:1]([C:3]1[C@@H:4]2[C@@H:20]([C@:21]3([CH3:29])[C:26]([CH:27]=1)=[CH:25][C:24](=[O:28])[CH2:23][CH2:22]3)[CH2:19][CH2:18][C@@:17]1([CH3:30])[C@H:5]2[CH2:6][CH2:7][C@@H:8]1[C@H:9]([CH3:16])[CH2:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[CH3:2]
Reactant: CCC1(O)C=C2C[C@@H](O)CC[C@]2(C)[C@H]2CC[C@]3(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@H]3[C@@H]21
Agent: [Pd]
Agent: C#CCCC(=O)OC
Product: CCC1=CC2=CC(=O)CC[C@]2(C)[C@H]2CC[C@]3(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@H]3[C@H]12

Procedure:
The synthesis of the acid 41 and 65 is published in J. Med. Chem. 1986 Vol. 29, p. 2300. The acids 45, 63, and 64 were prepared by the reaction sequence detailed in Example 226. Palladium catalyzed coupling of the Δ16 -17-triflate 60 with methyl 4-pentynoate using the procedures published in Synlett. 1991 p. 409; J. Org. Chem. 1992 Vol. 57, p. 973. gave the enyne 61. Hydrogenation catalyzed with palladium on carbon formed the saturated ester 62 and KOH saponification gave 45. Similar reaction sequences using methyl 5-hexynoate and 10-undecynoic acid gave the acids 63 and 64.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:12][Si:13]([C:16]#[CH:17])([CH3:15])[CH3:14].O>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.CCOCC>[CH3:12][Si:13]([C:16]#[C:17][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)([CH3:15])[CH3:14]
Reactant: C#C[Si](C)(C)C
Reactant: Brc1cnc2ccccc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: O
Product: C[Si](C)(C)C#Cc1cnc2ccccc2c1
Temperature: 70 °C

Procedure:
A mixture of 3-bromoquinoline (10.40 g, 0.05 mol), trimethylsilylacetylene (8.48 mL, 0.06 mol), cuprous iodide (0.5 g) and trans-dichlorobis(triphenylphosphine)palladium (1 g) and TEA (15 mL) was heated at 70° C. in a sealed tube for 1 h. H2O (150 mL) was added, followed by Et2O (300 mL). The organic layer was separated and the aqueous layer extracted with Et2O (200 mL). The combined organic layers were dried (Na2SO4) and concentrated. The residue was purified by flash column chromatography (eluent: 100% DCM) to give 3-(trimethylsilylethynyl)quinoline as a brown oil. 3-(Trimethylsilylethynyl)quinoline was dissolved in anhydrous MeOH (100 mL) and K2CO3 (0.69 g, 5 mmol) was added. The mixture was stirred at rt for 1 h and DCM (250 mL) was added. The mixture was filtered over celite. The filtrate was evaporated and the residue was purified by flash column chromatography to give Compound 13b as an off-white solid.
Reaction SMILES: [CH3:1][O:2][CH:3](OC)OC.[CH:8]1[C:9]([C:30]([F:33])([F:32])[F:31])=[CH:10][C:11]([Cl:29])=[C:12]([N:15]2[N:19]=[C:18]([C:20]#[N:21])[C:17]([S+:22]([O-:27])[C:23]([F:26])([F:25])[F:24])=[C:16]2[NH2:28])[C:13]=1[Cl:14].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:20]([C:18]1[C:17]([S:22]([C:23]([F:24])([F:25])[F:26])=[O:27])=[C:16]([N:28]=[CH:3][O:2][CH3:1])[N:15]([C:12]2[C:13]([Cl:14])=[CH:8][C:9]([C:30]([F:31])([F:33])[F:32])=[CH:10][C:11]=2[Cl:29])[N:19]=1)#[N:21]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1[S+]([O-])C(F)(F)F
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: COC=Nc1c(S(=O)C(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl

Procedure:
A substantial molar excess of trimethylorthoformat is reacted with fipronil (Compound IV) at reflux with 0.5 equivalents of paratoluensulfonic acid to provide 3-Cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-methoxymethylideneamino-4-trifluoromethylsulfinylpyrazole (Compound III).
Reaction SMILES: [O:1]1[C:5]2[CH2:6][NH:7][CH2:8][CH2:9][C:4]=2[CH:3]=[C:2]1[C:10]([O:12][CH3:13])=[O:11].[C:14]1([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](O)=[O:26])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N.[OH-].[Na+]>ClCCl>[C:14]1([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([N:7]2[CH2:8][CH2:9][C:4]3[CH:3]=[C:2]([C:10]([O:12][CH3:13])=[O:11])[O:1][C:5]=3[CH2:6]2)=[O:26])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)CCCCCc1ccccc1
Reactant: COC(=O)c1cc2c(o1)CNCC2
Agent: CCOP(=O)(C#N)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc2c(o1)CN(C(=O)CCCCCc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 95 mg (0.52 mmol) of methyl 4,5,6,7-tetrahydrofuro[2,3-c]pyridine-2-carboxylate, 0.12 g (0.63 mmol) of 6-phenylhexanoic acid and 0.15 ml (1.0 mmol) of triethylamine in 30 ml of dichloromethane, 0.10 ml (0.63 mmol) of diethyl cyanophosphonate was added dropwise under ice-cooling, followed by overnight stirring at room temperature. The reaction mixture was poured into aqueous sodium hydroxide and extracted with dichloromethane 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=3/1 to 2/1) to yield the desired product.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-:13])=[O:12].N1C=CC=CC=1.[C:21](Cl)(=[O:23])[CH3:22]>CCOCC>[C:21]([C:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-:13])=[O:12])=[CH:3][N:2]([CH3:1])[CH3:14])(=[O:23])[CH3:22]
Reactant: CC(=O)Cl
Reactant: CN(C)C=Cc1ccccc1[N+](=O)[O-]
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(=O)C(=CN(C)C)c1ccccc1[N+](=O)[O-]
Reaction time: 3 h

Procedure:
To a stirred solution of 3.84 g. of β-dimethylamino-2-nitrostyrene and 1.61 ml. of pyridine in 20 ml. of ether, was added dropwise a solution of 1.42 ml. of acetyl chloride in 5 ml. of ether. The mixture was stirred for 3 hours at 0° and filtered. The gummy solid was partitioned between methylene chloride and water. The organic phase was washed with dilute hydrochloride, dried and concentrated to a dark oil. The nmr spectrum was in agreement with the proposed structure. This product, i.e., α-acetyl-β-dimethylamino-2-nitrostyrene was used without further purification in the next step.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:5]([NH:7][C@H:8]([C:16]([NH:18][C@H:19]([C:24]([O:26][CH2:27][C@H:28]1[O:32][C@@H:31]([N:33]2[CH:40]=[C:39]([F:41])[C:37](=[O:38])[NH:36][C:34]2=[O:35])[C@H:30]([OH:42])[C@@H:29]1[OH:43])=[O:25])[C@H:20]([CH2:22][CH3:23])[CH3:21])=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6])[CH3:4].[CH2:44]([O:51][C:52]([NH:54][C@H:55]([C:71](O)=[O:72])[CH2:56][CH2:57][CH2:58][CH2:59][NH:60][C:61]([O:63][CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)=[O:62])=[O:53])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.C(P(C#N)(CC)=O)C.C(N(CC)CC)C>CN(C)C=O>[CH2:44]([O:51][C:52]([NH:54][C@H:55]([C:71]([NH:2][C@H:3]([C:5]([NH:7][C@H:8]([C:16]([NH:18][C@H:19]([C:24]([O:26][CH2:27][C@H:28]1[O:32][C@@H:31]([N:33]2[CH:40]=[C:39]([F:41])[C:37](=[O:38])[NH:36][C:34]2=[O:35])[C@H:30]([OH:42])[C@@H:29]1[OH:43])=[O:25])[C@H:20]([CH2:22][CH3:23])[CH3:21])=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6])[CH3:4])=[O:72])[CH2:56][CH2:57][CH2:58][CH2:59][NH:60][C:61]([O:63][CH2:64][C:65]1[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=1)=[O:62])=[O:53])[C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: CC[C@H](C)[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)N)C(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)[C@H](O)[C@@H]1O
Reactant: O=C(NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O)OCc1ccccc1
Agent: CCP(=O)(C#N)CC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1)C(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
1.04 Grams (1.65 mmol) of 5'-O-{N-(N-alanylphenylalanyl)isoleucyl}-5-fluorouridine hydrochloride obtained in Example 9 was dissolved in dimethylformamide (10 ml), and 0.815 g (1.97 mmol) of Nα,Nε -di-benzyloxycarbonyllysine and 0.375 g (2.30 mmol) of diethylphosphoryl cyanide were then added. To this solution was added under ice-cooling 0.60 g (5.90 mmol) of triethylamine, and the mixture was stirred for 1 hour at room temperature. The reaction liquid was concentrated under reduced pressure, and the residue was subjected to separation/purification by way of silica gel column chromatography (first time: a linear gradient of chloroform containing 2%→6% methanol; second time: a linear gradient of chloroform containing 3%→6% methanol) whereby 0.85 g (52.3%) of 5'-O-[N-[N-{N-(Nα,Nε -dibenzyloxycarbonyllysyl)alanyl}phenylalanyl]isoleucyl]-5-fluorouridine was obtained as a colorless powdery solid.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([N:8]([CH2:17][C:18]([OH:20])=O)[C:9]2[CH:16]=[CH:15][C:12]([O:13][CH3:14])=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[NH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([CH2:17][C:18]([NH:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:20])[C:9]2[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[CH:15][CH:16]=2)=[O:7])=[CH:21][CH:22]=1
Reactant: COc1ccc(N(CC(=O)O)C(=O)c2ccc(Cl)cc2)cc1
Reactant: CCOC(=O)CCN
Product: CCOC(=O)CCNC(=O)CN(C(=O)c1ccc(Cl)cc1)c1ccc(OC)cc1

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-(p-chlorobenzoyl)-2-(p-anisidino)acetic acid and ethyl 3-aminopropionate and suitable processing produces ethyl N-[N-(p-chlorobenzoyl)-2-(p-anisidino)acetyl]-3-aminopropionate (oil), saponification of which and processing of the reaction product yields N-[N-(p-chlorobenzoyl)-2-(p-anisidino)acetyl]-3-aminopropionic acid (M.P. 129° to 131°).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:23]=[O:24])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:14]3[C:19]([CH3:20])=[CH:18][C:17]([Cl:21])=[CH:16][C:15]=3[Cl:22])[CH2:12][CH2:13][N:7]21.[CH2:25]([Mg]Br)[CH3:26].O>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:14]4[C:19]([CH3:20])=[CH:18][C:17]([Cl:21])=[CH:16][C:15]=4[Cl:22])[CH2:12][CH2:13][N:7]3[C:6]=2[C:5]([CH:23]([OH:24])[CH2:25][CH3:26])=[CH:4][CH:3]=1
Reactant: Cc1cc(Cl)cc(Cl)c1N1CCn2c1nc1c(Cl)ccc(C=O)c12
Reactant: CC[Mg]Br
Solvent: O
Solvent: C1CCOC1
Product: CCC(O)c1ccc(Cl)c2nc3n(c12)CCN3c1c(C)cc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.2 %

Procedure:
To a solution of 8-chloro-1-(2,4-dichloro-6-methylphenyl)-2,3-dihydro-1H-imidazo[1,2-a]benzimidazole-5-carbaldehyde (140 mg, 0.368 mmol) in tetrahydrofuran (30 mL) was added ethylmagnesium bromide (3.0 M solution in diethyl ether, 0.50 mL, 15.0 mmol) at 0° C. The mixture was stirred at 0° C. for 2 hr. Water was added to the reaction mixture at 0° C. and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the title compound (150 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1([C:8]([O:10]C)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4]1.[Li+].[OH-]>C1COCC1.O>[CH3:1][O:2][C:3]1([C:8]([OH:10])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: COC(=O)C1(OC)CCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COC1(C(=O)O)CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.8 %

Procedure:
A solution of methyl 1-methoxycyclopentanecarboxylate (1.00 g, 6.32 mmol) in THF (10 mL) was treated with a solution of LiOH (0.531 g, 12.64 mmol) in water (5 mL), stirred at RT overnight and concentrated to dryness. The residue was diluted with water, acidified with HCl (2M, 6 mL), extracted with EtOAc (3×) and the combined organics were washed with brine, dried over Na2SO4 and concentrated to dryness to afford 1-methoxycyclopentanecarboxylic acid (900 mg, 99%). 1H NMR (400 MHz, CDCl3): δ 3.31 (s, 3H), 2.05-2.03 (m, 4H), 1.78-1.77 (m, 4H) [CO2H not observed].
Reaction SMILES: C[O:2][C:3](=[O:23])[C@@H:4]([N:8]1[CH2:12][C:11]([O:13][C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])=[CH:10][C:9]1=[O:22])[CH2:5][CH2:6][CH3:7].O.[OH-].[Li+].O>O1CCCC1.O>[F:21][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([F:20])[C:14]=1[O:13][C:11]1[CH2:12][N:8]([C@@H:4]([CH2:5][CH2:6][CH3:7])[C:3]([OH:23])=[O:2])[C:9](=[O:22])[CH:10]=1
Reactant: CCC[C@@H](C(=O)OC)N1CC(Oc2c(F)cccc2F)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCC[C@@H](C(=O)O)N1CC(Oc2c(F)cccc2F)=CC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 0.1 %

Procedure:
To a solution of (S)-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-pentanoic acid methyl ester (0.108 g, 0.33 mol) in tetrahydrofuran:water (1:1, 8 mL) was added lithium hydroxide monohydrate (0.042 g 1.00 mmol). The mixture was stirred at room temperature for 2 h. The reaction mixture was poured into water and washed with diethyl ether and the diethyl ether layer discarded. The aqueous phase was acidified with 1N aqueous hydrochloric acid (pH <2), and extracted with ethyl acetate (2×30 mL). The combined ethyl acetate layers were dried over magnesium sulfate, filtered and concentrated to afford (S)-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-pentanoic acid, (0.086 g, 87%), as an off-white solid: LR-ES-MS m/z calculated for C15H15F2NO4 [M+H]+ 312, observed 312.
Reaction SMILES: [C:1]12(COC3C(Cl)=CC(C(OC(C)(C)C)=O)=C(F)C=3)[CH2:7][CH:6]1CCCC2.Cl[C:26]1[C:27]([O:40][CH:41]2[CH2:46][CH2:45][CH2:44][C:43]([CH3:48])([CH3:47])[CH2:42]2)=[CH:28][C:29]([F:39])=[C:30]([CH:38]=1)[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]>>[CH:1]1([C:26]2[C:27]([O:40][CH:41]3[CH2:46][CH2:45][CH2:44][C:43]([CH3:48])([CH3:47])[CH2:42]3)=[CH:28][C:29]([F:39])=[C:30]([CH:38]=2)[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:7][CH2:6]1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(OCC23CCCCC2C3)cc1F
Reactant: CC1(C)CCCC(Oc2cc(F)c(C(=O)OC(C)(C)C)cc2Cl)C1
Product: CC1(C)CCCC(Oc2cc(F)c(C(=O)OC(C)(C)C)cc2C2CC2)C1

Procedure:
Following the procedure as described in Example 342 Step 4 and making variations as required to replace tert-butyl 4-(bicyclo[4.1.0]heptan-1-ylmethoxy)-5-chloro-2-fluorobenzoate with tert-butyl 5-chloro-4-((3,3-dimethyl- cyclohexyl)oxy)-2-fluorobenzoate, the title compound was obtained as an orange oil (1.29 g, 82%): MS (ES+) m/z 385.1 (M+23).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[N:13]/[OH:14])/[CH2:7][C:8]32[CH2:12][CH2:11]3)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C1COCC1>[CH3:22][S:23]([O:14]/[N:13]=[C:6]1\[CH2:7][C:8]2([CH2:12][CH2:11]2)[C:9]2[C:5]\1=[CH:4][CH:3]=[C:2]([Br:1])[CH:10]=2)(=[O:25])=[O:24]
Reactant: O/N=C1\CC2(CC2)c2cc(Br)ccc21
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O/N=C1\CC2(CC2)c2cc(Br)ccc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 99.9 %

Procedure:
To a 0° C. solution of (E)-6′-bromospiro[cyclopropane-1,1′-inden]-3′(2′H)-one oxime (500 mg, 1.98 mmol) in THF (5 mL) was added triethylamine (332 μL, 2.38 mmol) followed by slow addition of MsCl (170 μL, 2.18 mmol). The reaction was stirred 10 minutes at 0° C. then concentrated. The residue was triturated from methanol (5 mL) to afford (E)-6′-bromospiro[cyclopropane-1,1′-inden]-3′(2′H)-one O-methylsulfonyl oxime (653 mg, 100% yield) as a white solid after drying under high vacuum. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 7.64 (d, J=8.4 Hz, 1H), 7.42 (dd, J=8.3, 1.6 Hz, 1H), 6.98 (d, J=1.5 Hz, 1H), 3.26 (s, 3H), 3.15 (s, 2H), 1.06-1.42 (m, 4H); MS (EI) m/z=331.2 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]#[C:10][CH2:11][OH:12])[CH:5]=[CH:6][C:7]=1[Cl:8].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]#[C:10][CH:11]=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OCC#Cc1ccc(Cl)c(Cl)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=CC#Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 98.3 %

Procedure:
To a solution of 3-(3,4-dichlorophenyl)-2-propyn-1-ol (2.980 g, P7, from Method A and B described for P7) in dry DCM (74 mL) and Dess-Martin periodinane (9.43 g) was added. The mixture was stirred at room temperature over night. NaS2O3 (19 g) and NaHCO3 saturated solution were then added to the mixture and it was stirred at room temperature for 1 hour. Then the organic phase was separated and washed with brine. The organic layer was dried and concentrated under reduced pressure to give the crude title product (2.9 g) that was used without further purification.