Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Br)Br.[CH2:4](N(CC)CC)C.[Cl:11][C:12]1[CH:23]=[CH:22][C:15]([O:16][CH2:17][NH:18][C:19](=[S:21])[S-:20])=[CH:14][CH:13]=1.[K+].S1CCS1>O.CN(C)C=O>[Cl:11][C:12]1[CH:23]=[CH:22][C:15]([O:16][CH2:17][N:18]=[C:19]2[S:20][CH2:4][S:21]2)=[CH:14][CH:13]=1
Reactant: CCN(CC)CC
Reactant: S=C([S-])NCOc1ccc(Cl)cc1
Agent: C1CSS1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: BrCBr
Solvent: O
Product: Clc1ccc(OCN=C2SCS2)cc1

Procedure:
To a mixture of 19.3 g. of methylene bromide and 3.7 g. of triethylamine in 100 ml. of dimethylformamide was added 10.0 g. of potassium p-chlorophenoxymethyldithiocarbamate in portions. After another one to two hours, the mixture was poured into water and partitioned into ethylene chloride. The dried ethylene chloride mixture was saturated with dry hydrogen chloride and the resulting salt collected by filtration. Hydrolysis of the salt in a chloroform-water mixture followed by separation, drying and concentration of the chloroform layer gave 3.5 g. of the dithietane as pale yellow crystals, m.p. 64.5°-66.0° C.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1F)[N:8]=[C:7](C1C=CC=CC=1C)[C:6]([CH2:20]SC1N=CN=C3C=1NC=N3)=[CH:5]2.[NH2:31][C:32]1[N:37]=[C:36](Cl)[CH:35]=[C:34]([CH:39]([CH3:41])[CH3:40])[N:33]=1.[H-].[Na+].CN([CH:47]=[O:48])C>>[CH:39]([C:34]1[CH:35]=[C:36]([O:48][CH2:47][C:9]2[C:9]([C:10]3[CH:5]=[CH:4][CH:3]=[CH:2][CH:11]=3)=[N:8][C:7]3[C:11]([CH:10]=2)=[CH:2][CH:3]=[CH:4][C:6]=3[CH3:20])[N:37]=[C:32]([NH2:31])[N:33]=1)([CH3:41])[CH3:40]
Reactant: CC(C)c1cc(Cl)nc(N)n1
Reactant: CN(C)C=O
Reactant: Cc1ccccc1-c1nc2cc(F)c(F)cc2cc1CSc1ncnc2nc[nH]c12
Agent: [H-]
Agent: [Na+]
Product: Cc1cccc2cc(COc3cc(C(C)C)nc(N)n3)c(-c3ccccc3)nc12
Temperature: 100 °C
Reaction time: 0.75 h
Yield: 30 %

Procedure:
A mixture of Intermediate 6 (100 mg, 0.32 mmol), 2-amino-4-chloro-6-isopropylpyrimidine (58 mg, 0.38 mmol) and sodium hydride (60% in mineral oil, 18 mg, 0.45 mmol) in DMF (2 mL) was stirred at 100° C. for 45 minutes. Purification was by preparative HPLC (Method 1) followed by partitioning between DCM (20 mL) and 10% aqueous K2CO3 solution (10 mL). The organic layer was separated, dried (MgSO4) and concentrated in vacuo to give the title compound as a white solid (37 mg, 30%). δH (CDCl3) 8.32 (s, 1H), 7.71-7.77 (m, 2H), 7.69 (d, J 8.1 Hz, 1H), 7.57 (d, J 9 Hz, 1H), 7.41-7.53 (m, 4H), 6.03 (s, 1H), 5.47 (s, 2H), 4.82 (br s, 2H), 2.83 (s, 3H), 2.64-2.79 (m, 1H), 1.21 (d, J 7 Hz, 6H). LCMS (ES+) 385.2 (M+H)+, RT 2.92 minutes (Method 3).
Reaction SMILES: [CH3:1][C:2]1[NH:15][C:5]2=[N:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][C:9]([CH3:10])=[C:4]2[N:3]=1.[C:16]([O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[C:22]([Cl:28])[CH:21]=1)(=[O:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:16]([O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][N:15]2[C:5]3=[N:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][C:9]([CH3:10])=[C:4]3[N:3]=[C:2]2[CH3:1])=[C:22]([Cl:28])[CH:21]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)Oc1ccc(CBr)c(Cl)c1
Reactant: COC(=O)c1cc(C)c2nc(C)[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)c2nc(C)n(Cc3ccc(OC(C)=O)cc3Cl)c2n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 117.6 %

Procedure:
A mixture of methyl 2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (2.70 g), 4-acetoxy-2-chlorobenzylbromide (4.85 g), potassium carbonate (2.73 g) and N,N-dimethylformamide (27 ml) was stirred at room temperature for 5 hr and left standing overnight. The reaction mixture was partitioned between ethyl acetate and saturated brine, and the resulting precipitate was collected by filtration and washed with water and ethyl acetate to give methyl 3-(4-acetoxy-2-chlorobenzyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (6.0 g) as a pale-brown powder. The mother liquor and washing were combined and the organic layer was separated, dried over magnesium sulfate and concentrated to dryness under reduced pressure. The residue was powdered from diethyl ether to give the second lot (680 mg) as a pale-brown powder.
Reaction SMILES: S(C1C=CC(C)=CC=1)([O-])(=O)=O.[NH2:12][C@@H:13]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:14]([O:16][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:15].[P:26](Cl)(Cl)(=[O:38])[O:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1.C(Cl)[Cl:42]>>[Cl:42][C:29]1[CH:30]=[CH:31][C:32]2[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:28]=1[O:27][P:26](=[N:12][C@@H:13]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:14]([O:16][CH2:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:15])=[O:38]
Reactant: ClCCl
Reactant: CC(C)C[C@H](N)C(=O)OCC(C)(C)C
Reactant: O=P(Cl)(Cl)Oc1cccc2ccccc12
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CC(C)C[C@H](N=[P+]([O-])Oc1c(Cl)ccc2ccccc12)C(=O)OCC(C)(C)C
Yield: 77 %

Procedure:
Using the general procedure for synthesizing naphthyl (aminoacid ester) phosphorochloridates the tosylate salt of (S)-neopentyl 2-amino-4-methylpentanoate (2.33 g), naphthalen-1-yl phosphorodichloridate (1.63 g), TEA (1.74 mL) and DCM (70 mL) were combined to give (2S)-neopentyl 2-(chloro(naphthalen-1-yloxy)phosphorylamino)-4-methylpentanoate in an 77% yield (2.04 g), as a pale yellow thick oil.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.Cl.[OH:22][CH2:23][C@H:24]1[C@H:28]([C:29]([F:32])([F:31])[F:30])[CH2:27][NH:26][CH2:25]1.C(N(CC)CC)C>CS(C)=O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:26]4[CH2:27][C@@H:28]([C:29]([F:31])([F:32])[F:30])[C@H:24]([CH2:23][OH:22])[CH2:25]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: OC[C@@H]1CNC[C@H]1C(F)(F)F
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3C[C@@H](CO)[C@H](C(F)(F)F)C3)c(F)cc2c1=O
Temperature: 50 °C
Reaction time: 18 h
Yield: 95.4 %

Procedure:
In 6 ml of dimethylsulfoxide, is dissolved 283 mg (1 mmol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. To the above solution, are added 411 mg (2 mmol) of trans-3-hydroxymethyl-4-trifluoromethylpyrrolidine hydrochloride and 0.42 ml (3 mmol) of triethylamine. The mixture is stirred at 50° C. for 18 hours. The reaction mixture was concentrated under reduced pressure. Water was added to the residue. The resulting precipitate was obtained by filtration and washed successively with water, isopropanol and diethyl ether to give 412 mg of the objective substance as a slightly yellow powder (yield 95.4%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]=[C:6]([CH:12]=[O:13])[C:5]2=[O:14].BrN1[C:20](=[O:21])[CH2:19][CH2:18]C1=O.[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1>C(Cl)(Cl)(Cl)Cl>[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:29][C:12]([C:6]2[C:5](=[O:14])[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([C:18]#[C:19][CH2:20][OH:21])[CH:3]=3)[O:8][CH:7]=2)=[O:13])=[CH:26][CH:25]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: NCc1ccc(Cl)cc1
Reactant: O=Cc1coc2ccc(Br)cc2c1=O
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(NCc1ccc(Cl)cc1)c1coc2ccc(C#CCO)cc2c1=O
Reaction time: 0.5 h
Yield: 23 %

Procedure:
A mixture of 6-bromo-3-formylchromone (1.2 g) and N-bromosuccinimide (0.82 g) in carbon tetrachloride (30 mL) is irradiated with a sun lamp (625 watt) for 20 minutes. The cooled reaction is then treated with 4-chlorobenzylamine (2 mL) and stirred 30 minutes. The resulting amide intermediate is purified by chromatography on silica gel 60 in ethyl acetate/CH2Cl2 mixtures and then recrystallized from CH2Cl2/hexane. (54%, M.p. 182-183° C.) A portion of the resulting amide (0.2 g) in dioxane is combined under argon with bis(benzonitrile) palladium (II) chloride (6 mg), copper(I) iodide (4 mg), a 0.5 M solution of tri-t-butylphosphine in cyclohexane (0.064 mL), diisopropylamine (0.085 mL), and propargyl alcohol (0.037 mL). The reaction is stirred at room temperature overnight. The mixture is diluted with ethyl acetate and filtering. The crude product is purified by column chromatography on silica gel 60 in ethyl acetate/CH2Cl2 mixtures and is then crystallized from methanol/CH2Cl2/ethyl acetate to afford the title compound (23%). Physical characteristics: m.p. 185-186° C. 1H NMR (CDCl3) δ 1.95, 4.52,4.62, 7.30, 7.50, 7.75, 8.27, 8.98, 9.63; MS (ESI) [M+Na]+ 390.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([F:10])=[CH:4][C:3]=1[C:11](=[O:18])[CH2:12][C:13]([O:15]CC)=[O:14].[CH2:19](OC(OCC)OCC)C.C(OC(=O)C)(=O)C.[CH:36]1([NH2:39])[CH2:38][CH2:37]1.CC(C)([O-])C.[K+]>C(O)(C)(C)C>[CH:36]1([N:39]2[C:2]3[C:3](=[CH:4][C:5]([F:10])=[C:6]([F:9])[C:7]=3[F:8])[C:11](=[O:18])[C:12]([C:13]([OH:15])=[O:14])=[CH:19]2)[CH2:38][CH2:37]1
Reactant: CCOC(OCC)OCC
Reactant: CCOC(=O)CC(=O)c1cc(F)c(F)c(F)c1F
Reactant: NC1CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CC(=O)OC(C)=O
Product: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 81.9 %

Procedure:
To 17.6 g (66.6 mmol) of ethyl 2,3,4,5-tetrafluoro-β-oxobenzenepropanoate was added 14.6 g (~1.5 equivalents) of triethylorthoformate and 16.19 g (2.38 equivalents) of acetic anhydride. The mixture was refluxed for two hours at 120° C. (and was then cooled to 80° C. and concentrated in vacuo). The mixture was diluted with t-butanol, cooled to 10° C., and 3.8 g (1.05 equivalents) of cyclopropylamine in 120 ml of t-butanol was added. The mixture was stirred at 20° C. for 30 minutes and then warmed to 50° C. overnight. At this temperature 7.5 g of potassium t-butoxide was added in 50 ml of t-butanol and the mixture was stirred for four hours. It was filtered and the solids dissolved in 250 ml of hot acetic acid and 200 ml of 3N hydrochloric acid was added in portions over four hours at 100° C. The mixture was cooled and the solids collected to give 15.44 g (82%) of the 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid; mp 226°-228° C.
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:13]=[CH:12][C:9]([CH2:10][OH:11])=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1>C(Cl)Cl.CO.C(Cl)Cl.O=[Mn]=O>[O:1]1[C:5]([C:6]2[CH:7]=[CH:8][C:9]([CH:10]=[O:11])=[CH:12][CH:13]=2)=[CH:4][N:3]=[CH:2]1
Reactant: OCc1ccc(-c2cnco2)cc1
Agent: O=[Mn]=O
Solvent: ClCCl
Solvent: CO
Product: O=Cc1ccc(-c2cnco2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of the 4-(oxazol-5-yl)benzyl alcohol (prepared as described by Tanaka, A.; Terasawa, T.; Hagihara, H.; Sakuma, Y.; Ishibe, N.; Sawada, M.; Takasugi, H.; Tanaka, H. J. Med. Chem. 1998, 41, 2390–2410) (0.23 g, 1.31 mmol) in CH2Cl2/MeOH (20:1, 10.5 mL) was added activated MnO2 (1.01 g, 11.6 mmol) and the mixture stirred at room temperature overnight. The reaction was then diluted with CH2Cl2 (10 mL) and filtered through Celite®, washing with CHCl3. The filtrate was concentrated to give the crude aldehyde as a beige solid (0.164 g) which used without further purification in the next reaction. 1H NMR (CDCl3) δ 7.52 (s, 1H), 7.82 (d, 2H, J=9 Hz), 7.95 (d, 2H, J=9 Hz), 7.99 (s, 1H), 10.02 (s, 1H).
Reaction SMILES: Cl.[NH2:2][CH2:3][C@@H:4]([C:6]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]2[C:7]=1[CH:8]=[CH:9][C:10](=[O:17])[NH:11]2)[OH:5].C(N(CC)CC)C.[C:25]1([C@H:31]([NH:62][C:63]([O:65][C@@H:66]2[CH:71]3[CH2:72][CH2:73][N:68]([CH2:69][CH2:70]3)[CH2:67]2)=[O:64])[C:32]2[CH:33]=[C:34]([CH:59]=[CH:60][CH:61]=2)[O:35][CH2:36][C:37]2[CH:58]=[CH:57][C:40]([C:41]([N:43]3[CH2:48][CH2:47][CH:46]([C:49]([O:51][CH2:52][CH2:53][CH2:54][CH:55]=O)=[O:50])[CH2:45][CH2:44]3)=[O:42])=[CH:39][CH:38]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>CO>[C:25]1([C@H:31]([NH:62][C:63]([O:65][C@@H:66]2[CH:71]3[CH2:70][CH2:69][N:68]([CH2:73][CH2:72]3)[CH2:67]2)=[O:64])[C:32]2[CH:33]=[C:34]([CH:59]=[CH:60][CH:61]=2)[O:35][CH2:36][C:37]2[CH:58]=[CH:57][C:40]([C:41]([N:43]3[CH2:44][CH2:45][CH:46]([C:49]([O:51][CH2:52][CH2:53][CH2:54][CH2:55][NH:2][CH2:3][C@H:4]([OH:5])[C:6]4[CH:15]=[CH:14][C:13]([OH:16])=[C:12]5[C:7]=4[CH:8]=[CH:9][C:10](=[O:17])[NH:11]5)=[O:50])[CH2:47][CH2:48]3)=[O:42])=[CH:39][CH:38]=2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: NC[C@H](O)c1ccc(O)c2[nH]c(=O)ccc12
Reactant: O=CCCCOC(=O)C1CCN(C(=O)c2ccc(COc3cccc([C@@H](NC(=O)O[C@H]4CN5CCC4CC5)c4ccccc4)c3)cc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: O=C(N[C@@H](c1ccccc1)c1cccc(OCc2ccc(C(=O)N3CCC(C(=O)OCCCCNC[C@H](O)c4ccc(O)c5[nH]c(=O)ccc45)CC3)cc2)c1)O[C@H]1CN2CCC1CC2
Reaction time: 0.17 h
Yield: 16.5 %

Procedure:
To a suspension of (R)-5-(2-amino-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one hydrochloride (0.136 g, 0.53 mmol) in methanol (3.5 mL) was added triethylamine (0.148 mL, 1.06 mmol). The mixture was stirred for 10 minutes and then a solution of 4-oxobutyl 1-(4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)-phenoxy)methyl)benzoyl)piperidine-4-carboxylate (0.337 g, 0.50 mmol) in methanol (3.4 mL) was added. The mixture was stirred at RT for 1 hour. Sodium triacetoxyborohydride (0.267 g, 1.26 mmol) followed by acetic acid (0.121 mL, 2.12 mmol) was added and the reaction continued for a further 18 hours. The reaction mixture was quenched with water and evaporated at reduced pressure. The residue dissolved in iso-butanol and washed with water. The organic phase was evaporated at reduced pressure and the crude material was purified by reverse phase preparative HPLC to afford the title compound (0.072 g, 16%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:25][CH2:24][N:11]2[C:12](=[O:23])[C:13]3[C:18]([C@H:10]2[CH2:9]1)=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:22])([F:21])[F:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26]I.[H-].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:25][CH2:24][N:11]2[C:12](=[O:23])[C:13]3[C:18]([C:10]2([CH3:26])[CH2:9]1)=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:20])([F:22])[F:21])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)c3c(cccc3C(F)(F)F)[C@H]2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN2C(=O)c3c(C(F)(F)F)cccc3C2(C)C1
Reaction time: 3 h
Yield: 39.8 %

Procedure:
To a stirring solution of N-(t-butoxycarbonyl)-(S)-1,3,4,10b-tetrahydro-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one (150 mg, 0.4 mmol) and methyl iodide (125 mg, 0.9 mmol) in dry DMF (6 mL) was added sodium hydride (15 mg, 0.6 mmol). The reaction was stirred for 3 h and then quenched with brine. The reactionwas extracted with EtOAc (3×10 mL). The organic layers were combined, dried over Na2SO4, and conc. in vacuo to a brown oil. The oil was purified by flash chromatography (silica gel, 0–50% EtOAc in hexanes) to yield 59 mg of the desired product as a white solid. MS (ESI) 371 (M+H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:18])[CH3:17])=[CH:12][CH:11]=2)N)=[CH:5][CH:4]=1.[CH3:21][C:22]([CH3:41])([CH2:27][C:28](=O)[CH2:29][S:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH:37]([CH3:39])[CH3:38])[C:23]([O:25]C)=[O:24]>>[Cl:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:10]3[C:15](=[CH:14][C:13]([CH:16]([CH3:18])[CH3:17])=[CH:12][CH:11]=3)[C:29]([S:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[CH:37]([CH3:39])[CH3:38])=[C:28]2[CH2:27][C:22]([CH3:41])([CH3:21])[C:23]([OH:25])=[O:24])=[CH:5][CH:4]=1
Reactant: CC(C)c1ccc(N(N)Cc2ccc(Cl)cc2)cc1
Reactant: COC(=O)C(C)(C)CC(=O)CSc1ccccc1C(C)C
Agent: Cl
Product: CC(C)c1ccc2c(c1)c(Sc1ccccc1C(C)C)c(CC(C)(C)C(=O)O)n2Cc1ccc(Cl)cc1

Procedure:
Following the procedure of Example 104, but using 1-(p-chlorobenzyl)-1-[4-(i-propyl)phenyl]-hydrazine hydrochloride and methyl 2,2-dimethyl-4-oxo-5-(2-isopropylphenylthio)pentanoate as starting materials followed by hydrolysis at reflux gave the title compound, m.p. 142°-143°.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7](Cl)(=[O:9])=[O:8])[CH:2]=1.[H-].[Na+].[CH3:13][CH:14]([CH3:26])[C:15]([O:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16]>>[CH3:13][CH:14]([CH3:26])[C:15]([O:17][N:18]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[S:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)(=[O:9])=[O:8])=[O:16]
Reactant: CC(C)C(=O)ONC(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: [H-]
Agent: [Na+]
Product: CC(C)C(=O)ON(C(=O)OC(C)(C)C)S(=O)(=O)c1cccnc1

Procedure:
N-[(tert-Butoxy)carbonyl]pyridine-3-sulfonamido 2-methylpropanoate (78) is synthesised from 3-pyridine sulfonyl chloride, sodium hydride and [(tert-butoxy)carbonyl]amino 2-methylpropanoate according to Scheme 2. (0.6 g, 37%), 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 9.21 (1H, d, 1.6 Hz), 8.89 (1H, dd, 4.7, 1.3 Hz), 8.34 (1H, dd, 7.4, 1.4 Hz), 7.53 (1H, dd, 8.2, 4.9 Hz), 2.84 (1H, sept, 7.0 Hz), 1.42 (9H, s), 1.32 (6H, d, 6.9 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[NH2:6].F[C:13]1[C:18]([C:19]2[N:24]=[C:23]([CH3:25])[N:22]=[C:21]([N:26]([CH2:36][C:37]3[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=3)[CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)[N:20]=2)=[CH:17][CH:16]=[CH:15][N:14]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:6][C:13]2[C:18]([C:19]3[N:24]=[C:23]([CH3:25])[N:22]=[C:21]([N:26]([CH2:27][C:28]4[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=4)[CH2:36][C:37]4[CH:38]=[CH:39][C:40]([O:43][CH3:44])=[CH:41][CH:42]=4)[N:20]=3)=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3F)n2)cc1
Reactant: COc1ccc(N)cc1OC
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3Nc3ccc(OC)c(OC)c3)n2)cc1

Procedure:
The title compound was prepared in an analogous manner to that described in Example 164 using 3,4-dimethoxyaniline (Aldrich) and 4-(2-fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine, and isolated as a brown oil (100%). 1H NMR (400 MHz, CDCl3) δ 11.69 (s, 1H); 8.82 (dd, J=7.8, 2.0 Hz, 1H); 8.30 (dd, J=4.7, 1.8 Hz, 1H); 7.31 (d, J=2.2 Hz, 1H); 7.20 (d, J=8.2 Hz, 4H); 6.98 (dd, J=8.6, 2.3 Hz, 1H); 6.78-6.91 (m, 5H); 6.72 (dd, J=7.8, 4.7 Hz, 1H); 4.83 (s, 4H); 3.86 (s, 3H); 3.81 (s, 6H); 3.79 (s, 3H); 2.57 (s, 3H). m/z (ESI, +ve ion) 579.0 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][C:11]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)([C:13]([F:16])([F:15])[F:14])[O:10][N:9]=2)=[CH:4][C:3]=1[CH3:25].[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][NH2:33].CN([CH:37]=[O:38])C>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:24][C:19]1[CH:18]=[C:17]([C:11]2([C:13]([F:16])([F:15])[F:14])[O:10][N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:37]([NH:33][CH2:32][C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][N:26]=4)=[O:38])=[C:3]([CH3:25])[CH:4]=3)[CH2:12]2)[CH:22]=[C:21]([Cl:23])[CH:20]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1Br
Reactant: CN(C)C=O
Reactant: NCc1ccccn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCc1ccccn1
Temperature: 100 °C
Reaction time: 26 h
Yield: 34 %

Procedure:
A mixture of 3-(4-Bromo-3-methyl-phenyl)-5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazole (1.02 g, 2.24 mmol), 2-picolylamine (369 mg, 3.41 mmol), Pd(dppf)Cl2 (92 mg, 0.13 mmol) triethylamine (5.2 mL, 3.8 g. 37 mmol) and DMF (50 mL) was flushed with carbon monoxide and stirred under an atmosphere of CO at 100° C. for 26 h. The solvent was removed in vacuum and the residue was taken up in EtOAc, filtered and evaporated. The residue was chromatographed on SiO2 to give the title compound (391 mg, 34%).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:23])=[C:11]([N:16]4[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]4)[C:12]=3[CH2:14][OH:15])[C:7](=[O:24])[C:6]([C:25]([O:27][CH2:28]C)=[O:26])=[CH:5]2)[CH2:3][CH2:2]1.S(=O)(=O)(O)O.[C:35](=O)([O-])O.[Na+]>CO>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:23])=[C:11]([N:16]4[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]4)[C:12]=3[CH2:14][O:15][CH3:35])[C:7](=[O:24])[C:6]([C:25]([O:27][CH3:28])=[O:26])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C([O-])O
Reactant: CCOC(=O)c1cn(C2CC2)c2c(CO)c(N3CCN(C)CC3)c(F)cc2c1=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COCc1c(N2CCN(C)CC2)c(F)cc2c(=O)c(C(=O)OC)cn(C3CC3)c12

Procedure:
To a solution of ethyl 1-cyclopropyl-7-(4-methyl-1-piperazinyl)-6-fluoro-8-hydroxymethyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (160 mg) in methanol (10 ml) is added conc. sulfuric acid (2 ml), and the mixture is refluxed for 6.5 hours. The reaction mixture is adjusted to below pH 8 with aqueous saturated sodium hydrogen carbonate and extracted with dichloromethane. The extract is washed with aqueous saturated sodium chloride and then dried over magnesium sulfate and the solvent is distilled off. The residue is crystallized by adding thereto diethyl ether to give methyl 1-cyclopropyl-7-(4-methyl-1-piperazinyl)-6-fluoro-8-methoxymethyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (125 mg), as pale yellow powder, m.p. 200°-204° C.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:7]2[C:3]=1[CH2:4][N:5]([CH:14]([CH:32]([CH3:34])[CH3:33])[C:15]([O:17]CC1C=CC=C(OC3C=CC=CC=3)C=1)=[O:16])[CH2:6]2.[OH-].[K+].C(O)C>O>[F:13][C:8]1[C:9]([F:12])=[C:10]([F:11])[C:2]([F:1])=[C:3]2[C:7]=1[CH2:6][N:5]([CH:14]([CH:32]([CH3:34])[CH3:33])[C:15]([OH:17])=[O:16])[CH2:4]2
Reactant: CC(C)C(C(=O)OCc1cccc(Oc2ccccc2)c1)N1Cc2c(F)c(F)c(F)c(F)c2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)C(C(=O)O)N1Cc2c(F)c(F)c(F)c(F)c2C1

Procedure:
A mixture of m-phenoxybenzyl 2-(4,5,6,7-tetrafluoro-2-isoindolinyl)-3-methylbutanoate (0.4 g), potassium hydroxide (0.134 g), ethanol (8 ml) and water (2 ml) is heated to reflux for 4 hours. After cooling, the reaction mixture is concentrated under vacuum and 50 ml of water is added. This mixture is washed with ether (3×). The aqueous phase is carefully adjusted to pH 7 and then extracted with ether (3×). The combined ether extracts are washed with water, dried and solvent removed under vacuum to yield 2-(4,5,6,7-tetrafluoro-2-isoindolinyl)-3-methylbutanoic acid, a white powder.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:19])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([OH:18])([CH3:17])[CH2:9][CH2:8]2)(=[O:3])[CH3:2].CS(C)=O.[C-:24]#[N:25].[K+].OS(O)(=O)=O>O.C(OCC)C>[C:24]([C:10]([OH:18])([CH2:9][CH2:8][C:7]1[C:6]([CH3:19])=[C:5]([O:4][C:1](=[O:3])[CH3:2])[C:14]([CH3:15])=[C:13]([CH3:16])[C:12]=1[OH:11])[CH3:17])#[N:25]
Reactant: [C-]#N
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(O)O2
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)Oc1c(C)c(C)c(O)c(CCC(C)(O)C#N)c1C

Procedure:
A solution of 26.4 g. (0.1 mol.) of (±)-6-acetoxy-2-hydroxy-2,5,7,8-tetramethylchroman in 200 ml. of dimethylsulfoxide was rapidly stirred as 32.5 g. (0.5 mol.) of granular KCN was added by sifting so that a uniformly dispersed suspension was obtained. The resulting mixture was cooled to 15 degrees centigrade as 47.0 ml. of 12N aqueous H2SO4 was added over 1.25 hours as the internal temp. was maintained at 20° centigrade. Tlc at this point showed a major, slower-running spot in addition to traces of starting material. The material was poured into diethylether and H2O. The ether solutions were washed with water and brine, dried over NaSO4 and stripped of solvent to yield (±)-2-cyano-4-(5-acetoxy-2-hydroxy-3,4,6-trimethylphenyl)butan-2-ol as a gum.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:11]=1[NH2:12]>ClCCl>[Br:1][C:15]1[C:14]([F:17])=[CH:13][C:11]([NH2:12])=[C:10]([F:9])[CH:16]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cc(F)ccc1F
Solvent: ClCCl
Product: Nc1cc(F)c(Br)cc1F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
N-Bromosuccinimide (28.50 g, 0.160 mol) is added in small quantities over 1.5 hours to a stirred, cooled (-10° to 0° C.) solution of 2,5-difluoroaniline (20.00 g, 0.155 mol) in dry dichloromethane under dry nitrogen. This mixture is stirred at 0° C. for 2 hours (glc analysis revealing a complete reaction), and the red solution then washed with a large amount of water (×2) and dried (MgSO4). The solvent is removed in vacuo to afford a red solid with a yield of 32.19 g (100%).