Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([C:6]([NH2:11])=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.Cl[Si](C)(C)C.CC([Mg]Cl)C.[O:22]=[C:23]1[CH2:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24]1>C1COCC1>[NH2:11][C:6]1[C:5]2=[CH:4][CH:3]=[C:2]([C:23]3([OH:22])[CH2:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])[CH2:24]3)[N:10]2[N:9]=[CH:8][N:7]=1
Reactant: Nc1ncnn2c(Br)ccc12
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Agent: CC(C)[Mg]Cl
Agent: C[Si](C)(C)Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(O)(c2ccc3c(N)ncnn23)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
7-Bromopyrrolo[2,1-f][1,2,4]triazin-4-amine (17.29 g, 81 mmol) was dissolved in THF (214 mL) under argon at room temperature. Chlorotrimethylsilane (20.60 mL, 17.63 g, 162 mmol, 2 eq.) was added, and the mixture was stirred at room temperature for 3 h. Then, it was cooled to 0° C., and 2-propyl magnesium chloride (170 mL of a 2.0 M solution in THF, 340 mmol, 4.2 eq.) was added. The mixture was stirred for further 3 h while warming up to room temperature. Then, tert-butyl 3-oxopiperidine-1-carboxylate (25.00 g, 121 mmol, 1.5 eq.) was added, and stirring was continued for another 16 h. The reaction was quenched with a 1:1 mixture of concentrated aqueous ammonium chloride solution and ice until the pH value reached 6-7. The mixture was extracted with two portions of ethyl acetate, and the combined organic extracts were dried over anhydrous sodium carbonate and concentrated to dryness. The title compound crystallized upon trituration of the residue with diethyl ether (50 mL). The crystals were washed with diethyl ether and dried to give 17.20 g (64% of th.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=2)[C:10]([C:18]#[CH:19])=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:20]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)=[N+:21]=[N-:22].Cl>CN(C=O)C.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[CH3:30][O:29][C:27]([C:26]1[CH:25]=[CH:24][C:23]([N:20]2[CH:19]=[C:18]([C:10]3[C:11]4[C:16](=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=4)[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[N:9]=3)[N:22]=[N:21]2)=[CH:32][CH:31]=1)=[O:28]
Reactant: C#Cc1nn(C(=O)OC(C)(C)C)c2ccc(C)cc12
Reactant: COC(=O)c1ccc(N=[N+]=[N-])cc1
Agent: [Cu+2]
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(-n2cc(-c3nn(C(=O)OC(C)(C)C)c4ccc(C)cc34)nn2)cc1
Temperature: 80 °C

Procedure:
Copper sulfate pentahydrate (0.08 g; 0.33 mmol; 0.06 eq.) was added to a solution of tert-butyl-3-ethynyl-5-methyl-1H-indazole-1-carboxylate (1.55 g; 6.03 mmol; 1.0 eq.), methyl 4-azidobenzoate (prepared as described in JOC (2006), 71(15), 5822-5825; 1.20 g; 6.77 mmol; 1.1 eq.) and D-(−)-isoascorbic acid sodium salt (0.24 g; 1.22 mmol; 0.20 eq.) in DMF (15 mL) and water (0.50 mL). The reaction suspension was heated in MW at 80° C. for 45 min then poured into HCl (0.1 N solution) and extracted with EtOAc. Combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude was purified by flash chromatography on silica (n-heptane/EtOAc, gradient from 90:10 to 60:40) to give the title compound as a yellow solid. 1H NMR (300 MHz, DMSO) δ 9.66 (s, 1H), 8.35-8.25 (m, 3H), 8.20 (d, J=8.8 Hz, 2H), 8.05 (d, J=8.7 Hz, 1H), 7.54 (dd, J=1.5, 8.7 Hz, 1H), 3.91 (s, 3H), 2.53 (s, 3H), 1.69 (s, 9H). HPLC (Condition A): Rt 5.07 min (purity 96.8%). MS (ESI+): 434.4.
Reaction SMILES: C([Mg]Br)C.[CH3:5][CH:6]([CH2:9][CH3:10])[C:7]#[CH:8].[CH3:11][C:12]([CH3:22])([C:14](=[O:21])[CH2:15][N:16]1[CH:20]=[N:19][CH:18]=[N:17]1)[CH3:13].[Cl-].[NH4+]>C(OCC)C.ClCCl>[CH3:13][C:12]([CH3:22])([C:14]([OH:21])([C:8]#[C:7][CH:6]([CH3:5])[CH2:9][CH3:10])[CH2:15][N:16]1[CH:20]=[N:19][CH:18]=[N:17]1)[CH3:11]
Reactant: C#CC(C)CC
Reactant: CC(C)(C)C(=O)Cn1cncn1
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: ClCCl
Product: CCC(C)C#CC(O)(Cn1cncn1)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
10 To a solution of ethyl magnesium bromide (20 ml) of a 3M solution in diethyl ether) in dry diethyl ether (30 ml) under N2 at room temperature was added a solution of 3-methyl-1-pentyne (5 g, 0.06 mol) in diethyl ether (20 ml). The resulting mixture was heated under reflux for 1 hour, and then cooled to 0° C. To this mixture was added slowly a solution of 2,2-dimethyl-4-(1,2,4-triazol-1-yl)-butane-3-one (8.4 g, 0.05 mol) in dry dichloromethane (150 ml), and the mixture stirred for 45 minutes, a gelatinous precipitate formed. Ammonium chloride solution was added to the mixture, and the organic layer separated and washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was chromatographed on silica eluting with diethyl ether (20-100%) in petrol gave 2,2-dimethyl-3-hydroxy-3-(3-methyl-pent-1-yne-1-yl)-4-(1,2,4-triazol-1-yl)-butane) as a white solid (4.29 g) (mpt=59°-60° C.).
Reaction SMILES: C([N:9]1[C:17]2[CH:16]=[CH:15][C:14]([Br:18])=[C:13]3[CH2:19][C@@H:20]([N:22]([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])[CH2:21][C@H:11]([C:12]=23)[CH2:10]1)(=O)C1C=CC=CC=1.C([Li])CCC.Cl>O1CCCC1.CCCCCC>[Br:18][C:14]1[CH:15]=[CH:16][C:17]2[NH:9][CH2:10][C@@H:11]3[CH2:21][C@H:20]([N:22]([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])[CH2:19][C:13]=1[C:12]=23
Reactant: CCCN(CCC)[C@@H]1Cc2c(Br)ccc3c2[C@@H](C1)CN3C(=O)c1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCN(CCC)[C@@H]1Cc2c(Br)ccc3c2[C@H](CN3)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 98.1 %

Procedure:
To a stirred solution of 12.8 g (29 mmol) of (+)(2aR,4S)-1-benzoyl-6-bromo-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole in 200 ml of tetrahydrofuran cooled to -78° C. under a nitrogen atmosphere was added 20 ml (32 mmol) of a 1.6M solution of n-butyllithium in hexane. The reaction mixture was stirred at -78° C. for 30 minutes and then allowed to warm to -20° C. To the reaction mixture was added 50 ml of a 1N hydrochloric acid solution. The mixture was extracted once with diethyl ether. The acidic solution was made alkaline with the addition of cold 5N sodium hydroxide solution. The basic mixture was extracted twice with methylene chloride. The combined organic solution was washed with a saturated sodium chloride solution. The methylene chloride solution was dried over magnesium sulfate and evaporated to give 9.6 g of (-)(2aR,4S)-6-bromo-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH:10]=O)[CH:3]=[N:2]1.[CH2:12]([O:14][CH:15]([O:18][CH2:19][CH3:20])[CH2:16][NH2:17])[CH3:13].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:12]([O:14][CH:15]([O:18][CH2:19][CH3:20])[CH2:16][NH:17][CH2:10][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[NH:1][N:2]=[CH:3]2)[CH3:13]
Reactant: CCOC(CN)OCC
Reactant: O=Cc1cccc2cn[nH]c12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(CNCc1cccc2cn[nH]c12)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1H-Indazole-7-carbaldehyde (175 g, 12 mmol) in MeOH (50 mL) was added aminoacetaldehyde diethyl acetal (1.74 mL, 12 mmol) and acetic acid (1.03 mL, 18 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was added to a stirred solution of sodium cyanoborohydride (816 mg, 13 mmol). The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was concentrated under reduced pressure. Then H2O and ethyl acetate were added to the reaction mixture. The organic layer was washed with H2O and brine, dried over Na2SO4, and concentrated under reduced pressure. The crude compound was used next step without further purification.
Reaction SMILES: [CH2:1]([C:3]1[CH:35]=[CH:34][C:6]2[CH:7]([C:17]3[C:18](=[S:33])[NH:19][C:20](=[O:32])[N:21]([CH2:23][C:24]4[O:28][C:27]([C:29]([OH:31])=O)=[CH:26][CH:25]=4)[CH:22]=3)[C:8]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:9]=3[CH:10]=[CH:11][C:5]=2[CH:4]=1)[CH3:2].[NH2:36][C:37]1[NH:41][N:40]=[N:39][N:38]=1>>[CH2:1]([C:3]1[CH:35]=[CH:34][C:6]2[CH:7]([C:17]3[C:18](=[S:33])[NH:19][C:20](=[O:32])[N:21]([CH2:23][C:24]4[O:28][C:27]([C:29]([NH:36][C:37]5[NH:41][N:40]=[N:39][N:38]=5)=[O:31])=[CH:26][CH:25]=4)[CH:22]=3)[C:8]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:9]=3[CH:10]=[CH:11][C:5]=2[CH:4]=1)[CH3:2]
Reactant: Nc1nnn[nH]1
Reactant: CCc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1cn(Cc2ccc(C(=O)O)o2)c(=O)[nH]c1=S
Product: CCc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1cn(Cc2ccc(C(=O)Nc3nnn[nH]3)o2)c(=O)[nH]c1=S

Procedure:
The title compound was prepared from the product of example 31(0.93 g) and amino tetrazole (0.3 g) according to the method of example 10 step (i). Purification was by precipitation from ethyl acetate-iso-hexane. Yield 0.426 g.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=O.[C:12]([CH:17]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:14][CH2:15][CH3:16])=[O:13]>C(Cl)Cl>[CH2:15]([O:14][C:12](=[O:13])[CH:17]=[CH:7][C:6]1[CH:9]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[O:10][CH3:11])[CH3:16]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(F)cc1C=O
Solvent: ClCCl
Product: CCOC(=O)C=Cc1cc(F)ccc1OC
Temperature: 25 °C
Yield: 63.7 %

Procedure:
To a solution of 5-fluoro-2-methoxybenzaldehyde (4.3 g, 28 mmol) in dry CH2Cl2 (40 mL) at 0° C. was added carbethoxymethylenetriphenylphosphorane (10.7 g, 30 mmol) portionwise and the reaction was warmed to room temperature for 12 h. The solvent was then removed in vacuo and the residue was purified by flash column chromatography (8% EtOAc in Hexane, Rf=0.20) to yield the product (4 g, 95%) as an oil.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:11].Br[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=1>>[Cl:18][C:16]1[CH:15]=[CH:14][C:13]([C:19]2[N:20]=[CH:21][CH:22]=[CH:23][N:24]=2)=[C:12]([C:10]([N:4]2[CH2:5][CH2:6][CH2:7][C@@H:8]([CH3:9])[C@H:3]2[CH2:2][NH:1][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=2)=[O:11])[CH:17]=1
Reactant: Clc1ccc(Br)nc1
Reactant: C[C@@H]1CCCN(C(=O)c2cc(Cl)ccc2-c2ncccn2)[C@@H]1CN
Product: C[C@@H]1CCCN(C(=O)c2cc(Cl)ccc2-c2ncccn2)[C@@H]1CNc1ccc(Cl)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-chloro-2-(pyrimidin-2-yl)phenyl)methanone and 2-bromo-5-chloropyridine. MS (ESI) 456 (M+H).
Reaction SMILES: C([O:4][C@H:5]([CH2:10]Br)[CH2:6][C:7]([OH:9])=[O:8])(=O)C.[OH-].[Ca+2:13].[OH-]>O>[Ca+2:13].[O:4]1[CH2:10][C@@H:5]1[CH2:6][C:7]([O-:9])=[O:8].[O:4]1[CH2:10][C@@H:5]1[CH2:6][C:7]([O-:9])=[O:8]
Reactant: CC(=O)O[C@H](CBr)CC(=O)O
Agent: [Ca+2]
Agent: [OH-]
Solvent: O
Product: O=C([O-])C[C@H]1CO1
Reaction time: 2 h

Procedure:
To a 2 l of three-necked flask equipped with thermometer, pH meter and mechanical stirrer were charged distilled water (1 l), (S)-3-acetoxy-4-bromobutyric acid (90 g, 0.4 mol) and calcium hydroxide (45 g, 0.6 mol). The reaction mixture was stirred at 0˜5 for 2 hours to afford (S)-3,4-epoxybutyric acid calcium salt Over 99% of conversion was detected by NMR.
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.[CH3:11][C:12]([CH3:25])([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([CH3:24])([CH3:23])[CH2:21][OH:22])[CH2:13][OH:14]>N1C=CC=CC=1>[C:2]([O:22][CH2:21][C:20]([CH3:24])([CH3:23])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:12]([CH3:25])([CH3:11])[CH2:13][O:14][C:2](=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: CC(C)(CO)CCCCCC(C)(C)CO
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(CCCCCC(C)(C)COC(=O)c1cccnc1)COC(=O)c1cccnc1

Procedure:
106.2 Grams (0.6 mole) of nicotinoyl chloride hydrochloride in 300 ml of anhydrous pyridine were reacted with 21.6 grams (0.1 mole) of 2,2,8,8-tetramethyl-1,9-nonanediol according to the procedure described in the above example.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH:13]1[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH2:16][CH2:15][CH2:14]1)(=[O:12])=[O:11].S(=O)(=O)(O)O.[CH2:29](O)CC>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH:13]1[C:18]([C:19]([O:21][CH2:22][CH2:23][CH3:29])=[O:20])=[CH:17][CH2:16][CH2:15][CH2:14]1)(=[O:11])=[O:12]
Reactant: CCOC(=O)C1=CCCCC1S(=O)(=O)Nc1ccc(F)cc1F
Reactant: CCCO
Agent: O=S(=O)(O)O
Product: CCCOC(=O)C1=CCCCC1S(=O)(=O)Nc1ccc(F)cc1F

Procedure:
To a solution of ethyl 6-[N-(2,4-difluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate (Compound 3, 300 mg) obtained in Example 3 in 1-propanol (6 ml), concentrated sulfuric acid (0.3 ml) was added and the mixture was stirred under reflux for 50 hours. The reaction mixture was concentrated under reduced pressure and diluted with ethyl acetate (30 ml) and washed with water (30 ml). The ethyl acetate layer was washed with water (30 ml×2) and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography (eluent: ethyl acetate/hexane=1/5) and desired fractions were concentrated under reduced pressure. The residue was purified by column chromatography on octadecylsilica (ODS) (eluent: methanol/water=4/1) and then crystallized from diisopropyl ether to yield propyl 6-[N-(2,4-difluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate (Compound 23, 60 mg) as colorless crystals.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.O[C:38]1[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=1>[H-].[Na+].O1CCCC1>[CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([O:22][C:38]3[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=3)=[O:21])=[CH:18][CH:17]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Oc1cccnc1
Reactant: O=C(O)c1ccc(NCCCCCCCCC2CCCCC2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Oc1cccnc1)c1ccc(NCCCCCCCCC2CCCCC2)cc1

Procedure:
A 6 g. sample of 4-(8-cyclohexyloctylamino)benzoic acid and 2.7 g. 1,1'-carbonyldiimidazole in 50 ml. dry tetrahydrofuran is stirred for 2 hours. Then, 1.58 g. 3-hydroxypyridine and a trace of sodium hydride catalyst is added and the reaction is refluxed for 3 hours. The solution is cooled, filtered, and evaporated. The product is crystallized from isopropanol.
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:32]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:31])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:30])[C:13]=2[C@@H:14]2[CH2:20][CH2:19][C@@H:18]([NH:21]C(OC(C)(C)C)=O)[C@H:17]([F:29])[CH2:16][O:15]2)[N:6]=1.[F:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([CH3:47])[C:42]=1B(O)O>>[NH2:32][C:4]1[S:3][C:2]([C:42]2[C:43]([CH3:47])=[CH:44][CH:45]=[CH:46][C:41]=2[F:40])=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:30])[C:13]=1[C@@H:14]1[CH2:20][CH2:19][C@@H:18]([NH2:21])[C@H:17]([F:29])[CH2:16][O:15]1)=[O:31]
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Reactant: Cc1cccc(F)c1B(O)O
Product: Cc1cccc(F)c1-c1nc(C(=O)Nc2cnn(C)c2[C@@H]2CC[C@@H](N)[C@H](F)CO2)c(N)s1

Procedure:
Following the procedure for Example 101 starting from tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6S)-5-(tert-butoxycarbonylamino)-6-fluoro-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (Intermediate 95), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2-fluoro-6-methylphenyl)boronic acid gave 330. 1H NMR (400 MHz, DMSO-d6) δ 9.13 (s, 1H), 7.72 (s, 1H), 7.43-7.32 (m, 3H), 7.21-7.11 (m, 2H), 4.74 (dd, J=11.0, 3.6 Hz, 1H), 4.40-4.17 (m, 2H), 4.16-4.03 (m, 1H), 4.03-3.85 (m, 1H), 3.76 (s, 3H), 3.20-3.09 (m, 1H), 2.46 (s, 3H), 2.06-1.97 (m, 1H), 1.89-1.77 (m, 1H), 1.70-1.58 (m, 3H). LCMS (ES+) m/z 463 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12]O[C:10]=1[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:17][CH:18]([F:21])[CH2:19][NH2:20].Cl.C(N(CC)CC)C>N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:20]([CH2:19][CH:18]([F:21])[F:17])[C:10]=1[CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCC(F)F
Reactant: Cc1occc(=O)c1OCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: Cc1c(OCc2ccccc2)c(=O)ccn1CC(F)F
Temperature: 110 °C
Yield: 60.3 %

Procedure:
3-(Benzyloxy)-2-methyl-4H-pyran-4-one (432 mg, 2.0 mmol) was mixed with 2,2-difluoroethylamine (655 mg, 8.0 mmol) and triethylamine hydrochloride (1.10 g, 8.0 mmol) in pyridine (6 mL) in a sealed vial. The reaction mixture was heated at 110° C. for overnight. The solid was filtered and washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the residue was mixed with water, and then extracted with ethyl acetate. The organic layer was washed with water and brine. The product was purified by column chromatography on silica gel with 5% methanol in ethyl acetate as eluant to give 3-(benzyloxy)-1-(2,2-difluoroethyl)-2-methylpyridin-4(1H)-one (337 mg) as pale-yellow solid. Yield=60%; 1H NMR (MeOD-D4, 90 MHz) δ (ppm): 7.66 (d, J=7.1 Hz, 1H), 7.16-7.55 (m, 5H), 6.46 (d, J=7.1 Hz, 1H), 5.55 (t, J=55.0 Hz, 1H), 4.45 (t, J=14.8 Hz, 1H) and 2.20 (s, 3H); MS m/z 280 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[Br:9][C:10]1[O:11][C:12]2[C:13](=[C:15]([C:23](OC)=[O:24])[CH:16]=[C:17]([O:19][CH:20]([CH3:22])[CH3:21])[CH:18]=2)[CH:14]=1>>[Br:9][C:10]1[O:11][C:12]2[C:13](=[C:15]([C:23]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=3)=[O:24])[CH:16]=[C:17]([O:19][CH:20]([CH3:22])[CH3:21])[CH:18]=2)[CH:14]=1
Reactant: Cc1ccc(N)nc1
Reactant: COC(=O)c1cc(OC(C)C)cc2oc(Br)cc12
Product: Cc1ccc(NC(=O)c2cc(OC(C)C)cc3oc(Br)cc23)nc1

Procedure:
The title compound was prepared in a similar manner as described for Example 1, from 2-amino-5-methyl pyridine and methyl 2-bromo-6-isopropoxybenzofuran-4-carboxylate (345a) to give an off-white solid (1.45 g, 53% yield). 1H NMR (400 MHz, CDCl3) δ 8.47 (s, 1 H) 8.27 (d, J=8.31 Hz, 1 H) 8.14 (s, 1 H) 7.60 (dd, J=8.44, 1.89 Hz, 1 H) 7.30 (d, J=2.01 Hz, 1 H) 7.24 (s, 1 H) 7.16 (d, J=1.76 Hz, 1 H) 4.57-4.64 (m, 1 H) 2.34 (s, 3 H) 1.38 (d, J=6.04 Hz, 6 H); LCMS for C18H17BrN2O3 m/z 389.00 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[C:14]([CH3:22])[C:15]([F:21])=[C:16]([F:20])[C:17]=2[F:19])[C:12](=[O:23])[C:11]([C:24]([O:26]CC)=[O:25])=[CH:10]1.Cl>C(O)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[C:14]([CH3:22])[C:15]([F:21])=[C:16]([F:20])[C:17]=2[F:19])[C:12](=[O:23])[C:11]([C:24]([OH:26])=[O:25])=[CH:10]1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2c(F)c(F)c(F)c(C)c2c1=O
Agent: Cl
Solvent: CC(=O)O
Product: Cc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2-c1ccc(F)cc1F
Yield: 73.3 %

Procedure:
Employing ethyl 1-(2,4-difluorophenyl)-5-methyl-6,7,8-trifluoro-1,4-dihydro-4 -oxoquinoline-3-carboxylate (4.3 g) and conc. hydrochloric acid: 90% acetic acid (1:4) (80 ml), the procedure of Reference Example 23 is repeated to give 1-(2,4-difluorophenyl)-5-methyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (2.93 g), as white powder, m.p. 221°-222° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[C:12]([CH:15]([CH3:17])[CH3:16])([CH2:13][O:14][C:4]=2[CH:3]=1)[CH2:11][N:10]([C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1)=O)[N:9]=3.P(Cl)(Cl)(Cl)(Cl)[Cl:32].C(=O)(O)[O-].[Na+]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[C:12]([CH:15]([CH3:17])[CH3:16])([CH2:13][O:14][C:4]=2[CH:3]=1)[CH2:11][N:10]([C:18]([Cl:32])=[N:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1)[N:9]=3
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CC(C)C12COc3cc(Cl)ccc3C1=NN(C(=O)Nc1ccc(C(F)(F)F)cc1)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: CC(C)C12COc3cc(Cl)ccc3C1=NN(C(Cl)=Nc1ccc(C(F)(F)F)cc1)C2
Temperature: 25 °C
Yield: 7.3 %

Procedure:
To 0.50 g (0.0012 mol) of the product obtained in Step C in 20 mL of benzene was added 0.25 g (0.0012 mol) of phosphorous pentachloride. The reaction mixture was refluxed for 42 hours, cooled to room temperature, poured into a saturated solution of sodium bicarbonate (100 mL) and extracted with ethyl acetate (3×50 mL). The ethyl acetate was washed with brine (100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to afford an off-white solid. The solid was chromatographed on silica gel using ethyl acetate (15%) and hexanes (85%) as eluents which yielded 0.04 g of a white solid, mp 148° C. to 149° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[CH2:16][CH2:15][C@H:14]([NH:17][CH3:18])[CH2:13][CH2:12]2)=[C:7]([CH2:19][NH:20][CH3:21])[CH:6]=1.[C:22]([OH:28])(=O)[CH2:23][CH2:24][C:25]#[CH:26]>>[OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[CH2:16][CH2:15][C@H:14]([N:17]([CH3:18])[C:22](=[O:28])[CH2:23][CH2:24][C:25]#[CH:26])[CH2:13][CH2:12]2)=[C:7]([CH2:19][NH:20][CH3:21])[CH:6]=1
Reactant: C#CCCC(=O)O
Reactant: CNCc1cc(CCCO)ccc1[C@H]1CC[C@H](NC)CC1
Product: C#CCCC(=O)N(C)[C@H]1CC[C@H](c2ccc(CCCO)cc2CNC)CC1

Procedure:
from trans-4-[4-(3-hydroxypropyl)methylaminomethyl-phenyl)-N-methylcyclohexylamine, N,N'-carbonyldiimidazole and 4-pentynoic acid. Oil. Rf value: 0.66 (alumina/ethyl acetate/methanol=100:1, v:v).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32]C)[CH:10]1[CH2:19][CH2:18][CH2:17][C:16]2[CH:15]=[C:14]([C:20]([O:22][CH3:23])=[O:21])[CH:13]=[CH:12][C:11]1=2)C.B(Br)(Br)Br.CO>ClCCl>[OH:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][CH2:24][N:9]([CH2:8][CH2:7][CH2:6][CH2:5][C:4]([O:3][CH3:1])=[O:34])[CH:10]1[CH2:19][CH2:18][CH2:17][C:16]2[CH:15]=[C:14]([C:20]([O:22][CH3:23])=[O:21])[CH:13]=[CH:12][C:11]1=2
Reactant: CCOC(=O)CCCCN(CCc1ccccc1OC)C1CCCc2cc(C(=O)OC)ccc21
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: COC(=O)CCCCN(CCc1ccccc1O)C1CCCc2cc(C(=O)OC)ccc21
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Under argon, 653 mg (1.4 mmol) of the compound from Example 2A were dissolved in 12 ml of dichloromethane and the mixture was cooled to 0° C. 4.6 ml (4.6 mmol) of a 1 M solution of boron tribromide in dichloromethane were slowly added dropwise and the mixture was stirred at 0° C. for another 4 h (clear yellow solution). 7 ml of abs. methanol were then added and the mixture was heated under reflux overnight. The mixture was then concentrated to dryness under reduced pressure and the residue was partitioned between ethyl acetate and 10% strength aqueous sodium carbonate solution. The aqueous phase was re-extracted with ethyl acetate, and the combined organic phases were washed with saturated sodium chloride solution and dried over sodium sulphate. After concentration, the residue (519 mg of a brown oil) was purified by column chromatography on silica gel (mobile phase: gradient isohexane/4-32% ethyl acetate).