Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[C:35]([CH2:40][C:41]3[S:42][C:43]([C:46]4[CH:51]=[CH:50][C:49]([F:52])=[CH:48][CH:47]=4)=[CH:44][CH:45]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@:10]1([CH2:55][OH:56])[CH:53]=[O:54])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[C:35]([CH2:40][C:41]3[S:42][C:43]([C:46]4[CH:51]=[CH:50][C:49]([F:52])=[CH:48][CH:47]=4)=[CH:44][CH:45]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C:10]1([CH2:53][OH:54])[CH2:55][OH:56])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO[C@@]1(c2ccc(C)c(Cc3ccc(-c4ccc(F)cc4)s3)c2)O[C@@](C=O)(CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Product: CO[C@@]1(c2ccc(C)c(Cc3ccc(-c4ccc(F)cc4)s3)c2)OC(CO)(CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reaction time: 1 h
Yield: 25.8 %

Procedure:
(2S,3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl-phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-carbaldehyde 91 (2.0 g, 2.1 mmol) was dissolved in 30 mL of mixed solution (THF and MeOH, v:v=1:20), followed by addition of sodium borohydride (238 mg, 6.3 mmol) in batch. The reaction mixture was stirred for 1 hour. Thereafter, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography with elution systems B and E to obtain the title compound [(3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl-phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-yl]methanol 9j (420 mg, pale yellow solid), yield: 25.8%. 1H NMR (400 MHz, CD3OD): δ 7.55 (d, 2H), 7.48-7.45 (m, 3H), 7.32-7.28 (m, 5H), 7.25-7.21 (m, 9H), 7.16 (d, 2H), 7.07-7.03 (m, 3H), 6.63 (d, 1H), 4.91 (d, 1H), 4.83 (d, 1H), 4.75 (d, 1H), 4.54 (d, 1H), 4.26-4.17 (m, 2H), 4.10-4.04 (m, 5H), 3.94 (d, 1H), 3.78 (d, 1H), 3.36 (d, 1H), 3.26 (s, 3H), 2.34 (s, 3H).
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[C:5]([CH:21]([CH3:23])[CH3:22])=[N:6][C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2.[Li]CCCC>C1COCC1.CCCCCC>[C:3]([C:4]1[C:5]([CH:21]([CH3:23])[CH3:22])=[N:6][C:7]2[C:12]([C:13]=1[C:14]1[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)#[CH:2]
Reactant: CC(C)c1nc2ccccc2c(-c2ccc(F)cc2)c1C=C(Br)Br
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C#Cc1c(C(C)C)nc2ccccc2c1-c1ccc(F)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 71.3 %

Procedure:
A solution of 3-(2,2-Dibromoethenyl)-4-(4-fluorophenyl)-2-(1-methylethyl)quinoline (25.2 mmol) in dry THF (140 ml) was cooled to -78° C. and treated with n-BuLi (1.6M in hexane, 33 ml, 52.8 mmol) over a 1 minute period. After stirring at -78° C. for one hour, the dark brown solution was quenched with saturated NH4Cl, warmed to room temperature, diluted with H2O, and extracted with Et2O. The Et2O extract was washed with brine, dried (Na2SO4), filtered and stripped to give a yellow oil. The oil was boiled in hot hexane and cooled (-15° C.) to afford 3-Ethynyl-4-(4-fluorophenyl)-2-(1-methylethyl)-quinoline (5.198 gm) as yellow crystals. The mother liquor was stripped and chromatographed (flash, Merck SiO2, 4% EtOAc in hexane) to afford additional product which was recrystallized from hot hexane. A total of 6.793 gm (93%) of 3-Ethynyl-4-(4-fluorophenyl)-2-(1-methylethyl)quinoline was obtained.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11](=[O:27])[NH:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH2:15][CH2:14]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.I[CH3:29].[NH4+].[Cl-]>CN(C=O)C>[CH2:3]([O:10][C:11](=[O:27])[N:12]([C@H:13]1[CH2:18][CH2:17][C@H:16]([O:19][Si:20]([C:23]([CH3:24])([CH3:26])[CH3:25])([CH3:21])[CH3:22])[CH2:15][CH2:14]1)[CH3:29])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](NC(=O)OCc2ccccc2)CC1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CN(C(=O)OCc1ccccc1)[C@H]1CC[C@H](O[Si](C)(C)C(C)(C)C)CC1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a suspension of 0.58 g (55% in mineral oil, 13 mmol, 1.2 eq) sodium hydride in 20 ml DMF, a solution of 4.2 g (11 mmol) trans-[4-(tert-Butyl-dimethyl-silanyloxy)-cyclohexyl]-carbamic acid benzyl ester in 10 ml DMF was added slowly. The temperature was raised slowly to 50° C. and kept at that temperature for 1 h. At RT 0.9 ml (14 mmol; 1.3 eq) iodomethane were added and the mixture stirred over night. Additional 0.58 g (55% in mineral oil, 13 mmol, 1.2 eq) sodium hydride and 0.9 ml (14 mmol; 1.3 eq) iodomethane were added and the reaction mixture was stirred for 1 day. Aqueous NH4Cl solution was added and the inorganic phase was extracted with ether, washed with brine, dried over Na2SO4 and evaporated yielding 3.1 g (72%) trans-[4-(tert-Butyl-dimethyl-silanyloxy)-cyclohexyl]-methyl-carbamic acid benzyl ester.
Reaction SMILES: [F:1][CH:2]([F:14])[C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]([F:13])([F:12])[F:11])=[CH:5][CH:4]=1.[Br:15]N1C(=O)CCC1=O.O=O>ClC(Cl)(Cl)Cl>[Br:15][C:2]([F:1])([F:14])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]([F:11])([F:12])[F:13])=[CH:7][CH:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: FC(F)c1ccc(OC(F)(F)F)cc1
Agent: O=O
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(F)Oc1ccc(C(F)(F)Br)cc1
Temperature: 25 °C

Procedure:
A solution of 2.38 g (11.22 mmol) of 1-(difluoromethyl)-4-(trifluoromethoxy)benzene and 6.19 g (34.78 mmol) of N-bromosuccinimide (NBS) in 25 ml of tetrachloromethane is irradiated with exclusion of oxygen using a sun lamp. During this, the solvent reaches its boiling point. It is irradiated under reflux for 48 hours. The mixture is then allowed to cool to room temperature, precipitated succinimide is filtered off, and the filtrate is evaporated to dryness. The resulting crude product is purified by flash chromatography on silica gel (mobile phase: cyclohexane). 1.73 g (5.94 mmol, 53% of theory) of a yellowish oil are obtained.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:57])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][C:52](O)=[O:53])[CH:46]([O:55][CH3:56])[CH2:45]2)[CH:7]([CH3:58])[CH2:6][CH2:5][C:4]1=[O:59])[CH3:2].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:94][CH2:95][CH2:96][C:97]1[C:105]2[C:100](=[CH:101][CH:102]=[CH:103][CH:104]=2)[NH:99][CH:98]=1>C(Cl)Cl.C(OCC)(=O)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:57])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][C:52]([NH:94][CH2:95][CH2:96][C:97]3[C:105]4[C:100](=[CH:101][CH:102]=[CH:103][CH:104]=4)[NH:99][CH:98]=3)=[O:53])[CH:46]([O:55][CH3:56])[CH2:45]2)[CH:7]([CH3:58])[CH2:6][CH2:5][C:4]1=[O:59])[CH3:2]
Reactant: NCCc1c[nH]c2ccccc12
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCC(=O)O)C(OC)C3)C(C)CCC1=O)C(C)CC2OC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCC(=O)NCCc4c[nH]c5ccccc45)C(OC)C3)C(C)CCC1=O)C(C)CC2OC
Reaction time: 0.17 h
Yield: 49.3 %

Procedure:
To a solution of 17-ethyl-1-hydroxy-12-[2'-(4"-carboxymethyloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,-10,16-tetraone (13 mg) (STEP 12D) in methylene chloride (150 μl) was added benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (10.3 mg) followed by triethylamine (4.3 μl). After 10 minutes, tryptamine (5 mg) was added to the reaction mixture and stirred for 1 hour. The mixture was diluted with ethyl acetate and washed with 1N HCl, water, saturated sodium bicarbonate and brine, respectively. The organic portion was dried over magnesium sulfate and purified by flash chromatography on silica gel (ethyl acetate:hexane (1:1)+1% methanol) to give the title compound (7.5 mg). MASS (FAB) 983 (M+Li); partial 1H NMR δ: 8.32 (brs, 1H); 7.89 (m, 1H); 7.58 (d, J=8 Hz 1H); 7.31 (m, 1H); 7.10 (m, 3H); 4.51 (brd, J=3 Hz, 1H); 4.41 (brd, J=14 Hz, 1H).
Reaction SMILES: [CH:1]1[CH:2]=[C:3]([CH2:6][NH:7][C:8]2[C:13]([C:14]([OH:16])=O)=[CH:12][C:11]([S:17]([NH2:20])(=[O:19])=[O:18])=[C:10]([Cl:21])[CH:9]=2)[O:4][CH:5]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH2:36]([NH:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CN(C=O)C>[CH2:44]([N:43]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:14](=[O:16])[C:13]1[CH:12]=[C:11]([S:17]([NH2:20])(=[O:19])=[O:18])[C:10]([Cl:21])=[CH:9][C:8]=1[NH:7][CH2:6][C:3]1[O:4][CH:5]=[CH:1][CH:2]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: NS(=O)(=O)c1cc(C(=O)O)c(NCc2ccco2)cc1Cl
Reactant: c1ccc(CNCc2ccccc2)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1cc(C(=O)N(Cc2ccccc2)Cc2ccccc2)c(NCc2ccco2)cc1Cl

Procedure:
In similar manner to Example 8, furosemide can be reacted with EDC, HOBt and dibenzylamine in DMF to yield N,N-dibenzyl 5-aminosulfonyl-4-chloro-2-[(2-furanylmethyl)amino]benzamide.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:19])[NH:4][N:5]=[CH:6][C:7]=1[NH:8][C@@H:9]1[CH2:14][C@@H:13]2[CH2:15][C@@H:11]([C:12]2([CH3:17])[CH3:16])[C@H:10]1[CH3:18].Br[CH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[C:3](=[O:19])[N:4]([CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[N:5]=[CH:6][C:7]=1[NH:8][C@@H:9]1[CH2:14][C@@H:13]2[CH2:15][C@@H:11]([C:12]2([CH3:16])[CH3:17])[C@H:10]1[CH3:18]
Reactant: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cn[nH]c(=O)c1Br)C2(C)C
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(C3CCCC3)c(=O)c1Br)C2(C)C
Temperature: 80 °C
Reaction time: 8 h
Yield: 68.9 %

Procedure:
4-Bromo-5-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-3(2H)-one (30 mg, 0.092 mmol) in N,N-dimethylformamide (0.9 mL) was mixed with bromocyclopentane (20 mg, 0.138 mmol) and potassium carbonate (19 mg, 0.138 mmol) at room temperature and stirred at 80° C. overnight. After cooling, the reaction solution was concentrated, mixed with water and extracted with ethyl acetate three times. The resulting organic layer was filtered through silica gel and evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform/ethyl acetate=1/1) to give the desired product (25 mg, 67% yield).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:12][CH:13]=[CH2:14])=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].C(N(CC)CC)C.[C:22](OC(=O)C)(=[O:24])[CH3:23]>ClCCl>[CH3:1][C:2]1[C:3]([CH2:12][CH:13]=[CH2:14])=[C:4]([O:11][C:22](=[O:24])[CH3:23])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CC(=O)OC(C)=O
Reactant: C=CCc1c(O)ccc([N+](=O)[O-])c1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCc1c(OC(C)=O)ccc([N+](=O)[O-])c1C
Reaction time: 0.5 h
Yield: 75.9 %

Procedure:
To a solution of 3-methyl-4-nitro-2-(2-propenyl)-phenol (5.19 g, 26.9 mmol) in dichloromethane (200 ml) at 0° was added triethylamine (5.43 g, 53.8 mmol) and acetic anhydride (3.29 g, 32.3 mmol). After 30 min, the reaction mixture was evaporated to a residue which was purified by chromatography (silica, 2% to 10% ethyl acetate in hexane) to give an orange oil (4.80 g, 76%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.C([O-])([O-])=O.[Na+].[Na+].[S:15]1[C:19](B(O)O)=[CH:18][C:17]2[CH:23]=[CH:24][CH:25]=[CH:26][C:16]1=2.C(Cl)Cl>COCCOC.O.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]>[S:15]1[C:19]([C:5]2[N:4]=[N:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[CH:18][C:17]2[CH:23]=[CH:24][CH:25]=[CH:26][C:16]1=2
Reactant: OB(O)c1cc2ccccc2s1
Reactant: Clc1ccc(Cl)nn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: COCCOC
Product: Clc1ccc(-c2cc3ccccc3s2)nn1
Temperature: 85 °C
Yield: 34 %

Procedure:
To 3,6-dichloropyridazine (4.18 g, 28.1 mmol) and Na2CO3 (8.93 g, 84 mmol) in DME (100 mL) and water (25 mL) was added benzo[b]thiophen-2-ylboronic acid (5 g, 28.1 mmol) and PdCl2(dppf).CH2Cl2 (0.69 g, 0.84 mmol). The reaction was evacuated under vacuum and purged with N2 3×. The reaction was heated at 85° C. for 18 h and cooled to RT. The crude product was filtered through celite and was rinsed with EtOAc followed by CH2Cl2. The crude filtrate was concentrated under vacuum and diluted in CH2Cl2 and water. The organic layer was separated, and the remaining emulsion was acidified with 1 M HCl and extracted with EtOAc. The combined organic layers were washed with water, brine, dried over MgSO4, filtered, and concentrated. The crude product was purified by silica gel chromatography. The product was partially concentrated to provide a precipitate which was filtered to give 3-(benzo[b]thiophen-2-yl)-6-chloropyridazine (2.36 g) as a light yellow solid. The filtrate was recrystallized from CH3CN to give 3-(benzo[b]thiophen-2-yl)-6-chloropyridazine (0.46 g). LCMS Rt=1.57 minutes (condition B); (M+1)=247.1.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.I[C:11]1C=CC=CC=1C=O>>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[CH2:11]
Reactant: O=Cc1ccccc1I
Reactant: O=Cc1ccccc1F
Product: C=Cc1ccccc1F
Yield: 20 %

Procedure:
The substantially same method as described in Preparation Example 284 was conducted, except that 2-fluorobenzaldehyde (Aldrich No. F4807) was used instead of 2-iodobenzaldehyde (Preparation Example 63) to obtain the title compound (1.82 g, yield 20˜40%).
Reaction SMILES: [Mg].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:13][C:14]1[C:15]([F:24])=[C:16]([CH:20]=[CH:21][C:22]=1[F:23])[C:17](Cl)=[O:18].S(=O)(=O)(O)O>C(O)C.C1(C)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[Cl:13][C:14]1[C:15]([F:24])=[C:16]([CH:20]=[CH:21][C:22]=1[F:23])[C:17]([CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([O:10][CH2:11][CH3:12])=[O:9])=[O:18]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C(Cl)c1ccc(F)c(Cl)c1F
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(C(=O)OCC)C(=O)c1ccc(F)c(Cl)c1F
Temperature: 60 °C
Reaction time: 1 h

Procedure:
3.9 g (0.16 mol) of magnesium are initially introduced into 8.6 ml of ethanol and the reaction is started with carbon tetrachloride. A solution of 23.1 g (0.144 mol) of diethyl malonate in 16.3 ml of ethanol is added dropwise at an internal temperature of 50-60° C. such that this temperature is maintained. The mixture is then subsequently stirred at 60° C. for one hour. Thereafter, a solution of 31.3 g (0.148 mol) of 3-chloro-2,4-difluorobenzoyl chloride in 16 ml of toluene is added dropwise at -10 to -5° C. and the mixture is subsequently stirred at 0° C. for one hour and then overnight, while warming to room temperature. The reaction mixture is poured onto ice-water, acidified with 10 ml of concentrated sulphuric acid and extracted with toluene. The extract is washed with saturated sodium chloride solution and the solvent is removed in vacuo. Crude yield: 49.9 g
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:49][C:50]1C=[CH:53][S:52][C:51]=1CCCO.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[CH:17]=3)[N:12]([CH2:49][CH2:50][CH2:51][S:52][CH3:53])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(CN3CCOCC3)cc2c1O
Reactant: Cc1ccsc1CCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CSCCCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)ccc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A dry flask containing N-(4-chlorobenzyl)-4-hydroxy-6-(4-morpholinylmethyl)-3-quinolinecarboxamide (0.20 gm) from Preparation No. 40 in dry THF (5 mL) under an argon atmosphere is added triphenylphosphine (396 mg), 3-methylthiolpropanol (0.16 mL) and diethyl azodicarboxylate (0.18 mL). The mixture is stirred at room temperature 48 hours and then concentrated under reduced pressure. The crude product is purified by flash column chromatography eluting with 2% to 6% methanol in dichloromethane and then by recrystallization from toluene-cyclohexane to afford 0.14 gm of the title compound as a white solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]([CH:15]1[CH2:19][CH2:18][C:17]2([CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)[C:16]1=[O:32])[CH2:13][CH3:14].C(N(CC)CC)C>ClCCl>[O:11]=[C:12]([CH:15]1[CH2:19][CH2:18][C:17]2([CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][CH2:24]2)[C:16]1=[O:32])[CH2:13][CH3:14]
Reactant: CCC(O)C1CCC2(CCN(C(=O)OC(C)(C)C)CC2)C1=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCC(=O)C1CCC2(CCN(C(=O)OC(C)(C)C)CC2)C1=O
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 84.1 %

Procedure:
To a solution of oxalyl chloride (1.6 mL, 18.3 mmol) in dichloromethane (150 mL) at −78° C. was slowly added dimethyl sulfoxide (2.6 mL, 37 mmol). After 5 min, a solution of tert-butyl 2-(1-hydroxyprop-1-yl)-1-oxo-8-azaspiro[4.5]decane-8-carboxylate (4.75 g, 15.3 mmol) from Step H in dichloromethane (40 mL) was added via an addition funnel. The reaction mixture was stirred for 45 min at −78° C. and then triethylamine (10.2 mL, 73.2 mmol) was added. After 5 min, the reaction mixture was removed from the cooling bath, allowed to warm to room temperature for 1.5 h, poured into water, and extracted three times with dichloromethane. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered and concentrated to afford 4.65 g. The residue was purified by flash chromatography eluting with 15% ethyl acetate in hexanes to give the title compound (3.98 g) as a pink oil.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:17]=[CH:16][C:8]([O:9][CH:10]([CH3:15])[C:11](OC)=[O:12])=[C:7]([N+:18]([O-])=O)[CH:6]=1.ClC1C(OC2C=CC3OC(C)C(=O)NC=3C=2)=NC=C(C(F)(F)F)C=1>>[Cl:1][C:2]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:17]=[CH:16][C:8]2[O:9][CH:10]([CH3:15])[C:11](=[O:12])[NH:18][C:7]=2[CH:6]=1
Reactant: COC(=O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1[N+](=O)[O-]
Agent: CC1Oc2ccc(Oc3ncc(C(F)(F)F)cc3Cl)cc2NC1=O
Product: CC1Oc2ccc(Oc3ccc(C(F)(F)F)cc3Cl)cc2NC1=O

Procedure:
In Example 1, methyl 2-[4-(2-chloro-4-trifluoromethylphenoxy)-2-nitrophenoxy]propionate was used instead of methyl 2-[5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrophenoxy]propionate to prepare the title compound, and 6-(3-Chloro-5-trifluoromethyl-2-pyridyloxy)-2-methyl-2H-1,4-benzoxazine-3 (4H)-one (Example 16) was prepared in the same manner as described above.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:12][CH3:13])=[N:4][C:5]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][CH:7]=1.[C:14]([OH:18])(=O)[CH2:15]O>>[CH:9]([O:8][C:5]1[N:4]=[C:3]2[N:12]([CH3:13])[C:15]([CH2:14][OH:18])=[N:1][C:2]2=[CH:7][CH:6]=1)([CH3:11])[CH3:10]
Reactant: CNc1nc(OC(C)C)ccc1N
Reactant: O=C(O)CO
Product: CC(C)Oc1ccc2nc(CO)n(C)c2n1
Yield: 25 %

Procedure:
A procedure similar to that described in Preparation 43 was repeated, except that 1.90 g of 3-amino-6-isopropoxy- 2-methylaminopyridine (prepared as described in Preparation 101), and 2.39 g of glycolic acid were used, and that the product was purified by column chromatography through silica gel, using a 10:1 by volume mixture of ethyl acetate and methanol, to give 0.58 g of the title compound, melting at 125°-127° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:24][NH2:25])=[N:4][CH:5]=[C:6](/[CH:8]=[CH:9]/[CH:10]([C:15]2[CH:20]=[C:19]([Cl:21])[C:18]([Cl:22])=[C:17]([Cl:23])[CH:16]=2)[C:11]([F:14])([F:13])[F:12])[CH:7]=1.[F:26][C:27]([F:33])([F:32])[CH2:28][C:29](O)=[O:30].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.O.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[C:3]([CH2:24][NH:25][C:29](=[O:30])[CH2:28][C:27]([F:33])([F:32])[F:26])=[N:4][CH:5]=[C:6](/[CH:8]=[CH:9]/[CH:10]([C:15]2[CH:20]=[C:19]([Cl:21])[C:18]([Cl:22])=[C:17]([Cl:23])[CH:16]=2)[C:11]([F:14])([F:12])[F:13])[CH:7]=1
Reactant: O=C(O)CC(F)(F)F
Reactant: NCc1ncc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: O=C(CC(F)(F)F)NCc1ncc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Cl
Yield: 27.8 %

Procedure:
To a stirred solution of (E)-(3-chloro-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)pyridin-2-yl)methanamine (0.1 g, 0.2 mmol) in CH2Cl2 (5 mL) were added 3,3,3-trifluoropropanoic acid (45 mg, 0.350 mmol), EDC.HCl (67 mg, 0.350 mmol), HOBt.H2O (71 mg, 0.467 mmol) and DIPEA (60.2 mg, 0.467 mmol), and the reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was diluted with CH2Cl2 and washed with water. The combined CH2Cl2 layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; 15% EtOAc in petroleum ether) afforded the title compound as a pale yellow liquid (30 mg, 35%): 1H NMR (400 MHz, CDCl3) δ 8.41 (s, 1H), 7.77 (s, 1H), 7.47 (br s, 1H), 7.40 (s, 2H), 6.58 (d, J=16.0 Hz, 1H), 6.45 (dd, J=16.0, 8.0 Hz, 1H), 4.68 (d, J=4.0 Hz, 2H), 4.14 (m, 1H), 3.24 (q, J=10.8 Hz, 2H); ESIMS m/z 536.88 ([M−H]−); IR (thin film) 3320, 1674, 1114, 808.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[Cl:16][C:17]1[CH:22]=[N:21][CH:20]=[CH:19][N:18]=1.[N:23]12[CH2:29][CH:26]([CH2:27][CH2:28]1)[C:25](=[O:30])[CH2:24]2.Cl>C1COCC1.CCCCCC.C(O)C>[Cl:16][C:17]1[C:22]([C:25]2([OH:30])[CH:26]3[CH2:29][N:23]([CH2:28][CH2:27]3)[CH2:24]2)=[N:21][CH:20]=[CH:19][N:18]=1
Reactant: O=C1CN2CCC1C2
Reactant: Clc1cnccn1
Agent: CC1(C)CCCC(C)(C)N1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCO
Product: OC1(c2nccnc2Cl)CN2CCC1C2
Reaction time: 0.17 h

Procedure:
A solution of 7.2 ml of 2,2,6,6-tetramethylpiperidine in 300 ml of THF was cooled to -5° C. as 25 ml of 1.6M butyllithium (0.04 mol) in hexane was added dropwise. The reaction was stirred 10 min then cooled to -77° C. as 3 ml of 2-chloropyrazine in 7 ml of THF was added dropwise. After another 15 min, 4.4 g of 1-azabicyclo[2.2.1]heptan-3-one (0.0396 mol) in 10 ml of THF was added and the reaction stirred 1 h. A solution of 8 ml of conc. HCl in 4 ml of ethanol was added and the cooling was removed. When the temperature reached -10° C., 100 ml of water was added, the organics were evaporated, and the residue treated with 11 ml of 5N NaOH. The solvent was reduced to a small volume, ca. 50 ml, the mixture cooled in ice-water, and the solid collected by filtration. The aqueous fraction was extracted 3× with 50 ml of CHCl3, the extracts added to the solid filtrate, and the total volume of the mixture taken to 500 ml with more CHCl3. The mixture was heated to boiling, dried, filtered, and the solvent evaporated to give a brown solid. The solid was recrystallized from isopropanol to give 4.1 g of tan crystalline (26), mp 220° C. dec. NMR ppm (CDCl3) 1.55-1.9 (2H, m), 2.27 (1H, m), 2.42-2.58 (2H, m), 2.75 (2H, m), 2.95 (1H, m), 3.5 (1H, d) 3.6 (1H, d), 8.3 (1H, d) 8.42 (1H, d). Anal. C10H12ClN3O requires C: 53.22; H: 5.36; N: 18.62%. Found C: 53.10; H: 5.20; N: 18.41%.