Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][N:8]=[CH:9][CH:10]=2)[C:5](Cl)=[N:4][CH:3]=1.O=P(Cl)(Cl)Cl.P(Cl)(Cl)(Cl)(Cl)Cl.[NH3:24]>>[C:5]1([NH2:24])[C:6]2[C:11](=[CH:10][CH:9]=[N:8][CH:7]=2)[CH:2]=[CH:3][N:4]=1
Reactant: N
Reactant: Clc1ncc(Br)c2ccncc12
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Nc1nccc2ccncc12

Procedure:
Bromination gives 4-bromo-2,7-naphthyridin-1(2H)-one CAS 959558-27-1, which is converted into 4-bromo-1-chloro-2,7-naphthyridine by chlorinating compounds, such as POCl3 and/or PCl5. Reaction with ammonia or ammonia equivalents gives 2,7-naphthyridin-1-ylamine.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[N:11]([CH3:27])[C:12]([S:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)=[C:13]([CH:15]([CH3:18])[C:16]#[N:17])[N:14]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.O>O1CCCC1>[Cl:26][C:22]1[CH:21]=[C:20]([S:19][C:12]2[N:11]([CH3:27])[C:10]([CH2:9][OH:8])=[N:14][C:13]=2[CH:15]([CH3:18])[C:16]#[N:17])[CH:25]=[CH:24][CH:23]=1
Reactant: CC(C#N)c1nc(CO[Si](C)(C)C(C)(C)C)n(C)c1Sc1cccc(Cl)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C#N)c1nc(CO)n(C)c1Sc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97.9 %

Procedure:
In dry tetrahydrofuran (2 ml)was dissolved 70 mg of 2-(2-t-butyldimethylsilyloxymethyl-5-(3-chlorophenylthio)-1-methyl-1H-imidazol-4-yl)propiononitrile (50'), followed by addition of 0.33 ml of 1 M tetrabutylammoniumfluoride-tetrahydrofuran solution, and the reaction mixture was stirred at room temperature for 10 minutes. To the reaction mixture, water was added, extracted with methylene chloride, the organic layer was washed with water and dried over sodium sulfate. The solvent was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate)to obtain 50 mg of 2-[5-(3-chlorophenylthio)-2-hydroxymethyl-1-methyl-1H-imidazol-4-yl]propiononitrile (50) as oil (yield 98%).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH2:4].[CH:10]([NH:12][C:13]1[NH:17][N:16]=[C:15]([S:18](Cl)(=[O:20])=[O:19])[N:14]=1)=[O:11].[OH-].[Na+].Cl>N1C=CC=CC=1.C(Cl)(Cl)Cl>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH:4][S:18]([C:15]1[N:14]=[C:13]([NH:12][CH:10]=[O:11])[NH:17][N:16]=1)(=[O:19])=[O:20]
Reactant: O=CNc1nc(S(=O)(=O)Cl)n[nH]1
Reactant: Nc1c(F)cccc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: O=CNc1nc(S(=O)(=O)Nc2c(F)cccc2F)n[nH]1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
To a mixture of 1.3 g (10 mmol) of 2,6-difluoroaniline in 4 ml of pyridine was added 1.94 g (9.2 mmol) of 5-formylamino-3-chlorosulfonyl-1,2,4-triazole over a period of 5 minutes. The mixture was heated with stirring to 70° C. for 4 hours. It was then cooled and dispersed between 25 ml of 1N aqueous sodium hydroxide and 50 ml of chloroform. The aqueous layer was acidified with aqueous hydrochloric acid and filtered. The solids collected were dried to obtain 167 g (60 percent of theory) of the title compound, m.p. 258°-260° C. The infrared spectrum was consistent with the assigned structure.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[Na+].O.[F:7][C:8]([F:20])([F:19])[C:9]1[CH:10]=[C:11]([C:15]#[C:16][C:17]#[N:18])[CH:12]=[CH:13][CH:14]=1>CO>[F:7][C:8]([F:19])([F:20])[C:9]1[CH:10]=[C:11]([C:15]2[O:3][N:2]=[C:17]([NH2:18])[CH:16]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: N#CC#Cc1cccc(C(F)(F)F)c1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Nc1cc(-c2cccc(C(F)(F)F)c2)on1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Hydroxylamine hydrochloride (1.6 grams), and sodium hydroxide (1.6 grams) were dissolved in 32 ml. of a 1:1 mixture of water and methanol at 0°-5° C. 3-(3-(Trifluoromethyl)phenyl)propiolonitrile (2.8 grams) in 10 ml. of methanol was added portionwise, and the reaction mixture was stirred overnight (about 18 hours) at 25° C. Solvent was evaporated; water was added to the residue and the product extracted with ether, washed with water, dried and evaporated, yield 1.4 grams. The identity of the desired product was confirmed by NMR.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]([CH3:28])[O:11][C:12]1[CH:13]=[C:14]([CH:24]=[C:25]([OH:27])[CH:26]=1)[C:15]([NH:17][C:18]1[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=1)=[O:16])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:29]([O:31][C:32]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)=[O:33])[CH3:30].C(N(CC)CC)C>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Si:1]([O:8][CH2:9][C@H:10]([CH3:28])[O:11][C:12]1[CH:26]=[C:25]([CH:24]=[C:14]([C:15]([NH:17][C:18]2[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=2)=[O:16])[CH:13]=1)[O:27][C:37]1[CH:38]=[CH:39][C:34]([C:32]([O:31][CH2:29][CH3:30])=[O:33])=[CH:35][CH:36]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ccc(Oc2cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)cc(C(=O)Nc3ccn(C)n3)c2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 62.1 %

Procedure:
A suspension of 3-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyloxy)-5-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)benzamide (4.5 g, 0.011 mol), 4-ethoxycarbonylphenylboronic acid (3.24 g, 0.016-mol), copper (II) acetate (3.06 g, 0.016 mol), triethylamine (7.74 mL, 0.055 mol) and freshly activated 4 Å molecular sieves (13 g) in DCM (180 mL) was stirred at ambient temperature and under ambient atmosphere for 3 days. The reaction mixture was filtered through celite, washed with DCM (2×50 mL). The DCM was removed in vacuo and the residual oil partitioned between ethyl acetate (100 mL) and water (100 mL), filtered and the ethyl acetate layer washed with brine (50 mL), dried (MgSO4), and evaporated to a residue which was chromatographed on silica, eluting with a gradient of 50-100% ethyl acetate in isohexane, to give the desired compound (3.78 g).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:17][NH2:18]>C1(C)C=CC=CC=1>[CH3:17][NH:18][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CN
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CNc1ncccc1[N+](=O)[O-]

Procedure:
A procedure similar to that described in Preparation 66 was repeated, except that 24.9 g of 2-chloro-3-nitro-pyridine, 41.7 g of sodium carbonate, -2.7 ml of a 30 k ethanolic solution of methylamine were reacted in 250 ml of toluene. After working up the product as described in Preparation 66, the resulting crude product was crystallized by trituration with isopropanol, to give 24.0 g of the title compound, melting at 52°-53° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[C:20]([F:21])=[C:19]([F:22])[C:18]([F:23])=[C:17]([F:24])[C:9]=1[O:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[CH3:25][P:26]([CH2:29]Cl)([CH3:28])=[O:27].O>CN(C)C=O>[CH3:25][P:26]([CH2:29][N:14]1[CH2:15][CH2:16][CH:11]([O:10][C:9]2[C:17]([F:24])=[C:18]([F:23])[C:19]([F:22])=[C:20]([F:21])[C:8]=2[F:7])[CH2:12][CH2:13]1)([CH3:28])=[O:27]
Reactant: CP(C)(=O)CCl
Reactant: Fc1c(F)c(F)c(OC2CCNCC2)c(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CP(C)(=O)CN1CCC(Oc2c(F)c(F)c(F)c(F)c2F)CC1
Temperature: 80 °C
Reaction time: 30 h
Yield: 22.2 %

Procedure:
To a stirring mixture of 9.0 g of potassium carbonate in 100 ml of dimethylformamide was added 8.0 g of 4-(2,3,4,5,6-pentafluorophenoxy)piperidine and 9.5 g of dimethylphosphinylmethyl chloride. After stirring at 80° C. for 30 hours, the reaction mixture was cooled, poured into water, and extracted with ethyl acetate. The organic layer was washed with water followed by a saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After filtering, evaporation afforded a residue which was purified by means of high pressure liquid chromatography (silica gel; elution with 5% methanol/dichloromethane). The desired fractions were evaporated to yield a solid which was sublimed to afford 2.37 g (22.1%) of 1-[(dimethylphosphinyl)methyl]-4-(2,3,4,5,6-pentafluorophenoxy)piperidine, m.p. 120°-123° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][C:19]([C:21]([O:23]C)=O)=[N:18][N:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:25])[CH:4]=1.[NH:26]1[CH2:30][CH2:29][N:28]=[C:27]1[C:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][NH:39][CH3:40])=[CH:33][CH:32]=1.C[Al](C)C>C(Cl)Cl>[NH:28]1[CH2:29][CH2:30][N:26]=[C:27]1[C:31]1[CH:32]=[CH:33][C:34]([CH2:37][CH2:38][N:39]([CH3:40])[C:21]([C:19]2[O:20][C:16]([CH2:15][N:13]([S:10]([C:6]3[C:7]([CH3:9])=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[CH3:25])(=[O:11])=[O:12])[CH3:14])=[N:17][N:18]=2)=[O:23])=[CH:35][CH:36]=1
Reactant: CNCCc1ccc(C2=NCCN2)cc1
Reactant: COC(=O)c1nnc(CN(C)S(=O)(=O)c2c(C)cc(OC)cc2C)o1
Agent: C[Al](C)C
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2nnc(C(=O)N(C)CCc3ccc(C4=NCCN4)cc3)o2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AT using methyl 5-({[(4-methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)-1,3,4-oxadiazole-2-carboxylate (50 mg, 0.135 mmol), 2-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]-N-methylethanamine (110 mg, 0.54 mmol) and trimethylaluminium (2 M in toluene, 0.27 mL) in DCM (10 mL). A portion of the crude product was purified using prep method A, then prep method B.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[NH:12][C:13]([CH:15]1[CH2:17][CH2:16]1)=O)(=[O:3])[CH3:2].C(O[K])(C)(C)C>C(O)(C)(C)C>[CH:15]1([C:13]2[CH:2]=[C:1]([OH:3])[C:4]3[C:5](=[CH:6][C:7]([O:10][CH3:11])=[CH:8][CH:9]=3)[N:12]=2)[CH2:17][CH2:16]1
Reactant: COc1ccc(C(C)=O)c(NC(=O)C2CC2)c1
Agent: CC(C)(C)O[K]
Solvent: CC(C)(C)O
Product: COc1ccc2c(O)cc(C3CC3)nc2c1
Yield: 20 %

Procedure:
Step 68b) A solution of product (5.35 g, 22.72 mmol) of step 1 example 376 {cyclopropanecarboxylic acid (2-acetyl-5-methoxy-phenyl)-amide} and tert-BuOK (5.45 g, 48.6 mmol) in tert-butanol (130 g) was refluxed for 6 h. The reaction mixture was cooled, poured into ice cold buffer and adjusted to pH 7, filtered. The solid collection was recrystallized from MeOH/Et2O to provide the product (1 g, 20%): 1H NMR (methanol-d4) δ ppm 0.96 (m, 2H), 1.15 (m, 2H), 1.94 (m, 1H), 3.87 (s, 3H), 5.86 (m, 1H), 6.93 (m, 2H), 8.04 (d, J=8.85 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]([OH:30])[CH2:26][N:27]([CH3:29])[CH3:28])=[CH:21][CH:20]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:18][C:19]1[CH:20]=[CH:21][C:22]([CH:25]([OH:30])[CH2:26][N:27]([CH3:28])[CH3:29])=[CH:23][CH:24]=1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Reactant: CN(C)CC(O)c1ccc(N)cc1
Product: CN(C)CC(O)c1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)cc1
Yield: 53.5 %

Procedure:
Following general procedure C, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (240 mg, 0.770 mmol) was reacted with 1-(4-aminophenyl)-2-(dimethylamino)ethanol (139 mg, 0.770 mmol) to afford the desired product (187 mg, 53%) as a yellow solid: ESI MS m/z 454 [C23H24BrN3O2+H]+.
Reaction SMILES: [N+:1]([CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([O-:3])=[O:2].[Na].[C:13]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:14][C:15]([CH3:17])=[O:16]>CCOCC.CCOC(C)=O>[CH2:20]([O:19][C:13](=[O:18])[CH:14]([C:15](=[O:16])[CH3:17])[CH:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:4][N+:1]([O-:3])=[O:2])[CH3:21]
Reactant: CCOC(=O)CC(C)=O
Reactant: O=[N+]([O-])C=Cc1ccccc1
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCOC(=O)C(C(C)=O)C(C[N+](=O)[O-])c1ccccc1
Reaction time: 1 h
Yield: 106.8 %

Procedure:
To a solution of (2-nitro-vinyl)-benzene (2.135 g, 14.3 mmol) in ether (30 mL) at 0° C. was added ethyl acetoacetate sodium salt (2.29 g, 14.3 mmol) portionwise in half minute; after addition, the mixture was stirred at that temperature for 1 hour; then it was diluted with EtOAc, washed with diluted hydrochloride aqueous solution and saturated sodium chloride aqueous solution respectively, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, oil-pumped to dryness to give a brown oil, the crude titled product (4.266 g); 1H NMR (200 MHz, CDCl3): δ (ppm)=7.4-7.2 (m, 5H), 4.73 (d, 1H, J=5.9 Hz), 4.2-3.9 (m, 4H), 2.30 (s, 3H), 1.01 (m, 3H).
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:16][CH:15]=1.B(OC)(OC)[O:30]C.OO>C1COCC1.C(O)(=O)C>[F:6][C:7]1[C:12]([F:13])=[C:11]([OH:30])[CH:10]=[CH:9][C:8]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:16][CH:15]=1
Reactant: CCCCCCCCOc1ccc(-c2cccc(F)c2F)cc1
Reactant: COB(OC)OC
Agent: OO
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(-c2ccc(O)c(F)c2F)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 68.8 %

Procedure:
A solution of n-butyllithium (1.60 ml, 10.0 M in hexanes, 0.016 mol) was added dropwise to a stirred, cooled (−78° C.) solution of 2,3-difluoro-4′-octyloxybiphenyl [see M. Hird and K. L. Toyne, J. Mater. Chem., 1995, 5, 2239] (4.70 g, 0.015 mol) in dry THF (250 ml) under dry nitrogen. The mixture was stirred at −78° C. for 2 hr and a solution of trimethyl borate (3.15 g, 0.030 mol) in dry THF (10 ml) was added. The mixture was allowed to warm to room temperature overnight and a solution of 30% hydrogen peroxide (50 ml) in acetic acid (500 ml) was added dropwise at room temperature. The mixture was extracted into ether (3 times) and the combined ethereal extracts were washed with water and dried over MgSO4. The solvent was removed in vacuo and the residue was recrystallised from ethanol to yield colourless crystals (3.45 g, 69%), mp 145° C.
Reaction SMILES: [NH:1]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[C@H:2]([C:6]([N:8]1[CH2:57][CH2:56][CH2:55][C@H:9]1[C:10]([N:12]1[CH2:54][CH2:53][CH2:52][C@H:13]1[C:14]([NH:16][C@H:17]([C:22]([NH:24][CH2:25][C:26]([NH:28][C@H:29]([C:40]([NH:42][C@H:43]([C:48]([O:50]C)=O)[CH2:44][CH2:45][S:46][CH3:47])=[O:41])[CH2:30][C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[NH:33][CH:32]=1)=[O:27])=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])=[O:15])=[O:11])=[O:7])[CH:3]([CH3:5])[CH3:4].[NH3:65]>CO.C(O)CO>[NH:1]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[C@H:2]([C:6]([N:8]1[CH2:57][CH2:56][CH2:55][C@H:9]1[C:10]([N:12]1[CH2:54][CH2:53][CH2:52][C@H:13]1[C:14]([NH:16][C@H:17]([C:22]([NH:24][CH2:25][C:26]([NH:28][C@H:29]([C:40]([NH:42][C@H:43]([C:48]([NH2:65])=[O:50])[CH2:44][CH2:45][S:46][CH3:47])=[O:41])[CH2:30][C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[NH:33][CH:32]=1)=[O:27])=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])=[O:15])=[O:11])=[O:7])[CH:3]([CH3:5])[CH3:4]
Reactant: COC(=O)[C@H](CCSC)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Reactant: N
Solvent: OCCO
Solvent: CO
Product: CSCC[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)C(N)=O
Reaction time: 72 h

Procedure:
5.00 g (4.28 mmol) of BOC-Val-Pro-Pro-Leu-Gly-Trp-Met-OMe (XI) prepared in Example 1, Step 11, were dissolved in a solution of 100 ml of methanol and 2 ml of ethylene glycol, and saturated at 0° C. with ammonia. The reaction mixture was kept in the refrigerator for 3 days, and then the excess of ammonia and the solvent were removed in vacuo. The crude product was partially purified by column chromatography on silica gel (Merck) 0.040-0.063 mm eluting with AcOEt:MeOH=87:13 and used as such in the next Step (2.58 g of compound XV were obtained from iPrOH/iPr2O): RfC 0.31.
Reaction SMILES: Cl.[CH:2]1([C:5]2[C:13]3[C:8](=[CH:9][C:10]([OH:14])=[CH:11][CH:12]=3)[NH:7][N:6]=2)[CH2:4][CH2:3]1.N1C=CN=C1.[CH3:20][C:21]([Si:24](Cl)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([CH3:23])[CH3:22].O>CN(C=O)C>[Si:24]([O:14][C:10]1[CH:9]=[C:8]2[C:13]([C:5]([CH:2]3[CH2:4][CH2:3]3)=[N:6][NH:7]2)=[CH:12][CH:11]=1)([C:21]([CH3:23])([CH3:22])[CH3:20])([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: Oc1ccc2c(C3CC3)n[nH]c2c1
Agent: Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](Oc1ccc2c(C3CC3)n[nH]c2c1)(c1ccccc1)c1ccccc1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
3-Cyclopropylindazol-6-ol hydrochloride (5.18 g) which can be prepared according to the method described in Reference example 4, etc. and imidazole (4.21 g; manufactured by Tokyo Chemical Industry, Co., Ltd.) were dissolved in dehydrated DMF (122 mL; manufactured by Kanto Chemical Co., Inc.). Then, TBDPSCl (15.67 mL; manufactured by Tokyo Chemical Industry, Co., Ltd.) was added and the mixture was stirred overnight at 20° C. To the reaction solution, imidazole (1.8 g; manufactured by Tokyo Chemical Industry, Co., Ltd.) and TBDPSCl (6.27 mL; manufactured by Tokyo Chemical Industry, Co., Ltd.) were added and the mixture was stirred for 2 hours at 20° C. To the reaction solution, water was added and extraction was carried out twice with ethyl acetate. The organic layer was washed twice with water and once with brine and dried over anhydrous sodium sulfate. After the solvent was evaporated under reduced pressure, the residue was purified by column chromatography (“COLUMN-A”; n-hexane:ethyl acetate=95:5→74:26) to obtain the title compound (4.71 g).
Reaction SMILES: [C:1]([C:6]1[C:15](=O)[C:14]2[C:9](=[C:10]([C:17](=[O:19])[CH3:18])[CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)([Cl:22])=O>>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Cl:22])=[CH:13][CH:12]=[CH:11][C:10]=2[C:17](=[O:19])[CH3:18])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCC(=O)c1c[nH]c2c(C(C)=O)cccc2c1=O
Product: CCCC(=O)c1cnc2c(C(C)=O)cccc2c1Cl

Procedure:
A solution of 3-butyryl-8-acetyl-4(1H)-quinolone (8.4 g) in phosphoryl chloride (30 ml) was heated at reflux for 1 hour, then poured onto ice and the product extracted into ether. Drying and evaporation gave crude 3-butyryl-4-chloro-8-acetylquinoline as a dark solid, which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[CH:14]=[CH:13][C:12]([OH:16])=[C:11]4[S:17][CH:18]([CH3:20])[CH2:19][C:9]([C:10]=34)=[C:8]2[CH2:21][CH2:22][OH:23])=[CH:4][CH:3]=1.[C:26]1([C:32]2[CH:33]=[CH:34][C:35]([CH2:38]Cl)=[N:36][CH:37]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N.CCOC(C)=O>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[CH:14]=[CH:13][C:12]([O:16][CH2:38][C:35]4[CH:34]=[CH:33][C:32]([C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=5)=[CH:37][N:36]=4)=[C:11]4[S:17][CH:18]([CH3:20])[CH2:19][C:9]([C:10]=34)=[C:8]2[CH2:21][CH2:22][OH:23])=[CH:4][CH:3]=1
Reactant: CC1Cc2c(CCO)n(Cc3ccc(Cl)cc3)c3ccc(O)c(c23)S1
Reactant: ClCc1ccc(-c2ccccc2)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC1Cc2c(CCO)n(Cc3ccc(Cl)cc3)c3ccc(OCc4ccc(-c5ccccc5)cn4)c(c23)S1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of product from Step 5 (150 mg, 0.39 mmol), 5-phenyl-2-picolyl chloride (95 mg, 0.47 mmol) and Cs2CO3 (152 mg, 0.47 mmol) in CH3CN (5 mL) was stirred at r.t. for 20 hours, then at 60° C. for 1.5 hours. The mixture was diluted with EtOAc (25 mL), washed 3× with H2O, dried over Na2SO4, and evaporated. The residue was chromatographed on silica gel, eluting with a 1:1 mixture of EtOAc and hexane, to afford the title product as an oil which solidified.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH3:18])[CH:11]=2)[CH:6]=[CH:5][C:4]=1[OH:19].[Cl:22][C:23]([Cl:27])=[CH:24][CH2:25]Cl>[H-].[Na+].CN(C)C=O>[F:1][C:2]([F:20])([F:21])[C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH3:18])[CH:11]=2)[CH:6]=[CH:5][C:4]=1[O:19][CH2:25][CH:24]=[C:23]([Cl:27])[Cl:22]
Reactant: CCOc1cccc(Oc2ccc(O)c(C(F)(F)F)c2)c1
Reactant: ClCC=C(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1cccc(Oc2ccc(OCC=C(Cl)Cl)c(C(F)(F)F)c2)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 61.6 %

Procedure:
To a solution prepared by dissolving 0.44 g of 2-trifluoromethyl-4-(3-ethoxyphenoxy)phenol in 10 ml of N,N-dimethylfonnamide, 0.062 g of sodium hydride (60% oil-based) was added with stirring under ice cooling. After 10 minutes, a solution prepared by dissolving 0.24 g of 1,1,3-trichloro-1-propene in 5 ml of N,N-dimethylformamide was added dropwise under ice cooling. After stirring at room temperature for 10 hours, the reaction solution was poured into ice-water, and extracted twice with 50 ml of diethyl ether. Then, the ether layers were combined, washed with water, dried over anhydrous magnesium sulfate and concentrated to give a crude product. This crude product was subjected to silica gel chromatography to give 0.37 g of 2-trifluoromethyl-4-(3-ethoxyphenoxy)-1-(3,3-dichloro-2-propenyloxy)benzene, yield 62%; nD23.6 1.5369.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([S:29][CH3:30])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22]([OH:24])=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].ClC1C=C(C(OO)=[O:40])C=CC=1.CCOC(C)=O>C(Cl)Cl>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([S:29]([CH3:30])=[O:40])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22]([OH:24])=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1ccc(C(=O)O)cc1-c1nc(S(C)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Yield: 64.6 %

Procedure:
To a solution of 3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (30.0 mg, 0.068 mmol) in CH2Cl2 (5.0 ml) was added 3-chlorobenzenecarboperoxoic acid (23 mg. 0.103 mmol). The resultant mixture was stirred at room temperature 10 mins. Flash chromatography (EtOAc/Hex=1:1) then provided the title compound (20 mg, 64%). LC-MS (ES) m/z 456 (M+H)+.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH3:6][N:7]1[C:11]([CH3:12])=[CH:10][C:9]([C:13]([F:16])([F:15])[F:14])=[N:8]1>>[CH3:6][N:7]1[C:11]([CH3:12])=[C:10]([S:2]([Cl:1])(=[O:5])=[O:3])[C:9]([C:13]([F:14])([F:16])[F:15])=[N:8]1
Reactant: O=S(=O)(O)Cl
Reactant: Cc1cc(C(F)(F)F)nn1C
Product: Cc1c(S(=O)(=O)Cl)c(C(F)(F)F)nn1C
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To 53 mls of chlorosulfonic acid at 10° C. was added dropwise over fifteen minutes 1,5-dimethyl-3-(trifluoromethyl)pyrazole (24.0 grams). No significant exotherm resulted and after 15 minutes the cooling bath was removed and the reaction was heated to 110° C. for three hours. After standing overnight, the reaction was heated to 110° C. for an additional four hours and allowed to cool to 50° C. Then 19.0 g of thionyl chloride was dropwise over fifteen minutes. The reaction was then heated to 80° C. for twenty minutes and 110° C. for one hour. After cooling, the reaction was cautiously added to 600 g of ice. The aqueous phase was extracted with two 250 ml portions of ether. The combined organic extracts were dried with MgSO4 and concentrated under reduced pressure to yield 7.8 g of the desired product as a tan oil.