Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][C@@H:3]([CH2:7][NH:8][C:9]([C:11]1[C:12]([CH3:17])=[N:13][O:14][C:15]=1[CH3:16])=[O:10])[NH:2]2.[NH2:18][C:19]1[S:20][C:21]([C:27]2[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=2)=[C:22]([C:24](O)=[O:25])[N:23]=1>>[NH2:18][C:19]1[S:20][C:21]([C:27]2[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=2)=[C:22]([C:24]([N:2]2[C@H:3]([CH2:7][NH:8][C:9]([C:11]3[C:12]([CH3:17])=[N:13][O:14][C:15]=3[CH3:16])=[O:10])[CH2:4][C@H:5]3[C@@H:1]2[CH2:6]3)=[O:25])[N:23]=1
Reactant: Cc1noc(C)c1C(=O)NC[C@@H]1C[C@@H]2C[C@@H]2N1
Reactant: Cc1cccc(-c2sc(N)nc2C(=O)O)c1
Product: Cc1cccc(-c2sc(N)nc2C(=O)N2[C@H](CNC(=O)c3c(C)noc3C)C[C@@H]3C[C@@H]32)c1

Procedure:
prepared by reaction of 3,5-dimethyl-isoxazole-4-carboxylic acid [(1S,3S,5S)-2-aza-bicyclo[3.1.0]hex-3-ylmethyl]-amide with 2-amino-5-m-tolyl-thiazole-4-carboxylic acid. LC-MS (basic): tR=1.26 min; [M+H]+=452.2.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13].[N+:16]([C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1)([O-:18])=[O:17]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:15][O:14][C:12]([C:3]1[C:2]([C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:16]([O-:18])=[O:17])[CH:24]=2)=[CH:11][CH:10]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:4]=1)=[O:13]
Reactant: COC(=O)c1ccc(Br)c(C(=O)OC)c1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: COC(=O)c1ccc(-c2cccc([N+](=O)[O-])c2)c(C(=O)OC)c1

Procedure:
Electrospray MS (positive ion): (M+Na) 338; from dimethyl 4-bromoisophthalate (1.26 g), 3-nitrophenylboronic acid (795 mg) and tetrakis(triphenylphosphine)palladium(0) (167 mg).
Reaction SMILES: Cl.Cl[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([CH:9]=[O:10])=[N:5]1.[F:11][C:12]([F:21])([F:20])[CH2:13][CH2:14][CH:15]([C:18]#[N:19])[C:16]#[N:17].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:9]([C:6]1[CH:7]=[CH:8][N:4]([CH2:3][C:15]([CH2:14][CH2:13][C:12]([F:11])([F:20])[F:21])([C:16]#[N:17])[C:18]#[N:19])[N:5]=1)=[O:10]
Reactant: O=Cc1ccn(CCl)n1
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cn1ccc(C=O)n1
Yield: 2.1 %

Procedure:
1.57 g of 1-chloromethyl-3-formylpyrazole hydrochloride and 1.52 g of (3,3,3-trifluoropropyl) malononitrile were dissolved in 30 ml of N,N-dimethylformamide. 2.76 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for 5 hours. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.05 g of [(3-formyl-1H-pyrazole-1-yl)methyl](3,3,3-trifluoropropyl) malononitrile (referred as the compound of the present invention (8), hereinafter) shown by below formula.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[S:8][CH:9]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:11]=2)=[CH:4][C:3]=1[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].C([Li])CCC.CCCCCC.[CH3:47][Sn:48](Cl)([CH3:50])[CH3:49]>C1COCC1.C(OCC)C.O>[CH3:47][Sn:48]([CH3:50])([CH3:49])[C:2]1[S:6][C:5]([C:7]2[S:8][CH:9]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:11]=2)=[CH:4][C:3]=1[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CCCCCCCCCCCCc1csc(-c2cc(CCCCCCCCCCCC)c(Br)s2)c1
Reactant: C[Sn](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCCCCCCCCc1csc(-c2cc(CCCCCCCCCCCC)c([Sn](C)(C)C)s2)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of 5-bromo-4,4′-didodecyl-2,2′-bithiophene (29A, 100 mg, 0.172 mmol) in 4.0 mL of THF was added dropwise a solution of n-butyllithium in hexane (0.076 mL, 2.5 M, 0.189 mmol) at −78° C. The solution was stirred at −78° C. for 1 hour and a solution of trimethyltin chloride in THF (0.20 mL, 1.0 M, 0.20 mmol) was added in one portion. The solution was warmed to room temperature and 10.0 mL of water and 10.0 mL of diethylether were added. The organic layer was separated and washed twice with 20 mL of water and dried over magnesium sulfate. After filtration, the filtrate was concentrated in vacuo to yield 5-trimethylstannyl-4,4′-didodecyl-2,2′-bithiophene (29, 0.103 g, 90% yield) as a yellow oil. 1H NMR (CDCl3): δ 0.84-1.64 (m, 46H), 2.58 (m, 4H), 6.77 (s, 1H), 6.99 (s, 1H), 7.13 (s, 1H).
Reaction SMILES: C1([CH:7]([S:12]C(C2C=CC=CC=2)C=C(C)C)[CH:8]=[C:9]([CH3:11])[CH3:10])C=CC=CC=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.P(=O)(O)(O)O.[CH:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>>[CH3:10][C:9]1([CH3:11])[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[S:12][CH2:7][CH2:8]1
Reactant: CC(C)=CC(SC(C=C(C)C)c1ccccc1)c1ccccc1
Reactant: c1ccccc1
Agent: O=P(O)(O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: CC1(C)CCSc2ccccc21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 15.48 g (86.824 mmol) of phenyl-3-methylbut-2-enylsulfide (from Example I) in 160 ml benzene were added successively 12.6 g (88.767 mmol) of phosphorus pentoxide and 11 ml of 85% phosphoric acid. This solution was refluxed with vigorous stirring under argon for 20 hours, then cooled to room temperature. The supernatant organic layer was decanted and the syrupy residue extracted with 3×50 ml ether. Organic fractions were combined and washed with water, saturated NaHCO3 and saturated NaCl solution and then dried (MgSO4). Solvent was removed in vacuo and the residue purified by kugelrohr distillation (80° C., 0.5 mm) to give the title compound as a pale yellow oil.
Reaction SMILES: C(O)(=O)CC.[BH4-].[Na+].[CH2:8]([O:15][C:16]([C@@H:18]1[CH2:23][CH2:22][C:21](=[N:24][O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:20][N:19]1CC1C=CC=CC=1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.S(=O)(=O)(O)O.O.O.[C:47]([OH:52])(=[O:51])[C:48]([OH:50])=[O:49]>C(OCC)(=O)C.CO>[C:47]([OH:52])(=[O:51])[C:48]([OH:50])=[O:49].[CH2:26]([O:25][NH:24][C@H:21]1[CH2:20][NH:19][C@H:18]([C:16]([O:15][CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:17])[CH2:23][CH2:22]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCC(=NOCc2ccccc2)CN1Cc1ccccc1
Agent: O=C(O)C(=O)O
Agent: O=S(=O)(O)O
Agent: [BH4-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: O=C(OCc1ccccc1)[C@@H]1CC[C@@H](NOCc2ccccc2)CN1
Temperature: 45 °C

Procedure:
Propanoic acid (140.6 ml, 1878.6 mmol, 6 eq) was added to a suspension of sodium borohydride (23.2 g, 626.2 mmol, 2 eq) in ethyl acetate (600 ml) and held until the reaction was deemed to be complete. The resulting solution was added to a solution of benzyl (2S)-5-[(benzyloxy)imino]piperidine-2-carboxylic acid benzyl ester in ethyl acetate (600 ml total volume) and sulphuric acid (83.4 ml, 1565 mmol, 5 eq) at −20° C. and held until reaction was deemed to be complete. The reaction was quenched by the addition of water (1000 ml), then neutralized with aqueous ammonia solution. The organic layer was washed with water and concentrated in vacuo to 400 ml. The solution was warmed to 45° C. and held at this temperature. Methanol (200 ml) at 40° C. was added, followed by a freshly prepared solution of oxalic acid dihydrate (39.5 g, 313.1 mmol) in methanol (100 ml). The mixture was cooled and the product was isolated by filtration. The solid was washed with an ethyl acetate/methanol mixture, then with ethyl acetate. The solid was dried to give benzyl (2S,5R)-5-[(benzyloxy)amino]piperidine-2-carboxylate ethanedioate (1:1) as a single isomer (79.4 g, 185 mmol, 59%).
Reaction SMILES: [Br-].[O:2]1[CH2:6][CH2:5][O:4][CH:3]1[CH2:7][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[F:33][C:34]1[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:35]=1[CH:36]=O.O>C1COCC1>[F:33][C:34]1[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:35]=1[CH2:36][CH2:7][CH:3]1[O:4][CH2:5][CH2:6][O:2]1
Reactant: c1ccc([P+](CC2OCCO2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=Cc1cccc(F)c1F
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Fc1cccc(CCC2OCCO2)c1F
Temperature: -10 °C
Reaction time: 1 h
Yield: 83.8 %

Procedure:
Well-dried (1,3-dioxolan-2-yl)methyltriphenyl phosphonium bromide (s27) (108.8 g) was mixed with THF (500 ml) under an atmosphere of nitrogen, and cooled to −10° C. Potassium t-butoxide (t-BuOK; 28.4 g) was added in two portions in the temperature range of −10° C. to −5° C. After 60 minutes of stirring at −10° C., 2,3-difluorobenzaldehyde (s26) (30.0 g) dissolved in THF (30 ml) was added dropwise in the temperature range of −10 to −5° C. After 30 minutes of stirring at 0° C., the reaction mixture was treated with water, and the aqueous layer was extracted with toluene. The combined organic layers were washed with water, and then dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the residue was purified by column chromatography with toluene as an eluent and silica gel as a stationary phase powder. The purified product was dissolved in a mixed solvent of toluene (250 ml) and Solmix A-11 (250 ml), to which Pd/C (1.5 g) was added. The mixture was stirred at room temperature under a hydrogen atmosphere until hydrogen absorption had ceased. After the reaction had been completed, Pd/C was removed, and then solvent was distilled off. The residue was purified by column chromatography with toluene as an eluent and silica gel as a stationary phase powder, and then by recrystallization from heptane to give 2-(2,3-difluorophenethyl)-1,3-dioxolane (s28) (37.9 g). The yield based on the compound (s26) was 83.8%.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:18][C:17]2[CH:16]=[CH:15][C:14]3[N:13]=[C:12]([OH:19])[C:11]([OH:20])=[N:10][C:9]=3[C:8]=2[CH:7]=1)=[O:5])C>[OH-].[Na+]>[C:4]([C:6]1[S:18][C:17]2[CH:16]=[CH:15][C:14]3[N:13]=[C:12]([OH:19])[C:11]([OH:20])=[N:10][C:9]=3[C:8]=2[CH:7]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1cc2c(ccc3nc(O)c(O)nc32)s1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cc2c(ccc3nc(O)c(O)nc32)s1
Yield: 51.9 %

Procedure:
8-Ethoxycarbonyl-2,3-dihydroxythieno[3,2-f]quinoxaline (2.0 g, 6.9 mmol) was stirred in 30 ml of 2N sodium hydroxide at room temperature for 2 h. The solution was filtered and after acidification of the filtrate with 4M hydrochloric acid, the resulting precipitate was collected by filtration and washed with water. The crude product was dissolved in 2N sodium hydroxide and reprecipitated with 4M hydrochloric acid to give 0.94 g (52%) of the carboxylic acid, m.p.>350° C. dec.; IR (KBr): 3300-2200, 1690 cm-1.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[C@@H:20]12[CH2:26][C@@H:23]([CH:24]=[CH:25]1)[CH2:22][C@H:21]2[CH2:27][C:28](O)=[O:29]>>[C@@H:20]12[CH2:26][C@@H:23]([CH:24]=[CH:25]1)[CH2:22][C@H:21]2[CH2:27][C:28]([NH:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19])=[O:29]
Reactant: O=C(O)C[C@@H]1C[C@@H]2C=C[C@H]1C2
Reactant: Nn1nc(-c2ccc(F)cc2)c2ccccc2c1=O
Product: O=C(C[C@@H]1C[C@@H]2C=C[C@H]1C2)Nn1nc(-c2ccc(F)cc2)c2ccccc2c1=O

Procedure:
The product of Example 129A and 2-[(1S,2S,4S)-bicyclo[2.2.1]hept-5-en-2-yl]acetic acid were treated using a method similar to that described in Example 17C to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ 11.29 (s, 1H), 8.43-8.37 (m, 1H), 8.05-7.88 (m, 2H), 7.76-7.68 (m, 1H), 7.70-7.61 (m, 2H), 7.48-7.34 (m, 2H), 6.22 (dd, J=5.7, 2.9, 1H), 6.06 (dd, J=5.7, 2.8, 1H), 2.92-2.86 (m, 1H), 2.81-2.75 (m, 1H), 2.42-2.48 (m, buried), 2.19-1.98 (m, 2H), 1.90 (ddd, J=11.6, 9.0, 3.8, 1H), 1.39-1.30 (m, 1H), 1.30-1.22 (m, 1H), 0.60 (ddd, J=11.6, 4.2, 2.6, 1H); MS (APCI+) M/Z 390 (M+H)+.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8].[C:9]([C:11]1[CH:20]=[C:19]2[C:14]([CH2:15][C:16]([CH3:23])([CH3:22])[CH:17]3O[CH:18]32)=[CH:13][CH:12]=1)#[N:10].O>CS(C)=O>[C:9]([C:11]1[CH:20]=[C:19]2[C:14]([CH2:15][C:16]([CH3:23])([CH3:22])[CH:17]=[C:18]2[N:3]2[CH2:7][CH2:6][CH2:5][C:4]2=[O:8])=[CH:13][CH:12]=1)#[N:10]
Reactant: O=C1CCCN1
Reactant: CC1(C)Cc2ccc(C#N)cc2C2OC21
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC1(C)C=C(N2CCCC2=O)c2cc(C#N)ccc2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (0.18 g of 80% dispersion in oil) in dry dimethylsulphoxide (5 ml) was added 2-pyrrolidinone (0.51 g) in dimethylsulphoxide (5 ml) and the mixture was then stirred at room temperature, under nitrogen, for 1 hour. A solution of 7-cyano-1,2-epoxy-3,3-dimethyl-1,2,3,4,-tetrahydronaphthalene (1.0 g) in dimethylsulphoxide was then added dropwise, and the solution stirred for 18 hours at room temperature. The mixture was then poured into water and extracted into ethyl acetate. The combined organic layers were washed with water, then brine, and dried over sodium sulphate. Removal of drying agent and solvent, followed by chromatography of the residue on a silica gel column eluted with ethyl acetate-pentane (1:1), gave the title compound as a solid, which recrystallised from 60°-80° petrol-ethyl acetate (5:1) as yellow prisms (0.25 g) having mp 131°-2° C.;
Reaction SMILES: [NH2:1][C:2](=[N:20][N+:21]([O-:23])=[O:22])[NH:3][CH2:4][CH2:5][CH2:6][C@H:7]([C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)=[O:10])[NH2:8].[C:24](OC(=O)C)(=[O:26])[CH3:25]>C(O)(=O)C>[C:24]([NH:8][C@@H:7]([C:9]([NH:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=1)=[O:10])[CH2:6][CH2:5][CH2:4][NH:3][C:2]([NH2:1])=[N:20][N+:21]([O-:23])=[O:22])(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: NC(=N[N+](=O)[O-])NCCC[C@@H](N)C(=O)NCc1ccc(O)cc1
Solvent: CC(=O)O
Product: CC(=O)N[C@H](CCCNC(N)=N[N+](=O)[O-])C(=O)NCc1ccc(O)cc1
Temperature: 50 °C

Procedure:
0.3 g (0.925 mMol) of (R)-N5 -[amino(nitroimino) methyl]-N-[(4-hydroxyphenyl)methyl]-ornithinamide were dissolved in 3 ml of glacial acetic acid and after the addition of 3 ml (0.032 Mol) of acetic anhydride the mixture was heated to a reaction temperature of 50° C. for 30 minutes. The product remaining after the volatile components had evaporated off was further processed without purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][N:6]=1)=[O:4].[F:14][C:15]([F:31])([F:30])[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([N:22]2[CH2:27][CH2:26][CH:25]([CH2:28][NH2:29])[CH2:24][CH2:23]2)[N:17]=1.OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH:29][CH2:28][CH:25]2[CH2:26][CH2:27][N:22]([C:18]3[N:17]=[C:16]([C:15]([F:31])([F:30])[F:14])[CH:21]=[CH:20][N:19]=3)[CH2:23][CH2:24]2)=[O:11])=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(C(=O)O)cn1
Reactant: NCC1CCN(c2nccc(C(F)(F)F)n2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(=O)NCC2CCN(c3nccc(C(F)(F)F)n3)CC2)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.3 %

Procedure:
To a solution of 6-(methoxycarbonyl)nicotinic acid (250 mg, 1.39 mmol) and 1-{1-[4-(trifluoromethyl)pyrimidin-2-yl]piperidin-4-yl}methanamine (INTERMEDIATE 6, 361 mg, 1.39 mmol) in dimethylformamide (5.0 ml) were added hydroxybenzotriazole (225 mg, 1.67 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (320 mg, 1.67 mmol), and N,N-diisopropylethylamine (291 μl, 1.67 mmol). The reaction was allowed to stir at ambient temperature for 18 h. After removal of the solvent by evaporation, the residue was purified by flash chromatography on a silica gel column, eluting with a gradient of 0-100% ethyl acetate in hexanes to give the title compound as a white solid (272.2 mg). Mass spectrum (ESI) 425 (M+1). 1H NMR (500 MHz, CDCl3) δ 9.13 (s, 1H), 8.49 (d, 1H, J=4.8 Hz), 8.33 (d, 1H, J=8.0 Hz), 8.24 (d, 1H, J=8 Hz), 6.73-6.77 (m, 2H), 4.87 (d, 2H, J=13.5 Hz), 4.05 (s, 3H), 3.44-3.47 (m, 2H), 2.90-2.98 (m, 2H), 1.90-2.00 (m, 1H), 1.90 (d, 2H, J=12.6 Hz), 1.27-1.36 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](Cl)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1.Cl.[F:16][C:17]([CH3:22])([CH3:21])[C@H:18]([NH2:20])[CH3:19].FC(C)(C)[C@H](NC1C2N(C=CC=2)N=CC=1C(N)=O)C.C(N(C(C)C)CC)(C)C>CN1C(=O)CCC1.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:20][C@H:18]([CH3:19])[C:17]([F:16])([CH3:22])[CH3:21])=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Reactant: C[C@@H](N)C(C)(C)F
Agent: C[C@@H](Nc1c(C(N)=O)cnn2cccc12)C(C)(C)F
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: C[C@@H](Nc1c(C(N)=O)cnn2cc(Br)cc12)C(C)(C)F
Temperature: 25 °C

Procedure:
A solution of 6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (Preparation 5, 519 mg, 1.89 mmol), (R)-2-fluoro-1,2-dimethyl-propylamine hydrochloride salt (402 mg, 2.84 mmol, from Intermediate 2, step 3), and diisopropylethylamine (0.99 mL, 5.68 mmol) in NMP (2.0 mL) was heated to 100° C. for 1 hour in the CEM microwave. The mixture was cooled to rt, diluted with water and the resulting precipitate then filtered and allowed to air dry. This afforded 595 mg (92%) of a pale white solid as the title compound. HPLC (condition B): retention time=3.67 min. LCMS (condition B): m/z 343.1, 345.1. 1H NMR (500 MHz, CD3OD) δ ppm 8.16 (1 H, s), 7.67 (1 H, d, J=1.66 Hz), 7.04 (1 H, d, J=1.39 Hz), 4.11-4.60 (1 H, m), 1.45-1.54 (6 H, m), 1.43 (3 H, d, J=6.66 Hz).
Reaction SMILES: [OH-].[Ca+2:2].[OH-].[B:4]([OH:7])([OH:6])[OH:5].C1(C)C(C)=CC=CC=1>O>[B:4]([O-:7])([O-:6])[O-:5].[Ca+2:2].[B:4]([O-:7])([O-:6])[O-:5].[Ca+2:2].[Ca+2:2]
Reactant: OB(O)O
Agent: [Ca+2]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1C
Product: [O-]B([O-])[O-]
Temperature: 60 °C

Procedure:
200 g of the same neutral calcium alkylsalicylate (A) as used in Example 1, 26 g of calcium hydroxide (B), 43.4 g (2.0 moles per mole of the calcium hydroxide) of orthoboric acid (C) and 400 g of xylene (F) were put in a 1000-ml four-necked flask fitted with a condenser and heated to 60° C. while agitating. To this mixture was added 20 g of water, and the resulting mixture was heated up to a refluxing temperature (66° C.) under agitation and reacted for 4 hours to obtain a reaction product. The reaction product was further heated to 140° C. for 1.5 hours to distill out the water and xylene. Finally the reaction product was diluted twofold with hexane and filtered to remove any residual solids present, and the hexane was distilled out to obtain a calcium borate overbased alkylsalicylate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=O.[CH3:11][C:12]1([CH3:19])[C:16](=[O:17])[CH:15]=[C:14]([CH3:18])[O:13]1.[OH-].[Na+].[Cl-].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:18][C:14]2[O:13][C:12]([CH3:19])([CH3:11])[C:16](=[O:17])[CH:15]=2)[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: CC1=CC(=O)C(C)(C)O1
Reactant: O=Cc1ccc(F)c(F)c1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)OC(C=Cc2ccc(F)c(F)c2)=CC1=O
Temperature: 50 °C
Yield: 49.6 %

Procedure:
To a solution of 3,4-difluorobenzaldehyde (1.9 g, 13.2 mM) and 2,2,5-trimethyl-3(2H)-furanone (2.0 g, 15.9 mM) in ethanol (100 mL), was added 1N aqueous sodium hydroxide (1.6 mL, 1.6 mM). The reaction solution was heated at 50° C. for four hours. After the reaction solution was cooled to room temperature, saturated aqueous sodium chloride (400 mL) was added. The aqueous layer was extracted with diethyl ether (3×100 mL). The combined ethereal extracts were washed with saturated aqueous sodium chloride (50 mL), dried over MgSO4, filtered and concentrated to give a yellow solid. The crude product was triturated with 10% diethyl ether/pet. ether (50 mL) to give a pale yellow solid (1.66 g, 50% yield), m.p. 105°-106° C.
Reaction SMILES: C([O:3][C:4](=[O:39])[C:5]([CH3:38])([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:28]=[CH:27][C:26]([B:29]4[O:33][C:32]([CH3:35])([CH3:34])[C:31]([CH3:37])([CH3:36])[O:30]4)=[CH:25][CH:24]=3)[O:20][C:21]=2[CH3:22])=[CH:10][CH:9]=1)[CH3:6])C.Cl.O>CCO.[OH-].[Na+]>[CH3:38][C:5]([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:24]=[CH:25][C:26]([B:29]4[O:33][C:32]([CH3:35])([CH3:34])[C:31]([CH3:37])([CH3:36])[O:30]4)=[CH:27][CH:28]=3)[O:20][C:21]=2[CH3:22])=[CH:10][CH:9]=1)([CH3:6])[C:4]([OH:39])=[O:3]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)oc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1oc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)nc1CCOc1ccc(OC(C)(C)C(=O)O)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 93.8 %

Procedure:
A sample of 2-methyl-2-[4-(2-{5-methyl-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-oxazol-4-yl}-ethoxy)-phenoxy]-propionic acid ethyl ester (55 mg, 0.103 mmol) was dissolved in 10 mL of EtOH with 3 mL of 5 N NaOH. This mixture was allowed to stir at 60° C. for 1 h. The mixture was cooled to room temperature and then acidified to pH 2 by the dropwise addition of 5 N HCl. This acidic mixture was diliuted with 10 mL of H2O and then extracted with CH2Cl2 (2×25 mL). The organic layers were combined, dried over NaCl, and solvent removed in vacuo which provided 49 mg (94%) of desired acid: 1H NMR (400 MHz, CDCl3) δ 8.32 (d, 2 H), 7.95 (d, 2 H), 6.82 (d, 2 H), 6.74 (d, 2 H), 4.35 (t, 2 H), 3.25 (t, 2 H), 2.50 (s, 3 H), 1.44 (s, 6 H), 1.32 (s, 12 H); MS (EI) 508.0 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][Si:23]([CH:30]([CH3:32])[CH3:31])([CH:27]([CH3:29])[CH3:28])[CH:24]([CH3:26])[CH3:25])[C:15]=2[F:33])[C:11]([NH2:13])=[S:12])=[CH:5][CH:4]=1)#[N:2].F[B-](F)(F)F.[C:39](=O)([O-])O.[Na+].C(OCC)(=O)C>C(#N)C>[CH3:39][S:12][C:11](=[NH:13])[CH:10]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][Si:23]([CH:27]([CH3:29])[CH3:28])([CH:30]([CH3:32])[CH3:31])[CH:24]([CH3:26])[CH3:25])[C:15]=1[F:33]
Reactant: O=C([O-])O
Reactant: COc1cc(O[Si](C(C)C)(C(C)C)C(C)C)c(F)c(C(Nc2ccc(C#N)cc2)C(N)=S)c1
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1cc(O[Si](C(C)C)(C(C)C)C(C)C)c(F)c(C(Nc2ccc(C#N)cc2)C(=N)SC)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 57.96 g of 2-(4-cyanophenylamino)-2-(2-fluoro-5-methoxy-3-triisopropylsilanyloxyphenyl)thioacetamide in 200 ml of acetonitrile there was added 18.5 g of Me3O+BF4−, and the mixture was stirred at room temperature for 3 hours. After adding 2.1 g of Me3O+BF4− to the reaction mixture, it was further stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, and extraction was performed with ethyl acetate. After washing the organic layer with saturated brine, it was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off, and the filtrate was concentrated under reduced pressure to give 2-(4-cyanophenylamino)-2-(2-fluoro-5-methoxy-3-triisopropylsilanyloxyphenyl)thioacetimidic acid methyl ester (crude product).