Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])[CH2:2]1.[H][H].[BH4-].[Na+]>[Pd]>[OH:11][CH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])[CH2:2]1
Reactant: O=C1CC(=O)c2ccccc21
Reactant: [H][H]
Agent: [Pd]
Agent: [BH4-]
Agent: [Na+]
Product: O=C1CC(O)c2ccccc21
Yield: 95 %

Procedure:
A mixture of 73.25 g. (0.5 mole) of 1,3-indandione, 10.0 g. of 10% Pd on charcoal and 800 ml. of 2B-ethanol was added on the 1 liter flask of a Brown Hydrogenator, and hydrogen equivalent to 125 ml. of 1M sodium borohydride solution was added at room temperature and atmospheric pressure (0.5 mole H2). The solution was filtered through a bed of Celite Filter Aid, and the bed washed with ethanol. The ethanol solution was concentrated, and from the concentrate, a small amount of white solid separated, 1,3-indanediol, 1,6 g., m.p. 182°-187°. This by-product was filtered off and discarded. Evaporation of the filtrate gave 70.2 g. of nearly colorless oil (yield > 95%) which can be used directly in the aldehyde condensation. The IR spectrum of the product showed typical hydroxyl and carbonyl absorption.
Reaction SMILES: CC1(C)[O:6][CH:5]([CH2:7]O)[CH2:4][O:3]1.[C:10]([OH:27])(=[O:26])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>>[C:10]([O:27][CH2:7][CH:5]([CH2:4][OH:3])[OH:6])(=[O:26])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CC1(C)OCC(CO)O1
Reactant: CCCCCCCCCCCCCCCC(=O)O
Product: CCCCCCCCCCCCCCCC(=O)OCC(O)CO

Procedure:
This compound was synthesized according to the procedure described hereinabove (example 2a) starting from solketal and palmitic acid.
Reaction SMILES: C1(C)C=CC=CC=1.[Cl:8][C:9]1[C:10]([N+:17]([O-])=O)=[CH:11][C:12]([CH3:16])=[C:13]([CH:15]=1)[NH2:14].[OH-].[Na+]>C1(O)C2C(=CC=CC=2)C(O)=CC=1.O>[Cl:8][C:9]1[CH:15]=[C:13]([NH2:14])[C:12]([CH3:16])=[CH:11][C:10]=1[NH2:17]
Reactant: Cc1cc([N+](=O)[O-])c(Cl)cc1N
Agent: Oc1ccc(O)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(N)c(Cl)cc1N
Yield: 93.9 %

Procedure:
A reaction vessel was charged with 60 g of toluene, 50 g of water, 37.3 g of 5-chloro-2-methyl-p-nitroaniline, 6 g of sodium hydroxide and 0.3 g of 1,4-naphthalenediol, and then the same procedure as in Example 1 was followed, to obtain 29.4 g of 2-chloro-5-methyl-p-phenylenediamine.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:13]([CH:14]2[CH2:16][CH2:15]2)[C:12]2[CH:11]=[CH:10][N:9]=[CH:8][C:7]=2[C:6]=1[NH2:17])=[O:4].[F:18][C:19]1[CH:24]=[C:23]([Si:25]([CH3:28])([CH3:27])[CH3:26])[CH:22]=[CH:21][C:20]=1OS(C(F)(F)F)(=O)=O.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][O:2][C:3]([C:5]1[N:13]([CH:14]2[CH2:15][CH2:16]2)[C:12]2[CH:11]=[CH:10][N:9]=[CH:8][C:7]=2[C:6]=1[NH:17][C:20]1[CH:21]=[CH:22][C:23]([Si:25]([CH3:27])([CH3:26])[CH3:28])=[CH:24][C:19]=1[F:18])=[O:4]
Reactant: C[Si](C)(C)c1ccc(OS(=O)(=O)C(F)(F)F)c(F)c1
Reactant: COC(=O)c1c(N)c2cnccc2n1C1CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)c1c(Nc2ccc([Si](C)(C)C)cc2F)c2cnccc2n1C1CC1
Temperature: 105 °C
Reaction time: 17 h
Yield: 71.7 %

Procedure:
To a degassed suspension of 3-amino-1-cyclopropyl-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid methyl ester (215.0 mg, 0.93 mmol), and trifluoro-methanesulfonic acid 2-fluoro-4-trimethylsilanyl-phenyl ester (323.5 mg, 1.02 mmol, 1.1 eq) in anhydrous toluene (6.2 mL) was added Pd2dba3 (85.2 mg, 0.09 mmol, 0.1 eq), Xantphos (107.6 mg, 0.186 mmol, 0.2 eq) and Cs2CO3 (606.0 mg, 1.86 mmol, 2.0 eq). The reaction mixture was degassed with bubbling nitrogen for 10 minutes and stirred at 105° C. under N2 for 17 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (150 ml). The mixture was then filtered through a pad of Celite®. The celite pad was rinsed with EtOAc (2×50 mL), and the filtrate was concentrated under reduced pressure. The crude residue was then purified by flash column chromatography (silica, ISCO, 45 mL/min, 25 to 100% EtOAc in hexane) to afford the title compound as a yellow foam (265 mg, 71.7%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.52 (s, 1H), 8.33 (d, J=6.0 Hz, 1H), 7.86 (s, 1H), 7.55 (d, J=6.0 Hz, 1H), 7.29 (d, J=11.6 Hz, 1H), 7.13 (d, J=7.9 Hz, 1H), 6.90 (s, 1H), 3.82 (s, 3H), 3.57-3.46 (m, 1H), 1.27-1.03 (m, 2H), 0.96-0.71 (m, 2H), 0.23 (s, 9H); LC-MS (method D): [M+H]+=398.2, RT=2.69 min.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:20]=[C:19]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:25][C:26]1[C:27]([C:32]([NH:34][C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][N:36]=2)=[O:33])=[N:28][CH:29]=[CH:30][CH:31]=1>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:20]=[C:19]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:18]=[CH:17][C:13]=1[C:14]([NH:25][C:26]1[C:27]([C:32]([NH:34][C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][N:36]=2)=[O:33])=[N:28][CH:29]=[CH:30][CH:31]=1)=[O:16])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1cccnc1C(=O)Nc1ccc(Cl)cn1
Reactant: CC(C)(C)OC(=O)NCCOc1cc(S(C)(=O)=O)ccc1C(=O)O
Product: CC(C)(C)OC(=O)NCCOc1cc(S(C)(=O)=O)ccc1C(=O)Nc1cccnc1C(=O)Nc1ccc(Cl)cn1
Yield: 84 %

Procedure:
Using a procedure analogous to Example 1-G, 2-(2-t-butoxycarbonylaminoethoxy)-4-methylsulfonylbenzoic acid and 3-amino-N-(5-chloropyridin-2-yl)pyridine-2-carboxamide gave the desired product as a solid (4.0 g, 84%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.B1([C:15]2[CH:20]=[CH:19][CH:18]=[N:17][CH:16]=2)OCCCO1>C(O)C>[Br:8][C:4]1[CH:3]=[C:2]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)c1
Reactant: c1cncc(B2OCCCO2)c1
Solvent: CCO
Product: Brc1cccc(-c2cccnc2)c1
Yield: 63.8 %

Procedure:
This reaction was carried out as described in Example 37, step a, using 1,3-dibromobenzene (8.7 g, 36.8 mmol) and pyridine-3-boronic acid 1,3-propanediol cyclic ester (4.0 g, 24.5 mmol) in ethanol (60 ml) for 14 h. The resulting crude residue was purified by column chromatography (silica gel, 80% Et2O/hexane) to yield the title compound (3.66 g, 64%): 1H NMR (360 MHz, CDCl3) δ 7.30-7.42 (2H, m), 7.47-7.60 (2H, m), 7.72 (1H, s), 7.84 (1H, dt, J 8.0, 2.0 Hz), 8.62 (1H, dd, J 4.8, 1.5 Hz), 8.83 (1H, s).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:13])([F:12])[C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1.Cl[C:15]1[CH:16]=[C:17]([CH3:25])[C:18]([N+:22]([O-:24])=[O:23])=[CH:19][C:20]=1[CH3:21].O>CN1CCCC1=O>[N+:22]([C:18]1[CH:19]=[C:20]([CH3:21])[C:15]([O:11][C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([C:4]([F:12])([F:13])[F:3])[CH:6]=2)=[CH:16][C:17]=1[CH3:25])([O-:24])=[O:23]
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cc([N+](=O)[O-])c(C)cc1Oc1cccc(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
To a suspension of sodium hydride (0.4 g of 60% in oil) in dry N-methylpyrroli-dinone (10 ml) was slowly added 3-trifluoromethylphenol (1.62 g). When effervescence had ceased, 3-chloro-6-nitro-p-xylene (1.85 g) was added and the mixture stirred at 120-40° C. for 5 hours. On cooling, the mixture was poured into water and the mixture extracted with diethyl ether (x3). The combined ether extracts were dried (MgSO4), filtered and evaporated to give the title compound as a solid, m.p. 68-71° C.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[O:4][C:3]=1[CH:13]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH3:14].[CH2:23]([Sn](CCCC)(CCCC)C(OCC)=C)[CH2:24]CC>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Si:16]([O:15][CH:13]([C:3]1[O:4][C:5](=[O:12])[C:6]2[C:11]([C:2]=1[CH:23]=[CH2:24])=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH3:14])([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CC(O[Si](C)(C)C(C)(C)C)c1oc(=O)c2ccccc2c1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: C=Cc1c(C(C)O[Si](C)(C)C(C)(C)C)oc(=O)c2ccccc12
Temperature: 25 °C

Procedure:
To a degassed solution of 4-bromo-3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-1H-isochromen-1-one (intermediate A8, 6 g, 15.7 mmol) in toluene (120 ml), PdCl2(PPh3)2 (0.6 g, 079 mmol) was added followed by tributyl(1-ethoxyvinyl)tin (5 ml, 17.2 mmol) and the resulting mixture was heated to reflux overnight. Additional PdCl2(PPh3)2 (0.6 g) was added at room temperature, and the mixture was refluxed for 30 minutes. The mixture was cooled to room temperature, then filtered through a celite pad. The filtrate was evaporated to dryness and the crude was purified by flash chromatography on Biotage silica gel cartridges (cyclohexane to cyclohexane:EtOAc=80:20) to afford 3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-4-vinyl-1H-isochromen-1-one as a pale yellow oil (Intermediate B59.1, 5.8 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]2[N:15]=[C:16]([CH3:23])[C:17](C(OCC)=O)=[C:13]2[CH:12]=[CH:11][C:10]=1[CH3:24].[OH-].[Na+].C([O-])(O)=O.[Na+]>OS(O)(=O)=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]2[N:15]=[C:16]([CH3:23])[CH:17]=[C:13]2[CH:12]=[CH:11][C:10]=1[CH3:24]
Reactant: CCOC(=O)c1c(C)nn2c(-c3ccc(Cl)cc3Cl)c(C)ccc12
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Cc1cc2ccc(C)c(-c3ccc(Cl)cc3Cl)n2n1
Temperature: 150 °C

Procedure:
Ethyl 7-(2,4-dichlorophenyl)-2,6-dimethylpyrazolo[1,5-a]pyridine-3-carboxylate (930 mg, 2.56 mmol) was treated with 50% H2SO4 (10 mL) and heated to 150° C. for 2.5 hours. The reaction was cooled in an ice bath and treated with 4N NaOH (19 mL) and NaHCO3 (4.80 g).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH3:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:22]2[CH2:23][CH2:24][N:19]([C:13]3[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:12]=3[CH3:11])[CH2:20][CH2:21]2)=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Reactant: O=C(Cl)c1ccc(Br)cc1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3)CC2)c(C)c1
Yield: 72.9 %

Procedure:
Using 4-bromobenzoyl chloride (25 g) and 1-(2,4-dimethylphenyl)piperazine (22 g) and by the reaction and treatment in the same manner as in Preparation Example 108, the title compound (31 g) was obtained.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][C:16]([O:18]C)=[O:17])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[CH3:20][C:21]1[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=1>>[Cl:13][C:10]1[CH:9]=[CH:8][C:7]([C:5]2[N:6]=[C:2]([N:22]3[C:21]([CH3:20])=[CH:25][C:24]([CH3:26])=[N:23]3)[O:3][C:4]=2[CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:12][CH:11]=1
Reactant: Cc1cc(C)[nH]n1
Reactant: COC(=O)CCc1oc(Cl)nc1-c1ccc(Cl)cc1
Product: Cc1cc(C)n(-c2nc(-c3ccc(Cl)cc3)c(CCC(=O)O)o2)n1
Yield: 90 %

Procedure:
In the same manner as in Example 30, obtained was: 4-(4-chlorophenyl)-2-(3,5-dimethyl-1-pyrazolyl)-5-oxazolepropionic acid (yield: 90%) by reaction of methyl 2-chloro-4-(4-chlorophenyl)-5-oxazolepropionate with 3,5-dimethylpyrazole followed by hydrolysis of the resulting product. This was recrystallized from ethanol to give colorless needles. mp 201-202° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([C:13]2[CH:18]=[CH:17][C:16]([S:19]CC[Si](C)(C)C)=[CH:15][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.OS([O-])(=O)=O.[K+].[O-]S([O-])(=O)=O.[Na+].[Na+]>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([C:13]2[CH:18]=[CH:17][C:16]([SH:19])=[CH:15][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](c2ccc(SCC[Si](C)(C)C)cc2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: O=S(=O)([O-])[O-]
Product: CC(C)(C)OC(=O)N1CC[C@@H](c2ccc(S)cc2)C1
Reaction time: 8 h
Yield: 63.8 %

Procedure:
A mixture of (S)-3-[4-(2-trimethylsilanyl-ethylsulfanyl)-phenyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (613 mg, 1.615 mmol) and tetrabutylammoniumfluoride (1.0 M in THF, 10.5 mL) was stirred overnight. A solution of 10% KHSO4/Na2SO4 was then added and the resulting mixture was extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified via flash chromatography (hexane/EtOAc, 91/9) to give 288 mg (64% yield) of (S)-3-(4-mercapto-phenyl)-pyrrolidine-1-carboxylic acid tert-butyl ester as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH2:11])[N:7]([CH2:12][CH2:13][CH2:14][C:15]#[N:16])[C:6](=[O:17])[C:5]2([CH3:19])[CH3:18].CS[C:22](SC)=[N:23][C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C)C=O>[C:15]([CH2:14][CH2:13][CH2:12][N:7]1[C:8]2[CH:9]=[C:10]3[NH:11][C:22]([NH:23][C:24](=[O:31])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[N:1][C:2]3=[CH:3][C:4]=2[C:5]([CH3:19])([CH3:18])[C:6]1=[O:17])#[N:16]
Reactant: CSC(=NC(=O)c1ccccc1)SC
Reactant: CC1(C)C(=O)N(CCCC#N)c2cc(N)c(N)cc21
Solvent: CN(C)C=O
Product: CC1(C)C(=O)N(CCCC#N)c2cc3[nH]c(NC(=O)c4ccccc4)nc3cc21
Yield: 32.4 %

Procedure:
A solution of B37 (190 mg) and N-(bis-methylsulfanyl-methylene)-benzamide (150 mg; 0.67 mmol) in dry N,N-dimethylformamide (3 ml) is stirred at 150° C. for 24 h. The mixture is evaporated to dryness and the residue is purified by preparative RP-HPLC eluted with MeCN/water to yield the desired compound (84.2 mg).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]3[C:13]([C:20]4[CH:21]=[C:22]([CH3:26])[CH:23]=[CH:24][CH:25]=4)=[N:14][N:15]([CH2:17][CH:18]=O)[CH:16]=3)=[CH:11][C:6]=2[N:5]([CH2:27][CH3:28])[C:4]1=[O:29])[CH3:2].[CH3:30][O:31][CH2:32][CH2:33][NH2:34]>C1C=CC=CC=1>[CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]3[C:13]([C:20]4[CH:21]=[C:22]([CH3:26])[CH:23]=[CH:24][CH:25]=4)=[N:14][N:15]([CH2:17][CH2:18][NH:34][CH2:33][CH2:32][O:31][CH3:30])[CH:16]=3)=[CH:11][C:6]=2[N:5]([CH2:27][CH3:28])[C:4]1=[O:29])[CH3:2]
Reactant: COCCN
Reactant: CCn1c(=O)n(CC)c2cc(-c3cn(CC=O)nc3-c3cccc(C)c3)ccc21
Solvent: c1ccccc1
Product: CCn1c(=O)n(CC)c2cc(-c3cn(CCNCCOC)nc3-c3cccc(C)c3)ccc21
Reaction time: 1 h

Procedure:
To a benzene (3 mL) solution of [4-(1,3-Diethyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5-yl)-3-m-tolyl-pyrazol-1-yl]-acetaldehyde (0.034 g) was added methoxyethylamine (0.03 mL) and 4 Å molecular sieves. The reaction was allowed to stand at 23° C. for 1 hour then was filtered and concentrated. The resulting oil was diluted with methanol (2 mL), 4 Å molecular sieves were added and the mixture was treated with sodium cyanoborohydride (0.02 g). After stirring for 18 hours the mixture was poured onto ethyl acetate/saturated sodium bicarbonate and extracted. The organic layer was dried over sodium sulfate and concentrated. Preparative thin layer chromatography gave 1,3-Diethyl-5-{1-[2-(2-methoxy-ethylamino)-ethyl]-3-m-tolyl-1H-pyrazol-4-yl}-1,3-dihydro-benzoimidazol-2-one (0.014 g). Subsequent treatment with 1M hydrochloric acid in ether gave the hydrochloride salt.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[C:7]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[O:8])([O-])=O.[Sn](Cl)Cl.O.[OH-].[Na+]>C(O)C.Cl>[NH2:1][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[C:7]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[O:8]
Reactant: O=C(c1cccnc1)c1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1cccc(C(=O)c2cccnc2)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 95.9 %

Procedure:
3-(3-Nitrobenzoyl)pyridine (1.55 g, 0.006 mole) was suspended in ethanol (35 ml) and treated portionwise with a solution of tin (II) chloride (4.56, 0.024 mmole) in conc. HCl (7 ml). The reaction mixture was stirred at 50° C. for 2 hours. After allowing to cool to room temperature, water (50 ml) was added and the mixture basified with 10% aqueous sodium hydroxide, extracted into ethyl acetate, dried (Na2SO4) and evaporated in vacuo to afford the title compound (1.14 g, 85%) as a pale oil
Reaction SMILES: [Cl:1][C:2]1[C:20]([Cl:21])=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]([O:17][CH3:18])=[O:16])=[N:13][CH:14]=2)=[O:7])=[C:4](F)[CH:3]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[C:26]([O:31][CH3:32])[CH:25]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[C:20]([Cl:21])=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]([O:17][CH3:18])=[O:16])=[N:13][CH:14]=2)=[O:7])=[C:4]([O:30][C:27]2[CH:28]=[CH:29][C:24]([F:23])=[CH:25][C:26]=2[O:31][CH3:32])[CH:3]=1
Reactant: COC(=O)c1ccc(NC(=O)c2cc(Cl)c(Cl)cc2F)cn1
Reactant: COc1cc(F)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NC(=O)c2cc(Cl)c(Cl)cc2Oc2ccc(F)cc2OC)cn1
Temperature: 70 °C

Procedure:
Methyl 5-[(4,5-dichloro-2-fluoro-benzoyl)amino]pyridine-2-carboxylate (50 mg, 0.14 mmol), 4-fluoro-2-methoxy-phenol (18.27 μL, 0.16 mmol) and K2CO3 (60.41 mg, 0.44 mmol) were combined in DMF (0.5 mL) and heated at 70° C. for 1.5 hours to form methyl 5-[[4,5-dichloro-2-(4-fluoro-2-methoxy-phenoxy)benzoyl]amino]pyridine-2-carboxylate. Aqueous NaOH (145.7 μL of 3 M, 0.44 mmol) was then added and heating continued for 30 min. HPLC purification (1-99% CH3CN/5 mM HCl) provided 5-(4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)benzamido)picolinic acid (51) (35.28 mg, 54%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 13.05 (s, 1H), 10.96 (s, 1H), 8.93 (d, J=2.4 Hz, 1H), 8.30 (dd, J=8.7, 2.5 Hz, 1H), 8.08 (d, J=8.6 Hz, 1H), 7.97 (s, 1H), 7.27 (dd, J=8.9, 5.8 Hz, 1H), 7.12 (dd, J=10.7, 2.9 Hz, 1H), 6.91 (s, 1H), 6.84 (td, J=8.5, 2.9 Hz, 1H), 3.75 (s, 3H) ppm. ESI-MS m/z calc. 450.02. found 451.1 (M+1)+; Retention time: 1.61 minutes (3 minutes run).
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])=[N:14][N:13]3[CH:25]=2)=[CH:6][C:4]=1[NH2:5])#[CH:2].N1C=CC=CC=1.[CH3:32][C:33]([CH3:38])([CH3:37])[C:34](Cl)=[O:35]>C(#N)C>[C:1]([C:3]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])=[N:14][N:13]3[CH:25]=2)=[CH:6][C:4]=1[NH:5][C:34](=[O:35])[C:33]([CH3:38])([CH3:37])[CH3:32])#[CH:2]
Reactant: C#Cc1ccc(-c2cn3nc(-c4ccccc4F)ccc3n2)cc1N
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: C#Cc1ccc(-c2cn3nc(-c4ccccc4F)ccc3n2)cc1NC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
A solution of 2-ethynyl-5-(6-(2-fluorophenyl)imidazo[1,2-b]pyridazin-2-yl)aniline (0.030 g, 0.0913 mmol) in acetonitrile (1 mL) containing pyridine (0.273 mmol) is added trimethylacetylchloride (0.0958 mmol). The mixture is stirred at room temperature for 4 hours, then concentrated to dryness and residue purified via silica chromatography (hexanes to EtOAc) to afford the title compound (0.029 g, 78%) as a yellow solid: Rf 0.58 (1:1 EtOAc:hexanes); LCMS (m/z)=413.5 [M+H]+, tR=3.19 min. (compound same as Example 321)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([NH:12][C:13](=[O:17])[O:14][CH2:15][CH3:16])=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1.[CH3:21][O:22][C:23]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:24]=1[CH2:25]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:9])[F:11])[C:5]([N:12]([CH2:25][C:24]2[CH:27]=[CH:28][C:29]([O:31][CH3:32])=[CH:30][C:23]=2[O:22][CH3:21])[C:13](=[O:17])[O:14][CH2:15][CH3:16])=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1
Reactant: COc1ccc(CO)c(OC)c1
Reactant: CCOC(=O)Nc1c([N+](=O)[O-])cc(Br)cc1C(F)(F)F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)N(Cc1ccc(OC)cc1OC)c1c([N+](=O)[O-])cc(Br)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.5 %

Procedure:
To a solution of ethyl 4-bromo-2-nitro-6-(trifluoromethyl)phenylcarbamate (1049.3 mg), 2,4-dimethoxybenzyl alcohol (1.7217 g) and triphenylphosphine (3.0183 g) in tetrahydrofuran (15 ml) was added diethyl azodicarboxylate (2.2505 g). The mixture was stirred at room temperature for 8 hours, and then concentrated in vacuo. The resultant residue was purified by silica gel column (110 g, hexane:ethyl acetate=20:1→10:1) to give the title compound (796.8 mg, 53%) and recovered ethyl 4-bromo-2-nitro-6-(trifluoromethyl)phenylcarbamate (489.2 mg, 47%).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:12](O)=[O:13])[CH:10]=[CH:11][C:5]=2[S:4][CH2:3]1.COC(C1C=CC2SCC(=O)NC=2C=1)=O.[Li+].[OH-]>C1COCC1.O>[O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH:12]=[O:13])[CH:10]=[CH:11][C:5]=2[S:4][CH2:3]1
Reactant: O=C1CSc2ccc(C(=O)O)cc2N1
Agent: COC(=O)c1ccc2c(c1)NC(=O)CS2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccc2c(c1)NC(=O)CS2
Temperature: 25 °C
Reaction time: 24 h
Yield: 60 %

Procedure:
3-Oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid. To a solution of 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid methyl ester (1.5 g, 6.7 mmol) in a THF/H2O mixture (1:1, 63 mL) was added 4 N LiOH (8.0 mL, 32 mmol) and the resulting solution was stirred at RT for 24 h. The solution was partially concentrated and diluted with H2O (50 mL). The solution was acidified using concentrated HCl and a solid precipitated. The solid was collected via filtration, washed with H2O and dried in vacuo to provide 0.79 g (60%) of the title compound as a white solid. MS (ESI): exact mass calculated for C9H7NO3S, 209.01; m/z found, 210.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.65-7.61 (m, 2H), 7.40 (d, J=8.1, 1H), 3.48 (s, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:13])[C:10](Br)=[CH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:14]1([C:20]([NH:22][NH2:23])=[S:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.N12CCCC1=NCCC2.C(OCC)(=O)C>C1C=CC=CC=1.CN(C)C=O>[CH:14]1([C:20]2[S:21][CH2:11][CH:10]([C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:13])[NH:23][N:22]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: NNC(=S)C1CCCCC1
Reactant: C=C(Br)C(=O)OCc1ccccc1
Agent: C1CN=C2CCCN2C1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: O=C(OCc1ccccc1)C1CSC(C2CCCCC2)=NN1
Reaction time: 0.33 h
Yield: 49.7 %

Procedure:
A solution of 2-bromoprop-2-enoic acid benzyl ester (1.68 g) in dry benzene (10.2 ml) was added to cyclohexane carbothioic acid hydrazide (1.0 g) in dry dimethylformamide (10 ml). The mixture was cooled to 0° and stirred, under an atmosphere of nitrogen, during the gradual addition of 1,5-diazabicyclo[4.3.0]non-5-ene (0.78 g) and then for a further 20 minutes at 0°. Ethyl acetate (100 ml) was added and the mixture was washed with brine and dried over magnesium sulphate The solvent was evaporated under reduced pressure and the resulting oil purified by flash chromatography using 10% ethyl acetate/90% petroleum ether as eluent to yield the sub-title product (1.0 g) as a pink solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][C:8]([OH:10])=[CH:9][C:2]1=2.[CH3:11][C:12]([CH3:17])([CH3:16])[C:13](Cl)=[O:14]>N1C=CC=CC=1>[S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][C:8]([O:10][C:13](=[O:14])[C:12]([CH3:17])([CH3:16])[CH3:11])=[CH:9][C:2]1=2
Reactant: Oc1ccc2ccsc2c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Oc1ccc2ccsc2c1
Yield: 95.5 %

Procedure:
Dissolve benzo[b]thiophen-6-ol (10 g, 67 mmol) in pyridine (300 mL). Add 2,2-dimethyl-propionyl chloride (38 mL, 308 mmol) dropwise, and stir at room temperature for 8 hours. Concentrate in vacuo to ¼ Volume, partition between ethyl acetate (250 mL) and water (250 mL). Separate layers, wash organic layer with water (250 mL) and brine (200 mL). Dry with magnesium sulfate, filter, and concentrate in vacuo to give 15 g of 2,2-dimethyl-propionic acid benzo[b]thiophen-6-yl ester (98%).