Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([S:11][CH2:12][CH2:13][N:7]3[C@H:6]3[CH2:14][CH2:15][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][C@@H:5]23)[CH:10]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl:44][C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([Cl:51])[C:46]=1[Sn](C)(C)C>CN(C=O)C.C(OC(=O)C)C.O.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>[Cl:44][C:45]1[CH:46]=[C:47]([Cl:51])[CH:48]=[CH:49][C:50]=1[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([S:11][CH2:12][CH2:13][N:7]3[C@H:6]3[CH2:14][CH2:15][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19])[CH2:17][C@@H:5]23)[CH:10]=1
Reactant: C[Sn](C)(C)c1c(Cl)cccc1Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CCS3
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(-c3ccc(Cl)cc3Cl)cc3c1N2CCS3
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 50.5 %

Procedure:
General procedure for stannane coupling with aryl bromide: Degassed DMF (25 mL) was added to a mixture of tert-butyl(6bR,10aS)-5-bromo-1,2,6b,9,10,10a-hexahydropyrido[4,3-b][1,4]thiazino[2,3,4-hi]indole-8(7H)-carboxylate (316 mg, 0.768 mmol), PPh3 (40.4 mg, 0.154 mmol), CuBr (22 mg, 0.20 mmol) and Pd(PPh3)2Cl2 (55 mg, 0.0768 mmol) via cannula, at room temperature under N2 blanket. The reaction mixture was stirred at room temperature for 5 min and then 2,6-dichlorophenyl trimethylstannane (357 mg, 1.15 mmol) was added as a solution in degassed DMF (2.5 mL) and the reaction mixture was heated at 140° C. After 10 min, the solution began to turn black, and a second portion (178 mg, 0.575 mmol) was added after 1 hour, followed by a final portion (178 mg, 0.575 mmol) an hour later. Heating resumed for another 30 min, then the reaction mixture was cooled to room temperature and diluted with ethylacetate/water (20 mL/20 mL). Organic layer was separated, dried over sodium sulfate an concentrated to dryness under reduced pressure to a dark oil. This residue was purified by flash chromatography eluting with 10% EtOAc/Hexanes to give tert-butyl(6bR,10aS)-5-(2,4-dichlorophenyl)-1,2,6b,9,10,10a-hexahydropyrido[4,3-b][1,4]thiazino[2,3,4-hi]indole-8(7H)-carboxylate (185 mg, 50%). 1H NMR (CDCl3, 300 MHz) δ1.46 (s, 9H), 1.82-2.00 (m, 2H), 2.93-3.33 (m, 5H), 3.40-3.51 (m, 4H), 3.52-3.75 (m, 1H), 6.71 (s, 1H), 6.75 (s, 1H), 7.12 (t, 1H, J=7.9 Hz), 7.33 (d, 2H, J=7.9 Hz) ppm.
Reaction SMILES: [CH3:1][CH:2]([C:8]([O:10]CC)=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].N1C=CC=CC=1.[F:19][C:20]1[CH:21]=[CH:22][C:23]([CH3:27])=[C:24]([CH:26]=1)[NH2:25]>>[F:19][C:20]1[CH:21]=[CH:22][C:23]([CH3:27])=[C:24]([NH:25][C:8](=[O:10])[CH:2]([CH3:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:26]=1
Reactant: Cc1ccc(F)cc1N
Reactant: CCOC(=O)C(C)C(=O)OCC
Solvent: c1ccncc1
Product: CCOC(=O)C(C)C(=O)Nc1cc(F)ccc1C
Reaction time: 96 h

Procedure:
The ester was prepared according to procedure A using diethyl 2-methylmalonate (6.18 mL, 36.0 mmol), pyridine (3.88 mL, 47.9 mmol) and 5-fluoro-2-methyl aniline (3.00 g, 23.97 mmol). Heating continued for 4 days. The residue was purified by column chromatography on silica gel (0-30% EtOAc/hexanes) to give ethyl 3-(5-fluoro-2-methylphenylamino)-2-methyl-3-oxopropanoate as a tan solid. Mass Spectrum (ESI) m/e=254.2, (M+1).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:20]#[N:21])=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[N:5]([CH2:11]Cl)[C:6]=1[C:7]([F:10])([F:9])[F:8].[O-:22][CH2:23][CH3:24].[Na+]>C(O)C.O.CCOCC>[Br:1][C:2]1[C:3]([C:20]#[N:21])=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[N:5]([CH2:11][O:22][CH2:23][CH3:24])[C:6]=1[C:7]([F:10])([F:9])[F:8]
Reactant: N#Cc1c(Br)c(C(F)(F)F)n(CCl)c1-c1ccc(Cl)cc1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Solvent: O
Product: CCOCn1c(-c2ccc(Cl)cc2)c(C#N)c(Br)c1C(F)(F)F
Temperature: 25 °C
Yield: 85.9 %

Procedure:
A solution of 4-bromo-1-(chloromethyl)-2-(p-chlorophenyl)-5-(trifluoromethyl)pyrrole-3-carbonitrile (2.0 g, 0.005 mol) in absolute ethanol is treated with a 21% wt/wt ethanolic solution of sodium ethoxide (0.36 g, 0.0053 mol), heated to 75°-80° C. for 20-30 minutes, cooled to room temperature and diluted with water and ether. The organic phase is dried over anhydrous magnesium sulfate and concentrated in vacuo to give a solid which is recrystallized form heptane to give the title product as a white solid (1.75 g, mp 97°-98° C.).
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C@H:6]([CH3:20])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([S:16]([NH2:19])(=[O:18])=[O:17])[CH:9]=1)=[O:4].CC(C)([O-])C.[K+].[CH2:27]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[OH:36])[CH3:28].Cl>O1CCCC1.C(OCC)(=O)C>[CH2:27]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[O:36][CH2:2][C:3]([NH:5][C@H:6]([CH3:20])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([S:16]([NH2:19])(=[O:18])=[O:17])[CH:9]=1)=[O:4])[CH3:28]
Reactant: COc1ccc(C[C@@H](C)NC(=O)CBr)cc1S(N)(=O)=O
Reactant: CCOc1ccccc1O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOc1ccccc1OCC(=O)N[C@H](C)Cc1ccc(OC)c(S(N)(=O)=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.8 %

Procedure:
1.0 g of (R)-2-bromo-N-[2-(4-methoxy-3-aminosulfonyl-phenyl)-1-methyl-ethyl]-acetamide prepared in Example 2 was added to a stirring solution of 1.25 g of potassium t-butoxide and 1.5 g of 2-ethoxy phenol in 10 ml of tetrahydrofuran and stirred at 25° C. for 1 hour. After the reaction was completed, 50 ml of a 10% hydrochloric acid solution and then, 50 ml of ethyl acetate was added to the resultant solution and then, extracted. Next, the organic layer was separated and concentrated. 10 ml of methanol was added to the obtained concentrated residue and stirred for 12 hours. Then, the resultant product was filtered and dried to obtain the title compound as a white solid (0.9 g).
Reaction SMILES: N#N.C(Cl)(Cl)(Cl)Cl.C(=O)=O.[CH2:11]=[C:12]([CH2:18][CH3:19])[CH2:13][CH2:14][CH:15]([OH:17])[CH3:16].ClN1C(=O)CCC1=O.CSC>C1(C)C=CC=CC=1.CCOCC.C(N(CC)CC)C>[CH2:11]=[C:12]([CH2:18][CH3:19])[CH2:13][CH2:14][C:15](=[O:17])[CH3:16]
Reactant: C=C(CC)CCC(C)O
Agent: N#N
Agent: O=C1CCC(=O)N1Cl
Agent: O=C=O
Solvent: CSC
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C=C(CC)CCC(C)=O
Reaction time: 0.08 h
Yield: 36.2 %

Procedure:
With exclusion of moisture (N2) and cooling (-19° C., carbon tetrachloride-dry ice slush bath), a solution of 19.23 g 5-methylene-2-heptanol in toluene was added to a stirred mixture of 30.04 g N-chlorosuccinimide and 19.10 g dimethyl sulfide in toluene. The mixture was allowed to warm to ca 25° C. over a two-hour period. Then 23.2 g triethylamine was added. After five minutes, the reaction mixture was diluted two-fold with ether. Upon washing with 1% hydrochloric acid and then water, the organic phase was dried (magnesium sulfate) and concentrated. Distillation afforded 6.85 g product with bp 73°-76° C. (20 torr).
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)=[O:12])[C:8]([CH3:21])=[C:7]2[C:3]=1[C:4]1[CH:25]=[C:24]([CH3:26])[CH:23]=[N:22][C:5]=1[NH:6]2.[CH:27]1([NH:30][C:31]([C:33]2[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=2)=[O:32])[CH2:29][CH2:28]1>>[CH:27]1([NH:30][C:31]([C:33]2[CH:38]=[C:37]([C:2]3[CH:10]=[C:9]([C:11]([NH:13][CH:14]4[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]4)=[O:12])[C:8]([CH3:21])=[C:7]4[C:3]=3[C:4]3[CH:25]=[C:24]([CH3:26])[CH:23]=[N:22][C:5]=3[NH:6]4)[CH:36]=[CH:35][CH:34]=2)=[O:32])[CH2:28][CH2:29]1
Reactant: Cc1cnc2[nH]c3c(C)c(C(=O)NC4CCN(C)CC4)cc(Cl)c3c2c1
Reactant: O=C(NC1CC1)c1cccc(B(O)O)c1
Product: Cc1cnc2[nH]c3c(C)c(C(=O)NC4CCN(C)CC4)cc(-c4cccc(C(=O)NC5CC5)c4)c3c2c1

Procedure:
The title compound was synthesized from 5-chloro-3,8-dimethyl-N-(1-methylpiperidin-4-yl)-9H-pyrido[2,3-b]indole-7-carboxamide and 3-(cyclopropylcarbamoyl)phenylboronic acid using an analogous procedure to that described in the preparation of compound 88. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.77-0.82 (m, 4H) 1.53 (qd, J=11.66, 3.41 Hz, 2H) 1.79-1.82 (m, 3H) 1.95 (t, J=10.86 Hz, 2H) 2.15 (s, 3H) 2.27 (s, 3H) 2.59 (s, 3H) 2.74 (d, J=11.12 Hz, 2H) 3.75 (m, 1H) 6.98 (s, 1 H) 7.27 (d, J=7.58 Hz, 1H) 7.49 (t, J=7.96 Hz, 1H) 7.69 (d, J=2.02 Hz, 2H) 7.91 (s, 1H) 8.25-8.30 (m, 2H) 10.37 (s, 1H) 11.92 (br. s., 1H); [M+H] calc'd for C30H33N5O2, 496.3; found, 496.4.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1.[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:8][CH:7]=1
Reactant: O=Cc1ccc(OCCCCl)cc1
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: O
Product: ClCCCOc1ccc(CN2CCCCC2)cc1
Reaction time: 16 h

Procedure:
A solution of the product of Example 11 (5.0 g), piperidine (3.1 mL), and acetic acid (2.0 mL) in DCE (100 mL) was treated with sodium triacetoxyborohydride (9.3 g). After 16 h, the resulting mixture was diluted with water (100 mL) and extracted with DCM (3×50 mL). The combined organic phases were dried (magnesium sulfate) and evaporated, giving the title compound as an amber oil (5.3 g).
Reaction SMILES: [C:1]([CH:4]1[C:9](=O)[CH2:8][CH2:7][CH2:6][C:5]1=[O:11])(=O)[CH3:2].[CH2:12]([NH:14][NH2:15])[CH3:13]>>[CH2:12]([N:14]1[C:9]2[CH2:8][CH2:7][CH2:6][C:5](=[O:11])[C:4]=2[C:1]([CH3:2])=[N:15]1)[CH3:13]
Reactant: CCNN
Reactant: CC(=O)C1C(=O)CCCC1=O
Product: CCn1nc(C)c2c1CCCC2=O

Procedure:
Prepared analogously to Example 1 starting from 2-acetyl-cyclohexane-1,3-dione and ethylhydrazine.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:15])=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][C:7]([CH3:13])([CH3:12])[C:6]=2[CH:14]=1.[C:16]1([S:22]([CH2:24][CH2:25][CH2:26][CH2:27]Br)=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:16]1([S:22]([CH2:24][CH2:25][CH2:26][CH2:27][O:1][C:2]2[C:3]([CH3:15])=[CH:4][C:5]3[NH:10][C:9](=[O:11])[O:8][C:7]([CH3:12])([CH3:13])[C:6]=3[CH:14]=2)=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=S(CCCCBr)c1ccccc1
Reactant: Cc1cc2c(cc1O)C(C)(C)OC(=O)N2
Product: Cc1cc2c(cc1OCCCCS(=O)c1ccccc1)C(C)(C)OC(=O)N2

Procedure:
Prepared analogously to Example 4 from 6-hydroxy-4,4,7-trimethyl-4H-3,1-benzoxazin-2-one and 4-phenylsulfinylbutylbromide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH:9]([C:16]2[C:24]3[C:19](=[C:20]([CH2:25][S:26][CH3:27])[CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)[CH2:10][C:11](OCC)=[O:12])=[C:4]([F:28])[CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.C(#N)C>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([F:28])[C:5]([CH:9]([C:16]2[C:24]3[C:19](=[C:20]([CH2:25][S:26][CH3:27])[CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)[CH2:10][CH2:11][OH:12])=[C:6]([F:8])[CH:7]=1
Reactant: CCOC(=O)CC(c1c(F)cc(Cl)cc1F)c1c[nH]c2c(CSC)cccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CC#N
Solvent: C1CCOC1
Solvent: O
Product: CSCc1cccc2c(C(CCO)c3c(F)cc(Cl)cc3F)c[nH]c12
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A solution of 1.09 g (2.56 mmol) of the compound from Example 102A in 6 ml of tetrahydrofuran was added dropwise to 9.0 ml (9.0 mmol) of a 1N solution of lithium aluminum hydride in tetrahydrofuran in 12 ml of tetrahydrofuran at RT under argon. The mixture was stirred at 60° C. for 1 h and then water and acetonitrile were added, and the suspension was filtered through kieselguhr. The solvents were removed in a rotary evaporator, and the residue was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 0.88 g (90% of theory) of the title compound was obtained.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([CH2:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:7][CH:6]=1)=[O:4].O.[OH-].[Li+]>C1COCC1.O>[CH3:17][C:16]1[O:15][N:14]=[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[C:12]=1[CH2:11][CH2:10][C:8]1[S:9][C:5]([C:3]([OH:4])=[O:2])=[CH:6][N:7]=1
Reactant: COC(=O)c1cnc(CCc2c(-c3ccccn3)noc2C)s1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1onc(-c2ccccn2)c1CCc1ncc(C(=O)O)s1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 96 %

Procedure:
To a suspension of 2-[2-(5-methyl-3-pyridin-2-yl-isoxazol-4-yl)-ethyl]-thiazole-5-carboxylic acid methyl ester (835 mg, 2.54 mmol) in THF (8 mL) was added a solution of lithium hydroxide monohydrate (165 mg, 3.9 mmol) in water (8 mL) and the resulting mixture stirred at room temperature for 45 min. The mixture was then evaporated to half volume and then acidified to pH 1 with HCl (1N) and cooled to 0° C. for 15 min. A solid precipitated and was filtered off and dried to afford the title compound (769 mg, 96%) which was obtained as an off white solid. MS: m/e=314.1 [M−H]−.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([N:8]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:9]([C@H:11]1[CH2:16][O:15][CH2:14][CH2:13][N:12]1[C:17](OC(C)(C)C)=[O:18])=[O:10])C(OC)=O.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+].C1CCCCC1.C(OCC)(=O)C>C(Cl)Cl.CO>[OH:1][CH2:2][C@@H:3]1[C:17](=[O:18])[N:12]2[C@H:11]([CH2:16][O:15][CH2:14][CH2:13]2)[C:9](=[O:10])[N:8]1[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)[C@@H](CO)N(Cc1ccccc1)C(=O)[C@H]1COCCN1C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: O=C1[C@@H](CO)N(Cc2ccccc2)C(=O)[C@H]2COCCN12
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.6 %

Procedure:
To a stirred solution of 1,1-dimethylethyl (3R)-3-{[[(1R)-1-(hydroxymethyl)-2-(methyloxy)-2-oxoethyl](phenylmethyl)amino]carbonyl}-4-morpholinecarboxylate (D103, 38.7 g, 0.092 moles) in 400 ml of DCM at room temperature, trifluoroacetic acid (68.3 ml, 0.92 moles) was slowly added. The resulting orange solution was stirred at room temperature overnight. It was then cooled by an ice-water bath and brought to pH=7-8 by adding sodium hydrogen carbonate (sat. solution, 250 ml and as solid). Phases were separated and the aqueous layer was extracted with DCM (3×300 ml). The combined organic extracts were dried (Na2SO4), concentrated under vacuum to afford a residue, which was dissolved in 270 ml of methanol and heated to 56-58° C. for 2 hours. The mixture was then allowed to cool down to room temperature and the solvent was removed under vacuum to afford a solid residue, which was treated with 100 ml of a mixture cyclohexane/EtOAc 8/2. The resulting suspension was stirred at room temperature for 30-40 minutes and then the solid was filtered off and collected to afford the title compound (1 8.7 g) as white solid.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]([O:11][C:12]([NH:14][C@@H:15]1[CH2:19][CH2:18][CH2:17][C@@H:16]1[C:20](OC)=[O:21])=[O:13])([CH3:10])([CH3:9])[CH3:8].O>C1COCC1>[C:7]([O:11][C:12](=[O:13])[NH:14][C@@H:15]1[CH2:19][CH2:18][CH2:17][C@@H:16]1[CH2:20][OH:21])([CH3:10])([CH3:8])[CH3:9]
Reactant: COC(=O)[C@H]1CCC[C@H]1NC(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1CCC[C@@H]1CO
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75.1 %

Procedure:
To a well stirred suspension of 0.94 g (24.7 mmol, 2 equiv.) of LiAlH4 in 30 ml of THF at 0° C. was added dropwise at 0° C. a solution of (1S,2R)-methyl 2-(tert-butoxycarbonylamino)-cyclopentanecarboxylate (CAS: 592503-55-4) (3.0 g, 12.3 mmol) (gas evolution, lightly exotherm). After 15 minutes at 0° C. the reaction mixture was allowed to warm up to room temperature and was stirred for 2 h. The mixture was cooled to 0° C. and water was added dropwise. The precipitated inorganic salts were filtered through Celite and were washed with ethyl acetate. The filtrate was evaporated and the residue was purified by column chromatography on silica gel eluting with a 0% to 50% ethyl acetate in heptane gradient to yield 1.99 g (75%) of the title compound as a crystalline white solid which was directly used in the next step.
Reaction SMILES: CN(C)C(=O)C.[NH2:7][C:8]1[CH:9]=[C:10]([CH:19]=[CH:20][C:21]=1[NH2:22])[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12].S([O-])(O)=O.[Na+].[CH:28]([C:30]1[O:34][C:33]([C:35]([OH:37])=[O:36])=[CH:32][CH:31]=1)=O>O>[C:11]([C:10]1[CH:19]=[CH:20][C:21]2[N:22]=[C:28]([C:30]3[O:34][C:33]([C:35]([OH:37])=[O:36])=[CH:32][CH:31]=3)[NH:7][C:8]=2[CH:9]=1)(=[O:12])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1N
Reactant: O=Cc1ccc(C(=O)O)o1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=C(c1ccccc1)c1ccc2nc(-c3ccc(C(=O)O)o3)[nH]c2c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 63.2 %

Procedure:
N,N-Dimethylacetamide (5 ml) was heated to 130° C., and 3,4-diaminobenzophenone (63 mg, 0.30 mmol) and sodium hydrogensulfite (37 mg, 0.36 mmol) were added and the mixture was stirred for 5 minutes. 5-Formyl-furan-2-carboxylic acid (50 mg, 0.36 mmol) was added and stirred at 130° C. for 1.5 hours. The reaction mixture was allowed to cool to room temperature with stirring, and after addition of water to reaction mixture, precipitate was collected by filtration to afford 5-(5-benzoylbenzimidazol-2-yl)-furan-2-carboxylic acid (63 mg, 64%) as a pale yellow solid.
Reaction SMILES: [Cl-].[NH4+].[CH2:3]([O:5][C:6](=[O:20])/[CH:7]=[CH:8]/[C:9]1[CH:10]=[N:11][C:12]([N+:17]([O-])=O)=[C:13]([O:15][CH3:16])[CH:14]=1)[CH3:4]>C(O)C.O.[Fe]>[CH2:3]([O:5][C:6](=[O:20])/[CH:7]=[CH:8]/[C:9]1[CH:10]=[N:11][C:12]([NH2:17])=[C:13]([O:15][CH3:16])[CH:14]=1)[CH3:4]
Reactant: CCOC(=O)/C=C/c1cnc([N+](=O)[O-])c(OC)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)/C=C/c1cnc(N)c(OC)c1
Temperature: 25 °C
Yield: 73 %

Procedure:
Iron (1.6 g) and ammonium chloride (3 g) were added to the suspension of (E)-3-(5-methoxy-6-nitropyridin-3-yl)acrylic acid ethyl ester (787 mg) in ethanol (40 mL) and water (8 mL) obtained above, and the reaction solution was heated to reflux for 1 hour. After the reaction solution was allowed to be cooled to room temperature, deposited substance was filtered by celite. Ethyl acetate and saturated sodium bicarbonate water were added to the filtrate, and the organic layer was partitioned. After drying the obtained organic layer with anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate 2:1), and 506 mg (66%) (E)-3-(6-amino-5-methoxypyridin-3-yl)acrylic acid ethyl ester was obtained. The physical properties of the compound are as follows.
Reaction SMILES: [CH3:1][N:2]1[C:6]([N:7]2[C:11]([C:12](OCC)=[O:13])=[C:10]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:9]=[N:8]2)=[C:5]([N+:22]([O-])=O)[C:4]([CH3:25])=[N:3]1.[H][H]>[C].[Pd].C(O)(=O)C>[OH:13][C:12]1[C:11]2[N:7]([N:8]=[CH:9][C:10]=2[C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:6]2[N:2]([CH3:1])[N:3]=[C:4]([CH3:25])[C:5]=2[N:22]=1
Reactant: [H][H]
Reactant: CCOC(=O)c1cnn(-c2c([N+](=O)[O-])c(C)nn2C)c1C(=O)OCC
Agent: [Pd]
Solvent: CC(=O)O
Product: CCOC(=O)c1cnn2c1c(O)nc1c(C)nn(C)c12

Procedure:
50 gms. of 1-(1,3-dimethyl-4-nitro-1H-pyrazol-5-yl)-1H-pyrazole-4,5-dicarboxylic acid, diethyl ester, are hydrogenated with 0.2 gms. of palladium-carbon in 100 ml. of glacial acetic acid at 60° until the uptake of hydrogen stops. On cooling, the product, 5-hydroxy-1,3-dimethyl-1H-dipyrazolo[1,5-a:4',3'-e]pyrazine-6-carboxylic acid, ethyl ester, crystallizes in the form of white filamentous needles. On evaporating the solvent, the product is recrystallized from dimethylformamide, yield 22 gms. of white needles, m.p. 246°-247°.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C:9]2=[N:8][C:7]=1[N:15]([CH2:25][CH2:26][CH2:27][CH3:28])[C:16](=[O:24])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=1)=[O:5])C>CO.O1CCOCC1.O>[CH2:25]([N:15]([C:16](=[O:24])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=1)[C:7]1[N:8]=[C:9]2[CH2:14][CH2:13][CH2:12][CH2:11][N:10]2[C:6]=1[C:4]([OH:5])=[O:3])[CH2:26][CH2:27][CH3:28]
Reactant: CCCCN(C(=O)c1cccc(Cl)c1)c1nc2n(c1C(=O)OCC)CCCC2
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: CCCCN(C(=O)c1cccc(Cl)c1)c1nc2n(c1C(=O)O)CCCC2
Temperature: 25 °C

Procedure:
2-[butyl-(3-chloro-benzoyl)-amino]-5,6,7,8-tetrahydro-imidazo[1,2-a]pyridine-3-carboxylic acid ethyl ester (11.7 mmol) was dissolved in a solution of 190 mL MeOH/dioxan/4 M NaOH in water in a ratio of 15/4/1 and the solution was stirred over night at room temperature. The solvent was removed under vacuum, EtOAc (700 mL) was added thereto and the organic phase was washed with 0.5 M KHSO4 in water (700 mL). The aqueous phase was extracted with EtOAc (300 mL) and the combined organic phases were washed with saturated aqueous NaCl solution (700 mL) and dried over sodium sulphate, and the solvent was removed under vacuum. 4.13 g (94% over two stages) of the desired product 2-[butyl-(3-chloro-benzoyl)-amino]-5,6,7,8-tetrahydro-imidazo[1,2-a]pyridine-3-carboxylic acid were obtained.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([OH:21])[CH:5]=[C:6]([I:20])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15]C)=[C:11]([CH:17]([CH3:19])[CH3:18])[CH:10]=1.B(Br)(Br)Br>ClCCl>[I:1][C:2]1[CH:3]=[C:4]([OH:21])[CH:5]=[C:6]([I:20])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH:17]([CH3:19])[CH3:18])[CH:10]=1
Reactant: COc1ccc(Oc2c(I)cc(O)cc2I)cc1C(C)C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)c1cc(Oc2c(I)cc(O)cc2I)ccc1O
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 66 %

Procedure:
To a stirred solution of 3,5-diiodo-4-(4′-methoxy-3′-iso-propylphenoxy)phenol (0.28 g, 0.55 mmol) in dichloromethane (17.0 mL) at −78° C. was added BBr3 (13.1 mL, 13.1 mmol, 1.0 M solution in CH2Cl2). The reaction mixture was stirred at −78° C. for 10 min, allowed to warm to room temperature and stirred for 16 h. The reaction mixture was poured into ice and extracted with CH2Cl2 (20 mL×2). The organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with acetone-hexanes (3:7) to afford 3,5-diiodo-4-(4′-hydroxy-3′-iso-propylphenoxy)phenol as an off-white solid (0.18 g, 66%): 1H NMR (300 MHz, DMSO-d6): δ 9.95 (s, 1H), 8.91 (s, 1H), 7.27 (s, 2H), 6.62 (d, J=9.0 Hz, 1H), 6.56 (d, J=3.0 Hz, 1H), 6.18 (m, 1H), 3.72 (s, 3H), 3.14 (m, 1H), 1.10 (d, J=6.0 Hz, 6H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=hexanes-acetone (7:3); Rf=0.28.
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:29])=[C:16]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][CH2:11]2)=[CH:6][CH:5]=1)[CH3:3].C1COCC1.C(OC(C)C)(C)C>>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:29])=[C:16]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][CH2:11]2)=[CH:6][CH:5]=1)(=[O:1])[CH3:3]
Reactant: Cc1c(C)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)O)cc1)CO2
Solvent: C1CCOC1
Solvent: CC(C)OC(C)C
Product: CC(=O)c1ccc(C2COc3c(C)c(C)c(NC(=O)CC(C)(C)C)c(C)c32)cc1
Yield: 65 %

Procedure:
Using N-(3-(4-(1-hydroxyethyl)phenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 175, the title compound was synthesized in the same manner as in Example 32. Yield: 65%. Melting point: 181-182° C. (THF-diisopropyl ether).