Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][O:22][C:23]([C:25]2[CH:26]([C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([N+:43]([O-:45])=[O:44])[CH:38]=3)[C:27]([C:33]([O:35][CH3:36])=[O:34])=[C:28](O)[NH:29][C:30]=2[CH3:31])=[O:24])[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:48])=O>>[CH:1]([N:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][O:22][C:23]([C:25]2[CH:26]([C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([N+:43]([O-:45])=[O:44])[CH:38]=3)[C:27]([C:33]([O:35][CH3:36])=[O:34])=[C:28]([Cl:48])[NH:29][C:30]=2[CH3:31])=[O:24])[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)C1=C(O)NC(C)=C(C(=O)OCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)C1c1cccc([N+](=O)[O-])c1
Product: COC(=O)C1=C(Cl)NC(C)=C(C(=O)OCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)C1c1cccc([N+](=O)[O-])c1
Yield: 57.2 %

Procedure:
5-[2-(4-Benzhydrylpiperazin-1-yl)ethyl]oxycarbonyl-2-hydroxy-3-methoxycarbonyl-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine (390 mg) was dissolved in phosphorus oxychloride (5 ml) and the mixture was heated under reflux for 3 hours and 10 minutes. After excess phosphorus oxychloride had been distilled off under reduced pressure, the reaction mixture was diluted with saturated potassium carbonate and subjected to extraction with chloroform. The extract was distilled off and the residue was subjected to silica gel column chromatography (elution solvent: 1% chloroform/methanol), thereby obtaining crude crystals. This crude crystals were recrystallized from a solution of chloroform/isopropylether/hexane to yield 210 mg (57.2%) of the desired compound.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[F:16][C:17]([F:22])([F:21])[CH2:18][CH2:19]Br.C([O-])([O-])=O.[K+].[K+]>CC#N.CCOC(C)=O>[I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][N:11]([CH2:19][CH2:18][C:17]([F:22])([F:21])[F:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: N#CC1(c2ccc(I)cc2)CCNCC1
Reactant: FC(F)(F)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: N#CC1(c2ccc(I)cc2)CCN(CCC(F)(F)F)CC1
Temperature: 60 °C
Yield: 97.9 %

Procedure:
To a solution of the crude 4-(4-iodo-phenyl)-piperidine-4-carbonitrile (0.60 g, ˜1.9 mmol) in CH3CN (6 mL) was added (3,3,3-trifluoro)-propyl bromide (1.02 mL, 9.6 mmol, 5 eq.) and K2CO3 (1.33 g, 9.6 mmol, 5 eq.) and the resulting mixture was stirred and heated to 60° C. for 16 h. The reaction was cooled to room temperature, diluted with EtOAc (20 mL) and washed with H2O (25 mL) and saturated brine (2×25 mL). The organic phase was dried over anhydrous Na2SO4, filtered and concentrated by rotary evaporation to give the crude 4-(4-iodo-phenyl)-1-(3,3,3-trifluoro-propyl)-piperidine-4-carbonitrile as a red solid (0.761 g, 1.86 mmol, 98%). 1H NMR (300 MHz, CDCl3): δ 7.83 (dd, 2H), 7.33 (dd, 2H), 3.09 (d, 2H), 2.82 (dd, 2H), 2.66 (td, 2H), 2.45 (m, 2H), 2.18 (m, 4H); MS (ESI): 409.1/410.2 (M +1).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:9]=[CH:10][C:3]=12.[CH3:21][N:22](C)C(=O)C>[C-]#N.[Zn+2].[C-]#N.[Zn].Cl[Pd]Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[C:21]([C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:9]=[CH:10][C:3]=12)#[N:22]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)ccnc32)cc1
Reactant: CC(=O)N(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [C-]#N
Product: Cc1ccc(S(=O)(=O)n2ccc3c(C#N)ccnc32)cc1
Temperature: 140 °C

Procedure:
To a solution of 10 g of 4-chloro-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine in 200 cm3 of N,N-dimethylacetamide, under an inert atmosphere of argon, are added 6.9 g of zinc cyanide and 1.07 g of zinc powder. After stirring for 45 minutes at a temperature in the region of 20° C., 2.4 g of PdCl2, dppf are added. The reaction medium is heated at a temperature in the region of 140° C. for 1 hour 30 minutes. After cooling, the reaction medium is filtered through Celite and then rinsed with dichloromethane. 150 cm3 of water are added to the filtrate. After separation of the phases by settling, the organic phase is dried over sodium sulfate, filtered and then concentrated under reduced pressure. After purification by flash chromatography on a column (SiO2, cyclohexane/ethyl acetate, 75/25 by volume as eluent, Ar), 8.57 g of 4-cyano-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine are obtained with the following characteristics:
Reaction SMILES: O[CH:2]([CH3:19])[CH2:3][NH:4][C:5]([C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]=1[O:17][CH3:18])=[O:6].S(Cl)(Cl)=O>CCOCC>[CH3:18][O:17][C:8]1[CH:9]=[CH:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]=1[C:5]1[O:6][CH:2]([CH3:19])[CH2:3][N:4]=1
Reactant: COc1ccc2ccccc2c1C(=O)NCC(C)O
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Product: COc1ccc2ccccc2c1C1=NCC(C)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
This N-(2-hydroxy-1-propyl) 2-methoxy-1-naphthamide (4.00 g, 15.4 mmol) was added in portions to ice-water cooled thionyl chloride (7.4 g, 62 mmol). This was then stirred at room temperature and after 1 hour the slurry which had formed was diluted with ether and collected by filtration, then was partitioned between ether and aqueous sodium hydroxide. This ether solution was dried (MgSO4) and concentrated to afford 2-(2-methoxy-1-naphthyl)-5-methyloxazoline as an oil.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:16]2[NH:20][N:19]=[C:18]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[CH3:51][S:52]([C:55]1[CH:67]=[CH:66][CH:65]=[CH:64][C:56]=1[O:57][CH:58]1[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]1)(=[O:54])=[O:53]>CN(C=O)C.O>[CH3:51][S:52]([C:55]1[CH:67]=[CH:66][CH:65]=[CH:64][C:56]=1[O:57][CH:58]1[CH2:59][CH2:60][N:61]([C:25](=[O:27])[CH2:24][NH:23][C:21]([C:18]2[CH:17]=[C:16]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:20][N:19]=2)=[O:22])[CH2:62][CH2:63]1)(=[O:54])=[O:53]
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Reactant: CS(=O)(=O)c1ccccc1OC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CS(=O)(=O)c1ccccc1OC1CCN(C(=O)CNC(=O)c2cc(-c3ccccc3)[nH]n2)CC1
Reaction time: 8 h
Yield: 35.6 %

Procedure:
DIPEA (63 mg, 0.48 mmol) was added to a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (40 mg, 0.163 mmol) in DMF (1 mL) followed by HOBt (26 mg, 0.195 mmol) and EDCI.HCl (37 mg, 0.195 mmol). After 2 minutes 4-(2-methanesulfonyl-phenoxy)-piperidine hydrochloride (57 mg, 0.195 mmol) was added to the reaction mixture and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with cold water and extracted with ethyl acetate. The ethyl acetate was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure The residue was purified by preparative HPLC to afford 28 mg (26.66% Yield) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(2-methanesulfonyl-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 483, 98.59%. 1H NMR (300 MHz, CDCl3): δ 8.8 (bs, 1H), 8.0 (m, 1H), 7.7-7.6 (d, 2H), 7.6-7.5 (m, 1H), 7.5-7.3 (m, 3H), 7.2-7.0 (m, 3H), 5.1-4.9 (m, 3H), 4.6-4.5 (dd, 1H), 4.2-4.1 (m, 2H), 3.9-3.4 (m, 3H), 3.2 (s, 3H), 2.1-1.9 (m, 4H).
Reaction SMILES: [CH3:1][C@@H:2]([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:3][C@H:4]([O:22]C1CCCCO1)/[CH:5]=[CH:6]/[C@H:7]1[CH2:11][CH2:10][C:9](=[O:12])[C@@H:8]1[CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]/[C:19]([OH:21])=[O:20].C(O)(=O)C.O1CCCC1.O>C(OCC)(=O)C>[OH:22][C@@H:4]([CH2:3][C@@H:2]([CH3:1])[CH2:29][CH2:30][CH2:31][CH3:32])/[CH:5]=[CH:6]/[C@H:7]1[CH2:11][CH2:10][C:9](=[O:12])[C@@H:8]1[CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]/[C:19]([OH:21])=[O:20]
Reactant: CCCC[C@H](C)C[C@@H](/C=C/[C@H]1CCC(=O)[C@@H]1CCCC/C=C/C(=O)O)OC1CCCCO1
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCCC[C@H](C)C[C@H](O)/C=C/[C@H]1CCC(=O)[C@@H]1CCCC/C=C/C(=O)O
Temperature: 50 °C
Reaction time: 0.83 h
Yield: 85.6 %

Procedure:
To the compound 23 (171 mg) was added acetic acid/tetrahydrofuran/water (65:10:35) (4.00 mL) and the solution was stirred at 50° C. for 50 minutes. The reaction solution was diluted with ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:1), to give the title compound (119 mg) having the following physical data.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[I:9][C:10]1[CH:19]=[CH:18]C2C(=CC=CC=2)N=1.N1C2C(=CC=CC=2)C=CC=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:6]([C:10]([I:9])=[CH:19][CH:18]=[N:5]2)=[CH:7][CH:8]=1
Reactant: Ic1ccc2ccccc2n1
Reactant: Nc1cccc(Br)c1
Solvent: c1ccc2ncccc2c1
Product: Brc1ccc2c(I)ccnc2c1

Procedure:
The 7-bromo-4-iodoquinoline 40a is synthesized from 3-bromoaniline using the same protocols as those described for the preparation of iodoquinoline fragment 1i in Example 1.
Reaction SMILES: N1C=CC=CC=1.[C:7]([O:11][C:12]([N:14]1[CH2:18][CH2:17][CH:16](O)[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].C(OC(=O)C)(=[O:22])C.C(OCC)(=O)C>C(Cl)Cl.[O-2].[Cr+6].[O-2].[O-2]>[C:7]([O:11][C:12]([N:14]1[CH2:18][CH2:17][CH2:16][C:15]1=[O:22])=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Agent: [Cr+6]
Agent: [O-2]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Chromium (vi) oxide (800 mg, 8.0 mmol) was added to pyridine (1.6 mL) in CH2Cl2 (10 mL) and the resulting solution was stirred for 15 min at room temperature. A solution of tert.butyl-3-hydroxy-1-pyrrolidinecarboxylate (374.5 mg, 2.0 mmol) in CH2Cl2 (5 mL) was added, immediately followed by acetic anhydride and the reaction mixture kept at room temperature for 15 min. After addition of ethyl acetate, decanted and filtered through a short column of silica gel. The filtrate was concentrated to give the subtitled product (193 mg) and was used directly in the next step.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([NH:12][C:13]1[C:18]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25]O)=[CH:21][CH:20]=2)=[N:17][CH:16]=[CH:15][N:14]=1)(=[O:11])=[O:10].S(Cl)([Cl:31])=O>>[Cl:31][CH2:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]2[C:13]([NH:12][S:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:2]([F:28])([F:27])[F:1])(=[O:11])=[O:10])=[N:14][CH:15]=[CH:16][N:17]=2)=[CH:20][CH:21]=1
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CO)cc1)c1ccccc1C(F)(F)F
Reactant: O=S(Cl)Cl
Product: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1ccccc1C(F)(F)F
Yield: 96 %

Procedure:
Following the general method as outlined for Intermediate 8, starting from 2-trifluoromethyl-N-{3-[4-(hydroxymethyl)phenyl]pyrazin-2-yl}benzene sulfonamide and thionyl chloride, the title compound was isolated, after evaporation and recrystallization, as a white solid in 96% yield (97% purity by HPLC).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[NH2:14][C:15]1[C:23]([C:24](=[O:32])[NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](O)=[O:18].O>N1C=CC=CC=1>[O:18]=[C:17]1[O:6][C:5]([C:4]2[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=2[C:2]([F:13])([F:12])[F:1])=[N:14][C:15]2[C:23]([C:24]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)=[O:32])=[CH:22][CH:21]=[CH:20][C:16]1=2
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: Nc1c(C(=O)O)cccc1C(=O)Nc1ccccn1
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1ccccn1)c1cccc2c(=O)oc(-c3ccccc3C(F)(F)F)nc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 37.7 %

Procedure:
2-(trifluoromethyl)benzoyl chloride 24 (180 mg, 0.88 mmol) was added to a suspension of 2-amino-3-(pyridin-2-ylcarbamoyl)benzoic acid 23 (150 mg, 0.58 mmol) in pyridine (8 mL). The reaction mixture was stirred at room temperature for 12 h then poured into ice cooled H2O. The resulting precipitate was collected by filtration, rinsed with H2O, and dried under vacuum to give 25 (90 mg, 38% yield) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6].[Br:10][CH2:11][CH2:12]Br.C(=O)([O-])[O-].[Na+].[Na+]>O>[Br:10][CH2:11][CH2:12][NH:6][CH2:5][C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([F:1])[CH:3]=1
Reactant: BrCCBr
Reactant: NCc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Fc1cccc(CNCCBr)c1

Procedure:
Combine 3-fluorobenzylamine (5.0 g, 0.0400 mol), fused sodium acetate (3.28 g, 0.0400 mol) and 1,2-dibromoethane (7.51 g, 0.0400 mol) and reflux for several hours. Pour the mixture into water and add sodium carbonate to create a basic pH. Remove the unreacted 1,2-dibromoethane by distillation. Extract the left-over residue with ether and evaporate to obtain the final, desired compound. The compound can form the hydrochloride salt.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([F:37])=[C:13]([NH:15][C:16]([NH:18][C:19]3[N:23]([C:24]4[CH:25]=[C:26]5[C:31](=[CH:32][CH:33]=4)[N:30]=[CH:29][CH:28]=[CH:27]5)[N:22]=[C:21]([CH:34]([CH3:36])[CH3:35])[CH:20]=3)=[O:17])[CH:14]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:44](OC(=O)C)(=[O:46])[CH3:45]>C(Cl)Cl>[C:44]([NH:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([F:37])=[C:13]([NH:15][C:16]([NH:18][C:19]3[N:23]([C:24]4[CH:25]=[C:26]5[C:31](=[CH:32][CH:33]=4)[N:30]=[CH:29][CH:28]=[CH:27]5)[N:22]=[C:21]([CH:34]([CH3:35])[CH3:36])[CH:20]=3)=[O:17])[CH:14]=2)=[CH:4][CH:3]=1)(=[O:46])[CH3:45]
Reactant: CC(C)c1cc(NC(=O)Nc2cc(Oc3ccc(N)nc3)ccc2F)n(-c2ccc3ncccc3c2)n1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1ccc(Oc2ccc(F)c(NC(=O)Nc3cc(C(C)C)nn3-c3ccc4ncccc4c3)c2)cn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 43.8 %

Procedure:
1-(5-(6-aminopyridin-3-yloxy)-2-fluorophenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea (0.0495 g, 0.099 mmol) was dissolved in DCM (1.0 mL), to which pyridine (0.49 mL, 6.0 mmol) and acetic anhydride (0.066 mL, 0.65 mmol) were added. The reaction mixture was stirred at RT for 12 h. The completed reaction was quenched with 2M NaHCO3 (12 mL) and extracted with EtOAc (25 mL). The organic layer was washed with H2O (15 mL) and brine (10 mL), dried (MgSO4), concentrated in vacuo and purified by chromatography to afford 1-(5-(6-acetamidopyridin-3-yloxy)-2-fluorophenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea (0.0234 g, 44% yield) as a yellow foam. It was converted to corresponding mesylate salt by reacting with MsOH (1.0 eq.). 1H NMR (400 MHz, DMSO-d6) δ 10.54 (s, 1H), 9.09 (s, 1H), 9.07-9.04 (m, 2H), 8.65 (d, J=8.0 Hz, 1H), 8.25 (d, J=2.0 Hz, 1H), 8.21 (d, J=8.8 Hz, 1H), 8.11-8.07 (m, 2H), 8.02 (dd, J=8.8, 2.4 Hz, 1H), 7.85 (m, 1H), 7.75 (m, 1H), 4.48 (dd, J=8.8, 3.2 Hz, 1H), 7.24 (m, 1H), 6.67 (m, 1H), 6.40 (s, 1H), 2.92 (m, 1H), 2.31 (s, 3H), 2.08 (s, 3H), 1.24 (d, J=7.2 Hz, 6H); MS (ESI) m/z: 540.0 (M+H+).
Reaction SMILES: Br[CH2:2][C:3]1[N:8]=[C:7]([NH:9]C(=O)C(C)(C)C)[CH:6]=[CH:5][CH:4]=1.C([O-])([O-])=[O:17].[K+].[K+]>OS(O)(=O)=O>[NH2:9][C:7]1[N:8]=[C:3]([CH2:2][OH:17])[CH:4]=[CH:5][CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)C(=O)Nc1cccc(CBr)n1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Nc1cccc(CO)n1
Temperature: 25 °C
Yield: 71 %

Procedure:
The product of Example 2 (24.89 g, 96 mmol) and 10% (v/v) H2SO4 (100 mL) were combined in a 250 mL flask. The reaction was heated to reflux for 8 h and then cooled to room temperature. The reaction was made basic with aq K2CO3 and extracted with EtOAc. The extracts were dried (MgSO4), decolorized with activated charcoal, and filtered. Removal of all solvent in vacuo gave 8.49 g (71%) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]([O-:13])=[O:12])[CH:10]=[C:6]2[N:5]=[C:4]([CH3:14])[C:3]=1[CH:15]([OH:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17].[CH3:22][C:23](OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]([O:13][CH2:22][CH3:23])=[O:12])[CH:10]=[C:6]2[N:5]=[C:4]([CH3:14])[C:3]=1[C:15](=[O:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C(O)c1c(C)nc2cc(C(=O)[O-])nn2c1Cl
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=O)c1c(C)nc2cc(C(=O)OCC)nn2c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.1 %

Procedure:
To a mixture of 7-chloro-6-(2-ethoxy-1-hydroxy-2-oxoethyl)-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (5.9 g 13.81 mmol) in CH2Cl2 (100 mL) was added Dess-Martin (5.86 g, 13.81 mmol) and the resulting mixture was stirred at rt for 1 h. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with sat. aq. NaHCO3 solution (30 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (5-70% EtOAc/hexane) to afford the desired ethyl 7-chloro-6-(2-ethoxy-2-oxoacetyl)-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (3.5 g, 9.27 mmol, 67.1% yield) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 7.24 (s, 1H), 4.56-4.43 (m, 4H), 2.63 (s, 3H), 1.50-1.41 (m, 6H). LCMS (M+1)=340.13.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:12]=[C:11]([O:13][CH:14]([CH3:16])[CH3:15])[CH:10]=[C:6]([C:7]([OH:9])=O)[CH:5]=1.[CH3:18][NH:19][CH2:20][CH2:21][CH3:22].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>ClCCl>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:12]=[C:11]([O:13][CH:14]([CH3:16])[CH3:15])[CH:10]=[C:6]([C:7]([N:19]([CH3:18])[CH2:20][CH2:21][CH3:22])=[O:9])[CH:5]=1
Reactant: COC(=O)c1cc(OC(C)C)cc(C(=O)O)c1
Reactant: CCCNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CCCN(C)C(=O)c1cc(OC(C)C)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Mix 5-isopropoxy-isophthalic acid monomethyl ester (3 g, 12.7 mmol), methyl propyl amine (1.3 mL, 12.7 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (2.4 g, 12.7 mmol), and 1-hydroxybenzotriazole hydrate (1.7 g, 12.7 mmol) in dichloromethane (50 mL) and stir overnight at room temperature. Dilute with dichloromethane (50 mL), wash with water, 5% aqueous ammonium chloride solution, 5% aqueous sodium bicarbonate solution, dry (sodium sulfate) and concentrate to give the title product which is used directly without further purification.
Reaction SMILES: [CH:1]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=[C:3]([I:10])[CH:2]=1.S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+].[CH2:22](O)[CH3:23]>>[CH2:22]([O:8][C:7](=[O:9])[C:6]1[CH:5]=[CH:4][C:3]([I:10])=[CH:2][CH:1]=1)[CH3:23]
Reactant: CCO
Reactant: O=C(O)c1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)c1ccc(I)cc1
Temperature: 0 °C

Procedure:
A solution of 100 grams (0.403 mole) of p-iodobenzoic acid in 600 ml. of abs. ethanol containing 30 ml. of concentrated sulfuric acid is refluxed for 5 days. The cooled solution is poured over 350 grams of ice and is neutralized with saturated sodium carbonate solution. The oil that separates is extracted with six 150 ml. portions of ether. These ether extracts are combined, washed with water, dried over magnesium sulfate, and filtered. Evaporation of the ether gives 131.3 grams of ethyl-4-iodobenzoate as a chromatographically pure, clear, light oil.
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][OH:32])=[CH:27][CH:26]=1>CN(C=O)C.CCOC(C)=O.O.CO>[OH:32][CH2:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][CH2:23][N:12]2[CH:13]=[CH:14][C:9]([CH2:1][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)=[CH:10][C:11]2=[O:15])=[CH:26][CH:27]=1
Reactant: O=c1cc(CCc2ccccc2)cc[nH]1
Reactant: OCc1ccc(CCI)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CO
Product: O=c1cc(CCc2ccccc2)ccn1CCc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 200 mg (1.01 mmol) 4-phenethyl-1H-pyridin-2-one in 1.0 mL DMF is added at 0° C. 650 mg (2.01 mmol) cesium carbonate and the mixture is stirred 15 min at 0° C. Then 0.53 g (2.01 mmol) [4-(2-iodo-ethyl)-phenyl]-methanol (preparation 1b) is added, the mixture is warmed to RT and is stirred overnight at RT. The reaction mixture is diluted with EtOAc, water and a few drops of MeOH, the layers are separated and the organic phase is washed with water, dried over MgSO4, filtered and the solvent is evaporated. The residue is dissolved in MeOH/DMF and is purified via HPLC chromatography (Zorbax stable bond, C18; water (0.15% formic acid)/acetonitrile 95:5 to 10:90).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[C:11]([C:17]([F:20])([F:19])[F:18])[C:10]=1[CH3:21])=O)(=[O:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C[Si]([N:59]=[N+:60]=[N-:61])(C)C>O1CCCC1>[C:1]([O:4][CH2:5][C:6]1[N:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[C:11]([C:17]([F:20])([F:19])[F:18])[C:10]=2[CH3:21])[N:61]=[N:60][N:59]=1)(=[O:3])[CH3:2]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC(=O)OCC(=O)Nc1ccc(C#N)c(C(F)(F)F)c1C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)OCc1nnnn1-c1ccc(C#N)c(C(F)(F)F)c1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 42.8 %

Procedure:
To a solution of 2-{[4-cyano-2-methyl-3-(trifluoromethyl)phenyl]amino}-2-oxoethyl acetate (Intermediate 46, 710 mg, 2.37 mmol) in tetrahydrofuran (20 mL) was added triphenylphosphine (1.24 g, 4.73 mmol), DIAD (0.920 mL, 4.73 mmol) and trimethylsilylazide (0.628 mL, 4.73 mmol). The reaction was stirred at room temperature for 18 hours. Solvent was removed under vacuum and residue was purified by silica chromatography (Biotage SP4, eluting 0% ethyl acetate in iso-hexane (2 column volumes), then a gradient from 0-50% ethyl acetate in iso-hexane (over 10 column volumes)). Pure fractions were combined and the solvent removed to yield the titled compound as a white solid (330 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:19][CH3:20])=[CH:5][C:6]2[S:12][CH2:11][CH2:10][CH:9]([C:13]([O:15]C)=[O:14])[C:8](=O)[C:7]=2[CH:18]=1.[BH4-].[Na+].Cl>CO.C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([O:19][CH3:20])=[CH:5][C:6]2[S:12][CH2:11][CH2:10][C:9]([C:13]([OH:15])=[O:14])=[CH:8][C:7]=2[CH:18]=1
Reactant: COC(=O)C1CCSc2cc(OC)c(OC)cc2C1=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1cc2c(cc1OC)SCCC(C(=O)O)=C2
Reaction time: 6 h
Yield: 63.4 %

Procedure:
In a mixture solvent of methanol (50 ml) and methylene chloride (50 ml) is dissolved methyl 7,8-dimethoxy-5-oxo-2,3,4,5-tetrahydro-1-benzothiepin-4-carboxylate (11.4 g) obtained in Reference Example 8. To the solution is added sodium borohydride (2.1 g) in limited amounts taking 6 hours with stirring. Excess sodium borohydride is decomposed with dilute hydrochloric acid, followed by extraction with methylene chloride. The organic layer is washed with a small volume of saturated aqueous saline, dried, and concentrated under reduced pressure. The residue is dissolved in methanol (50 ml), to the solution is added a 7.5 N aqueous solution of sodium hydroxide (10 ml), and the mixture is stirred at room temperature for 1.5 hour. To the reaction mixture is added water. The mixture is acidified (pH 3) with dilute hydrochloric acid, followed by extraction with methylene chloride. The organic layer is concentrated under reduced pressure, and the concentrate is dissolved in dioxane (35 ml). To the solution is added 10N hydrochloric acid (7 ml), and the mixture is stirred at 50° C. for 30 minutes. The reaction mixture is cooled and diluted with water. Then precipitating crude crystals are collected by filtration, washed with water and dried, followed by recrystallization from methylene chloride-ether to give 7,8-dimethoxy-2,3-dihydro-1-benzothiepin-4-carboxylic acid as colorless prisms (6.5 g),