Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[C:11]([C:25]#[N:26])=[CH:12][N:13]=[C:14]([NH:15][C:16]4[C:21]([F:22])=[CH:20][C:19]([F:23])=[CH:18][C:17]=4[F:24])[C:5]=3[C:4]=2[CH:3]=1.C([O-])([O-])=[O:28].[K+].[K+].OO>CS(C)=O>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[C:11]([C:25]([NH2:26])=[O:28])=[CH:12][N:13]=[C:14]([NH:15][C:16]4[C:21]([F:22])=[CH:20][C:19]([F:23])=[CH:18][C:17]=4[F:24])[C:5]=3[C:4]=2[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1cnc(Nc2c(F)cc(F)cc2F)c2c1[nH]c1ccc(F)cc12
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)c1cnc(Nc2c(F)cc(F)cc2F)c2c1[nH]c1ccc(F)cc12
Temperature: 70 °C

Procedure:
8-Fluoro-1-[(2,4,6-trifluorophenyl)amino]-5H-pyrido[4,3-b]indole-4-carbonitrile (46.5 mg, 0.13 mmol) and K2CO3 (108 mg, 0.78 mmol) was dissolved in DMSO (2.6 ml). Hydrogen peroxide (30%, 0.100 ml, 1.04 mmol) was added and the solution was heated at 70° C. for three hours. HPLC/MS then showed complete conversion. The solution was cooled to ambient temperature and directly purified by reverse phase HPLC. Desired fractions were combined, diluted with ethyl acetate, and washed with saturated aqueous sodium bicarbonate solution: The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the title compound. 1H NMR (600 MHz, CD30OD) δ 8.37 (s, 1H); 8.16 (dd, 1H); 7.64 (dd, 1H); 7.21 (dt, 1H); 6.98 (dd, 2H). LRMS (APCI) calc'd for (C18H10F4N4O) [M+H]+, 375.1. found 375.0.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([CH:26]([F:28])[F:27])[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][C:12]=2[CH3:34])=[O:10])[CH2:4]1.[CH3:35][O:36][CH2:37][C:38](Cl)=[O:39]>>[CH:31]1([CH2:30][O:29][C:21]2[CH:22]=[CH:23][C:24]([CH:26]([F:28])[F:27])=[CH:25][C:20]=2[C:19]2[C:14]3[NH:13][C:12]([CH3:34])=[C:11]([C:9]([NH:8][C@H:5]4[CH2:6][CH2:7][C@H:3]([NH:2][C:38](=[O:39])[CH2:37][O:36][CH3:35])[CH2:4]4)=[O:10])[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:33][CH2:32]1
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](N)C1
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)F)ccc4OCC4CC4)ncnc23)C1

Procedure:
Starting from N-[(1S,3S)-3-aminocyclopentyl]-4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f64) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][N:2]([C@@H:10]([CH3:38])[C:11](=[O:37])[NH:12][C@@H:13]([CH2:34][C:35]#[CH:36])[C:14](=[O:33])[N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[C:20](=[O:32])[NH:21][C@H:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24][CH2:23]1)C(=O)OC(C)(C)C.C(OCC)(=O)C.[ClH:45]>O1CCOCC1>[ClH:45].[CH3:1][NH:2][C@@H:10]([CH3:38])[C:11]([NH:12][C@@H:13]([CH2:34][C:35]#[CH:36])[C:14]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[C:20]([NH:21][C@H:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24][CH2:23]1)=[O:32])=[O:33])=[O:37]
Reactant: C#CC[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C#CC[C@H](NC(=O)[C@H](C)NC)C(=O)N1CCC[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Reaction time: 0.25 h

Procedure:
The title compound of Example 3 (33 mg) was dissolved in 4N HCl in dioxane (2 mL). This was stirred for approximately 15 mins. By TLC (100% ethyl acetate), UV spot was baseline. Excess 4N HCl in dioxane was removed via vacuum. For final compounds, material was left on vacuum pump overnight. For batch 2, material was dissolved in HPLC grade water, filtered through a 0.45 micron filter, and lyophilized overnight to give the title compound as a white semi-fluffy solid. 1H NMR (CD3OH): consistent with proposed structure. MS (m/z): 424.3.
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:11]([N:13]1[C:17]([NH2:18])=[CH:16][C:15]([CH3:19])=[N:14]1)[CH3:12].CN(C=O)C.C(=O)([O-])[O-].[K+].[K+]>CC([O-])=O.CC([O-])=O.[Cu+2].C(O)(=O)C.O>[CH2:11]([N:13]1[C:17]([NH:18][C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]([OH:6])=[O:5])=[CH:16][C:15]([CH3:19])=[N:14]1)[CH3:12]
Reactant: O=C(O)c1ccccc1I
Reactant: CCn1nc(C)cc1N
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CC(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: CCn1nc(C)cc1Nc1ccccc1C(=O)O
Temperature: 25 °C
Yield: 48.2 %

Procedure:
A mixture of 2-iodobenzoic acid (14.88 g, 0.06 mol), 1-ethyl-3-methyl-5-aminopyrazole (7.5 g, 0.06 mol), DMF (50 ml), Cu(OAc)2. H2O (0.5 g) and potassium carbonate (8.3 g, 0.06 mol) is refluxed for 20 hours. The reaction mixture is cooled to room temperature, poured into ice waterl and neutralized with acetic acid. A solid forms which is collected by filtration, washed with water and dried to give 7.1 g (98%) of N-(1-ethyl-3-methylpyrazol-5-yl) anthranilic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[CH3:10][O:11][P:12]([O:15]C)[O:13][CH3:14]>>[CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][P:12](=[O:15])([O:13][CH3:14])[O:11][CH3:10])=[CH:4][CH:3]=1
Reactant: Cc1ccc(CBr)cc1
Reactant: COP(OC)OC
Product: COP(=O)(Cc1ccc(C)cc1)OC

Procedure:
Following the procedure of Compound 11, 4-methylbenzyl bromide is reacted with trimethylphosphite.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[F:22][C:23]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:24]=1[CH2:25][NH2:26]>C(O)C>[F:22][C:23]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:24]=1[CH2:25][NH:26][CH2:19][C@@H:17]([OH:18])[CH2:16][O:15][C:12]1[CH:11]=[CH:10][C:9]([C:6]2[C:5]3[CH:20]=[CH:21][C:2]([F:1])=[CH:3][C:4]=3[O:8][N:7]=2)=[CH:14][CH:13]=1
Reactant: NCc1ccc(F)cc1F
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Solvent: CCO
Product: O[C@H](CNCc1ccc(F)cc1F)COc1ccc(-c2noc3cc(F)ccc23)cc1

Procedure:
The title compound is prepared from (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole, 2,4-difluorobenzylamine, and ethanol essentially as described above in Example 112. Purity by LC/MS=96%, [M+H]+=429.
Reaction SMILES: [C:1](O)(=O)/[CH:2]=[CH:3]/[C:4]1C=CC=C[CH:5]=1.OOS([O-])=O.[K+].[O-]S([O-])=O.[Na+].[Na+].CC[O:26][C:27]([CH3:29])=[O:28]>CN(C=O)C.O=[Os](=O)(=O)=O>[C:27]([OH:26])(=[O:28])[C:29]1[CH:5]=[CH:4][CH:3]=[CH:2][CH:1]=1
Reactant: O=C(O)/C=C/c1ccccc1
Reactant: CCOC(C)=O
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])OO
Agent: O=S([O-])[O-]
Solvent: CN(C)C=O
Product: O=C(O)c1ccccc1
Reaction time: 0.08 h
Yield: 97 %

Procedure:
trans-Cinnamic Acid (74 mg) was dissolved in DMF (5 mL), and OsO4 (0.06 mL, 2.5% in tBuOH) was added and stirred for 5 min. OXONE (1.23 g) was added in one portion and the reaction had a final volume (7 mL). The reaction was stirred at room temperature for 3 hours or until the solution becomes colorless. This usually marks the completion of the reaction which was verified by TLC or GC. Na2SO3 (450 mg) was added, to reduce the remaining Os(VIII), and stirred for an additional hour or until solution became dark brown/black. EtOAc was added to extract the products and 1N HCl was used to dissolve the salts. The organic extract was washed with 1N HCl (30 mL×3) and brine (30 mL), dried over Na2SO4, and the solvent was removed under reduced pressure to obtain the crude product. Benzoic acid was obtained in 97% yield without the need for further purification.
Reaction SMILES: O(C(C)(C)C)[K].Cl[C:8]1[C:13]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)=[N:12][CH:11]=[CH:10][N:9]=1.[CH2:27]([OH:30])[CH2:28][OH:29]>N1C=CC=CC=1>[C:23]([O:22][C:20]([N:17]1[CH2:18][CH2:19][N:14]([C:13]2[C:8]([O:29][CH2:28][CH2:27][OH:30])=[N:9][CH:10]=[CH:11][N:12]=2)[CH2:15][CH2:16]1)=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: OCCO
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2Cl)CC1
Agent: CC(C)(C)O[K]
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCN(c2nccnc2OCCO)CC1
Temperature: 0 °C
Reaction time: 15 h
Yield: 85.8 %

Procedure:
KO-t-Bu (9.92 g, 103 mmol) was added to a mixture of the product obtained in Step 1 (1 8.14 g, 60.7 mmol) and ethylene glycol (25 mL, 448 mmol) in pyridine (125 mL) at 85° C. The reaction mixture was stirred for 15 h and then poured into ice-water and extracted with toluene. The organic phase was dried (MgSO4) and concentrated. The residue was purified by chromatography on silica gel using toluene/EtOAc (1:1) as eluent to give 16.9 g (85%) of the title product. HRMS m/z calcd for C15H24N4O4 (M)+ 324.1798, found 324.1784.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([O:13][CH2:14][CH:15]=[C:16]([Cl:18])[Cl:17])[CH:10]=[C:9]([Cl:19])[C:3]=1[O:4][CH2:5][C:6](=O)[CH3:7].Cl.[CH2:21]([O:23][NH2:24])[CH3:22].Cl>N1C=CC=CC=1>[CH2:21]([O:23][N:24]=[C:6]([CH2:5][O:4][C:3]1[C:2]([Cl:1])=[CH:12][C:11]([O:13][CH2:14][CH:15]=[C:16]([Cl:18])[Cl:17])=[CH:10][C:9]=1[Cl:19])[CH3:7])[CH3:22]
Reactant: CCON
Reactant: CC(=O)COc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: Cl
Solvent: c1ccncc1
Product: CCON=C(C)COc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 83.6 %

Procedure:
To a mixture of 0.34 g of (2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)-phenoxy)acetone and 10 ml of pyridine was added 0.11 g of O-ethylhydroxylamine hydrochloride. After stirring at room temperature for 24 hours, the reaction mixture was poured into diluted hydrochloric acid, and extracted twice with diethyl ether. The diethyl ether layers were combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated to give a crude product. This crude product was subjected to silica gel chromatography, which afforded 0.32 g (yield, 81%) of (2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)acetone O-ethyloxime, m.p., 65.4° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][CH2:12][C:13]2[O:14][C:15]([CH2:21][OH:22])=[C:16]([OH:20])[C:17](=[O:19])[CH:18]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH2:23](OC1C(=O)C=C(CNS(C2C=CC=CC=2)(=O)=O)OC=1CO)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([O:20][C:16]1[C:17](=[O:19])[CH:18]=[C:13]([CH2:12][NH:11][S:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)(=[O:10])=[O:9])[O:14][C:15]=1[CH2:21][OH:22])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=c1cc(CNS(=O)(=O)c2cccc(Cl)c2)oc(CO)c1O
Reactant: O=c1cc(CNS(=O)(=O)c2ccccc2)oc(CO)c1OCc1ccccc1
Product: O=c1cc(CNS(=O)(=O)c2cccc(Cl)c2)oc(CO)c1OCc1ccccc1
Yield: 24.88 %

Procedure:
N-(5-Benzyloxy-6-hydroxymethyl-4-oxo-4H-pyran-2-ylmethyl)-3-chloro-benzenesulfonamide (10-05) (2.2 g, 24.88%) was synthesized as a white solid from 3-chloro-N-(5-hydroxy-6-hydroxymethyl-4-oxo-4H-pyran-2-ylmethyl)-benzenesulfonamide (9-05) (7.0 g, 20.29 mmol) following the procedure described for N-(5-benzyloxy-6-hydroxymethyl-4-oxo-4H-pyran-2-ylmethyl)-benzenesulfonamide (10-01).
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([C@H:9]3[CH2:12][C@H:11]([N:13]4[CH2:17][CH2:16][CH2:15][C@H:14]4C)[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:21][C:22]1[C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][CH:25]=[C:24]([CH3:37])[N:23]=1.N1C=C(B(O)O)C=NC=1>>[CH3:21][C:22]1[C:27]([C:2]2[CH:20]=[CH:19][C:5]3[N:6]=[C:7]([C@H:9]4[CH2:12][C@H:11]([N:13]5[CH2:14][CH2:15][CH2:16][CH2:17]5)[CH2:10]4)[S:8][C:4]=3[CH:3]=2)=[CH:26][CH:25]=[C:24]([CH3:37])[N:23]=1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(C)n1
Reactant: C[C@@H]1CCCN1[C@H]1C[C@H](c2nc3ccc(Br)cc3s2)C1
Agent: OB(O)c1cncnc1
Product: Cc1ccc(-c2ccc3nc([C@H]4C[C@H](N5CCCC5)C4)sc3c2)c(C)n1

Procedure:
The title compound was prepared according to the procedure described in Example 1F. substituting the product of Example 62A for the product of Example 1E and substituting the product of Example 2A for pyrimidine-5-boronic acid. 1H NMR (300 MHz, CDCl3) δ ppm 8.02 (d, J=8.48 Hz, 1H) 7.76 (d, J=1.36 Hz, 1H) 7.45 (d, J=7.80 Hz, 1H) 7.40 (dd, J=8.31, 1.86 Hz, 1H) 7.07 (d, J=7.80 Hz, 1H) 3.95-4.07 (m, 1H) 3.25-3.45 (m, 1H) 2.59 (s, 3H) 2.50 (s, 3H) 2.43-2.78 (m, 6H) 1.77-2.00 (m, 4H) 1.47-1.68 (m, 2H). MS: (M+H)+=364.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]([CH2:12][NH2:13])[CH2:10][NH2:11])[CH:6]=[CH:7][CH:8]=1.[CH3:14][O:15][C:16]([NH:18][C:19](=NC(OC)=O)SC)=[O:17]>CO>[CH3:14][O:15][C:16]([NH:18][C:19]1[NH:11][CH2:10][CH:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:12][N:13]=1)=[O:17]
Reactant: COc1cccc(C(CN)CN)c1
Reactant: COC(=O)N=C(NC(=O)OC)SC
Solvent: CO
Product: COC(=O)NC1=NCC(c2cccc(OC)c2)CN1
Yield: 68.7 %

Procedure:
A solution of 2.61 g (14.5 m. mole) of 2-(3-methoxyphenyl)-1,3-propanediamine in 200 ml of methanol is combined with a solution of 3.0 g (14.55 m. mole) of 1,3-bis(methoxycarbonyl)-S-methylisothiourea in 200 ml of methanol and allowed to stand at room temperature over night. The crystalline product which separates is collected, washed with methanol and dried at 78° under vacuum to give 2.62 g of 2-methoxycarbonylamino-5-(3-methoxyphenyl)-1,4,5,6-tetrahydropyrimidine, mp 218°-221°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][CH2:11][OH:12])=[CH:7][C:6]=2[CH:13]=1.C(N(CC)CC)C.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:31][C:21]1[CH:26]=[CH:25][C:24]([S:27]([O:12][CH2:11][CH2:10][C:8]2[O:9][C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:13][C:6]=3[CH:7]=2)(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCc1cc2cc(Br)ccc2o1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCc2cc3cc(Br)ccc3o2)cc1
Temperature: 50 °C
Yield: 48.1 %

Procedure:
The product from Example 4A (1.21 g, 5.0 mmol), 4-dimethylaminopyridine (0.06 g, 0.5 mmol), and triethylamine (1.5 mL, 10.5 mmol) were combined in dichloromethane (20 mL) stirred briefly and treated with para-toluenesulfonyl chloride (1.91 g, 10.0 mmol) in dichloromethane (2 mL) over about 5 minutes. After stirring at about 22° C. for 3 hours, the mixture was then washed with saturated NaHCO3 solution (20 mL, 2×), brine (20 mL), dried over Na2SO4, and distilled to dryness. The residue in acetonitrile (˜5 mL) was heated at 50° C. to effect dissolution, allowed to cool to room temperature slowly, and then cooled to about 0° C. The slurry was filtered and the obtained solid dried under reduced pressure at 40° C. to provide the title compound (0.95 g, 48% yield). MS-DCI (M+NH4)+ observed m/z at 412, 414; 1H NMR (CDCl3 at 400 MHz) δ 2.38 (s, 3H), 3.11 (m, 2H), 4.35 (m, 2H), 6.35 (m, 1H), 7.1-7.18 (m, 3H), 7.27 (dd, 1H), 7.56 (d, 1H), 7.64-7.67 (m, 2H); 13C NMR (CDCl3 at 100 MHz) δ 21.9, 28.8, 67.1, 103.7, 112.0, 115.5, 122.9, 126.3, 127.4, 129.4, 130.1, 132.3, 144.4, 153.0, 154.2 with 2 peaks overlapping.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][N:11]=[C:10]3[C:13]4[C:18]([CH2:19][C:9]=23)=[CH:17][CH:16]=[CH:15][CH:14]=4)=[CH:4][CH:3]=1.[H-].[K+].C([Li])(C)(C)C.C([O:30][B:31](OC(C)C)[O:32]C(C)C)(C)C.Cl>C1COCC1>[OH:30][B:31]([OH:32])[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][N:11]=[C:10]3[C:13]4[C:18]([CH2:19][C:9]=23)=[CH:17][CH:16]=[CH:15][CH:14]=4)=[CH:4][CH:3]=1
Reactant: Brc1ccc(-c2[nH]nc3c2Cc2ccccc2-3)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: OB(O)c1ccc(-c2[nH]nc3c2Cc2ccccc2-3)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 34 %

Procedure:
A solution of 3-(4-bromophenyl)-4H-indeno[1,2-c]pyrazole (2.0 g, 6.43 mmol) in dry THF (50 ml) was added to a stirred suspension of potassium hydride (35% wt dispersion in mineral oil, 0.365 g, 6.75 mmol) in dry THF (50 ml) in an atmosphere of nitrogen. After 10 mins the mixture was cooled to about −78° C. and tert-butyl lithium (1.5M solution in pentane, 8.78 ml, 13.18 mmol) was added and the mixture stirred for about 15 mins. A solution of tri-isopropylborate in THF (1.56 ml, 6.75 mmol) was added to the red solution and the mixture was allowed to warm up to room temp and stirred overnight. Hydrochloric acid (1M, 150 ml) was added and the solution stirred for about 30 mins and extracted with ether (3×200 ml). The combined ether extracts were then extracted with sodium hydroxide (3×100 ml). The combined alkaline extracts were acidified with hydrochloric acid (2M) and the precipitated off solid was filtered and dried at the pump to give dihydroxy 4-(4H-indeno-[1,2-c]pyrazol-3-yl)phenylborane (602 mg, 34%). Mpt >300° C.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[OH-].[Na+]>CO>[CH3:8][CH:7]([CH3:9])[CH2:6][CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:26][CH:27]=2)[CH:13]=[C:14]([CH:16]2[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]2)[CH:15]=1)[C:4]([OH:32])=[O:3]
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCNCC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)CC(C(=O)O)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCNCC2)c1
Temperature: 50 °C

Procedure:
To a solution of a mixture of 4-methyl-2-(5-piperidin-4-yl-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester and methyl ester (43 mg, 0.10 mmol) in MeOH (1 mL) was added 3N NaOH (0.10 mL) and heated to 50° C. for 2 h. The reaction was concentrated in vacuo to remove MeOH. The thick liquid was acidified to pH=2 by 2N HCl. The resulting acidic solution was extracted with EtOAc. The organic fraction was dried (MgSO4) and concentrated in vacuo. The crude mixture was purified by Gilson reverse phase column chromatography to obtain 4-methyl-2-(5-piperidin-4-yl-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2/[CH:18]=[C:19](\[CH3:31])/[C:20]([O:22]CCCCCCCC)=[O:21])[C:10]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[C:9]([CH3:37])[NH:8][C:7]=1[CH3:38])=[O:5])[CH3:2]>C(Cl)Cl.CC(C)=O>[CH2:35]([O:34][C:32]([C:10]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2/[CH:18]=[C:19](\[CH3:31])/[C:20]([O:22][CH:6]([CH3:4])[CH2:7][CH3:38])=[O:21])[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:7]([CH3:38])[NH:8][C:9]=1[CH3:37])=[O:33])[CH3:36]
Reactant: CCCCCCCCOC(=O)/C(C)=C/c1ccccc1C1C(C(=O)OCC)=C(C)NC(C)=C1C(=O)OCC
Solvent: ClCCl
Solvent: CC(C)=O
Product: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1ccccc1/C=C(\C)C(=O)OC(C)CC

Procedure:
2(e) (E)-4-(2-(3-Octyloxy-3-oxo-2-methyl-1-propenyl)phenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid diethyl ester T.l.c. (methylene chloride/acetone, 100:15) Rf 0.52
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([C:6](=[O:25])[CH2:7][NH:8][C:9]2[C:17]3[C:12](=[CH:13][C:14]([Cl:19])=[CH:15][C:16]=3[Cl:18])[NH:11][C:10]=2[C:20]([O:22]CC)=[O:21])=[CH:4][CH:3]=1.[OH-].[Li+].O1CCCC1.Cl>O.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6](=[O:25])[CH2:7][NH:8][C:9]2[C:17]3[C:12](=[CH:13][C:14]([Cl:19])=[CH:15][C:16]=3[Cl:18])[NH:11][C:10]=2[C:20]([OH:22])=[O:21])=[CH:26][CH:27]=1
Reactant: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1NCC(=O)c1ccc(F)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=C(CNc1c(C(=O)O)[nH]c2cc(Cl)cc(Cl)c12)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.9 %

Procedure:
Mix 3-[(p-fluorophenacyl)amino)-2-carbethoxy-4,6-dichloroindole (600 mg, 1.52 mmol) , lithium hydroxide (191 mg, 4.55 mmol), tetrahydrofuran (20 mL) and water (20 mL). Stir overnight at room temperature. Dilute with water (20 mL) and ethyl acetate (40 mL). Acidify with 1N HCl while stirring and separate the layers. Dry the organic phase over magnesium sulfate, filter and concentrate in vacuo. Recrystallize the residue (ethyl acetate/hexane) to yield the title compound as a white powder (440 mg, 79%); mp 259°-261° C.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]([CH2:24][OH:25])[CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=2)(=O)=O)=CC=1.C([Li])CCC>O1CCCC1>[Br:23][C:20]1[CH:19]=[CH:18][C:17]([O:16][CH2:15][CH2:14][CH:13]2[CH2:12][O:25][CH2:24]2)=[CH:22][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)OCC(CO)CCOc2ccc(Br)cc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Brc1ccc(OCCC2COC2)cc1
Yield: 37.4 %

Procedure:
To a solution of 4-(4-bromophenoxy)-2-(hydroxymethyl)butyl 4-methylbenzenesulfonate (0.450 g, 1.04 mmol) in anhydrous tetrahydrofuran (10 mL) was added n-butyl lithium (0.42 mL, 2.5M, 1.04 mmol) dropwise at 0° C. After complete addition of the n-butyl lithium solution, the resulting mixture was heated at reflux overnight. The reaction was carefully quenched with water and extracted with ethyl acetate (5×20 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography (0-20% ethyl acetate/petroleum ether) to afford the title compound (0.10 g, 37%) as a white solid. 1H NMR (400 MHz, CDCl3) ppm 7.37 (d, 2H), 6.74 (d, 2H), 4.89-4.78 (m, 2H), 4.56-4.45 (m, 2H), 3.94-3.87 (m, 2H), 3.30-3.17 (m, 1H), 2.23-2.12 (m, 2H)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:15])[C:12]([CH3:14])=[CH2:13])=[CH:6][CH:5]=1)([O-])=O.[Sn](Cl)Cl>C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:15])[C:12]([CH3:14])=[CH2:13])=[CH:8][CH:9]=1
Reactant: C=C(C)C(=O)Nc1ccc([N+](=O)[O-])cc1
Agent: Cl[Sn]Cl
Solvent: CCO
Product: C=C(C)C(=O)Nc1ccc(N)cc1
Temperature: 0 °C
Reaction time: 20 h
Yield: 71 %

Procedure:
Into a reaction vessel fitted with a cooling pipe, a stirrer, a thermometer and a nitrogen feed pipe, 20 parts of the N-(4-nitrophenyl)methacrylamide and 315 parts of ethanol were fed, which were dissolved therein, and thereafter the solution formed was cooled to 0° C. While the reaction solution obtained was kept at 0° C., 65 parts of tin(II) chloride was dividedly added thereto. After its addition was completed, the reaction solution was heated to room temperature, and, as it was, the reaction was carried out for 20 hours. After the reaction was completed, the solvent was evaporated off under reduced pressure, then 200 parts of ion-exchanged water was added to the reaction solution, and its pH was adjusted to 7 with use of an aqueous 12 mol/liter sodium hydroxide solution. To the solid having come precipitated, 200 parts of ethyl acetate was added, and insoluble matter was separated by filtration. The filtrate obtained was washed with 200 parts of ion-exchanged water, which was then dried with sodium sulfate, and thereafter the solvent was evaporated off under reduced pressure. The residue obtained was purified by silica gel column chromatography to obtain 12 parts of an intermediate N-(4-aminophenyl)methacrylamide (yield: 71%).
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12])(=O)C.O=S(Cl)Cl.[CH3:22][N:23]1[C:27]([CH2:28][N:29]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][C:36]=3[NH2:38])[CH:31]=[CH:30]2)=[CH:26][N:25]=[CH:24]1>C1COCC1>[OH:4][C:5]1[CH:6]=[C:7](/[CH:13]=[CH:14]/[C:15]([NH:38][C:36]2[CH:35]=[CH:34][CH:33]=[C:32]3[C:37]=2[N:29]([CH2:28][C:27]2[N:23]([CH3:22])[CH:24]=[N:25][CH:26]=2)[CH:30]=[CH:31]3)=[O:17])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: COc1ccc(/C=C/C(=O)O)cc1OC(C)=O
Reactant: Cn1cncc1Cn1ccc2cccc(N)c21
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: COc1ccc(/C=C/C(=O)Nc2cccc3ccn(Cc4cncn4C)c23)cc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.1 %

Procedure:
(E)-3-(3-Acetoxy-4-methoxyphenyl)acrylic acid (0.099 g, 0.420 mmol) was suspended in dry THF (8 ml). SOCl2 (0.037 ml, 0.504 mmol) was added and the mixture was stirred at RT for 1 h. The solvent was evaporated to dryness and the residue was dissolved in dry THF (8.00 ml). TEA (0.059 ml, 0.420 mmol) and 1-(3-methyl-3H-imidazol-4-ylmethyl)-1H-indol-7-ylamine (0.095 g, 0.420 mmol) were added. The mixture was stirred at RT for 18 hrs, heated at reflux for 5 hrs and then at RT for 48 hrs. The solvent was removed in vacuo and the residue was partitioned between EtOAc (10 ml) and H2O (2×10 ml). Organic phase was dried over sodium sulphate and concentrated to dryness. The crude was charged onto a SCX cartridge and eluted firstly with MeOH and then with NH3/MeOH. The title (E)-3-(3-hydroxy-4-methoxy-phenyl)-N-[1-(3-methyl-3H-imidazol-4-ylmethyl)-1H-indol-7-yl]-acrylamide (56 mg) was obtained after column chromatography (eluent: DCM 100% to DCM/MeOH 98:2).