Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:11][CH2:12][CH3:13])[CH:3]=1.C(OC([NH:21][CH2:22][C:23]1[CH:24]=[C:25]([CH2:31][CH:32]([O:36][CH:37]([CH3:39])[CH3:38])[C:33]([O-:35])=[O:34])[CH:26]=[CH:27][C:28]=1[O:29][CH3:30])=O)(C)(C)C>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:21][CH2:22][C:23]2[CH:24]=[C:25]([CH2:31][CH:32]([O:36][CH:37]([CH3:39])[CH3:38])[C:33]([OH:35])=[O:34])[CH:26]=[CH:27][C:28]=2[O:29][CH3:30])=[O:8])=[C:4]([O:11][CH2:12][CH3:13])[CH:3]=1
Reactant: CCOc1cc(Cl)ccc1C(=O)O
Reactant: COc1ccc(CC(OC(C)C)C(=O)[O-])cc1CNC(=O)OC(C)(C)C
Product: CCOc1cc(Cl)ccc1C(=O)NCc1cc(CC(OC(C)C)C(=O)O)ccc1OC

Procedure:
Using 4-chloro-2-ethoxybenzoic acid and 3-[3-([(tert-butoxycarbonyl)amino)methyl]-4-methoxyphenyl]-2-isopropoxypropanoate, 3-(3-[(4-chloro-2-ethoxybenzoyl)amino]methyl-4-methoxyphenyl)-2-isopropoxypropanoic acid was obtained in the same method as in Example 38).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][NH:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][S:17]([C:20]([F:23])([F:22])[F:21])(=[O:19])=[O:18])[N:5]2[CH:24]=1.[CH2:25]=O>C(O)(=O)C>[CH3:1][C:2]1[N:3]=[C:4]2[N:5]3[C:6]([CH2:10][N:11]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][S:17]([C:20]([F:21])([F:22])[F:23])(=[O:19])=[O:18])[CH2:25][C:24]=13)=[CH:7][CH:8]=[CH:9]2
Reactant: Cc1cn2c(CNCCCCNS(=O)(=O)C(F)(F)F)cccc2n1
Reactant: C=O
Solvent: CC(=O)O
Product: Cc1nc2cccc3n2c1CN(CCCCNS(=O)(=O)C(F)(F)F)C3
Temperature: 100 °C
Yield: 72 %

Procedure:
In 6 ml of acetic acid was dissolved 2.02 g (5.54 mmol) of 2-methyl-5-[N-[4-(trifluoromethanesulfonamido) butan-1-yl]aminomethyl]imidazo(1,2-a]pyridine. To the solution was added 6.2 ml (83.15 mmol) of a 37% aqueous solution of formalin, and the mixture was heated for 30 minutes at 100° C. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was dissolved in 100 ml of a saturated aqueous solution of potassium carbonate. This solution was neutralized by the addition of 1N HCl under ice-cooling, which was extracted twice with 100 ml of chloroform. The extract was dried over magnesium sulfate, then the solvent was distilled off under reduced pressure. The residue was purified by silicagel column chromatography (eluent: chloroform/methanol=20:1) to afford 1.45 g of the desired compound (72.0%, colorless liquid).
Reaction SMILES: [CH:1]1(Br)[CH2:3][CH2:2]1.[Mg].[CH2:6]([N:10]=[CH:11][C:12]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][C:15]([C:22]([F:25])([F:24])[F:23])=[CH:14][C:13]=1F)[CH2:7][CH2:8][CH3:9]>C(OCC)C.[Cl-].[Mn+2].[Cl-]>[CH2:6]([N:10]=[CH:11][C:12]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][C:15]([C:22]([F:25])([F:24])[F:23])=[CH:14][C:13]=1[CH:1]1[CH2:3][CH2:2]1)[CH2:7][CH2:8][CH3:9]
Reactant: CCCCN=Cc1c(F)cc(C(F)(F)F)cc1C(F)(F)F
Reactant: BrC1CC1
Agent: [Mn+2]
Agent: [Cl-]
Agent: [Mg]
Solvent: CCOCC
Product: CCCCN=Cc1c(C2CC2)cc(C(F)(F)F)cc1C(F)(F)F

Procedure:
Cyclopropylbromide (3.84 g, 32 mmol) was added to magnesium (771 mg, 32 mmol) in 20 mL diethylether and refluxed for 10 min. Manganese(II) chloride (160 mg, 1.27 mmol) and butyl-[1-(2-fluoro-4,6-bis-trifluoromethyl-phenyl)-methylidene]-amine (intermediate M, 4 g, 13 mmol) was added. The reaction mixture was refluxed for 2 h. The reaction mixture was quenched with 8 mL water and filtered through dicalite. The organic phase was separated and dried on sodium sulfate, filtered and evaporated. The crude material, brown oil (3.54 g, 82%) was used without further purification.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:16](C1C=C(C=CC=1)C(Br)Br)C1C=CC=CC=1.C1N2CN3CN(C2)CN1C3.Cl>C(O)C.C(O)(=O)C>[O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1cccc(Oc2ccccc2)c1
Reactant: BrC(Br)c1cccc(Oc2ccccc2)c1
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Product: O=Cc1cccc(Oc2ccccc2)c1

Procedure:
A process according to claim 1, wherein the mixture of m-phenoxybenzyl bromide (II) and m-phenoxybenzal bromide (X = bromine) is reacted with 1 to 2 molar equivalents of hexamethylenetetramine in hot aqueous ethanol or hot aqueous acetic acid and hydrolyzing the mixture with dilute hydrochloric acid to yield m-phenoxybenzaldehyde (I).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH:4]([C:12]#[N:13])[CH:5]([CH:9]([CH3:11])[CH3:10])[CH2:6][CH2:7][CH3:8].[H-].[Na+].Br[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>C1COCC1>[CH3:1][O:2][C:3](=[O:14])[C:4]([C:12]#[N:13])([CH:5]([CH:9]([CH3:11])[CH3:10])[CH2:6][CH2:7][CH3:8])[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]
Reactant: CCCC(C(C)C)C(C#N)C(=O)OC
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC(C(C)C)C(C#N)(CC(=O)OC(C)(C)C)C(=O)OC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 2-cyano-3-isopropyl-hexanoic acid methyl ester (1.9 g, 9.6 mmol) in 10 mL of THF is added to a slurry of NaH (washed with hexane, 0.23 g, 9.6 mmol) in 20 mL of THF which is cooled in an ice water bath under argon. The solution is stirred for 10 minutes, and t-butyl bromoacetate (2.1 g, 10.6 mmol) is added. The solution is warmed to room temperature. After 12 hours, the reaction is quenched by addition of 50 mL of saturated KH2PO4 and the THF is evaporated. The organic products are extracted into Et2O (3×50 mL), and the combined organic layers are dried over MgSO4. The solvent is evaporated, and the remaining oil is chromographed under medium pressure over silica gel in 25% hexane/CH2Cl2. Yield of 2-cyano-2-(1-isopropyl-butyl)-succinic acid 4-tert-butyl ester 1-methyl ester=1.3 g (42%) as an oil.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[C:11]([O:13][C:14]([F:17])([F:16])[F:15])[CH:10]=[CH:9][C:8]=1[F:18].[N:19]1[CH:24]=[CH:23][C:22]([CH:25]=[O:26])=[CH:21][CH:20]=1.O>O1CCCC1.C([Mg]Cl)CCC>[F:18][C:8]1[CH:9]=[CH:10][C:11]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:12][C:7]=1[CH:25]([C:22]1[CH:23]=[CH:24][N:19]=[CH:20][CH:21]=1)[OH:26]
Reactant: Fc1ccc(OC(F)(F)F)cc1Br
Reactant: O=Cc1ccncc1
Agent: CCCC[Mg]Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: OC(c1ccncc1)c1cc(OC(F)(F)F)ccc1F
Temperature: 25 °C

Procedure:
To a solution in tetrahydrofuran (3 mL) at 0° C. of 2.3M n-butyllithium in hexanes (0.95 mL) and 2M n-butylmagnesium chloride in tetrahydrofuran (0.55 mL) is added a solution of 2-bromo-1-fluoro-4-trifluoromethoxybenzene in tetrahydrofuran (4 mL). After stirring at 0° C. for 20 minutes 4-pyridinecarboxaldehyde (193 μL) is added and the mixture stirred at room temperature for one night. After hydrolysis with water, the aqueous phase is extracted with ethyl acetate. The pooled organic extracts are washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography over silica gel (gradient heptane/ethyl acetate from 2/1 to 1/1) to give pure (2-fluoro-5-trifluoromethoxyphenyl)pyridin-4-ylmethanol.
Reaction SMILES: [CH2:1]([C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([OH:15])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.Cl.[C:48]1([C:54]2([OH:59])[CH2:58][CH2:57][NH:56][CH2:55]2)[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>CN(C=O)C>[CH2:1]([C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([N:56]1[CH2:57][CH2:58][C:54]([C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)([OH:59])[CH2:55]1)=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1(c2ccccc2)CCNC1
Reactant: O=C(O)c1cnoc1Cc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1cnoc1Cc1ccccc1)N1CCC(O)(c2ccccc2)C1
Reaction time: 2 h
Yield: 23 %

Procedure:
A solution of 5-benzylisoxazole-4-carboxylic acid (10 mg, 0.05 mmol), TBTU (19 mg, 0.06 mmol, 1,2 equ.) and N-ethyl-N-isopropylpropan-2-amine (17 μL, 0.10 mmol, 2 equ) in DMF (0.3 mL) was added to 3-phenylpyrrolidin-3-ol hydrochloride (10 mg, 0.05 mmol) and the reaction mixture was left at rt for 2 h. The solvent was evaporated and the crude product was purified by RP-HPLC. After evaporation of the solvents the product was dried in vacuum to yield the title compound (4 mg). MS (ESI, pos. ion) m/z calcd for C21H20N2O3: 348.1474, found 348.1481.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([O:23][CH3:24])[O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si](C(C)(C)C)(C)C)(=O)=O.[NH4+].[Cl-]>C(Cl)Cl>[CH3:24][O:23][CH:14]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: COC(OCc1ccccc1)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: COC(OCc1ccccc1)C1CCNCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
410 mg (1.2 mmol) of 1-t-butoxycarbonyl-4-(methoxybenzyloxymethyl)piperidine and 0.28 mL (2.4 mmol) of 2,6-lutidine were combined in 2.5 mL of CH2Cl2. 0.42 mL (1.8 mmol) of t-butyldimethylsilyl trifluoromethane sulfonate were added and the mixture was stirred for 1 h at rt. 10 mL of sat'd NH4Cl-solution were added and the mixture was extracted with CH2Cl2. The combined organic fractions were washed with sat'd NaCl solution, dried over MgSO4, filtered and the filtrate was concentrated. The residue was redissolved in 3 mL of THF. 2 mL of a solution of tetrabutylammonium fluoride (1M in THF) were added and the mixture was stirred for 2 h at rt. 10 mL of sat'd NaHCO3-solution were added and the mixture was extracted with CH2Cl2. The combined organic fractions were washed with sat'd NaCl solution, dried over MgSO4, filtered and the filtrate was concentrated to give the title compound which was used without further purification.
Reaction SMILES: [F:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[C:4]([CH:6]=[C:7](F)[CH:8]=1)[NH2:5].C([O-])([O-])=O.[Cs+].[Cs+].[OH:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1.O>CS(C)=O>[NH2:5][C:4]1[CH:6]=[C:7]([O:19][C:20]2[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=2)[CH:8]=[C:2]([F:1])[C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: O=Cc1ccc(O)cc1
Reactant: Nc1cc(F)cc(F)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1cc(Oc2ccc(C=O)cc2)cc(F)c1[N+](=O)[O-]
Yield: 84.4 %

Procedure:
A solution of 3,5-difluoro-2-nitroaniline (0.400 g, 2.30 mmol), Cs2CO3 (1.87 g, 5.74 mmol), and 4-hydroxybenzaldehyde (0.309 g, 2.53 mmol) in dimethylsulfoxide (5 mL) was heated at 80 degrees Centigrade for 2 hours and then cooled. Water was added and the organics extracted using ethyl acetate (2×50 mL). The combined organics were washed once in brine and dried (Na2SO4), filtered and concentrated. Chromatography on silica gel using a gradient of 20%-60% ethyl acetate/hexanes eluted the product to give 0.536 g of 4-[(3-amino-5-fluoro-4-nitrophenyl)oxy]benzaldehyde as a yellow solid.
Reaction SMILES: C([O:3][P:4]([CH2:9][CH2:10][C:11]([NH:29]C(OCC1C=CC=CC=1)=O)([CH3:28])[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:16][CH:15]=1)(=[O:8])[O:5]CC)C.CO>C(Cl)Cl>[NH2:29][C:11]([CH3:28])([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:16][CH:15]=1)[CH2:10][CH2:9][P:4](=[O:3])([OH:8])[OH:5]
Reactant: CCCCCCCCc1ccc(CCC(C)(CCP(=O)(OCC)OCC)NC(=O)OCc2ccccc2)cc1
Solvent: ClCCl
Solvent: CO
Product: CCCCCCCCc1ccc(CCC(C)(N)CCP(=O)(O)O)cc1
Reaction time: 1 h
Yield: 79.8 %

Procedure:
To a solution of (±)-diethyl 3-benzyloxycarbonylamino-3-methyl-5-(4-(octyl)phenyl)pentylphosphonic acid (0.097 g, 0.173 mmol) in methylene chloride (1 ml) was added aodotrimethylsilane (0.100 ml, 0.690 mmol). After stirring for 1 h, methanol was added (1 ml) and the reaction was concentrated. HPLC purification (YMC-Pack pro C18, 150×20 mm, acetonitrile/water+0.1% TFA 10/90 to 0/100 over 15 minutes, 20 ml/min, 254 nM) yielded a waxy solid (0.051 g): 1H NMR (500 MHz , CDCl3): δ7.09-7.14 (m, 4H), 2.64 (t, J=8.7 Hz, 2H), 2.56 (t, J=7.7 Hz, 3H), 1.98-2.02 (m, 2H), 1.88-1.92 (m, 2H), 1.75-1.82 (m, 2H), 1.56-1.59 (m, 2H), 1.39 (s, 3H), 1.24-1.34 (m, 12H), 0.89 (t, J=6.89 Hz, 3H); MS m/e 370.3 (M+).
Reaction SMILES: [O:1]1[CH2:20][CH:2]1[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:14]3[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=3[O:12][N:11]=2)[CH2:6][CH2:5]1.[F:21][C:22]1[CH:36]=[CH:35][C:25]2[C:26]([CH:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[N:27][O:28][C:24]=2[CH:23]=1.[ClH:37]>C(O)(C)C.C(O)C>[ClH:37].[ClH:37].[F:19][C:17]1[CH:16]=[CH:15][C:14]2[C:10]([CH:7]3[CH2:8][CH2:9][N:4]([CH2:3][CH:2]([OH:1])[CH2:20][N:32]4[CH2:31][CH2:30][CH:29]([C:26]5[C:25]6[CH:35]=[CH:36][C:22]([F:21])=[CH:23][C:24]=6[O:28][N:27]=5)[CH2:34][CH2:33]4)[CH2:5][CH2:6]3)=[N:11][O:12][C:13]=2[CH:18]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: Fc1ccc2c(C3CCN(CC4CO4)CC3)noc2c1
Agent: Cl
Solvent: CC(C)O
Solvent: CCO
Product: OC(CN1CCC(c2noc3cc(F)ccc23)CC1)CN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 65 °C
Reaction time: 16 h

Procedure:
A stirred mixture of 1-(2,3-epoxypropyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (1.19 g, 4.3 mmol) and 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (0.95 g, 4.3 mmol) in isopropyl alcohol (50 ml) was heated at reflux for 1 hour, then stirred at 65° C. for 16 hours. The solvent was removed on a rotary evaporator. The solid residues were purified by flash chromatography over a silica gel column (SiO2, 35 g; eluted with methylene chloride, DCM, and CH3OH in DCM). The product thus obtained, weighed 2.55 g. This material was dissolved in ethanol and was treated with a solution of HCl (1 M in ether). The salt collected weighed 2.35 g, m.p.>270° C. dec.
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH2:11][O:12][CH3:13].[O:14]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:14]1[CH:18]=[CH:17][C:16]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[O:10][CH2:11][O:12][CH3:13])=[CH:15]1
Reactant: OB(O)c1ccoc1
Reactant: COCOc1cc(C#N)ccc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COCOc1cc(C#N)ccc1-c1ccoc1
Temperature: 100 °C
Yield: 83.9 %

Procedure:
4-Iodo-3-methoxymethoxy-benzonitrile (150 mg, 0.52 mmol) and 3-furanboronic acid (96 mg, 0.86 mmol) and Pd(PPh3)4 (60 mg, 0.052 mmol) and Cs2CO3 (500 mg, 1.53 mmol) is mixed in N,N-dimethylformamide (10 mL) and degassed and then heated at 100° C. for 4 hours. After which, the mixture is allowed to cool to room temperature and an aqueous work up is performed and the residue purified to afford the desired product (100 mg, 84%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][CH2:14][C:15]([O:17]CC)=[O:16])=[CH:11][N:10]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]4[CH:34]=[CH:33][C:32]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)=[CH:31][N:30]=4)=[CH:23][CH:22]=3)[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:11][N:10]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]4[CH:34]=[CH:33][C:32]([C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=5)=[CH:31][N:30]=4)=[CH:23][CH:22]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3ccc(-c4ccccc4)cn3)cc2)nc1-c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)CCc1cn(Cc2ccc(OCc3ccc(-c4ccccc4)cn3)cc2)nc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.3 %

Procedure:
After a mixture of ethyl 3-[3-(4-fluorophenyl)-1-[4-(5-phenyl-2-pyridylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (800 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (3 ml) and ethanol (3 ml) was stirred at room temperature for 5 hours, 1 N hydrochloric acid (3 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[3-(4-fluorophenyl)-1-[4-(5-phenyl-2-pyridylmethoxy)benzyl]-1H-pyrazol-4-yl]propionic acid (700 mg, yield: 93%). This was recrystallized from ethanol-water. Melting point: 162–163° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH2:16]2)(=[O:12])=[O:11].[CH:23]([C:25]1[NH:29][C:28]([CH3:30])=[C:27]([C:31]([OH:33])=[O:32])[C:26]=1[CH3:34])=O>>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:25]1[NH:29][C:28]([CH3:30])=[C:27]([C:31]([OH:33])=[O:32])[C:26]=1[CH3:34])(=[O:12])=[O:11]
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)O
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3c(Cl)cccc3Cl)ccc2N1
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)O

Procedure:
5-(2,6-Dichloro-phenylmethanesulfonyl)-1,3-dihydro-indol-2-one was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid using the general condensation method to give 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid. This was then coupled with cyclopropyl-piperidin-4-yl-amine TFA salt (prepared as in lit. procedure by H. C. Hansen et al. Bioorg. Med. Chem. Lett. 10, 2000, 2435-2439.) using the general amidation procedure to give an orange solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:9]=[C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:11]=1[OH:12])[NH2:8])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[Cl:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28](Cl)=[O:29]>CCOCC>[C:1]([C:5]1[CH:6]=[C:7]([NH:8][C:28](=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24][Cl:23])[CH:9]=[C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:11]=1[OH:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)CCCCCl
Reactant: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1O
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(C)(C)c1cc(NC(=O)CCCCCl)cc(C(C)(C)C)c1O
Temperature: 0 °C
Reaction time: 15 h
Yield: 100 %

Procedure:
To a stirred mixture of 3.6 g (16 mmol) of 3,5-di-tert-butyl-4-hydroxyaniline and 1.3 g (16 mmol) of pyridine in 50 ml of ether cooled to 0° C. there was slowly added 2.5 g (16 mmol) of 5-chlorovalerylchloride. The reaction mixture was allowed to warm to 25° C. and stirred for 15 hours following which the mixture was diluted with 100 ml of ether, washed with water, dried over anhydrous magnesium sulfate and concentrated to 5.8 g of solid. The solid was triturated in hexane and filtered to yield 5.5 g (16 mmol) of N-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-chlorovaleramide.
Reaction SMILES: [F:1][C:2]1[C:7]([CH2:8]O)=[CH:6][CH:5]=[CH:4][N:3]=1.P(Br)(Br)[Br:11]>ClCCl>[Br:11][CH2:8][C:7]1[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: BrP(Br)Br
Reactant: OCc1cccnc1F
Solvent: ClCCl
Product: Fc1ncccc1CBr
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The crude (2-fluoropyridin-3-yl)methanol was dissolved in dichloromethane (30 mL) at 0° C. under nitrogen. Phosphorus tribromide (4.2 mL, 42 mmol) was added dropwise. The resulting mixture was stirred at room temperature overnight. The reaction was quenched by addition of 10% NaHCO3 solution (5 mL). After 10 minutes, Na2SO4 (30 g) was added. The solvent was filtered and evaporated to provide 3-(bromomethyl)-2-fluoropyridine, which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])[CH2:13][C@H:12]2[CH3:28])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[NH:37]1[CH:41]=[CH:40][N:39]=[CH:38]1>O1CCOCC1.NC[C@@H]1CCCC[C@H]1CN>[F:23][C:20]1[CH:21]=[CH:22][C:17]([N:14]2[CH2:15][CH2:16][N:11]([S:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([N:37]4[CH:41]=[CH:40][N:39]=[CH:38]4)[CH:3]=3)(=[O:10])=[O:9])[C@H:12]([CH3:28])[CH2:13]2)=[C:18]([C:24]([F:27])([F:26])[F:25])[CH:19]=1
Reactant: c1c[nH]cn1
Reactant: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1cccc(Br)c1
Agent: NC[C@@H]1CCCC[C@H]1CN
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1cccc(-n2ccnc2)c1
Temperature: 120 °C
Yield: 75 %

Procedure:
A suspension of (R)-1-(3-bromophenylsulfonyl)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylpiperazine (168 mg, 0.35 mmol), 1,2-trans-diaminomethylcyclohexane (2.9 mg, 0.015 mmol), K3PO4 (8.5 mmg, 0.06 mmol) and Imidazole (41 mg, 0.6 mmol) in dioxane (0.6 mL) was degassed and heated to 120° C. in a sealed tube till disappearance of starting material as monitored by LCMS. The crude reaction mixture was filtered through a pad of Celite and washed with EtOAc. The crude product was purified on SiO2 column eluted with hexanes/EtOAc to give the desired product as a white solid (123 mg, 75%). HRMS: calcd for C21H20F4N4O2S+H+, 469.13158. found (ESI-FTMS, [M+H]1+), 469.13336.
Reaction SMILES: [N+](=[C:3]([C:9](=[O:15])[CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[N-].Cl>C(Cl)Cl.C([O-])(=O)C.[Rh+3].C([O-])(=O)C.C([O-])(=O)C>[CH3:13][C:12]1([CH3:14])[CH2:11][CH2:10][C:9](=[O:15])[CH:3]1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(=[N+]=[N-])C(=O)CCC(C)C
Agent: [Rh+3]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)C1C(=O)CCC1(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 1737.3 %

Procedure:
Rhodium acetate (170 mg) was added to a solution of ethyl 2-diazo-6-methyl-3-oxoheptanoate (0.5 g) in DCM (80 mL). A solution of ethyl 2-diazo-6-methyl-3-oxoheptanoate (7.652 g) in DCM (50 mL) was added in portions. The mixture was stirred at room temperature for 1 hour. 1N HCl (100 mL) was added. The organic phase was separated. The aqueous phase was extracted with DCM (100 mL). The combined DCM solutions were dried (Na2SO4). After filtration and concentration, the crude material was purified with flash chromatography to give ethyl 2,2-dimethyl-5-oxocyclopentanecarboxylate (7.54 g). 1H NMR (CDCl3, 400 MHz) δ (ppm): 4.25-4.09 (m, 2H), 2.52-2.37 (m, 2H), 2.03-1.99 (m, 2H), 1.80-1.67 (m 1H), 1.33-1.26 (m, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=O)[C:6]([CH3:14])([CH3:13])[N:5]2[C:15]([N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:16].[N+:22]([CH2:24][C:25]1[N:29]=[C:28]([CH:30]([CH3:32])[CH3:31])[O:27][N:26]=1)#[C-:23]>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:23]=[N:22][C:24]([C:25]3[N:29]=[C:28]([CH:30]([CH3:32])[CH3:31])[O:27][N:26]=3)=[C:7]1[C:6]([CH3:14])([CH3:13])[N:5]2[C:15]([N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:16]
Reactant: [C-]#[N+]Cc1noc(C(C)C)n1
Reactant: CC1(C)C(=O)Nc2ccc(F)cc2N1C(=O)N1CCCC1
Product: CC(C)c1nc(-c2ncn3c2C(C)(C)N(C(=O)N2CCCC2)c2cc(F)ccc2-3)no1

Procedure:
Following the general procedure for EXAMPLE 30 and making non-critical variation but starting with 6-fluoro-1,2,3,4-tetrahydro-3,3-dimethyl-4-[(pyrrolidino)carbonyl]quinoxalin-2-one (XXXII, EXAMPLE 32, 0.647 g) and 3-isocyanomethyl-5-isopropyl-1,2,4-oxadiazole (0.403 g) the title compound is obtained which is crystallized from methylene chloride/ethyl ether/hexane, mp 154.5°-155.5°; MS (m/z) at 424; IR (mineral oil) 1527, 1657, 1414, 1172 and 1395 cm-1 ; NMR (CDCl3) 1.45, 1.7-2.0, 3.0, 3.3, 3.33, 3.58, 6.55, 6.74, 7.45 and 8.06 δ.