Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[F:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>CCO.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>[F:10][C:5]1[CH:4]=[CH:3][C:2]([C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([F:11])[CH:17]=2)=[CH:9][C:6]=1[CH:7]=[O:8]
Reactant: OB(O)c1cccc(F)c1
Reactant: O=Cc1cc(Br)ccc1F
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: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCO
Product: O=Cc1cc(-c2cccc(F)c2)ccc1F
Temperature: 100 °C
Yield: 34.1 %

Procedure:
To a stirred mixture of 5-bromo-2-fluoro-benzaldehyde (3.0 g, 14.8 mmol, 1 eq), (3-fluorophenyl)boronic acid (2.48 g, 17.7 mmol, 1.2 eq) and K2CO3 (4.13 g, 44.4 mmol, 3 eq) in a mixture of EtOH (30 mL), DMF (30 mL) and water (10 mL) under N2 was added Pd(PPh3)4 (1.71 g, 1.48 mmol, 0.1 eq). The reaction was heated at 100° C. for 3 h, then filtered through Celite. The filtrate was diluted with water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (petroleum ether:EtOAc, 300:1) to give the title compound as a yellow oil (1.1 g, 34%).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][CH:15]=[CH:16][C:9]=23)[C:5]([C:17]2[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=2)=[N:4]1)[CH3:2].C(N(CC)CC)C.[N:31]1([C:37](Cl)=[O:38])[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.O>ClCCl>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][CH:15]=[CH:16][C:9]=23)[C:5]([C:17]2[CH:23]=[CH:22][C:20]([NH:21][C:37]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[O:38])=[CH:19][CH:18]=2)=[N:4]1)[CH3:2]
Reactant: O=C(Cl)N1CCOCC1
Reactant: CCn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc(N)cc2)n1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc(NC(=O)N3CCOCC3)cc2)n1
Temperature: 50 °C
Reaction time: 18 h
Yield: 50 %

Procedure:
A solution of 4-[1-ethyl-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl]aniline (0.19 mmol) in dichloromethane (1 mL) was treated with triethylamine (0.39 mmol) and 4-morpholinecarbonyl chloride (0.39 mmol). The reaction mixture was stirred for 18 h at 50° C. and poured into water (1 mL), followed by extraction with (3×3 mL) ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. Purification of the residue by Gilson reverse phase HPLC provided the title product as a yellow powder (50%). ESMS [M+H]+: 417.4
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH2:2][OH:3].C(N)CN.C(O)(=[O:14])C(C)C.[C:16]([O-:20])(=[O:19])[CH2:17][OH:18]>>[C:1]([OH:5])(=[O:4])[CH:2]=[O:3].[C:17]([OH:14])(=[O:18])[C:16]([OH:20])=[O:19]
Reactant: CC(C)C(=O)O
Reactant: O=C([O-])CO
Reactant: O=C(O)CO
Solvent: NCCN
Product: O=C(O)C(=O)O
Product: O=CC(=O)O
Temperature: 5 °C
Reaction time: 23 h

Procedure:
A 300-mL EZE-Seal stirred autoclave reactor equipped with Dispersimax Impeller (Autoclave Engineers) was charged with 100 mL of a solution containing glycolic acid (0.750M), ethylenediamine (0.863M), isobutyric acid (0.100M, HPLC internal standard), and flavin mononucleotide (0.01 mM), at pH 9.2, and the solution cooled to 5° C. To the reactor was then added 30 g of E. coli transformant d01 (72 IU glycolate oxidase and 29,600 IU catalase), and the mixture stirred at 1000 rpm, which bubbled oxygen through the mixture via the action of the turbine impeller, and at 5° C. under 120 psig of oxygen. The reaction was monitored by taking a 0.40 mL aliquot of the reaction mixture at regular intervals, filtering the aliquot using a Millipore Ultrafree-MC 10,000 NMWL Filter Unit, and analyzing the filtrate by HPLC. After 23 h, the yields of glyoxylic acid, oxalic acid, and formic acid were 74.4%, 1.1%, and 5.6%, respectively, with 6.3% glycolic acid remaining. The recovered activities of microbial glycolate oxidase and catalase were 30% and 199% of their initial values, respectively.
Reaction SMILES: [ClH:1].C([O:9][C:10]1[CH:11]=[C:12]([CH:38]=[C:39]([F:41])[CH:40]=1)[CH2:13][C@H:14]([NH:34][C:35](=[O:37])[CH3:36])[C@H:15]([OH:33])[CH2:16][NH:17][C:18]1([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:32])[CH3:31])[CH:25]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)C1C=CC=CC=1.[H][H].Cl>C(O)C.[Pd]>[ClH:1].[OH:9][C:10]1[CH:11]=[C:12]([CH:38]=[C:39]([F:41])[CH:40]=1)[CH2:13][C@H:14]([NH:34][C:35](=[O:37])[CH3:36])[C@H:15]([OH:33])[CH2:16][NH:17][C:18]1([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:32])[CH3:31])[CH:25]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CC(=O)N[C@@H](Cc1cc(F)cc(OCc2ccccc2)c1)[C@H](O)CNC1(c2cccc(C(C)C)c2)CCCCC1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC(=O)N[C@@H](Cc1cc(O)cc(F)c1)[C@H](O)CNC1(c2cccc(C(C)C)c2)CCCCC1
Reaction time: 21 h

Procedure:
To a solution of compound 10 (0.70 g, 1.2 mmol) in 70 mL of ethanol in a Parr bottle is added 0.33 g of 10% palladium on carbon. The mixture is placed under 20 psi of hydrogen and shaken for 21 h. The mixture is filtered and the catalyst is washed with ethanol. Concentration in vacuo affords a colorless oil, which is treated with ethereal HCl to give a quantitiative yield of hydrochloride 11 as a white solid: 1H NMR (CDCl3+CD3OD drop) δ 7.44 (s, 1 H), 7.37 (m, 2 H), 7.28 (m, 1 H), 6.59 (s, 1 H), 6.40 (m, 1 H), 6.31 (m, 1 H), 4.0 (m, 1 H), 3.79 (m, 1 H), 2.95 (m, 2 H), 2.63 (m, 4 H), 2.44 (m, 1 H), 2.05 (m, 2 H), 1.90 (s, 3 H), 1.79 (m, 2 H), 1.59 (m, 1 H), 1.5-1.3 (m, 3 H), 1.26 (d, J=7 Hz, 6 H); MS (CI) m/z 457.4 (MH+).
Reaction SMILES: [CH:1]12[NH:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][C:3]([C:9]1[NH:26][C:12]3=[N:13][CH:14]=[CH:15][C:16]([C:17]4[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=4[O:24][CH3:25])=[C:11]3[CH:10]=1)=[CH:2]2.[CH3:27][S:28](Cl)(=[O:30])=[O:29].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>CN(C)C=O.[Cl-].[Na+].O>[F:23][C:21]1[CH:20]=[CH:19][C:18]([O:24][CH3:25])=[C:17]([C:16]2[CH:15]=[CH:14][N:13]=[C:12]3[NH:26][C:9]([C:3]4[CH2:4][CH:5]5[N:8]([S:28]([CH3:27])(=[O:30])=[O:29])[CH:1]([CH2:7][CH2:6]5)[CH:2]=4)=[CH:10][C:11]=23)[CH:22]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(F)cc1-c1ccnc2[nH]c(C3=CC4CCC(C3)N4)cc12
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(F)cc1-c1ccnc2[nH]c(C3=CC4CCC(C3)N4S(C)(=O)=O)cc12
Reaction time: 3 h

Procedure:
To a solution of Example 223C (80.0 mg, 0.189 mmol) in N,N-dimethylformamide (2 mL) was added methanesulfonyl chloride (0.030 mL, 0.379 mmol) and triethylamine (0.158 mL, 1.137 mmol) and the mixture was stirred for 3 hours. The mixture was treated with brine and aqueous sodium bicarbonate and extracted with ethyl acetate (twice). The combined organic layers were dried over magnesium sulfate, filtered, concentrated, and purified on silica gel using an ISCO Companion eluting with heptanes/ethyl acetate (1:9 to 0:10) to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ 1.63-1.74 (m, 1H), 1.91-2.14 (m, 2H), 2.15-2.27 (m, 1H), 2.92-3.00 (m, 4H), 3.74 (s, 3H), 4.32-4.40 (m, 1H), 4.44 (t, J=5.8 Hz, 1H), 6.22 (s, 1H), 6.79 (d, J=6.0 Hz, 1H), 7.03 (d, J=4.9 Hz, 1H), 7.15-7.31 (m, 3H), 8.20 (d, J=4.9 Hz, 1H), 11.73-11.86 (m, 1H). MS (ESI+) m/z 428.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH3:21])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.NC1C=C[N:45]([CH2:48][C:49]2[CH:56]=[CH:55][C:52](C#N)=[CH:51][CH:50]=2)N=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:52]3[CH:55]=[CH:56][C:49]([C:48]#[N:45])=[CH:50][CH:51]=3)[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Reactant: N#Cc1ccc(Cn2ccc(N)n2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(Cc3ccc(C#N)cc3)n2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.8 %

Procedure:
To a solution containing 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 100 mg, 0.30 mmol) in methylene chloride (20 mL), was then added a 2.0 M solution of oxalylchloride in methylene chloride (181 μL, 0.36 mmol) at 0° C. and allowed to stir at 25° C. for 1 h, after which time 2,6-lutidine (70 μL, 0.61 mmol) was added to the solution at 0° C. After 1 h, crude 4-(3-amino-pyrazol-1-ylmethyl)-benzonitrile (0.42 mmol based on theory) was added and the reaction was allowed to proceed for 16 h. The reaction solution was washed with 1.0 M aqueous hydrochloric acid solution, dried over sodium sulfate, concentrated in vacuo and purified by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 0% methanol/methylene chloride to 10% methanol/methylene chloride) to afford 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-N-[1-(4-cyano-benzyl)-1H-pyrazol-3-yl]-3-cyclopentyl-propionamide (35 mg, 23%) as a white solid: ESI-LRMS m/e calcd for C26H27ClN4O3S [M+] 510.2, found 511.5 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.06-1.21 (m, 2H, CH2), 1.44-1.92 (m, 8H, 4×CH2), 2.09-2.35 (m, 1H, CH), 3.25 (s, 3H, SO2CH3), 3.56 (t, J=7.5 Hz, 1H, CH), 5.20 (s, 2H, NCH2), 6.74 (d, J=2.3 Hz, 1H, Ar), 7.19 (d, Jo=8.4 Hz, 2H, Ar), 7.35 (d, J=2.3 Hz, 1H, Ar), 7.44 (dd, Jo=8.2, Jm=1.7 Hz. 1H, Ar), 7.54-7.63 (m, 3H, Ar), 7.99 (s, 1H, NH), 8.06 (d, Jo=8.2 Hz, 1H, Ar).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C@:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=2)([CH2:14][F:15])[N:13]=1)([CH3:4])([CH3:3])[CH3:2].[Br:24][C:25]1[CH:26]=[CH:27][C:28]([C:31](O)=[O:32])=[N:29][CH:30]=1.C1C=NC2N(O)N=NC=2C=1.CCN(CC)CC.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CCOC(C)=O>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C@:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:31]([C:28]3[CH:27]=[CH:26][C:25]([Br:24])=[CH:30][N:29]=3)=[O:32])[CH:17]=2)([CH2:14][F:15])[N:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1ccc(Br)cn1
Reactant: CC(C)(C)OC(=O)NC1=N[C@](CF)(c2cccc(N)c2)COC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1=N[C@](CF)(c2cccc(NC(=O)c3ccc(Br)cn3)c2)COC1

Procedure:
To an at 0° C. stirred solution of 105 mg (0.325 mmol) (R)-[5-(3-amino-phenyl)-5-fluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester, 72 mg (0.357 mmol) 5-bromo-pyridine-2-carboxylic acid, 57 mg (0.422 mmol) HOAt and 82 mg (0.812 mmol) Et3N in 3 ml DCM were added 81 mg (0.422 mmol) EDC.HCl. After 18 h the mixture was diluted with EtOAc and washed with water, 5% aqueous NaHCO3 and brine. Chromatography on silica gel (hexane/EtOAc 3:1) gave the desired product as a colorless solid.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]([CH3:14])[O:12][CH3:13])(=[O:10])=[O:9].[N:15]([O-])=O.[Na+].[S:19]([O-:23])(O)(=O)=[O:20].[Na+]>>[CH3:14][N:11]([S:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[S:19]([NH2:15])(=[O:23])=[O:20])(=[O:10])=[O:9])[O:12][CH3:13]
Reactant: CON(C)S(=O)(=O)c1ccccc1N
Reactant: O=N[O-]
Reactant: O=S(=O)([O-])O
Agent: [Na+]
Product: CON(C)S(=O)(=O)c1ccccc1S(N)(=O)=O
Yield: 1174.2 %

Procedure:
2-amino-N-methyl-N-methoxyphenylsulfonamide [Xn=2-SO2N(OCH3)CH3 in Compound (XXV)] (5.4 g, 25 mmol) was diazotized with sodium nitrite (2.07 g, 25×1.2 mmol) and the resultant diazonium compound was allowed to react with sodium hydrogen sulfate (7.28 g, 25×2.8 mmol) to obtain 3.95 g (percent yield: 56.37%) of 2-[(N-methyl-N-methoxyamino)sulfonyl] phenylsulfonamide [Compound (III-18)].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([OH:13])=O)[CH:5]=[CH:6][C:7]=1[F:8].S(Cl)([Cl:16])=O>C1(C)C=CC=CC=1.N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([Cl:16])=[O:13])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(O)/C=C/c1ccc(F)c(F)c1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: O=C(Cl)/C=C/c1ccc(F)c(F)c1
Temperature: 65 °C
Reaction time: 0.25 h
Yield: 99.8 %

Procedure:
A stirred mixture of (E)-3-(3,4-difluorophenyl)-2-propenoic acid (8.2 kg), toluene (7.4 kg) and pyridine (0.18 kg) was heated to 65° C. and then thionyl chloride (7.4 kg) was added over 30 minutes. The reaction was stirred for a further 2 h 15 minutes after the addition was complete, then diluted with toluene (8.7 kg). Excess thionyl chloride, sulfur dioxide and hydrogen chloride were then distilled out, together with toluene (10 L), under reduced pressure, yielding a solution of the (E)-3-(3,4-difluorophenyl)-2-propenoyl chloride (approximately 9 kg) in toluene.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[CH:9][C:5]=1[C:6](Cl)=[O:7])([O-:3])=[O:2].C([SH:24])C.[CH:25]1[CH:30]=CC=CC=1.C(Cl)(=O)C1C=CC=CC=1>C(OCC)C>[N+:1]([C:4]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[CH:9][C:5]=1[C:6]([O:7][CH2:30][CH3:25])=[S:24])([O-:3])=[O:2]
Reactant: CCS
Reactant: O=C(Cl)c1cc(Oc2ccc(Cl)cc2Cl)ccc1[N+](=O)[O-]
Reactant: c1ccccc1
Solvent: CCOCC
Solvent: O=C(Cl)c1ccccc1
Product: CCOC(=S)c1cc(Oc2ccc(Cl)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
A mixture of 2-nitro-5-(2',4'-dichlorophenoxy)benzoyl chloride (4.16 g., 0.012 mole) and ethanethiol (2.24 g., 0.036 mole) in 40 ml. benzene was heated at reflux for 2 hours and 50 minutes and then cooled. The mixture was diluted with diethyl ether, washed twice with 10% aqueous NaOH, once with NaCl solution, dried, and evaporated to dryness to give 4.2 g. of an oil. Infrared analysis showed a large amount of initial benzoyl chloride and some desired product. The oil was dissolved in 100 ml. benzene and 3.0 g. ethanethiol and about 1.5 g. triethylamine were added. A precipitate formed immediately. The reaction mixture was refluxed for 1.5 hours, cooled, filtered and evaporated to dryness to give 4.65 g. of the desired product.
Reaction SMILES: [C:1](=[O:4])(O)[O-].[Na+].[N:6]1[C:13](Cl)=[N:12][C:10](Cl)=[N:9][C:7]=1[Cl:8].[CH3:15][OH:16]>O>[Cl:8][C:7]1[N:9]=[C:10]([O:16][CH3:15])[N:12]=[C:13]([O:4][CH3:1])[N:6]=1
Reactant: O=C([O-])O
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CO
Agent: [Na+]
Solvent: O
Product: COc1nc(Cl)nc(OC)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 54.8 %

Procedure:
To a vigorously-stirred suspension of 54.6 g of sodium bicarbonate in 146 g of methanol and 16 ml water was added 60.0 g of cyanuric chloride in portions over a period of 30 minutes. The temperature rose to 30°-35° C. and, following the addition, was allowed to drop to 25° C. and the mixture was then heated to 50°±2° C. for 21/2 hours. The solution was allowed to cool and 600 ml ice-water was added and stirred for 15 minutes. Filtration of the thick reaction mixture followed by crystallization from hot hexanes gave 31.3 g of 2-chloro-4,6-dimethoxy-1,3,5-triazine as a colorless crystalline solid, m.p. 76°-78° C.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1.C(OO)(=[O:17])C.C(O)(C)C>C(O)(=O)C>[Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][C:5]1[CH:6]=[N+:7]([O-:17])[CH:8]=[CH:9][CH:10]=1
Reactant: CC(=O)OO
Reactant: Clc1ccccc1Oc1cccnc1
Solvent: CC(=O)O
Solvent: CC(C)O
Product: [O-][n+]1cccc(Oc2ccccc2Cl)c1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A solution of 74.3 g of 3-(o-chlorophenoxy)pyridine [Agr. Biol. Chem. 34, 68 (1970)] in 75 ml of glacial acetic acid at 35° C. is treated with 76 g of 40% peractic acid in acetic acid in three equal portions. The mixture is held at 35° C. for 16 hours, refluxed 1 hour, cooled to 60° C. and 75 ml of isopropanol is added. The mixture is refluxed for 1 hour, cooled and concentrated at reduced pressure. The oil is dissolved in 700 ml of dichloromethane, washed with excess 25% sodium hydroxide solution, concentrated at reduced pressure and distilled to yield 3-(o-chlorophenoxy)pyridine N-oxide, bp 150°-155° C. at 0.15 mm.
Reaction SMILES: [C:1](=[N:14][OH:15])([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.Cl[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([S:24][C:25]2[CH:26]=[C:27]([C:32]3([O:38][CH3:39])[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH:28]=[C:29]([F:31])[CH:30]=2)=[CH:20][CH:19]=1>>[F:31][C:29]1[CH:28]=[C:27]([C:32]2([O:38][CH3:39])[CH2:33][CH2:34][O:35][CH2:36][CH2:37]2)[CH:26]=[C:25]([S:24][C:21]2[CH:22]=[CH:23][C:18]([CH2:17][O:15][N:14]=[C:1]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:19][CH:20]=2)[CH:30]=1
Reactant: ON=C(c1ccccc1)c1ccccc1
Reactant: COC1(c2cc(F)cc(Sc3ccc(CCl)cc3)c2)CCOCC1
Product: COC1(c2cc(F)cc(Sc3ccc(CON=C(c4ccccc4)c4ccccc4)cc3)c2)CCOCC1
Yield: 44 %

Procedure:
Using an analogous procedure to that described in Example 1, benzophenone oxime was reacted with 4-[3-(4-chloromethylphenylthio)-5-fluorophenyl]-4-methoxytetrahydropyran to give benzophenone O-{4-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenylthio]benzyl}oxime as an oil in 44% yield.
Reaction SMILES: [I:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([O:8]OC(C)(C)C)=O)=[CH:4][C:3]=1[O:16][CH3:17].C([N:20](C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:49][N:50]1[CH2:55][CH2:54][CH:53](N)[CH2:52][CH2:51]1>CN(C)C=O.O>[I:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([NH:20][CH:51]2[CH2:52][CH2:53][CH2:54][CH2:55][N:50]2[CH3:49])=[O:8])=[CH:4][C:3]=1[O:16][CH3:17]
Reactant: CN1CCC(N)CC1
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1cc(C(=O)OOC(C)(C)C)ccc1I
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NC2CCCCN2C)ccc1I
Temperature: 25 °C
Reaction time: 24 h
Yield: 74.2 %

Procedure:
A solution of tert-butyloxy 4-iodo-3-methoxybenzoate (250 mg, 0.90 mmol) in anhydrous dimethylformamide (8 mL) was treated with N-ethyl-N,N-diisopropylamine (0.63 mL, 3.6 mmol) and TBTU (404 mg, 1.26 mmol). The mixture was then treated with 1-methylpiperidin-4-amine (0.160 mL, 1.26 mmol). The reaction mixture was stirred at room temperature for 24 h. The reaction was diluted with water and the resulting precipitate was collected by filtration to afford the title compound (250 mg, 71% yield).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:10]=1[CH2:11][O:12][CH2:13][CH3:14])=[O:5])C.O.[OH-].[Li+].[OH-].[Na+]>CO.O>[C:15]([N:9]1[C:10]([CH2:11][O:12][CH2:13][CH3:14])=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]1)([CH3:16])([CH3:17])[CH3:18]
Reactant: CCOCc1c(C(=O)OCC)cnn1C(C)(C)C
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCOCc1c(C(=O)O)cnn1C(C)(C)C
Temperature: 100 °C
Yield: 87.8 %

Procedure:
A solution of 1-tert-butyl-5-ethoxymethyl-1H-pyrazole-4-carboxylic acid ethyl ester (99.8 mg, 0.39 mmol) in methanol (0.5 mL) and water (0.5 mL) at 25° C. was treated with lithium hydroxide monohydrate (20.2 mg, 0.48 mmol). The reaction mixture was fitted with a reflux condenser and was then heated to 100° C. for 2 h. At this time, the reaction was concentrated in vacuo. The resulting residue was acidified to pH=1 with a 1N aqueous hydrochloric acid solution. A cloudy mixture resulted. The material was brought to a basic pH by treatment with a 1N aqueous sodium hydroxide solution. This solution was extracted with ethyl acetate (1×10 mL). These organics were discarded. The aqueous layer was re-acidified to pH=1 with a 1N aqueous hydrochloric acid solution. This solution was extracted with ethyl acetate (2×10 mL). These organics were dried over magnesium sulfate, filtered and concentrated in vacuo to afford 1-tert-butyl-5-ethoxymethyl-1H-pyrazole-4-carboxylic acid (77.5 mg, 87%) as a yellow solid. The material was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:7])[NH:5][N:6]=1.O=[C:9]([CH3:15])[CH2:10][C:11](OC)=[O:12].O>Cl>[CH3:15][C:9]1[CH:10]=[C:11]([OH:12])[N:1]=[C:2]2[NH:6][N:5]=[C:4]([OH:7])[C:3]=12
Reactant: COC(=O)CC(C)=O
Reactant: Nc1cc(O)[nH]n1
Agent: Cl
Solvent: O
Product: Cc1cc(O)nc2[nH]nc(O)c12

Procedure:
20 g (201.8 mmol) of 5-amino-2H-pyrazol-3-ol and 26 g (224 mmol) of methyl 3-oxo-butyrate were heated under reflux in 63 ml of conc. hydrochloric acid and 17 ml of water for 1 h. After cooling, the product crystallized and was filtered off with suction and dried. Yield: 16.54 g (50%), M+H+: 166.07.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][CH:8]([CH3:27])[C:9]([NH:11][C:12]1[CH:17]=[C:16](Cl)[CH:15]=[C:14]([C:19]#[C:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:13]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].OB1OB(O)OB(O)O1.[C:38](=O)([O-])[O-].[K+].[K+].COCCOC>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>[C:1]([O:5][C:6](=[O:28])[NH:7][CH:8]([CH3:27])[C:9]([NH:11][C:12]1[CH:17]=[C:16]([CH3:38])[CH:15]=[C:14]([C:19]#[C:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:13]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)Nc1cc(Cl)cc(C#Cc2ccccc2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: OB1OB(O)OB(O)O1
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1cc(C#Cc2ccccc2)nc(NC(=O)C(C)NC(=O)OC(C)(C)C)c1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
A mixture of tert-butylN-[1-[[4-chloro-6-(2-phenylethynyl)pyridin-2-yl]amino]-1-oxopropan-2-yl]carbamate D3a (40 mg, 0.10 mmol), 2,4,6-trihydroxy-1,3,5,2,4,6-trioxatriborinane (36 μl, 0.26 mmol), Tetrakis(triphenylphosphine)palladium(0) (16.6 mg, 0.01 mmol), potassium carbonate (41.5 mg, 0.30 mmol), 1,2-dimethoxyethane (600 μl) and water (100 μl) is stirred for 2 day at 80° C. The mixture is concentrated in vacuo and the product purified by RP HPLC. Yield: 2 mg (5%). HPLC-MS: M+H=380; tR=2.18 min (*Method—2).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.[CH3:15][N:16]1[C:21](=[O:22])[N:20]([CH3:23])[C:19](=[O:24])[C:18]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[N:17]1>>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:28]2[CH2:27][CH2:26][N:25]([C:18]3[C:19](=[O:24])[N:20]([CH3:23])[C:21](=[O:22])[N:16]([CH3:15])[N:17]=3)[CH2:30][CH2:29]2)=[O:7])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.[F:12][C:11]([F:14])([F:13])[C:4]1[CH:3]=[CH:2][C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:5]=1[C:6]([N:28]1[CH2:27][CH2:26][N:25]([C:18]2[C:19](=[O:24])[N:20]([CH3:23])[C:21](=[O:22])[N:16]([CH3:15])[N:17]=2)[CH2:30][CH2:29]1)=[O:7]
Reactant: O=C(Cl)c1ccc(F)cc1C(F)(F)F
Reactant: Cn1nc(N2CCNCC2)c(=O)n(C)c1=O
Product: Cn1nc(N2CCN(C(=O)c3cc(C(F)(F)F)ccc3C(F)(F)F)CC2)c(=O)n(C)c1=O
Product: Cn1nc(N2CCN(C(=O)c3ccc(F)cc3C(F)(F)F)CC2)c(=O)n(C)c1=O
Yield: 61 %

Procedure:
The compound 41 (solid) is prepared from 4-fluoro-2-trifluoromethyl-benzoyl chloride and from the intermediate 12a according to the synthesis method 2 under the operating conditions described for Example 40 (yield: 61%).