Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[CH:2]([CH3:4])[CH3:3].[Br:5][C:6]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[F:19])=[C:10]([F:20])[C:9]([OH:21])=[C:8]([CH:22]=[O:23])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Br:5][C:6]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[F:19])=[C:10]([F:20])[C:9]([O:21][CH:2]([CH3:4])[CH3:3])=[C:8]([CH:22]=[O:23])[CH:7]=1
Reactant: O=Cc1cc(Br)c(-c2ccc(F)cc2F)c(F)c1O
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1c(C=O)cc(Br)c(-c2ccc(F)cc2F)c1F
Reaction time: 3 h
Yield: 94.5 %

Procedure:
2-Iodopropane (461 mg) was added at room temperature to a mixture of 6-bromo-2,2′,4′-trifluoro-3-hydroxybiphenyl-4-carbaldehyde (598 mg), potassium carbonate (499 mg), and DMF (10 mL), and the mixture was stirred at 60 C for 3 hours in a nitrogen atmosphere. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was separated, then washed with water and saturated saline in this order, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (637 mg).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:17])[N:4]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])[C:5](=[O:8])[NH:6][N:7]=1.C(N(CC)CC)C.[CH:25]([CH:27]=[CH2:28])=[O:26]>CN(C)C=O>[Br:1][C:2]1[C:3](=[O:17])[N:4]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])[C:5](=[O:8])[N:6]([CH2:28][CH2:27][CH:25]=[O:26])[N:7]=1
Reactant: C=CC=O
Reactant: O=C(c1ccccc1)n1c(=O)[nH]nc(Br)c1=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=CCCn1nc(Br)c(=O)n(C(=O)c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 103.7 %

Procedure:
To a stirring solution of 6-bromo-4-(phenylcarbonyl)-1,2,4-triazine-3,5(2H,4H)-dione (1.46 g, 4.93 mmol) in dry N,N-Dimethylformamide (DMF) (64.9 ml), TRIETHYLAMINE (0.825 ml, 5.92 mmol) was added and the mixture was stirred at room temperature for 15 minutes. Acrolein (0.366 ml, 4.93 mmol) was then added and the mixture was left stirring at room temperature for 3 hours. It was then quenched with NH4Cl saturated solution and diluted with AcOEt. Phases were separated, organic phase was washed with cold water, dried over sodium sulphate, filtered and concentrated under reduced pressure affording 3-[6-bromo-3,5-dioxo-4-(phenylcarbonyl)-4,5-dihydro-1,2,4-triazin-2(3H)-yl]propanal (1.8 g, 5.11 mmol). The compound was used for next step without purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([OH:7])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[Cl:33][C:34]1[CH:35]=[C:36]([C@H:40]([NH2:42])[CH3:41])[CH:37]=[CH:38][CH:39]=1>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([NH:42][C@@H:40]([C:36]1[CH:37]=[CH:38][CH:39]=[C:34]([Cl:33])[CH:35]=1)[CH3:41])=[O:7]
Reactant: C[C@@H](N)c1cccc(Cl)c1
Reactant: O=C(O)c1ccc(Cl)c(Br)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)c1ccc(Cl)c(Br)c1)c1cccc(Cl)c1
Reaction time: 0.25 h
Yield: 99.7 %

Procedure:
To a solution of 3-bromo-4-chlorobenzoic acid 31 (4.209 g, 17.9 mmol) in DMF (40 mL) at room temperature was added HOBT (3.31 g, 21.6 mmol) and EDCI (4.13 g, 21.5 mmol). The solution was stirred for 15 min and (R)-1-(3-chlorophenyl)ethanamine (2.92 g, 18.8 mmol) was added. The reaction mixture was stirred at room temperature for 14 h and diluted with EtOAc. The aqueous phase was extracted with EtOAc (1×), and the combined organic extracts were washed with water (2×), brine, dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash column chromatography on silica gel (eluted with 20% to 40% EtOAc in hexanes) gave (R)-3-bromo-4-chloro-N-(1-(3-chlorophenyl)ethyl)benzamide 32 (6.659 g, 99.9% yield) as a white solid. Mass spectrum: calculated for C15H12BrCl2NO 371.0. found 372.0 (M++1).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH:9]([Si:12]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[N:13]1[CH:17]=[CH:16][CH:15]=[CH:14]1)([CH3:11])[CH3:10]>C1COCC1>[Br:8][C:15]1[CH:16]=[CH:17][N:13]([Si:12]([CH:9]([CH3:11])[CH3:10])([CH:18]([CH3:20])[CH3:19])[CH:21]([CH3:23])[CH3:22])[CH:14]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cccc1
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
NBS (6.4 g) was added in one portion to a stirred solution of 1-(triisopropylsilyl)pyrrole (8.00 g) in dry THF (80 mL) at -78° C. The mixture was stirred at this temperature for 2 h, and was then allowed to warm to room temperature overnight. The solvent was removed, water was added to the residue, and the product extracted with CH2Cl2, dried (anhyd Na2SO4), filtered, and evaporated. The residue was chromatographed over silica gel (hexanes) and concentrated to provide 10.00 g of 3-bromo-1-(triisopropylsilyl)pyrrole as a colorless oil.
Reaction SMILES: [P:1]([O:13][CH2:14][C:15]1[C:20]([CH:21]2[C:26]3[S:27][C:28]4[CH2:32][C:31]([CH3:34])([CH3:33])[CH2:30][C:29]=4[C:25]=3[CH2:24][CH2:23][NH:22]2)=[CH:19][CH:18]=[CH:17][C:16]=1[C:35]1[CH:40]=[C:39]([NH:41][C:42]2[CH:47]=[CH:46][N:45]=[CH:44][N:43]=2)[C:38](=[O:48])[N:37]([CH3:49])[CH:36]=1)([O:8]CCC#N)([O:3]CCC#[N:7])=[O:2].C(#[N:52])C>C(N(CC)CC)C>[P:1]([O-:3])([O-:8])([O:13][CH2:14][C:15]1[C:20]([CH:21]2[C:26]3[S:27][C:28]4[CH2:32][C:31]([CH3:33])([CH3:34])[CH2:30][C:29]=4[C:25]=3[CH2:24][CH2:23][NH:22]2)=[CH:19][CH:18]=[CH:17][C:16]=1[C:35]1[CH:40]=[C:39]([NH:41][C:42]2[CH:47]=[CH:46][N:45]=[CH:44][N:43]=2)[C:38](=[O:48])[N:37]([CH3:49])[CH:36]=1)=[O:2].[NH4+:7].[NH4+:52]
Reactant: CC#N
Reactant: Cn1cc(-c2cccc(C3NCCc4c3sc3c4CC(C)(C)C3)c2COP(=O)(OCCC#N)OCCC#N)cc(Nc2ccncn2)c1=O
Solvent: CCN(CC)CC
Product: Cn1cc(-c2cccc(C3NCCc4c3sc3c4CC(C)(C)C3)c2COP(=O)([O-])[O-])cc(Nc2ccncn2)c1=O
Product: [NH4+]
Temperature: 0 °C
Reaction time: 40 h
Yield: 52 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer and nitrogen inlet was charged with 216a (450 mg, 0.631 mmol) and acetonitrile (8 mL), and the mixture was cooled to 0° C. Triethylamine (4 mL) was added followed bis trimethyl-silyl trifluoroacetamide (4 mL), and the mixture was stirred at room temperature for 40 h. After this time, the mixture was concentrated under reduced pressure and the resulting residue was purified by flash column chromatography (silica, 40:20:40 chloroform/methanol/ammonia) to afford 216b in 52% yield (210 mg) as an amorphous yellow solid: mp 260-262° C. d; 1H NMR (500 MHz, DMSO-d6) d 9.12 (s, 1H), 8.66 (s, 1H), 8.62 (d, J=2.0 Hz, 1H), 8.27 (d, J=4.0 Hz, 1H), 7.54 (s, 1H), 7.43 (t, J=7.5 Hz, 1H), 7.32-7.27 (m, 3H), 7.15 (br s, 2H), 4.69 (d, J=9.0 Hz, 1H), 4.46 (d, J=7.0 Hz, 1H), 3.87-3.83 (m, 3H), 3.57 (s, 3H), 3.36-3.17 (br s, 8H), 2.77-2.63 (m, 3H), 1.23 (s, 3H), 1.21 (s, 3H); MS (ESI+) m/z 608.2 (M+H for C29H30N5O6PS).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:17](O)(=[O:24])[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccncc1
Reactant: COc1ccc(N)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1ccc(NC(=O)c2ccncc2)cc1
Temperature: 23 °C
Reaction time: 4 h
Yield: 87.6 %

Procedure:
A solution of p-anisidine (2.46 g, 20 mmol) and triethylamine (13.9 mL, 100 mmol) in ethyl acetate (200 mL) was treated with isonicotinic acid (2.46 g, 20 mmol) followed by 1-propanephosphonic acid cyclic anhydride (50% in ethyl acetate, 15.1 mL, 24 mmol). After stirring at 23° C. for 4 h, the reaction mixture was diluted with ethyl acetate, was washed with water and with brine, and the organic layer was dried (MgSO4), was filtered, and was concentrated in vacuo. Purification by silica gel chromatography with chloroform-methanol (40:1) gave 4 g (88% yield) of the title compound; diagnostic 13C NMR signals (100 MHz, CD3OD/CDCl3) δ 164.825, 157.213, 149.758, 143.349, 130.989, 123.085, 122.068, 55.285; MS (AP/Cl) 229.3 (M+H)+.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].C([O:11][P:12]([CH3:16])OCC)C.P(Cl)(Cl)(Cl)(Cl)[Cl:18]>C1C=CC=CC=1.[Ni](Cl)Cl>[CH3:16][P:12]([Cl:18])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8])=[O:11]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CCOP(C)OCC
Reactant: Cc1ccccc1I
Agent: Cl[Ni]Cl
Solvent: c1ccccc1
Product: Cc1ccccc1P(C)(=O)Cl
Temperature: 160 °C

Procedure:
A mixture of o-iodotoluene and anhydrous nickel chloride is stirred under a nitrogen atmosphere at 160° C. While maintaining the temperature in a range of 160°-170° C., diethylmethylphosphonite is added dropwise to the mixture. Ethyliodide distills rapidly from the mixture. Following the addition of the phosphonite, the reaction mixture is heated at 165°-175° C., for an hour, then cooled. Upon cooling, the reaction mixture is poured onto ice-water and extracted with chloroform. The chloroform extracts are washed with water, dried over magnesium sulfate and then concentrated in vacuo to yield a colorless oil. This oil is treated directly with a solution containing phosphorous pentachloride in benzene and the resulting mixture is refluxed for 1 hour, then concentrated in vacuo to yield an oil. This oil is distilled to yield methyl-o-tolylphosphinyl chloride. The methyl-o-tolylphosphinyl chloride is added to a liter of carbon tetrachloride and the resulting mixture is heated to reflux temperatures by irradiating the mixture using a 275 watt sunlamp mounted below the pyrex glass flask. Chlorine gas is bubbled into the reaction vessel until formation of o-chloromethylphenylmethylphosphinyl chloride is 60-75% complete in order to prevent formation of the dichloro derivative. The irradiation is then stopped and the reaction mixture is concentrated in vacuo to yield an oily residue. The oily residue is fractionally distilled to remove any unreacted methyl-o-tolylphosphinyl chloride to yield o-chloromethylphenylmethylphosphinyl chloride.
Reaction SMILES: [CH:1]1([N:7]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(NC(C)C)(C)C.ClC(OC)=O.[NH2:33][C:34]1[CH:39]=[CH:38][C:37]([S:40]([CH2:43][CH2:44][CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])(=[O:42])=[O:41])=[CH:36][CH:35]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH:1]1([N:7]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:33][C:34]3[CH:39]=[CH:38][C:37]([S:40]([CH2:43][CH2:44][CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])(=[O:42])=[O:41])=[CH:36][CH:35]=3)=[O:16])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)CCCS(=O)(=O)c1ccc(N)cc1
Reactant: O=C(O)c1cc(N(CC2CC2)C2CCCCC2)ncn1
Agent: COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: CCOC(=O)CCCS(=O)(=O)c1ccc(NC(=O)c2cc(N(CC3CC3)C3CCCCC3)ncn2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A cooled (0° C.) solution of 6-(cyclohexyl(cyclopropylmethyl)amino)pyrimidine-4-carboxylic acid (Intermediate 13, 130 mg; 0.47 mmol) in DCM was treated with diisopropylamine (90 mL; 0.52 mmol) and methyl chloroformate (40 mL; 0.52 mmol). After stirring at 0° C. for 15 minutes, ethyl 4-(4-aminophenylsulfonyl)butanoate (Intermediate 48, 130 mg; 0.48 mmol) was added. After stirring at 0° C. for 30 minutes and RT for 1 hour, saturated sodium bicarbonate solution was added and the mixture stirred for 15 minutes. DCM was added and the layers separated. The organic extract was filtered through a hydrophobic frit and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C@H:12]1[C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[O:28][CH2:29][C:30]([OH:32])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:33]#[C:34][NH2:35].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[Cl:27][C:25]1[CH:24]=[CH:23][C:22]([O:28][CH2:29][C:30]([NH:35][C:34]#[N:33])=[O:32])=[C:21]([C@@H:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:19][CH2:20][N:11]2[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH:26]=1
Reactant: O=C(O)COc1ccc(Cl)cc1[C@@H]1c2ccccc2CCN1C(=O)OCc1ccccc1
Reactant: N#CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#CNC(=O)COc1ccc(Cl)cc1[C@@H]1c2ccccc2CCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-1-(2-carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (138 mg, 0.30 mmol, 1.0 eq.), cyanamide (16 mg, 0.36 mmol, 1.2 eq.), and NEt3 (84 μL, 0.60 mmol, 2 eq.) in DMF (3.3 mL), HATU (137 mg, 0.36 mmol, 1.2 eq.) was added. The reaction mixture was stirred at r.t. for 1 hour. The mixture was purified by prep. HPLC (column: Waters XBridge, 30×75 mm, 10 um, UV/MS, basic conditions) and evaporated to give a pale yellow oil, contaminated with NEt3. The contaminated product was redissolved in AcOEt and washed with 1M aq. HCl soln. and sat. aq. NaCl soln. The org. phase was dried over MgSO4, filtered and concentrated in vacuo to give the desired product as a pale yellow oil.
Reaction SMILES: CCCCCC.C([Li])CCC.[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=[O:33])=[CH:30][CH:29]=1.O>C1COCC1>[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:32]([C:31]1[CH:34]=[CH:35][C:28]([CH3:27])=[CH:29][CH:30]=1)[OH:33])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: Brc1ccccc1OCc1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C(O)c2ccccc2OCc2ccccc2)cc1
Reaction time: 0.5 h
Yield: 71.3 %

Procedure:
In a nitrogen stream, an n-butyllithium hexane solution (2.44 M, 5.65 mL) was added dropwise to a solution of 1-benzyloxy-2-bromobenzene (3.3 g, 12.54 mmol) in THF (126 mL) at −78° C. and the mixture was stirred at the same temperature for 30 minutes. To this mixture, a solution of 4-methylbenzaldehyde (1.28 g, 10.6 mmol) in THF (42 mL) was added at −78° C. The reaction mixture was stirred at the same temperature for one hour, and then water was added thereto and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:5)] to obtain the title compound (2.3 g, 71%).
Reaction SMILES: [OH-:1].[K+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([C:11]([CH3:15])([CH3:14])[C:12]#N)[CH:8]=[CH:9][CH:10]=1.C[OH:17]>O>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([C:11]([CH3:15])([CH3:14])[C:12]([OH:17])=[O:1])[CH:8]=[CH:9][CH:10]=1
Reactant: CO
Reactant: COc1cccc(C(C)(C)C#N)c1
Reactant: [OH-]
Agent: [K+]
Solvent: O
Product: COc1cccc(C(C)(C)C(=O)O)c1
Temperature: 130 °C

Procedure:
Into a round bottom flask, potassium hydroxide (35.4 g, 631 mmol) and water (225 mL, 12500 mmol) was added at 100° C. 2-(3-methoxy-phenyl)-2-methyl-propionitrile (44.20 g, 252.2 mmol) in Methanol (25.0 mL, 617 mmol) was added to the reaction mixture. The reaction was then heated to reflux at 130° C. over night. TLC suggested starting material. Potassium hydroxide (35.4 g, 631 mmoles) in water (50 mL) was added. The reaction was heated for 5 days. The reaction was partitioned with water (700 mL). The aqueous was acidified with concentrated HCl to pH 1. The solid was filtered and washed with water and EtOAc. The organic layer was separated. The aqueous was extracted with EtOAc (3×400 mL). The combined organic was washed with brine, and dried over MgSO4. The solid was then filtered and washed with EtOAc. The solvent was removed under vacuum to afford a brown oil. The oil was triturated with hexane to afford 2-(3-methoxy-phenyl)-2-methyl-propionic acid as a light yellow solid (36.2 g. 74%). H-NMR (DMSO-D6, 400 MHz): δ 12.30 (s, 1H), 7.24 (t, 1H), 6.90 (d, 1H), 6.75-6.88 (m, 2H), 3.74 (s, 3H), 1.45 (s, 6H)
Reaction SMILES: [CH3:1][Mg]Br.CON(C)[C:7](=[O:22])[C:8]1[CH:13]=[C:12]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:11]=[N:10][CH:9]=1>C(OCC)C.O1CCCC1.C(OCC)(=O)C>[C:16]1([C:15]#[C:14][C:12]2[CH:13]=[C:8]([C:7](=[O:22])[CH3:1])[CH:9]=[N:10][CH:11]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CON(C)C(=O)c1cncc(C#Cc2ccccc2)c1
Reactant: C[Mg]Br
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)c1cncc(C#Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
Add a 3.0 M solution of methylmagnesium bromide (1.25 mL, 3.8 mmol) in diethyl ether dropwise to a cooled solution of N-methoxy-N-methyl-5-phenylethynyl -nicotinamide, (prepared as described in PREPARATION 2), (1.00 g, 3.7 mmol) in tetrahydrofuran (8.0 mL) at 0° C. Warm to room temperature, stir overnight and dilute with ethyl acetate. Wash with an aqueous saturated solution of ammonium chloride, dry (magnesium chloride), filter and concentrate. Purify the residue by silica gel chromatography, eluting with 10:90 to 30:70 tetrahydrofuran:hexanes, to give the title compound as a white solid (0.70 g, 84%).
Reaction SMILES: [C:1](O)(=O)/C=C\C(O)=O.[C:9]([O:16][CH3:17])(=[O:15])/[CH:10]=[CH:11]\[C:12]([O-:14])=[O:13]>CO>[C:12]([O:14][CH3:1])(=[O:13])/[CH:11]=[CH:10]\[C:9]([O:16][CH3:17])=[O:15]
Reactant: O=C(O)/C=C\C(=O)O
Reactant: COC(=O)/C=C\C(=O)[O-]
Solvent: CO
Product: COC(=O)/C=C\C(=O)OC

Procedure:
This example relates particularly to FIG. 3 and illustrates use of a side heater in the reaction column. In this example a 95 wt % solution of aqueous maleic acid is provided as described in Example 1. The aqueous maleic acid feed is mixed with recycle methanol from the refining section (line 38/16a′) and fed to a plug flow, mono-ester reactor (36), where more than 80% of the maleic acid is converted to mono-methyl maleate. The product from this is fed to reaction column (19′) to react to the mono-methyl maleate with methanol to produce di-methyl maleate. This reaction column includes a heater near the feed point. The heater helps to drive off water from the column. 350 moles per hour of methanol (lines 42 and 41) are fed to the bottom of the reaction column (19′). Essentially water free, fully converted di-methyl maleate (line 26′) is fed to hydrogenation (20). Recycle methanol from the refining section is fed to the top of the reaction column as wash (line 16b′) to minimize the di-methyl maleate and maleic acid in the overhead of the column. Methanol or water from the overhead (line 31′) of the reaction column is fed to the methanol column (25′) where the methanol is separated and recycled to the reaction column (line 39). Water and a small amount of recovered maleic acid and di-methyl maleate from the bottom of the methanol column are recycled to the absorber (2) in line 3′.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:11](=[O:16])[N:10]([S:17]([C:20]3[CH:25]=[CH:24][C:23]([CH:26]=[O:27])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[N:9]=2)=[CH:4][CH:3]=1.CC(=CC)C.Cl([O-])=[O:34].[Na+]>CC(C)=O.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:11](=[O:16])[N:10]([S:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([OH:34])=[O:27])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[N:9]=2)=[CH:4][CH:3]=1
Reactant: [O-][Cl+][O-]
Reactant: O=Cc1ccc(S(=O)(=O)n2nc(-c3ccc(Cl)cc3)n(C3CC3)c2=O)cc1
Agent: CC=C(C)C
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(S(=O)(=O)n2nc(-c3ccc(Cl)cc3)n(C3CC3)c2=O)cc1
Reaction time: 16 h

Procedure:
An amount of 345 mg (0.73 mmol) of the compound from Example 14A and also 0.58 ml (5.45 mmol) of 2-methyl-2-butene were dissolved in 3 ml of acetone and admixed at RT with a solution of 376 mg (2.73 mmol) of sodium dihydrogenphosphate-1-hydrate and 460 mg (4.07 mmol) of sodium chlorite in 9 ml of water. The mixture was stirred at this temperature for 16 hours thereafter and then diluted with 15 ml of water and with 15 ml of ethyl acetate. After the phases had been separated, the aqueous phase was further extracted with 15 ml of ethyl acetate, and the combined organic phases were washed with saturated sodium chloride solution and dried over magnesium sulphate. Following filtration, the solvent was concentrated and the residue was dried in a high vacuum. This gave 337 mg (104% of theory) of the target compound, which was reacted further without additional purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[N:11]=[C:12]4[C:18]([C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:17][N:16](COCC[Si](C)(C)C)[C:13]4=[N:14][CH:15]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C(O[C:38]([N:40]1CCC(OS(C)(=O)=O)[CH2:42][CH2:41]1)=O)(C)(C)C.Cl.Cl[CH2:53][C:54]1C=CC=CN=1>>[CH3:21][C:20]([CH3:23])([CH3:22])[C:19]([C:18]1[C:12]2[C:13](=[N:14][CH:15]=[C:10]([C:6]3[CH:7]=[C:2]4[C:3]([CH:53]=[CH:54][N:1]4[CH:9]4[CH2:8][CH2:38][NH:40][CH2:41][CH2:42]4)=[CH:4][CH:5]=3)[N:11]=2)[NH:16][CH:17]=1)=[O:24]
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3ccc4[nH]ccc4c3)nc12
Reactant: ClCc1ccccn1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: Cl
Product: CC(C)(C)C(=O)c1c[nH]c2ncc(-c3ccc4ccn(C5CCNCC5)c4c3)nc12

Procedure:
Substituting 1-[2-(1H-indol-6-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one for 1-[2-(1H-indol-5-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one and 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester for 2-chloromethylpyridine hydrochloride. MP=201-207 C., (M+H)+=402.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([CH2:15][C:16]([OH:18])=[O:17])[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=1)=[O:22]>>[C:1]([O:5][C:6]([NH:8][C:9]1([CH2:15][C:16]([O:18][CH2:20][C:21](=[O:22])[C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]([F:31])([F:32])[F:33])=[CH:25][CH:24]=2)=[O:17])[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(CC(=O)O)CCOCC1
Reactant: O=C(CBr)c1ccc(OC(F)(F)F)cc1
Product: CC(C)(C)OC(=O)NC1(CC(=O)OCC(=O)c2ccc(OC(F)(F)F)cc2)CCOCC1
Temperature: 50 °C
Reaction time: 0.83 h
Yield: 105.1 %

Procedure:
Prepared by Method F using {4-[(tert-butoxycarbonyl)amino]tetrahydro-2H-pyran-4-yl}acetic acid (0.259 g, 1.00 mmol) and 2-bromo-1-[4-(trifluoromethoxy)phenyl]-ethanone (0.283 g, 1.00 mmol). The reaction was stirred at 50° C. for 50 minutes. The residue was isolated as a crude oil that crystallised to afford the title compound as a solid (0.485 g, 105% yield).