Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C2OC(C)=C(COC3C=CC(CO[C:20]4[C:24]([CH:25]=O)=[CH:23][N:22]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[N:21]=4)=CC=3)N=2)C=CC=CC=1.Cl.NO.[N:39]1C=CC=CC=1.C(O)C>O>[C:27]1([N:22]2[CH:23]=[C:24]([C:25]#[N:39])[CH:20]=[N:21]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: c1ccncc1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2nn(-c3ccccc3)cc2C=O)cc1
Agent: Cl
Agent: NO
Solvent: CCO
Solvent: O
Product: N#Cc1cnn(-c2ccccc2)c1
Yield: 137.6 %

Procedure:
A mixture of 3-[{4-[(2-phenyl-5-methyl-1,3-oxazol-4-yl)methoxy]benzyl}oxy]-1-phenyl-1H-pyrazole-4-carbaldehyde (0.70 g), hydroxylamine hydrochloride (0.16 g), pyridine (0.30 g) and ethanol (30 mL) was heated under reflux for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. Acetic anhydride (20 mL) was added to residue, and the mixture was heated under reflux for 2 hrs. The reaction mixture was concentrated and ethyl acetate was added to the residue. The ethyl acetate layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 3-({4-[(2-phenyl-5-methyl-1,3-oxazol-4-yl)methoxy]benzyl}oxy)}-1-phenyl-1H-pyrazole-4-carbonitrile as colorless crystals (0.35 g, 51%) from a fraction eluted with ethyl acetate-hexane (1:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 162-163° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8]O)[CH:5]=[N:6][CH:7]=1.C1(P([N:24]=[N+:25]=[N-:26])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>C1COCC1>[N:24]([CH2:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1)=[N+:25]=[N-:26]
Reactant: OCc1cncc(Br)c1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: [N-]=[N+]=NCc1cncc(Br)c1
Reaction time: 8 h
Yield: 93.3 %

Procedure:
To a solution of (5-bromo-pyridin-3-yl)-methanol 249 (1.4 g, 7.5 mmol, 1.00 equiv) and diphenylphosphoryl azide (2.4 mL, 9.0 mmol, 1.2 equiv) in THF (15 mL) at it was added 1,8-diazabicyclo[5.4.0]undec-7-ene (1.4 mL, 9.0 mmol, 1.2 equiv). The resulting solution was stirred overnight, concentrated and chromatographically purified (15% ethyl acetate in hexanes) to give 3-azidomethyl-5-bromo-pyridine 250 (1.49 g). LCMS (MH)+=212.9, rt=1.50 min.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[C:15](Cl)[N:14]=[C:13]([O:18][CH3:19])[N:12]=2)[CH2:7][CH2:6]1)=[O:4].[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[CH2:28][CH2:29][NH2:30].C(=O)(O)[O-].[Na+].CN1CCCC1=O>O>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[C:15]([NH:30][CH2:29][CH2:28][C:22]3[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:21]=3[Cl:20])[N:14]=[C:13]([O:18][CH3:19])[N:12]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1CCN(c2cc(Cl)nc(OC)n2)CC1
Reactant: NCCc1ccc(Cl)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)C1CCN(c2cc(NCCc3ccc(Cl)cc3Cl)nc(OC)n2)CC1
Temperature: 140 °C
Reaction time: 12 h
Yield: 44.3 %

Procedure:
In a tube is combined 1-(6-chloro-2-methoxy-pyrimidin-4-yl)-piperidine-4-carboxylic acid methyl ester [103 mg, 0.36 mmol], 2-(2,4-dichloro-phenyl)-ethylamine (0.163 mL, 1.08 mmol), sodium bicarbonate (181 mg, 2.16 mmol) and N-methylpyrrolidinone (2 mL). The mixture is heated at 140° C. for 12 h. Additional 2-(2,4-dichloro-phenyl)-ethylamine (0.2 mL, 1.33 mmol) is added and heating at 140° C. is continued for another 12 h. The mixture is diluted with water (30 mL) and extracted twice with EtOAc (30 mL). The organic extracts are washed twice with water (40 mL) and once with brine (30 mL), combined, dried over magnesium sulfate, filtered and concentrated. The residue is subjected to chromatography on silica gel eluting with 40% ethyl acetate:heptane to afford 1-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-piperidine-4-carboxylic acid methyl ester [70 mg, 44%] as a solid.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[NH2:19][C:20]1([CH2:24][C:25]([NH:27][CH3:28])=[O:26])[CH2:23][O:22][CH2:21]1>>[CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([NH:19][C:20]3([CH2:24][C:25]([NH:27][CH3:28])=[O:26])[CH2:23][O:22][CH2:21]3)=[O:12])=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2CC2)cn1
Reactant: CNC(=O)CC1(N)COC1
Product: CNC(=O)CC1(NC(=O)c2cc(OCC(F)(F)F)c(C3CC3)cn2)COC1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-Cyclopropyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 48c) and 2-(3-aminooxetan-3-yl)-N-methyl-acetamide (example 231a) as starting materials and isolated (25 mg, 43%); MS (ESI, m/z): 388.6 (M+H+).
Reaction SMILES: [C:1]([O:9]CC)(=O)[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[H][H].[CH2:16]([N:23]1[C:28]2[CH:29]=[CH:30][C:31]([F:33])=[CH:32][C:27]=2[C:26](=O)[O:25]C1=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl>CC(N(C)C)=O>[CH2:6]([O:5][C:3]([C:2]1[C:1](=[O:9])[N:23]([CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:28]2[C:27]([C:26]=1[OH:25])=[CH:32][C:31]([F:33])=[CH:30][CH:29]=2)=[O:4])[CH3:7]
Reactant: O=c1oc(=O)n(Cc2ccccc2)c2ccc(F)cc12
Reactant: [H][H]
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1c(O)c2cc(F)ccc2n(Cc2ccccc2)c1=O
Temperature: 90 °C
Yield: 70.7 %

Procedure:
Neat diethyl malonate (0.89 mL, 5.8 mmol) was added slowly to a suspension of sodium hydride (60% in mineral oil, 256 mg, 6.41 mmol) in dimethylacetamide under N2 atmosphere. The mixture was stirred at room temperature until the evolution of hydrogen gas ceased, then the mixture was heated to 90° C. for 30 min and cooled to room temperature. A solution of Compound 36 (1.74 g, 6.41 mmol) in dimethylacetamide was added slowly to the mixture, which was heated overnight at 110° C. The mixture was cooled to room temperature, poured into ice water, and acidified by cold 10% HCl. The solids formed were filtered, washed several times by water, and dried at room temperature under vacuum to yield 1.4 g (64%) of white solids. M.P. 129° C. 1H NMR (DMSO-d6): δ 1.30 (t, J=6.9 Hz, 3H), 4.34 (q, J=6.9 Hz, 2H), 5.46 (s, 2H), 7.17–7.24 (m, 5H), 7.38 (dd, J=4.6, 9.6 Hz, 1H), 7.50 (td, J=2.9, 8.3 Hz, 1H), 7.80 (dd, J=3.1, 9.4 Hz, 1H). EIMS m/z 342 (M+1), 364 (M+23). Anal. (C19H16FNO4) C, H, N.
Reaction SMILES: [O:1]=[C:2]([CH3:20])[CH2:3][CH2:4][C:5]1[CH:19]=[CH:18][C:8]([O:9][CH2:10][CH2:11][CH2:12][C:13]([O:15]CC)=[O:14])=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+]>CO.O>[O:1]=[C:2]([CH3:20])[CH2:3][CH2:4][C:5]1[CH:19]=[CH:18][C:8]([O:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:7][CH:6]=1
Reactant: CCOC(=O)CCCOc1ccc(CCC(C)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(=O)CCc1ccc(OCCCC(=O)O)cc1
Yield: 59.9 %

Procedure:
4-[4-(3-Oxobutyl)phenoxy]butanoic acid, ethyl ester (716 mg, 2.57 mmol) is dissolved in 5 mL of methanol/water (3:2) and treated with 1.24 g (9.0 mmol) of potassium carbonate according to the procedure described for Example 4 to give 385 mg (60%) of 4-[4-(3-oxobutyl)phenoxy]butanoic acid as a white powder: m.p. 97°-99°; the 1H NMR (300 MHz, CDCl3) is consistent with the desired product; IR (neat) 1730, 1700, 1620, 1520 cm-1 ; Analysis calculated for C14H18O4 : C, 67.18; H, 7.25; found: C, 66.55; H, 7.09.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:8]([O:18][CH:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)[C:9]2[S:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1.C(O)CO.C(=O)([O-])[O-].[K+].[K+].[CH2:36]([NH2:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>[Cu]I.CC(O)C>[S:10]1[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=[C:9]1[CH:8]([O:18][CH:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1)[C:4]1[CH:3]=[C:2]([NH:43][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: NCc1ccccc1
Reactant: CN1CCC(OC(c2cccc(I)c2)c2nc3ccccc3s2)CC1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CC(C)O
Product: CN1CCC(OC(c2cccc(NCc3ccccc3)c2)c2nc3ccccc3s2)CC1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
A screw-capped tube is charged with 2-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole (example 41, 190 mg), copper(I) iodide (4 mg), ethylene glycol (45 μL), potassium carbonate (173 mg), benzylamine (54 μL), and propan-2-ol (1 mL). The tube is evacuated, filled with argon and sealed. After stirring at 80° C. for 15 h, the mixture is diluted with ethyl acetate and water and the aqueous phase is extracted with ethyl acetate. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography (gradient dichloromethane/methanol/ammonia from 98/2/0.5 to 95/5/0.5). The base is converted into its dioxalate salt in acetone to give {3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}benzyl-amine, dioxalate melting at 75° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].Cl[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16](CC([O-])=O)[CH:17]=2)[N:12]=[CH:11][N:10]=1.C(=O)([O-])[O-:24].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([OH:24])[CH:17]=2)[N:12]=[CH:11][N:10]=1
Reactant: Nc1ccccn1
Reactant: O=C([O-])[O-]
Reactant: O=C([O-])Cc1ccc2ncnc(Cl)c2c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: Oc1ccc2ncnc(Nc3ccccn3)c2c1
Temperature: 120 °C
Reaction time: 2 h
Yield: 64.4 %

Procedure:
To a solution of pyridin-2-amine (101 mg, 1.08 mmol) and 4-chloroquinazolin-6-ylacetate (200 mg, 0.90 mmol) in toluene (4 ml), tris(dibenzylideneacetone)dipalladium (0) (82.0 mg, 0.090 mmol), (±)BINAP (112.0 mg, 0.180 mmol) and cesium carbonate (585 mg, 1.80 mmol) were added, and the mixture was stirred under nitrogen atmosphere at 120° C. for 2 hours. The reaction liquid was filtered, followed by vacuum concentration of the filtrate. The residue was suspended in water and then extracted with chloroform, and thereafter the combined organic layers were washed with water and a saturated saline solution and dried over anhydrous sodium sulfate, followed by being concentrated under reduced pressure. The resultant residue was dissolved in ammonia water (1 ml) and methanol (4 ml), and the solution was stirred at 50° C. for 2 hours. The reaction solution was cooled to room temperature and then concentrated under reduced pressure, the resultant residue was suspended in ether, and the precipitate was obtained through filtration, washed with ether and then dried to give 4-(pyridin-2-ylamino)quinazolin-6-ol (138 mg, yield: 64%) as a brown solid.
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([OH:16])=O)[C:9]1=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][C:19]1[CH:34]=[CH:33][C:22]([O:23][C:24]2[CH:29]=[CH:28][N:27]=[C:26]([C:30]([NH2:32])=[O:31])[CH:25]=2)=[C:21]([F:35])[CH:20]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([NH:18][C:19]2[CH:34]=[CH:33][C:22]([O:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26]([C:30]([NH2:32])=[O:31])[CH:25]=3)=[C:21]([F:35])[CH:20]=2)=[O:16])[C:9]1=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1cc(Oc2ccc(N)cc2F)ccn1
Reactant: O=C(O)c1cccn(Cc2ccccc2)c1=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)c1cc(Oc2ccc(NC(=O)c3cccn(Cc4ccccc4)c3=O)cc2F)ccn1
Reaction time: 12 h
Yield: 69.2 %

Procedure:
A homogeneous solution of 1-benzyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (0.10 g, 0.41 mmol, 1.0 eq), 4-(4-amino-2-fluorophenoxy)picolinamide (0.10 g, 0.41 mmol, 1.0 eq) and TBTU (0.17 g, 0.45 mmol, 1.1 eq) in DMF (2 mL) was treated with DIPEA (0.18 mL, 1.0 mmol, 2.5 eq) at room temperature and the reaction mixture was stirred for 12 h. The reaction mixture was quenched with 10% aqueous LiCl (15 mL) and the resulting solution was extracted with ethyl acetate (4×40 mL). The combined organic extracts were washed with 10% aqueous LiCl (4×50 mL), dried (Na2SO4), filtered and the filtrate concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, eluting with ethyl acetate) to afford the product (0.13 g, 67%) as a solid. 1H NMR (DMSO-d6) δ 12.26 (s, 1H), 8.49-8.56 (m, 2H), 8.33-8.36 (m, 1H), 8.15 (br m, 1H), 8.03-8.07 (m, 1H), 7.74-7.75 (m, 1H), 7.51-7.54 (m, 1H), 7.41-7.46 (m, 4H), 7.20-7.24 (m, 3H), 6.71 (dd, 1H, J=6.89 Hz), 5.32 (s, 2H) HRMS (ESI+), Calcd.: 477.1374. found: 477.1378.
Reaction SMILES: [C:1]1([CH2:9]O)[C:2]([CH2:7][OH:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.C(Br)(Br)(Br)[Br:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[OH:8][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH2:9][Br:12]
Reactant: OCc1ccccc1CO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: OCc1ccccc1CBr
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 1.2 benzenedimethanol (1.41 g, 10 mmol), carbontetrabromide (3.648 g, 11 mmol), triphenylphosphine (2.885 g, 11 mmol) in dry methylene chloride (50 ml) was stirred at rt over 2 days under argon. The solvent was removed under reduced pressure and the residue chromotographed (flash silica gel, 1:1 t-butyl methyl ether: hexanes) to afford the title compound as a white solid. (0.99 g, 49%)
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH2:12]([N+:30]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:33]([CH3:34])=[CH:32][CH:31]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].Cl[C:42]1[CH:47]=[CH:46][C:45]([N+:48]([O-:50])=[O:49])=[CH:44][C:43]=1[C:51]([F:54])([F:53])[F:52].C(N(C(C)C)CC)(C)C>C(#N)C>[N+:48]([C:45]1[CH:46]=[CH:47][C:42]([CH:34]=[C:33]2[C:35]3[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:30]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:31]=[CH:32]2)=[C:43]([C:51]([F:52])([F:53])[F:54])[CH:44]=1)([O-:50])=[O:49]
Reactant: O=[N+]([O-])c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CCCCCCCCCCCCCCCCCC[n+]1ccc(C)c2ccccc21
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCCCCCCCCCCCCCCCCCN1C=CC(=Cc2ccc([N+](=O)[O-])cc2C(F)(F)F)c2ccccc21

Procedure:
A mixture of 1-octadecyllepidinium p-toluenesulfonate (24.6 g.), 2-chloro-5-nitrobenzotrifluoride (10 g.) and acetonitrile (700 ml.) was treated with diisopropylethylamine (20.7 g.) and refluxed for 6 hours with stirring. After filtering and evaporating, 1,4-dihydro-4-(4-nitro-2-trifluoromethylbenzylidene)-1-octadecylquinoline was formed. This colored dye was changed to the colorless compound having the formula: ##STR5## by reacting with a molar equivalent of p-toluenesulfonic acid in methanol.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([S:18]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)(=[O:20])=[O:19])[CH2:14][C@@H:13]2[CH2:26][NH:27][CH:28]([CH3:30])[CH3:29])=[CH:8][CH:7]=1)([OH:5])[CH3:4].[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([S:39](Cl)(=[O:41])=[O:40])[CH:34]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:30][CH:28]([N:27]([CH2:26][C@H:13]1[CH2:14][N:15]([S:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)(=[O:20])=[O:19])[CH2:16][CH2:17][N:12]1[C:9]1[CH:8]=[CH:7][C:6]([C:3]([OH:5])([CH3:4])[C:2]([F:1])([F:31])[F:32])=[CH:11][CH:10]=1)[S:39]([C:35]1[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=1)(=[O:41])=[O:40])[CH3:29]
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: CC(C)NC[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc(C(C)(O)C(F)(F)F)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)N(C[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc(C(C)(O)C(F)(F)F)cc1)S(=O)(=O)c1cccnc1
Reaction time: 2 h
Yield: 93.4 %

Procedure:
To a solution of 1,1,1-trifluoro-2-(4-((2S)-2-(((1-methylethyl)amino)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (0.100 g, 0.203 mmol, Example 195, Step 1) in CH2Cl2 (5.0 mL) was added 4-dimethylaminopyridine (0.005 g, 0.061 mmol), pyridine-3-sulfonyl chloride (0.072 g, 0.407 mmol, WAKO, Richmond, Va.) and Hünig's base (0.106 mL, 0.610 mmol). After 2 h at room temperature, the solvent was removed and the crude product was purified by column chromatography (40 g of silica, 20 to 40% acetone in hexanes) to give N-(1-methylethyl)-N-(((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-pyridinesulfonamide (0.120 g) as a mixture of two isomers.
Reaction SMILES: [CH3:1][SiH:2]([O:5][CH3:6])[O:3][CH3:4].[CH2:7]([Cl:11])[C:8](=[CH2:10])[CH3:9]>[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Ru].[Ru].[Ru]>[Cl:11][CH2:7][CH:8]([CH3:9])[CH2:10][Si:2]([CH3:1])([O:5][CH3:6])[O:3][CH3:4]
Reactant: C=C(C)CCl
Reactant: CO[SiH](C)OC
Agent: [Ru]
Agent: [C-]#[O+]
Product: CO[Si](C)(CC(C)CCl)OC
Temperature: 80 °C
Yield: 69.7 %

Procedure:
The procedure of Example 3 was repeated using 30.1 g of methyldimethoxysilane (1.15 equiv.), 0.0030 g of Ru3 (CO)12 (27 ppm of Ru), and 22.7 g of methallyl chloride (MAC). The MAC was added dropwise to the reactor containing the methyldimethoxysilane over 2 hours at 60° C., followed by heating the reaction mixture at 80° C. for 19 additional hours. Vacuum distillation at 5° C./22 mm provided 34.4 g (63% yield) of 3-chloro-2-methylpropylmethyldimethoxysilane. This example demonstrates that good yields are obtained when MAC is substituted for AC, and methyldimethoxysilane is substituted for TMS, in the absence of inert solvent and using only 27 ppm of Ru.
Reaction SMILES: N[C:2]1[C:10]2[N:9]=[C:8]3[CH2:11][CH2:12][CH2:13][N:7]3[C:6]=2[CH:5]=[C:4]([CH3:14])[CH:3]=1.P([O-])([O-])([O-])=[O:16].[K+].[K+].[K+].[O]N(S(=O)([O-])=O)S(=O)([O-])=O.[K+].[K+].[K+].[Br-].[OH2:37]>C(Cl)(Cl)Cl.CO>[CH3:14][C:4]1[C:5](=[O:37])[C:6]2[N:7]3[CH2:13][CH2:12][CH2:11][C:8]3=[N:9][C:10]=2[C:2](=[O:16])[CH:3]=1
Reactant: O=P([O-])([O-])[O-]
Reactant: O
Reactant: Cc1cc(N)c2nc3n(c2c1)CCC3
Agent: [Br-]
Agent: [K+]
Agent: [O]N(S(=O)(=O)[O-])S(=O)(=O)[O-]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC1=CC(=O)c2nc3n(c2C1=O)CCC3
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 218 mg (0.83 mmol) of 25 in 10 mL of water, containing 200 mg of monobasic potassium phosphate, was added a solution of 1.34 g of Fremy's salt in 50 mL of water containing 500 mg of monobasic potassium phosphate. The reaction mixture was stirred at room temperature for 2 hours and extracted with 3×50 mL portions of chloroform. The dried extracts (sodium sulfate) were concentrated and then chromatographed over silica gel, employing chloroform as the eluant, to afford yellow-colored 26, 105 mg (61%) yield. Recrystallization from chloroform/hexane afforded analytically pure 26: mp 162°-164° C.; TLC (methanol chloroform[10:90]), Rf =0.62; IR(KBr pellet) 1675, 1659, 1647, 1515, 1154 cm-1 ; 1H NMR (dimethyl sulfoxide-d6) δ6.54 (1 H, quartet, J=1.6 Hz, C(6) proton coupled to 7-methyl), 4.16 (2 H, t, J~7 Hz, C(1) methylene), 2.86 (2 H, t, J~7 Hz, C(3) methylene), 2.62 (2 H, quintet, J~7 Hz, C(2) methylene), 2.00 (3 H, d, J=1.6 Hz, 7-methyl coupled to C(6) proton); mass spectrum (EI mode) m/z 202 (P+), 174 (P+ -CO), 146 (P+ -2CO), Anal. Calcd for C11H10N2O2 : C, 65.33; H, 4.98; N, 13.85. Found: C, 65.15; H, 4.70; N, 13.61.
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([CH3:10])[N:7]=[C:6]([C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([O:22][CH3:23])[CH:16]=2)=[O:12])[CH:5]=1)(=[O:3])[CH3:2].[CH:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[N:27][CH:26]=1.[Cl-].[Al+3].[Cl-].[Cl-].O>C(Cl)Cl>[F:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][NH:13][C:11]([C:6]2[CH:5]=[C:4]([C:1](=[O:3])[CH:2]=[CH:24][C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)[N:9]=[C:8]([CH3:10])[N:7]=2)=[O:12])=[CH:16][C:17]=1[O:22][CH3:23]
Reactant: COc1cc(CNC(=O)c2cc(C(C)=O)nc(C)n2)ccc1F
Reactant: O=Cc1cccnc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: COc1cc(CNC(=O)c2cc(C(=O)C=Cc3cccnc3)nc(C)n2)ccc1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 23.4 %

Procedure:
To a cold solution of 6-acetyl-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide (0.050 g, 0.158 mmol, Preparation #23) and nicotinaldehyde (0.0168 mg, 0.158 mmol) in DCM (2 mL) was added aluminium chloride (0.02311 g, 0.173 mmol). The reaction mixture was allowed to stir for 15 minutes and added TEA (0.033 mL, 0.236 mmol). The reaction mixture was slowly warmed to RT and stirred for 3 h. The reaction mixture was heated to about 50° C. for 0.5 h then cooled to RT and poured into cold water (20 mL) and the product was extracted with diethyl ether (2×20 mL). The organic layer was washed successively with water (1×20 mL), brine (1×20 mL), dried over sodium sulphate and evaporated to dryness. The residue obtained was purified by preparative TLC eluting with 50% EtOAC/hexane to afford N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(3-(pyridin-3-yl)acryloyl)pyrimidine-4-carboxamide 0.015 g, (23.42%), 1H NMR (400 MHz, DMSO): δ 9.59 (bs, 1H) 9.00 (s, 1H) 8.67 (s, 1H) 8.33-8.17 (m, 3H) 8.00-7.96 (m, 1H) 7.52-7.51 (m, 1H) 7.19-7.17 (m, 2H) 6.92-6.91 (m, 1H) 4.51-4.49 (m, 2H) 3.82 (s, 3H) 2.89 (s, 3H), MS m/z: 407 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:8]([C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=3)[CH:9]=[CH:10][N:11]=2)=[CH:3][CH:2]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=1[N:30]=[C:31]=[O:32]>C(Cl)Cl.CN(C=O)C>[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=1[NH:30][C:31]([NH:18][C:15]1[CH:16]=[CH:17][C:12]([N:8]2[CH:9]=[CH:10][N:11]=[C:7]2[C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)=[CH:13][CH:14]=1)=[O:32]
Reactant: Nc1ccc(-n2ccnc2-c2ccncc2)cc1
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(-n2ccnc2-c2ccncc2)cc1)Nc1cc(C(F)(F)F)ccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(2-Pyridin-4-yl-imidazol-1-yl)-phenylamine (100 mg, 0.424 mmol) in DCM (4.0 mL) and DMF (1.0 mL) is added 1-fluoro-2-isocyanato-4-trifluoromethyl-benzene (91 mg, 0.445 mmol, 1.05 equiv) and allowed to stir for 2 h at RT. All solvent is then removed under reduced pressure and the resulting solid was purified by column chromatography (5% MeOH:95% DCM) to afford 1-(2-Fluoro-5-trifluoromethyl-phenyl)-3-[4-(2-pyridin-4-yl-imidazol-1-yl)-phenyl]-urea as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[NH:9][C:10](=[O:12])[CH3:11].[C:13](Cl)(Cl)=[O:14]>C(#N)C>[C:10]([N:9]1[C:3]2[C:4]([Br:8])=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][C:13]1=[O:14])(=[O:12])[CH3:11]
Reactant: O=C(Cl)Cl
Reactant: CC(=O)Nc1c(N)cccc1Br
Solvent: CC#N
Product: CC(=O)n1c(=O)[nH]c2cccc(Br)c21
Reaction time: 0.17 h

Procedure:
To a solution of N-(2-amino-6-bromophenyl)acetamide from Step A (3.5 g, 15.28 mmol) in acetonitrile (100 mL) was added phosgene (1.9 M in toluene, 8 mL, 15.2 mmol). After 10 min, the mixture was concentrated, redissolved in water, and the solid was collected by filtration, washed with H2O and dried in vacuo to give the title compound. MS: m/z=256 (M+1).