Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:11]2[CH2:16][CH2:15][N:14]([S:17]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH2:13][CH2:12]2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[CH3:27][N:28](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[CH3:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([C:27]#[N:28])=[CH:3][CH:4]=1)([N:11]1[CH2:16][CH2:15][N:14]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:13][CH2:12]1)[CH3:10]
Reactant: Cc1ccc(S(=O)(=O)N2CCN(C(C)(C)c3ccc(Br)cc3)CC2)cc1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1ccc(S(=O)(=O)N2CCN(C(C)(C)c3ccc(C#N)cc3)CC2)cc1
Yield: 47 %

Procedure:
To a solution of 1-[1-(4-bromo-phenyl)-1-methyl-ethyl]-4-(toluene-4-sulfonyl)-piperazine (200 mg, 0.45 mmol) in DMF (3 mL) was added zinc cyanide (64.41 mg, 0.54 mmol) and tetrakis(triphenylphosphine)palladium(0) (52 mg, 0.045 mmol) and the reaction mixture degassed for 10 min under N2. The reaction mixture was then subjected to microwave irradiation for 30 min at 180° C., afterwhich time the reaction was diluted with 1:1 CH2Cl2/EtOAc (20 mL), washed with water (2×10 mL), passed through a phase separation cartridge and concentrated in vacuo. The crude residue was purified by reverse phase preparative HPLC-MS to afford 4-{1-methyl-1-[4-(toluene-4-sulfonyl)-piperazin-1-yl]-ethyl]-benzonitrile as a cream solid (70 mg, 47%).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=[CH:22][N:21]=1>CC(C)=O>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=[CH:22][N:21]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Reactant: Clc1ncnc2ccccc12
Solvent: CC(C)=O
Product: c1cc(CN2CCCCC2)cc(OCCCNc2ncnc3ccccc23)c1
Yield: 16 %

Procedure:
3-[3-(Piperidinomethyl)phenoxy]propylamine (2.48 g) and 4-chloroquinazoline (1.64 g) were stirred in acetone (30 ml) at room temperature for 7 days. The acetone was evaporated and the oily residue was dissolved in 2 Normal hydrochloric acid. The acidic solution was extracted with ethyl acetate. The aqueous solution was then basified to pH 9 and was extracted with ethyl acetate. A solid crystallised from the basic ethyl acetate extract and was collected and dissolved in chloroform. The chloroform solution was washed with water, dried and evaporated to dryness. The residue was recrystallised from ethyl acetate to yield the title compound (0.6 g), m.p. 111° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[C:10]2[S:15](Cl)(=[O:17])=[O:16])(=[O:3])[CH3:2].[CH3:19][NH2:20]>C(O)C>[CH3:19][NH:20][S:15]([C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[CH:12]=[CH:13][CH:14]=[C:5]2[NH:4][C:1](=[O:3])[CH3:2])(=[O:17])=[O:16]
Reactant: CC(=O)Nc1cccc2c(S(=O)(=O)Cl)cccc12
Reactant: CN
Solvent: CCO
Product: CNS(=O)(=O)c1cccc2c(NC(C)=O)cccc12

Procedure:
1.10 g of 5-acetylaminonaphthalene-1-sulfonyl chloride is dissolved in 8 mL of ethanol and 8 mL of methylamine solution in ethanol are added dropwise. Then the resulting mixture is stirred at reflux temperature for 3.5 hours and the solvent is distilled off in vacuo. The residue is purified by chromatography. Yield: 0.50 g.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[CH:22]([O:25][CH2:26][CH:27]1[CH2:29][O:28]1)([CH3:24])[CH3:23]>>[OH:28][CH:27]([CH2:26][O:25][CH:22]([CH3:24])[CH3:23])[CH2:29][N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: CC(C)OCC1CO1
Product: CC(C)OCC(O)CN1CCC2(CC1)CSC1=C(O2)c2ccccc2C(=O)C1=O

Procedure:
Compound 169 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 2-(isopropoxymethyl)oxirane and conditions outlined in procedure X. M.p.=97-99° C.; 400 MHz 1H NMR (DMSO-d6) δ: 7.95-7.9 (m, 1H), 7.94-7.7 (m, 2H), 7.65-7.5 (m, 1H), 4.42 (br. s, 1H), 3.72 (br. s, 1H), 3.6-3.45 (m, 1H), 3.35-3.2 (m, 2H), 3.07 (s, 2H), 2.8 (m, 2H), 2.5-2.2 (m, 4H), 2.05-1.7 (m, 4H), 1.07 (d, J=5.2 Hz, 6H); LCMS: 418 [M+H].
Reaction SMILES: [NH2:1][C@@H:2]([CH2:12][CH:13]([CH3:15])[CH3:14])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=1)[OH:4].I[C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[N:21]=[CH:20]2.C(=O)([O-])[O-].[Cs+].[Cs+].C(#N)C(C)C>[Cu]I>[F:11][C:7]1[CH:6]=[C:5]([CH:3]([O:4][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[N:21]=[CH:20]3)[C@H:2]([CH2:12][CH:13]([CH3:15])[CH3:14])[NH2:1])[CH:10]=[CH:9][CH:8]=1
Reactant: Fc1ccc(-n2ncc3cc(I)ccc32)cc1
Reactant: CC(C)C[C@H](N)C(O)c1cccc(F)c1
Agent: [Cu]I
Agent: CC(C)C#N
Agent: O=C([O-])[O-]
Product: CC(C)C[C@H](N)C(Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1cccc(F)c1
Yield: 23.3 %

Procedure:
(2S)-2-Amino-1-(3-fluorophenyl)-4-methyl-pentane-1-ol (350 mg, 1.66 mmol), 5-iodo-1-(4-fluorophenyl)-1H-indazole (672.2 mg, 1.99 mmol), cesiumcarbonate (1.08 g, 3.31 mmol), copper (I)-iodide (157.8 mg, 0.83 mmol) and isobutyronitrile (1.75 mL) are stirred in a glass pressure tube at 120° C. for 20 h. The reaction mixture is filtered via a glass microfibre filter, the solvent evaporated and the residue purified by chromatography (silicagel, eluents: ethylacetate/methanol). 162.8 mg (23.3%) of the title compound are obtained.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)[C:11]([C:21]([O:23][CH3:24])=[O:22])=[C:10]([CH3:25])[N:9]=[C:8]1[CH2:26][O:27][CH3:28].Cl.[CH3:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]1([C:43]2[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=2)[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CC(C)=O>[F:20][C:15]1[CH:14]=[C:13]([CH:12]2[N:7]([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:40]3[CH2:41][CH2:42][C:37]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[CH3:30])([C:43]4[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=4)[CH2:38][CH2:39]3)[C:8]([CH2:26][O:27][CH3:28])=[N:9][C:10]([CH3:25])=[C:11]2[C:21]([O:23][CH3:24])=[O:22])[CH:18]=[CH:17][C:16]=1[F:19]
Reactant: Cc1ccc(C2(c3ccccc3C)CCNCC2)cc1
Reactant: COCC1=NC(C)=C(C(=O)OC)C(c2ccc(F)c(F)c2)N1CCCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(C)=O
Product: COCC1=NC(C)=C(C(=O)OC)C(c2ccc(F)c(F)c2)N1CCCCCN1CCC(c2ccc(C)cc2)(c2ccccc2C)CC1
Yield: 89 %

Procedure:
A mixture of (+)-1-(5-bromopentyl)-6-(3,4-difluorophenyl)-1,6-dihydro-5-methoxycarbonyl-2-methoxymethyl-4-methylpyrimidine (0.08 g, 0.17 mmol.), 4-(2-methylphenyl)-4-(4-methylphenyl)piperidine hydrochloride (0.063 g, 0.21 mmol.), potassium carbonate (0.14 g, 1.0 mmol.), sodium iodide (26 mg, 0.17 mmol.) and acetone (6 mL) was refluxed overnight. The undissolved solid was then filtered off and the solvent was evaporated. The residue was flash chromatographed over silica gel (eluent: 10:1 ethyl acetate/2M ammonia in methanol) to give the title compound in 89% yield (0.1 g) as a yellow oil. Treatment of the free base with 2 equivalents of 1M HCl in ether gave the HCl salt as a pale yellow solid: mp 137-140° C.; [α]D=56.5 (1.65 mg/mL, MeOH). Anal. Calc. for C39H47F2N3O3.2HCl.2H2O.0.75CHCl3: C, 56.68; H, 6.43; N, 4.99. Found: C, 56.55; H, 6.19; N, 5.02.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH2:12]([NH:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24])[CH3:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:12]([N:14]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1)[CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24])[CH3:13]
Reactant: CCNCCOc1ccccc1C
Reactant: Clc1ncnc2ccccc12
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCN(CCOc1ccccc1C)c1ncnc2ccccc12
Reaction time: 5.5 h
Yield: 54.2 %

Procedure:
To a solution of 2.5 g (0.015 mole) of 4-chloroquinazoline in toluene were added 2.7 g (0.015 mole) of N-ethyl-2-(2-methylphenoxy)ethylamine and 1.5 g (0.015 mole) of triethylamine. The mixture was then refluxed, with stirring, for 5.5 hours. After completion of the reaction, the toluene was removed from the reaction mixture by evaporation under reduced pressure. Water was then added to the residue and the mixture was extracted with chloroform and the extract was dried. The chloroform was removed by evaporation and the crystals which separated out were recrystallized from isopropanol, giving 2.5 g (54%) of the desired Compound No. 2, in the form of colourless prisms melting at 85°-87° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([O:24][C:25]([NH:27][CH:28]1[CH2:33][CH2:32][CH2:31][N:30]([C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:35])[CH:29]1[CH2:44][CH2:45]O)=[O:26])([CH3:23])([CH3:22])[CH3:21].C1(P([N:61]=[N+:62]=[N-:63])(C2C=CC=CC=2)=O)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1.O1CCCC1>[N:61]([CH2:45][CH2:44][CH:29]1[CH:28]([NH:27][C:25]([O:24][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:26])[CH2:33][CH2:32][CH2:31][N:30]1[C:34]([O:36][CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)=[O:35])=[N+:62]=[N-:63]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)NC1CCCN(C(=O)OCc2ccccc2)C1CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCCN(C(=O)OCc2ccccc2)C1CCN=[N+]=[N-]
Temperature: 0 °C

Procedure:
Triphenylphosphine (202 mg) was added to the compound 14 (146 mg), tetrahydrofuran (1 mL), diphenylphosphoryl azide (0.17 mL) and 2.2 mol/L of a solution (0.35 mL) of diethyl azodicarboxylate in toluene with stirring at 0° C. The reaction solution was stirred at room temperature for 1 hour and then concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→1:3) to obtain the title compound (136 mg) having the following physical properties.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:27][C:28]([NH:30]C(=O)OCC2C=CC=CC=2)=[S:29])([C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([F:26])[CH:17]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=1.[Li+].[OH-]>CO.C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:27][C:28]([NH2:30])=[S:29])([C:16]2[CH:21]=[C:20]([C:22]([F:24])([F:23])[F:25])[CH:19]=[C:18]([F:26])[CH:17]=2)[CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:6][CH:7]=1
Reactant: O=C(NC(=S)NC(Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1)OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: NC(=S)NC(Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Yield: 77.1 %

Procedure:
To benzyl 1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethylcarbamothioylcarbamate (269 mg, 0.483 mmol) in Methanol/THF (2 mL/2 mL) was added LiOH (2M, 483 mL, 0.966 mmol). The reaction was refluxed for 40 minutes. The solvents were removed and the residue dissolved in EtOAc. The resulting solution was washed with H2O, brine, dried over MgSO4 and concentrated. The crude mixture was purified by silica gel ISCO chromatography (12 g column) using hexanes/EtOAc (0-50% over 18 min) to give 1-(1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)thiourea as a pale yellow foam (169 mg, 78% yield). LCMS: 3.8 min [M+1] 454.2 (4 min gradient, MeOH/H2O 0.1% TFA); 1H NMR (400 MHz, CDCl3) δ ppm 5.62 (s, 3H), 6.71 (d, J=7.34 Hz, 3H), 7.11 (d, J=8.56 Hz, 6H), 7.32 (s, 2H), 7.50-7.57 (m, 1H), 7.69 (dd, J=8.56, 2.20 Hz, 1H), 8.28 (s, 1H), 8.64 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=1[CH3:18])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].Cl[CH2:21][C:22]1[S:26][C:25]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)=[N:24][C:23]=1[CH3:37].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:21][C:22]2[S:26][C:25]([C:27]3[CH:28]=[CH:29][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:31][CH:32]=3)=[N:24][C:23]=2[CH3:37])=[CH:13][C:12]=1[CH3:18])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCC(Cc1ccc(O)cc1C)C(=O)OC
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Product: CCCCCC(Cc1ccc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C)C(=O)OC

Procedure:
In analogy to the procedure described in example 14 b], [rac]-2-(4-hydroxy-2-methyl-benzyl)-heptanoic acid methyl ester was reacted with 5-chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole [PCT Int. Appl. (2002), WO 0292590 A1] in the presence of cesium carbonate and potassium iodide to yield [rac]-2-{2-methyl-4-(4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-benzyl}-heptanoic acid methyl ester as colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][C:11]([O:13]CC)=O)=[CH:4][C:3]=1[O:22][CH3:23]>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][C:3]=1[O:22][CH3:23])[NH:8][C:9]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[CH:10][C:11]2=[O:13]
Reactant: CCOC(=O)C=C(Nc1ccc(Br)c(OC)c1)c1ccccc1
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COc1cc2[nH]c(-c3ccccc3)cc(=O)c2cc1Br
Temperature: 300 °C
Yield: 86 %

Procedure:
DOWTHERM A (0.19 M) was heated to reflux (˜300° C.). A mixture of the product 113 in DOWTHERM A (2.5 M) was added to the heated DOWTHERM A solution portionwise. The mixture was stirred at reflux for 1 h after the addition was complete. The mixture was cooled to RT, filtered, and the solid was washed with hexane to give the title compound 114 (86%). 1H NMR (DMSO-d6) (ppm) 11.69 (s, 1H), 8.19 (s, 1H), 7.82 (m, 2H), 7.59 (m, 3H), 7.35 (s, 1H), 6.33 (s, 1H), 3.96 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:18]([F:20])[F:19])=[C:6]([C:8]2[CH:13]=[C:12]([O:14]C)[N:11]=[CH:10][C:9]=2[C:16]#[N:17])[CH:7]=1.Cl.[NH+]1C=CC=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:18]([F:20])[F:19])=[C:6]([C:8]2[C:9]([C:16]#[N:17])=[CH:10][NH:11][C:12](=[O:14])[CH:13]=2)[CH:7]=1
Reactant: COc1cc(-c2cc(Cl)ccc2C(F)F)c(C#N)cn1
Agent: Cl
Agent: c1cc[nH+]cc1
Product: N#Cc1c[nH]c(=O)cc1-c1cc(Cl)ccc1C(F)F

Procedure:
143 mg (purity 65%, 0.32 mmol) of 4-[5-chloro-2-(difluoromethyl)phenyl]-6-methoxypyridin-3-carbonitrile and pyridinium hydrochloride were reacted according to General Method 3A. Yield: 88 mg (99% of theory)
Reaction SMILES: [BH4-].[Na+].[C:3]1([C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[CH:12]=[O:13])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CO>[C:3]1([C:9]2[CH:10]=[C:11]([CH2:12][OH:13])[CH:14]=[CH:15][CH:16]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=Cc1cccc(-c2ccccc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1cccc(-c2ccccc2)c1
Reaction time: 1 h
Yield: 63.7 %

Procedure:
Under nitrogen atmosphere, at 0° C., to a stirred solution of NaBH4 (0.56 g, 14.7 mmol) in dry MeOH (10 mL), 3-phenylbenzaldehyde (0.67 g, 3.68 mmol) in dry MeOH (7 mL) was added via a cannula. After 1 h, the crude was quenched with water and concentrated to dryness. The resulting oil was dissolved in AcOEt and extracted with water. The organic fraction was dried over Na2SO4, filtered and subsequently purified by column chromatography using a Teledyne ISCO apparatus, eluting with Cy/TBME (from 100:0 to 50:50) to afford the title compound (0.432 g, 64%) as a pure product. 1H NMR (CDCl3): δ 1.62-1.78 (m, 1H), 4.80 (d, J=6.0, 1H), 7.33-7.75 (m, 9H).
Reaction SMILES: C([O-])=O.[NH4+].C1(C[N:12]2[C:16](=[O:17])[CH:15]([CH2:18][CH2:19][CH3:20])[N:14]([CH2:21][CH3:22])[S:13]2(=[O:24])=[O:23])C=CC=CC=1>CO.[Pd]>[NH4+:12].[CH2:18]([CH:15]1[N:14]([CH2:21][CH3:22])[S:13](=[O:24])(=[O:23])[NH:12][C:16]1=[O:17])[CH2:19][CH3:20]
Reactant: CCCC1C(=O)N(Cc2ccccc2)S(=O)(=O)N1CC
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CCCC1C(=O)NS(=O)(=O)N1CC
Temperature: 25 °C
Reaction time: 20 h
Yield: 191.3 %

Procedure:
A mixture of 2 g of 10% Pd/C, ammonium formate (3.35 g), and 2-phenylmethyl-4-propyl-5-ethyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (5.25 g) in 300 ml of methanol was stirred at room temperature for 20 hours, filtered through a pad of CELITE®, and the residue was washed with methanol. The combined filtrate was concentrated in vacuo to afford 3.8 g of 4-propyl-5-ethyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide ammonium salt (Formula IV: R1 =H; R2 =propyl; R3 =ethyl; as NH4+ salt) as a solid.
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)([C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].Br[C:40]1[CH:41]=[C:42]([CH:48]=[CH:49][CH:50]=1)[C:43]([NH:45][CH2:46][CH3:47])=[O:44]>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>[CH2:46]([NH:45][C:43]([C:42]1[CH:41]=[C:40]([C:33]2[CH:34]=[CH:35][C:30]([C:2]([OH:1])([C:6]3[N:7]=[CH:8][N:9]([C:11]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:10]=3)[CH:3]([CH3:4])[CH3:5])=[CH:31][CH:32]=2)[CH:50]=[CH:49][CH:48]=1)=[O:44])[CH3:47]
Reactant: CC(C)C(O)(c1ccc(B(O)O)cc1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CCNC(=O)c1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCNC(=O)c1cccc(-c2ccc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)cc2)c1
Yield: 43.8 %

Procedure:
By the reaction in the same manner as in Example 33-(ii) using 4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenylboronic acid (7.40 g, 14.7 mmol), 3-bromo-N-ethylbenzamide (2.20 g) and tetrakis(triphenylphosphine)palladium(0) (0.441 g), the title compound (2.56 g) was obtained as a yellow amorphous powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:13]=[CH:12][NH:11][CH:10]=2)[O:3]1.CC1(C)C(C)(C)OB(C2C=NNC=2)O1.[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:29]([N:11]1[CH:12]=[CH:13][C:9]([B:4]2[O:3][C:2]([CH3:14])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)=[CH:10]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: BrCc1ccccc1
Reactant: CC1(C)OB(c2cc[nH]c2)OC1(C)C
Agent: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: CC1(C)OB(c2ccn(Cc3ccccc3)c2)OC1(C)C

Procedure:
The title compound was prepared by substituting 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole for and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and benzyl bromide for EXAMPLE 4A in EXAMPLE 4B.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][CH2:13][CH2:14][CH2:15][OH:16].Br[CH2:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:20]=1[O:21][CH2:22][C:23]#[N:24]>>[CH3:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][O:16][CH2:15][CH2:14][CH2:13][O:12][CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)[C:20]=1[O:21][CH2:22][C:23]#[N:24]
Reactant: Cc1cccc(CBr)c1OCC#N
Reactant: OCCCOCc1ccc2ccccc2n1
Product: Cc1cccc(COCCCOCc2ccc3ccccc3n2)c1OCC#N

Procedure:
MS (ESI) 377 (M+H)+. Prepared from 3-(quinolin-2-ylmethoxy)-propan-1-ol (EXAMPLE 34a) and (2-bromomethyl-6-methyl-phenoxy)-acetonitrile.
Reaction SMILES: Cl[C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][N:7]=1.[C:10]1([CH3:19])[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+].N#N.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(COC)OC.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[C:10]1([CH3:19])[CH:15]=[CH:14][C:13]([C:2]2[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][N:7]=2)=[CH:12][CH:11]=1
Reactant: N#Cc1nccnc1Cl
Reactant: Cc1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: N#N
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2nccnc2C#N)cc1
Temperature: 90 °C
Yield: 126.3 %

Procedure:
3-Chloropyrazine-2-carbonitrile (3.0 g; 21.5 mmol) was dissolved in dimethoxyethane (65 ml) and 4-tolylboronic acid (3.2 g; 23.65 mmol) was added, followed by the addition of K2CO3 (8.2 g; 59 mmol) and water (30 ml). The reaction mixture was deoxygenized with N2 (g) for 3 minutes followed by the addition of triphenylphosphine (842 mg; 3.2 mmol) and palladium(II)acetate (237 mg; 1.06 mmol). The reaction mixture was heated to 90° C. for 14 h, cooled to rt, diluted with EtOAc, filtered over a plug of celite and dried with magnesiumsulfate. The organic solvent was evaporated under reduced pressure to give 5.3 g of 3-p-tolyl-pyrazine-2-carbonitrile. The intermediate nitrile was dissolved in MeOH (110 ml) followed by the addition of 4M aq NaOH (180 ml). The resulting mixture was heated to 85° C. for 14 h, cooled to rt and the MeOH was evaporated under reduced pressure. The residual aq. phase was acidified to pH=2 by the addition of conc. HCl and the precipitated product was filtered off, dissolved in DCM/EtOAc and dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 2.30 g of 3-p-tolyl-pyrazine-2-carboxylic acid. LC-MS: tR=0.40 min; [M−H]+=213.14.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[CH:11]([NH2:14])([CH3:13])[CH3:12]>>[CH:11]([NH:14][C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1)([CH3:13])[CH3:12]
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: CC(C)N
Product: CC(C)Nc1ccc([N+](=O)[O-])nc1
Yield: 93 %

Procedure:
Using analogous procedures to those described in the portion of Note [9] immediately above that is concerned with the preparation of starting materials, 5-bromo-2-nitropyridine was reacted with isopropylamine to give 5-isopropylamino-2-nitropyridine in 93% yield; 1H NMR: (CDCl3) 1.3 (d, 6H), 3.74 (m, 1H), 4.46 (br s, 1H), 6.9 (m, 1H), 7.84 (m, 1H), 8.15 (d, 1H); Mass Spectrum: M+H+ 182; which in turn was converted into 5-(N-tert-butoxycarbonyl-N-isopropylamino)-2-nitropyridine in 84% yield; 1H NMR: (CDCl3) 1.19 (d, 6H), 1.4 (s, 9H), 4.55 (m, 1H), 7.76 (m, 1H), 8.26 (m, 1H), 8.38 (m, 1H); Mass Spectrum: M+H+ 282; which in turn was converted into 2-amino-5-(N-tert-butoxycarbonyl-N-isopropylamino)pyridine in 84% yield; 1H NMR: (CDCl3) 1.05 (d, 6H), 1.36 (br s, 9H), 4.46 (br s, 2H), 6.48 (d, 1H), 7.14 (m, 1H), 7.78 (m, 1H); Mass Spectrum: M+H+ 252; and which in turn was converted into N-[5-(N-tert-butoxycarbonyl-N-isopropylamino)pyridin-2-yl]-2-[4-(6,7-dimethoxyquinazolin-4-yloxy) phenyl]acetamide; Mass Spectrum: M+H+ 560.