Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.[CH2:13]1[O:23][C:16]2([CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]2)[O:15][CH2:14]1>CCOCC.C1COCC1>[CH2:14]1[O:15][C:16]2([CH2:21][CH2:20][C:19]([OH:22])([C:7]3[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=3)[CH2:18][CH2:17]2)[O:23][CH2:13]1
Reactant: Brc1cccnc1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: OC1(c2cccnc2)CCC2(CC1)OCCO2
Temperature: -20 °C
Reaction time: 0.17 h

Procedure:
To a solution of n-BuLi (2.5 M in hexanes, 88.4 mL, 221.0 mmol) in Et2O (250 mL) at −78° C. was added a chilled solution (−78° C.) of 3-bromopyridine (35 g, 221.0 mmol) in Et2O (125 mL) via cannula. After being stirred for 10 min, a solution of 1,4-cyclohexanedione monoethylene ketal (34.5 g, 221.0 mmol) in THF (125 mL) was added via cannula The reaction mixture was stirred for 1 h at −78° C., then slowly warmed to −20° C. over 1 h. The reaction was quenched by pouring into saturated aqueous NH4Cl, and the layers were separated. The aqueous layer was extracted with CH2Cl2 (100 mL×3) and the combined organic layers were washed with brine (200 mL), dried with MgSO4 and concentrated in vacuo. The crude product was triturated with Et2O to afford 4-hydroxy-4-(3-pyridyl)cyclohexanone ethylene ketal as a white solid.
Reaction SMILES: O1CCCC1.[Si]([O:23][CH2:24][CH2:25][C@H:26]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]1[CH:40]=[CH:39][C:38]([C:41]([N:43]2[CH2:48][CH2:47][CH:46]([N:49]3[C:58]4[C:53](=[N:54][CH:55]=[C:56]([Cl:59])[CH:57]=4)[CH2:52][C:51]([CH3:61])([CH3:60])[C:50]3=[O:62])[CH2:45][CH2:44]2)=[O:42])=[C:37]([F:63])[CH:36]=1)[CH3:27])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(OCC)(=O)C>[Cl:59][C:56]1[CH:57]=[C:58]2[C:53]([CH2:52][C:51]([CH3:60])([CH3:61])[C:50](=[O:62])[N:49]2[CH:46]2[CH2:45][CH2:44][N:43]([C:41]([C:38]3[CH:39]=[CH:40][C:35]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[O:28][C@H:26]([CH3:27])[CH2:25][CH2:24][OH:23])=[CH:36][C:37]=3[F:63])=[O:42])[CH2:48][CH2:47]2)=[N:54][CH:55]=1
Reactant: C[C@H](CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)Oc1ccccc1-c1ccc(C(=O)N2CCC(N3C(=O)C(C)(C)Cc4ncc(Cl)cc43)CC2)c(F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@H](CCO)Oc1ccccc1-c1ccc(C(=O)N2CCC(N3C(=O)C(C)(C)Cc4ncc(Cl)cc43)CC2)c(F)c1
Reaction time: 3 h
Yield: 80.9 %

Procedure:
To a tetrahydrofuran solution (11 ml) of 1-{1-[(2′-{[(1R)-3-{[tert-butyl(diphenyl)silyl]oxy}-1-methylpropyl]oxy}-3-fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}-7-chloro-3,3-dimethyl-3,4-dihydro-1,5-naphthyridin-2(1H)-one (525 mg) was added at room temperature a tetrahydrofuran solution (1 M, 1.28 ml) of tetrabutylammonium fluoride, followed by stirring for 3 hours. The reaction solution was diluted with ethyl acetate, washed sequentially with a saturated aqueous ammonium chloride solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford 7-chloro-1-{1-[(3-fluoro-2′-{[(1R)-3-hydroxy-1-methylpropyl]oxy}biphenyl-4-yl)carbonyl]piperidin-4-yl}-3,3-dimethyl-3,4-dihydro-1,5-naphthyridin-2(1H)-one (301 mg).
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:40][O:41][CH3:42])[C:8]([NH:10][CH:11]2[C:38](=[O:39])[N:13]3[C:14]([C:22]([O:24]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:23])=[C:15]([CH:18]=[CH:19][CH2:20]I)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1.[CH:43]([NH:45][C:46]1[CH:47]=[N:48][CH:49]=[CH:50][CH:51]=1)=[O:44].C(OCC)(=O)C>CS(C)=O>[NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:40][O:41][CH3:42])[C:8]([NH:10][CH:11]2[C:38](=[O:39])[N:13]3[C:14]([C:22]([O-:24])=[O:23])=[C:15]([CH:18]=[CH:19][CH2:20][N+:48]4[CH:49]=[CH:50][CH:51]=[C:46]([NH:45][CH:43]=[O:44])[CH:47]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=CCI)CS[C@H]12)c1nsc(N)n1
Reactant: O=CNc1cccnc1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C=CC[n+]3cccc(NC=O)c3)CS[C@H]12)c1nsc(N)n1
Reaction time: 1.33 h
Yield: 2.9 %

Procedure:
A mixture of diphenylmethyl 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-(3-iodo-1-propen-1-yl)-3-cephem-4-carboxylate (IX-1) (E, 716 mg, 1 mmole) and 3-formylaminopyridine [prepared according to the procedure of N. Enomoto et al., Bull. Chem. Soc. Japan, 45, 2665 (1972)] (244 mg, 2 mmoles) in DMSO (2 ml) was stirred at room temperature for 1 hour, and poured into ethyl acetate (200 ml). The precipitate was collected by filtration, washed well with ethyl acetate and dried. A mixture of the quaternized salt (500 mg) and sodium bisulfite (50 mg) in HCOOH (5 ml) was stirred at 40°-50° C. for 80 minutes and evaporated to dryness in vacuo. The residue was dissolved in water (40 ml), neutralized with NaHCO3 and then filtered to remove insoluble material. The clear filtrate was chromatographed on a reverse phase column, PrepPAK-500/C18 (100 ml), with water and 5% CH3OH, 10% CH3OH, 20% CH3OH and 30% CH3OH. The fractions containing the desired compound were combined, concentrated in vacuo and lyophilized to give 16 mg (2.9%) of the title compound (I-1F) (E) as a tan powder. Mp. >170° C. (dec.).
Reaction SMILES: Br[C:2]1([O:24][CH3:25])[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:8]2[N:7]([C:15](=[O:23])[NH:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH2:6][CH2:5][C:4]=2[CH2:3]1.[CH3:26][C:27]1[CH:32]=[CH:31][N:30]=[CH:29][C:28]=1B(O)O.O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC>[CH3:26][C:27]1[CH:32]=[CH:31][N:30]=[CH:29][C:28]=1[C:21]1[CH:22]=[C:17]([NH:16][C:15]([N:7]2[C:8]3[C:4](=[CH:3][C:2]([O:24][CH3:25])=[C:10]([C:11]([F:14])([F:13])[F:12])[CH:9]=3)[CH2:5][CH2:6]2)=[O:23])[CH:18]=[N:19][CH:20]=1
Reactant: Cc1ccncc1B(O)O
Reactant: COC1(Br)CC2=C(C=C1C(F)(F)F)N(C(=O)Nc1cccnc1)CC2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc2c(cc1C(F)(F)F)N(C(=O)Nc1cncc(-c3cnccc3C)c1)CC2
Yield: 66.7 %

Procedure:
1-[5-Bromo-(3-pyridylcarbamoyl]-5-methoxy-6-trifluoromethylindoline (D26) (0.3 g 0.7 mmoles) and 4-methyl-3-pyridylboronic acid (0.12 g, 0.9 mmoles) was heated under reflux in dimethoxyethane (80 ml) and water (10 ml) with sodium carbonate (0.15 g, 1.4 mmoles) and palladium tetrakis triphenylphosphine (0.1 g, 12 mole %) under an inert atmosphere for 18 hours. After cooling the mixture was partitioned between ethyl acetate (250 ml) and water (200 ml). The organic layer was separated and washed with saturated sodium chloride solution then dried (Na4SO4). Evaporation of the solvent followed by flash chromatography on silica gel eluting with 3-7% MeOH/CH2Cl2 and recrystallisation from ethyl acetate/60-80 petrol gave the title compound (E35) (0.2 g, 65%) m.p. 125-8° C.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.[Li]CCCC.CN([CH:20]=[O:21])C>C1COCC1>[CH:20]([C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1)=[O:21]
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(C=O)ccc1C(=O)O
Temperature: -78 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
To a stirred solution of 4-bromo-2-methylbenzoic acid (10 g, 46.4 mmol) in dry THF (360 mL) at −78° C. was added n-BuLi (1.6 M solution in hexane; 58.17 mL, 93.0 mmol) and DMF (8 mL). The reaction mixture was stirred at −78° C. for 1 h then was warmed to 25° C. and stirred for 1 h. The reaction mixture was quenched with 1 N HCl solution and extracted with EtOAc. The combined EtOAc extracts were washed with brine and dried over Na2SO4 and concentrated under reduced pressure. The residue was washed with n-hexane to afford the title compound as a solid (3.0 g, 40%): mp 196-198° C.; 1H NMR (400 MHz, DMSO-d6) δ 13.32 (br s, 1H), 10.05 (s, 1H), 7.98 (m, 1H), 7.84 (m, 2H), 2.61 (s, 3H); ESIMS m/z 163.00 ([M−H]−).
Reaction SMILES: [P:1]([O:5][CH2:6][C@:7]([NH:31]C(=O)OC(C)(C)C)([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH:20]3[CH2:25][CH2:24][C:23]4([CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[CH2:22][CH2:21]3)[CH:15]=2)[CH:10]=1)[CH3:8])([OH:4])([OH:3])=[O:2].C(O)(=O)C.Cl>O>[P:1]([OH:3])([OH:4])([O:5][CH2:6][C@:7]([NH2:31])([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH:20]3[CH2:21][CH2:22][C:23]4([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]4)[CH2:24][CH2:25]3)[CH:15]=2)[CH:10]=1)[CH3:8])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@](C)(COP(=O)(O)O)c1ccc2cc(OC3CCC4(CCCCC4)CC3)ccc2c1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: C[C@](N)(COP(=O)(O)O)c1ccc2cc(OC3CCC4(CCCCC4)CC3)ccc2c1
Yield: 36 %

Procedure:
tert-Butyl (2R)-1-(phosphonooxy)-2-(6-(spiro[5.5]undecan-3-yloxy)naphthalen-2-yl)propan-2-ylcarbamate (13.6 mg, 0.0000248 mol) was dissolved in acetic acid (0.78 mL, 0.014 mol) and 10 M of hydrogen chloride in water (0.2 mL) was added and the mixture was stirred for Id. Lypholyzing gave (2R)-2-amino-2-(6-(spiro[5.5]undecan-3-yloxy)naphthalen-2-yl)propyl dihydrogen phosphate as a white solid (4.0 mg, 36%). LCMS give a single peak Rf=1.64 min (431.41, [M−16]+, 100%, 895.73, [M+M+1], 20%). 1H NMR (400 MHz, MeOD) δ=7.82-7.89 (m, 3H), 7.56 (d, J=5.5 Hz, 1H), 7.27 (s, 1H), 7.21 (d, J=8.6 Hz, 1H), 4.54-4.47 (m, 1H), 4.14-4.17 (m, 2H), 1.99-1.90 (m, 2H), 1.86 (s, 3H), 1.78-1.66 (m, 4H), 1.50 (m, 8H), 1.42-1.30 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10](I)[CH:11]=1)[C:8](=[O:13])[N:7]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=1)[CH2:6]2.[C-:26]#[N:27].[Na+]>C(#N)C.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.[Cu]I>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([C:26]#[N:27])[C:9]2[C:8](=[O:13])[N:7]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:6][C:5]=2[CH:4]=1
Reactant: [C-]#N
Reactant: COc1cc(I)c2c(c1)CN(Cc1ccc(OC(F)(F)F)cc1)C2=O
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CC#N
Product: COc1cc(C#N)c2c(c1)CN(Cc1ccc(OC(F)(F)F)cc1)C2=O
Temperature: 80 °C
Reaction time: 18 h
Yield: 67.9 %

Procedure:
A mixture of 5-methoxy-7-iodo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.060 g, 0.13 mmol), Pd(PPh3)4 (0.015 g, 0.013 mmol), sodium cyanide (0.013 g, 0.26 mmol), and CuI (0.003 g, 0.013 mmol) in acetonitrile (5 mL) was stirred at 80° C. for 18 h. Workup and silica gel column chromatography using 2:1 hexanes-ethyl acetate afforded 6-methoxy-3-oxo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-1H-isoindole-4-carbonitrile (0.032 g, 68%). 1H NMR (300 MHz, CDCl3): δ (ppm) 3.89 (s, 3H), 4.36 (s, 2H), 4.77 (s, 2H), 7.10 (s, 1H), 7.17 (d, 2H), 7.25 (s, 1H), 7.36 (d, 2H). GC-MS: m/z 362 (M+.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC1C=CC(S(O[CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][C:26]#[CH:27])(=O)=O)=CC=1>C(O)C>[CH2:25]([O:24][CH2:23][CH2:22][O:21][CH2:20][CH2:19][NH:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:26]#[CH:27]
Reactant: C#CCOCCOCCOS(=O)(=O)c1ccc(C)cc1
Reactant: NC1CCCCC1
Solvent: CCO
Product: C#CCOCCOCCNC1CCCCC1
Yield: 37.1 %

Procedure:
Cyclohexylamine (150 mg, 1.5 mmol, 1 equiv.) and 2-(2-(prop-2-ynyloxy)ethoxy)ethyl 4-methylbenzenesulfonate (s-8) (100 mg, 0.335 mmol, 0.2 equiv.) were dissolved in 1 mL of ethanol. The reaction was allowed to proceed under microwave irradiation at 80° C. for 10 minutes, after which it was concentrated under reduced pressure and chromatographed (Silica Gel, 25 g RediSep pre-packed column, 10% EtOAc:Hexanes→50% EtOAc:Hexanes, followed by EtOAc flush) to give N-(2-(2-(prop-2-ynyloxy)ethoxy)ethyl)cyclohexanamine (s-10) as a clear oil (28 mg, 37%). IR (thin film) 3253 (w), 2924 (s), 2852 (s), 2113 (w), 1449 (m), 1349 (m), 1263 (w), 1102 (s), 919 (w), 839 (w); 1H NMR (400 MHz, CDCl3) δ 4.19 (d, J=2.4 Hz, 2H), 3.70-3.65 (m, 2H), 3.65-3.60 (m, 2H), 3.59 (t, J=5.4 Hz, 2H), 2.80 (t, J=5.4 Hz, 2H), 2.42 (t, J=2.3 Hz, 1H), 2.40-2.34 (m, 1H), 1.90-1.84 (m, 2H), 1.72-1.69 (m, 2H), 1.64-1.54 (m, 1H), 1.30-1.15 (m, 3H), 1.15-0.99 (m, 2H), 0.92-0.81 (m, 1H). 13C NMR (100 MHz, CDCl3) δ 79.6, 74.6, 70.9, 70.1, 69.0, 58.4, 56.8, 42.3, 33.4, 26.2, 25.1. HRMS (ES+) calc'd for C13H23NO2 (M+H) m/z 226.1762 Found 226.1797.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:5]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[C:8]([NH2:16])[C:7]=2[N:17]=1.[CH3:25][SH:26].C[O-].[Na+]>CO>[CH3:25][S:26][CH2:3][C:4]1[N:5]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[C:8]([NH2:16])[C:7]=2[N:17]=1
Reactant: CS
Reactant: Nc1nc2ccccc2c2c1nc(CCl)n2Cc1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CSCc1nc2c(N)nc3ccccc3c2n1Cc1ccccc1
Temperature: 25 °C

Procedure:
2-Chloromethyl-1-phenylmethyl-1H-imidazo[4,5-c]quinolin-4-amine hydrochloride (Example 28, prepared from 2.11 g of the alcohol) was added to a solution of methanethiol (1.33 g; 0.028 mol) and sodium methoxide (1.5 g; 0.028 mol) in methanol. The solid dissolved upon addition and a cream colored solid precipitated during addition. After stirring at room temperature for several hours the mixture was diluted with water. The solid was filtered from the mixture, washed with water, and dried. A crude yield of 2.3 g was obtained. The product was purified by silica gel flash chromatography (10% methanol in ethyl acetate eluent) and recrystallized from methanol/dichloromethane to give a cream colored solid, m.p. 217°-219° C. Analysis: Calculated: C, 68.2; H, 5.4; N, 16.8. Found: C, 67.5; H, 5.3; N, 16.6.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:9]([CH:10]=O)=[CH:8][N:7]=[C:6]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:5]=1)[CH3:2].[C:19]([CH:24]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:21][CH2:22][CH3:23])=[O:20]>O1CCCC1>[CH2:1]([NH:3][C:4]1[C:9]([CH:10]=[CH:24][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:8][N:7]=[C:6]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCNc1nc(Nc2ccccc2)ncc1C=O
Solvent: C1CCOC1
Product: CCNc1nc(Nc2ccccc2)ncc1C=CC(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.6 %

Procedure:
To a room temperature solution of 4-ethylamino-2-phenylamino-pyrimidine-5-carboxaldehyde (320 mg, 1.32 mmol) in 12 mL of tetrahydrofuran was added (carbethoxymethylene)triphenylphosphorane (720 mg, 2.07 mmol). The reaction mixture was heated at reflux for 7 hours then stirred at room temperature overnight. An additional amount of (carbethoxymethylene)triphenylphosphorane (300 mg, 0.86 mmol) was added, and the reaction mixture was heated at reflux for an additional 8 hours then stirred at room temperature for 3 days. The reaction mixture was concentrated in vacuo, and the residue was purified by flash chromatography, eluting with 1:2 ethyl acetate:hexane, to provide 357 mg (86%) of ethyl 3-(4-ethylamino-2-phenylamino-pyrimidin-5-yl)acrylate, mp 125-126° C.
Reaction SMILES: [C:1]1([CH:7]2[NH:13][CH2:12][CH2:11][NH:10][C:9](=[O:14])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:21](Cl)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(#N)C>[CH2:21]([N:13]1[CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][C:9](=[O:14])[NH:10][CH2:11][CH2:12]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C1CC(c2ccccc2)NCCN1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1CC(c2ccccc2)N(Cc2ccccc2)CCN1
Yield: 83.9 %

Procedure:
1.9 g hexahydro-7-phenyl-1,4-diazepin-5-one (for preparation see Example 1C) in 30 ml acetonitrile were heated to boiling with 2.0 g potassium carbonate and 1.2 g benzyl chloride with reflux cooling for 36 hours. Then filtration was carried out and the filtrate reduced in volume. The remaining residue was shaken with 10% aqueous citric acid solution, the organic phase was separated, dried over magnesium sulfate and reduced in volume under a vacuum. 2.23 g crude 1-benzyl-hexahydro-7-phenyl-1,4-diazepin-5-one were obtained as an oil, which was used for the next synthesis stage without further purification or characterization.
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]([NH:46][C:47](=[O:50])[CH2:48][CH3:49])[CH:43]=[CH:44][CH:45]=1>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>[OH:1][C:2]([C:30]1[CH:35]=[CH:34][C:33]([C:44]2[CH:45]=[CH:40][CH:41]=[C:42]([NH:46][C:47](=[O:50])[CH2:48][CH3:49])[CH:43]=2)=[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]
Reactant: CC(C)C(O)(c1ccc(B(O)O)cc1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CCC(=O)Nc1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCC(=O)Nc1cccc(-c2ccc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)cc2)c1
Yield: 33.5 %

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 (3.12 g), N-(3-bromophenyl)propanamide (1.56 g) and tetrakis(triphenylphosphine)palladium(0) (0.133 g), the title compound (1.26 g) was obtained as a colorless amorphous powder.
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH3:8])[N:5]=[C:4]([CH3:9])[C:3]=1[CH:10]=[O:11].[Cl:12][C:13]1[CH:14]=[C:15]([SH:20])[CH:16]=[C:17]([Cl:19])[CH:18]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:12][C:13]1[CH:14]=[C:15]([S:20][C:2]2[N:6]([CH2:7][CH3:8])[N:5]=[C:4]([CH3:9])[C:3]=2[CH:10]=[O:11])[CH:16]=[C:17]([Cl:19])[CH:18]=1
Reactant: CCn1nc(C)c(C=O)c1Cl
Reactant: Sc1cc(Cl)cc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1nc(C)c(C=O)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 100 °C
Reaction time: 18 h
Yield: 72.6 %

Procedure:
A mixture of 9.2 g of 5-chloro-1-ethyl-3-methyl-1H-pyrazole-4-carbaldehyde, 14.3 g of 3,5-dichlorothiophenol and 11.8 g of potassium carbonate in 40 ml of anhydrous N,N-dimethylformamide was stirred under nitrogen at 100° C. for 18 hours. Water (200 ml) was added and the mixture was extracted three times with 100 ml of dichloromethane. The combined extracts were dried over magnesium sulphate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using dichloromethane/petroleum ether (bp 40–60° C.) for the elution to give 12.2 g of 5-(3,5-dichloro-phenylsulphanyl)-1-ethyl-3-methyl-1H-pyrazole-4-carbaldehyde as an orange solid. Mass spectrum (ES) m/z 356 [M+CH3CH+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[NH2:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][NH2:22]>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([NH:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[NH2:18])[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: NCc1ccccc1N
Solvent: COCCOC
Product: N#Cc1c(NCc2ccccc2N)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile and 2-aminobenzylamine in DME. ES-MS m/e (%): 307 (M+H+, 100).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[C:11]([CH3:13])[C:10]([CH3:14])=[C:9]1[CH:15]=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17]([Mg]Cl)#[CH:18]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH:12]=[C:11]([CH3:13])[C:10]([CH3:14])=[C:9]1[CH:15]([OH:16])[C:17]#[CH:18])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cn(C(=O)OC(C)(C)C)c(C=O)c1C
Reactant: C#C[Mg]Cl
Solvent: C1CCOC1
Product: C#CC(O)c1c(C)c(C)cn1C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
To a solution of 3,4-dimethyl-2-formyl-pyrrole-1-carboxylic acid tert-butyl ester (3.18 g, 14.2 mmol) (prepared as described in Tietze et al., supra,) in dry THF(40 mL) was added ethynylmagnesium chloride (Aldrich, 0.5 M solution in THF, 57 mL, 28.5 mmol) dropwise at −65° C. and the reaction mixture was stirred at the same temperature for 0.5 hour. The cooling bath was then removed and the reaction mixture was stirred for another 2 hours to give a clear solution. The reaction was quenched by slowly adding EtOH (8 mL) and a saturated aqueous NH4Cl solution (26 mL) at 5° C. The mixture was extracted several times with ethyl acetate. The combined organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (silica gel, 95:5 hexanes/ethyl acetate) purification of the crude oil afforded 3,4-dimethyl-2-(1-hydroxy-prop-2-ynyl)-pyrrole-1-carboxylic acid tert-butyl ester as a yellow oil. (Yield 3.54 g, 100.0%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:24])=[C:4]([C:8]2[N:9]=[C:10]([C:20]([CH3:23])([CH3:22])[CH3:21])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[N:14]=2)[CH:5]=[CH:6][CH:7]=1.[O:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[S:30](Cl)(=[O:32])=[O:31]>>[NH2:19][C:15]1[N:14]=[C:13]([C:12]2[S:11][C:10]([C:20]([CH3:21])([CH3:23])[CH3:22])=[N:9][C:8]=2[C:4]2[C:3]([F:24])=[C:2]([NH:1][S:30]([C:26]3[O:25][CH:29]=[CH:28][CH:27]=3)(=[O:32])=[O:31])[CH:7]=[CH:6][CH:5]=2)[CH:18]=[CH:17][N:16]=1
Reactant: O=S(=O)(Cl)c1ccco1
Reactant: CC(C)(C)c1nc(-c2cccc(N)c2F)c(-c2ccnc(N)n2)s1
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3ccco3)c2F)c(-c2ccnc(N)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 4-[4-(3-amino-2-fluorophenyl)-2-(1,1-dimethylethyl)-1,3-thiazol-5-yl]-2-pyrimidinamine (100 mg, 0.291 mmol) and furan-2-sulfonyl chloride (72 mg, 0.437 mmol), the title compound was obtained as a white solid (87 mg, 63% yield). MS (ESI): 474 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][S:10]([CH2:13][CH3:14])(=[O:12])=[O:11])=[N:7][CH:8]=1.[N+:17]([O-])([OH:19])=[O:18]>C(O)(=O)C>[N+:17]([C:5]1[C:6]([NH:9][S:10]([CH2:13][CH3:14])(=[O:12])=[O:11])=[N:7][CH:8]=[C:3]([C:2]([F:1])([F:15])[F:16])[CH:4]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])O
Reactant: CCS(=O)(=O)Nc1ccc(C(F)(F)F)cn1
Solvent: CC(=O)O
Product: CCS(=O)(=O)Nc1ncc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 90.2 %

Procedure:
45 g of N-(5-trifluoromethyl-2-pyridyl)ethanesulfonamide was dissolved in 112.5 ml of acetic acid. While heating it to a temperature of from 100° to 105° C., 26 g of fuming nitric acid (94%) was dropwise added, and the mixture was reacted for further 6 hours. The reaction product was left to cool to 80° C., and then poured into 2 l of ice water. Precipitated crystals were collected by filtration, washed with water and dried to obtain 47.8 g of N-(3-nitro-5-trifluoromethyl-2-pyridyl)ethanesulfonamide.