Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C2C(C3C=CC=CC=3)=CC=CN=2)C=CC=CC=1.[C:19]1([C:25]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(C1C(C2C=CC=CC=2)=CC=CN=1)C1C=CC=CC=1.C1(CC(CC2C=CC=CC=2)=O)C=CC=CC=1.Br.BrCCCN.C(O[CH:78](OCC)[CH:79]=[CH:80][N:81]([CH3:83])[CH3:82])C>CN(C)C=O.[Pd]>[CH3:82][N:81]([CH3:83])[CH:80]=[CH:79][CH:78]=[C:27]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:25]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:26]
Reactant: CCOC(C=CN(C)C)OCC
Reactant: O=C(Cc1ccccc1)c1ccccc1
Agent: [Pd]
Agent: Br
Agent: NCCCBr
Solvent: CN(C)C=O
Product: CN(C)C=CC=C(C(=O)c1ccccc1)c1ccccc1

Procedure:
It is known to produce pyridines having aromatic substituents in the 2- and 3-positions from ketones, namely, 2,3-diphenyl pyridine from desoxybenzoin and 2-benzyl-3-phenyl pyridine from 1,3-diphenylacetone. The ketone for this purpose is first converted to the enamine, this reacted with 3-bromo-propylamine hydrobromide in dimethyl formamide to the tetrahydropyridines and these finally dehydrogenated in the presence of palladium catalyst to the pyridines (Org. Chem. Vol. 28 (1963) pages 3468 to 3473). In the case of the production of 2,3-diphenyl pyridine from desoxybenzoin this can also be reacted with 3,3-diethoxy-1-dimethylamino-1-propene to form 5-dimethylamino-1,2-diphenyl-2,4-pentadien-1-one and this reacted with triethyloxonium tetrafluoroborate and further with dimethylamine to 5-dimethylamino-N,N-dimethyl-1,2-diphenyl-2,4-pentadieniminium-tetrafluoroborate and finally this converted into the 2,3-diphenyl pyridine by heating in an ammonium chloride-ammonia solution (Liebigs Ann. Chem. 1975 pages 874 to 900).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[CH2:7][CH:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:9]2)=[CH:4][C:3]=1[C:19]1[C:20]([F:25])=[N:21][CH:22]=[CH:23][CH:24]=1.C[Si]([N:30]=[C:31]=[N:32][Si](C)(C)C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[N:32][C:31]#[N:30])[CH2:7][CH:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:9]2)=[CH:4][C:3]=1[C:19]1[C:20]([F:25])=[N:21][CH:22]=[CH:23][CH:24]=1
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Reactant: O=C1CC(c2ccccc2)Oc2cc(F)c(-c3cccnc3F)cc21
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: N#CN=C1CC(c2ccccc2)Oc2cc(F)c(-c3cccnc3F)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 120.3 %

Procedure:
To a solution of 7-fluoro-6-(2-fluoropyridin-3-yl)-2-phenylchroman-4-one (78 mg, 0.23 mmol) in CH2Cl2 (5 mL) under N2 was added TiCl4 (1 M solution in DCM, 1.15 mL, 1.15 mmol) dropwise within 15 minutes at room temperature under dark. After addition, the reaction mixture was stirred for 1 h. To this mixture was added bis-trimethylsilylcarbodiimide (94.3 mg, 0.506 mmol) dropwise. The resulting mixture was stirred overnight. The reaction mixture was poured into ice-water and extracted with DCM. The combined organic phases were dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated to give 7-fluoro-6-(2-fluoro-pyridin-3-yl)-2-phenylchroman-4-ylidene-cyanamide (100 mg, 100%).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:24])[C:6]1[CH:11]=[C:10]([CH3:12])[C:9](Br)=[C:8]([S:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=2[OH:23])[CH:7]=1>CN(C=O)C>[CH3:3][O:4][C:5]([C:6]1[CH:11]=[C:10]([CH3:12])[C:9]2[O:23][C:17]3[C:18]([Cl:22])=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][S:14][C:8]=2[CH:7]=1)=[O:24]
Reactant: COC(=O)c1cc(C)c(Br)c(SCc2cccc(Cl)c2O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)c2c(c1)SCc1cccc(Cl)c1O2
Temperature: 80 °C
Reaction time: 10 h

Procedure:
Sodium hydride (1.65 g, 0.068 mol) was added portionwise to a solution of compound of Example 15a (23 g, 0.057 mol) in DMF (600 mL) and stirred at 80° C. for 10 h. The solvent was removed, and chloroform (300 mL) was added. The organic layer was washed with 10% HCl (2×80 mL), followed by water (100 mL), and brine and dried over anhydrous sodium sulphate. The solvent was removed and the crude product obtained was purified by column chromatography (silica gel, ethyl acetate/pet ether) to obtain the title compound. Yield: 9 g, (49%); 1H NMR (CDCl3, 300 MHz): δ 2.50 (s, 3H, CH3), 3.91 (s, 3H, OCH3), 4.21 (s, 2H, CH2), 7.05 (m, 2H, Ar), 7.28 (d, 1H, Ar), 7.60 (d, 2H, Ar); MS: m/e (EI) 320 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]([O:15][CH3:16])=[CH:7][C:3]=1[C:4](O)=[O:5].CN.C1C=CC2N(O)N=[N:25][C:23]=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.Cl>[Br:1][C:2]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]([O:15][CH3:16])=[CH:7][C:3]=1[C:4]([NH:25][CH3:23])=[O:5]
Reactant: COc1cc(C(=O)O)c(Br)cc1C(C)(C)C
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(OC)c(C(C)(C)C)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.3 %

Procedure:
step 1—To a solution of 58 (150 mg) in DMF (10 mL) cooled to 0° C. was added MeNH2 (0.52 mL, 2.0 M in THF,), HOBt (140 mg) and EDCI (200 mg). The reaction mixture was then stirred overnight at RT then diluted with 1N aq HCl solution and extracted with EtOAc. The organic layer was washed sequentially with water and brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified by SiO2 chromatography eluting with a MeOH/DCM gradient (0 to 10% MeOH) to afford 140 mg of 2-bromo-4-tert-butyl-5-methoxy-N-methyl-benzamide (60) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([CH:21]3[CH2:24][CH2:23][CH2:22]3)([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)O)[C:6]3[CH2:25][CH2:26][N:27]([CH3:29])[CH2:28][C:5]=3[C:4]=2[CH:3]=1.[OH-].[K+]>S(Cl)(Cl)=O.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:11]=[C:12](\[CH:21]3[CH2:22][CH2:23][CH2:24]3)/[C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[C:6]3[CH2:25][CH2:26][N:27]([CH3:29])[CH2:28][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2c(c3cc(Cl)ccc3n2CC(O)(c2ccc(F)cc2)C2CCC2)C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: O=S(Cl)Cl
Product: CN1CCc2c(c3cc(Cl)ccc3n2/C=C(/c2ccc(F)cc2)C2CCC2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-(8-Chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-1-cyclobutyl-1-(4-fluorophenyl)ethanol (500 mg, 1.2 mmol) was dissolved in thionyl chloride (5 mL) and the solution was stirred at RT for 3 h. Excess thionyl chloride was removed under reduced pressure and the residue was dissolved in N-methyl-2-pyrrolidone (3 mL) and the solution was stirred for 5 min. at RT. Powdered KOH (637 mg, 11 mmol) was added and the reaction mixture was heated at 100° C. for 3 h. The reaction mixture was cooled to RT and diluted with water. The precipitate obtained was filtered and washed with hexane, followed by purification by HPLC. 1H NMR (DMSO-d6, oxalate salt) δ (ppm): 7.58 (m, 1H), 7.45 (d, 1H), 7.25 (m, 1H), 7.10 (d, 1H), 7.0 (m, 3H), 6.70 (m, 1H), 4.30-4.20 (m, 3H), 3.65 (m, 2H), 3.50 (m, 2H), 2.90 (m, 2H), 2.80 (s, 3H), 2.20 (m, 2H), 1.80 (m, 1H), 1.60-1.30 (m, 1H).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7](Cl)[C:6]([O:10][CH2:11][CH3:12])=[CH:5][N:4]=1.[NH2-].[Na+].[CH2:15]([OH:18])[C:16]#[CH:17].O>C1C=CC=CC=1>[CH3:1][S:2][C:3]1[N:8]=[C:7]([O:18][CH2:15][C:16]#[CH:17])[C:6]([O:10][CH2:11][CH3:12])=[CH:5][N:4]=1
Reactant: CCOc1cnc(SC)nc1Cl
Reactant: C#CCO
Agent: [NH2-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: C#CCOc1nc(SC)ncc1OCC
Reaction time: 5 h

Procedure:
A solution comprising 3 grams of 2-methylthio-4-chloro-5 ethoxy pyrimidine in 30 milliliters of benzene was treated with 1 gram of sodium amide and 1.5 ml of propargyl alcohol. The reaction mixture was refluxed with stirring for 5 hours. Upon cooling, the unreacted sodium amide was decomposed with water, the benzene layer separated and the solvent evaporated under reduced pressure. Crystallization of the residue from ethanol yielded 2.8 grams of 2-methylthio-4-propargyloxy-5-ethoxy pyrimidine having a melting point ranging from 84°-85° C.
Reaction SMILES: [SH:1][C:2]1[N:6]([CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH:25]1([CH2:31][CH2:32]Br)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>CC(C)=O>[C:11]([O:10][C:8](=[O:9])[CH2:7][N:6]1[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]=[C:2]1[S:1][CH2:32][CH2:31][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)([CH3:13])([CH3:14])[CH3:12]
Reactant: BrCCC1CCCCC1
Reactant: CC(C)(C)OC(=O)Cn1c(S)nc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)Cn1c(SCCC2CCCCC2)nc2ccccc21

Procedure:
To a suspension of tert-butyl (2-mercapto-benzoimidazol-1-yl)-acetate (Intermediate 3-I, 53 mg, 0.2 mmol) and K2CO3 (41.4 mg, 0.4 mmol) in acetone (0.8 ml) is added 2-cyclohexylethyl bromide (28.8 mg, 22.6 μl). The reaction mixture is kept stirring at reflux for 5 h then filtered on a short plug of silica gel. The solvents are evaporated and the crude is purified by preparative HPLC yielding the title compound in 60% as a colourless oil: tR=7.39 min (LC-1), ESI-MS (pos.): m/z 321.36 [M+H]+; 1H NMR (CDCl3): δ (ppm) 0.80-0.91 (m, 2H), 1.04-1.23 (m, 3H), 1.35 (s, 9H, tBu), 1.35 (m, 1H), 1.54-1.72 (m, 6H), 1.83 (br. s, 1H), 3.32 (t, 2H, SCH2), 4.65 (s, 2H, CH2CO2), 7.07-7.17 (m, 3Harom), 7.61 (m, 1Harom).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:38]1([CH2:44][CH2:45][NH:46][C:47](=[O:49])[CH3:48])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:41]3[CH2:42][CH2:43][N:38]([CH2:44][CH2:45][NH:46][C:47](=[O:49])[CH3:48])[CH2:39][CH2:40]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CC(=O)NCCN1CCNCC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCNC(C)=O)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with N-(2-piperazin-1-yl-ethyl)-acetamide (prepared as described in Fotouhi, N. et al. WO 2005110996) to give the title compound. HR-MS (ES, m/z) calculated for C37H47Cl2N6O3 [(M+H)+] 693.3081, observed 693.3082.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CC(C)=O.[CH3:11][C:12]1([CH3:30])[C:16]([CH3:18])([CH3:17])[O:15][B:14]([C:19]2[CH:20]=[C:21]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[O:13]1.IC>ClCCl>[CH3:1][N:25]([C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([B:14]2[O:13][C:12]([CH3:30])([CH3:11])[C:16]([CH3:17])([CH3:18])[O:15]2)[CH:20]=1)[S:26]([CH3:29])(=[O:28])=[O:27]
Reactant: CC1(C)OB(c2cccc(NS(C)(=O)=O)c2)OC1(C)C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: ClCCl
Solvent: CC(C)=O
Product: CN(c1cccc(B2OC(C)(C)C(C)(C)O2)c1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A round bottom flask was charged with potassium carbonate (0.56 g, 4.0 mmol) and acetone (20 mL). To the suspension was added N-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-methanesulfonamide (1.0 g, 3.4 mmol) followed by iodomethane (0.25 mL, 4.0 mmol). The mixture was stirred at room temperature for 18 hours. The mixture was diluted with dichloromethane (20 mL), filtered through a plug of diatomaceous earth, rinsed with dichloromethane and evaporated to a viscous oil. The material was subjected to high vacuum for 18 hours. N-Methyl-N-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-methanesulfonamide was isolated as pale yellow solid (1.03 g, 98%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.76-7.70 (m, 2H), 7.53 (d, J=7.9 Hz, 1H), 7.39 (t, J=7.5 Hz, 1H), 3.34 (s, 3H), 2.86 (s, 3H), 1.35 (s, 12H). MS=312 (MH)+. 127b) N-[3-(2-Amino-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-phenyl]-N-methyl-methanesulfonamide was prepared from 8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (500.0 mg, 2.347 mmol) and N-methyl-N-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-methanesulfonamide (800.0 mg, 2.571 mmol) in a manner analogous to Example 2c. Product isolated as a white foam (0.529 g, 71%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.57 (d, J=6.5 Hz, 1H), 8.13-8.10 (m, 1H), 8.07 (d, J=7.9 Hz, 1H), 7.75 (d, J=7.5 Hz, 1H), 7.53 (t, J=8.0 Hz, 1H), 7.45 (d, J=8.0 Hz, 1H), 6.99 (t, J=6.9 Hz, 1H), 6.12 (s, 2H), 3.31 (s, 3H), 3.01 (s, 3H). MS=318 (MH)+. 127c) N-Methyl-N-(3-{2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-yl}-phenyl)-methanesulfonamide was prepared from N-[3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-phenyl]-N-methyl-methanesulfonamide (75.0 mg, 0.236 mmol) and 1-(4-bromo-phenyl)-4-methyl-piperazine (67.0 mg, 0.262 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a yellow foam (0.033 g, 28%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.41 (d, J=6.6, 1H), 8.13 (s, 3H), 7.93 (d, J=7.9 Hz, 1H), 7.59 (d, J=7.4 Hz, 1H), 7.56-7.45 (m, 3H), 7.44 (dd, J=8.2, 1.2 Hz, 1H), 6.98-6.92 (m, 3H), 6.64 (s, 1H), 3.42 (s, 3H), 3.19-3.14 (m, 4H), 2.89 (s, 3H), 2.63-2.57 (m, 4H), 2.36 (s, 3H). MS=492 (MH)+.
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][CH:3]=1.[CH3:15][N:16]1CCCC1=O.[C-]#N.[Na+]>O>[C:15]([C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][CH:3]=1)#[N:16]
Reactant: O=[N+]([O-])c1c(Cl)ccc2ccncc12
Reactant: CN1CCCC1=O
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Product: N#Cc1ccc2ccncc2c1[N+](=O)[O-]

Procedure:
7-Chloro-8-nitroisoquinoline (0.125 mole) and cuprous cyanide (0.225 mole) are refluxed in 125 ml. of distilled N-methylpyrrolidinone under a nitrogen atmosphere for 16 hours. The reaction mixture is poured into a solution of 40 g. of sodium cyanide in 120 ml. of water. The mixture is cooled and extracted with benzene. The benzene extracts are combined, washed with water, dried over sodium sulfate and evaporated. The residue is recrystallized from benzene to give 7-cyano-8-nitroisoquinoline.
Reaction SMILES: [S:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH:21]([O:25][CH2:26][CH3:27])[C:22]([OH:24])=[O:23])=[CH:16][CH:15]=2)[CH2:3][CH2:2]1.[N+:28]([C:31]1[CH:36]=[CH:35][C:34](O)=[CH:33][CH:32]=1)([O-:30])=[O:29]>>[S:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH:21]([O:25][CH2:26][CH3:27])[C:22]([O:24][C:34]3[CH:35]=[CH:36][C:31]([N+:28]([O-:30])=[O:29])=[CH:32][CH:33]=3)=[O:23])=[CH:18][CH:19]=2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CCOC(Cc1ccc(OCCN2CCSc3ccccc32)cc1)C(=O)O
Product: CCOC(Cc1ccc(OCCN2CCSc3ccccc32)cc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Yield: 38 %

Procedure:
The title compound (0.15 g, 38%) was prepared as a yellow liquid from 3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoic acid (0.3 g, 0.77 mmol) obtained in example 29 and 4-nitrophenol by an analogous procedure to that described in example 32.
Reaction SMILES: [NH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:22])=[C:8]([NH:10][C:11]([C:13]2[N:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]3=[N:15][CH:14]=2)=[O:12])[CH:9]=1)[C:2]#[N:3].[NH2:23][OH:24]>CCO>[OH:24][N:23]=[C:2]([NH2:3])[NH:1][C:4]1[CH:5]=[CH:6][C:7]([CH3:22])=[C:8]([NH:10][C:11]([C:13]2[N:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]3=[N:15][CH:14]=2)=[O:12])[CH:9]=1
Reactant: Cc1ccc(NC#N)cc1NC(=O)c1cnc2ccccn12
Reactant: NO
Solvent: CCO
Product: Cc1ccc(NC(N)=NO)cc1NC(=O)c1cnc2ccccn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of N-(5-cyanamido-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (68) 3.52 g (12.1 mmol) in 200 mL of EtOH was added 0.75 mL NH2OH (50 wt % in water, 12.1 mmol). The resulting mixture was stirred at room temperature overnight. The precipitate was filtered, washed with EtOH (10 mL) and air dried to give N-(5-(2-hydroxyguanidino)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (69) as a white solid, which was used directly in the next step without further purification. 1H NMR (400 MHz, d6-DMSO) δ 9.44 (s, 1H), 9.46 (dd, J=6.8, 0.8 Hz, 1 H), 8.54 (s, 1 H), 8.34 (s, 1 H), 7.76 (dd, J=7.2, 2.2 Hz, 1 H), 7.59 (s, 1 H), 7.52-7.43 (m, 2 H), 7.18-7.06 (m, 2 H), 2.13 (s, 3 H). MS m/z 325.1 (M+1)+.
Reaction SMILES: CN(C=O)C.[C:6]([C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1)([O:8][CH2:9][CH3:10])=[O:7].[CH:18]([S:20]([F:23])(=[O:22])=[O:21])=[CH2:19]>O>[C:6]([C:11]1[CH:12]=[CH:13][C:14]([NH:15][CH:19]=[CH:18][S:20]([F:23])(=[O:22])=[O:21])=[CH:16][CH:17]=1)([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: C=CS(=O)(=O)F
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(NC=CS(=O)(=O)F)cc1
Temperature: 110 °C
Yield: 49.8 %

Procedure:
To a 75 mL DMF solution of 4-carboethoxyaniline (3.88 g, 23.5 mmol) was added ethenesulfonyl fluoride (3.3 mL, 30 mmol) under nitrogen. The solution was warmed to 100-120° C. for 6 hours. The cooled solution was slowly Poured into water and chilled in ice. The yellow solid precipitate was collected, dissolved in methylene chloride, washed with brine and dried (Na2SO4). After the solvent had been removed by distillation, the brown solid (5.4 g) was crystallized from methylene chloride/ether/hexane. The title compound (3.2 g, 49% yield) was obtained as a tan solid, mp 109.5°-111.5° C.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH2:7]Cl)[S:5][CH:6]=1.[NH:9]1[CH:13]=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:11]=[N:10]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[N:3]=[C:4]([CH2:7][N:9]2[CH:13]=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:11]=[N:10]2)[S:5][CH:6]=1
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: ClCc1nc(Br)cs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(Cc2nc(Br)cs2)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 64.6 %

Procedure:
To a solution (4 mL) of the compound (1.57 g, 7.39 mmol) obtained in Example 30b in N,N-dimethylformamide were added ethyl 1H-pyrazole-4-carboxylate (1.3 g, 9.28 mmol) and potassium carbonate (1.5 g, 10.9 mmol), and the mixture was stirred at 80° C. overnight. The reaction mixture was allowed to cool to room temperature, water was added and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained crude product was purified by column chromatography (hexane-hexane/ethyl acetate=70/30) to give the title compound (1.51 g, 66%) as a pale-brown oil.
Reaction SMILES: [CH2:1]([Cl:4])[CH:2]=[CH2:3].[CH3:5][Si:6](C)([O:9][CH3:10])[O:7][CH3:8].C1(C)C=CC=CC=1.C([Si](C=C)(C)O[Si](C)(C)C)=C>C(O)(=O)C>[Cl:4][CH2:1][CH2:2][CH2:3][Si:6]([CH3:5])([O:9][CH3:10])[O:7][CH3:8]
Reactant: C=CCCl
Reactant: CO[Si](C)(C)OC
Agent: C=C[Si](C)(C=C)O[Si](C)(C)C
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CO[Si](C)(CCCCl)OC
Temperature: 50 °C
Yield: 40 %

Procedure:
306 mg Of allyl chloride, 530 mol of dimethyldimethoxysilane, and 77 mg of toluene were placed in a glass reaction tube and 0.01 ml of acetic acid was added to this mixture. Then, 0.005 mol of a toluene solution of a 0-valent platinum complex of divinyltetramethyldisiloxane (platinum content: 0.4 wt %) was added to this mixture. The reaction tube was sealed and heated for 2 hours in an oil bath at 50° C. When the contents were analyzed by GC-MS following cooling, the conversion rate of allyl chloride was 100% and γ-chloropropylmethyldimethoxysilane was produced at a yield of 40%.
Reaction SMILES: N[C@H:2]([C:10]([OH:12])=[O:11])CC1C=CC=CC=1.[NH2:13][C@H:14]([C:16]([OH:18])=[O:17])[CH3:15].N[C@H](C(O)=O)CC1C=CC(O)=CC=1.NCC(O)=O.N[C@H](C(O)=O)CCCNC(=N)N.CC(CC(O)=O)=O>>[NH2:13][C@H:14]([C:16]([OH:18])=[O:17])[CH2:15][CH2:2][C:10](=[O:11])[OH:12]
Reactant: C[C@H](N)C(=O)O
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: CC(=O)CC(=O)O
Agent: N=C(N)NCCC[C@H](N)C(=O)O
Agent: NCC(=O)O
Product: N[C@@H](CCC(=O)O)C(=O)O

Procedure:
1.03 His: 0.97 Phe: 2.00 Ala: 0.95 Tyr: 1.04 Gly: 0.97 Arg: 0.94 Pro: 0.96 Recovery: 85% (calculated as the diacetate).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6](/[CH:9]=[C:10]2/[C:11]([NH:16][CH2:17][C:18]#[CH:19])=[N:12][C:13](=[O:15])[S:14]/2)[CH2:5][CH2:4]1.[Cl:20][C:21]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:22]=1[CH:23]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>CN(C=O)C.C(N(CC)CC)C>[Cl:20][C:21]1[CH:28]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:26]=[CH:25][C:22]=1[CH2:23][N:3]1[CH2:8][CH2:7][CH:6](/[CH:9]=[C:10]2/[C:11]([NH:16][CH2:17][C:18]#[CH:19])=[N:12][C:13](=[O:15])[S:14]/2)[CH2:5][CH2:4]1
Reactant: C#CCNC1=NC(=O)S/C1=C\C1CCNCC1
Reactant: O=Cc1ccc(C(F)(F)F)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C#CCNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.1 %

Procedure:
To a solution of (5Z)-5-(piperidin-4-ylmethylidene)-4-(prop-2-yn-1-ylamino)-1,3-thiazol-2(5H)-one dihydrochloride (200 mg) in DMF (3 mL) were added triethylamine (0.35 mL) and 2-chloro-4-(trifluoromethyl)benzaldehyde (129 mg). The reaction mixture was stirred at room temperature for 1 hr, and sodium triacetoxyborohydride (554 mg) was added. The reaction mixture was stirred at room temperature for 3 hr, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (85 mg).
Reaction SMILES: C([C:4]1[C:8]([CH3:9])=[C:7]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[O:11])[N:6]([CH3:19])[C:5]=1[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])(O)=O.N1C2C(=CC=CC=2)C=CC=1>[Cr]([O-])([O-])=O.[Cu+2]>[CH3:19][N:6]1[C:7]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[O:11])=[C:8]([CH3:9])[CH:4]=[C:5]1[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)Cc1c(C(=O)O)c(C)c(C(=O)c2ccc(C)cc2)n1C
Agent: O=[Cr]([O-])[O-]
Agent: [Cu+2]
Solvent: c1ccc2ncccc2c1
Product: CCOC(=O)Cc1cc(C)c(C(=O)c2ccc(C)cc2)n1C
Temperature: 200 °C
Reaction time: 0.5 h

Procedure:
A solution of 33.0 g. (0.096 mole) of ethyl 3-carboxy-1,4-dimethyl-5 -(p-toluoyl)-pyrrole-2-acetate in 200 ml. of quinoline with 0.1 g. copper chromite added is heated under nitrogen for 6 hours at 200° C., then for 30 minutes at 220° C. The quinoline is distilled off in vacuo. The residue is dissolved in ether and washed successively with dilute hydrochloric acid, dilute sodium hydroxide, and brine; dried over magnesium sulfate; and the solvent evaporated in vacuo to give a brown oily residue which crystallizes. It is recrystallized from methanol, sublimed at 150° C. (0.025 mm/Hg) and recrystallized from hexane to give ethyl 1,4-dimethyl-5-(p-toluoyl)-pyrrole-2-acetate as a white solid, m.p. 90-93° C.