Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClCCC1NC(C2C=C(C=CC=2C)C([N:15]2[CH2:20][CH2:19][CH:18](C3C=CC(C#N)=CC=3)CC2)=O)=C(C)N=1.O[CH2:34][CH2:35][C:36]1[NH:37][C:38]([C:41]2[CH:42]=[C:43]([CH:48]=[CH:49][C:50]=2[CH3:51])[C:44]([O:46][CH3:47])=[O:45])=[CH:39][N:40]=1.OCCC1NC(C2C=C(C=CC=2C)C(N2CCC(C3C=CC(C#N)=CC=3)CC2)=O)=C(C)N=1.N1CCC1>>[N:15]1([CH2:34][CH2:35][C:36]2[NH:37][C:38]([C:41]3[CH:42]=[C:43]([CH:48]=[CH:49][C:50]=3[CH3:51])[C:44]([O:46][CH3:47])=[O:45])=[CH:39][N:40]=2)[CH2:18][CH2:19][CH2:20]1
Reactant: Cc1ccc(C(=O)N2CCC(c3ccc(C#N)cc3)CC2)cc1-c1[nH]c(CCCl)nc1C
Reactant: COC(=O)c1ccc(C)c(-c2cnc(CCO)[nH]2)c1
Agent: C1CNC1
Agent: Cc1ccc(C(=O)N2CCC(c3ccc(C#N)cc3)CC2)cc1-c1[nH]c(CCO)nc1C
Product: COC(=O)c1ccc(C)c(-c2cnc(CCN3CCC3)[nH]2)c1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compounds 24.1 and 24, except methyl 3-(2-(2-hydroxyethyl)-1H-imidazol-5-yl)-4-methylbenzoate (compound 157.1) was used in place of 4-(1-(3-(2-(2-hydroxyethyl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile (compound 23) and azetidine was used in place of dimethylamine.
Reaction SMILES: [C:1]1([CH2:7][O:8][N:9]2[C:15](=[O:16])[N:14]3[CH2:17][C@H:10]2[CH2:11][CH2:12][C@H:13]3[C:18]([OH:20])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[NH2:57][C@H:58]1[CH2:63][CH2:62][N:61]([C:64]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:65])[CH2:60][C@H:59]1[F:71]>CN(C)C=O.ClCCl>[C:67]([O:66][C:64]([N:61]1[CH2:62][CH2:63][C@H:58]([NH:57][C:18]([C@@H:13]2[CH2:12][CH2:11][C@@H:10]3[CH2:17][N:14]2[C:15](=[O:16])[N:9]3[O:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:20])[C@H:59]([F:71])[CH2:60]1)=[O:65])([CH3:70])([CH3:68])[CH3:69]
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)[C@H](F)C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)[C@H](F)C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of (2S,5R)-6-(phenylmethoxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (2.108 g, 7.63 mmol) in anhydrous dimethylformamide (15 mL) was added BOP (4.05 g, 9.15 mmol) and the resulting mixture was stirred at room temperature under nitrogen for 5 minutes. Diisopropyl ethyl amine (2.66 mL, 15.26 mmol) was then added followed by a solution of tert-butyl (3R,4S)-4-amino-3-fluoropiperidine-1-carboxylate (1.665 g, 7.63 mmol) in 20 mL of dichloromethane. The resulting solution was stirred at room temperature under nitrogen for 2 hours then concentrated under vacuum and the residue partitioned between ethyl acetate and water. The aqueous layer was washed twice with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified via silica gel flash chromatography (Isco Combiflash apparatus—120 g silica gel, 80 mL/min, 254 nM, 0% to 100% EtOAc/hexane over 6 column volumes then 100% EtOAc for 9 column volumes; title compound eluted at 100% EtOAc). Fractions containing pure title compound were collected and concentrated in vacuo to give a tan solid. Fractions containing impure product were also collected and repurified by HPLC (30×100 mm Sunfire column, 5 microns, 35 mL/min, 10% to 100% CH3CN+0.1% TFA/water+0.1% TFA over 15 min.; title compound eluted at 70% CH3CN+0.1% TEA). Fractions containing pure product were combined and concentrated in vacuo. The resulting aqueous residue was then extracted with ethyl acetate. The organic layer was collected and dried over magnesium sulfate. Concentration in vacuo gave a white solid which was combined with the material isolated from silica gel chromatography to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].C(N(CC)CC)C.Cl[P:16]([O:22][CH3:23])[N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([P:16]([O:22][CH3:23])[N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[NH:5][C:6]=1[Cl:7]
Reactant: COP(Cl)N1CCCC1
Reactant: Clc1nc[nH]c1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COP(c1nc(Cl)c(Cl)[nH]1)N1CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 146.5 %

Procedure:
To a stirred solution of 4,5-dichloroimidazole (4.62 g, 33.7 mmol) and triethylamine (18.8 mL, 13.65 g, 134.9 mmol) in THF (40 mL) was added dropwise Chloro(methoxy)pyrrolidinophosphine (3.31 g, 19.76 mmol) CH2Cl2 (13.4 mL) at room temperature. The mixture was stirred for 3 h at room temperature. The reaction mixture was filtered to remove the resulting salt, and the solvent was removed under reduced pressure to give the crude product as a pale yellow oil (7.76 g, 86%). 31P NMR (CDCl3) δ 125.9.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:6]=[N:7][C:8]([C:11]#[CH:12])=[CH:9][CH:10]=2)[CH2:3][CH2:2]1.I[C:14]1[CH:15]=[C:16]([CH:36]=[CH:37][C:38]=1[CH3:39])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH:30]=[C:29]([CH3:31])[N:28]=[CH:27]2)=[C:22]([C:32]([F:35])([F:34])[F:33])[CH:21]=1)=[O:18]>>[CH:1]1([NH:4][C:5]2[N:6]=[N:7][C:8]([C:11]#[C:12][C:37]3[CH:36]=[C:16]([CH:15]=[CH:14][C:38]=3[CH3:39])[C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH:30]=[C:29]([CH3:31])[N:28]=[CH:27]4)=[C:22]([C:32]([F:33])([F:34])[F:35])[CH:21]=3)=[O:18])=[CH:9][CH:10]=2)[CH2:3][CH2:2]1
Reactant: C#Cc1ccc(NC2CC2)nn1
Reactant: Cc1cn(-c2ccc(NC(=O)c3ccc(C)c(I)c3)cc2C(F)(F)F)cn1
Product: Cc1cn(-c2ccc(NC(=O)c3ccc(C)c(C#Cc4ccc(NC5CC5)nn4)c3)cc2C(F)(F)F)cn1

Procedure:
The title compound was synthesized from N-cyclopropyl-6-ethynylpyridazin-3-amine and 3-iodo-4-methyl-N-(4-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl)benzamide (as prepared above) in a manner similar to that described for in Example 1. The product was obtained as a pale yellow solid. Mp: 125-126° C.; 1H NMR (300 MHz, CDCl3) δ: 9.94 (1H, s), 8.34 (1H, s), 8.20-8.23 (1H, d, J=8.7 Hz), 8.02 (1H, s), 7.86-7.89 (1H, d, J=8.1 Hz), 7.53 (1H, s), 7.39-7.42 (1H, d, J=9.0 Hz), 7.30-7.32 (2H, m), 7.02-7.05 (1H, d, J=9.2 Hz), 6.80 (1H, s), 6.02 (1H, s), 2.58 (1H, m), 2.48 (3H, s), 2.29 (3H, s), 0.87 (2H, m), 0.64 (2H, brs). HRMS (ESI-TOF+): m/z [M+2H]+2 calcd for C28H25F3N6O: 259.1015. found: 259.1023.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16]C)[CH:14]=2)[C:9](=[O:20])[CH2:8][CH:7]1[CH3:21])=[O:5])[CH3:2].[C-]#N.[Na+].O.[Cl-].[NH4+]>CS(C)=O>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([OH:16])[CH:14]=2)[C:9](=[O:20])[CH2:8][CH:7]1[CH3:21])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2cc(OC)c(OC)cc2C(=O)CC1C
Agent: [C-]#N
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)N1c2cc(O)c(OC)cc2C(=O)CC1C
Yield: 53.6 %

Procedure:
A solution of 6,7-dimethoxy-2-methyl-4-oxo-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (10.0 g, 34.1 mmol) and sodium cyanide (8.35 g, 170 mmol) in dimethylsulfoxide (35 mL) was heated at 130° C. for 16 h. Water (100 mL) was added, the mixture was saturated with ammonium chloride, and then extracted with ethyl acetate (4×100 mL). The combined organic extracts were washed with saturated sodium bicarbonate solution (50 mL), brine (25 mL), dried over sodium sulfate, filtered and concentrated in vacuo. Purification by silica gel chromatography using 0-50% ethyl acetate/hexanes as eluent afforded the title compound (5.10 g, 54%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.[OH-].[CH2:13]([N+](CCCC)(CCCC)CCCC)[CH2:14]CC.[OH-].[Na+].BrCCBr>C1(C)C=CC=CC=1.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([C:10]#[N:11])[CH2:14][CH2:13]2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: COc1cccc(CC#N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: BrCCBr
Solvent: CCOC(C)=O
Product: COc1cccc(C2(C#N)CC2)c1
Reaction time: 16 h

Procedure:
To a stirred solution of 2-(3-methoxyphenyl)acetonitrile (6.5 g, 44.1 mmol), 40% aq tetrabutylammonium hydroxide (4.5 ml) and 50% aq NaOH (30 ml) in toluene (30 ml) was added 1,2-dibromoethane (10 ml, 116 mmol) at room temperature. The reaction mixture was stirred for 16 hours, diluted with EtOAc and washed with water and brine. The organic layer was dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on a short silica gel column (hex:ethyl acetate, 9:1) to give the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:12]=[N:13][N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:15]=1)=[O:10].Br[CH2:23][C:24]([O:26]CC)=[O:25]>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([O:1][CH2:23][C:24]([OH:26])=[O:25])=[C:3]([C:9]([C:11]2[CH:12]=[N:13][N:14]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:15]=2)=[O:10])[CH:4]=1
Reactant: O=C(c1cnn(-c2ccccc2)c1)c1cc(Cl)ccc1O
Reactant: CCOC(=O)CBr
Product: O=C(O)COc1ccc(Cl)cc1C(=O)c1cnn(-c2ccccc2)c1

Procedure:
Prepared from (2-hydroxy-5-chlorophenyl)-(1-phenyl-1H-pyrazol-4-yl)-methanone and ethyl bromoacetate according to GP2 and GP3: LC/MS (an10p8): Rt 3.08 min, m/z 356.6 [M+1]+; 1H NMR (CDCl3): δ 4.75 (s, 2H), 6.95 (d, J=8.9 Hz, 1H), 7.33-7.41 (m, 1H), 7.44-7.52 (m, 3H), 7.55 (d, J=2.6 Hz, 1H), 7.69-7.75 (m, 2H), 8.18 (s, 1H), 8.52 (s, 1H).
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[C:22]2[CH2:21][S:20][CH2:19][C@@H:18]([C:23]([O:25][CH3:26])=[O:24])[NH:17][C:16](=[O:27])[C@@H:15]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:14][O:13][C:12](=[O:36])[C:11]=2[CH:10]=[C:9]([N:37]2C(=O)C3[C:39](=CC=CC=3)[C:38]2=[O:47])[CH:8]=1)(C)(C)C.N1C=CC=CC=1>C(OC(=O)C)(=O)C>[C:38]([NH:37][C:9]1[CH:8]=[C:7]([OH:6])[C:22]2[CH2:21][S:20][CH2:19][C@@H:18]([C:23]([O:25][CH3:26])=[O:24])[NH:17][C:16](=[O:27])[C@@H:15]([NH:28][C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])[CH2:14][O:13][C:12](=[O:36])[C:11]=2[CH:10]=1)(=[O:47])[CH3:39]
Reactant: COC(=O)[C@@H]1CSCc2c(O[Si](C)(C)C(C)(C)C)cc(N3C(=O)c4ccccc4C3=O)cc2C(=O)OC[C@H](NC(=O)OC(C)(C)C)C(=O)N1
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COC(=O)[C@@H]1CSCc2c(O)cc(NC(C)=O)cc2C(=O)OC[C@H](NC(=O)OC(C)(C)C)C(=O)N1
Temperature: 20 °C
Reaction time: 3 h
Yield: 39.1 %

Procedure:
A mixture of 25 mg of the product of Example 159 and 0.1 ml of pyridine in 1.5 ml of acetic anhydride was stirred at 20° C. for 3 hours. The precipitate was collected by filtration, washed with pentane, and dissolved in 1.5 ml of methanol. After the addition of 2.6 mg of potassium carbonate, the mixture was stirred for 1.5 hours at 20° C., and then evaporated in vacuo. Water was added to the residue, and the insoluble material was isolated by filtration, to yield 7 mg of tert-butyl (4R,7S)-12-acetylamino-1,3,4,5,6,7,8,10-octahydro-14-hydroxy-4-methoxycarbonyl-6,10-dioxo-9,2,5-benzoxathiaazacyclododecine-7-carbamate as a white solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[CH3:27][N:28]([CH3:41])[S:29]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)(=[O:31])=[O:30].C(=O)(O)[O-].[Na+].O>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH3:27][N:28]([CH3:41])[S:29]([C:32]1[CH:33]=[CH:34][C:35]([C:2]2[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]3[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=3[CH3:24])=[O:15])[C:5]3[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=3[N:7]=2)=[CH:36][CH:37]=1)(=[O:30])=[O:31]
Reactant: CN(C)S(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2cnn3C(C)C)c(=O)[nH]1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: COCCOC
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(S(=O)(=O)N(C)C)cc3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 110 °C
Yield: 57.4 %

Procedure:
In a 25 mL sealable tube under nitrogen were combined 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (85 mg, 0.23 mmol) and {4-[(dimethylamino)sulfonyl]phenyl}boronic acid (104 mg, 0.46 mmol) in DME/water (3 ml:1 ml). PdCl2(dppf)-CH2Cl2 adduct (9.3 mg, 0.011 mmol) was added and the resulting mixture was degassed with nitrogen for 10 min. Sodium bicarbonate (57.3 mg, 0.68 mmol) was added and the insoluble light brown mixture was heated in an oil bath at 110° C. for 3 hrs. After cooling, 2 mL of water was added to the black mixture and solids that precipitated were filtered. DMF was added along with a few drops of water and solids were filtered. DCM/MeOH (1:1) was added to the grey solids and they were filtered and dried to afford the title compound (69 mg, 57%) as a grayish solid. LCMS E-S (M+H)=523.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.59 (br. s., 1H), 9.01 (br. s., 1H), 8.51 (m, J=8.34 Hz, 2H), 8.44 (s, 1H), 8.27 (s, 1H), 7.93 (m, J=8.34 Hz, 2H), 5.91 (s, 1H), 5.36 (dt, J=13.14, 6.57 Hz, 1H), 4.43 (d, J=4.55 Hz, 2H), 2.66 (s, 6H), 2.23 (s, 3H), 2.13 (s, 3H), 1.56 (d, J=6.57 Hz, 6H).
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:32][OH:33])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:40](I)[CH:41]=[CH2:42].O>C(OCC)(=O)C>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:32][O:33][CH2:42][CH:41]=[CH2:40])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCI
Reactant: CCOC(=O)C(=NO)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: C=CCON=C(C(=O)OCC)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 6.86 g of the anti isomer of ethyl 2-(2-tritylamino-4-thiazolyl)-2-hydroxyiminoacetate [Step A of Example 14], 3.51 g of potassium carbonate, 15 ml of diemethylformamide and 7 ml of allyl iodide was stirred under an inert atmosphere at room temperature for 5 hours and then 250 ml of water and 150 ml of ethyl acetate were added thereto with stirring. The mixture was decanted and the aqueous phase was washed and reextracted with ethyl acetate. The extracts were dried, vacuum filtered and evaporated to dryness. The residue was taken up in ethanol and crystallizaton was started. The mixture was cooled in an ice bath with stirring for half an hour and was then vacuum filtered. The crystals were rinsed with ethanol to obtain 4.72 g of the anti isomer of ethyl 2-(2-tritylamino-4-thiazolyl)-2-(2-propenyloxyimino)-acetate. 215 mg of the product were dissolved in 2 ml of ethanol and 2 ml of methylene chloride and the mixture was filtered. The filtrate was concentrated and diluted with ethanol. Crystallization was effected in an ice bath and the mixture was vacuum filtered. The crystals were rinsed with ethanol and dried to obtain 70 mg of the pure product which melted at 90° C. (pasty) and 160° C. (pure).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][C:5](=O)[CH:4]([CH2:9][C:10](=O)[C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH2:3]1.[NH2:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1>>[CH3:1][CH:2]1[CH2:7][CH2:6][C:5]2[N:18]([C:19]3[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=3)[C:10]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)=[CH:9][C:4]=2[CH2:3]1
Reactant: CC1CCC(=O)C(CC(=O)c2cccnc2)C1
Reactant: Nc1ccc(C(=O)O)cc1
Product: CC1CCc2c(cc(-c3cccnc3)n2-c2ccc(C(=O)O)cc2)C1
Yield: 63 %

Procedure:
Following the general methods as outlined under Intermediate 13, starting from 4-methyl-2-(2-oxo-2-pyridin-3-ylethyl)cyclohexanone and 4-aminobenzoic acid, the title compound was isolated in 63% yield (98% purity by HPLC). MS(ESI+): 333.5; MS(ESI−): 331.4.
Reaction SMILES: [CH3:1][C:2]([N:10]([CH2:20][CH2:21][C:22](=O)[CH3:23])[C:11](=[O:19])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[K+]>C(O)C>[CH3:1][C:2]([N:10]1[CH2:20][CH2:21][C:22]([CH3:23])=[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:11]1=[O:19])([CH3:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(=O)CCN(C(=O)Cc1ccccc1)C(C)(C)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC1=C(c2ccccc2)C(=O)N(C(C)(C)c2ccccc2)CC1
Yield: 67 %

Procedure:
7.1 g (0.022 mol) of N-(α,α-dimethylbenzyl)-N-(3-oxobutyl)phenylacetamide prepared by the method of Reference Example 10, was dissolved in 50 ml of ethanol, and 0.33 g (0.005 mol) of potassium hydroxide powder was added thereto. The mixture was reflux under heating for 1.5 hours. Then, the reaction mixture was returned to room temperature, and ethanol was distilled off under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. Then ethyl acetate layer was washed with water and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue thereby obtained was recrystallized from ethanol to obtain 4.5 g (yield: 67.2%) of the desired compound.
Reaction SMILES: [CH:1](O)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1.S(=O)(=O)(O)O>>[C:2]1([CH:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:19]2[CH:20]=[CH:21][C:16](=[O:15])[NH:17][CH:18]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC(c1ccccc1)c1ccccc1
Reactant: Oc1ccccn1
Agent: O=S(=O)(O)O
Product: O=c1ccc(C(c2ccccc2)c2ccccc2)c[nH]1

Procedure:
To a mixture of 92.1 g (0.5 mole) of benzhydrol and 142.7 g. (1.5 mole) of 2-hydroxypyridine heated at 180°, add with stirring 1.5 ml. of concentrated sulfuric acid. Heat the mixture at 250°-255° for 2 hours with the removal of water. Pour the cooled reaction mixture into water, stir, and extract with chloroform. Concentrate the chloroform extracts to a residue containing 5-(diphenylmethyl)-2-pyridone. Triturate the residue with ethyl acetate and filter the solids to obtain 5-(diphenylmethyl)-2-pyridone plus other isomers. Recrystallize from acetonitrile to obtain the product of this example, m.p. 174°-176° C.
Reaction SMILES: Cl[C:2]1[C:3]([N:12]2[CH:16]=[CH:15][CH:14]=[CH:13]2)=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.[CH3:17][O:18][CH2:19][CH2:20][OH:21].[OH-].[K+]>CS(C)=O>[CH3:17][O:18][CH2:19][CH2:20][O:21][C:2]1[C:3]([N:12]2[CH:16]=[CH:15][CH:14]=[CH:13]2)=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1
Reactant: Nc1cc(Cl)c(-n2cccc2)cc1[N+](=O)[O-]
Reactant: COCCO
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COCCOc1cc(N)c([N+](=O)[O-])cc1-n1cccc1

Procedure:
The title compound was prepared from 5-chloro-2-nitro-4-pyrrol-1-yl-phenylamine (Example F3) (1.01 g, 4 mmol), 2-methoxyethanol (1.58 mL, 20 mmol) and KOH (316 mg, 4.8 mmol) in DMSO (5 mL) according to the general procedure E. Obtained as an orange solid (870 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:24])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH:12]1[CH2:17][CH2:16][N:15]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:14][CH2:13]1)[CH2:7]2.CI.[CH3:27][Si]([N-][Si](C)(C)C)(C)C.[Na+]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([F:24])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH:12]1[CH2:13][CH2:14][N:15]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:16][CH2:17]1)[CH:7]2[CH3:27]
Reactant: O=C1c2c(Br)cc(F)cc2CN1C1CCN(C2CCCCC2)CC1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CC1c2cc(F)cc(Br)c2C(=O)N1C1CCN(C2CCCCC2)CC1
Reaction time: 1.5 h

Procedure:
To a stirred solution of 7-bromo-2-(1-cyclohexylpiperidin-4-yl)-5-fluoro-2,3-dihydro-1H-isoindol-1-one (70 mg, 0.177 mmol) and methyliodide (1.1 equiv., 0.195 mmol, 0.012 mL) in anhydrous tetrahydrofuran (3.5 mL) under nitrogen at −78° C., 1M sodium bis(trimethylsilyl)amide in tetrahydrofuran (1.2 equiv., 0.212 mL) was slowly added. The reaction mixture was stirred for 90 min and quenched by adding dropwise a 10% ammonium hydroxide solution. Dichloromethane was added, the layers were separated, and the aqueous layer was extracted twice dichloromethane. Organic layers were collected, dried and evaporated. Crude (58 mg) was used without further purification.
Reaction SMILES: S(O)(O)(=O)=O.[C:6]([N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10]1)(=[NH:8])[NH2:7].[OH-].[Na+].[CH2:24]([N:26]1[CH2:31][CH2:30][C:29](=O)[C:28](=[CH:33]OC)[C:27]1=[O:36])[CH3:25]>C(O)C>[CH2:15]([N:12]1[CH2:13][CH2:14][N:9]([C:6]2[N:7]=[CH:33][C:28]3[C:27](=[O:36])[N:26]([CH2:24][CH3:25])[CH2:31][CH2:30][C:29]=3[N:8]=2)[CH2:10][CH2:11]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: N=C(N)N1CCN(Cc2ccccc2)CC1
Reactant: CCN1CCC(=O)C(=COC)C1=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCN1CCc2nc(N3CCN(Cc4ccccc4)CC3)ncc2C1=O
Yield: 80.8 %

Procedure:
1.56 g of 1-amidino-4-benzylpiperazine sulfate was added to an ethanol solution containing 0.23 g of sodium hydroxide. To the resulting suspension was added 1.07 g of 1-ethyl-3-methoxymethylenepiperidine-2,4-dione, and they were refluxed for 2 hours. Ethanol was distilled off. Then, water was added and extraction by chloroform was conducted. The chloroform layer was dried and concentrated to obtain 1.4 g of 2-(4-benzylpiperazino)-6-ethyl-5-oxo-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine with an yield of 69%.
Reaction SMILES: C(N)CN.ClCC1SC=CN=1.[S:12]1[CH:16]=[CH:15][N:14]=[C:13]1[CH2:17][NH:18][CH2:19][CH2:20][NH2:21].[C:22]([NH:24][C:25](=[N:28][CH3:29])SC)#[N:23]>>[C:22]([NH:24][C:25]([NH:28][CH3:29])=[N:21][CH2:20][CH2:19][NH:18][CH2:17][C:13]1[S:12][CH:16]=[CH:15][N:14]=1)#[N:23]
Reactant: NCCNCc1nccs1
Reactant: CN=C(NC#N)SC
Agent: ClCc1nccs1
Solvent: NCCN
Product: CNC(=NCCNCc1nccs1)NC#N

Procedure:
Reacting ethylenediamine with 2-chloromethylthiazole by the procedure of Example 34, then reacting the resulting N-(2-thiazolylmethyl)ethylenediamine with N-cyano-N',S-dimethylisothiourea by the procedure of Example 3(a), gives N-cyano-N'-methyl-N"-[2-(2-thiazolylmethylamino)ethyl]guanidine. Hydrolysis of this compound by the procedure of Example 3(e) gives N-methyl-N'-[2-(2-thiazolylmethylamino)ethyl]guanidine trihydrochloride.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:6][N:5]=[C:4]([CH:14]([F:16])[F:15])[N:3]=1>C(O)C>[Cl:1][C:2]1[C:7]([CH:8]([OH:13])[C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:6][N:5]=[C:4]([CH:14]([F:16])[F:15])[N:3]=1
Reactant: CC(C)(C)C(=O)c1cnc(C(F)F)nc1Cl
Solvent: CCO
Product: CC(C)(C)C(O)c1cnc(C(F)F)nc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
1.5 g of 4-chlorodifluoromethyl-5-pivaloylpyrimidine was dissolved in 50 ml of ethanol, then 1 g of a boron ammonia complex was added, and the mixture was stirred at room temperature for 1 hour. After the solvent was distilled off under reduced pressure, water was added, and extraction with chloroform was carried out. The extract layer was washed with water and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by thin-layer chromatography (developing solvent: chloroform/ethyl acetate=7/3) to obtain 1.1 g of the desired product as a viscous liquid. nD19.8 1.4623