Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([NH2:12])=O)=[CH:7][C:6]=2[CH:13]=1.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O.O>C1COCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]#[N:12])=[CH:7][C:6]=2[CH:13]=1
Reactant: Cc1ccc2oc(C(N)=O)cc2c1
Solvent: O
Solvent: C1CCOC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Cc1ccc2oc(C#N)cc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 78.7 %

Procedure:
To the suspension of 5-methylbenzofuran-2-carboxamide (5.17 g, 29.5 mmol) in 66 mL of anhydrous THF was added TEA (8.23 mL, 59.0 mmol). TFAA (6.25 mL, 44.3 mmol) was added dropwise to the above mixture at 0° C. (internal temperature did not exceed 15° C.). After stirring at 0° C. for 1 hr, the reaction was complete by TLC. The reaction mixture was poured into 610 mL of H2O, and extracted with EtOAc 3 times. The organic layer was washed with sat. NaHCO3, brine and dried over Na2SO4, filtered and concentrated under reduced pressure, and the resulting residue was purified by silica gel flash chromatography, 100% Heptane-8% Ethyl Acetate/92% Heptane, to yield 5-methylbenzofuran-2-carbonitrile (3.65 g). 1H NMR (400 MHz, DMSO-d6) δ 2.42 (s, 3H), 7.42 (dd, J=8.6, 1.8 Hz, 1H), 7.59-7.67 (m, 2H), 8.03 (d, J=0.9 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH:15](CC)[CH2:16][N:17]4C(=O)C5=CC=CC=C5C4=O)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:6]=2[CH:36]=1.O.NN.[CH2:40](O)[CH3:41]>>[NH2:17][CH:16]([CH2:40][CH3:41])[CH2:15][C:12]1[N:11]2[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:36][C:6]=3[C:7]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[N:8][CH2:9][C:10]2=[N:14][N:13]=1
Reactant: CCO
Reactant: CCC(CN1C(=O)c2ccccc2C1=O)c1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Agent: NN
Solvent: O
Product: CCC(N)Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2

Procedure:
In the manner given in Example 21, N-[2-(8-chloro-6-phenyl-4H-s-triazolo[4,3-a][ 1,4]benzodiazepin-1-yl)butyl]-phthalimide in ethanol is warmed with hydrazine hydrate to give 1-(2-aminobutyl)-8-chloro-6-phenyl-4H-s-triazolo[4,3-a]-[1,4]benzodiazepine.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][CH:3]=1.Br[CH2:10][C:11]([CH:13]1[CH2:15][CH2:14]1)=O>C(COC)OC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:10]=[C:11]([CH:13]3[CH2:15][CH2:14]3)[N:8]=2)[N:7]=1
Reactant: Nc1ccc(Cl)nn1
Reactant: O=C(CBr)C1CC1
Solvent: COCCOC
Product: Clc1ccc2nc(C3CC3)cn2n1
Temperature: 25 °C
Yield: 42 %

Procedure:
A mixture of 6-chloropyridazin-3-amine x104 (24.63 g, 0.19 mol) and 2-bromo-1-cyclopropylethanone (31 g, 0.190 mol, 1 eq) in dimethoxyethane (400 ml) is refluxed under inert atmosphere for 2 days. After cooling to room temperature, the solvent is removed under reduced pressure, the crude is taken up in water (100 ml) and extracted with ethyl acetate (2×300 ml). The cumulated organic layers are dried over MgSO4, filtered and condensed under reduced pressure to furnish 6-chloro-2-cyclopropylimidazo[1,2-b]pyridazine x105 (Yield: 42%) which is used as such in the next step. Note that further title compound x105 can be extracted from aqueous layer after neutralization to pH 5 by addition of sodium hydroxyde, extraction with dichloromethane, drying (MgSO4), filtration and condensation under reduced pressure (additional 11.13 g are then collected).
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[N:9]1[C:17]2[C:12](=[CH:13][C:14]([C:18]#[C:19][CH2:20][OH:21])=[CH:15][CH:16]=2)[CH:11]=[N:10]1.I[CH3:23]>C1COCC1>[CH3:23][O:21][CH2:20][C:19]#[C:18][C:14]1[CH:13]=[C:12]2[C:17](=[CH:16][CH:15]=1)[N:9]([CH:4]1[CH2:5][CH2:6][CH2:7][CH2:8][O:3]1)[N:10]=[CH:11]2
Reactant: CI
Reactant: OCC#Cc1ccc2c(cnn2C2CCCCO2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCC#Cc1ccc2c(cnn2C2CCCCO2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
Sodium hydride (60% in mineral oil, 0.42 g, 10.5 mmol) was added to a solution of 3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)prop-2-yn-1-ol (1.01 g, 3.94 mmol; Intermediate 19) in THF (20 mL) at 0° C. The mixture was stirred at 0° C. for 30 minutes, and then iodomethane (1.67 g, 11.8 mmol) was added. The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was poured into ice water (100 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (EtOAc/petroleum ether=1:30) to afford the title compound (0.714 g, yield 67.3%). 1H NMR (DMSO-d6, 300 MHz): δ 8.21 (s, 1H), 7.93 (s, 1H), 7.73 (d, 1H), 7.47-7.45 (m, 1H), 5.85-5.83 (m, 1H), 4.38 (s, 2H), 3.76-3.71 (m, 2H), 3.35 (s, 3H), 2.40-2.37 (m, 1H), 2.03-1.94 (m, 2H), 1.73-1.72 (m, 1H), 1.57-1.55 (m, 2H). LCMS: 271 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([C:15](O)=[O:16])[CH:14]=1)[NH:11][C:10]1[CH2:9][CH:8]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:7][CH2:6][C:5]2=1.C(Cl)CCl.O.O[N:29]1C2C=CC=CC=2N=N1.[OH-].[NH4+]>C1COCC1.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([C:15](=[O:16])[NH2:29])[CH:14]=1)[NH:11][C:10]1[CH2:9][CH:8]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:7][CH2:6][C:5]2=1
Reactant: On1nnc2ccccc21
Reactant: CCOC(=O)C1CCc2c([nH]c3c(C(=O)O)cc(Br)cc23)C1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C1CCc2c([nH]c3c(C(N)=O)cc(Br)cc23)C1
Temperature: 25 °C
Yield: 97.5 %

Procedure:
To a suspension of 6-bromo-2-(ethoxycarbonyl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid (18.5 g, 42.4 mmol), EDC (10.58 g, 55 2 mmol), and 1-hydroxybenzotriazole hydrate (8.45 g, 55.2 mmol) in THF/CH2Cl2 (5/1) (480 mL) was added ammonium hydroxide (9.91 mL, 76 mmol) and it turned into a thick light yellow suspension and it was stirred at room temperature over the weekend. CAUTION: A mild exotherm was observed. The reaction mixture warmed up to 31° C. If reaction is done on larger scale, consider cooling or slow addition of one of the reagents. The reaction mixture was concentrated and then titurated with 500 ml water (sonicate for 2 minutes), then filtered through a medium porosity glass frit. The solids were washed with water and dried in a nitrogen stream to give 15.1 g ethyl 6-bromo-8-carbamoyl-2,3,4,9-tetrahydro-1H-carbazole-2-carboxylate. MS (ESI) m/e−=363/365, m/e+=365/367 [1Br isotope pattern]. 1H NMR (DMSO-d6) δ ppm 10.97 (s, 1H), 8.10 (b, 1H), 7.74 (d, 1H, J=1.8), 7.68 (d, 1H, J=1.5), 7.44 (b, 1H), 4.16-4.06 (m, 2H), 3.04 (dd, 1H, J=16.2, 5.0), 2.95-2.83 (m, 2H), 2.75-2.68 (m, 1H), 2.67-2.58 (m, 1H), 2.18-2.12 (m, 1H), 1.87-1.79 (m, 1H), 1.21 (t, 3H, J=7.0).
Reaction SMILES: Cl.[CH:2]([O:5][NH2:6])([CH3:4])[CH3:3].Cl[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][C:9]=1[NH:18][C:19](=O)[CH3:20]>C(O)C>[CH:2]([O:5][N:6]1[C:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:18]=[C:19]1[CH3:20])([CH3:4])[CH3:3]
Reactant: CC(=O)Nc1cnc2ccccc2c1Cl
Reactant: CC(C)ON
Agent: Cl
Solvent: CCO
Product: Cc1nc2cnc3ccccc3c2n1OC(C)C
Yield: 94.7 %

Procedure:
O-isopropylhydroxylamine hydrochloride (2.14 g, 1.7 eq) was added to a solution of N-(4-chloroquinolin-3-yl)acetamide (2.51 g, 1.0 eq) in ethanol (75 mL). The reaction mixture was heated at reflux for 2 hours and then concentrated under reduced pressure. The residue was partitioned between dichloromethane and aqueous saturated sodium bicarbonate. The organic layer was separated and concentrated under reduced pressure to provide 2.60 g of 1-isopropoxy-2-methyl-1H-imidazo[4,5-c]quinoline.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.S(OC)(O[CH2:19][C:20]1([CH2:24][O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:23][O:22][CH2:21]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH2:26]([O:25][CH2:24][C:20]1([CH2:19][N:12]2[CH:13]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]3)[CH:10]=[N:11]2)[CH2:23][O:22][CH2:21]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: COS(=O)(=O)OCC1(COCc2ccccc2)COC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)OB(c2cnn(CC3(COCc4ccccc4)COC3)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.9 %

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (0.825 g, 4.25 mmol) and {3-[(benzyloxy)methyl]oxetan-3-yl}methyl methyl sulfate (Compound 44D, 1.35 g, 4.46 mmol) in DMF (3.90 mL) was charged with potassium carbonate (588 mg, 4.25 mmol) and allowed to stir at rt for 16 hrs. The reaction mixture was diluted with EtOAc and washed with brine (2×), dried over sodium sulfate, filtered and concentrated in vacuo and purified using a Teledyne ISCO Combiflash® Rf system [0→40% Acetone/Heptanes] to afford 1.37 g of the title compound (84%). 1H NMR (400 MHz, CD3OD) δ 7.76 (s, 1H), 7.66 (s, 1H), 7.25-7.37 (m, 5H), 4.67 (d, J=6.6 Hz, 2H), 4.48-4.52 (m, 4H), 4.42 (d, J=6.6 Hz, 2H), 3.45 (s, 2H), 1.20 (s, 12H). MS (ESI): m/z=385.20 [M+H]+. HPLC: tR=1.08 min (UPLC-TOF: polar—2 min).
Reaction SMILES: [C:1]([CH2:8][N:9]1[CH2:22][CH2:21][CH2:20][NH:19][CH2:18][CH2:17][N:16]([CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:15][CH2:14][CH2:13][N:12]([CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-])=O)=[CH:35][CH:34]=2)[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCOCC>C(O)C.[Pd].C([O-])([O-])=O.[Ca+2]>[C:1]([CH2:8][N:9]1[CH2:22][CH2:21][CH2:20][NH:19][CH2:18][CH2:17][N:16]([CH2:23][C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:15][CH2:14][CH2:13][N:12]([CH2:31][CH2:32][C:33]2[CH:34]=[CH:35][C:36]([NH2:39])=[CH:37][CH:38]=2)[CH2:11][CH2:10]1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(C)(C)OC(=O)CN1CCCN(CCc2ccc([N+](=O)[O-])cc2)CCN(CC(=O)OC(C)(C)C)CCCNCC1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CCOCC
Solvent: CCO
Product: CC(C)(C)OC(=O)CN1CCCN(CCc2ccc(N)cc2)CCN(CC(=O)OC(C)(C)C)CCCNCC1
Yield: 100 %

Procedure:
To a solution of compound (8) (1.15 g, 1.99 mmol) in absolute ethanol (100 ml) was added 5% Pd/CaCO3 (0.31 g) to which lead (Pb) had been added as an inhibitor. The resultant mixture was stirred at an ambient temperature under H2 atmosphere for 12 hours. The reaction mixture was filtered through a celite pad and washed with ethanol (2×20 ml). The solvent was evaporated from the combined filtrate in vacuo to give an oily residue, which was then treated with Et2O to obtain a white solid of compound (10) (1.09 g, 98% yield). 1H NMR (500 MHz, CDCl3): δ 6.90-6.88 (dd, 2H), 6.55-6.54 (dd, 2H), 3.28-3.25 (dd, 4H), 2.96-2.94 (m, 2H), 2.88-2.86 (m, 2H), 2.81-2.79 (m, 2H), 2.70-2.68 (m, 2H), 2.64-2.62 (m, 2H), 2.56 (brs, 8H), 2.47 (brs, 2H), 1.86 (brs, 2H), 1.60 (brs, 2H), 1.39-1.37 (dd, 18H); 13C NMR (125 MHz, CDCl3): δ 178.1, 170.5, 170.4, 144.5, 129.9, 129.2, 115.1, 81.1, 80.9, 55.3, 55.0, 54.8, 52.0, 51.7, 51.3, 50.4, 48.6, 48.3, 48.22, 45.8, 30.9, 28.1, 24.4, 23.8, 22.8; HRMS (FAB) calculated for C30H54N5O4: 548.4176 [(M+H)+], measured value: 548.4172 [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH3:12][O:13][C:14](=[O:31])[C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][C:23]=2[CH:29]=O)=[CH:17][CH:16]=1.N1CCCC1>CO>[CH3:12][O:13][C:14](=[O:31])[C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][C:23]=2/[CH:29]=[C:6]2\[C:7](=[O:11])[NH:8][C:9]3[C:5]\2=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=3)=[CH:17][CH:16]=1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: COC(=O)c1ccc(Oc2ccc(Br)cc2C=O)cc1
Solvent: C1CCNC1
Solvent: CO
Product: COC(=O)c1ccc(Oc2ccc(Br)cc2/C=C2\C(=O)Nc3cc(Cl)ccc32)cc1
Yield: 73.7 %

Procedure:
In a manner similar to the method described in Example 1a, 6-chlorooxindole (1.6 g, 9.2 mmol) (Crescent) was reacted with 4-(4-bromo-2-formyl-phenoxy)-benzoic acid methyl ester (2.8 g, 8.4 mmol) and pyrrolidine in methanol at 90° C. for 2 h to give E/Z-4-[4-bromo-2-(6-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-phenoxy]-benzoic acid methyl ester as a bright yellow solid (Yield 3 g, 81%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([O:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([N:20]3[CH2:44][CH2:43][C:23]4([CH2:27][N:26]([C:28]([O:30][CH2:31][C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)=[O:29])[CH:25]([C:38]([O:40]CC)=[O:39])[CH2:24]4)[CH2:22][CH2:21]3)[CH:15]=2)[C:9]([F:12])([F:11])[F:10])=[C:4]([N:45]2[CH:49]=[CH:48][C:47]([CH3:50])=[N:46]2)[CH:3]=1.[Li+].[OH-]>>[CH2:31]([O:30][C:28]([N:26]1[CH:25]([C:38]([OH:40])=[O:39])[CH2:24][C:23]2([CH2:43][CH2:44][N:20]([C:16]3[CH:15]=[C:14]([O:13][C@H:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=4[N:45]4[CH:49]=[CH:48][C:47]([CH3:50])=[N:46]4)[C:9]([F:10])([F:12])[F:11])[CH:19]=[CH:18][N:17]=3)[CH2:21][CH2:22]2)[CH2:27]1)=[O:29])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CCOC(=O)C1CC2(CCN(c3cc(O[C@H](c4ccc(Cl)cc4-n4ccc(C)n4)C(F)(F)F)ccn3)CC2)CN1C(=O)OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Product: Cc1ccn(-c2cc(Cl)ccc2[C@@H](Oc2ccnc(N3CCC4(CC3)CC(C(=O)O)N(C(=O)OCc3ccccc3)C4)c2)C(F)(F)F)n1

Procedure:
Hydrolysis of 2-benzyl 3-ethyl 8-(4-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyridin-2-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate using the LiOH general method provided 2-((benzyloxy)carbonyl)-8-(4-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyridin-2-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:16]=1)[C:7]([NH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:8].[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[CH3:28])[CH:23]=O)[CH3:18]>>[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[CH3:28])[CH2:23][N:13]1[CH2:12][CH2:11][CH:10]([NH:9][C:7](=[O:8])[C:6]2[CH:16]=[C:2]([CH3:1])[CH:3]=[N:4][CH:5]=2)[CH2:15][CH2:14]1)[CH3:18]
Reactant: Cc1cncc(C(=O)NC2CCNCC2)c1
Reactant: CCOc1cc(C=O)ccc1C
Product: CCOc1cc(CN2CCC(NC(=O)c3cncc(C)c3)CC2)ccc1C
Yield: 35 %

Procedure:
The title compound (13 mg, 35%) was prepared analogously to example 30 from 5-methyl-N-(piperidin-4-yl)-nicotinamide and 3-ethoxy-4-methyl-benzaldehyde. MS: 368.5 (MH+).
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:6][C:7](=[O:13])[N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:4].[CH3:20][C:21]1[CH:22]=[C:23]([N:27]=[C:28]=[O:29])[CH:24]=[CH:25][CH:26]=1>>[CH3:20][C:21]1[CH:22]=[C:23]([NH:27][C:28](=[O:29])[NH:1][CH2:2][C:3]([N:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:6][C:7](=[O:13])[N:8]2[CH2:9][CH2:10][CH2:11][CH2:12]2)=[O:4])[CH:24]=[CH:25][CH:26]=1
Reactant: NCC(=O)N(CC(=O)N1CCCC1)c1ccccc1
Reactant: Cc1cccc(N=C=O)c1
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)N2CCCC2)c2ccccc2)c1
Yield: 52.1 %

Procedure:
Working in a manner similar to that described in Example 1, but starting with 2-amino-N-phenyl-N-[2-oxo-2-(1-pyrrolidinyl)ethyl]acetamide (0.7 g) and 3-methylphenyl isocyanate (0.36 g), and after recrystallization in acetonitrile, 2-[3-(3-methylphenyl)ureido]-N-phenyl-N-[2-oxo-2-(1-pyrrolidinyl) ethyl)acetamide (0.55 g), m.p. 206° C., is obtained.
Reaction SMILES: [S-:1][C:2]#[N:3].[NH4+].II.[Cl:7][C:8]1[C:9]([CH3:15])=[C:10]([CH:12]=[CH:13][CH:14]=1)[NH2:11].O>CO>[NH2:11][C:10]1[CH:12]=[CH:13][C:14]([S:1][C:2]#[N:3])=[C:8]([Cl:7])[C:9]=1[CH3:15]
Reactant: N#C[S-]
Reactant: Cc1c(N)cccc1Cl
Agent: II
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: Cc1c(N)ccc(SC#N)c1Cl
Yield: 89.3 %

Procedure:
To a stirred solution of ammonium thiocyanate (1.61 g, 0.02 mol) and iodine (1.79 g, 7.1 mmol) in methanol was added 3-chloro-2-methylaniline (0.84 mL, 7.1 mmol) dropwise. The mixture was allowed to stir at room temperature for 2 days after which time water (50 mL) was added and the mixture was extracted with dichloromethane (4×50 mL). The extracts were washed with a 15% aqueous solution of sodium thiosulfate (100 mL) then dried (Na2SO4) and the solvent removed in vacuo to afford 4-amino-2-chloro-3-methylphenyl thiocyanate as a brown solid (1.26 g, 90%). Material was used crude in subsequent steps.
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:24]([CH:29]([CH2:32]O)[CH2:30][OH:31])[CH2:25][CH2:26][CH2:27][CH3:28].S(=O)(=O)(O)O.O>C1(C)C=CC=CC=1>[CH2:24]([C@@H:29]1[CH2:30][O:31][C@@H:20]([C:19]2[CH:18]=[CH:17][C:16]([O:15][CH2:14][CH2:13][CH2:12][C@H:9]3[CH2:10][CH2:11][C@H:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:7][CH2:8]3)=[CH:23][CH:22]=2)[O:21][CH2:32]1)[CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCC[C@H]1CC[C@H](CCCOc2ccc(C=O)cc2)CC1
Reactant: CCCCCC(CO)CO
Agent: O=S(=O)(O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCC[C@H]1CC[C@H](CCCOc2ccc([C@H]3OC[C@H](CCCCC)CO3)cc2)CC1

Procedure:
A solution of 2.1 g of 4-[3-(trans-4-pentylcyclohexyl)-1-propyloxy]benzaldehyde and 1.2 g of 2-pentyl-1,3-propanediol in 50 ml of toluene was treated with 2 drops of 10% (vol., sulfuric acid. The mixture was heated to boiling for 2.5 hours, with the resulting water being distilled off simultaneously. Then, 4 drops of triethylamine were added to the reaction mixture. After cooling the mixture was washed with 20 ml of 1N sodium hydrogen carbonate solution and twice with 20 ml of water each time, dried over sodium sulfate, filtered and concentrated. Chromatography of the residue on silica gel with toluene gave 0.6 g of trans-5-pentyl-2-(4-[3-(trans-4-pentylcyciohexyl)-1-propyloxy]phenyl)-1,3-dioxane. M.p. (C-SB) 65° C. transition SB -N 73° C., cl.p (N-I) 128° C.
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:35])[C:11]([C:32]([OH:34])=O)=[CH:12][N:13]([CH2:26][CH:27](OC)OC)[C:14]=1[C:15](=[O:25])[NH:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1)C1C=CC=CC=1.S(Cl)(Cl)=O.[CH:40]([NH2:43])([CH3:42])[CH3:41].S([O-])(O)=O.[K+]>O1CCCC1.C(N(CC)CC)C>[CH:40]([NH:43][C:32]([C:11]1[C:10](=[O:35])[C:9]([OH:8])=[C:14]2[C:15](=[O:25])[N:16]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)[CH:27]=[CH:26][N:13]2[CH:12]=1)=[O:34])([CH3:42])[CH3:41]
Reactant: COC(Cn1cc(C(=O)O)c(=O)c(OCc2ccccc2)c1C(=O)NCc1cccc(Cl)c1)OC
Reactant: CC(C)N
Agent: O=S([O-])O
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)NC(=O)c1cn2ccn(Cc3cccc(Cl)c3)c(=O)c2c(O)c1=O

Procedure:
To a solution of 5-benzyloxy-6-(3-chlorobenzylcarbamoyl)-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (25.4 mg) obtained in Example 161, Step 4 in tetrahydrofuran (0.3 ml) were successively added triethylamine (0.021 ml) and thionyl chloride (0.0056 ml) at 0° C. with stirring. After stirring at room temperature for 10 min, the mixture was ice-cooled again and isopropylamine (0.0086 ml) was added. After stirring at room temperature for 30 min, 5% aqueous potassium hydrogen sulfite solution was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried and concentrated. Trifluoroacetic acid was added to the obtained residue and the mixture was stirred at 70° C. for 5.5, hr. Trifluoroacetic acid was evaporated, toluene was added and the mixture was concentrated, which operations were performed twice. Crystallization from ethyl acetate (2 ml) gave 2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazine-7-carboxylic acid isopropylamide (13.6 mg)
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:17][C@@H:16](OS(C(F)(F)F)(=O)=O)[C@@H:15]2[C@H:12]1[C:13](=[O:37])[N:14]2[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.O.[F-:41].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:17][C@H:16]([F:41])[C@@H:15]2[C@H:12]1[C:13](=[O:37])[N:14]2[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CN2C(=O)[C@@H]3[C@H]2[C@H](OS(=O)(=O)C(F)(F)F)CN3C(=O)OCc2ccccc2)cc1OC
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CN2C(=O)[C@@H]3[C@H]2[C@@H](F)CN3C(=O)OCc2ccccc2)cc1OC

Procedure:
(1S,4R,5S)-6-(3,4-Dimethoxy-benzyl)-7-oxo-4-trifluoromethanesulphonyloxy-2,6-diazabicyclo[3.2.0]heptane-2-carboxylic acid benzyl ester (1.1 g, 2.02 mmol) and tetrabutylammonium fluoride trihydrate (704 mg, 2.23 mmol) were stirred together in 10 ml of tetrahydrofuran at room temperature for 10 min. Thereafter, the solvent was removed in a vacuum, the oily residue was taken up in ethyl acetate and extracted three times with water and once with saturated aqueous sodium chloride solution. The organic phase was dried over magnesium sulphate and concentrated. The residual brown oil was chromatographed over silica gel with ethyl acetate and a pale yellow oil was obtained.
Reaction SMILES: Cl[C:2]([C:4]1[CH:16]=[CH:15][C:7]([CH:8]=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1)=O.[Br:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=C)=[CH:20][CH:19]=1.C(N(C)C)C1C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC1C=CC(C)=CC=1>[Br:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[CH:2][C:4]2[CH:16]=[CH:15][C:7]([CH:8]=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=2)=[CH:20][CH:19]=1
Reactant: C=Cc1ccc(Br)cc1
Reactant: CCOC(=O)C=Cc1ccc(C(=O)Cl)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CN(C)Cc1ccccc1
Solvent: Cc1ccc(C)cc1
Product: CCOC(=O)C=Cc1ccc(C=Cc2ccc(Br)cc2)cc1
Temperature: 130 °C
Reaction time: 1.5 h
Yield: 10.2 %

Procedure:
4.77 g (20 mmols) of ethyl 4-chloroformylcinnamate, 4.04 g (20 mmols) of 4-bromostyrene, 2.72 g (20 mmols) of N-benzyldimethylamine and 0.0448 g (0.2 mmol) of palladium acetate are added under argon to 50 ml of p-xylene, and the reaction mixture is stirred at 130° C. for 1.5 hours. The product which has been precipitated is filtered off at room temperature and is then recrystallised from methanol. 0.73 g (10% of theory) of ethyl 4-bromostilbene-4'-acrylate is obtained in the form of yellow crystals; melting point 166.9° C.
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:18])[NH:5][C:6](=[O:17])[N:7]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:8]=1)#[N:2].FC1C=C(F)C=CC=1N.[Cl:28][C:29]([Cl:33])([Cl:32])[S:30]Cl>>[C:1]([C:3]1[C:4](=[O:18])[N:5]([S:30][C:29]([Cl:33])([Cl:32])[Cl:28])[C:6](=[O:17])[N:7]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:8]=1)#[N:2]
Reactant: ClSC(Cl)(Cl)Cl
Reactant: N#Cc1cn(-c2ccc(F)cc2F)c(=O)[nH]c1=O
Agent: Nc1ccc(F)cc1F
Product: N#Cc1cn(-c2ccc(F)cc2F)c(=O)n(SC(Cl)(Cl)Cl)c1=O

Procedure:
In like manner, 5-cyano-1-(2,4-difluorophenyl)uracil is prepared, starting with 2,4-difluoroaniline, and is then reacted with trichloromethanesulphenyl chloride, giving 5-cyano-1-(2,4-difluorophenyl)-3-trichloromethanesulphenyluracil, m.p. 196°-198°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:23])[N:13]([C:16]3[CH:21]=[CH:20][NH:19][C:18](=[O:22])[CH:17]=3)[C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1.I[CH2:25][CH2:26][OH:27]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:23])[N:13]([C:16]3[CH:21]=[CH:20][N:19]([CH2:25][CH2:26][OH:27])[C:18](=[O:22])[CH:17]=3)[C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1
Reactant: OCCI
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c(C)n1-c1cc[nH]c(=O)c1
Product: Cc1nc(C#Cc2ccnc(Cl)c2)c(C)n1-c1ccn(CCO)c(=O)c1

Procedure:
The title compound, orange solid, MS: m/e=369.0, 371.2 (M+H+), was prepared in accordance with the general method of example 3 from 4-[4-(2-chloro-pyridin-4-ylethynyl)-2,5-dimethyl-imidazol-1-yl]-1H-pyridin-2-one and 2-iodoethanol.