Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](Cl)=[O:4].[NH2:8][C:9]1[C:10]([F:22])=[CH:11][C:12]([Cl:21])=[C:13]([CH:20]=1)[C:14]([O:16][CH:17]([CH3:19])[CH3:18])=[O:15]>C(C(C)=O)C>[Cl:21][C:12]1[CH:11]=[C:10]([F:22])[C:9]([NH:8][C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1])=[CH:20][C:13]=1[C:14]([O:16][CH:17]([CH3:19])[CH3:18])=[O:15]
Reactant: CC(C)OC(=O)c1cc(N)c(F)cc1Cl
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCC(C)=O
Product: CC(C)OC(=O)c1cc(NC(=O)C(C)(C)C)c(F)cc1Cl
Yield: 79 %

Procedure:
A solution of trimethylacetyl chloride (2.53 g, 0.021 mole) and 1-methylethyl 5-amino-2-chloro-4-fluorobenzoate (4.62 g, 0.020 mole) in methyl ethyl ketone was stirred at room temperature for 16 hours and then refluxed for 2 hours. The solvent was removed and the residue triturated with diethyl ether to give a tan solid, m.p. 81°-83° C. (5.0 g, 79% yield).
Reaction SMILES: [CH3:1][C:2]1([C:8]([O:10]C(C)(C)C)=[O:9])[CH2:6][C:5](=[CH2:7])[CH2:4][O:3]1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1([C:8]([OH:10])=[O:9])[CH2:6][C:5](=[CH2:7])[CH2:4][O:3]1
Reactant: C=C1COC(C)(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=C1COC(C)(C(=O)O)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 77 %

Procedure:
At 0° C., to a solution of 2-methyl-4-methylene-2-tetrahydrofuroic acid, tert-butyl ester dissolved in 0.3 mL dichloromethane was added 461 mL of a 1:1 solution of trifluoroacetic acid and dichloromethane. After 20 min, the ice bath was removed and the reaction mixture allowed to stir at room temperature for 5 h. The excess trifluoroacetic acid was removed by a stream of nitrogen, and the residue coevaporated with dichloromethane 3 times. The crude product was chromatographed via silica gel (gradient elution 0-12% MeOH/CH2Cl2) to give 55 mg of the desired acid as a glass (77%). Mass Spectrum: EI m/e 142 (M)+.
Reaction SMILES: Br[C:2]1[CH:27]=[CH:26][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH2:19][C:20]5[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=5)[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.[CH3:28][C:29]([OH:46])([CH3:45])[CH2:30][N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1>>[CH3:28][C:29]([OH:46])([CH3:45])[CH2:30][N:31]1[CH:35]=[C:34]([C:2]2[CH:27]=[CH:26][C:5]3[C:6]4[N:7]=[C:8]([C:14]5[N:15]([CH2:19][C:20]6[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=6)[N:16]=[CH:17][N:18]=5)[S:9][C:10]=4[CH2:11][CH2:12][O:13][C:4]=3[CH:3]=2)[CH:33]=[N:32]1
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Brc1ccc2c(c1)OCCc1sc(-c3ncnn3Cc3ccncc3)nc1-2
Product: CC(C)(O)Cn1cc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4Cc4ccncc4)nc2-3)cn1

Procedure:
Following the procedure for 114, 8-Bromo-2-(2-pyridin-4-ylmethyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene was reacted with 2-Methyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-propan-2-ol to give 354. MS(ESI+) 500.1. 1H NMR (400 MHz, DMSO) δ 8.56 (dd, J=4.5, 1.6, 2H), 8.24 (s, 1H), 8.15 (s, 1H), 8.03 (d, J=8.3, 1H), 7.93 (s, 1H), 7.32 (dd, J=8.3, 1.8, 1H), 7.26 (d, J=1.8, 1H), 7.23-7.19 (m, 2H), 6.12 (s, 2H), 4.71 (s, 1H), 4.35 (t, J=5.0, 2H), 4.03 (s, 2H), 3.43 (t, J=5.0, 2H), 1.09 (s, 6H)
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].[NH2:20][CH2:21][CH:22]1[CH:26]([CH3:27])[CH2:25][NH:24][CH2:23]1.C1CCN2C(=NCCC2)CC1>C(#N)C>[NH2:20][CH2:21][CH:22]1[CH:26]([CH3:27])[CH2:25][N:24]([C:10]2[C:11]([F:13])=[C:12]3[C:7]([C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4][N:3]3[CH2:1][CH3:2])=[CH:8][C:9]=2[F:15])[CH2:23]1
Reactant: CC1CNCC1CN
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CC(C)C(CN)C3)c(F)c21
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.9 %

Procedure:
A mixture of 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.5 g), anhydrous acetonitrile (5 ml), 3-aminomethyl-4-methylpyrrolidine (0.22 g) and DBU (0.28 g) was refluxed for an hour and then stirred at room temperature for 3 hours. The resulting precipitate was collected by filtration and washed with ether to give the title compound (0.39 g) as pale yellow powder, mp 222°-224° C.
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][C:10]=1[S:20](=[O:23])(=[O:22])[NH2:21])=O)C.Cl>[OH-].[Na+]>[CH3:19][S:16]([NH:15][C:12]1[CH:13]=[CH:14][C:9]2[NH:8][C:6]([CH2:5][C:4]([OH:3])=[O:24])=[N:21][S:20](=[O:23])(=[O:22])[C:10]=2[CH:11]=1)(=[O:18])=[O:17]
Reactant: CCOC(=O)CC(=O)Nc1ccc(NS(C)(=O)=O)cc1S(N)(=O)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 82.6 %

Procedure:
N-(4-Methanesulfonylamino-2-sulfamoyl-phenyl)-malonamic acid ethyl ester (prepared as described in Example 1e, 9.55 g, 26.16 mmol) was dissolved in 8% aqueous sodium hydroxide solution (262 mL) and heated at 100° C. for 1.5 h. The reaction mixture was cooled to 0° C. and the solution was acidified by slowly adding 12.0 M aqueous hydrochloric acid solution until pH 1-2 was reached. A precipitate started to form and the suspension was allowed to stir for 30 min at 0° C. The precipitate was collected by vacuum filtration, washed with cold water, and dried under high vacuum to afford the desired product, (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (7.20 g, 21.621 mmol, 82.6%), as a pinkish solid. 1H NMR (400 MHz, DMSO-d6) δ: 3.03 (3H, s), 3.56 (2H, s), 7.33 (1H, d, J=9.1 Hz), 7.52-7.54 (2H, m), 10.09 (1H, s), 12.24 (1H, s), 13.02 (1H, bs). LC-MS (ESI) calcd for C10H11N3O6S2333.01, found 334.1 [M+H+].
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:23]2[O:24][CH:25]=[CH:26][N:27]=2)(=O)=O)C=CC=CC=1.[OH-].[K+].CO>O>[O:24]1[CH:25]=[CH:26][N:27]=[C:23]1[C:11]1[NH:10][C:14]2=[N:15][CH:16]=[C:17]([S:19]([CH3:22])(=[O:20])=[O:21])[CH:18]=[C:13]2[CH:12]=1
Reactant: CS(=O)(=O)c1cnc2c(c1)cc(-c1ncco1)n2S(=O)(=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)c1cnc2[nH]c(-c3ncco3)cc2c1
Temperature: 22.5 °C
Reaction time: 0.5 h
Yield: 83.2 %

Procedure:
A mixture of 1-benzenesulfonyl-2-(oxazol-2-yl)-5-methanesulfonyl-1H-pyrrolo[2,3-b]pyridine (0.35 g), potassium hydroxide (0.34 g) and methanol (30 ml) was stirred at 15 to 30° C. for 30 minutes. To the reaction mixture was added water, the resulting mixture was extracted with dichloromethane, washed with a saturated aqueous NaCl solution, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain 0.19 g of the desired product.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1)#[N:2].C([O-])([O-])=O.[K+].[K+].[NH:17]1[CH2:21][CH2:20][NH:19][C:18]1=[O:22].O>CS(C)=O>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N:17]2[CH2:21][CH2:20][NH:19][C:18]2=[O:22])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: O=C1NCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1ccc(CN2CCNC2=O)cc1
Reaction time: 0.5 h
Yield: 20.2 %

Procedure:
A mixture of 20.95 g (0.107 mole) of 4-cyanobenzyl bromide, 14.7 g (0.107 mole) K2CO3, 5.0 g KI, and 10.32 g (0.12 mole) 2-imidazolidinone in 125 ml dimethylsulfoxide was stirred at 100°-110° for 30 minutes, cooled, and poured into 400 ml cold tap water. The mixture was stirred at room temperature for 30 minutes and extracted with 250 ml chloroform. The chloroform extract was washed with 3 × 250 ml H2O, dried (MgSO4), and concentrated to dryness in vacuo to give an oily residue. Crystallization from 60 ml toluene gave 5.50 g of the crude product. Further recrystallization from toluene gave 4.34 g (20%) of the nitrile, m.p. 127°-133°. The analytical sample, m.p. 134°-136°, was obtained by recrystallization from toluene.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]1([C:11]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:14]3[NH:21][N:22]=[C:23]([C:24]([OH:26])=[O:25])[C:13]=3[N:12]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:27](=O)([O-])O.[Na+]>CO>[C:5]1([C:11]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:14]3[NH:21][N:22]=[C:23]([C:24]([O:26][CH3:27])=[O:25])[C:13]=3[N:12]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C([O-])O
Reactant: O=C(O)c1n[nH]c2c1nc(-c1ccccc1)c1ccccc12
Agent: [Na+]
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1n[nH]c2c1nc(-c1ccccc1)c1ccccc12
Reaction time: 0.5 h

Procedure:
18 μL of thionyl chloride were initially introduced into 0.5 ml of methanol and the mixture was stirred for 30 min. 19 mg of 5-phenyl-1H-pyrazolo[4,3-c]isoquinoline-3-carboxylic acid (60) in 0.5 ml of methanol were then added dropwise. The mixture was stirred at RT for 12 h, after which a saturated solution of sodium hydrogen carbonate was added and the whole was extracted, in each case 1×, with ethyl acetate and methylene chloride. The organic phases were combined, dried over magnesium sulfate and concentrated under reduced pressure and the residue was purified by means of HPLC (Merk-Hibar-Lichrospher 100-RP-18, water (0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoroacetic acid)=80/20→10/90). The following was obtained: 61. C18H13N3O2 (303.32) MS (ESI) 304 (M+H)
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([N:9]([C@H:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([C:23](=[O:32])[C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C@@H:15]([CH3:33])[CH2:14]2)[C:10](=[O:12])[CH3:11])[CH:6]=[CH:7][CH:8]=1.[C:34](O)(=[O:37])[CH2:35][OH:36].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>>[C:35]([NH:1][CH2:2][C:3]1[CH:4]=[C:5]([N:9]([C@H:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([C:23](=[O:32])[C:24]3[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=3)[C@@H:15]([CH3:33])[CH2:14]2)[C:10](=[O:12])[CH3:11])[CH:6]=[CH:7][CH:8]=1)(=[O:36])[CH2:34][OH:37]
Reactant: O=C(O)CO
Reactant: COc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3cccc(CN)c3)C[C@@H]2C)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Product: COc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3cccc(CNC(=O)CO)c3)C[C@@H]2C)cc1

Procedure:
N-[3-(aminomethyl)phenyl]-N-[(2S,4R)-1-(4-methoxybenzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]acetamide was then further coupled with glycolic acid using coupling reagent such as EDCI with HOBt to afford N-{3-[(glycoloylamino)methyl]phenyl}-N-[(2S,4R)-1-(4-methoxybenzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]acetamide
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][C@@H:10]([N:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH3:14])[CH2:9][C@H:8]2[C:19]([O:21][CH3:22])=[O:20])[C:3]1=[O:23].[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](O)=[O:30].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>C(Cl)Cl>[C:15]([N:13]([CH3:14])[C@H:10]1[CH2:9][C@@H:8]([C:19]([O:21][CH3:22])=[O:20])[C@@H:7]([N:4]2[CH2:5][CH2:6][C@H:2]([NH:1][C:29](=[O:30])[C:28]3[CH:32]=[CH:33][CH:34]=[C:26]([C:25]([F:24])([F:35])[F:36])[CH:27]=3)[C:3]2=[O:23])[CH2:12][CH2:11]1)([CH3:18])([CH3:17])[CH3:16]
Reactant: COC(=O)[C@@H]1C[C@H](N(C)C(C)(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@H](N(C)C(C)(C)C)CC[C@@H]1N1CC[C@H](NC(=O)c2cccc(C(F)(F)F)c2)C1=O
Yield: 38 %

Procedure:
A solution of (1R,2S,5R)-methyl 2-((S)-3-amino-2-oxopyrrolidin-1-yl)-5-(tert-butyl(methyl) amino)-cyclohexanecarboxylate (58 mg, 0.18 mmol), 3-(trifluoromethyl)benzoic acid (42 mg, 0.22 mol), EDCI (30 mg, 0.21 mmol), HOBT (30 mg, 0.21 mmol), and Et3N (21 mg 0.21 mmol) in CH2Cl2 was stirred overnight at room temperature. The solution was washed with water and brine, concentrated in vacuo and the residue chromatographed on silica gel (3%-5%-10% (NH4OH/MeOH)/CH2Cl2) to give 34 mg of the title product, (1R,2S,5R)-methyl 5-(tert-butyl(methyl)amino)-2-((S)-2-oxo-3-(3-(trifluoromethyl)-benzamido)pyrrolidin-1-yl)cyclohexanecarboxylate, as a white solid. MS found: (M+H)+=498.40.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=3)[C:6]=2[CH:17]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:29](B(O)O)=[CH:28][CH:27]=[N:26]2)=[CH:21][CH:20]=1>>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([N:7]2[C:6]3[CH:17]=[C:2]([C:29]4[N:25]([C:22]5[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=5)[N:26]=[CH:27][CH:28]=4)[CH:3]=[CH:4][C:5]=3[N:9]=[CH:8]2)=[CH:11][CH:12]=1
Reactant: OB(O)c1ccnn1-c1ccc(Cl)cc1
Reactant: Clc1ccc(-n2cnc3ccc(Br)cc32)cc1
Product: Clc1ccc(-n2nccc2-c2ccc3ncn(-c4ccc(Cl)cc4)c3c2)cc1

Procedure:
The title compound, light brown solid (29 mg, 22%), MS (ISP) m/z=405.4 [(M+H)+], mp 182° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-(4-chloro-phenyl)-1H-benzo[d]imidazole (intermediate H) (100 mg, 325 μmol) and 1-(4-chloro-phenyl)-1H-pyrazol-5-ylboronic acid (intermediate D) (79.6 mg, 358 μmol).
Reaction SMILES: [Mg].II.Cl[CH2:5][CH:6]([CH3:11])[CH2:7][CH2:8][CH2:9][CH3:10].BrCCBr.[CH2:16]=[O:17].S(=O)(=O)(O)O>O1CCCC1>[CH3:11][CH:6]([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:5][CH2:16][OH:17]
Reactant: CCCCC(C)CCl
Reactant: C=O
Agent: II
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: CCCCC(C)CCO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Magnesium turnings (2.0 g, 82.3 mmol) are etched with iodine, and 1 ml of a solution of 96% 1-chloro-2-methylhexane (11 g, 78.5 mmol) in tetrahydrofuran (10 ml) is added at 60° C. The reaction is started by the addition of 1,2-dibromoethane (0.2 ml), then the rest of the solution of 1-chloro-2-methylhexane is added dropwise. After dilution with tetrahydrofuran (15 ml) the mixture is stirred under reflux for 2.5 h. Gaseous formaldehyde is passed through the solution, whose temperature is kept at from 40° C. to 50° C. The mixture is stirred for a further 1 h at room temperature, then 30% sulfuric acid (10 ml) is added to hydrolyze the Grignard compound. The mixture is steam distilled and the distillate is extracted several times with ether. The extract is washed with sodium chloride solution, dried over sodium sulfate, and evaporated down.
Reaction SMILES: [CH:1]1([O:5][C:6]2[C:15]([O:16][CH3:17])=[C:14]([O:18][CH3:19])[CH:13]=[C:12]3[C:7]=2[C:8](Cl)=[N:9][C:10]([Cl:20])=[N:11]3)[CH2:4][CH2:3][CH2:2]1.[NH3:22]>>[NH2:22][C:8]1[C:7]2[C:12](=[CH:13][C:14]([O:18][CH3:19])=[C:15]([O:16][CH3:17])[C:6]=2[O:5][CH:1]2[CH2:4][CH2:3][CH2:2]2)[N:11]=[C:10]([Cl:20])[N:9]=1
Reactant: COc1cc2nc(Cl)nc(Cl)c2c(OC2CCC2)c1OC
Reactant: N
Product: COc1cc2nc(Cl)nc(N)c2c(OC2CCC2)c1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
5-Cyclobutyloxy-2,4-dichloro-6,7-dimethoxyquinazoline (300 mg, 0.0009 mol) was suspended in a saturated ethanolic ammonia solution (10 ml) and the reaction stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, resuspended in a minimum volume of diethyl ether and the resulting solid filtered off. Drying under suction gave the subtitle compound as a white solid (189 mg, 68%). Rf 0.69 (diethyl ether). 1H-NMR (CDCl3): Γ=1.56 (1H, m), 1.82 (1H, m), 2.26 (2H, m), 2.42 (2H, m), 3.85 (3H, s), 3.94 (3H, s), 4.92 (1H, m), 5.82 (1H, bs), 6.94 (1H, s), 7.72 (1H, bs).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[CH3:22])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16](=[O:18])[CH3:17])[N:14]=2)[N:11]=1.[CH3:23][N:24]1[C:28]([C:29](Cl)=[O:30])=[CH:27][C:26]([CH3:32])=[N:25]1>CN(C)C(=O)C>[C:16]([NH:15][C:13]1[N:14]=[C:9]2[CH:8]=[CH:7][C:6]([O:5][C:4]3[CH:19]=[CH:20][C:21]([CH3:22])=[C:2]([NH:1][C:29]([C:28]4[N:24]([CH3:23])[N:25]=[C:26]([CH3:32])[CH:27]=4)=[O:30])[CH:3]=3)=[N:11][N:10]2[CH:12]=1)(=[O:18])[CH3:17]
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Reactant: CC(=O)Nc1cn2nc(Oc3ccc(C)c(N)c3)ccc2n1
Solvent: CC(=O)N(C)C
Product: CC(=O)Nc1cn2nc(Oc3ccc(C)c(NC(=O)c4cc(C)nn4C)c3)ccc2n1
Yield: 77.5 %

Procedure:
In the same manner as in Example 264 and using N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]acetamide (840 mg, 2.8 mmol), 1,3-dimethyl-1H-pyrazole-5-carbonylchloride (540 mg, 3.4 mmol) and N,N-dimethylacetamide (35 mL), the title compound (910 mg, 77%) was obtained as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:25][CH2:26][C:27]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:28]=1[C:29](=[O:46])[N:30]([CH:38]1[CH2:43][CH2:42][C:41](=[O:44])[NH:40][C:39]1=[O:45])[C:31]([CH3:37])=[N:32]2>CN(C=O)C>[O:45]=[C:39]1[CH:38]([N:30]2[C:29](=[O:46])[C:28]3[C:33](=[CH:34][CH:35]=[CH:36][C:27]=3[CH2:26][NH:25][C:9](=[O:11])[CH2:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[N:32]=[C:31]2[CH3:37])[CH2:43][CH2:42][C:41](=[O:44])[NH:40]1
Reactant: Cc1nc2cccc(CN)c2c(=O)n1C1CCC(=O)NC1=O
Reactant: O=C(O)Cc1ccc(F)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: Cc1nc2cccc(CNC(=O)Cc3ccc(F)cc3)c2c(=O)n1C1CCC(=O)NC1=O
Reaction time: 1 h
Yield: 73.3 %

Procedure:
To a stirred solution of (4-fluoro-phenyl)-acetic acid (0.23 g, 1.5 mmol) in DMF (8 mL) in a 40° C. oil bath, was added 1,1′carbonyldiimidazole (0.26 g, 1.6 mmol) and stirred for one hour. To the mixture, 3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.49 g, 1.5 mmol) was added, and the mixture was stirred for 15 minutes. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-2-(4-fluoro-phenyl)-acetamide as a white solid (480 mg, 76% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, grad. to 95/5 in 5 min, kept 5 min, 5.83 min (99.2%); mp, decomposed at 290° C.; 1HNMR (DMSO-d6)2.12-2.19 (m, 1H, CHH), 2.57-2.91 (m, 6H, CHCH2, CH3), 3.53 (s, 2H, ArCH2), 4.68-4.83 (m, 2H, CH2NH), 5.23 (dd, J=6, 11 Hz, 1H, CH), 7.09-7.72 (m, 7H, Ar), 8.36 (t, J=6 Hz, 1H, CH2NH), 11.02 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.74, 23.28, 30.58, 41.36, 41.70, 56.48, 114.89 (d, JC-F=21 Hz), 117.69, 124.72, 125.58, 130.86 (d, JC-F=7 Hz), 132.45 (d, JC-F=3 Hz), 133.82, 140.68, 148.44, 154.80, 160.91, 161.00 (d, JC-F=242 Hz), 169.50, 170.15, 172.59. LCMS MH=437; Anal Calcd For C23H21N4O4F: C, 63.30; H, 4.85; N, 12.84; F, 4.35. Found: C, 63.25; H, 4.66; N, 12.73; F, 4.21.
Reaction SMILES: [C:1]1([NH:7][C:8]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[NH:17][CH:18]2[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:25]1[N:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27]([NH2:29])=[O:28]>>[C:1]1([NH:7][C:8](=[O:9])[NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[NH:17][C@H:18]2[CH2:23][CH2:22][CH2:21][N:20]([C:25]3[N:33]=[CH:32][CH:31]=[CH:30][C:26]=3[C:27]([NH2:29])=[O:28])[CH2:19]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Nc1ccccc1)N[C@@H]1CCCC[C@H]1NC1CCCNC1
Reactant: NC(=O)c1cccnc1Cl
Product: NC(=O)c1cccnc1N1CCC[C@H](N[C@@H]2CCCC[C@H]2NC(=O)Nc2ccccc2)C1

Procedure:
2-((S)-3-((1R,2R)-2-(3-Phenylureido)cyclohexylamino)piperidin-1-yl)nicotinamide was synthesized using 1-phenyl-3-((1R,2R)-2-(piperidin-3-ylamino)cyclohexyl)urea (from intermediate C, Example 1) (100 mg, 0.32 mmol) and 2-chloronicotinamide (49 mg, 0.32 mmol) according to General Procedure A to give 9 mg (6.5%) of pale brown oil. Anal. Calcd. for C24H32N6O2 m/z 436.3, found: 437.2 (M+H)+; 1H NMR (400 MHz, CD3OD) δ ppm 8.2 (d, J=3.8 Hz, 1H), 7.65 (dd, J=2 Hz, 1H), 7.21 (m, 4H), 7.01 (m, 1H), 6.86 (m, 1H), 3.66 (m, 4H), 3.21 (m, 3H), 2.35 (m, 1H), 2.10 (m, 2H), 1.89 (m, 4H), 1.74 (m, 1H), 1.68 (d, J=1.68 Hz, 1H), 1.60 (m, 1H), 1.45 (m, 3H).
Reaction SMILES: [NH2:1][C:2]12[CH2:9][CH2:8][C:5]([C:10]3[NH:18][C:17]4[C:16](=[O:19])[N:15]([CH2:20][CH2:21][CH3:22])[C:14](=[O:23])[N:13]([CH2:24][CH2:25][CH3:26])[C:12]=4[N:11]=3)([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.[S:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[CH:32]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C>[CH2:20]([N:15]1[C:16](=[O:19])[C:17]2[NH:18][C:10]([C:5]34[CH2:8][CH2:9][C:2]([NH:1][CH2:32][C:28]5[S:27][CH:31]=[CH:30][CH:29]=5)([CH2:7][CH2:6]3)[CH2:3][CH2:4]4)=[N:11][C:12]=2[N:13]([CH2:24][CH2:25][CH3:26])[C:14]1=[O:23])[CH2:21][CH3:22]
Reactant: O=Cc1cccs1
Reactant: CCCn1c(=O)c2[nH]c(C34CCC(N)(CC3)CC4)nc2n(CCC)c1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCCn1c(=O)c2[nH]c(C34CCC(NCc5cccs5)(CC3)CC4)nc2n(CCC)c1=O
Reaction time: 24 h

Procedure:
To a solution of 100 mg of 8-(4-Amino-bicyclo[2.2.2]oct-1-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione (Example 20) (0.28 mmol) and 37 mg of thiophene-2-carboxaldehyde (0.33 mmol) in CH2Cl2 (5 ml) was added 5 drops of glacial acetic acid and 100 mg of sodium triacetoxyborohydride (0.47 mmol). Complete conversion occurs over 24 h at rt. The reaction mixture was quenched with 2 ml of ethanol and 2 ml of 2N HCl and then concentrated in vacuo to afford a colorless oil which was purified from anhydrous acetonitrile to afford 50.8 mg (40%) as a white solid (MH+=456.29). The following compounds were prepared in an analogous manner:
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][C:15]=2[C:16]([F:19])([F:18])[F:17])[NH:12][C:11](=[O:20])[C:10](=[O:21])[NH:9]3)[CH:5]=[CH:4][CH:3]=[CH:2]1.Br[CH2:23][C:24]([O:26][CH3:27])=[O:25]>C(Cl)Cl.C(OCC)(=O)C>[CH3:27][O:26][C:24]([CH2:23][N:9]1[C:8]2[C:13](=[CH:14][C:15]([C:16]([F:17])([F:18])[F:19])=[C:6]([N:1]3[CH:5]=[CH:4][CH:3]=[CH:2]3)[CH:7]=2)[NH:12][C:11](=[O:20])[C:10]1=[O:21])=[O:25]
Reactant: COC(=O)CBr
Reactant: O=c1[nH]c2cc(-n3cccc3)c(C(F)(F)F)cc2[nH]c1=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)Cn1c(=O)c(=O)[nH]c2cc(C(F)(F)F)c(-n3cccc3)cc21
Yield: 39.7 %

Procedure:
35 g (118.6 mmol) of 6-(1-pyrrolyl)-7-trifluoromethyl-2,3(1H,4H)-quinoxalinedione (Example 2) were reacted with 23.8 g (155.5 mmol) of methyl bromoacetate as in Example 23. The mobile phase used for the chromatography was methylene chloride/ethyl acetate=3/2. 17.3 g (40%) of the product were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:17][CH2:16][N:15]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:14]2=[O:24])=[CH:9][CH:8]=1)=[O:4].Br.C(S[C:29](=[NH:31])[NH2:30])C.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[C:29]([N:21]1[CH2:22][CH2:23][CH:18]([N:15]2[CH2:16][CH2:17][N:13]([C:10]3[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])=[CH:8][CH:9]=3)[C:14]2=[O:24])[CH2:19][CH2:20]1)(=[NH:30])[NH2:31]
Reactant: COC(=O)CCc1ccc(N2CCN(C3CCNCC3)C2=O)cc1
Reactant: CCSC(=N)N
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCc1ccc(N2CCN(C3CCN(C(=N)N)CC3)C2=O)cc1

Procedure:
Prepared from 1-[4-(2-methoxycarbonyl-ethyl)-phenyl]-3-(4-piperidinyl)-imidazolidin-2-one and S-ethylisothiourea-hydrobromide by heating to 100° C. for four hours in dimethylformamide in the presence of sodium carbonate.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]([NH:10][CH:11]2[CH:15]([OH:16])[CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12]2)[N:4]=1.[ClH:25].C(OCC)C>C(OCC)(=O)C>[ClH:25].[ClH:25].[CH3:24][N:2]([CH3:1])[C:3]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]([NH:10][CH:11]2[CH2:12][NH:13][CH2:14][CH:15]2[OH:16])[N:4]=1
Reactant: Cc1cc(N(C)C)nc(NC2CN(C(=O)OC(C)(C)C)CC2O)n1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: Cc1cc(N(C)C)nc(NC2CNCC2O)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
t-Butyl (3RS,4RS)-3-(4-dimethylamino-6-methylpyrimidin-2-ylamino)-4-hydroxypyrrolidine-1-carboxylate (1.0 g) was dissolved in ethyl acetate (10 mL), followed by addition of a solution (7.5 mL) of 4 M HCl in ethyl acetate, and the mixture was stirred at room temperature for 2 h. Diethyl ether was added to the solution, and the precipitated crystals were collected by filtration to obtain the title compound (0.89 g).