Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([O:23]CC)=[O:22])=[CH:15][CH:14]=3)[C:9]2=[O:26])=[CH:4][CH:3]=1.O1CCCC1.[OH-].[Na+]>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:15][CH:14]=3)[C:9]2=[O:26])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCc1ccc(N2CCN(c3ccc(Br)cc3)C2=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCc1ccc(N2CCN(c3ccc(Br)cc3)C2=O)cc1
Reaction time: 2 h

Procedure:
12.7 g of 3-(4-bromophenyl)-1-[4-[2-(ethoxycarbonyl)-ethyl]-phenyl]-imidazolidin-2-one, 300 ml of tetrahydrofuran, 100 ml of water and 23.6 ml of 4N sodium hydroxide solution are stirred overnight at ambient temperature. The precipitate is suction filtered, suspended in 1 litre of water, acidified with concentrated hydrochloric acid and stirred for 2 hours. It is then suction filtered, washed with water and dried at 60° C.
Reaction SMILES: [CH3:1][O:2][N:3]=[CH:4][C:5]1[CH:20]=[CH:19][C:8]2[N:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14](Br)[CH:13]=3)[CH:10]=[N:11][C:7]=2[CH:6]=1.C([Sn](CCCC)(CCCC)[C:26]1[S:27][CH:28]=[CH:29][CH:30]=1)CCC>CN(C=O)C.O>[CH3:1][O:2][N:3]=[CH:4][C:5]1[CH:20]=[CH:19][C:8]2[N:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:26]4[S:27][CH:28]=[CH:29][CH:30]=4)[CH:13]=3)[CH:10]=[N:11][C:7]=2[CH:6]=1
Reactant: CON=Cc1ccc2c(c1)ncn2-c1cccc(Br)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Solvent: CN(C)C=O
Solvent: O
Product: CON=Cc1ccc2c(c1)ncn2-c1cccc(-c2cccs2)c1
Temperature: 80 °C

Procedure:
A mixture of 29a from Example 8 (0.7 g, 2.1 mmol), 2-(tributylstannyl)thiophene (1.59 g, 4.3 mmol) and tris(triphenylphosphine)palladium dichloride (50 mg) in DMF (5 ml) is heated to 80° C. over night. The cooled reaction mixture is diluted with 4 volumes of water and extracted with ethyl acetate. The combined organic extracts are dried over sodium sulfate and concentrated under reduced pressure. The residue is purified by column-chromatography on silica gel using a mixture of ethyl acetate and petroleum ether (1:1) as the eluent. Yield: 0.56 g (80%). Mp 184-185° C.
Reaction SMILES: C([O:3][C:4]([CH2:6][C:7]1([NH:25][C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)=[O:27])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:16][CH:17]([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])[C:8]1=[O:24])=[O:5])C.[OH-].[K+]>CO>[CH2:22]([O:21][CH:17]([O:18][CH2:19][CH3:20])[CH2:16][N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([CH2:6][C:4]([OH:5])=[O:3])([NH:25][C:26]([NH:28][C:29]2[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=2)=[O:27])[C:8]1=[O:24])[CH3:23]
Reactant: CCOC(=O)CC1(NC(=O)Nc2ccc(C)cc2)C(=O)N(CC(OCC)OCC)c2ccccc21
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCOC(CN1C(=O)C(CC(=O)O)(NC(=O)Nc2ccc(C)cc2)c2ccccc21)OCC
Reaction time: 6 h
Yield: 85.7 %

Procedure:
To a solution of 8.21 g of (RS)-3-(ethoxycarbonylmethyl)-1-(2,2-diethoxyethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one in 100 ml of methanol was added 30 ml of an aqueous solution of 2.0 g of potassium hydroxide (85%) at room temperature, followed by stirring for 6 hours. The reaction mixture was concentrated, and the concentrate was diluted with water, which was washed with chloroform. The aqueous layer was adjusted to pH 2 by addition of 2N hydrochloric acid, and extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate and concentrated to yield 6.63 g (86%) of the title compound.
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][C:8]1[C:13]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([C:39]2[C:43]([CH3:44])=[CH:42][S:41][CH:40]=2)[CH:38]=1)[C:33](O)=[O:34])=[O:5])C.[CH:45]1([NH2:48])[CH2:47][CH2:46]1>>[C:4]([CH2:6][CH2:7][C:8]1[C:9]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]2[CH:38]=[C:37]([C:39]3[C:43]([CH3:44])=[CH:42][S:41][CH:40]=3)[CH:36]=[C:32]([C:33](=[O:34])[NH:48][CH:45]3[CH2:47][CH2:46]3)[CH:31]=2)=[CH:10][CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])([OH:5])=[O:3]
Reactant: NC1CC1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)O)cc(-c3cscc3C)c2)c1CCC(=O)OCC
Product: Cc1cscc1-c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(C(=O)NC2CC2)c1

Procedure:
The title compound was prepared according to the general procedure described above starting from 3-{6-[2-(2-ethoxycarbonyl-ethyl)-3-(3-ethoxycarbonyl-propoxy)-phenyl]-hexyloxy}-5-(4-methyl-thiophen-3-yl)-benzoic acid and cyclopropylamine (10% yield after two steps).
Reaction SMILES: C([O-])(=[O:3])C.[NH4+].Cl[C:7]1[C:16]([C:17]#[N:18])=[C:15]([Cl:19])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH3:20])[CH:13]=2)[N:8]=1>C(O)(=O)C>[Cl:19][C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH3:20])[CH:13]=2)[NH:8][C:7](=[O:3])[C:16]=1[C:17]#[N:18]
Reactant: CC(=O)[O-]
Reactant: Cc1ccc2nc(Cl)c(C#N)c(Cl)c2c1
Agent: [NH4+]
Solvent: CC(=O)O
Product: Cc1ccc2[nH]c(=O)c(C#N)c(Cl)c2c1
Temperature: 140 °C
Yield: 69 %

Procedure:
Ammonium acetate was added to a suspension of Compound 105 (7.1 g, 29.95 mmol) in glacial acetic acid and heated at 140° C. for 4 h. The solution was cooled and poured into ice water. The solids formed were filtered, washed by water, and dried under vacuum to yield 4.5 g (69%) of white solids. M.P. 264° C. 1H NMR (DMSO-d6): δ 2.32 (s, 3H), 7.34 (d, J=8.4 Hz, 1H), 7.63 (dd, J=1.5, 8.4 Hz, 1H), 7.75 (s, 1H). EIMS m/z 219 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][S:7][CH:8]([CH2:11][OH:12])[CH2:9][OH:10])=[CH:4][CH:3]=1.[F:15][C:16]([F:29])([F:28])[C:17]1[CH:27]=[CH:26][C:20](/[CH:21]=[C:22](\[CH3:25])/[CH:23]=O)=[CH:19][CH:18]=1>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][S:7][C@@H:8]2[CH2:11][O:12][C@@H:23](/[C:22](/[CH3:25])=[CH:21]/[C:20]3[CH:26]=[CH:27][C:17]([C:16]([F:15])([F:28])[F:29])=[CH:18][CH:19]=3)[O:10][CH2:9]2)=[CH:13][CH:14]=1
Reactant: OCC(CO)SCc1ccc(Cl)cc1
Reactant: C/C(C=O)=C\c1ccc(C(F)(F)F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: C/C(=C\c1ccc(C(F)(F)F)cc1)[C@H]1OC[C@H](SCc2ccc(Cl)cc2)CO1

Procedure:
In 12 ml of benzene were dissolved 341 mg (1.46 mmol) of 2-[(4-chlorobenzyl)thio]-1,3-propanediol and 375 mg (1.75 mmol) of (E)-4-(trifluoromethyl)-α-methylcinnamaldehyde, and 3 mg of p-toluenesulfonic acid were added to the solution, followed by heating of the resulting mixture with reflux under nitrogen atmosphere for 2 hours. After cooling, the reaction mixture was washed with an aqueous sodium hydrogencarbonate solution. The residue obtained by evaporation of the solvent was subjected to column chromatography using 15 g of silica gel. The fractions eluted with a mixed solvent of hexane-ethyl acetate (9:1) were collected and the thus obtained solid was washed with hexane to obtain 370 mg (yield: 59%) of the title compound having a melting point of 93 to 95° C.
Reaction SMILES: C[O:2][C:3](=[O:48])[CH2:4][NH:5][C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:16]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([S:28]([C:31]2[CH:35]=[C:34]([C:36]([NH:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[NH:37])[S:33][C:32]=2[S:46][CH3:47])(=[O:30])=[O:29])[CH:23]=1)=[O:13])=[O:7].[OH-].[Na+]>CO.O>[C:42]([O:41][C:39]([NH:38][C:36](=[NH:37])[C:34]1[S:33][C:32]([S:46][CH3:47])=[C:31]([S:28]([C:24]2[CH:23]=[C:22]([C:16]3[C:17]([CH3:21])=[CH:18][CH:19]=[CH:20][C:15]=3[NH:14][C:12](=[O:13])[NH:11][CH2:10][CH2:9][NH:8][C:6](=[O:7])[NH:5][CH2:4][C:3]([OH:48])=[O:2])[CH:27]=[CH:26][CH:25]=2)(=[O:30])=[O:29])[CH:35]=1)=[O:40])([CH3:45])([CH3:43])[CH3:44]
Reactant: COC(=O)CNC(=O)NCCNC(=O)Nc1cccc(C)c1-c1cccc(S(=O)(=O)c2cc(C(=N)NC(=O)OC(C)(C)C)sc2SC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2NC(=O)NCCNC(=O)NCC(=O)O)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83 %

Procedure:
A solution of {3-[2-(3-{3′-[5-(tert-butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-biphenyl-2-yl}-ureido)-ethyl]-ureido}-acetic acid methyl ester ((Example 197: step a) 0.031 g, 0.042 mmol) in MeOH:water (2:1, 15 mL) was treated with NaOH (10 N, 0.042 mL, 0.420 mmol) and stirred at room temperature 18 h. MeOH was evaporated in vacuo and the remaining aqueous solution was acidified to pH 5 with glacial acetic acid. The solution was extracted with CH2Cl2 (3×50 mL). The combined organic layers were dried over MgSO4 and evaporated in vacuo to afford the product {3-[2-(3-{3′-[5-(tert-butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-biphenyl-2-yl}-ureido)-ethyl]-ureido}-acetic acid (0.025 g, 83%) as an off-white solid. The crude material was used directly in the next reaction.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3([C:14]4[N:18]5[CH:19]=[C:20]([C:23]([O:25]C)=[O:24])[CH:21]=[N:22][C:17]5=[N:16][CH:15]=4)[CH2:13][CH2:12]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-].[Li+].CO.Cl>O>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3([C:14]4[N:18]5[CH:19]=[C:20]([C:23]([OH:25])=[O:24])[CH:21]=[N:22][C:17]5=[N:16][CH:15]=4)[CH2:12][CH2:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1cnc2ncc(C3(c4ccc5ncccc5c4)CC3)n2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cnc2ncc(C3(c4ccc5ncccc5c4)CC3)n2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidine-6-carboxylate (14 mg, 0.040 mmol, isomer-I from Step 1), 1M lithium hydroxide in water (0.16 mL), and methanol (1.0 mL) was stirred overnight at RT. The mixture was neutralized with 1N HCl (0.16 mL) and concentrated under reduced pressure. The residue was dried to yield the desired product which was directly used in next step. LCMS: (M+H)=331.0.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([NH:9][C:10]([C:12]2[CH:13]=[N:14][N:15]3[CH:20]=[CH:19][CH:18]=[N:17][C:16]=23)=[O:11])[C:6]([C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=2[O:28][CH:29]([F:31])[F:30])=[N:5]1.C(N(CC)CC)C.Cl.[NH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43]>C(O)C>[Cl:27][C:25]1[CH:24]=[CH:23][C:22]([O:28][CH:29]([F:31])[F:30])=[C:21]([C:6]2[C:7]([NH:9][C:10]([C:12]3[CH:13]=[N:14][N:15]4[CH:20]=[CH:19][CH:18]=[N:17][C:16]=34)=[O:11])=[CH:8][N:4]([CH2:3][CH2:2][NH:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[N:5]=2)[CH:26]=1
Reactant: O=C(Nc1cn(CCBr)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)CNCCn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Temperature: 80 °C
Reaction time: 24 h
Yield: 15.3 %

Procedure:
A mixture of N-[1-(2-bromoethyl)-3-[5-chloro-2-(difluoromethoxy)-phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (200 mg, 0.39 mmol), triethylamine (394 mg, 3.89 mmol), ethyl 2-aminoacetate hydrochloride (271 mg, 1.94 mmol) in ethanol (20 mL) was stirred at 80° C. for 24 hours then concentrated under reduced pressure. The crude product was purified by high pH Prep-HPLC to afford the title compound as an off-white solid (31.9 mg, 15%). LCMS (Method 14) [M+H]+=534.2, RT=1.13 min. 1H NMR (300 MHz, CD3OD-d4) δ: (ppm) 9.11 (dd, J=1.5, 7.0 Hz, 1H), 8.66-6.65 (m, 2H), 8.36 (s, 1H), 7.68 (d, J=2.4 Hz, 1H), 7.58 (dd, J=2.7, 8.7 Hz, 1H), 7.42 (d, J=8.7 Hz, 1H), 7.39 (dd, J=4.5, 7.2 Hz, 1H), 6.55 (t, J=73.5 Hz, 1H), 4.35 (t, J=5.7 Hz, 2H), 4.17 (q, J=7.2 Hz, 2H), 3.41 (s, 2H), 3.15 (t, J=6.0 Hz, 2H), 1.25 (t, J=7.2 Hz, 3H).
Reaction SMILES: [S:1]1[C:5]2=[CH:6][CH:7]=[CH:8][C:9]([CH:10]=O)=[C:4]2[N:3]=[CH:2]1.[CH2:12]([O:14][CH:15]([O:18][CH2:19][CH3:20])[CH2:16][NH2:17])[CH3:13].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([CH2:10][NH:17][CH2:16][CH:15]([O:18][CH2:19][CH3:20])[O:14][CH2:12][CH3:13])[C:4]=2[N:3]=[CH:2]1
Reactant: CCOC(CN)OCC
Reactant: O=Cc1cccc2scnc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(CNCc1cccc2scnc12)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of Benzothiazole-4-carbaldehyde (1.96 g, 12 mmol) in MeOH (50 mL) was added aminoacetaldehyde diethyl acetal (1.74 mL, 12 mmol) and acetic acid (1.03 mL, 18 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was added to a stirred solution of sodium cyanoborohydride (816 mg, 13 mmol). The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was concentrated under reduced pressure. Then H2O and ethyl acetate were added to the reaction mixture. The organic layer was washed with H2O and brine, dried over Na2SO4, and concentrated under reduced pressure. The crude compound was used next step without further purification.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:25]([OH:27])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O[N:29]=[C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)[NH2:31]>>[N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:19][CH:20]=3)[CH2:12][CH:11]([C:25]3[O:27][N:31]=[C:30]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=4)[N:29]=3)[CH2:10]2)=[O:8])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Reactant: NC(=NO)c1ccccn1
Product: O=C(N1CCOCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(-c3ccccn3)no2)C1

Procedure:
250 mg (about 0.520 mmol) of the compound from Example 49A and 79 mg (0.580 mmol) of N′-hydroxypyridine-2-carboximidamide (Example 69A) were reacted according to the General Method 1. Yield: 49 mg (19% of theory).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2)=O.[BH4-].[Na+].Cl>CO>[Cl:1][CH2:2][CH2:3][CH:4]=[CH:5][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2
Reactant: O=C1CCc2cc(C(=O)CCCCl)ccc2N1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C1CCc2cc(C=CCCCl)ccc2N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4.0 Grams of 6-(4-chloro-1-oxobutyl)-3,4-dihydrocarbostyril was disposed in 200 ml of methanol, and the suspension was stirred at a room temperature. Then 2.0 g of sodium borohydride was added to the suspension gradually and the reaction was continued for 1 hour. Next, 3 ml of concentrated hydrochloric acid was added to the reaction mixture and the mixture was concentrated under a reduce pressure with heat-refluxing condition to obtain a residue. The residue was extracted with chloroform and the chloroform layer was washed with water and dried. Then chloroform was removed by distillation under a reduced pressure to obtain a residue, and the residue was recrystallized from ethanol to obtain 2.4 g of 6-(4-chloro-1-butenyl)-3,4-dihydrocarbostyril in yellow needle-like crystals. Melting point: 153°-155° C.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.[N:26]1([C:32]([NH2:34])=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[NH2:25][C:14]1[N:13]=[C:12]([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][C:2]([NH:34][C:32]([N:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)=[O:33])=[CH:3][CH:4]=3)[CH2:9]2)[CH:17]=[C:16]([N:18]2[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]2)[N:15]=1
Reactant: NC(=O)N1CCCCC1
Reactant: CN1CCN(c2cc(N3CCc4ccc(Br)cc4C3)nc(N)n2)CC1
Product: CN1CCN(c2cc(N3CCc4ccc(NC(=O)N5CCCCC5)cc4C3)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 34 starting from 4-(7-bromo-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine and 1-piperidinecarboxamide (Aldrich Cat. No. 344753). LCMS (M+H)+: m/z=451.2.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([I:10])[CH:7]=[CH:6][C:3]=1[CH2:4]Br.[CH3:11][S-:12].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH3:11][S:12][CH2:4][C:3]1[CH:6]=[CH:7][C:8]([I:10])=[CH:9][C:2]=1[Cl:1]
Reactant: C[S-]
Reactant: Clc1cc(I)ccc1CBr
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSCc1ccc(I)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.7 %

Procedure:
A solution of 2-chloro-4-iodobenzyl bromide (4.82 g, 14.54 mmol) in N,N-dimethylformamide (30 mL) was treated with sodium thiomethoxide (2.04 g, 29.08 mmol). After the addition, the solution became cloudy and turned to a yellow color. The resulting reaction mixture was stirred for 3 h at 25° C. The reaction mixture was then diluted with ethyl acetate (100 mL). The organic layer was washed successively with water (2×100 mL) and a saturated aqueous sodium chloride solution (1×100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford 2-chloro-4-iodobenzyl methyl sulfide (4.24 g, 97%) as a colorless oil which was used without further purification: EI-HRMS m/e calcd for C8H8CIIS (M+) 297.9080, found 297.9078.
Reaction SMILES: [CH3:1][N:2]1[O:9][CH2:8][C:7]2([CH3:10])[CH:3]1[CH2:4][N:5](C(OCC)=O)[CH2:6]2>O>[CH3:1][N:2]1[O:9][CH2:8][C:7]2([CH3:10])[CH:3]1[CH2:4][NH:5][CH2:6]2
Reactant: CCOC(=O)N1CC2N(C)OCC2(C)C1
Solvent: O
Product: CN1OCC2(C)CNCC12

Procedure:
13 g (60.6 mmol ) of ethyl 2,5-dimethyl-3-oxa-2,7-diazabicyclo[3.3.0]octane-7-carboxylate are heated under reflux with 33 g of Ba(OH)2 ·8H2O in 330 ml of water overnight. The BaCO3 is filtered off with suction, K2CO3 is added to the filtrate, the solid is filtered off with suction again and the filtrate is extracted ten times with 100 ml of CHCl3 each time. The extracts are dried over K2CO3 and concentrated and the residue is distilled.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.[CH:13](O)=O.C=O>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[CH3:13])=[CH:6][CH:7]=1
Reactant: O=CO
Reactant: Brc1ccc(C2CCCN2)cc1
Agent: C=O
Solvent: O
Product: CN1CCCC1c1ccc(Br)cc1
Temperature: 150 °C
Yield: 90.9 %

Procedure:
A mixture of 2-(4-bromophenyl)pyrrolidine (0.5 g, 2.2 mmol), formic acid (0.11 mL, 2.42 mmol), formaldehyde (0.2 mL, 2.42 mmol, 37% in water), water (4 mL) in a sealed tube was heated to 150° C. under microwave for 5 minutes. After cooling to room temperature the reaction mixture was extracted with EtOAc (3×15 mL), the combined organic phase was washed consecutively with saturated NaHCO3 (5 mL) and brine (5 mL), dried over Na2SO4 and concentrated in vacuo to give the crude product (0.48 g, 91%), which was used directly in the next step. LC-MS (ESI) m/z: 240 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]3[C:12]([CH3:15])=[N:13][N:14]=[C:6]3[N:5]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:4]=2[N:3]=1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29]Br)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[N:10]([CH2:29][C:26]2[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=2)[C:9]2[C:8](=[O:11])[N:7]3[C:12]([CH3:15])=[N:13][N:14]=[C:6]3[N:5]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:4]=2[N:3]=1
Reactant: COc1ccc(CBr)cc1
Reactant: CCCCCn1c2nc(Br)[nH]c2c(=O)n2c(C)nnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCn1c2nc(Br)n(Cc3ccc(OC)cc3)c2c(=O)n2c(C)nnc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
The mixture of 7-bromo-3-methyl-9-pentyl-6,9-dihydro-5h-[1,2,4]triazolo[4,3-a]purin-5-one (200 mg, 0.59 mmol), 4-methoxyphenyl methylbromide (0.094 mL, 0.65 mmol), potassium carbonate (244 mg, 1.77 mmol) in DMF (10 ml) was stirred at room temperature for 2 hours. The reaction was quenched with water and the solid formed was filtered and dried over to yield the desired product (270 mg, 99.7%). LCMS calculated for C2OH BrN6O2: 459.1. found 460.1.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@:9]1([CH3:16])[C:13]([OH:15])=O)=O)(C)(C)C.[F:17][C:18]1[N:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>CN1CCCC1=O>[F:17][C:18]1[N:23]=[CH:22][C:21]([NH:24][C:13]([C@:9]2([CH3:16])[CH2:10][CH2:11][CH2:12][NH:8]2)=[O:15])=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@]1(C)C(=O)O
Reactant: Nc1ccc(F)nc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: C[C@@]1(C(=O)Nc2ccc(F)nc2)CCCN1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
To a stirred solution of (5)-1-(tert-butoxycarbonyl)-2-methylpyrrolidine-2-carboxylic acid (1.0 g, 4.37 mmol) and 6-fluoropyridin-3-amine (1.47 g, 13.1 mmol), 1-hydroxybenzotriazole (0.65 mg, 4.81 mmol), and N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide (2.5 g, 13.1 mmol) in N-methylpyrrolidinone (10 mL) was added diisopropylethylamine (3.8 mL, 21.8 mmol). The reaction mixture was heated to 65° C. for 12 h and the solvent was evaporated to dryness. The residue was separated by preparative HPLC. The crude product was dissolved in methanol and 4N HCl in dioxane (4 mL) was added. The reaction mixture was stirred at room temperature overnight and the crude product was used in the next step without further purification. LC/MS [M+H]+: 224; Ret time (Method F): 0.78 min.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[O:11][CH2:10][CH2:9][CH2:8]1)=[O:6].[F:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([CH:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)=[CH:28][CH:27]=2)=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([CH:32]3[CH2:33][CH2:34][N:35]([CH2:2][CH2:3][CH2:4][C:5]([N:7]4[C:13]5[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=5[O:11][CH2:10][CH2:9][CH2:8]4)=[O:6])[CH2:36][CH2:37]3)=[CH:28][CH:27]=2)=[CH:23][CH:24]=1
Reactant: O=C(CCCCl)N1CCCOc2ccccc21
Reactant: Fc1ccc(Cc2ccc(C3CCNCC3)cc2)cc1
Product: O=C(CCCN1CCC(c2ccc(Cc3ccc(F)cc3)cc2)CC1)N1CCCOc2ccccc21

Procedure:
The compound (16) synthesized in Reference Example 16 and the compound (7) synthesized in Reference Example 7 were used to produce the above compound in the same way as Example 1.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[OH:15].C(N(CC)CC)C.[CH2:23]([O:30][C:31](ON1C(=O)CCC1=O)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>ClCCl>[CH2:23]([O:30][C:31]([NH:1][C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])[CH2:4][C@H:3]1[OH:15])=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@H](O)C1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)OCc2ccccc2)[C@H](O)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.8 %

Procedure:
To a stirred mixture of trans-tert-butyl 4-amino-3-hydroxypiperidine-1-carboxylate (1.05 g, 4.86 mmol) in 80 mL of dichloromethane was added triethyl amine (5.89 g, 5.83 mmol), followed by the addition of N-(benzyloxycarbonyloxy)succinimide (1.27 g, 5.10 mmol) at 0° C. The reaction was stirred at room temperature for 16 hours and then diluted with 100 mL of dichloromethane. The solution mixture was washed with 5% citric acid solution (2×100 mL), 5% potassium carbonate solution (2×100 mL) and brine (200 mL). The organic layer was dried over anhydrous sodium sulfate and filtered, followed by concentration under reduced pressure. The resultant oily matter was purified by silica gel column chromatography (ethyl acetate: petroleum ether=1:4˜1:2) to afford the title compound (1.7 g, ˜100%, crude) as a colorless oil. MS (ES+) C18H26N2O5 requires: 350, found: 251 [M+H−100]+.