Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[CH2:2][CH:3]([C:5]1[C:10]([O:11]C(NC)=O)=[CH:9][CH:8]=[CH:7][CH:6]=1)C.C=CC1C=CC=CC=1.C([O:32][O:33][C:34](=[O:41])C1C=CC=CC=1)(=O)C1C=CC=CC=1.O=O>CO>[CH2:2]=[CH:3][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:34]([O:33][O-:32])(=[O:41])[O-:11]
Reactant: O=C(OOC(=O)c1ccccc1)c1ccccc1
Reactant: CCC(C)c1ccccc1OC(=O)NC
Agent: O=O
Solvent: C=Cc1ccccc1
Solvent: CO
Product: O=C([O-])O[O-]
Reaction time: 1 h

Procedure:
A glass ampoule having an inner volume of 20 ml was filled with 2.08 g of BPMC (purity 96.0% by weight), 8.0 g of refined styrene, and 0.1 g of benzoyl peroxide (purity 99.8% by weight), displaced with nitrogen gas, and then sealed by fusion. This ampoule was kept immersed in a constant oil bath at 100° C. for one hour. Then, the ampoule was taken out of the bath, cooled, and opened. The reaction product was dropped into 500 ml of methanol and allowed to precipitate therein. The white solid consequently formed was separated by filtration and dried under a vacuum. The product consequently obtained weighed 5.8 g. The active oxygen content of the product was found to be 1.20%. In the infrared absorption spectrum of this product, absorptions by carbonyl group were observed at 1725 and 1795 cm-1 and a characteristic absorption by benzene ring was observed below 1600 cm-1. The data indicate that the white solid was a copolymer formed of styrene structural units and peroxycarbonate structural units. The conditions of copolymerization and the analyses of the produced copolymer are shown in Table 4A and the data on the copolymer's stability of storage are shown in Table 7.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].C(OC(=O)C)(=O)C.[Br:16]Br>C(O)(=O)C>[Br:16][C:5]1[CH:4]=[CH:3][C:2]([NH2:7])=[C:1]([NH2:8])[CH:6]=1
Reactant: Nc1ccccc1N
Reactant: BrBr
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: Nc1ccc(Br)cc1N
Temperature: 65 °C
Reaction time: 12 h
Yield: 40 %

Procedure:
In 64 ml of acetic acid, 8.0 g of o-phenylene diamine was dissolved, to which 15.3 ml of acetic anhydride was added drop-wise under cooling. Then the mixture was heated for 30 minutes in an oil bath at 65° C. After cooling to room temperature, a solution of bromine (4.6 ml bromine in 16 ml acetic acid) was quickly added, followed by heating for 40 minutes in an oil bath at 50° C. About 10 minutes after adding bromine, crystals started to precipitate. The reaction mixture was cooled to room temperature, and poured into 300 ml ice water containing 4.0 g sodium hydrogen sulfite. The resulting white precipitates were collected by filtration, washed with water and dried under reduced pressure (14.0 g; yield 70%). Into a 150 ml solution of water:methanol (2:1) containing 33.6 g potassium hydroxide, the white solid was dissolved and heated with stirring for 12 hours in an oil bath at 75°-80° C. After cooling the reaction mixture, and adding 400 ml water thereto, the mixture was extracted with 100 ml ether five times. The ether phase was washed with 200 ml of saturated salt water two times, and dried with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1 to 1:1) so as to obtain compound 13 as colorless crystals (5.5 g, total yield 40%).
Reaction SMILES: Cl.[F:2][C:3]([F:24])([F:23])[C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[CH:6]([O:14][CH:15]1[CH2:18][NH:17][CH2:16]1)[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.[C:25]([N:29]=[C:30]=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[F:24][C:3]([F:2])([F:23])[C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[CH:6]([O:14][CH:15]1[CH2:18][N:17]([C:30]([NH:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])[CH2:16]1)[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1
Reactant: FC(F)(F)c1ccccc1C(OC1CNC1)c1ccc(Cl)cc1
Reactant: CC(C)(C)N=C=O
Agent: Cl
Product: CC(C)(C)NC(=O)N1CC(OC(c2ccc(Cl)cc2)c2ccccc2C(F)(F)F)C1

Procedure:
This material was prepared from 3-[2-(trifluoromethyl)-4′-chlorobenzhydryloxy]azetidine hydrochloride (98) (1.32 mmol) and tert-butyl isocyanate (1.32 mmol) using the procedure described for compound (10) (474 mg, 81%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[CH2:10][OH:11].C1COCC1.C(=O)(O)[O-].[Na+].[CH2:22]([O:29][C:30](Cl)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O>[OH:11][CH2:10][CH:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:1]1[C:30]([O:29][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:31]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: OCC1Cc2ccccc2N1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1c2ccccc2CC1CO
Reaction time: 8 h
Yield: 99 %

Procedure:
A solution containing 2,3-dihydro-1H-indol-2-ylmethanol (Preparation 5, 4.31 g) and THF (60 mL) is added to a flask containing sodium bicarbonate (24.27 g) and water (15 mL). Benzylchloroformate (4.5 mL) is slowly added. Once addition is complete, the mixture is stirred overnight. The crude mixture is filtered and washed with a large amount of CH2Cl2. The filtrate is poured into water and the separated organic phase is washed with 5% HCl and brine. The organic layer is dried (Na2SO4), filtering, and concentrated to give a yellow oil. The crude product is chromatographed eluting with EtOAc/heptane (1/1) to give 8.11 g (99%) of the title compound as a pale colored oil. Physical characteristics: MS (ESI+) m/z 284 (M+H)+.
Reaction SMILES: [CH:1](=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[N:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16](=[O:18])[CH3:17])[CH:11]=1.Cl>[OH-].[Na+].O.CCO>[OH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1/[CH:1]=[CH:17]/[C:16]([C:12]1[CH:11]=[N:10][CH:15]=[CH:14][CH:13]=1)=[O:18]
Reactant: CC(=O)c1cccnc1
Reactant: O=Cc1ccccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(/C=C/c1ccccc1O)c1cccnc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 73.8 %

Procedure:
To a vigorously stirred solution of salicylaldehyde (45 mL, 0.42 mol) in 2.5 M NaOH (330 mL) at 0° C. was added 1-(pyridin-3-yl)ethanone (46.2 mL, 0.422 mol) dropwise over 50 min. After stirring at 0° C. for 2 h, the reaction mixture was diluted with water (150 mL) and EtOH (150 mL). The mixture was acidified with conc. HCl to pH=3. The resulting yellow solid was filtered and dried to give (2E)-3-(2-hydroxyphenyl)-1-pyridin-3-ylprop-2-en-1-one (69.8 g, 73%) which was used without further purification. LCMS: (FA) ES+ 226.2, ES-224.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]([CH2:11][CH3:12])[C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.[CH2:13](N)[CH2:14][NH2:15]>>[F:1][C:2]1[CH:3]=[C:4]([CH:8]([C:9]2[NH:15][CH2:14][CH2:13][N:10]=2)[CH2:11][CH3:12])[CH:5]=[CH:6][CH:7]=1
Reactant: NCCN
Reactant: CCC(C#N)c1cccc(F)c1
Product: CCC(C1=NCCN1)c1cccc(F)c1

Procedure:
rac-2-[1-(3-Fluoro-phenyl)-propyl]-4,5-dihydro-1H-imidazole was prepared from rac-2-(3-fluoro-phenyl)-butyronitrile and ethylene diamine in analogy to Example 19 b): colourless powder; MS (ISP): 207.1 ((M+H)+.).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH3:22][NH:23][S:24](Cl)(=[O:26])=[O:25].[BH4-].[Na+].CO>N1C=CC=CC=1>[CH3:21][O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH:12]1[C:3]2[CH:4]=[CH:5][C:6]3[C:11](=[N:10][CH:9]=[CH:8][CH:7]=3)[C:2]=2[NH:1][S:24](=[O:26])(=[O:25])[N:23]1[CH3:22]
Reactant: COc1ccccc1C(=O)c1ccc2cccnc2c1N
Reactant: CNS(=O)(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CO
Product: COc1ccccc1C1c2ccc3cccnc3c2NS(=O)(=O)N1C
Yield: 43.5 %

Procedure:
In a similar fashion using route 27 general procedure 70, (8-amino-quinolin-7-yl)-(2-methoxy-phenyl)-methanone (Intermediate 369) (152 mg, 0.55 mmol), N-methylsulamoyl chloride (Intermediate 213) (212 mg, 1.64 mmol) and NaBH4 (21 mg, 0.55 mmol) in pyridine (10 ml) gave the title compound (85 mg, 44%) after trituration from MeOH.
Reaction SMILES: [CH:1]1[CH:6]=[N:5][CH:4]=[C:3]2[CH2:7][O:8][C:9]3[CH:10]=[C:11]([O:15][CH2:16][CH:17]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:18][CH:19]([CH3:21])[CH3:20])[CH:12]=[CH:13][C:14]=3[C:2]=12.C1C(=O)N([Br:37])C(=O)C1>C(#N)C>[Br:37][C:12]1[C:11]([O:15][CH2:16][C@@H:17]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[CH2:18][CH:19]([CH3:21])[CH3:20])=[CH:10][C:9]2[O:8][CH2:7][C:3]3[C:2]([C:14]=2[CH:13]=1)=[CH:1][CH:6]=[N:5][CH:4]=3
Reactant: CC(C)CC(COc1ccc2c(c1)OCc1cnccc1-2)NC(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CC(C)C[C@@H](COc1cc2c(cc1Br)-c1ccncc1CO2)NC(=O)OC(C)(C)C
Reaction time: 0.03 h
Yield: 38.7 %

Procedure:
A solution of tert-butyl (1-((5H-chromeno[3,4-c]pyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (0.072 g, 0.181 mmol) in acetonitrile (5 mL) cooled to 0° C. and stirred for 2 min. NBS (0.029 g, 0.163 mmol) was added in single portion and the reaction mixture stirred at 0° C. for 2 h. The solvent was removed under reduced pressure and water 10 mL) was added. The product was extracted with ethyl acetate (3×15 mL). The combined organic extracts were washed with water (1×20 mL) dried over sodium sulfate and concentrated under reduced pressure. The residue was purified via preparative TLC (40% EtOAc:pet ether) to obtain (S)-tert-butyl 1-(9-bromo-5H-chromeno[3,4-c]pyridin-8-yloxy)-4-methylpentan-2-ylcarbamate (30 mg, 0.063 mmol, 35% yield). 1H NMR (400 MHz, CD3OD) δ 8.48 (d, J=5.4 Hz, 1H), 8.38 (s, 1H), 8.07 (s, 1H), 7.68 (d, J=5.4 Hz, 1H), 6.73 (s, 1H), 5.21 (s, 2H), 4.02-3.98 (m, 3H), 1.92-1.71 (m, 1H), 1.56-1.52 (m, 2H), 0.97 (t, J=6.8 Hz, 6H).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[NH2:7][C@@H:8]1[CH2:10][C@H:9]1[C:11]1[CH:26]=[CH:25][C:14]([O:15][CH2:16][C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1.CCN(C(C)C)C(C)C>CC#N>[CH3:6][O:5][C:3](=[O:4])[CH2:2][NH:7][C@@H:8]1[CH2:10][C@H:9]1[C:11]1[CH:12]=[CH:13][C:14]([O:15][CH2:16][C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=2)=[CH:25][CH:26]=1
Reactant: COC(=O)CBr
Reactant: N#Cc1ccc(COc2ccc([C@@H]3C[C@H]3N)cc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)CN[C@@H]1C[C@H]1c1ccc(OCc2ccc(C#N)cc2)cc1
Reaction time: 22 h
Yield: 43.5 %

Procedure:
A solution of methyl bromoacetate (0.08 mL, 0.91 mmol) in CH3CN (6 mL) was added, over a period of 15 min, to a solution of 4-({4-[(trans)-2-aminocyclopropyl]phenoxy}methyl)benzonitrile (0.22 g, 0.82 mmol) and DIPEA (0.28 mL, 1.64 mmol) in CH3CN (8 mL) at −10° C. The reaction was allowed to reach room temperature and stirred for 22 h. After removal of the solvent, the crude residue was purified by column chromatography on silica gel (2-5% MeOH/CH2Cl2) affording 0.12 g of methyl[((trans)-2-{4-[(4-cyanobenzyl)oxy]phenyl}cyclopropyl)amino]acetate [Rf=0.5 (5% MeOH/CH2Cl2), pale yellow oil, 44% yield].
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]([O:14][CH3:15])=[O:13].FC(F)(F)C(O)=O.[Br:23]N1C(C)(C)C(=O)N(Br)C1=O.S(=O)(=O)(O)O.C([O-])(=O)C.[Na+]>C(O)(=O)C>[Br:23][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[C:3]([C:12]([O:14][CH3:15])=[O:13])=[C:2]([CH3:1])[CH:11]=[CH:10]2
Reactant: COC(=O)c1c(C)ccc2ccccc12
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: COC(=O)c1c(C)ccc2cccc(Br)c12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.8 %

Procedure:
Methyl 2-methylnaphthalene-1-carboxylate (5.6 g) was dissolved in acetic acid (12 ml) and trifluoroacetic acid (12 ml) and cooled in an ice bath. 1,3-Dibromo-5,5-dimethylhydantoin (4.8 g) was added in one portion then concentrated sulphuric acid was added dropwise. The mixture was then stirred at 0° C. for 30 minutes. Sodium acetate (6.12 g) was added and the mixture was partitioned between DCM and water. The organic layer was separated, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of DCM and pentane with a gradient of 20-70% to give methyl 8-bromo-2-methylnaphthalene-1-carboxylate (3.27 g) as a colourless oil.
Reaction SMILES: C([O:3][C:4]([C:6]1([CH3:12])[N+:10]([O-:11])=[CH:9][CH2:8][CH2:7]1)=O)C.[OH-].[NH4+].COC1C=C(C=CC=1OC)C(O)=O.[NH2:28]C(N)=O>CO.C(OCC)(=O)C>[C:4]([C:6]1([CH3:12])[N+:10]([O-:11])=[CH:9][CH2:8][CH2:7]1)(=[O:3])[NH2:28]
Reactant: CCOC(=O)C1(C)CCC=[N+]1[O-]
Reactant: NC(N)=O
Agent: COc1ccc(C(=O)O)cc1OC
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC1(C(N)=O)CCC=[N+]1[O-]

Procedure:
AMPO was prepared from EMPO based on the procedure described previously with minor modification.2 A solution of 0.5 g of EMPO was mixed with 10 mL of concentrated ammonium hydroxide in a sealed tube for 5 days at room temperature with shaking. The mixture was rotary evaporated to yield a viscous dark oil and passed through a silica gel column (200-400 mesh 60 Å) twice using methanol-ethyl acetate (30:70) as solvent. White crystalline product was obtained (0.10 g, 24%), mp. 134-135° C. (lit. 137° C.)., (corrected using 3,4 dimethoxybenzoic acid, m.p., 180° C. and urea, m.p., 135° C.). 1H NMR (400 MHz, D2O) δ 1.64 (3 H, s, C(5)Me), 2.21-2.29 and 2.54-2.61 (2 H, m, C(4)H), 2.73-2.73 (2 H, m, C(3)H), 7.36 (1 H, t, C(2)H). 1H NMR (400 MHz, CDCl3) 1.90 (3 H, s, C(5)Me), 2.27-2.34 and 3.14-3.20 (2 H, m, C(4)H), 2.79 (2 H, m, C(3)H), 7.19 (1 H, t, C(2)H), 5.85 and 8.46 (2 H, br, NH2). 13C NMR (100 MHz, CDCl3) δ 24.2 (s, —CH3), 25.0 (s, C-3), 30.5 (s, C-4), 79.1 (C-5), 137.4 (C-2), 172.9 (—C═O). IR (Neat film) 1676 (C═O), 1585 (C═N), 1215 (N—O). ESI-MS calcd for C6H10N2O2Na+ m/z 165.0634, found 165.0637 amu. Anal. Calcd. for C6H10N2O2: C, 50.81; H, 7.23; N, 19.14. Found: C, 50.61; H, 7.25; N, 19.31.
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[C:5]([S:11]([NH2:14])(=[O:13])=[O:12])[CH:6]=[CH:7][CH:8]=2)[NH:3]1.C[O:16][C:17](=O)[NH:18][C:19]1[N:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([CH3:27])[N:20]=1.C[Al](C)C.Cl>C(Cl)Cl.C1(C)C=CC=CC=1>[CH3:26][O:25][C:23]1[CH:22]=[C:21]([CH3:27])[N:20]=[C:19]([NH:18][C:17]([NH:14][S:11]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[NH:3][CH:2]([CH3:1])[CH2:10]3)(=[O:13])=[O:12])=[O:16])[N:24]=1
Reactant: CC1Cc2cccc(S(N)(=O)=O)c2N1
Reactant: COC(=O)Nc1nc(C)cc(OC)n1
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc(C)nc(NC(=O)NS(=O)(=O)c2cccc3c2NC(C)C3)n1
Yield: 11.2 %

Procedure:
To a solution of 2,3-dihydro-2-methyl-1H-indole-7-sulfonamide (1.0 g) and (4-methoxy-6-methylpyrimidin-2-yl)carbamic acid methyl ester (1.0 g) in methylene dichloride (100 ml) was added trimethylaluminum (3.0 ml of a 2.0 M solution in toluene). The mixture was heated at reflux for 18 hours under a nitrogen atmosphere. Work-up was achieved by careful addition of 100 ml of 1N HCl followed by separation of the organic layer. The methylene chloride was dried over MgSO4 and evaporated to dryness. The residue was chromatographed on a silica gel column to give the pure product (0.2 g, m.p. 175°-177° C.).
Reaction SMILES: Br[CH2:2][C:3]1C2C(=CC=CC=2)NC(=O)[CH:4]=1.[Br:14][CH2:15][CH2:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][C:19](=[O:27])[CH:18]=1.BrCCCC1C2C(=CC=CC=2)NC(=O)C=1>>[Br:14][CH2:15][CH2:16][C:17]1[C:26]2[C:21](=[C:22]([CH:3]([CH3:4])[CH3:2])[CH:23]=[CH:24][CH:25]=2)[NH:20][C:19](=[O:27])[CH:18]=1
Reactant: O=c1cc(CBr)c2ccccc2[nH]1
Reactant: O=c1cc(CCBr)c2ccccc2[nH]1
Agent: O=c1cc(CCCBr)c2ccccc2[nH]1
Product: CC(C)c1cccc2c(CCBr)cc(=O)[nH]c12

Procedure:
In addition, 4-bromomethyl-2(1H)-quinolinone (II-1), 4-(2-bromoethyl)-2(1H)-quinolinone (II-2) and 4-(3-bromopropyl)-2(1H)-quinolinone (II-3) were prepared according to Chemical and Pharmaceutical Bull., 33(9), 3775-3786(1985).
Reaction SMILES: [NH2:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]3[CH:12]=[CH:13][C:14](=[O:17])[NH:15][N:16]=3)[CH:8]=2)[CH2:3]1.Br.Cl[C:20]([O:22][CH:23]=[CH2:24])=[O:21]>>[CH:23]([O:22][C:20]([NH:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]3[CH:12]=[CH:13][C:14](=[O:17])[NH:15][N:16]=3)[CH:8]=2)[CH2:3]1)=[O:21])=[CH2:24]
Reactant: C=COC(=O)Cl
Reactant: NC1Cc2ccc(-c3ccc(=O)[nH]n3)cc2C1
Agent: Br
Product: C=COC(=O)NC1Cc2ccc(-c3ccc(=O)[nH]n3)cc2C1

Procedure:
2-Amino-5-[pyridazin-3(2H)-on-6-yl]indane·hydrobromide and vinyl chloroformate were treated in the same manner as in Example 49 to obtain 2-vinyloxycarbonylamino-5-[pyridazin-3(2H)-on-6-yl]indane.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH:7]=O)[S:4][N:3]=1.[CH2:9]([NH2:11])[CH3:10]>C1COCC1>[CH2:9]([NH:11][CH2:7][C:5]1[S:4][N:3]=[C:2]([CH3:1])[CH:6]=1)[CH3:10]
Reactant: CCN
Reactant: Cc1cc(C=O)sn1
Solvent: C1CCOC1
Product: CCNCc1cc(C)ns1

Procedure:
prepared by reaction of 3-methyl-isothiazole-5-carbaldehyde (Buttimore D. et al J. Chem. Soc. 1963, 2032-2039) with 2M ethylamine in THF.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]2[C@H:13]([NH2:16])[CH2:14][CH2:15][C@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([CH:24]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:25](O)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1([C@H](CC)C(O)=O)C=CC=CC=1>>[CH2:17]([CH:24]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:25]([NH:16][C@@H:13]1[C@@H:11]2[C@@H:10]([CH2:9][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:12]2)[CH2:15][CH2:14]1)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)C(Cc1ccccc1)C(=O)O
Reactant: N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21
Agent: CC[C@H](C(=O)O)c1ccccc1
Product: CC(C)(C)C(Cc1ccccc1)C(=O)N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21

Procedure:
The title compound was prepared by substituting (3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine from Step A of Example 33 for (3aS,4R,6aR)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine and 2-benzyl-3,3-dimethylbutanoic acid for (S)-2-phenylbutanoic acid in Step F of the procedure used to prepare Example 16: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.08 (dd, J=7.4, 13.6, 1H), 7.46 (d, J=7.3, 1H), 7.44-7.40 (m, 1H), 7.38 (dd, J=7.6, 15.7, 2H), 7.34 (d, J=4.3, 2H), 7.31-7.23 (m, 4H), 4.36-4.29 (m, 1H), 3.59 (d, J=13.1, 0.5H), 3.53 (dd, J=13.2, 32.6, 1H), 3.40 (d, J=13.1, 0.5H), 3.25 (q, J=12.0, 1H), 2.79-2.67 (m, 2H), 2.48-2.42 (m, J=7.0, 1H), 2.41-2.23 (m, 3.5H), 2.20 (t, J=8.3, 0.5H), 2.12 (d, J=6.7, 0.5H), 2.06 (dd, J=5.9, 11.7, 0.5H), 1.88 (dd, J=5.8, 11.7, 0.5H), 1.74 (dd, J=9.4, 16.4, 0.5H), 1.60 (dd, J=7.0, 13.2, 0.5H), 1.51-1.42 (m, 0.5H), 1.37-1.21 (m, 2H), 1.15 (s, 9H); MS (ESI+) m/z 405 (M+H)+.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:16]2[N:15]=[C:14]([NH2:17])[N:13]3[N:18]=[C:19]([C:21]4[O:22][CH:23]=[CH:24][CH:25]=4)[N:20]=[C:12]3[C:11]=2[CH:10]=[CH:9]1)(=O)=O.[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[CH:34]1[CH2:35][CH2:36][N:37]([CH2:6][CH2:7][N:8]2[C:16]3[N:15]=[C:14]([NH2:17])[N:13]4[N:18]=[C:19]([C:21]5[O:22][CH:23]=[CH:24][CH:25]=5)[N:20]=[C:12]4[C:11]=3[CH:10]=[CH:9]2)[CH2:38][CH2:39]1
Reactant: CS(=O)(=O)OCCn1ccc2c1nc(N)n1nc(-c3ccco3)nc21
Reactant: Fc1ccc(C2CCNCC2)c(F)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc2c(ccn2CCN2CCC(c3ccc(F)cc3F)CC2)c2nc(-c3ccco3)nn12
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To a solution of the title D compound of Example 1, 2-{5-amino-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-7-yl}ethyl methanesulfonate (0.06 g, 0.165 mmol) in dry DMF (5 mL), 4-(2,4-difluorophenyl)piperidine (0.33 mmol) and 0.06 mL of DIEA are added, and the solution is stirred at 100° C. for 5 h. The reaction mixture is cooled to RT, and the solvent is removed under reduced pressure. The crude product is purified by flash chromatography using a 95/5.0/0.5-mixture of DCM/MeOH/NH4OH as an eluent to give 7-(2-(4-(2,4-difluorophenyl)piperidin-1-yl)ethyl)-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine: LC/MS (M+1=463.98). 1H NMR (DMSO-d6, 400 MHz), δ 1.68 (m, 4H), 2.12 (m, 2H), 2.55 (m, 1H), 2.73 (t, 2H, J=6.0 Hz), 3.04 (m, 2H), 4.26 (t, 2H, J=6.4 Hz), 6.59 (d, 1H, J=3.6 Hz), 6.71 (m, 1H), 7.09 (m, 1H), 7.18 (m, 2H), 7.26 (m, 1H), 7.33 (m, 1H), 7 49 (br s, 2H, NH2), 7.91 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Cl[C:13]([F:18])([F:17])C([O-])=O.[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:13]([F:18])[F:17])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: O=C([O-])C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC(F)F)cc1
Temperature: 125 °C
Yield: 45.9 %

Procedure:
Under N2 flow, 1.3 g of 4-hydroxy-benzoic acid methyl ester (8.3 mmol, 1.0 eq) and 1.5 g of sodium chlorodifluoroacetate (10.0 mmol, 1.2 eq) were dissolved in DMF (25 mL) in a two neck round bottom flask; potassium carbonate (1.4 g, 10.0 mmol, 1.2 eq) was added and the mixture was heated at 125° C. for 3.5 hours. The mixture was then diluted with water and extracted with DCM; organic phases were dried and evaporated, the crude was purified with Si column (eluent: cycloexane/EtOAc 80/20) to obtain 0.77 g of product (yield 46%) which was used directly for the next step.
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[N:6]2[CH2:9][CH2:10][N:11]([CH2:12][CH2:13][OH:14])[C:5]2=[N:4][C:3]=1[C:15]([O:17]CC)=O.[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1>C(O)C.C(OCC)(=O)C>[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH:26][C:15]([C:3]2[N:4]=[C:5]3[N:11]([CH2:12][CH2:13][OH:14])[CH2:10][CH2:9][N:6]3[C:7](=[O:8])[C:2]=2[OH:1])=[O:17])=[CH:23][CH:22]=1
Reactant: NCc1ccc(F)cc1
Reactant: CCOC(=O)c1nc2n(c(=O)c1O)CCN2CCO
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(NCc1ccc(F)cc1)c1nc2n(c(=O)c1O)CCN2CCO
Yield: 81.6 %

Procedure:
A solution of ethyl 6-hydroxy-1-(2-hydroxyethyl)-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylate (0.110 g, 0.408 mmol) and 4-fluorobenzylamine (0.200 g, 1.6 mmol) in anhydrous ethanol (5 ml) was heated under reflux for 6 h. The reaction mixture was then diluted with ethyl acetate, washed successively with 0.1 N hydrochloric acid and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Crystallization of the residual solid from ethanol gave 0.116 g (82% yield) of the title amide as white cubes; mp 203° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.54 (2H, t, J=5.0 Hz, CH2), 3.80 (2H, t, J=8.5 Hz, CH2), 3.89 (2H, t, J=5.0 Hz, CH2), 4.15 (2H, t, J=8.5 Hz, CH2), 4.57 (2H, d, J=6.0 Hz, NCH2), 7.07 (2H, m, aromatics), 7.34 (2H, m, aromatics), 7.92 (1H, broad t, NH), 11.68 (1H, s, OH). Anal. Calcd for C16H17FN4O4: C, 55.17; H, 4.92; N, 16.08. Found: C, 55.22; H, 5.06; N, 15.89.
Reaction SMILES: CC[O-].[Na+].[F:5][C:6]([F:16])([F:15])[C:7](=[O:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].Br[CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>CCO>[F:5][C:6]([F:15])([F:16])[C:7]([CH:8]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:14]
Reactant: CCOC(=O)CCBr
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CCC(C(=O)OCC)C(=O)C(F)(F)F
Reaction time: 0.17 h
Yield: 90.7 %

Procedure:
To a solution of NaOEt (0.217 mol) in EtOH (prepared from 5.0 g of Na and 220 mL of EtOH) was added ethyl triflouroacetoacetate (40.0 g, 0.217 mol). After 10 min, ethyl 3-bromopropionate (35.0 g, 0.194 mol) was added and the mixture was heated under reflux for 24 h. The reaction mixture was concentrated, taken up in ether, and washed with water. The ether layers were dried (MgSO4) and concentrated to give 50 g of a yellow oil. Distillation (100°-110° C./25 mm) gave 14.0 g (23%) of product as a colorless oil.