Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10](=[S:13])SC)([OH:3])=[O:2].[N-:14]=[N+:15]=[N-:16].[Na+].[OH-].[Na+]>>[C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:10]([SH:13])=[N:16][N:15]=[N:14]1)([OH:3])=[O:2]
Reactant: CSC(=S)NCCCCCC(=O)O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCCCn1nnnc1S

Procedure:
Reaction of methyl 5-carboxypentyldithiocarbamate with sodium azide and sodium hydroxide as described in Example 7 gave 1-(5-carboxypentyl)tetrazole-5-thiol, m.p. 100°-100.5°.
Reaction SMILES: Br[CH:2]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:3]([NH:5][C:6]1[S:7][C:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[CH:9][N:10]=1)=[O:4].[CH3:25][OH:26]>>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][C:8]1[S:7][C:6]([NH:5][C:3](=[O:4])[CH:2]([O:26][CH3:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:10][CH:9]=1
Reactant: CO
Reactant: O=C(Nc1ncc(Cc2ccccc2Cl)s1)C(Br)c1ccccc1
Product: COC(C(=O)Nc1ncc(Cc2ccccc2Cl)s1)c1ccccc1

Procedure:
2-Bromo-N-[5-(2-chloro-benzyl)-thiazol-2-yl]-2-phenyl-acetamide (42 mg, 0.10 mmol) was dissolved in 5 mL of methanol. The reaction vessel was sealed and then subjected to microwave irradiation for 15 minutes at 125° C. The crude mixture was evaporated to dryness, dissolved in 1 mL of dimethylsulfoxide and purified by reverse-phase preparative liquid chromatography (16 mg, 0.043, 43%). ESI-MS m/z calc. 372.1. found 373.2 (M+1)+ Retention time 3.43 minutes. 1H NMR (400 MHz, CD3CN) δ 3.42 (s, 3H), 4.23 (s, 2H), 4.94 (s, 1H), 7.21-7.53 (m, 10H)
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[N:25]=[C:24]([C:26](=O)[C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:23]([F:33])=[C:22]([Cl:34])[C:21]=1[N:35]1[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl.[NH2:50][OH:51]>C(O)(C)C>[Si:1]([O:18][CH2:19][C:20]1[N:25]=[C:24]([C:26](=[N:50][OH:51])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:23]([F:33])=[C:22]([Cl:34])[C:21]=1[N:35]1[CH2:36][C@H:37]([CH3:42])[O:38][C@H:39]([CH3:41])[CH2:40]1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=O)c1nc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(N2C[C@@H](C)O[C@@H](C)C2)c(Cl)c1F
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(C)O
Product: CCOC(=O)C(=NO)c1nc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(N2C[C@@H](C)O[C@@H](C)C2)c(Cl)c1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Ethyl 2-(6-((tert-butyldiphenylsilyloxy)methyl)-4-chloro-5-((2R,6S)-2,6-dimethylmorpholino)-3-fluoropyridin-2-yl)-2-oxoacetate (Intermediate 121, 13.4 g, 21.85 mmol) was slurried in isopropanol (150 ml), and pyridine (124 ml, 1529.70 mmol) was added to give a yellow solution. Hydroxylamine hydrochloride (1.670 g, 24.04 mmol) was added, and the suspension was stirred at room temperature for approximately 16 hours. The resulting solution was concentrated to an oil. The residue was purified by chromatography on SiO2 using 5-40% EtOAc/hexane. A total of 11.93 g (87%) of the title product as a mixture of oxime isomers was obtained as a yellow oil.
Reaction SMILES: [Br-].C[O:3][C:4]1[CH:29]=[CH:28][C:7]([CH2:8][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:6][CH:5]=1.C([Li])CCC.C[O:36][C:37]1[CH:38]=[C:39]([CH:42]=[C:43]([O:45]C)[CH:44]=1)[CH:40]=O.O>O1CCCC1>[OH:3][C:4]1[CH:5]=[CH:6][C:7](/[CH:8]=[CH:40]/[C:39]2[CH:42]=[C:43]([OH:45])[CH:44]=[C:37]([OH:36])[CH:38]=2)=[CH:28][CH:29]=1
Reactant: COc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: COc1cc(C=O)cc(OC)c1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Oc1ccc(/C=C/c2cc(O)cc(O)c2)cc1
Reaction time: 3 h
Yield: 36.7 %

Procedure:
To a solution of 4-methoxy-benzyltriphenylphosphonium bromide (12.5 g) in anhydrous tetrahydrofuran (200 mL) at −78° C. was added n-butyllithium (2.44 M, 1.0 equiv), and the resulting red solution was stirred under argon for 2-4 h. A solution of 3,5-dimethoxybenzaldehyde (4.5 g) in tetrahydrofuran was added dropwise over 30 min and the mixture stirred for 6-15 h. The resulting cream suspension was poured into water and extracted with dichloromethane. The organic phase was washed with water, and removal of the solvent in vacuo afforded an oil. The oil was separated by flash column chromatography (49:1 hexane/ethyl acetate). The cis-stilbene eluted first as a clear oil followed by the trans isomer as a colorless solid or oil. Overall yield: 91%. To a solution of the trans isomer (3.1.g) in anhydrous dichloromethane (150 mL) at −78° C. was added (dropwise) boron tribromide (1.0 M, 34.5 mL), and the resulting red solution was stirred under argon for 30 min. The solution was poured into water and extracted with dichloromethane. The organic phase was washed with water, and removal of the solvent in vacuo afforded an oil, which was separated by flash column chromatography (1:1 hexane/ethyl acetate) to afford a colorless solid (2.26 g, 86%): mp 260° C.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[CH3:19][C:20]([O:23][C:24](=[O:31])[C@H:25]([CH2:27][CH:28]([CH3:30])[CH3:29])[NH2:26])([CH3:22])[CH3:21]>>[C:20]([O:23][C:24](=[O:31])[C@@H:25]([NH:26][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])[CH2:27][CH:28]([CH3:29])[CH3:30])([CH3:21])([CH3:19])[CH3:22]
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Reactant: CC(C)C[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Product: CC(C)C[C@H](NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1)C(=O)OC(C)(C)C

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and L-leucine 1,1-dimethylethyl ester hydrochloride (1:1) (CAN 2748-02-9) as starting materials; LC-MS (UV peak area/ESI) 98.7%, 403.2599 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[CH3:28][N:29]([CH2:37][CH2:38][CH2:39][NH:40][CH3:41])[C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33]>C(Cl)Cl>[F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([N:40]([CH3:41])[CH2:39][CH2:38][CH2:37][N:29]([CH3:28])[C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:33])[CH3:34])=[O:6]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1F
Reactant: CNCCCN(C)C(=O)OC(C)(C)C
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CCCN(C)C(=O)c1ccc([N+](=O)[O-])cc1F)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 100.3 %

Procedure:
2-Fluoro-4-nitrobenzoic acid (150 mg, 0.810 mmol) was dissolved in methylene chloride (8 mL), triethylamine (0.135 mL, 0.972 mmol) and pivaloyl chloride (0.100 mL, 0.810 mmol) were added under ice cooling, and the mixture was stirred at room temperature for 15 minutes. A solution of tert-butyl methyl[3-(methylamino)propyl]carbamate (described in J. Med. Chem. 1990, 33, 97-101) (164 mg, 0.810 mmol) in methylene chloride (4 mL) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=1:2→0:100, v/v) to give the title compound (300 mg; yield, 100%) as a yellow oily substance.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:8]=[CH:7][C:6]=1[CH:15]1[CH2:24][CH2:23][C:18]2(OCC[O:19]2)[CH2:17][CH2:16]1.Cl.C(=O)(O)[O-].[Na+]>CO>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:8]=[CH:7][C:6]=1[CH:15]1[CH2:24][CH2:23][C:18](=[O:19])[CH2:17][CH2:16]1
Reactant: COCOc1ccc(C2CCC3(CC2)OCCO3)c(OCOC)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COCOc1ccc(C2CCC(=O)CC2)c(OCOC)c1
Reaction time: 1.5 h
Yield: 78.9 %

Procedure:
A round bottomed flask equipped with magnetic stirrer was charged with 8-[2, 4-bis(methoxymethoxy)phenyl]-1,4-dioxaspiro[4.5]decane (3.20 g 9.47 mmol) and methanol (50 ml). Over a 20 min period, aqueous hydrochloric acid (50 ml, 1.00M) was added to the stirred solution, at room temperature and the reaction mixture stirred for 1.5 hr. Solid sodium bicarbonate was added until the reaction mixture was neutralised and the solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate (30 ml) and water (10 ml), and the aqueous layer was extracted with ethyl acetate (3×20 ml). The combined organic layers were washed with brine (10 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified via flash column chromatography (SiO2, ethyl acetate/petroleum ether, 1:4, v/v), affording the title compound (2.20 g, 60%) as a white powder. δH(CDCl3) 1.85-1.96 (2H, m), 2.14-2.22 (2H, m), 2.46-2.59 (4H, m), 3.39 (1H, tt), 3.49 (3H, s), 3.52 (3H, s), 5.16 (2H, s), 5.23 (2H, s), 6.67-6.71 (1H, m), 6.85 (1H, m), 7.08 (1H, d).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7]1[CH:13]2[CH2:14][N:10]([C:11](=[O:23])[N:12]2[O:15]CC2C=CC=CC=2)[CH:9]([C:24]([NH2:26])=[O:25])[CH:8]=1)(=[O:3])[CH3:2].C(NCCC1[C@@H]2CN(C(=O)N2OCC2C=CC=CC=2)[C@H](C(N)=O)C=1)(=O)C>CCOC(C)=O.C(O)C.[Pd]>[C:1]([NH:4][CH2:5][CH2:6][C:7]1[C@@H:13]2[CH2:14][N:10]([C:11](=[O:23])[N:12]2[OH:15])[C@H:9]([C:24]([NH2:26])=[O:25])[CH:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NCCC1=CC(C(N)=O)N2CC1N(OCc1ccccc1)C2=O
Agent: [Pd]
Agent: CC(=O)NCCC1=C[C@@H](C(N)=O)N2C[C@@H]1N(OCc1ccccc1)C2=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(=O)NCCC1=C[C@@H](C(N)=O)N2C[C@@H]1N(O)C2=O
Reaction time: 1 h
Yield: 101.7 %

Procedure:
To a solution of 4-(2-acetamidoethyl)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-ene-2-carboxamide (Intermediate 247, 0.120 g, 0.33 mmol) in EtOAc (20 mL) and ethanol (6.67 mL) was added Pd/C (0.036 g, 0.33 mmol). The reaction mixture was stirred under hydrogen at 1 atm for 1 hour, then filtered through celite and concentrated to dryness to afford the title compound as a white solid (0.09 g, 100%).
Reaction SMILES: [CH2:1]1[S:5](=[O:7])(=[O:6])[O:4][CH2:3][CH2:2]1.[CH2:8]([NH2:12])[CH2:9][CH2:10][CH3:11]>CO>[CH2:8]([NH:12][CH2:3][CH2:2][CH2:1][S:5]([OH:4])(=[O:7])=[O:6])[CH2:9][CH2:10][CH3:11]
Reactant: CCCCN
Reactant: O=S1(=O)CCCO1
Solvent: CO
Product: CCCCNCCCS(=O)(=O)O
Reaction time: 0.67 h
Yield: 96 %

Procedure:
Propanesultone (61g; 0.5 mole) was added to a stirred solution of n-butylamine (36.5g; 0.5 mole) in methanol (200 ml) in 10 min. The reaction temperature was kept at 50°-55° by cooling. After stirring 40 min, a white solid began to separate. After stirring overnight filtration yielded 3-butylaminopropylsulfonic acid 94g (96%).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:50])[N:20]([CH2:39][C:40]([C:42]2[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=2)=[O:41])[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:50])[N:20]([CH2:39][C:40]([C:42]2[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=2)=[O:41])[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:28][CH:29]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCc1nc(C)n(CC(=O)c2ccc(OC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCCc1nc(C)n(CC(=O)c2ccc(OC)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 6.7 %

Procedure:
A mixture of hydroxylammonium chloride (1.12 g), sodium hydrogen carbonate (1.69 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-({4-butyl-1-[2-(4-methoxyphenyl)-2-oxoethyl]-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (0.68 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.19 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.17 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.051 g, 7%).
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H-].[Na+].[Cl:10][C:11]1[C:16](Cl)=[N:15][CH:14]=[CH:13][N:12]=1>C1COCC1>[Cl:10][C:11]1[C:16]([O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[N:15][CH:14]=[CH:13][N:12]=1
Reactant: CCCCCCO
Reactant: Clc1nccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCOc1nccnc1Cl
Temperature: -5 °C
Reaction time: 0.5 h

Procedure:
Hexanol was added to a slurry of sodium hydride in THF, and the mixture stirred for 30 minutes. The slurry was cooled to -5° C. and a solution of 2,3-dichloropyrazine added. The mixture was stirred for 1.5 hours, filtered and the filtrate evaporated. The residue was purified by column chromatography on silica gel using varying concentrations of methanol in chloroform. Fractions containing the desired product were evaporated, yielding 2-chloro-3-hexyloxypyrazine as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([OH:9])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[H-].[Na+].C1OCCOCCOCCOCCOC1.[Br:27][C:28]1[CH:33]=[CH:32][C:31](O)=[C:30]([N+:35]([O-:37])=[O:36])[C:29]=1F>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1([O:9][C:31]2[CH:32]=[CH:33][C:28]([Br:27])=[CH:29][C:30]=2[N+:35]([O-:37])=[O:36])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: O=[N+]([O-])c1c(O)ccc(Br)c1F
Reactant: CCOC(=O)C1(O)CC1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(Oc2ccc(Br)cc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 51.9 %

Procedure:
To a stirred solution of ethyl-1-hydroxycyclopropane carboxylate (2.93 g, 20.5 mmol) in THF (50 mL) was added sodium hydride (60% in mineral oil, 981 mg, 24.5 mmol) under argon atmosphere. After 10 min, 15-crown-5 (0.2 mL) followed by 4-bromo-2-nitro-fluorophenol (4.5 g, 20.5 mmol) were added. The reaction mixture was stirred at room temperature overnight then quenched by the addition of methanol (1.5 mL) and diluted with ethyl acetate. The mixture was washed with brine, and the organic layer was dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography to give 1-(4-bromo-2-nitro-phenoxy)-cyclopropanecarboxylic acid ethyl ester (3.51 g).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[C:12]([CH3:13])=[CH:11][C:6]2N=C(C)[Se:9][C:5]=2[CH:4]=1.C[I:16]>C(Cl)(Cl)Cl>[I-:16].[CH3:14][N:2]([CH3:1])[C:3]1[C:12]([CH3:13])=[CH:11][C:6]2[C:3]([CH3:4])=[N+:2]([CH3:1])[Se:9][C:5]=2[CH:4]=1
Reactant: Cc1nc2cc(C)c(N(C)C)cc2[se]1
Reactant: CI
Solvent: ClC(Cl)Cl
Product: Cc1cc2c(C)[n+](C)[se]c2cc1N(C)C
Product: [I-]
Yield: 187.4 %

Procedure:
An autoclave was charged with 1.06 g of 6-dimethylamino-2,5-dimethylbenzoselenazole, 2.42 g of methyl iodide and 45 ml of chloroform. Then, the air in the autoclave was displaced by argon gas and the tube was sealed. After carrying out the reaction at 80° C. for 8 days, the solvent was distilled off and the residue was washed with diethyl ether, giving 1.55 g of 6-dimethylamino-2,3,5-trimethylbenzoselenazolenium iodide as pale yellow solids (yield 94%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][C:16](=[O:18])[C:15]2[C:10](=[CH:11][C:12]([O:19][CH3:20])=[CH:13][CH:14]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:21]=[N+]=[N-].[Na+].O.[OH-].[Na+]>CS(O)(=O)=O>[CH2:1]([N:8]1[CH2:9][C:10]2[CH:11]=[C:12]([O:19][CH3:20])[CH:13]=[CH:14][C:15]=2[NH:21][C:16](=[O:18])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)CN(Cc1ccccc1)CC2=O
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc2c(c1)CN(Cc1ccccc1)CC(=O)N2
Temperature: 65 °C
Yield: 73 %

Procedure:
To a solution of 2-benzyl-7-methoxy-2,3-dihydro-1H-isoquinolin-4-one (7.0 g, 26.2 mmol) in methanesulfonic acid (50 mL) was added sodium azide (3.4 g, 52.4 mmol) portionwise with stirring (Caution: mild exotherm, gas evolution). The mixture was heated to 65° C. for two hours before being cooled to ambient temperature. Water (100 mL) was added, the mixture was cooled in an ice-water bath, and the pH was adjusted to 7-8 (10N NaOH). The gummy precipitate was extracted (DCM), the organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated. Further purification by flash chromatography over silica gel (DCM/MeOH) gave 4-benzyl-7-methoxy-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (5.4 g, 73%) as a tan solid; 1H NMR (400 MHz, DMSO-d6) δ 9.80 (s, 1H), 7.33 (m, 5H), 6.97 (d, J=8 Hz, 1H), 6.87 (d, J=8 Hz, 1H), 6.82 (s, 1H), 3.73 (s, 3H), 3.67 (s, 4H), 3.09 (s, 2H); MS (m/e) 283 (M+1); mp 134° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[Br:11]Br.C(=O)(O)[O-].[Na+]>C(OCC)C>[Br:11][CH2:9][C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=1)=[O:10]
Reactant: CC(=O)c1cccc(C)c1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: Cc1cccc(C(=O)CBr)c1

Procedure:
To a solution of 1-(3-methylphenyl)ethanone (2 g) in ethyl ether (20 mL) is added bromine (726 μL) at 0° C. The mixture is treated with an aqueous solution of sodium bicarbonate, extracted with ethyl ether, dried over magnesium sulfate, concentrated and purified on silica gel (ethyl acetate/cyclohexane 0/100) to give the desired compound.
Reaction SMILES: C1([N:6]2[CH2:11][CH2:10][CH:9]([N:12]3[CH2:16]C[C@H:14]([NH:17][S:18]([C:21]4[CH:30]=[CH:29][C:28]5[C:23](=[CH:24][CH:25]=[C:26]([Cl:31])[CH:27]=5)[CH:22]=4)(=[O:20])=[O:19])[C:13]3=[O:32])[CH2:8][CH2:7]2)CCCC1.[CH3:33][CH2:34]N(C(C)C)C(C)C.[CH3:42][N:43]([CH3:48])[CH2:44][C:45](O)=[O:46].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1.CN(C=O)C>[CH3:42][N:43]([CH3:48])[CH2:44][C:45]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]2[CH2:16][CH2:34][CH2:33][C@H:14]([NH:17][S:18]([C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[C:26]([Cl:31])[CH:27]=4)[CH:22]=3)(=[O:19])=[O:20])[C:13]2=[O:32])[CH2:8][CH2:7]1)=[O:46]
Reactant: CN(C)CC(=O)O
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C1[C@@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1C1CCN(C2CCCC2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CN(C)CC(=O)N1CCC(N2CCC[C@H](NS(=O)(=O)c3ccc4cc(Cl)ccc4c3)C2=O)CC1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a mixture of the product obtained from Example 3 (20 mg, 0.047 mmol) in THF/DMF (2.5/1.0 mL) were added DIEA (0.1 mL), N,N-dimethylglycine (50 mg), and BOP reagent (100 mg). The resulting mixture was stirred at 0° C. for 1.5 hr. The solvent was evaporated. HPLC separation (30% to 100% acetonitrile/water) gave the title compound as a white solid. LC-MS found: (M+1)+=507.26.
Reaction SMILES: [N:1]1([C:6]2[N:11]=[C:10]3[N:12]([CH:27]([CH3:29])[CH3:28])[C:13](=[O:26])[N:14]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)[C:15](=[O:16])[C:9]3=[CH:8][N:7]=2)[CH:5]=[CH:4]N=C1.[CH2:30]([N:32]([CH2:43][CH3:44])[CH2:33][CH2:34][O:35][C:36]1[CH:42]=CC(N)=[CH:38][CH:37]=1)[CH3:31].C1(=O)OC(=O)CC1.CN(C)C=O>C(Cl)(Cl)Cl>[CH2:43]([N:32]([CH2:30][CH3:31])[CH2:33][CH2:34][O:35][C:36]1[CH:42]=[CH:4][C:5]([NH:1][C:6]2[N:11]=[C:10]3[N:12]([CH:27]([CH3:28])[CH3:29])[C:13](=[O:26])[N:14]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)[C:15](=[O:16])[C:9]3=[CH:8][N:7]=2)=[CH:38][CH:37]=1)[CH3:44]
Reactant: COc1ccc(Cn2c(=O)c3cnc(-n4ccnc4)nc3n(C(C)C)c2=O)cc1
Reactant: CCN(CC)CCOc1ccc(N)cc1
Agent: O=C1CCC(=O)O1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCN(CC)CCOc1ccc(Nc2ncc3c(=O)n(Cc4ccc(OC)cc4)c(=O)n(C(C)C)c3n2)cc1
Temperature: 180 °C
Yield: 62.2 %

Procedure:
A mixture of 700 mg (1.78 mmol) of 7-(imidazol-1-yl)-1-isopropyl-3-(4-methoxybenzyl)-1H-pyrimido[4,5-d]pyrimidine-2,4-dione and 1.1 g (5.35 mmol) of 4-(2-diethylaminoethoxy)aniline is heated at 180° C. for 4 hours, then cooled. To the reaction mixture is added 357 mg (3.6 mmol) of succinic anhydride, 1 mL of chloroform, and 3 mL of dimethylformamide. The reaction mixture is heated at 50° C. for 2 hours, cooled, and diluted with chloroform. The mixture is washed with a saturated solution of sodium bicarbonate and brine. The organic phase is dried over magnesium sulfate, filtered, and concentrated. The residue is chromatographed on silica eluting with 5:95 methanol/chloroform to give a yellow solid which is crystallized from methanol/water to give 590 mg (61%) of the title compound: mp 139-141° C.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([C@H:15]1[CH2:19][O:18][C:17](=[O:20])[NH:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:21](Cl)(=[O:26])[CH2:22][CH:23]([CH3:25])[CH3:24]>CN(C)C1C=CN=CC=1.ClCCl>[CH2:8]([C@H:15]1[CH2:19][O:18][C:17](=[O:20])[N:16]1[C:21](=[O:26])[CH2:22][CH:23]([CH3:25])[CH3:24])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)CC(=O)Cl
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
4-Dimethylaminopyridine (2.55 g, 21.3 mmol) and triethylamine (46.9 ml, 340.8 mmol) in dichloromethane (100 ml) are added to a solution of (S)-(−)-4-benzyl-2-oxazolidinone (37.7 g, 213 mmol) in dichloromethane (300 ml). Next, isovaleroyl chloride (33.75 ml, 207 mmol) in dichloromethane (50 ml) is added to the previously prepared mixture and cooled to 0° C. keeping the internal temperature below 10° C. The reaction mixture is stirred for 30 minutes at 10° C., then the formed salts are filtered. Water (100 ml) is added and the phases are separated. The organic phase is washed with water (100 ml) and brine (100 ml), dried over sodium sulphate and evaporated to dryness obtaining 53 g of a yellow oil, which solidifies over time (yield 95%).
Reaction SMILES: CN(C)P(N(C)C)N(C)C.Br[C:12](Br)([F:14])[F:13].[CH3:16][C:17]([CH3:37])([CH2:20][O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[C:25]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:24]=1)[CH:18]=O.C(OCC)C>COCCOCCOCCOC>[CH3:16][C:17]([CH3:37])([CH:18]=[C:12]([F:14])[F:13])[CH2:20][O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[C:25]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:24]=1
Reactant: FC(F)(Br)Br
Reactant: CC(C)(C=O)COCc1ccc(F)c(Oc2ccccc2)c1
Agent: CN(C)P(N(C)C)N(C)C
Solvent: COCCOCCOCCOC
Solvent: CCOCC
Product: CC(C)(C=C(F)F)COCc1ccc(F)c(Oc2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 13.5 %

Procedure:
Hexamethylphosphorous triamide (0.65 g) was added portionwise to a stirred solution of dibromodifluoromethane (0.42 g) in triglyme (3 cm3) whilst being maintained at 0° C. under an atmosphere of nitrogen. After a period of 10 minutes a pale yellow colouration was observed and a solution of 2,2-dimethyl-3-(4-fluoro-3-phenoxybenzyloxy)propan-1-al (0.3 g) in triglyme (2 cm3) was added. After stirring for a further two hours, whilst being maintained at 0° C., the reaction mixture was allowed to warm to the ambient temperature. When GLC examination of a worked-up portion of the reaction mixture showed an absence of further reaction, the reaction mixture was poured into diethylether and sequentially washed with water and brine. The solvent was removed by evaporation under reduced pressure to give a pale yellow liquid which was subjected to short-path distillation (boiling point 75° C./0.01 mm Hg). The residue was then subjected to column chromatography on silica gel using petroleum ether (boiling range 40°-60° C.) containing 5% by volume diethyl ether as eluent to give 2,2-dimethyl-1-(4-fluoro-3-phenoxybenzyloxy)-4,4-difluorobut-3-ene (0.045 g).