Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:18])[CH:3]([PH:15](=[O:17])[OH:16])[NH:4][C:5](=[O:14])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C[Si](C)(C)N[Si](C)(C)C.[CH2:28]([O:35][C:36]([NH:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43](=[CH2:49])[C:44]([O:46][CH2:47][CH3:48])=[O:45])=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([O:35][C:36]([NH:38][CH2:39][CH2:40][CH2:41][CH2:42][CH:43]([CH2:49][P:15]([CH:3]([NH:4][C:5](=[O:14])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:2]([CH3:18])[CH3:1])([OH:16])=[O:17])[C:44]([O:46][CH2:47][CH3:48])=[O:45])=[O:37])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CC(C)C(NC(=O)CCc1ccccc1)[PH](=O)O
Reactant: C=C(CCCCNC(=O)OCc1ccccc1)C(=O)OCC
Agent: C[Si](C)(C)N[Si](C)(C)C
Product: CCOC(=O)C(CCCCNC(=O)OCc1ccccc1)CP(=O)(O)C(NC(=O)CCc1ccccc1)C(C)C
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 40.8 %

Procedure:
The 2-methyl-1-(3-phenylpropanoyl)aminopropylphosphinic acid (255 mg) obtained in (a) of Example 2 was added with hexamethyldisilazane (0.3 ml), and the mixture was stirred at 110° C. for 30 minutes. The mixture was then added with the ethyl 2-(4-benzyloxycarbonylaminobutyl)acrylate (356 mg) obtained in the above step (e), and further stirred at the same temperature for 18 hours. The organic substances were extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and then the residue was purified by Sephadex LH-20 (300 cc, methylene chloride:methanol=1:1) to obtain crude ethyl 6-benzyloxycarbonylamino-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)hydroxyphosphinoyl)methylhexanoate (222 mg, 41%). This compound was used in the following reaction without further purification. (g) The crude ethyl 6-benzyloxycarbonylamino-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)hydroxyphosphinoyl)methylhexanoate (222 mg) obtained in the above step (f) was dissolved in a mixed solvent of ethanol:water (10:7) (3.4 ml). The mixture was added with 1 N aqueous sodium hydroxide (0.6 ml) and stirred at room temperature for 3 hours, at 50° C. for 2 hours, and then at room temperature for 16 hours. The reaction mixture was acidified with hydrochloric acid and the organic substances were extracted with ethyl acetate, and then the extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue was concentrated to obtain crude 6-benzyloxycarbonylamino-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)hydroxyphosphinoyl)methylhexanoic acid (181 mg, 86%). This compound was subjected to the measurement of molecular weight and then used in the following reaction without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([NH:9][CH2:10][CH2:11][N:12]2[C:17](=[O:18])[CH:16]=[CH:15][C:14]([C:19]([OH:21])=[O:20])=[CH:13]2)=[O:8])[CH:2]=1.S(Cl)(Cl)=O.N1C=C[CH:29]=[CH:28][CH:27]=1>>[CH3:27][CH:28]([O:20][C:19]([C:14]1[CH:15]=[CH:16][C:17](=[O:18])[N:12]([CH2:11][CH2:10][NH:9][C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[O:8])[CH:13]=1)=[O:21])[CH3:29]
Reactant: O=C(O)c1ccc(=O)n(CCNC(=O)c2cccnc2)c1
Reactant: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CC(C)OC(=O)c1ccc(=O)n(CCNC(=O)c2cccnc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a 25 ml round bottomed flask fitted with a magnetic stirrer bar, reflux condensor, and nitrogen inlet was added 1,6-dihydro-l-[2-(3-pyridinylcarbonylamino)ethyl]-6-oxo-3-pyridinecarboxylicacid (0.20 g, 0.70 mmol) and thionyl chloride (5.0 ml). The mixture was heated at reflux for 2 hours, cooled to room temperature, and concentrated. The residue was suspended in 2-propanol (5.0 ml) and 4-dimethylaminopyridine (1 mg). Pyridine (0.17 ml, 2.1 mmol) was added with stirring at room temperature. After 16 hours, the reaction mixture was concentrated. Purification via flash column chromotography (silica gel, 5% methanol/dichloromethane) and repurification via medium pressure liquid chromotography (silica gel, 5% methanol/dichloromethane) gave the desired product, MP: 160°-161 ° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:12])[C:5]([N:9]=[C:10]=[O:11])=[C:6]([F:8])[CH:7]=1.[CH:13]1([C:16]([N:18]2[CH2:22][CH2:21][C@@H:20]([CH2:23][C:24]([NH:26][NH2:27])=[O:25])[CH2:19]2)=[O:17])[CH2:15][CH2:14]1>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([F:12])[C:5]([NH:9][C:10]([NH:27][NH:26][C:24](=[O:25])[CH2:23][C@@H:20]2[CH2:21][CH2:22][N:18]([C:16]([CH:13]3[CH2:15][CH2:14]3)=[O:17])[CH2:19]2)=[O:11])=[C:6]([F:8])[CH:7]=1
Reactant: O=C=Nc1c(F)cc(Br)cc1F
Reactant: NNC(=O)C[C@@H]1CCN(C(=O)C2CC2)C1
Solvent: ClCCl
Product: O=C(C[C@@H]1CCN(C(=O)C2CC2)C1)NNC(=O)Nc1c(F)cc(Br)cc1F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
In a round-bottom flask, 5-bromo-1,3-difluoro-2-isocyanatobenzene (1550 mg, 6.62 mmol) was dissolved in dichloromethane (10 mL) under nitrogen and cooled to −78° C. In a separate vial, 2-[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]acetohydrazide (1357 mg, 6.42 mmol) was dissolved in 10 mL of dichloromethane and then added to the cooled solution. The resultant reaction mixture was allowed to warm to room temperature and stirred for 1 h. A precipitate began to form and analysis by LCMS indicated formation of the desired product. The precipitated product was collected under vacuum filtration and washed with dichloromethane to afford the title product as a white solid (2850 mg, 99%). MS(ES)+ m/e 445.2, 447.1 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:39][S:40]([CH2:43][CH:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)(=[O:42])=[O:41]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:47]3[CH2:48][CH2:49][CH:44]([CH2:43][S:40]([CH3:39])(=[O:42])=[O:41])[CH2:45][CH2:46]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CS(=O)(=O)CC1CCNCC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CS(C)(=O)=O)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with 4-methanesulfonylmethyl-piperidine hydrochloride to give the title compound. HR-MS (ES, m/z) calculated for C36H45N4O4SCl2 [(M+H)+] 699.2533, observed 699.2533.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([Cl:37])[CH:31]=2)[CH:7]=[C:8]2[C:16]=1[NH:15][C:14]1[CH:13]=[C:12]([N:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)[CH:11]=[CH:10][C:9]2=1)(=[O:3])[NH2:2].C([O-])([O-])=O.[K+].[K+].[Br:44][CH2:45][CH2:46]Br.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[Br:44][CH2:45][CH2:46][O:36][C:33]1[CH:34]=[CH:35][C:30]([C:6]2[CH:7]=[C:8]3[C:16](=[C:4]([C:1](=[O:3])[NH2:2])[CH:5]=2)[NH:15][C:14]2[CH:13]=[C:12]([N:17]4[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:22]4)[CH:11]=[CH:10][C:9]3=2)=[CH:31][C:32]=1[Cl:37]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3c(c2)[nH]c2c(C(N)=O)cc(-c4ccc(O)c(Cl)c4)cc23)CC1
Reactant: BrCCBr
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3c(c2)[nH]c2c(C(N)=O)cc(-c4ccc(OCCBr)c(Cl)c4)cc23)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 155.6 %

Procedure:
A 100 ml round bottom flask was loaded with tert-butyl 4-(8-carbamoyl-6-(3-chloro-4-hydroxyphenyl)-9H-carbazol-2-yl)piperazine-1-carboxylate (estimated purity ˜50%, 365 mg, ˜0.35 mmol, Example 409B), K2CO3 (1.12 g, 8.10 mmol), DMF (20 ml) and 1,2-dibromoethane (0.64 ml, 7.4 mmol) and stirred at room temperature for 17 hours. The reaction mixture was poured into a separating funnel that was loaded with 500 ml water+citric acid (0.5 M solution in water) (60 ml, 30 mmol) and extracted with ethyl acetate. The organic layer was washed with dilute (1+5) aq. NaHCO3 solution, then brine, dried over MgSO4, filtered and evaporated to dryness to give 342 mg tert-butyl 4-(6-(4-(2-bromoethoxy)-3-chlorophenyl)-8-carbamoyl-9H-carbazol-2-yl)piperazine-1-carboxylate, which was used without further purification. Estimated purity (from LCMS) ˜55%. MS (ESI) m/e+=627/629/631, m/e−=625/627/629 consistent with isotope pattern for 1 Br and 1 Cl.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][C@@H:8]([OH:11])[CH2:9]O)=[CH:4][CH:3]=1.CC(C)(C)[O-].[K+]>O1CCCC1>[F:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][C@H:8]2[CH2:9][O:11]2)=[CH:4][CH:3]=1
Reactant: OC[C@H](O)COc1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Fc1ccc(OC[C@H]2CO2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.3 %

Procedure:
To a stirred mixture of 13.4 parts of (+)-(S)-3-(4-fluorophenoxy)-1,2-propanediol, O1 -4-methylbenzenesulfonate and 45 parts of tetrahydrofuran were added 4.9 parts of kalium 1,1-dimethyl ethoxide. The whole was stirred for 30 minutes at room temperature. It was filtered over Hyflo, washed with tetrahydrofuran and the filtrate was evaporated. The residue was distilled, yielding 3.8 parts (57.3%) of (-)-(R)-[(4-fluorophenoxy)methyl]oxirane; bp. 54° C. at 66.5 Pa; [α]D =-4.08 (c=0.5% in trichloromethane) (148).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=1[CH2:10][CH2:11][C:12](O)=[O:13].[H]1[BH2][H][BH2]1.O>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=1[CH2:10][CH2:11][CH2:12][OH:13]
Reactant: N#Cc1ccc(CCC(=O)O)c(Cl)c1
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(CCCO)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3-(2-chloro-4-cyanophenyl)-propanoic acid (14.3 g, 0.068 mol) in 70 mL of dry THF at -18° C. was added B2H6 (72 ml, 0.068 mol) in THF. The mixture was stirred at room temperature overnight. After addition of water, the layers were separated and the aqueous phase was extracted with ether. Evaporation and distillation gave 3-(2-chloro-4-cyanophenyl)propanol as an oil: 11.0 g; bp 55°-60° C. (0.005 mm Hg). Anal. calcd for C10H10ClNO: C, 61.39; H, 5.15; N, 7.16. Found: C, 61.02; H, 5.19; N, 6.76.
Reaction SMILES: C([O:3][C:4]([CH2:6][N:7]1[CH2:12][CH2:11][CH:10]([N:13]2[CH:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][C:14]2=[O:29])[CH2:9][CH2:8]1)=O)C.[NH3:30].CO>>[C:4]([CH2:6][N:7]1[CH2:8][CH2:9][CH:10]([N:13]2[CH:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][C:14]2=[O:29])[CH2:11][CH2:12]1)(=[O:3])[NH2:30]
Reactant: CCOC(=O)CN1CCC(N2C(=O)Nc3ccccc3C2c2ccccc2)CC1
Reactant: N
Solvent: CO
Product: NC(=O)CN1CCC(N2C(=O)Nc3ccccc3C2c2ccccc2)CC1

Procedure:
A solution of 200 mg (0.508 mmol) of 3-(1-ethoxycarbonylmethylpiperidin-4-yl)-4-phenyl-3,4-dihydro -2(1H)-quinazolinone in ammonia/methanol (6.09M, 30 mL) was stirred in an autoclave for 6 hours at temperature of approximately 150° C. After being cooled, the reaction mixture was concentrated in vacuo, and the residue was purified by means of column chromatography (silica gel, 1:9 methanol:chloroform) to give 167 mg (0.45 mmol) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:3]=1[CH2:4][N:5]([CH3:7])[CH3:6].[Br:14]Br>C(Cl)Cl>[NH2:1][C:2]1[C:11]([Br:14])=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:3]=1[CH2:4][N:5]([CH3:7])[CH3:6]
Reactant: COc1ccc(N)c(CN(C)C)c1
Reactant: BrBr
Solvent: ClCCl
Product: COc1cc(Br)c(N)c(CN(C)C)c1

Procedure:
2-Amino-3-bromo-N,N-dimethyl-5-methoxy-benzylamine was prepared from 2-amino-N,N-dimethyl-5-methoxy-benzylamine and bromine analogous to Example 9. Proof of structure by IR-, UV- and NMR-spectra. IR-spectrum (methylenechloride): 3250 cm-1NH2 ; 3410 cm-1NH2 ; 2780 cm-1N(CH3)2 ; 2830 cm-1OCH3 ; 1590 cm-1C=C; 1600 cm-1C=C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.[NH2:10][CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13]>O1CCCC1>[Cl:9][C:4]1[CH:5]=[C:6]([Cl:8])[N:7]=[C:2]([NH:10][CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[N:3]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: CC(C)(C)CN
Solvent: C1CCOC1
Product: CC(C)(C)CNc1nc(Cl)cc(Cl)n1

Procedure:
After dropwise adding 25 g (136.3 mmoles) of 2,4,6-trichloropyrimidine to a solution of 23.84 g (273.5 mmoles) of 1-amino-2,2-dimethylpropane in 200 ml of tetrahydrofuran at a temperature between 10° and 15° C. while cooling under stirring, the reaction mixture is stirred at room temperature for 30 minutes, then evaporated. The residue is distributed between 300 ml of chloroform and 50 ml of 10% sodium hydroxide solution. After separation the organic phase is washed 4 times with 100 ml of water each, dried and evaporated. The residue is subjected to chromatography on a silica gel column by using mixtures of hexane/ethyl acetate elution. By eluting with a 19:1 mixture, 4,6-dichloro-2-(2,2-dimethylpropylamino) pyrimidine is obtained which is recrystallized from a mixture of ether and hexane to give a yield of 13.60 g (42.6%), m.p.:63°-66° C.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN(CC)CC.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[CH3:23][S:24]([O:15][CH2:14][CH:11]1[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Reaction time: 1.5 h
Yield: 102 %

Procedure:
A mixture of N-Boc-4-piperidinemethanol (1.0 g, 4.51 mmol), Et3N (1.30 mL, 9.01 mmol) in CH2Cl2 (20 mL) at 0° C. was treated dropwise with methanesulfonyl chloride (0.39 mL, 4.96 mmol). The reaction mixture was stirred at 0° C. to 5° C. for 1.5 h, was diluted with CH2Cl2 (100 mL) and washed with 1M NaH2PO4 (50 mL×2) and brine (25 mL). The CH2Cl2 layer was dried over Na2SO4, filtered, and the filtrate was concentrated to a brown oil, which solidified upon cooling to give 1.35 g (100%) of 1,1-dimethylethyl 4-{[(methylsulfonyl)oxy]methyl}-1-piperidinecarboxylate as a brown solid, which was used without further purification. 1H NMR (400 MHz, CDCl3): δ 4.20-4.10 (m, 2H), 4.04 (d, 2H, J=6.5 Hz), 2.99 (s, 3H), 2.75-2.60 (m, 2H), 1.95-1.85 (m, 1H), 1.75-1.65 (m, 2H), 1.43 (s, 9H), 1.30-1.10 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:5][CH:4]=1)#[N:2].[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Cl)=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][N:9]([N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)[C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[CH:18][CH:17]=1
Reactant: N#Cc1ccc(Nn2cncn2)cc1
Reactant: ClCc1ccc(Cl)cc1
Product: N#Cc1ccc(N(Cc2ccc(Cl)cc2)n2cncn2)cc1

Procedure:
Starting Compounds: 1-[N-(4-cyanophenyl)amino]-1H-1,2,4-triazole and 4-chlorobenzyl chloride
Reaction SMILES: ClCCl.[C:4]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29](O)=[O:30])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(OC(Cl)=O)C(C)C.[C:40](#[N:44])[CH2:41][C:42]#[N:43]>C(N(CC)CC)C>[C:4]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29](=[C:41]([C:40]#[N:44])[C:42]#[N:43])[OH:30])([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(O)CCCCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N#CCC#N
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#CC(C#N)=C(O)CCCCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 2 h
Yield: 87.3 %

Procedure:
To a dichloromethane solution of 6-(tritylamino)-caproic acid (20.0 g, 53 mmole) and triethylamine (20 mL) in an ice bath was added dropwise over 30 min isobutylchloroformate (8.3 mL, 64 mmole). After the mixture was stirred for 2 hr in an ice bath, freshly distilled malononitrile (4.2 g, 64 mmole) was added all at once. The solution was stirred for 2 hr in an ice bath and for 2 hr at RT. The dichloromethane solution was washed with ice cold 2N HCl (300 mL) and the biphasic mixture was filtered to remove product that precipitated (13.2 g). The phases were separated and the organic layer dried and evaporated to a thick syrup. The syrup was covered with dichloromethane and on standing deposited fine crystals of product. The crystals were filtered and dried to give 6.3 g for a total yield of 19.5 g (87%) of the product, which is useful as an intermediate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=[O:6].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[O:10][CH2:19][C:18]1[CH:21]=[CH:22][CH:23]=[C:16]([O:15][CH3:14])[CH:17]=1)[CH:5]=[O:6]
Reactant: COc1cccc(CO)c1
Reactant: O=Cc1cc(Br)c(O)c([N+](=O)[O-])c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cccc(COc2c(Br)cc(C=O)cc2[N+](=O)[O-])c1
Reaction time: 17 h

Procedure:
To a solution of 3-bromo-4-hydroxy-5-nitro-benzaldehyde (87.4 mg) in dry dichloromethane (7.5 ml) was added 3-methoxybenzyl alcohol (35 μl), triphenylphosphine (103 mg) and diethyl azodicarboxylate (45 μl). The mixture was stirred under a nitrogen atmosphere for 17 h and then concentrated in vacuo. The residue was purified by chromatography on silicagel in heptane/ethyl acetate 9/1→1/1 (v/v) as eluent.
Reaction SMILES: [F:1][C:2]1[CH:18]=[C:17]([CH:19]=[CH2:20])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:6]=[N:7][C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][CH:10]=1.B1C2CCCC1CCC2.[OH-:30].[Na+].OO>C1COCC1>[F:1][C:2]1[CH:18]=[C:17]([CH2:19][CH2:20][OH:30])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:10]=[N:9][C:8]([C:11]([F:12])([F:13])[F:14])=[N:7][CH:6]=1
Reactant: C=Cc1ccc(Oc2cnc(C(F)(F)F)nc2)c(F)c1
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: OCCc1ccc(Oc2cnc(C(F)(F)F)nc2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 131.6 %

Procedure:
To the solution of 5-(2-fluoro-4-vinylphenoxy)-2-(trifluoromethyl)pyrimidine (540 mg, 1.900 mmol) in dry THF (8 mL), was added 9-BBN (5.70 mL, 2.85 mmol) at 0° C. The mixture was stirred at room temperature overnight, and quenched with water (1 mL), followed by aq. NaOH (2.5 mL, 7.50 mmol), and 30% H2O2 (2.585 g, 22.80 mmol). The reaction mixture was heated at 50° C. for 3 h. Then THF was removed under reduced pressure, and the residue was diluted with EA. The organic layer was washed with water and brine, dried over anhydrous Na2SO4 and concentrated and purified by flash chromatography to afford the title compound (756 mg, 2.501 mmol, 132% yield) as a white oil. LCMS: rt=3.63 min, [M+H+]=285
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:14])[C:6](=[C:10]([O:12][CH3:13])[CH:11]=1)[C:7]([OH:9])=[O:8].[C:15](Cl)(Cl)=[O:16]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[NH:14][C:15](=[O:16])[O:9][C:7](=[O:8])[C:6]2=[C:10]([O:12][CH3:13])[CH:11]=1
Reactant: COc1cc(N)c(C(=O)O)c(OC)c1
Reactant: O=C(Cl)Cl
Product: COc1cc(OC)c2c(=O)oc(=O)[nH]c2c1

Procedure:
4,6-Dimethoxyisatoic anhydride is prepared from 4,6-dimethoxyanthranilic acid (H. Newman & R. Anzier, J. Org. Chem. 34, 3484 (1969)) and phosgene according to the method of E. C. Wagner and M. F. Fegley, Org. Synthesis 27, 45 (1947).
Reaction SMILES: [C:1]([Cu])#[N:2].[CH3:4][O:5][C:6]([C@H:8]1[N:12]2[C:13](=[O:35])[C:14](Br)=[C:15]([CH2:23][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=[CH:26][CH:25]=3)[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:11]2[S:10][CH2:9]1)=[O:7]>CN1C(=O)CCC1>[CH3:4][O:5][C:6]([C@H:8]1[N:12]2[C:13](=[O:35])[C:14]([C:1]#[N:2])=[C:15]([CH2:23][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=[CH:26][CH:25]=3)[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:11]2[S:10][CH2:9]1)=[O:7]
Reactant: COC(=O)[C@@H]1CSc2c(-c3ccccc3)c(Cc3cccc4ccccc34)c(Br)c(=O)n21
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Product: COC(=O)[C@@H]1CSc2c(-c3ccccc3)c(Cc3cccc4ccccc34)c(C#N)c(=O)n21
Temperature: 220 °C
Yield: 81 %

Procedure:
CuCN (120 mg, 1.3 mmol) was added to a stirred solution of 5a (150 mg, 0.30 mmol) in NMP (1.0 mL) at rt. The reaction mixture was heated at 220° C. for 20 min using microwave irradiation and the solvent was then removed by lyophilisation from deionised water. The residue was thoroughly extracted with CH2Cl2, dried and concentrated. Purification by silica gel chromatography (heptane:EtOAc, 1:1) gave 6a as a white foam (110 mg, 82%):[α]D−83 (c 1.0, CHCl3); IR λ 3012, 2956, 2217, 1751, 1654, 1486, 1442, 1369 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J=7.8, 1H), 7.70 (d, J=8.1, 1H), 7.62 (d, J=8.2, 1H), 7.47-7.29 (m, 3H), 7.19-6.92 (m, 5H), 6.87 (d, J=7.3, 1H), 5.79 (dd, J=8.9, 2.3, 1H), 4.41-4.27 (m, 2H), 3.89 (s, 3H), 3.75 (dd, J=11.9, 8.9, 1H), 3.52 (dd, J=11.9, 2.3, 1H); 13C NMR (100 MHz, CDCl3) δ 167.6, 160.7, 158.7, 155.2, 134.4, 133.6, 132.4, 131.4, 129.7, 129.2, 128.8 (broad and splitted), 128.6, 127.6, 126.1, 125.7, 125.3, 125.2, 122.7, 117.1, 115.2, 101.3, 64.4, 53.7, 35.3, 31.8; HRMS (EI+) calcd for C27H20N2O3S 452.1195, obsd 452.1192.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[CH2:3][CH:4]([OH:7])[CH2:5][OH:6].[S:9](Cl)([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10].CCN(CC)CC>C(Cl)Cl>[CH3:16][C:15]1[CH:17]=[CH:18][C:12]([S:9]([O:6][CH2:5][CH:4]([OH:7])[CH2:3][N:2]([CH3:8])[CH3:1])(=[O:11])=[O:10])=[CH:13][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CN(C)CC(O)CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC(O)CN(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-(dimethylamino)propane-1,2-diol (934 mg, 7.84 mmol) in CH2Cl2 (8 mL) were added Bu2SnO (42 mg, 0.16 mmol), tosyl chloride (1.49 g, 7.84 mmol), and Et3N (1.10 mL, 7.92 mmol). The reaction mixture was stirred at rt for 2 hrs. The mixture was quenched with water (30 mL) and extracted with EtOAc (two×30 mL). The combined organic layers were dried over MgSO4 and concentrated to afford 3-dimethylamino-2-hydroxypropyl 4-methylbenzenesulfonate; [m/z (APCI+) 274.10 (M+H)+]. The residue was dissolved in THF (10 mL), then DBU (2.56 mL, 16.6 mmol) and 4-nitro-1H-pyrazole (602 mg, 5.32 mmol) were added and the resulting mixture was stirred at rt for 30 min. The mixture was then quenched with water (30 mL) and extracted with EtOAc (two×30 mL). The combined organic layer were dried over MgSO4 and concentrated to give the title compound as a pale yellow oil (526 mg, 46° A yield) which was used without purification. m/z (APCI+) for C8H14N4O3 215.10 (M+H)+.