Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14](Br)[C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:27])[N:22]([CH2:24][CH2:25][OH:26])[CH3:23])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][C:37]=2B(O)O)[CH:32]=[CH:31][CH:30]=1.C([O-])([O-])=O.[K+].[K+]>CC(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14]([C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:27])[N:22]([CH2:24][CH2:25][OH:26])[CH3:23])=[CH:17][CH:16]=2)[C:37]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:38]=2[N:29]=[CH:30][CH:31]=[CH:32]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1cccc2cccnc12
Reactant: CN(CCO)C(=O)c1ccc(C(Br)=C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: CN(CCO)C(=O)c1ccc(C(=C2CCN(C(=O)OC(C)(C)C)CC2)c2cccc3cccnc23)cc1
Yield: 108.6 %

Procedure:
Compound 1A (4.0 g, 8.8 mmol), 8-quinolineboronic acid (3.0 g, 17 6 mmol), POPd (0.088 g, 0.18 mmol), and K2CO3 (3.6 g, 26 4 mmol) in iPrOH (90 mL) were stirred in a preheated 100° C. oil bath under nitrogen for 20 h. The reaction was filtered through celite and concentrated. The material was purified by chromatography on silica gel (gradient 2-5% MeOH in CH2Cl2) to give a yellow solid 1B (3.27 g, 74%). 1H NMR (500.333 MHz, CDCl3) δ 8.91 (dd, J=4.0, 1.6 Hz, 1H), 8.13 (dd, J=8.2, 1.5 Hz, 1H), 7.74 (dt, J=9.5, 3.5 Hz, 1H), 7.50 (d, J=2.5 Hz, 2H), 7.37-7.33 (m, 5H), 3.86 (br s, 2H), 3.68 (br s, 2H), 3.59 (br s, 2H), 3.52-3.43 (m, 3H), 3.34-3.23 (m, 2H), 3.03 (s, 3H), 2.57-2.52 (m, 2H), 2.01 (dd, J=19.3, 7.6 Hz, 2H), 1.44 (s, 9H). MS ES+ 502.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.[CH3:19][C:20]1[C:24]([C:25]([N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)=[O:26])=[C:23]([CH3:34])[NH:22][C:21]=1[CH:35]=O>C(O)C.N1CCCCC1>[CH3:19][C:20]1[C:24]([C:25]([N:27]2[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]2)=[O:26])=[C:23]([CH3:34])[NH:22][C:21]=1[CH:35]=[C:11]1[C:10]2[C:14](=[CH:15][CH:16]=[CH:17][C:9]=2[C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[NH:13][C:12]1=[O:18]
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1CCN(C)CC1
Reactant: COc1cccc(-c2cccc3c2CC(=O)N3)c1
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1cccc(-c2cccc3c2C(=Cc2[nH]c(C)c(C(=O)N4CCN(C)CC4)c2C)C(=O)N3)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 52.7 %

Procedure:
To a solution of 4-(3-methoxy-phenyl)-1,3-dihydro indol-2-one (59.8 mg, 0.25 mmol) and 3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.25 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. The reaction solution was evaporated, and purified on a silica gel column eluting with MeOH—CH2Cl2 5:95 to provide 3-[3,5-dimethyl 4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one as a yellow solid (62 mg, 53%)
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]#[N:5].C(N(CC)CC)C.[N+:13]([C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1)([O-:15])=[O:14]>C(Cl)(Cl)Cl>[C:4]([CH2:3][NH:2][C:20](=[O:21])[C:19]1[CH:18]=[CH:17][C:16]([N+:13]([O-:15])=[O:14])=[CH:24][CH:23]=1)#[N:5]
Reactant: N#CCN
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: N#CCNC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.7 %

Procedure:
To a stirred mixture of 9.3 g (0.1 mole) aminoacetonitrile hydrochloride in 200 ml chloroform, 20.2 g (0.2 moles) triethylamine were added at once. After stirring one hour, 18.6 g (0.1 mole) p-nitrobenzoyl chloride were added in portions over about 15 minutes. The reaction mixture was stirred about 11/2 hours. Ice water, 100 ml, was added, resulting in separation of solids. The reaction mixture was allowed to stand in an ice bath for 30 minutes and then was filtered. The solids were air dried, washed with 200 ml water and then filtered to give yellow solids. The solids were dried in a vacuum oven at 50° C. until constant weight was attained, yielding 18.0 g of the above-identified product as a light yellow solid, melting point 147° C. to 149° C.
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([CH:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:18])[CH:14]=2)[C:9]21[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:5]=CC>ClCCl.CO>[O:1]=[CH:5][CH2:4][CH:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:18])[CH:14]=2)[C:9]21[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2
Reactant: CC=CCC1C(=O)c2cc(C)ccc2C12CCCCC2
Reactant: O=[O+][O-]
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc2c(c1)C(=O)C(CC=O)C21CCCCC1
Reaction time: 1.25 h
Yield: 97 %

Procedure:
An ozone stream (3 g ozone/hour) was conducted for 75 minutes while stirring through a solution, cooled to -70°, of 18.4 g of (RS)-2'-(2-buten-1-yl)-5'-methyl-2',3'-dihydro-spiro[cyclohexane-1,1'-[1H]indene]-3'-one in 300 ml of anhydrous dichloromethane and 60 ml of anhydrous methanol. Subsequently, the solution was flushed with oxygen for 5 minutes and with argon for 10 minutes. After the addition of 7.55 ml of dimethyl sulfide, the mixture was stirred at room temperature for 16 hours. The reaction mixture was evaporated in a vacuum, the residue was treated with 200 ml of dichoromethane and, after the addition of 30 ml of water and 30 ml of trifluoroacetic acid, stirred at room temperature for 3 hours. The mixture was subsequently poured into 200 ml of water and neutralized by the spatula-wise addition of sodium hydrogen carbonate while stirring. An additional 50 ml of water were added, the phases were separated and the aqueous phase was extracted twice with 150 ml of dichloromethane each time. The combined organic phases were dried over magnesium sulfate and concentrated in a vacuum. 17.0 g (97%) of (RS)-2'-(2-oxoethyl)-5'-methyl-2',3'-dihydro-spiro[cyclohexane-1,1'-[1H]indene]-3'-one were obtained as a yellow oil.
Reaction SMILES: [CH:1]([S:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH:15]=O)[CH:13]=2)[N:8]=[CH:7][C:6]=1[C:17]#[N:18])([CH3:3])[CH3:2].COC1C=CC(/C=[C:34]2/[C:35]([NH:37][C:38]([S:40]/2)=[NH:39])=[O:36])=CC=1OC1CCCC1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[NH2:39][C:38]1[S:40]/[C:34](=[CH:15]\[C:12]2[CH:13]=[C:14]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:17]#[N:18])=[C:5]3[S:4][CH:1]([CH3:3])[CH3:2])/[C:35](=[O:36])[N:37]=1
Reactant: CC(C)Sc1c(C#N)cnc2ccc(C=O)cc12
Reactant: COc1ccc(/C=C2\SC(=N)NC2=O)cc1OC1CCCC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)Sc1c(C#N)cnc2ccc(/C=C3\SC(N)=NC3=O)cc12

Procedure:
Similar procedure as described in example 38 was used, starting from 4-isopropylsulfanyl-6-formyl-quinoline-3-carbonitrile (example 40b), pseudothiohydantoin, sodium acetate and acetic acid to give 6-[2-amino-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-4-isopropylsulfanyl-quinoline-3-carbonitrile. LC-MS m/e 355 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C:10](OC(=O)C)(=[O:12])[CH3:11]>N1C=CC=CC=1>[C:10]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: O=Cc1ccc(O)cc1
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(C=O)cc1

Procedure:
4-Hydroxybenzaldehyde was acetylated with pyridine and acetic anhydride as in Example 12 to give 4-acetoxybenzaldehyde which was subjected to dehydration condensation with ethylene glycol to give 2-(4-acetoxyphenyl)-1,3-dioxolan. To a solution of 2-4-acetoxyphenyl)-1,3-dioxolan (13 g) in dichloromethane, bis(trimethylsilyl)-5-fluorouracil prepared as in Example 1 from 5-fluorouracil (10 g) was added followed by treating as in Example 10 to give 4.5 g of crystalline 1-[α-(2-hydroxyethoxy)-4-acetoxybenzyl]-5-fluorouracil.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([CH:12]=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([Mg]Br)[CH:19]=[C:20]([O:24][CH3:25])[C:21]=1[O:22][CH3:23]>C1COCC1>[C:1]1([C:7]2[O:11][N:10]=[C:9]([CH:12]([C:18]3[CH:19]=[C:20]([O:24][CH3:25])[C:21]([O:22][CH3:23])=[C:16]([O:15][CH3:14])[CH:17]=3)[OH:13])[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1cc([Mg]Br)cc(OC)c1OC
Reactant: O=Cc1cc(-c2ccccc2)on1
Solvent: C1CCOC1
Product: COc1cc(C(O)c2cc(-c3ccccc3)on2)cc(OC)c1OC
Reaction time: 0.5 h

Procedure:
To a solution of 5-phenylisoxazole-3-carbaldehyde 38i (0.365 g, 2.1 mmol) in 15 mL THF was added a THF solution of 3,4,5-trimethoxyphenylmagnesiumbromide (0.5 N, 5.5 mL, 2.74 mmol) at 0° C. The mixture was allowed to stir for 30 min and quenched with satd. NH4Cl, extracted with ethyl ether, dried with MgSO4. The solvent was removed under reduced pressure to yield a crude product, which was purified by column chromatography to obtain pure compound 40i as a white solid. (48.8%). 1H NMR (CDCl3) δ 7.78-7.77 (m, 2H), 7.48-7.46 (m, 3H), 6.74 (s, 2H), 6.45 (s, 1H), 5.98 (d, 1H, J=3.5 Hz) 3.89 (s, 6H), 3.86 (s, 3H), 2.77 (d, 1H, J=3.5 Hz); MS (ESI) m/z 364.1 (M+Na)+.
Reaction SMILES: CN1CCOCC1.[C:8]([O:12][C:13]([NH:15][CH:16]([CH3:20])[C:17]([OH:19])=O)=[O:14])([CH3:11])([CH3:10])[CH3:9].ClC(OCC(C)C)=O.S(C1C=CC(C)=CC=1)(O)(=O)=O.[NH2:40][CH:41]([C:47](=[O:49])[CH3:48])[C:42]([O:44][CH2:45][CH3:46])=[O:43]>C1COCC1>[C:8]([O:12][C:13]([NH:15][CH:16]([CH3:20])[C:17]([NH:40][CH:41]([C:47](=[O:49])[CH3:48])[C:42]([O:44][CH2:45][CH3:46])=[O:43])=[O:19])=[O:14])([CH3:9])([CH3:10])[CH3:11]
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCOC(=O)C(N)C(C)=O
Agent: CC(C)COC(=O)Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CCOC(=O)C(NC(=O)C(C)NC(=O)OC(C)(C)C)C(C)=O
Temperature: -25 °C
Reaction time: 0.5 h
Yield: 68.7 %

Procedure:
A solution of 4-methylmorpholine (900 g) in THF (15 L) was added to 2-(tert-butoxycarbonylamino)propanoic acid (1690 g, 8933.17 mmol). The mixture was cooled to −25° C. and isobutyl chloroformate (1.164 L, 8933.17 mmol) was added. After 20 minutes the second equivalent of 4-methylmorpholine (900 g) was added followed by ethyl 2-amino-3-oxobutanoate Tosylate salt (see J-P. Genet et al, Eur. J. Org. Chem., 2004, 3017-3026) (2700 g, 8507.78 mmol) suspended in THF (2.5 L). The mixture was stirred at −25° C. for 30 minutes and then left to warm to ambient temperature overnight. The reaction was quenched with water (15 L), extracted with EtOAc (3×5 L) and the combined extracts washed with 50% saturated brine (5 L). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 50 to 80% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford ethyl 2-(2-(tert-butoxycarbonylamino)propanamido)-3-oxobutanoate (1850 g, 68.7%).
Reaction SMILES: Cl.CO[C:4](=[NH:14])[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1.[C:15]([O:19][C:20]([NH:22][NH2:23])=[O:21])([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C>C(O)C>[C:15]([O:19][C:20]([NH:22][NH:23][C:4](=[NH:14])[C:5]1[CH:6]=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: COC(=N)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)NN
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NNC(=N)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
To a stirred solution of 4-nitro-benzimidic acid methyl ester hydrochloride (500 mg, 2.31 mmol) in ethanol (8 mL), hydrazinecarboxylic acid tert-butyl ester (305 mg, 2.31 mmol) was added followed by triethylamine. The mixture was stirred at rt over night. The solvent was removed and the residue was suspended in methylene chloride (10 mL). The mixture was filtered and the filtrate was concentrated to about 4 mL and loaded on a 20 g silica gel column. Eluting with 40-90% EtOAc/Hexanes on an ISCO machine gave a yellow solid. 410 mg. Which was directly used for the next step.
Reaction SMILES: C(O)(=O)/C=C\C(O)=O.[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:18]2([CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)[CH2:17]1.C(=O)([O-])[O-].[K+].[K+].[N:37]#CBr>C(Cl)(Cl)Cl>[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:18]2([CH2:23][CH2:22][N:21]([C:24]#[N:37])[CH2:20][CH2:19]2)[CH2:17]1
Reactant: N#CBr
Reactant: CN1CCC2(CC1)CN(c1ccccc1Cl)c1ccccc12
Agent: O=C(O)/C=C\C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: N#CN1CCC2(CC1)CN(c1ccccc1Cl)c1ccccc12
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To 1.0 g of 1-(2-chlorophenyl)-1'-methylspiro[indoline-3,4'-piperidine] of Example 17 in 16 ml of dry chloroform is added 2.4 g of anhydrous potassium carbonate and 0.73 g of cyanogen bromide. The reaction is stirred 7 hours at room temperature and then is filtered through paper. Approximately one ml of methanol is added and the solution is rotary evaporated to a glass. The glass is chromatographed on 80 cc of silica gel with 1:1, ether:dichloromethane to give a crystalline solid. The solid is recrystallized thrice from acetone-hexane to give a solid of 1-(2-chlorophenyl)-1'-cyanospiro(indoline3,4'-piperidine), mp 157.5°-159.5° C.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:21]1[CH:25]=[CH:24][CH2:23][CH2:22]1>N1C=CC=CC=1>[O:21]1[CH2:25][CH2:24][CH2:23][CH:22]1[N:6]1[CH:7]=[C:2]([F:1])[C:3](=[O:9])[NH:4][C:5]1=[O:8]
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Reactant: C1=COCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccncc1
Product: O=c1[nH]c(=O)n(C2CCCO2)cc1F

Procedure:
In 50 ml of pyridine were dissolved 2.5 g of 5-fluorouracil and 0.4 g of p-toluenesulfonic acid. To this solution were added 1.5 ml of 2,3-dihydrofuran and the mixture was reacted for 6 hours at 120° C. in an oil bath. Further, 3 ml of 2,3-dihydrofuran in 4 portions were added and the mixture was reacted for 15 hours. After completion of the reaction, pyridine was removed from the reaction liquid by distillation and the residue was dissolved in 100 ml of chloroform and filtered to separate insoluble matters. The filtrate was washed with water, dried and concentrated by removing chloroform by distillation. The precipitated crystals were collected by filtration, washed with a small amount of ether and dried to obtain 2.0 g of 1-(2-tetrahydrofuryl)-5-fluorouracil. The crystals had a melting point of 167°-168° C. and were identical in IR-absorption spectra with the standard sample.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][C:7]([C@@:11]([C@@H:14]3[C@@H:19]([CH3:20])[CH2:18][CH2:17][CH2:16][C:15]3([CH3:22])[CH3:21])([OH:13])[CH3:12])=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.C(N(CC)CC)C.[N:30]([Si](C)(C)C)=[C:31]=[O:32]>ClCCl>[OH:13][C@@:11]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[CH2:1][N:2]([C:31]([NH2:30])=[O:32])[CH2:3][CH2:4]2)([C@@H:14]1[C@@H:19]([CH3:20])[CH2:18][CH2:17][CH2:16][C:15]1([CH3:21])[CH3:22])[CH3:12]
Reactant: C[C@H]1CCCC(C)(C)[C@@H]1[C@@](C)(O)c1ccc2c(c1)CCNC2
Reactant: C[Si](C)(C)N=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H]1CCCC(C)(C)[C@@H]1[C@@](C)(O)c1ccc2c(c1)CCN(C(N)=O)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.5 %

Procedure:
To a solution of compound of the crude product of Example 13c (28 mg, 0.1 mmol) in dichloromethane (2 mL) was added triethylamine (55 mg, 0.5 mmol) and isocyanatotrimethylsilane (47 mg, 0.4 mmol). The reaction was stirred at room temperature overnight. The mixture was diluted with dichloromethane and washed with water, saturated aqueous ammonium chloride, saturated aqueous sodium bicarbonate and brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the title compound as a yellow oil (15 mg). Mass spectrum (LC ESI +ve) m/z 345 (M+H+).
Reaction SMILES: [CH3:1][CH:2]1[CH2:13][CH:12]=[CH:11][CH2:10][CH2:9][CH:8]=[CH:7][CH2:6][CH:5]([CH:14]([CH:16]=[CH:17][CH3:18])[CH3:15])[N:4]=[CH:3]1.S(O)(O)(=O)=O.[NH2:24][OH:25].Cl>O>[CH3:1][CH:2]([CH2:13][CH:12]=[CH:11][CH2:10][CH2:9][CH:8]=[CH:7][CH2:6][CH:5]([CH:14]([CH:16]=[CH:17][CH3:18])[CH3:15])[NH2:4])[CH:3]=[N:24][OH:25]
Reactant: CC=CC(C)C1CC=CCCC=CCC(C)C=N1
Reactant: NO
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: CC=CC(C)C(N)CC=CCCC=CCC(C)C=NO
Yield: 195.2 %

Procedure:
The procedure described in Example (1b) is repeated, except that 122.7 g (0.5 mol) of 3-methyl-12-(3-penten-2-yl)-1-aza-1,5,9-cyclododecatriene, 41.1 g (0.25 mol) of hydroxylamine sulfate, 50 ml of concentrated hydrochloric acid and 250 ml of water are used. Working up yields 135.9 g (0.488 mol) of 2-methyl-11-(3-penten-2-yl)-11-amino-undeca-4,8-dienal oxime; yield 97.6% of theory. nD20 =1.5091.
Reaction SMILES: [N+](=C)=[N-].[CH3:4][O:5][C:6]1[C:7]([OH:17])=[C:8]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:9]([OH:11])=[O:10].[C:18](O)(=O)C>C(OCC)C>[CH3:4][O:5][C:6]1[C:7]([OH:17])=[C:8]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:9]([O:11][CH3:18])=[O:10]
Reactant: COc1ccc(C(=O)O)c(O)c1OC
Reactant: CC(=O)O
Agent: C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)c1ccc(OC)c(OC)c1O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94 %

Procedure:
A solution of diazomethane in diethyl ether (30 ml, 0.25M, 0.0075 mol) was added to a solution of 3,4-dimethoxy-2-hydroxybenzoic acid (1.5 g, 0.0075 mol) in diethyl ether (50 ml) and the reaction stirred at room temperature for 10 minutes. Glacial acetic acid was then added and stirring continued for a further 18 hours. The reaction mixture was concentrated under reduced pressure and the residue partitioned between dichloromethane (40 ml) and aqueous sodium hydrogen carbonate solution (40 ml). The aqueous phase was further extracted with dichloromethane (100 ml), the combined organic extracts dried (MgSO4), filtered and evaporated under reduced pressure to give the subtitle compound as a white crystalline solid (1.5 g, 94%). 1H-NMR (CDCl3): δ=3.82 (9H, m), 6.48 (1H, d), 7.58 (1H, d), 10.84 (1H, s).
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[O:6]=[CH:7][C@H:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9]>C1COCC1.C(OCC)(=O)C>[CH:1]1([CH:7]([OH:6])[C@H:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:15])([CH3:14])[CH3:16])[CH3:9])[CH2:3][CH2:2]1
Reactant: Br[Mg]C1CC1
Reactant: C[C@H](C=O)NC(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@@H](NC(=O)OC(C)(C)C)C(O)C1CC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 54.5 %

Procedure:
Cyclopropylmagnesium bromide (32 mL, 16.00 mmol) was added dropwise to a solution of (R)-tert-butyl 1-oxopropan-2-ylcarbamate (1.10 g, 6.35 mmol) in anhydrous THF (Volume: 25.4 mL) at −78° C. The reaction mixture was then allowed to warm to 0° C. and stirred at this temp for 4 hrs before quenching with sat. ammonium chloride solution. The evaporated organic was then purified by column chromatography using hexane:ethyl acetate as eluent to give tert-butyl (2R)-1-cyclopropyl-1-hydroxypropan-2-ylcarbamate (745 mg, 3.46 mmol, 54.5% yield). 1H NMR (500 MHz, CCl3D) δ 4.80 (br. s., 1H), 3.94-3.66 (m, 1H), 3.07-2.90 (m, 1H), 2.87-2.65 (m, 1H), 2.44-2.13 (m, 1H), 1.48-1.37 (m, 9H), 1.24-1.12 (m, 3H), 1.06-0.91 (m, 1H), 0.91-0.78 (m, 1H), 0.64-0.46 (m, 2H), 0.42-0.15 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:10][CH:9]([CH3:11])[O:8][C:7]([CH3:18])([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]=2[CH:19]=1.[C:20]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[C:26]([F:28])[CH:27]=1)#[N:21].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:11][C@H:9]1[O:8][C@@:7]([CH3:18])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]2[CH:19]=[C:2]([C:24]3[CH:23]=[C:22]([CH:27]=[C:26]([F:28])[CH:25]=3)[C:20]#[N:21])[CH:3]=[CH:4][C:5]=2[NH:10]1
Reactant: N#Cc1cc(F)cc(B(O)O)c1
Reactant: CC1Nc2ccc(Br)cc2C(C)(c2ccccc2)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: C[C@@H]1Nc2ccc(-c3cc(F)cc(C#N)c3)cc2[C@](C)(c2ccccc2)O1
Temperature: 85 °C
Yield: 13.2 %

Procedure:
A mixture of 6-bromo-2,4-dimethyl-4-phenyl-1,4-dihydro-2H-3,1-benzoxazine (0.6 g, 1.9 mmol), 3-cyano-5-fluorobenzene boronic acid (0.45 g, 2.7 mmol), tetrakis(triphenylphosphine)palladium(0) (0.2 g, 0.17 mmol), sodium carbonate (0.6 g, 5.7 mmol) in a mixture of DME and water (20/5 mL) was subject to a positive nitrogen flow to remove oxygen and then heated to 85° C. under a blanket of nitrogen for 2 hours. The mixture was allowed to cool to ambient temperature. Brine (30 mL) and ethyl acetate (100 mL) were added. The organic layer was separated and aqueous layer was extracted with ethyl acetate (3×30 mL). The combined organic layers were dried (MgSO4), and evaporated. The residue was purified by a silica gel column chromatography (hexane:ethyl acetate/4:1) to afford the title compound as off-white solid (0.09 g, 13%): mp 128-129° C.; 1H-NMR (DMSO-d6) δ 8.08 (s, 1H), 7.91 (dt, 1H, J=10.7, 1.9 Hz), 7.71 (d, 1H, J=2.0 Hz), 7.65 (m, 1H), 7.57 (dd, 1H, J=8.8, 2.4 Hz), 7.32-7.36 (m, 2H), 7.24-7.29 (m, 3H), 6.71 (d, 1H, J=1.6 Hz), 6.69 (d, 1H, J=8.3 Hz), 4.33 (m, 1H), 1.84 (s, 3H), 1.24 (d, 3H, J=5.5 Hz); MS (ESI) m/z 357 [M−H]−.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH:4]([NH:24][CH:25]=[O:26])[CH:5](O)[C:6](=[CH2:22])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].C=CCCC=C.S(Br)([Br:36])=O>O1CCCC1>[CH3:1][O:2][C:3](=[O:27])[CH:4]([NH:24][CH:25]=[O:26])[CH:5]=[C:6]([CH2:22][Br:36])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]
Reactant: O=S(Br)Br
Reactant: C=C(CCCCNC(=O)OCc1ccccc1)C(O)C(NC=O)C(=O)OC
Agent: C=CCCC=C
Solvent: C1CCOC1
Product: COC(=O)C(C=C(CBr)CCCCNC(=O)OCc1ccccc1)NC=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To 2.46 g (6.5 mmol) of 8-(N-benzyloxycarbonylamino)-2-formylamino-3-hydroxy-4-methylene-octanoic acid methyl ester in 25 ml of tetrahydrofuran there are added 5.5 ml (46 mmol) of hexa-1,5-diene and then, dropwise at -50°, 2.6 ml (32.5 mmol) of thionyl bromide. The mixture is stirred at from 0° to 5° for 2 hours, poured into 25 ml of ice-cold saturated sodium hydrogen carbonate solution and extracted twice with 20 ml of methylene chloride each time. The organic phase is washed with 10 ml of saturated sodium chloride solution, dried over magnesium sulfate and concentrated to dryness by evaporation. The resulting oil is purified by chromatography on silica gel with hexane/ethyl acetate (3:1). 8-(N-benzyloxycarbonylamino)-4-bromomethyl-2-formylamino-oct-3-enoic acid methyl ester is obtained.