Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C@@H:11]([C:13]3[C:18]([O:19][CH:20]([F:22])[F:21])=[CH:17][CH:16]=[C:15]([F:23])[C:14]=3[Cl:24])[CH3:12])=[CH:9][N:8](C(OC(C)(C)C)=O)[C:5]2=[N:6][CH:7]=1.CC1(C)[O:37][C@@H:36]([CH2:38][N:39]2[C:43]([CH3:44])=[C:42](B3OC(C)(C)C(C)(C)O3)[CH:41]=[N:40]2)[CH2:35][O:34]1.C([O-])([O-])=O.[K+].[K+].O.[ClH:62].CCOCC>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.O1CCOCC1>[Cl:24][C:14]1[C:15]([F:23])=[CH:16][CH:17]=[C:18]([O:19][CH:20]([F:21])[F:22])[C:13]=1[C@H:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:42]3[CH:41]=[N:40][N:39]([CH2:38][C@H:36]([OH:37])[CH2:35][OH:34])[C:43]=3[CH3:44])[CH:3]=2)[NH:8][CH:9]=1)[CH3:12].[ClH:62]
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cnn1C[C@H]1COC(C)(C)O1
Reactant: C[C@H](c1c(OC(F)F)ccc(F)c1Cl)c1cn(C(=O)OC(C)(C)C)c2ncc(Br)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: O
Product: Cc1c(-c2cnc3[nH]cc([C@H](C)c4c(OC(F)F)ccc(F)c4Cl)c3c2)cnn1C[C@H](O)CO
Temperature: 25 °C

Procedure:
A mixture of tert-butyl 5-bromo-3-{(1S)-1-[2-chloro-6-(difluoromethoxy)-3-fluorophenyl]ethyl}-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (45.0 mg, 0.0866 mmol), 1-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (41.85 mg, 0.1299 mmol), Pd(PPh3)4 (5.002 mg, 0.004329 mmol), K2CO3 (35.90 mg, 0.2597 mmol) and 4:1 dioxane:H2O (2 mL, 20 mmol) was heated to 95° C. for 2 h. The solution was cooled to rt, and 12 M of HCl in H2O (0.072 mL, 0.87 mmol) was added. The material was concentrated in vacuo, and extracted with DCM and sat. NaHCO3. The organic layer was dry-loaded onto silica gel and purified via column chromatography, eluting with 2-4% (7N NH3 in MeOH)/DCM. The fractions containing the pure product were concentrated in vacuo, redissolved in MeOH, and 2.0 M of HCl in Et2O (0.4329 mL, 0.8658 mmol) was added at rt. The solution was concentrated in vacuo to afford the title compound as an HCl salt. 1H NMR (400 MHz, CD3OD): δ=1.85 (d, J=7.3 Hz, 3H), 2.27 (s, 3H), 3.50-3.63 (m, 2H), 4.00-4.09 (m, 1H), 4.15 (dd, J=14.1, 7.6 Hz, 1H), 4.25 (dd, J=14.3, 4.4 Hz, 1H), 5.12 (q, J=7.1 Hz, 1H), 6.44 (br. s., 1H), 7.14 (dd, J=8.7, 4.4 Hz, 1H), 7.20 (t, J=8.7 Hz, 1H), 7.35-7.45 (m, 2H), 7.52 (s, 1H), 8.16 (d, J=2.0 Hz, 1H). MS (ES+): m/z=494.99/496.98 (100/50) [MH+]. HPLC: tR=1.29 min (polar—3 min, UPLC-ACQUITY).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O)#[N:2].[CH3:11][O:12][CH:13]([O:21][CH3:22])[C:14](=[O:20])[CH2:15][C:16]([O:18][CH3:19])=[O:17].C(O)(=O)C.N1CCCCC1>C1C=CC=CC=1>[C:1]([C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[C:15]([C:14]([CH:13]([O:12][CH3:11])[O:21][CH3:22])=[O:20])[C:16]([O:18][CH3:19])=[O:17])#[N:2]
Reactant: COC(=O)CC(=O)C(OC)OC
Reactant: N#Cc1ccccc1C=O
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: COC(=O)C(=Cc1ccccc1C#N)C(=O)C(OC)OC
Yield: 62.6 %

Procedure:
To a mixture of 2-cyanobenzaldehyde (5.0 g), methyl 4,4-dimethoxyacetoacetate (7.39 g) and acetic acid (0.458 g) in benzene (15 ml) was added portionwise each one third of a solution of piperidine (390 mg) in benzene (5 ml) for each 20 minutes' interval. The mixture was heated to reflux for 2 hours and the resulting water was removed off azeotropically during the reaction course. After cooling, the reaction mixture was shaken with a mixture of benzene (50 ml) and water (30 ml), and the organic layer was separated and washed with diluted aqueous sodium bicarbonate solution and water. The aqueous washings were extracted with benzene (30 ml). The benzene extract was combined with the above organic layer, washed with water, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The oily residue (14.8 g) was chromatographed on a column of silica-gel (200 g) and eluted with a mixture of benzene and ethyl acetate (25:1, v/v) to give an oily methyl 2 -(2-cyanobenzylidene)-4,4-dimethoxyacetoacetate (6.90 g). The thin layer chromatogram and N.M.R. spectrum of this product show that it consisted of a mixture of two stereoisomers.
Reaction SMILES: C[O-].[Na+].Cl.[CH3:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([NH2:13])=[NH:12])=[CH:9][CH:8]=1.[C:16](OCC)(=[O:23])[CH2:17][C:18](OCC)=[O:19]>CO.C(O)C>[CH3:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]2[N:13]=[C:18]([OH:19])[CH:17]=[C:16]([OH:23])[N:12]=2)=[CH:9][CH:8]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: COc1ccc(C(=N)N)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: COc1ccc(-c2nc(O)cc(O)n2)cc1
Yield: 83.9 %

Procedure:
338 g of a 30% solution of sodium methylate in methanol are added over 10 minutes to a suspension of 112 g of p-methoxybenzamidine hydrochloride and 101 g of diethyl malonate in 520 ml of ethanol, and the mixture is subsequently refluxed for 5 hours. The reaction mixture is then concentrated by rotary evaporation and the residue is dissolved in 1000 ml of warm water of 80° C. The solution is filtered and the filtrate is acidified to pH 1. The precipitate is isolated by filtration and vacuum dried at 80° C., affording 109.8 g of 2-p-methoxyphenyl-4,6-dihydroxypyrimidine with a melting point of 318° C. (decompos.).
Reaction SMILES: S(Cl)(Cl)=O.[NH:5]1[C:9]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:8][N:7]=[CH:6]1.[CH3:15]O>>[NH:5]1[C:9]([CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:8][N:7]=[CH:6]1
Reactant: O=C(O)CCc1cnc[nH]1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)CCc1cnc[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
Add thionyl chloride (0.75 mL) to a −78° C. solution of 3-(1H-imidazol-5-yl)propanoic acid (2.0 g; 1.0 equiv; 14.27 mmoles) in methanol (18 mL). Allow the reaction mixture to warm to ambient temperature and stir for 30 minutes. Add saturated sodium bicarbonate (10 mL) to the reaction mixture and concentrate. Suspended the resulting residue in methanol (10 mL) and filter, then concentrate to afford methyl 3-(1H-imidazol-5-yl)propanoate (2.2 g; 100%) as a white solid: MS (m/z): 155(M+1).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1Br>CCOC(C)=O>[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:7]1[CH:8]=[CH:9][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccc(B(O)O)cc1
Reactant: Brc1ccccc1Br
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(-c2ccccc2Br)cc1

Procedure:
Prepared according to the general procedure Coupling-1 using 4-acetylbenzeneboronic acid and 1,2-dibromobenzene as starting material. Flash chromatography (Hex:EtOAc; 95:5) afforded the title compound.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:39](=[O:40])[N:6]2[C:7]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=3)=[O:27])=[C:8](OP(C3C=CC=CC=3)(C3C=CC=CC=3)=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[OH:41][CH:42]([C@@H:65]1[CH2:69][C@H:68]([SH:70])[CH2:67][N:66]1[C:71]([O:73][CH2:74][C:75]1[CH:80]=[CH:79][C:78]([N+:81]([O-:83])=[O:82])=[CH:77][CH:76]=1)=[O:72])[CH2:43][C:44]([N:46]1[CH2:50][CH2:49][C@@H:48]([NH:51][C:52]([O:54][CH2:55][C:56]2[CH:61]=[CH:60][C:59]([N+:62]([O-:64])=[O:63])=[CH:58][CH:57]=2)=[O:53])[CH2:47]1)=[O:45]>>[OH:1][C@@H:2]([C@H:4]1[C:39](=[O:40])[N:6]2[C:7]([C:26]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][C:33]([N+:36]([O-:38])=[O:37])=[CH:34][CH:35]=3)=[O:27])=[C:8]([S:70][C@@H:68]3[CH2:67][N:66]([C:71]([O:73][CH2:74][C:75]4[CH:76]=[CH:77][C:78]([N+:81]([O-:83])=[O:82])=[CH:79][CH:80]=4)=[O:72])[C@H:65]([CH:42]([OH:41])[CH2:43][C:44]([N:46]4[CH2:50][CH2:49][C@@H:48]([NH:51][C:52]([O:54][CH2:55][C:56]5[CH:57]=[CH:58][C:59]([N+:62]([O-:64])=[O:63])=[CH:60][CH:61]=5)=[O:53])[CH2:47]4)=[O:45])[CH2:69]3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: O=C(N[C@@H]1CCN(C(=O)CC(O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1)OCc1ccc([N+](=O)[O-])cc1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(O)CC(=O)N4CC[C@@H](NC(=O)OCc5ccc([N+](=O)[O-])cc5)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Yield: 97.5 %

Procedure:
By using 4-nitrobenzyl (1R,5R,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-(diphenylphosphoryloxy)-1-carbapen-2-em-3-carboxylate (1.47 g) and (2S,4S)-2-[1-hydroxy-2-[(3R)-3-(4-nitrobenzyloxycarbonylamino)pyrrolidin-1-ylcarbonyl]ethyl]-4-mercapto-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.454 g), reaction and purification were carried out in a similar manner to that described in Example 40-(1), whereby 4-nitrobenzyl (1R,5S,6S)-6-[(1R)-1-hydroxyethyl]-2-[(2S,4S)-2-[1-hydroxy-2-[(3R)-3-(4-nitrobenzyloxycarbonylamino)pyrrolidin-1-ylcarbonyl]ethyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-1-methyl-1-carbapen-2-em-3-carboxylate (2.207 g) was obtained.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:23])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15](=[O:22])[N:16]([CH3:21])[CH:17]=[C:18]([Br:20])[CH:19]=2)=[CH:10][CH:9]=1)[NH2:6].[Br:24][C:25]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:26]=1[C:27](O)=[O:28].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:2][O:3][C:4](=[O:23])[C@H:5]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:15](=[O:22])[N:16]([CH3:21])[CH:17]=[C:18]([Br:20])[CH:19]=2)=[CH:12][CH:13]=1)[NH:6][C:27]([C:26]1[CH:30]=[C:31]([O:34][CH3:35])[CH:32]=[CH:33][C:25]=1[Br:24])=[O:28]
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2cc(Br)cn(C)c2=O)cc1
Reactant: COc1ccc(Br)c(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(-c2cc(Br)cn(C)c2=O)cc1)NC(=O)c1cc(OC)ccc1Br
Yield: 74.9 %

Procedure:
A solution of 4-(5-bromo-1-methyl-2-oxo-3-pyridinyl)-L-phenylalanine methyl ester hydrochloride (120 mg, 0.30 mmol), 2-bromo-5-methoxybenzoic acid (82 mg, 0.36 mmol), DIEA (260 μL, 1.5 mmol) and HBTU (157 mg, 0.41 mmol) in DMF (4 mL) was stirred at room temperature for 18 hr. The mixture was concentrated, the residue was dissolved in ethyl acetate (15 mL), was washed with 0.5 N HCl (1×5 mL), sat. NaHCO3 (1×5 mL), brine (1×5 mL) and was dried (MgSO4). The residue obtained upon evaporation (180 mg) was chromatographed on 25 g of silica gel, eluting with 3:1 ethyl acetate:hexane to give N-[(2-bromo-5-methoxyphenyl)carbonyl]-4-(5-bromo-1-methyl-2-oxo-3-pyridinyl)-L-phenylalanine methyl ester (130 mg, 76%). HRMS: Obs. Mass 576.9959. Calcd. Mass 576.9973 (M+H)
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:16][CH2:15][NH:14][C:13](=[O:17])[CH2:12]1)=[O:10].F[B-](F)(F)F.[CH2:23]([O+](CC)CC)[CH3:24].C(=O)(O)[O-]>ClCCl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:12][C:13]([O:17][CH2:23][CH3:24])=[N:14][CH2:15][CH2:16]1)=[O:10]
Reactant: O=C1CN(C(=O)c2cccc(Cl)c2Cl)CCN1
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: ClCCl
Product: CCOC1=NCCN(C(=O)c2cccc(Cl)c2Cl)C1
Temperature: 25 °C
Yield: 88.9 %

Procedure:
To a suspension of 4-[(2,3-dichlorophenyl)carbonyl]-2-piperazinone (1 g, 3.66 mmol, e.g. prepared as described in Intermediate 3) in dry Dichloromethane (DCM) (9.15 ml) was added triethyloxonium tetrafluoroborate (1.739 g, 9.15 mmol). The suspension turned shortly to a yellow solution and it was stirred at room temperature under argon. After 5 minutes the mixture was diluted with Dichloromethane (20 mL) and treated with ice (15 mL). The pH was adjusted to circa 7 with saturated bicarbonate solution, the phases were separated and the aqueous extracted with Dichloromethane (50 mL). The combined organics were washed with brine and dried over MgSO4. Evaporation gave 1-[(2,3-dichlorophenyl)carbonyl]-5-(ethyloxy)-1,2,3,6-tetrahydropyrazine (0.98 g) as an orange oil which was used without further purification.
Reaction SMILES: [C:1]12([CH2:11][N:12]3[C:20]4[C:15](=[CH:16][CH:17]=[C:18](Br)[CH:19]=4)[CH2:14][C:13]3=[O:22])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(=O)([O-])[O-].[Na+].[Na+].[C:29]([C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)#[N:30]>C1(C)C=CC=CC=1.C(O)C.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>[C:1]12([CH2:11][N:12]3[C:20]4[C:15](=[CH:16][CH:17]=[C:18]([C:34]5[CH:35]=[CH:36][C:31]([C:29]#[N:30])=[CH:32][CH:33]=5)[CH:19]=4)[CH2:14][C:13]3=[O:22])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C1Cc2ccc(Br)cc2N1CC12CC3CC(CC(C3)C1)C2
Reactant: N#Cc1ccc(B(O)O)cc1
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: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: N#Cc1ccc(-c2ccc3c(c2)N(CC24CC5CC(CC(C5)C2)C4)C(=O)C3)cc1
Temperature: 100 °C
Yield: 30.3 %

Procedure:
To a solution of 1-adamantan-1-ylmethyl-6-bromo-1,3-dihydro-indol-2-one (1.85 g, 5.13 mmol) in toluene (23 ml) and ethanol (21 ml) were added tetrakis(triphenylphosphine)palladium (0.60 g, 0.513 mmol), sodium carbonate (1.09 g, 10.27 mmol) in water (11 ml) and solid 4-cyanophenylboronic acid (1.51 g, 10.27 mmol). The mixture was heated at 100° C. overnight. The reaction mixture was partitioned between chloroform and aqueous saturated potassium carbonate (50 ml). The organic layer was washed with brine, dried over MgSO4, filtered and concentrated under vacuum to give the crude product. This was chromatographed on flash silica gel eluting with a 15% ethyl acetate in hexane to give the title compound of 9C as a white solid (0.594 g, 30.3% yield).
Reaction SMILES: C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[I:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][C:38]([OH:40])=O)=[CH:33][CH:32]=1.[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>CN(C=O)C>[I:30][C:31]1[CH:32]=[CH:33][C:34]([CH2:37][C:38]([N:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)=[O:40])=[CH:35][CH:36]=1
Reactant: O=C(O)Cc1ccc(I)cc1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Cc1ccc(I)cc1)N1CCOCC1
Temperature: 0 °C
Yield: 62.3 %

Procedure:
Triethylamine (5.30 mL, 38.0 mmol), HOBt (3.96 g, 28.5 mmol) and EDC.HCl (5.47 g, 28.5 mmol) were added to a solution of (4-iodo-phenyl)-acetic acid (5.0 g, 19.0 mmol) in DMF (100 mL) and stirred. After 5 min morpholine (2.0 mL, 22.9 mmol) was added at RT. The reaction mixture was stirred at RT for 16 h. The reaction mixture was poured into ice-cold water (50 mL) and obtained solid was filtered, dried to get 3.92 g (Yield: 62.1%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:9])=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1.[CH:10]([N:13]=[C:14]=S)([CH3:12])[CH3:11].CC1C=CC(S([O-])(=O)=O)=CC=1.C[N+]1(CCN=C=NC2CCCCC2)CCOCC1>N1C=CC=CC=1>[Cl:1][C:2]1[C:3]2[N:9]=[C:14]([NH:13][CH:10]([CH3:12])[CH3:11])[NH:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(Cl)c1N
Reactant: CC(C)N=C=S
Agent: C[N+]1(CCN=C=NC2CCCCC2)CCOCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: c1ccncc1
Product: CC(C)Nc1nc2c(Cl)cccc2[nH]1
Yield: 57.8 %

Procedure:
3-Chloro-1,2-phenylenediamine (6.41 g, 44.95 mmol), isopropyl isothiocyanate (5.20 g, 51.6 mmol), 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate (25.0 g, 59.02 mmol) and pyridine (300 mL) were used according to general procedure I. The product was recrystallized from 1,4-dioxane afford 5.45 g (58%) of a brownish solid. MS (EI): m/z 210.1 (M+H). Anal. calcd for C10H12ClN3-(0.5 C4H8O2): C, 56.80; H, 6.36; N, 16.56. Found: C, 57.00; H, 6.34; N, 16.69.
Reaction SMILES: [C:1]([CH:9]([CH3:15])[CH:10]([CH3:14])[C:11](O)=[O:12])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:17][NH2:18]>C(O)C>[CH3:14][CH:10]1[CH:9]([CH3:15])[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:18][NH:17][C:11]1=[O:12]
Reactant: CC(C(=O)O)C(C)C(=O)c1ccccc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CC1C(=O)NN=C(c2ccccc2)C1C

Procedure:
A 200 g. portion of 3-benzoyl-2,3-dimethyl-propionic acid and 60 g. of hydrazine hydrate are added to one liter of ethyl alcohol and stirred at reflux for 18 hours. The reaction mixture is then cooled in an ice bath and collected in a conventional manner to afford 4,5-dihydro-4,5-dimethyl-6-phenyl-3(2H)-pyridazinone as a cream colored solid. This product is partially dissolved in 600 ml. of glacial acetic acid. To this is added, portionwise, a solution of 50 ml. of bromine in 100 ml. of glacial acetic acid, while warming on a steam bath (approximately 15% of the bromine solution is added to the reaction mixture before warming is started and about one hour is required to complete the addition during which time quantities of hydrogen bromide gas are given off). After the addition is completed, the reaction mixture is heated on the steam bath for one hour, and then the mixture is poured onto crushed ice. The resulting solid is vacuum filtered, washed copiously with water, and air dried to give 4,5-dimethyl-6 -phenyl-3(2H)-pyridazinone as a cream colored solid. This material is added to 800 ml. of phosphorus oxychloride and is heated on a steam bath for 5 hours. The reaction mixture is concentrated to remove the excess phosphorus oxychloride and is then diluted with cold water. The resulting solid is vacuum filtered, washed copiously with water, and air dried to give 3-chloro-4,5-dimethyl-6-phenylpyridazine as a pinkish solid. A 10 g. portion of this product plus 8 g. of N-acetylhydrazine and 100 ml. of n-butyl alcohol is allowed to stir at reflux for 48 hours. The reaction mixture is cooled in an ice bath and the resulting solid is vacuum filtered, washed first with petroleum ether and then with water, and is air dried. The solid is recrystallized from ethyl alcohol after treatment with activated charcoal and is dried in vacuo to give 3,7,8-trimethyl-6-phenyl-1,2,4-triazolo[4,3-b]pyridazine as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[NH:11][CH2:12][CH2:13][NH:14]C(=O)C.Cl>CO>[NH2:14][CH2:13][CH2:12][NH:11][C:3]1[N:2]([CH3:1])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=1
Reactant: CC(=O)NCCNc1nc2ccccc2n1C
Agent: Cl
Solvent: CO
Product: Cn1c(NCCN)nc2ccccc21
Yield: 77.4 %

Procedure:
A mixture of N-[2-[(1-methyl-1H-benzimidazol-2-yl)amino]ethyl]acetamide (2.32 g, 9.98 mmol), 2N HCl (20 mL), and MeOH (20 mL) was heated under reflux for 20 hours. The mixture was concentrated, diluted with H2O, made basic (pH9) with 2.5N NaOH, and extracted with EtOAc. The combined extracts were dried and concentrated to give a brown oil. Purification by flash chromatography (eluent 10% MeOH/CH2Cl2) gave a yellow oil 1.47 g (77%).
Reaction SMILES: [NH4+:1].[OH-].[CH:3]1([O:9][CH2:10][C:11](Cl)=[O:12])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1>C(Cl)Cl>[CH:3]1([O:9][CH2:10][C:11]([NH2:1])=[O:12])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: [NH4+]
Reactant: O=C(Cl)COC1CCCCC1
Agent: [OH-]
Solvent: ClCCl
Product: NC(=O)COC1CCCCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 56 %

Procedure:
To 15 mL of NH4OH (25-28%) was added a solution of 2-(cyclohexyloxy)acetyl chloride (1.01 g, 5.72 mmol) in DCM (2 mL) in an ice bath and the mixture was stirred at rt for 5 min and extracted with DCM (20 mL×3). The combined organic layers were washed with brine (20 mL×2), dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound as a white solid (0.5 g, 56%).
Reaction SMILES: COC[O:4][C:5]1[CH:6]=[C:7]([C:11](=[O:18])[CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:8]=[CH:9][CH:10]=1.Cl>C1COCC1>[OH:4][C:5]1[CH:6]=[C:7]([C:11](=[O:18])[CH:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)[CH:8]=[CH:9][CH:10]=1
Reactant: COCOc1cccc(C(=O)C2CCOCC2)c1
Agent: Cl
Solvent: C1CCOC1
Product: O=C(c1cccc(O)c1)C1CCOCC1
Yield: 96.4 %

Procedure:
The methyloxymethoxy group was removed by treatment of 4-[(3-methyloxymethoxyphenyl)oxomethyl]tetrahydropyran (0.82 g, 3.27 mmol), prepared as in step 2 with concentrated hydrochloric acid (2.45 mL, 0.75 mL/mmol) in THF (13 mL) at ambient temperature for 0.5 hours. The reaction mixture was partitioned between water and ethyl acetate and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium bicarbonate and brine, dried over MgSO4, filtered, and concentrated in vacuo to provide 4-[(3-hydroxyphenyl)oxomethyl]tetrahydropyran as a brown solid (0.65 g, 96%) which was used without further purification.
Reaction SMILES: [OH:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH:3]1[CH2:12][CH2:13][OH:14]>C(Cl)Cl.O=[Mn]=O>[OH:14][CH2:13][CH2:12][CH:3]1[CH2:4][CH2:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]1=[O:1]
Reactant: OCCC1CCc2ccccc2C1O
Agent: O=[Mn]=O
Solvent: ClCCl
Product: O=C1c2ccccc2CCC1CCO
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.4 %

Procedure:
A solution of isomeric mixture of 1-hydroxyl-2-(2-hydroxyethyl)-1,2,3,4-tetrahydronaphthalene (3.00 g, 15.6 mmol) in CH2Cl2 (100 mL) was treated with MnO2 (20.4 g, 0.234 mole). The suspension was stirred at room temperature for 16 h and the solids were removed by filtration. Concentration of the filtrate in vacuo gave a brown oil, which was further purified by flash chromatography (MeOH/CHCl3, 5/95), giving a yellow oil (2.00 g, 67.4%): 1H NMR δ 1.76 (m, 1H), 1.98 (m, 1H), 2.21 (m, 2H), 2.57 (br, 1H), 2.70 (m, 2H), 3.20 (m, 2H), 3.81 (m, 2H), 7.00-8.20 (m, 4H); CI mass spectrum (M+1)+ at m/z 191.
Reaction SMILES: [CH2:1]=[CH:2][C:3](=[CH2:10])[CH2:4][CH2:5][CH2:6][C:7](=[CH2:9])[CH3:8].Cl[CH2:12][C:13]([CH2:15][CH2:16][CH2:17][C:18](=[CH2:21])[CH:19]=[CH2:20])=[CH2:14].CC(C)([Mg]Cl)CCCCCCC>>[CH2:10]=[C:3]([CH2:4][CH2:5][CH2:6][C:7](=[CH2:8])[CH2:9][CH2:20][CH2:19][CH:18]([CH3:21])[CH2:17][CH2:16][CH2:15][CH:13]([CH3:14])[CH3:12])[CH:2]=[CH2:1]
Reactant: C=CC(=C)CCCC(=C)CCl
Reactant: C=CC(=C)CCCC(=C)C
Agent: CCCCCCCC(C)(C)[Mg]Cl
Product: C=CC(=C)CCCC(=C)CCCC(C)CCCC(C)C

Procedure:
Alpha-myrcene (6-methylene-2-methylocta-1,7-diene) is chlorinated to 2-chloromethyl-6-methyleneocta-1,7-diene. This is reacted with dimethyloctyl magnesium chloride to produce 3,7-dimethylene-11,15-dimethylhexadec-1-ene. This compound yields 7-methylene-3,11,15-trimethylhexadec-2-en-1-ol which, when reacted with TMHQ and hydrogenated, produces Vitamin E.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][S:8][C:9]2[N:14]=[C:13]([C:15](Cl)=[O:16])[CH:12]=[CH:11][C:10]=2[C:18]#[N:19])=[CH:5][CH:4]=1.[CH:22]([N:25](CC)C(C)C)(C)C>CN(C)C=O>[Cl:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][S:8][C:9]2[N:14]=[C:13]([C:15]([NH:25][CH3:22])=[O:16])[CH:12]=[CH:11][C:10]=2[C:18]#[N:19])=[CH:5][CH:4]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: N#Cc1ccc(C(=O)Cl)nc1SCc1ccc(Cl)cc1
Agent: Cl
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(C#N)c(SCc2ccc(Cl)cc2)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 74 %

Procedure:
A mixture of 6-(4-chlorobenzylthio)-5-cyanopicolinoyl chloride hydrochloride 81 (60 mg, 0.17 mmol) and N,N-diisopropylethylamine (89 ul, 0.51 mmol) in dimethylformamide (2 ml) was stirred for 6 hrs at room temperature. After removal of the solvent, the residue was triturated with ether and the resulting solid was collected by filtration to afford 40 mg (74%) of the desired product 84. 1H NMR (600 MHz, DMSO-d6) δ 8.79 (d, 1H, J=4.8 Hz), 8.37 (d, 1H, J=7.8 Hz), 7.84 (d, 1H, J=8.4 Hz), 7.49 (d, 2H, J=9 Hz), 7.38 (d, 2H, 9 Hz), 4.76 (s, 2H), 2.89 (d, 3H, J=4.8 Hz). MS: m/z Calcd 317.8 Found MH+ 318.0