Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([SH:11])[CH2:9][CH3:10].[C:12](=[S:14])=[S:13].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>C(Cl)(Cl)Cl>[C:12](=[S:14])([S:13][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[S:11][CH2:8][CH2:9][CH3:10]
Reactant: S=C=S
Reactant: BrCc1ccccc1
Reactant: CCCS
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCSC(=S)SCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
Triethylamine (4.78 g, 0.047 mol) is gradually added to a solution of propanethiol (3.00 g, 0.039 mol) in chloroform (200 ml). The reaction mixture is stirred at room temperature for one hour. This is followed by the addition of carbon disulfide (7.50 g, 0.098 mol) and the reaction mixture is stirred at room temperature for a further two hours. This is followed by the addition of benzyl bromide (8.08 g, 0.047 mol) and the reaction solution is stirred at room temperature for 24 hours. This is followed by the addition of 10% hydrochloric acid (200 ml). The organic phase is separated off and washed with water (3 times 100 ml). The combined organic phases are dried over sodium sulfate and the solvent is removed in a high vacuum. The desired product is obtained as a yellowish oil (9.36 g) in a yield of 98%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH:5]=O.C(O)(=O)[CH2:12][C:13]([OH:15])=[O:14].N1CCCCC1>Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:12][C:13]([OH:15])=[O:14])[CH:7]=[C:8]([Cl:10])[CH:9]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1cc(Cl)cc(Cl)c1
Agent: Cl
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1cc(Cl)cc(Cl)c1
Temperature: 150 °C
Yield: 61.8 %

Procedure:
A mixture of 3,5-dichlorobenzaldehyde (15.0 g, 85.7 mmol), malonic acid (12.5 g, 120.2 mmol), and piperidine (5 mL) was heated at 100° C. for 2 h and at 150° C. for 1 h. The reaction was poured onto 3N HCl (200 mL) and the precipitate was removed via filtration. The product was purified by recrystallization (100 mL hot EtOH) to afford 3-(3,5-dichlorophenyl)-acrylic acid (11.5 g). 1H NMR (250 MHz, DMSO-d6) δ 12.6 (bs, 1H), 7.83 (m, 2H), 7.64-7.51 (m, 2H), 6,72 (d, 1H).
Reaction SMILES: [C:1]([C:9]1[CH:18]=[CH:17][C:12]([O:13][CH2:14][CH2:15][NH2:16])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([O:21][C:22](Cl)=[O:23])[CH3:20].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:19]([O:21][C:22](=[O:23])[NH:16][CH2:15][CH2:14][O:13][C:12]1[CH:11]=[CH:10][C:9]([C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:18][CH:17]=1)[CH3:20]
Reactant: CCOC(=O)Cl
Reactant: NCCOc1ccc(C(=O)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)NCCOc1ccc(C(=O)c2ccccc2)cc1
Reaction time: 30 h
Yield: 53.2 %

Procedure:
5.5 g of 2-(p-benzoylphenoxy)ethylamine and 13 g of chloroformic acid ethyl ester are dissolved in 200 ml of acetone. 19.3 g of potassium carbonate are added to the solution and the mixture is heated under reflux with stirring for 30 hours. The mixture is then filtered and the crystals are washed with acetone. The filtrate is evaporated in vacuo. The residue is dissolved in ethyl acetate. The organic phase is washed with water, dried over sodium sulfate and evaporated in vacuo. The residue is dissolved in ether and crystallized by the addition of cyclohexane to yield 3.8 g (61%) of 2-(p-benzoylphenoxy)ethylcarbamic acid ethyl ester, m.p.--84°-86° C.
Reaction SMILES: CO[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[F:11].Cl.Cl[CH2:15][C:16]1[N:17]=[C:18]([CH3:21])[S:19][CH:20]=1.[NH:22]1[CH2:26][CH2:25][CH2:24][C@H:23]1[CH2:27][N:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>>[F:11][C:5]1[CH:6]=[C:7]([O:10][CH2:15][C:16]2[N:17]=[C:18]([CH3:21])[S:19][CH:20]=2)[CH:8]=[CH:9][C:4]=1[C:3]([N:22]1[CH2:26][CH2:25][CH2:24][C@H:23]1[CH2:27][N:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:12]
Reactant: COC(=O)c1ccc(O)cc1F
Reactant: C1CN[C@H](CN2CCCC2)C1
Reactant: Cc1nc(CCl)cs1
Agent: Cl
Product: Cc1nc(COc2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)c(F)c2)cs1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedures D and E using 2-fluoro-4-hydroxy-benzoic acid methyl ester [CAS 197507-22-5], 4-chloromethyl-2-methylthiazole hydrochloride [CAS 39238-07-8], and (S)(+)-1-(2-pyrrolidinylmethyl)pyrrolidine. MS (ES+) m/e 404.2
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([Cl:13])[C:8]=1F)=O.NC(N)=[S:24].N1C=CC=CC=1.CCN(CC)CC>C(O)(C)C>[Cl:13][C:9]1[C:8]2[S:24][C:4]([C:3]3[C:15]([N+:19]([O-:21])=[O:20])=[CH:16][CH:17]=[CH:18][C:2]=3[Cl:1])=[N:6][C:7]=2[CH:12]=[CH:11][N:10]=1
Reactant: NC(N)=S
Reactant: O=C(Nc1ccnc(Cl)c1F)c1c(Cl)cccc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC(C)O
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cccc(Cl)c1-c1nc2ccnc(Cl)c2s1
Temperature: 25 °C
Yield: 97.2 %

Procedure:
A stirred suspension of 2-chloro-N-(2-chloro-3-fluoropyridin-4-yl)-6-nitrobenzamide (3.90 g, 11.2 mmol), thiourea (3.40 g, 44.8 mmol) and pyridine (3.1 mL, 38.1 mmol) in isopropanol (35 mL) under a nitrogen atmosphere, was heated under reflux for 4 hours. After this time, Et3N (9.4 mL, 67.2 mmol) was added and the reaction mixture was heated under reflux for 16 hours. After cooling to room temperature, the volatiles were removed under reduced pressure. The crude residue was triturated with ethyl acetate and the solid was removed by filtration. The resultant filtrate was washed with 10% citric acid, brine, dried over MgSO4 and evaporated under reduced pressure to afford the title compound as a pale orange solid (3.55 g, 97%). 1H NMR (400 MHz, CDCl3): δ 8.51 (d, J=5.5 Hz, 1H), 8.13 (dd, J=1.2, 8.4 Hz, 1H), 7.91 (d, J=5.7 Hz, 1H), 7.87 (dd, J=1.2, 8.3 Hz, 1H), 7.72 (t, J=8.1 Hz, 1H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[P:13]([O:20]CC)([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16]>>[CH2:15]([O:14][P:13]([CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)([O:17][CH2:18][CH3:19])=[O:20])[CH3:16]
Reactant: CCOP(OCC)OCC
Reactant: COC(=O)c1ccc(CBr)cc1
Product: CCOP(=O)(Cc1ccc(C(=O)OC)cc1)OCC

Procedure:
A solution of methyl 4-(bromomethyl)benzoate (12.5 g, 54.6 mmol) in triethyl phosphite (20 mL, 114 mmol) was heated at 150° C. for 2 hours. After cooling, the solution was concentrated under vacuum. Purification by chromatography (silica gel, 0-2% methanol in dichloromethane) afforded the title compound. MS (ESI) m/z 287 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[CH:22]=[CH:21][C:10]3[N:11]=[C:12]([CH2:14][C:15]4[O:19][C:18]([OH:20])=[N:17][N:16]=4)[S:13][C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.BrC1C=CC2N=C(CC3[O:36]C(O)=NN=3)SC=2C=1.OO>C(O)(=O)C.O>[OH:20][C:18]1[O:19][C:15]([C:14]([C:12]2[S:13][C:9]3[CH:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:22]=[CH:21][C:10]=3[N:11]=2)=[O:36])=[N:16][N:17]=1
Reactant: Oc1nnc(Cc2nc3ccc(Br)cc3s2)o1
Reactant: Oc1nnc(Cc2nc3ccc(-c4ccccc4)cc3s2)o1
Agent: OO
Solvent: O
Solvent: CC(=O)O
Product: O=C(c1nnc(O)o1)c1nc2ccc(-c3ccccc3)cc2s1
Temperature: 50 °C
Yield: 80 %

Procedure:
To a suspension of 5-((6-phenylbenzo[d]thiazol-2-yl)methyl)-1,3,4-oxadiazol-2-ol (25 mg, 0.081 mmol) in acetic acid (1 mL) (prepared according to a similar procedure described for Compound 51a) was added 30% hydrogen peroxide in water (0.17 mL, 1.6 mmol) and the reaction mixture heated at 50° C. for 16 h. The reaction mixture was allowed to cool to rt then diluted with water and filtered. The solid was washed with water and rinsed with ether, then dried under vacuum to afford Compound 88a (21 mg, 80% yield) as a yellow solid. LCMS=0.96 min using analytical method (M), 324.1 (M+H). 1H NMR (400 MHz, DMSO-d6) δ 8.64 (d, J=1.5 Hz, 1H), 8.40 (d, J=8.5 Hz, 1H), 8.02 (dd, J=8.5, 1.8 Hz, 1H), 7.89-7.79 (m, 2H), 7.63-7.50 (m, 2H), 7.50-7.41 (m, 1H), 5.76 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:39]=[CH:38][C:5]([C:6](/[N:8]=[C:9]2\[NH:10][C:11]3[CH:26]=[CH:25][C:24]([CH2:27][N:28]4[CH2:33][CH2:32][CH:31]([C:34]([OH:37])([CH3:36])[CH3:35])[CH2:30][CH2:29]4)=[CH:23][C:12]=3[N:13]\2[C@@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]([OH:22])=[O:21])[CH2:16][CH2:15]2)=[O:7])=[CH:4][CH:3]=1.[CH:40]12[NH:47][CH:44]([CH2:45][CH2:46]1)[CH2:43][N:42]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:41]2>>[F:1][C:2]1[CH:39]=[CH:38][C:5]([C:6](/[N:8]=[C:9]2\[NH:10][C:11]3[CH:26]=[CH:25][C:24]([CH2:27][N:28]4[CH2:33][CH2:32][CH:31]([C:34]([OH:37])([CH3:35])[CH3:36])[CH2:30][CH2:29]4)=[CH:23][C:12]=3[N:13]\2[C@@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]([N:47]3[CH:40]4[CH2:46][CH2:45][CH:44]3[CH2:43][N:42]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:41]4)=[O:21])[CH2:16][CH2:15]2)=[O:7])=[CH:4][CH:3]=1.[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6](/[N:8]=[C:9]2\[NH:10][C:11]3[CH:26]=[CH:25][C:24]([CH2:27][N:28]4[CH2:29][CH2:30][CH:31]([C:34]([OH:37])([CH3:35])[CH3:36])[CH2:32][CH2:33]4)=[CH:23][C:12]=3[N:13]\2[C@H:14]2[CH2:19][CH2:18][C@@H:17]([C:20]([N:42]3[CH2:43][CH2:44][NH:47][CH2:40][CH2:41]3)=[O:22])[CH2:16][CH2:15]2)=[O:7])=[CH:38][CH:39]=1
Reactant: CC(C)(C)OC(=O)N1CC2CCC(C1)N2
Reactant: CC(C)(O)C1CCN(Cc2ccc3[nH]/c(=N\C(=O)c4ccc(F)cc4)n([C@H]4CC[C@@H](C(=O)O)CC4)c3c2)CC1
Product: CC(C)(C)OC(=O)N1CC2CCC(C1)N2C(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(CN4CCC(C(C)(C)O)CC4)cc32)CC1
Product: CC(C)(O)C1CCN(Cc2ccc3[nH]/c(=N\C(=O)c4ccc(F)cc4)n([C@H]4CC[C@@H](C(=O)N5CCNCC5)CC4)c3c2)CC1

Procedure:
The title compound was prepared from cis-4-((E)-2-(4-fluorobenzoylimino)-6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylic acid and tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate using a method analogous to that used in the preparation of (E)-4-fluoro-N-(6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1-(cis-4-(piperazine-1-carbonyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide (70 mg, 51% yield). MS, m/z (C41H55FN6O5): calcd, 730.4. found, 731.1 [M+H].
Reaction SMILES: [CH2:1]([Si:3]([CH3:10])([O:7][CH2:8][CH3:9])OCC)[CH3:2].[Mg].Br[C:13]1[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=1>O1CCCC1>[CH2:1]([Si:3]([CH3:10])([O:7][CH2:8][CH3:9])[C:13]1[CH:18]=[CH:17][C:16]([Si:3]([CH2:1][CH3:2])([CH3:10])[O:7][CH2:8][CH3:9])=[CH:15][CH:14]=1)[CH3:2]
Reactant: CCO[Si](C)(CC)OCC
Reactant: Brc1ccc(Br)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: CCO[Si](C)(CC)c1ccc([Si](C)(CC)OCC)cc1
Reaction time: 3 h
Yield: 67.7 %

Procedure:
16.2 g of ethylmethyldiethoxysilane, 2.43 g of magnesium and 10 ml of tetrahydrofuran were charged into a 500-ml, three-necked flask provided with a stirrer, a cooler and a dropping funnel and stirred under a nitrogen gas stream, while 100 ml of a tetrahydrofuran solution containing 11,8 g of p-dibromobenzene was dropwise added thereto from the dropping funnel over about 3 hours. After the dropwise addition, the mixture was further stirred and refluxed for about 5 hours. After the refluxing, the resulting polymer was separated by filtration, and then the solvent was removed therefrom by distillation. The residues were then subjected to distillation under reduced pressure, whereby 10.5 g of p-bis(ethylmethylethoxysilyl)benzene was obtained (yield: 68%, boiling point: 122°-125° C./3 mmHg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][S:10][CH:11]([C:22]([O:24][CH2:25][C:26]([Cl:29])([Cl:28])[Cl:27])=[O:23])[CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[CH3:30][C:31]1[O:35][C:34]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[N:33][C:32]=1[CH2:42][CH2:43]O.C1(C2OC(C(F)(F)F)=C(COC(=O)C3C=CC(CC(SCCC4C=CC(F)=CC=4)C(OCC(Cl)(Cl)Cl)=O)=CC=3)N=2)C=CC=CC=1>>[CH3:30][C:31]1[O:35][C:34]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)=[N:33][C:32]=1[CH2:42][CH2:43][O:18][C:17](=[O:19])[C:16]1[CH:20]=[CH:21][C:13]([CH2:12][CH:11]([S:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:22]([O:24][CH2:25][C:26]([Cl:29])([Cl:27])[Cl:28])=[O:23])=[CH:14][CH:15]=1
Reactant: O=C(O)c1ccc(CC(SCCc2ccc(F)cc2)C(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: Cc1oc(-c2ccccc2)nc1CCO
Agent: O=C(OCc1nc(-c2ccccc2)oc1C(F)(F)F)c1ccc(CC(SCCc2ccc(F)cc2)C(=O)OCC(Cl)(Cl)Cl)cc1
Product: Cc1oc(-c2ccccc2)nc1CCOC(=O)c1ccc(CC(SCCc2ccc(F)cc2)C(=O)OCC(Cl)(Cl)Cl)cc1
Yield: 91.5 %

Procedure:
The title compound was prepared from 4-[2-[2-(4-fluoro-phenyl)-ethylsulfanyl]-2-(2,2,2-trichloro-ethoxycarbonyl)-ethyl]-benzoic acid (220 mg, 0.46 mmol) and 2-(5-methyl-2-phenyl-oxazol-4-yl)-ethanol (103 mg, 0.50 mmol) in the same manner as described for 4-[2-[2-(4-fluoro-phenyl)-ethylsulfanyl]-2-(2,2,2-trichloro-ethoxy-carbonyl)-ethyl]-benzoic acid 2-phenyl-5-trifluoromethyl-oxazol-4-ylmethylester. The crude product was purified by flash chromatography using n-heptane/EtOAc 7:3 as the eluent to afford the final product as an oil (280 mg, 83.5%). 1H NMR (400 MHz, CDCl3): δ 7.91-7.96 (m, 3H), 7.39-7.41 (m, 3H), 7.22-7.25 (m, 3H), 7.06-7.09 (m, 2H), 6.94 (t, 2H), 4.71 (m, 1H), 4.64 (m, 1H), 4.56 (t, 1H), 3.88-3.92 (m, 2H), 3.55 (m 1H), 3.29 (m, 1H), 2.69-2.04 (m, 6H), 2.32 (s, 3H). Mass Spectrum: M+H+ 666.14, M−H+ 664.39.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH3:9][C:10]1[C:11]([N:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20]2)=[N:12][C:13]([Cl:18])=[N:14][C:15]=1[CH2:16][CH3:17]>CN(C)C=O>[ClH:18].[CH3:9][C:10]1[C:11]([N:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20]2)=[N:12][C:13]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=2)=[N:14][C:15]=1[CH2:16][CH3:17]
Reactant: Nc1ccc(F)cc1
Reactant: CCc1nc(Cl)nc(N2CCc3ccccc3C2)c1C
Solvent: CN(C)C=O
Product: CCc1nc(Nc2ccc(F)cc2)nc(N2CCc3ccccc3C2)c1C
Product: Cl
Yield: 52.2 %

Procedure:
After 4-fluoroaniline(0.45 ml, 3.6 mmol) was added to a mixture solution of 5-methyl-6-ethyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-2-chloropyrimidine(0.7 g, 2.4 mmol) and dimethylformamide(5 ml), 0.50 g of the titled compound was obtained in accordance with the same procedure as in Step 2 of Example 1.
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4](=[O:6])[CH3:5].[Br:9]Br>CCOCC>[Br:9][CH2:5][C:4](=[O:6])[C:3]([CH3:8])([CH3:7])[CH2:2][Cl:1]
Reactant: CC(=O)C(C)(C)CCl
Reactant: BrBr
Solvent: CCOCC
Product: CC(C)(CCl)C(=O)CBr
Yield: 79.2 %

Procedure:
134.5 g (1 mol) of 1-chloro-2,2-dimethyl-butan-3-one were dissolved in 500 ml of ether. 51 ml (1 mol) of bromine were added dropwise at room temperature, with slight cooling, at a rate such that the bromine was steadily consumed. The solution was then stirred into 1,000 ml of ice-water and the organic phase was separated off, rinsed with 250 ml of water, dried over sodium sulphate and distilled. 169 g (80% of theory) of 1-bromo-4-chloro-3,3-dimethyl-butan-2-one of boiling point 95°-106° C./13 mm Hg were obtained.
Reaction SMILES: [CH3:1][CH2:2][C:3]1[CH2:14][N:12]2[CH2:13][C@@H:5]([CH2:6][C@:7]([C:55]([O:57][CH3:58])=[O:56])([C:22]3[CH:27]=[C:26]4[C@@:28]56[C@@H:39]([N:40]([CH3:41])[C:25]4=[CH:24][C:23]=3[O:53][CH3:54])[C@@:38]([OH:46])([C:42]([O:44][CH3:45])=[O:43])[C@H:37]([O:47][C:48]([CH3:50])=[O:49])[C@:33]3([CH2:51][CH3:52])[CH:34]=[CH:35][CH2:36][N:31]([C@H:32]53)[CH2:30][CH2:29]6)[C:8]3[NH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:9]=3[CH2:10][CH2:11]2)[CH:4]=1.CN(C)C=[O:62]>>[CH3:1][CH2:2][C@@:3]12[O:62][C@@H:4]1[C@H:5]1[CH2:13][N:12]([CH2:11][CH2:10][C:9]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[NH:21][C:8]=3[C@@:7]([C:55]([O:57][CH3:58])=[O:56])([C:22]3[CH:27]=[C:26]4[C@:28]56[C@@H:32]7[C@:33]([CH2:51][CH3:52])([C@@H:37]([O:47][C:48]([CH3:50])=[O:49])[C@:38]([OH:46])([C:42]([O:44][CH3:45])=[O:43])[C@@H:39]5[N:40]([CH3:41])[C:25]4=[CH:24][C:23]=3[O:53][CH3:54])[CH:34]=[CH:35][CH2:36][N:31]7[CH2:30][CH2:29]6)[CH2:6]1)[CH2:14]2
Reactant: CN(C)C=O
Reactant: CCC1=C[C@H]2CN(CCc3c([nH]c4ccccc34)[C@@](C(=O)OC)(c3cc4c(cc3OC)N(C)[C@H]3[C@@](O)(C(=O)OC)[C@H](OC(C)=O)[C@]5(CC)C=CCN6CC[C@]43[C@@H]65)C2)C1
Product: CC[C@]12CN3CCc4c([nH]c5ccccc45)[C@@](C(=O)OC)(c4cc5c(cc4OC)N(C)[C@H]4[C@@](O)(C(=O)OC)[C@H](OC(C)=O)[C@]6(CC)C=CCN7CC[C@]54[C@@H]76)C[C@H](C3)[C@H]1O2
Reaction time: 18 h
Yield: 61 %

Procedure:
0.6 g. of 3',4'-anhydro-vinblastine are dissolved in 75 ml. of dimethyl formamide. Oxygen is bubbled through the solution slowly for 10 minutes, whereupon the reaction mixture is allowed to stand at room temperature for 16 to 20 hours. The pH is adjusted to 8.5 with a concentrated aqueous ammonium hydroxide solution. The alkaline mixture obtained is extracted with three 100-ml. portions of benzene. The combined extracts are dried with sodium sulphate, filtered and the filtrate is evaporated. The residue is dissolved in 3 ml. of ethanol and allowed to stand at 5° C. for 16 hours. The precipitated crystals are filtered off, washed with a small portion of cool methanol and dried. 0.366 mg. (61.0%) of the named compound is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]([OH:15])=[C:13]2[C:8]([CH:9]=[CH:10][C:11](=[O:23])[N:12]2[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:7][N:6]=1)=[O:4].CC1C=C(C)N=C(C)C=1.CC1C([IH+:40])=C(C)N=C(C)C=1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:14]([OH:15])=[C:13]2[C:8]([CH:9]=[CH:10][C:11](=[O:23])[N:12]2[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:7]([I:40])[N:6]=1)=[O:4]
Reactant: Cc1cc(C)c([IH+])c(C)n1
Reactant: COC(=O)c1ncc2ccc(=O)n(Cc3ccccc3)c2c1O
Agent: F[P-](F)(F)(F)(F)F
Solvent: Cc1cc(C)nc(C)c1
Solvent: ClCCl
Product: COC(=O)c1nc(I)c2ccc(=O)n(Cc3ccccc3)c2c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 40.2 %

Procedure:
A mixture of 1-benzyl-8-hydroxy-2-oxo-1,2-dihydro-[1,6]naphthyridine-7-carboxylic acid methyl ester (200 mg, 0.645 mmol) and bis(2,4,6-trimethylpyridine)iodine(I) hexafluorophosphate (0.83 g, 1.61 mmol) in 10 mL of CH2Cl2 was stirred at r.t. for 16 h. The mixture was diluted with CH2Cl2 and washed with dilute NaHSO3 and 1 M HCl. The organic layer was dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (100% CH2Cl2) to give 113 mg of the title compound as a pale yellow solid. MS: (+) m/z 437.13 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:20]=[C:19]2[C:5]([C:6](=[O:22])[C:7](=[O:21])[C:8]3[S:18][CH2:17][C:11]4([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]4)[O:10][C:9]=32)=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:34]=[CH:33][C:27]([O:28][CH2:29][C@@H:30]2[CH2:32][O:31]2)=[CH:26][CH:25]=1>>[Br:1][C:2]1[CH:20]=[C:19]2[C:5]([C:6](=[O:22])[C:7](=[O:21])[C:8]3[S:18][CH2:17][C:11]4([CH2:16][CH2:15][N:14]([CH2:32][C@H:30]([OH:31])[CH2:29][O:28][C:27]5[CH:33]=[CH:34][C:24]([Cl:23])=[CH:25][CH:26]=5)[CH2:13][CH2:12]4)[O:10][C:9]=32)=[CH:4][CH:3]=1
Reactant: Clc1ccc(OC[C@@H]2CO2)cc1
Reactant: O=C1C(=O)c2ccc(Br)cc2C2=C1SCC1(CCNCC1)O2
Product: O=C1C(=O)c2ccc(Br)cc2C2=C1SCC1(CCN(C[C@H](O)COc3ccc(Cl)cc3)CC1)O2

Procedure:
Compound 190 was synthesized using 9-bromospiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (2S)-2-[(4-chlorophenoxy)methyl]oxirane and conditions outlined in procedure Y. M.p.=150-152° C.; 400 MHz 1H NMR (CDCl3) δ: 7.92-7.89 (m, 1H), 7.87-7.85 (m, 1H), 7.65-7.62 (m, 1H), 7.27-7.22 (m, 2H), 6.88-6.84 (m, 2H), 4.20-4.08 (m, 1H), 4.03-3.95 (m, 2H), 2.96 (s, 3H), 2.85-2.74 (m, 2H), 2.74-2.60 (m, 2H), 2.60-2.50 (m, 1H), 2.21-2.12 (m, 2H), 2.00-1.85 (m, 2H); LCMS: 564 [M+H].
Reaction SMILES: Cl[CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4]1.[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.[C:24]([OH:36])(=[O:35])[CH2:25][C:26]([CH2:31][C:32]([OH:34])=[O:33])([C:28]([OH:30])=[O:29])[OH:27]>CCOCC>[C:24]([OH:36])(=[O:35])[CH2:25][C:26]([CH2:31][C:32]([OH:34])=[O:33])([C:28]([OH:30])=[O:29])[OH:27].[C:24]([OH:36])(=[O:35])[CH2:25][C:26]([CH2:31][C:32]([OH:34])=[O:33])([C:28]([OH:30])=[O:29])[OH:27].[O:11]([CH2:10][CH2:9][N:5]1[CH2:6][CH2:7][CH2:8][CH:3]([CH2:2][N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:4]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C1CCNCC1
Reactant: ClCC1CCCN(CCOc2ccccc2)C1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCOCC
Product: c1ccc(OCCN2CCCC(CN3CCCCC3)C2)cc1

Procedure:
A mixture of 3-chloromethyl-1-(2-phenoxyethyl)piperidine (2.8 g) and piperidine (15 ml) was heated on a steam bath for 24 hours. The excess piperidine was removed under reduced pressure and the residue purified by azeotropic distillation with toluene. The residue was dissolved in ether/water and then basified to pH 14. The mixture was extracted with ether and the combined ether extracts yielded an oil which was dissolved in ether and acidified with ethereal citric acid to give a solid which was collected by filtration to give 1-(2-phenoxyethyl)-3-(piperidin-1-ylmethyl)piperidine dicitrate, m.p. 88°-89° C. (with decomposition).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH:6]([NH2:8])[CH:5]([CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:3]1.[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17](Cl)=[O:18]>>[CH:9]([C@@H:5]1[CH2:4][CH2:3][C@@H:2]([CH3:1])[CH2:7][C@@H:6]1[NH:8][C:17]([C:13]1[O:12][CH:16]=[CH:15][CH:14]=1)=[O:18])([CH3:11])[CH3:10].[CH:9]([C@H:5]1[CH2:4][CH2:3][C@H:2]([CH3:1])[CH2:7][C@H:6]1[NH:8][C:17]([C:13]1[O:12][CH:16]=[CH:15][CH:14]=1)=[O:18])([CH3:11])[CH3:10]
Reactant: O=C(Cl)c1ccco1
Reactant: CC1CCC(C(C)C)C(N)C1
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1NC(=O)c1ccco1
Product: CC(C)[C@H]1CC[C@H](C)C[C@H]1NC(=O)c1ccco1

Procedure:
The aforementioned product is obtained as a colorless solid containing in total 94.7% of the desired neomenthylamine derivatives from racemic neomenthylamine, as in the GP, by reaction with furan-2-carbonyl chloride. Furthermore, two further isomeric menthylamine derivatives are present at 3.8% and 1.3%, corresponding to a purity over all stereoisomers of 99.8%.
Reaction SMILES: [CH3:1][CH:2]([CH3:45])[CH2:3][C@H:4]([N:15]([CH2:37][O:38][C:39](=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41])[C:16](=[O:36])[C@@H:17]([NH:26][C:27](=[O:35])[CH2:28][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:5]([O:7]CC1C=CC=CC=1)=[O:6]>CO.O.CO.[Pd]>[CH3:1][CH:2]([CH3:45])[CH2:3][C@H:4]([N:15]([CH2:37][O:38][C:39](=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41])[C:16](=[O:36])[C@@H:17]([NH:26][C:27](=[O:35])[CH2:28][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:5]([OH:7])=[O:6]
Reactant: CC(C)C[C@@H](C(=O)OCc1ccccc1)N(COC(=O)C(C)(C)C)C(=O)[C@H](CCc1ccccc1)NC(=O)CN1CCOCC1
Agent: [Pd]
Solvent: O
Solvent: CO
Product: CC(C)C[C@@H](C(=O)O)N(COC(=O)C(C)(C)C)C(=O)[C@H](CCc1ccccc1)NC(=O)CN1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.4 %

Procedure:
Referring to FIG. 45, a slurry of Pd/C (10%) (200 mg) in MeOH/water (9:1) (10 mL) was added to a solution of (S)-benzyl 4-methyl-2-((S)-2-(2-morpholinoacetamido)-4-phenyl-N-((pivaloyloxy)methyl)butanamido)pentanoate (440 mg, 0.7 mmol) in MeOH (100 mL) and the suspension was stirred overnight under an atmosphere of hydrogen at RT. The reaction mixture was filtered over Celite, washed with MeOH and concentrated in vacuo to yield product (345 mg, 92%) as a colorless oil.
Reaction SMILES: O.[NH2:2][NH2:3].[Br:4][C:5]1[N:9]([CH2:10][C:11]#[C:12][CH3:13])[C:8]([C:14]([O:16]C)=O)=[C:7]([CH:18]=O)[N:6]=1.C(O)(=O)C>C(O)C>[Br:4][C:5]1[N:9]([CH2:10][C:11]#[C:12][CH3:13])[C:8]2[C:14](=[O:16])[NH:3][N:2]=[CH:18][C:7]=2[N:6]=1
Reactant: CC#CCn1c(Br)nc(C=O)c1C(=O)OC
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: CC#CCn1c(Br)nc2cn[nH]c(=O)c21

Procedure:
0.31 ml hydrazine hydrate, dissolved in 1 ml of ethanol, are added dropwise at ambient temperature to a solution of 1.80 g methyl 2-bromo-3-(2-butyn-1-yl)-5-formyl-3H-imidazole-4-carboxylate in 25 ml of ethanol. Five minutes later 1.5 ml concentrated acetic acid are added, and the mixture is refluxed for 30 minutes. After cooling the solid precipitate is suction filtered, washed with 10 ml of ethanol and 20 ml diethyl ether and dried.