Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[C:15]2[N:14]=[C:13]([NH:22][C:23]3[CH:24]=[C:25]([CH2:29][CH2:30][OH:31])[CH:26]=[CH:27][CH:28]=3)[N:12]=[CH:11][C:10]=2[CH2:9]1.C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>ClCCl>[CH3:39][S:40]([O:31][CH2:30][CH2:29][C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([NH:22][C:13]2[N:12]=[CH:11][C:10]3[CH2:9][C@@H:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15]=3[N:14]=2)[CH:24]=1)(=[O:42])=[O:41]
Reactant: OCCc1cccc(Nc2ncc3c(n2)-c2ccccc2[C@H](c2ccccc2F)C3)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1cccc(Nc2ncc3c(n2)-c2ccccc2[C@H](c2ccccc2F)C3)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
To a solution of (R)-2-(3-(6-(2-fluorophenyl)-5,6-dihydrobenzo[h]quinazolin-2-ylamino)phenyl)ethanol (4.59 g, 11.17 mmol) in dichloromethane (50 mL) was added triethylamine (2.33 mL, 16.75 mmol) and methanesulfonyl chloride (0.95 mL, 12.28 mmol). The mixture was stirred at room temperature for 1 h, washed with water (60 mL×3), dried over sodium sulfate and concentrated to yield the title compound as a yellow solid (5.37 g, 98% yield). 1H-NMR (DMSO-d6) δ 9.59 (s, 1 H), 8.37-8.35 (dd, 1 H), 8.33 (s, 1 H), 7.80 (s, 1 H), 7.71 (d, J=10.4 Hz, 1 H), 7.54-7.45 (m, 2 H), 7.29-7.22 (m, 3 H), 7.07-7.02 (m, 2 H), 6.82-6.78 (m, 2 H), 4.67 (t, J=6.8 Hz, 1 H), 4.45 (t, J=6.8 Hz, 2 H), 3.22-3.08 (m, 2 H), 3.13 (s, 3 H), 3.01 (t, J=6.4 Hz, 2 H). LCMS m/e 490 [M+H].
Reaction SMILES: [N+:1]([C:4]1[C:9]([Cl:10])=[C:8]([N+:11]([O-:13])=[O:12])[CH:7]=[C:6]([CH3:14])[C:5]=1[C:15](Cl)=[O:16])([O-:3])=[O:2].[NH3:18].O>CC(C)=O>[N+:1]([C:4]1[C:9]([Cl:10])=[C:8]([N+:11]([O-:13])=[O:12])[CH:7]=[C:6]([CH3:14])[C:5]=1[C:15]([NH2:18])=[O:16])([O-:3])=[O:2]
Reactant: Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1C(=O)Cl
Reactant: N
Solvent: O
Solvent: CC(C)=O
Product: Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1C(N)=O

Procedure:
3,5-Dinitro-4-chloro-o-toluoyl chloride is treated with two equivalents of ammonia in cold acetone. The mixture is poured into water and the desired product as a precipitated solid collected by filtration.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:25]=[C:24]([O:26][C@H:27]3[C@H:31]4[O:32][CH2:33][C@@H:34]([OH:35])[C@H:30]4[O:29][CH2:28]3)[N:23]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=1.Br[C:45]1[CH:50]=[CH:49][C:48]([S:51](=[N:56][CH3:57])([N:53]([CH3:55])[CH3:54])=[O:52])=[CH:47][CH:46]=1>O1CCOCC1>[OH:35][C@H:34]1[C@H:30]2[O:29][CH2:28][C@@H:27]([O:26][C:24]3[N:23]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:41])([CH3:42])[CH3:43])[C:5]4=[N:6][C:7]([C:8]5[CH:13]=[CH:12][C:11]([C:45]6[CH:46]=[CH:47][C:48]([S:51](=[N:56][CH3:57])([N:53]([CH3:54])[CH3:55])=[O:52])=[CH:49][CH:50]=6)=[CH:10][CH:9]=5)=[C:2]([Cl:1])[CH:3]=[C:4]4[N:25]=3)[C@H:31]2[O:32][CH2:33]1
Reactant: CN=S(=O)(c1ccc(Br)cc1)N(C)C
Reactant: CC1(C)OB(c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O)n4COCC[Si](C)(C)C)cc2)OC1(C)C
Solvent: C1COCCO1
Product: CN=S(=O)(c1ccc(-c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O)n4COCC[Si](C)(C)C)cc2)cc1)N(C)C

Procedure:
The title compound is prepared from (3R,3aR,6R,6aR)-6-(6-chloro-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazo[4,5-b]pyridin-2-yloxy)hexahydrofuro[3,2-b]furan-3-ol and 4-bromo-N,N,N′-trimethyl-benzenesulfonimidamide following a procedure analogous to that described for Intermediate 3 (Step 3) using 1,4-dioxane as a solvent. LC (method 1): tR=1.06 min; Mass spectrum (ESI+): m/z=700 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9](Cl)=[O:10])[CH2:6]1.[CH3:17][NH2:18]>O1CCCC1.O>[Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9]([NH:18][CH3:17])=[O:10])[CH2:6]1
Reactant: O=C(Cl)N1CC(Oc2ccc(Cl)cc2Cl)C1
Reactant: CN
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)N1CC(Oc2ccc(Cl)cc2Cl)C1
Reaction time: 5 h

Procedure:
A stirred solution of 4.8 g (0.017 mole) of 3-(2,4-dichlorophenoxy)-1-azetidinecarbonyl chloride in 20 mL of tetrahydrofuran was treated with 4 mL (0.05 mole) of 40% aqueous monomethylamine. After stirring for 5 h, the reaction mixture was diluted with 200 mL of water and the precipitated solid collected by filtration (4.6 g). The crude product was recrystallized from acetonitrile yielding 3.4 g (72.7%) of coarse white powder, mp 140°-141° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:36])[NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[C:30]([CH3:35])[CH:29]=4)[N:23]=3)=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:37]([O:39]C)=[O:38])#[N:2].O.[OH-].[Li+].O.Cl.O1CCOCC1>C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:36])[NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[C:30]([CH3:35])[CH:29]=4)[N:23]=3)=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:37]([OH:39])=[O:38])#[N:2]
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4cccc(-c5ccc(C)c(C)c5)n4)cc3)c(C#N)cc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(-c2cccc(NC(=O)c3ccc(Oc4cc5c(cc4C#N)C(C(=O)O)CCO5)cc3)n2)cc1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 86 %

Procedure:
A mixture of methyl 6-cyano-7-(4-(6-(3,4-dimethylphenyl)pyridin-2-ylcarbamoyl)phenoxy)-chroman-4-carboxylate (51.1 mg, 0.09577 mmol), 1.0 M lithium hydroxide monohydrate solution in water (191.5 μl, 0.1915 mmol), and THF (1.5 ml) was stirred for 3 days at ambient temperature. The mixture was quenched with 4.0 M HCl solution in 1,4-dioxane (71.83 μl, 0.2873 mmol). The mixture was purified on silica gel (MeOH in dichloromethane gradient with 1% acetic acid) to provide 42.8 mg of the title compound was obtained as a thin film (86%). MS (apci) m/z=520.2 (M+H).
Reaction SMILES: [H-].[Na+].FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[OH:17][C:18]1[CH:19]=[CH:20][C:21]2[C:22]3[N:23]([CH2:39][CH2:40][N:41]=3)[C:24]([NH:30][C:31]([C:33]3[CH:34]=[N:35][CH:36]=[N:37][CH:38]=3)=[O:32])=[N:25][C:26]=2[C:27]=1[O:28][CH3:29].Cl.Cl[CH2:44][CH2:45][N:46]([CH3:48])[CH3:47]>CN(C=O)C>[CH3:47][N:46]([CH3:48])[CH2:45][CH2:44][O:17][C:18]1[CH:19]=[CH:20][C:21]2[C:22]3[N:23]([CH2:39][CH2:40][N:41]=3)[C:24]([NH:30][C:31]([C:33]3[CH:34]=[N:35][CH:36]=[N:37][CH:38]=3)=[O:32])=[N:25][C:26]=2[C:27]=1[O:28][CH3:29]
Reactant: COc1c(O)ccc2c1N=C(NC(=O)c1cncnc1)N1CCN=C21
Reactant: CN(C)CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: COc1c(OCCN(C)C)ccc2c1N=C(NC(=O)c1cncnc1)N1CCN=C21
Temperature: 25 °C
Yield: 55.9 %

Procedure:
Sodium hydride (865 mg, 22 mmol, 60% dispersion in mineral oil) was diluted in DMF (35 mL). N-(8-Hydroxy-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)pyrimidine-5-carboxamide bis(trifluoroacetate) (1.75 g, 3.1 mmol) was added, followed by 2-chloro-N,N-dimethylethanamine hydrochloride (890 mg, 6.2 mmol). The reaction mixture was stirred at rt until gas evolution ceased and then was heated to 50° C. for 2 h. At this time, the mixture was cooled to rt, and an additional equivalent of 2-chloro-N,N-dimethylethanamine hydrochloride (445 mg, 3.1 mmol) was added. The resulting reaction mixture was stirred at 50° C. overnight. After cooling to rt, the excess sodium hydride was carefully quenched by the addition of water and the mixture was extracted several times with DCM. The combined organic layers were dried (sodium sulfate) and concentrated under reduced pressure. The resultant solid was triturated with EtOAc and hexanes to afford the title compound as a solid (710 mg, 56%): HPLC MS RT=1.09 min, MH+=410.1; 1H NMR (DMSO-d6+2 drops TFA-d) δ: 9.47 (2H, s), 9.39 (1H, s), 8.12 (1H, d), 7.52 (1H, d), 4.61 (4H, m), 4.26 (2H, m), 4.03 (3H, s), 3.67 (2H, br t), 2.93 (6H, s).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C@H:11]([NH2:28])[C:12]1[N:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[C:15]2[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:14]=2[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:30]1[N:38]=[CH:37][N:36]=[C:35]2[C:31]=1[N:32]=[CH:33][N:34]2C1CCCCO1.CCN(C(C)C)C(C)C>CC(O)C>[CH2:1]([O:8][CH2:9][CH2:10][C@H:11]([NH:28][C:30]1[N:38]=[CH:37][N:36]=[C:35]2[C:31]=1[NH:32][CH:33]=[N:34]2)[C:12]1[N:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[C:15]2[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:14]=2[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N[C@@H](CCOCc1ccccc1)c1nc2ccc(F)cc2n1-c1ccccn1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Fc1ccc2nc([C@H](CCOCc3ccccc3)Nc3ncnc4nc[nH]c34)n(-c3ccccn3)c2c1
Temperature: 90 °C
Yield: 100 %

Procedure:
A mixture of (S)-3-benzyloxy-1-(6-fluoro-1-pyridin-2-yl-1H-benzoimidazol-2-yl)propylamine (355 mg, 0.94 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (230 mg, 0.94 mmol) and DIPEA (0.82 mL, 4.7 mmol) in IPA (2 mL) was heated for 16 h at 90° C. After cooling to RT, the volatiles were removed in vacuo and the resulting residue loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-5% MeOH in DCM) to afford the title compound as a yellow solid (465 mg, 86%). LCMS (Method B): RT 3.56 min [M+H]+ 495.1.
Reaction SMILES: [C:1]([CH2:3][CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10])#[N:2].C(O)[CH2:12][CH2:13][CH2:14][OH:15].C(#N)C=C>>[C:14]([O:10][CH2:9][CH2:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][C:1]#[N:2])(=[O:15])[CH:13]=[CH2:12]
Reactant: N#CCCOCCCCO
Reactant: OCCCCO
Solvent: C=CC#N
Product: C=CC(=O)OCCCCOCCC#N

Procedure:
Following the procedures described in Example 1, 4-(2-cyanoethoxy)-1-butanol (bp 148°-152° C./4.5 mm Hg) is prepared from 1,4-butanediol and acrylonitrile, acrylation of which gives the desired product.
Reaction SMILES: [C:1]([NH:22][CH2:23][CH2:24][O:25][P:26](=[O:28])=[O:27])(=[O:21])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH:8]=[CH:9][CH2:10][CH:11]=[CH:12][CH2:13][CH:14]=[CH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(O)(=O)CCC/C=C\CC=CCC=CCC=CCC=CCC>>[C:1]([NH:22][CH2:23][CH2:24][O:25][P:26](=[O:28])=[O:27])(=[O:21])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH:8]=[CH:9][CH2:10][CH:11]=[CH:12][CH2:13][CH:14]=[CH:15][CH2:16][CH:17]=[CH:18][CH2:19][CH3:20]
Reactant: CCCCCC=CCC=CCC=CC/C=C\CCCC(=O)NCCOP(=O)=O
Agent: CCC=CCC=CCC=CCC=CC/C=C\CCCC(=O)O
Product: CCC=CCC=CCC=CCC=CC/C=C\CCCC(=O)NCCOP(=O)=O

Procedure:
This compound was prepared as described above for (5) using 0.5 mmol (151 mg) of cis-5,8,11,14,17-eicosapentaenoic acid; yield 98 mg, (46%); Rf 0.10-0.15 (system B); 1H-NMR (CD3SOCD3, 200 MHz) δ0.9-1.0 (t, 3H, ω-CH3); 1.5-1.6 (t, 2H, CH2); 2.0-2.2 (m, 6H, CH2CO and 2CH2CH═CH); 2.7-2.9 (br s, 8H, 4HC═CH—CH2—CH═CH); 3.2-3.3 (br s, 2H, CH2NH); 3.8-3.9 (br s, 2H, CH2OP); 5.2-5.4 (br s, 10H, 5 HC═CH); 8.2-8.4 (m, 3H, NH and 2POH)
Reaction SMILES: [C:1]1([S:7]([N-:10][C:11](=[O:16])[CH2:12][CH2:13][CH:14]=C)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I([O-])(=O)(=O)=[O:18].[Na+]>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[C:1]1([S:7]([N:10]2[CH:11]([OH:16])[CH2:12][CH2:13][C:14]2=[O:18])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCCC(=O)[N-]S(=O)(=O)c1ccccc1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C1CCC(O)N1S(=O)(=O)c1ccccc1
Reaction time: 0.33 h
Yield: 40.5 %

Procedure:
50 mg of osmium tetraoxide is added to a solution of 5 g of N-benzenesulphonyl-4-pentenoylamide in 150 cm3 of dioxan and 50 cm3 of water. After about 20 minutes, 5.10 g of sodium metaperiodate is added, and after agitating for 1 hour, a further 5.10 g of sodium metaperiodate is added, with agitation for a further 2 hours at ambient temperature. The precipitate formed is filtered off, the filtrate is evaporated to dryness and the residue is dissolved in 50 cm3 of ethyl acetate, treated with activated charcoal, then evaporated to dryness. The residue is triturated in anhydrous ethyl ether, and 2.05 g of the expected product is obtained, which is re-crystallizxed from isopropanol m.p. 121° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].Br[C:20]1[CH:21]=[C:22]([S:27]([N:30]([CH2:32][CH2:33][CH2:34][N:35]([CH3:37])[CH3:36])[CH3:31])(=[O:29])=[O:28])[CH:23]=[CH:24][C:25]=1[CH3:26]>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:20]1[CH:21]=[C:22]([S:27]([N:30]([CH2:32][CH2:33][CH2:34][N:35]([CH3:36])[CH3:37])[CH3:31])(=[O:29])=[O:28])[CH:23]=[CH:24][C:25]=1[CH3:26])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)N(C)CCCN(C)C)cc1Br
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Product: Cc1ccc(S(=O)(=O)N(C)CCCN(C)C)cc1C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C

Procedure:
Following the general method as outlined in Intermediate 20, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 3-bromo-N-(3-dimethylamino-propyl)-4,N-dimethyl-benzenesulfonamide (Intermediate 151), the title compound was obtained after purification by preparative HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[Se](=O)=[O:18]>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[C:9]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[O:18])=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccncc1)c1ccc(Cl)cc1
Reactant: O=[Se]=O
Solvent: C1COCCO1
Product: O=C(C(=O)c1ccc(Cl)cc1)c1ccncc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 89.4 %

Procedure:
A solution of 25 g of 1-(4-chlorophenyl)-2-pyridin-4-yl-ethanone in 285 ml of dioxan was treated with 20 g of selenium dioxide. The mixture was stirred at 100° C. for 1 hour and filtered. The solvent was evaporated and the residue was dissolved in dichloromethane. The solution was washed three times with water, dried over anhydrous magnesium sulphate and evaporated. The residue was dissolved in ethyl acetate, the solution was filtered over silica gel and evaporated to yield 23.7 g of 1-(4-chlorophenyl)-2-pyridin-4-yl-ethanedione, m.p. 119-120° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:36]=[CH:35][C:6]([CH2:7][O:8][C@@H:9]2[C@@H:17](/[CH:18]=[CH:19]/[O:20]C)[O:16][C@H:15]3[C@H:11]([N:12]=[C:13]([N:22]([CH3:24])[CH3:23])[S:14]3)[C@H:10]2[O:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)=[CH:5][CH:4]=1.[I-].[K+]>C(#N)C.O.[Hg](OC(C)=O)OC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C@@H:9]2[C@@H:17]([CH2:18][CH:19]=[O:20])[O:16][C@H:15]3[C@H:11]([N:12]=[C:13]([N:22]([CH3:24])[CH3:23])[S:14]3)[C@H:10]2[O:25][CH2:26][C:27]2[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)=[CH:35][CH:36]=1
Reactant: CO/C=C/[C@H]1O[C@@H]2SC(N(C)C)=N[C@@H]2[C@@H](OCc2ccc(OC)cc2)[C@@H]1OCc1ccc(OC)cc1
Agent: CC(=O)O[Hg]OC(C)=O
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1ccc(CO[C@@H]2[C@H]3N=C(N(C)C)S[C@H]3O[C@H](CC=O)[C@H]2OCc2ccc(OC)cc2)cc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a cold solution of 37 (100 mg, 0.18 mmol) in acetonitrile (20 mL) at −5° C. was added a solution of Hg(OAc)2 (68 mg, 0.21 mmol) in water (10 mL) dropwise. After stirred at 0° C. for 4 h, the reaction mixture was treated with potassium iodide (40 mg, 0.24 mmol) in water (1.6 mL) for 10 min. The reaction solution was quenched with water, extracted with dichloromethane (40 mL), and dried over MgSO4. Removal of solvents gave crude 2-((3aR,5R,6R,7R,7aR)-6,7-bis(4-methoxybenzyloxy)-2-(dimethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-5-yl)acetaldehyde. To a solution of the crude product in dry THF (20 mL) was added NaBH4 (16 mg, 0.42 mmol) at 0° C. in portions. After stirred at 0° C. overnight, the reaction solution was quenched with water (25 mL) and extracted with ethyl acetate (2×20 mL). The combined organic phases were washed with saturated aqueous NH4Cl, dried over MgSO4, and concentrated to give a residue, which was purified by silica gel chromatography, eluted with 20-50% ethyl acetate in petroleum ether to give the product 38 as a light yellow oil (50 mg, 48%). (ES, m/z)[M+H]+ 503.0; 1H NMR (300 MHz, CDCl3) δ 7.15-7.35 (m, 4H), 6.84-6.98 (m, 4H), 6.28 (d, J=6.3 Hz, 1H), 4.45-4.89 (m, 4H), 4.18 (t, J=5.7 Hz, 1H), 3.94 (t, J=4.8 Hz, 1H), 3.87-3.91 (m, 1H), 3.78 (s, 6H), 3.56-3.65 (m, 3H), 2.92 (s, 6H), 1.89-1.98 (m, 1H), 1.62-1.73 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]([CH3:21])([O:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([N+:18]([O-])=O)[CH:9]=1)[CH3:6])[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:22])[C:5]([O:7][C:8]1[CH:13]=[C:12]([C:14]([F:16])([F:17])[F:15])[CH:11]=[C:10]([NH2:18])[CH:9]=1)([CH3:21])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1cc(N)cc(C(F)(F)F)c1
Yield: 87.8 %

Procedure:
13.8 g (43 mmol) of 2-methyl-2-(3-nitro-5-trifluoromethyl-phenoxy)-propionic acid ethyl ester was dissolved in 300 ml of ethanol and hydrogenated with 1.14 g of Pd—C (10%), 1 bar H2, 25° C., for two hours. The reaction mixture was then filtered (Celite), the filter cake was washed twice with ethanol and the filtrate was evaporated. The crude product was purified by flash chromatography (SiO2, heptane/EtOAc) which gave 11.0 g of the title compound as yellow oil.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]12[CH2:13][C:8]3([CH3:14])[CH2:9][CH:10]([CH2:12][C:6]([CH3:15])([CH2:7]3)[CH2:5]1)[CH2:11]2>C1(C)C=CC=CC=1>[CH3:14][C:8]12[CH2:13][C:4]3([CH2:3][CH3:2])[CH2:11][CH:10]([CH2:12][C:6]([CH3:15])([CH2:5]3)[CH2:7]1)[CH2:9]2
Reactant: CC12CC3CC(C)(C1)CC(CCBr)(C3)C2
Solvent: Cc1ccccc1
Product: CCC12CC3CC(C)(CC(C)(C3)C1)C2
Reaction time: 3 h
Yield: 86 %

Procedure:
Dissolve 0.5 mol of 1-(2-bromoethyl)-3,5-dimethyl adamantane (II) in toluene, mix with 0.55 mol of sodium-bis(2-methoxy-ethoxy)dihydro aluminate, and heat to boiling for 3 hrs. After hydrolysis, separate the organic phase, dry with magnesium sulfate, and evaporate to dryness under vacuum. Purify the residue by vacuum distillation. (Yield: 86%).
Reaction SMILES: CS(O[CH:6]1[CH2:13][CH:12]2[CH2:14][CH:8]([O:9][CH:10]([CH2:15][O:16][S:17]([CH3:20])(=[O:19])=[O:18])[O:11]2)[CH2:7]1)(=O)=O.[OH-].[K+].C(=O)(O)[O-].[Na+]>C(O)(C)C>[CH3:20][S:17]([O:16][CH2:15][CH:10]1[O:11][CH:12]2[CH2:14][CH:8]([CH2:7][CH:6]=[CH:13]2)[O:9]1)(=[O:18])=[O:19]
Reactant: CS(=O)(=O)OCC1OC2CC(CC(OS(C)(=O)=O)C2)O1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)O
Product: CS(=O)(=O)OCC1OC2C=CCC(C2)O1

Procedure:
To a hot suspension of 280 mg of 7-methylsulphonyloxy-3-methylsulphonyloxymethyl-2,4-dioxabicyclo[3,3,1]nonane in 2,5 ml of isopropanol is added 2,5 ml of a boiling 2n potassium hydroxide solution in isopropanol while stirring vigorously, and the resulting reaction mixture is boiled under reflux for 3 minutes. The reaction mixture is cooled and treated with 5 ml of an 8% sodium bicarbonate solution, then extracted 3 times with methylene chloride. The combined extracts are dried over sodium sulphate and the solvent is distilled off in vacuo uner reduced pressure to leave as residue the racemic 3-methylsulphonyloxymethyl-2,4-dioxabicyclo[3,3,1]non-6-ene in the form of a colourless oil, which soon congeals to a crystalline solid (m.p. 53°-56°C).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[O:11])=[CH:4][CH:3]=1.B([C:30]1[CH:38]=[CH:37][C:33]([C:34]([OH:36])=[O:35])=[CH:32][CH:31]=1)(O)O>>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:30]3[CH:38]=[CH:37][C:33]([C:34]([OH:36])=[O:35])=[CH:32][CH:31]=3)=[CH:3][CH:4]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[O:11])=[C:20]([CH3:26])[CH:21]=1
Reactant: Cc1cc(C(=O)C[C@@H](c2ccc(Br)cc2)c2ccc(Cl)cc2C)ccn1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Product: Cc1cc(C(=O)C[C@@H](c2ccc(-c3ccc(C(=O)O)cc3)cc2)c2ccc(Cl)cc2C)ccn1

Procedure:
In analogy to example 74, step 6, from (S)-3-(4-bromo-phenyl)-3-(4-chloro-2-methyl-phenyl)-1-(2-methyl-pyridin-4-yl)-propan-1-one (example 282, step 1) and 4-boronobenzoic acid was prepared the title compound as an yellow foam.
Reaction SMILES: [CH2:1]([N:8]([CH2:14][CH2:15][OH:16])[CH2:9][CH:10](Cl)[C:11]#[N:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(C)(C)C.[K+].C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1>[CH2:1]([N:8]1[CH2:14][CH2:15][O:16][CH:10]([C:11]#[N:12])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CC(Cl)CN(CCO)Cc1ccccc1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#CC1CN(Cc2ccccc2)CCO1
Reaction time: 2 h
Yield: 44.7 %

Procedure:
The crude compound 3-(benzyl(2-hydroxyethyl)amino)-2-chloro-propanenitrile 2b (8 g, 0.03 mol) was dissolved in 70 mL of tetrahydrofuran followed by the addition of potassium tert-butanolate (5.50 g, 0.05 mol) in an ice-water bath. The resulting solution was stirred for 2 hours, heated to reflux for 1 hour, added with 50 mL of saturated sodium carbonate solution, and extracted with ethyl acetate (40 mL×3). The combined organic phase was washed with saturated sodium chloride solution (50 mL×3), then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 4-benzylmorpholine-2-carbonitrile 2c (2.71 g, yield: 41.0%) as a yellow oil liquid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13]C(=O)C)=[C:9]([Br:17])[CH:8]=2)[N:6]=1.Cl.[OH-].[Na+]>O>[CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]([Br:17])[CH:8]=2)[N:6]=1
Reactant: CC(=O)Nc1ccc(-c2c[nH]c(C)n2)cc1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1nc(-c2ccc(N)c(Br)c2)c[nH]1
Temperature: 25 °C
Yield: 77.8 %

Procedure:
A mixture of 2-methyl-4-(3-bromo-4-acetamido-phenyl)-1H-imidazole (15 g), concentrated hydrochloric acid (10 ml) and water (30 ml) was refluxed for 45 minutes. The resulting solution was cooled to room temperature and was made alkaline with 10% sodium hydroxide. The base was filtered off, washed with water and dried to give 10 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15][C:5]=3[C:4]=2[C:3]=1[Cl:23].[H-].[Na+].Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:6]3[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:14][CH2:15][C:5]=3[C:4]=2[C:3]=1[Cl:23]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3ccc(Cl)c(Cl)c3c2CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c2c(c3c(Cl)c(Cl)ccc31)CCN(C(=O)OC(C)(C)C)CC2
Reaction time: 0.25 h
Yield: 68.8 %

Procedure:
To a solution of tert-butyl 9,10-dichloro-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.10 g; 0.28 mmol) in DMF (2 mL), sodium hydride (60% dispersion in mineral oil, 17 mg, 0.42 mmol) was added. After 15 min, ethyl bromoacetate (0.060 mL, 0.56 mmol) was added. The reaction was quenched with saturated aqueous NH4Cl after 2.5 h and extracted with EtOAc (3×15 mL). The combined organic extracts were washed with brine, dried over Na2SO4, decanted, and concentrated. The crude product was purified by column chromatography (Biotage, 40S) with heptane/EtOAc (3:1) to give 85 mg (70%) of a white solid: mp 136.5-138.0° C.; 1H NMR (300 MHz, CDCl3) δ 7.19 (d, J=8.7 Hz, 1H), 6.99 (d, J=8.7 Hz, 1H), 4.74 (s, 2H), 4.21 (dd, J=7.1, 7.1 Hz, 2H), 3.75 (m, 4H), 3.53 (m, 2H), 2.93 (m, 2H), 1.48 (s, 9H), 1.26 (t, J=7.1 Hz, 3H); IR (diffuse reflectance) 2985, 2976, 1737, 1685, 1466, 1450, 1414, 1367, 1344, 1249, 1213, 1169, 1156, 1115, 926 cm−1; MS (EI) m/z 440 (M+), 307, 305, 301, 299, 298, 272, 225, 189, 58, 56; Anal. Calcd for C21H26Cl2N2O4: C, 57.15; H, 5.94; N, 6.35; found: C, 57.16; H, 5.98; N, 6.27.