Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3[CH:8]=[CH:9][C:10]([O:21][CH3:22])=[C:11]4[O:12][C@H:13]5[C:14]([CH:16]=[CH:17][C@@H:18]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1)=[O:15].CO.[CH:25](OC)(OC)OC.CS(O)(=O)=O>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3[CH:8]=[CH:9][C:10]([O:21][CH3:22])=[C:11]4[O:12][C@H:13]5[C:14]([O:15][CH3:25])=[CH:16][CH:17]=[C:18]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1
Reactant: COc1ccc2c3c1O[C@H]1C(=O)C=C[C@H]4[C@@H](C2)N(C)CC[C@]314
Reactant: COC(OC)OC
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Solvent: CO
Product: COC1=CC=C2[C@H]3Cc4ccc(OC)c5c4[C@@]2(CCN3C)[C@H]1O5
Temperature: 25 °C

Procedure:
To a dried 4-neck 5-liter round bottom flask equipped with a mechanical stirrer, heating mantle, pressure equalizing dropping funnel, and reflux condenser under a nitrogen atmosphere were added 100 g of codeinone, 500 mL of methanol and 73.5 mL of trimethyl orthoformate. The resulting mixture was allowed to stir at a temperature of from about 10° to about 15° C. Methanesulfonic acid (42 g) was then added to the flask at a temperature of about 10° C. to about 20° C. over a time period of about 10 minutes. To the resultant solution was added 500 mL of toluene, and the resulting mixture was allowed to reflux for about 3 h at a temperature of about 62° C. to about 64° C. until at least 93% of the codeinone was consumed. The reflux condenser was replaced with a distillation apparatus, the mixture was heated at a temperature of from about 91° C. to about 93° C., and methanol was allowed to distill from the reaction mixture until substantially all the methanol was removed. At various intervals an aliquot of the reaction mixture was removed, quenched in a phosphate buffer solution having a pH value of about 8, and analyzed using HPLC. The reaction mixture was monitored hourly until HPLC analysis showed that the peak corresponding to thebaine was at least about 95 percent of the total peak area (about 3 to 4 h). Dimethylformamide (22.4 mL) was then added to the reaction mixture, and the reaction mixture was heated at a temperature of from about 90° C. to about 95° C. for from about 3 to about 4 h. The mixture was cooled to about 25° C., deionized distilled water (500 mL) was added, and the resultant biphasic mixture was stirred at 25° C. for 0.5 h. The aqueous phase was collected, and to it was added iso-propanol (166 mL). The resultant mixture was heated to reflux, and treated with 25% NaOH (120 mL). The resultant slurry was slowly cooled with stirring to about 25° C. then further cooled to 0° C. to 5° C. and filtered. The solid was then washed with 3×50 mL of 3:1 (v:v) deionized distilled water:iso-propanol and dried under reduced pressure (40 mm Hg) at a temperature of from about 45° to about 50° C. for about 16 h to provide dry thebaine (67–80 g) as an off-white solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CC1(C)COB([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22][C:21]3=[O:30])=[CH:16][C:15]=2[F:31])OC1.Br[C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][C@@:42]([CH3:57])([S:53]([CH3:56])(=[O:55])=[O:54])[C:43]([NH:45][O:46][CH:47]2[CH2:52][CH2:51][CH2:50][CH2:49][O:48]2)=[O:44])=[CH:36][CH:35]=1.O>O1CCOCC1.[Pd+2]>[C:27]([NH:26][CH2:25][C@H:23]1[O:22][C:21](=[O:30])[N:20]([C:17]2[CH:18]=[CH:19][C:14]([C:34]3[CH:35]=[CH:36][C:37]([CH2:40][CH2:41][C@@:42]([CH3:57])([S:53]([CH3:56])(=[O:54])=[O:55])[C:43]([NH:45][O:46][CH:47]4[CH2:52][CH2:51][CH2:50][CH2:49][O:48]4)=[O:44])=[CH:38][CH:39]=3)=[C:15]([F:31])[CH:16]=2)[CH2:24]1)(=[O:29])[CH3:28]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(B3OCC(C)(C)CO3)c(F)c2)C(=O)O1
Reactant: C[C@@](CCc1ccc(Br)cc1)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: [Pd+2]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)NC[C@@H]1CN(c2ccc(-c3ccc(CC[C@](C)(C(=O)NOC4CCCCO4)S(C)(=O)=O)cc3)c(F)c2)C(=O)O1
Temperature: 90 °C

Procedure:
Palladium (II) EnCat (230 mg, 0.07 mmol) was added to a mixture of potassium carbonate (207 mg, 1.5 mmol), N-({(5S)-3-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3-fluorophenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide (234 mg, 0.644 mmol), and 111a (2R)-4-(4-bromophenyl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide which was prepared as in Preparation 7 (200 mg, 0.46 mmol) in dioxane:water (6 mL, 5:1) in a 20 mL sealed vial. The vial was heated overnight at 90° C. The reaction was cooled to ambient temperature, filtered through celite and the filtrate was washed with ethyl acetate (30 mL) and methanol (15 mL). The combined organics were concentrated in vacuo and purified by chromatography on silica gel (gradient: 80:20 heptanes:ethyl acetate to 0:100 heptanes:ethyl acetate, followed by ethyl acetate:methanol 90:10) to furnish the title compound as a light brown gum. Yield 50 mg, 18% theoretical yield. LCMS m/z 604.3 (M−1)
Reaction SMILES: [C:1]1([S:7]([NH:10][NH2:11])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:12](=O)[C:13]1[O:17][CH:16]=[CH:15][CH:14]=1>CO>[O:17]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH:12]=[N:11][NH:10][S:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:8])=[O:9]
Reactant: NNS(=O)(=O)c1ccccc1
Reactant: O=Cc1ccco1
Solvent: CO
Product: O=S(=O)(NN=Cc1ccco1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A four neck flask (1 liter) equipped with a thermometer, a reflux condenser and a stirrer was charged with 86 g (0.5 mol) of benzenesulfonohydrazide and 700 ml of methanol, and 57.6 g (0.6 mol) of furfural was dropwise added thereto in one hour while stirring at room temperature and heated under reflux for about 5 hours. The reaction liquid was cooled down to 20° C. or lower, and then crystal was filtered off and dried under reduced pressure, whereby white crystal was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:11]([O:17][CH3:18])(=[O:16])[CH2:12][C:13]([CH3:15])=[O:14]>N1C=CC=CC=1.C(O)(=O)CCCCC.C1C=CC=CC=1>[CH3:18][O:17][C:11](=[O:16])[C:12](=[CH:4][C:3]1[CH:6]=[CH:7][CH:8]=[C:9]([Cl:10])[C:2]=1[Cl:1])[C:13](=[O:14])[CH3:15]
Reactant: O=Cc1cccc(Cl)c1Cl
Reactant: COC(=O)CC(C)=O
Solvent: CCCCCC(=O)O
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: COC(=O)C(=Cc1cccc(Cl)c1Cl)C(C)=O
Reaction time: 4 h

Procedure:
A mixture containing 8.7 g of 2,3-dichlorobenzaldehyde, 5.8 g of methyl acetoacetate, 28 drops of pyridine and 38 drops of hexanoic acid in 280 ml of benzene is brought to reflux with stirring for 4 hours. It is transferred to a separating funnel and washed with 10% strength sodium bicarbonate solution, then with N hydrochloric acid solution and then with water. The mixture is dried and evaporated. The crystals obtained are washed with isopropyl ether.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([N:8]2[CH2:14][C:13]([O:16][CH3:17])([CH3:15])[CH2:12][N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1.[Cl:25][C:26]1[N:31]=[CH:30][C:29]2[CH:32]=[N:33][NH:34][C:28]=2[CH:27]=1.CNCCNC.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.[Cu]I>[Cl:25][C:26]1[N:31]=[CH:30][C:29]2[CH:32]=[N:33][N:34]([C:2]3[N:7]=[C:6]([N:8]4[CH2:14][C:13]([O:16][CH3:17])([CH3:15])[CH2:12][N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10][CH2:9]4)[CH:5]=[CH:4][CH:3]=3)[C:28]=2[CH:27]=1
Reactant: COC1(C)CN(C(=O)OC(C)(C)C)CCN(c2cccc(Br)n2)C1
Reactant: Clc1cc2[nH]ncc2cn1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COC1(C)CN(C(=O)OC(C)(C)C)CCN(c2cccc(-n3ncc4cnc(Cl)cc43)n2)C1
Temperature: 100 °C
Yield: 70.9 %

Procedure:
To a mixture of tert-butyl 4-(6-bromopyridin-2-yl)-6-methoxy-6-methyl-1,4-diazepane-1-carboxylate (530 mg, 1.33 mmol) and 6-chloro-1H-pyrazolo[4,3-c]pyridine (203 mg, 1.33 mmol) in 1,4-dioxane (30 mL) was added CuI (101 mg, 0.53 mmol), N1,N2-dimethylethane-1,2-diamine (94 mg, 1.06 mmol), and K2CO3 (734 mg, 5.32 mmol). The mixture was heated at 100° C., which was monitored by LCMS. After completion of the reaction, it was concentrated under reduced pressure. The crude material was purified by silica gel chromatography using petroleum ether:EtOAc (3:1˜1:1) as eluting solvents to afford tert-butyl 4-(6-(6-chloro-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-6-methoxy-6-methyl-1,4-diazepane-1-carboxylate as yellow solid (446 mg, 71%). MS (ESI) m/z: 473 [M+H]+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(N2CCOCC2)cc1
Temperature: 60 °C
Reaction time: 48 h
Yield: 88.1 %

Procedure:
To a stirred solution of 4-fluoronitrobenzene (5.0 g, 35.43 mmol) in DMF (40 mL) were added morpholine (4.7 mL, 53.15 mmol) and cesium carbonate (17.3 g, 53.15 mmol). The reaction mixture was stirred at 60° C. for 48 h, then water (50 mL) was added. The solid formed was filtered and washed with water (5×100 mL), then Et2O (3×50 mL) to give the title compound (6.5 g, 88%) as a yellow solid that was used without further purification. δH (DMSO-d6) 8.12-8.02 (2H, m), 7.09-7.00 (2H, m), 3.79-3.68 (4H, m), 4.46-3.37 (4H, m). LCMS (ES+) 208.9 (M+H)+, RT 2.49 minutes (Method 3).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([C:14]23[CH2:21][CH2:20][C:17]([CH2:22][CH2:23][O:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])([CH2:18][CH2:19]2)[CH2:16][O:15]3)[CH:11]=[CH:12][CH:13]=1)[C:2]1C=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:33](C1C=C(C23CCC(CC(O)=O)(CC2)CO3)C=CC=1)C1C=CC=CC=1.O1CCCCC1OC1C=C(C23CCC(CC(OC)=O)(CC2)CO3)C=CC=1>>[O:33]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:1][C:8]1[CH:9]=[C:10]([C:14]23[CH2:21][CH2:20][C:17]([CH2:22][CH2:23][O:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])([CH2:18][CH2:19]2)[CH2:16][O:15]3)[CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)COCCC12CCC(c3cccc(Oc4ccccc4)c3)(CC1)OC2
Reactant: O=C(O)CC12CCC(c3cccc(Oc4ccccc4)c3)(CC1)OC2
Agent: COC(=O)CC12CCC(c3cccc(OC4CCCCO4)c3)(CC1)OC2
Product: CC(C)(C)OC(=O)COCCC12CCC(c3cccc(OC4CCCCO4)c3)(CC1)OC2

Procedure:
tert-Butyl 2-(2-(1-(3-(tetrahydro-2H-pyran-2-yloxy)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)ethoxy)acetate was prepared using a procedure analogous to tert-butyl 2-(2-(1-(3-phenoxyphenyl)-2-oxabicyclo[2.2.2]octan-4-yl)ethoxy)acetate except that 2-(1-(3-phenoxyphenyl)-2-oxabicyclo[2.2.2]octan-4-yl)acetic acid was replace with methyl 2-(1-(3-(tetrahydro-2H-pyran-2-yloxy)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)acetate. The title compound was obtained (1 g, 2.24 mmol, 91% yield) as a clear oil. 1H NMR (500 MHz, CDCl3) δ 7.23-7.19 (m, 1H), 7.12-7.09 (m, 1H), 7.02-6.98 (m, 1H), 6.93 (ddd, J=8.3, 2.5, 0.8 Hz, 1H), 5.43 (t, J=3.3 Hz, 1H), 5.31 (s, 1H), 3.94 (s, 2H), 3.88-3.86 (m, 2H), 3.63-3.54 (m, 3H), 2.05-1.99 (m, 5H), 1.88-1.82 (m, 2H), 1.75-1.69 (m, 5H), 1.69-1.56 (m, 4H), 1.55-1.51 (m, 2H), 1.50 (s, 9H).
Reaction SMILES: CO.[NH2:3][C:4]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:5]=1[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][NH:15][C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:9]=1)=[O:7].[BH4-].[Na+]>C(OC(=O)C)C>[NH2:3][C:4]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:5]=1[CH:6]([OH:7])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][NH:15][C:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:9]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1cccc(CNC(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1ccc(Cl)cc1C(O)c1cccc(CNC(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.6 %

Procedure:
To a methanol (20 ml) solution of 2-amino-3′-tritylaminomethyl-5-chlorobenzophenone (2 g) was added sodium borohydride (227 mg). The mixture was stirred for 3 hours at room temperature, to which was added acetic acid ethyl ester (100 ml). The mixture was washed with water and then dried over anhydrous MgSO4. The solvent was then distilled off, and the residue was purified by means of a silica gel column chromatography to give the-object 2-amino-5-chloro-α-(3-tritylaminomethylphenyl)benzyl alcohol (2.0 g) as a colorless oily product.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=O.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:24])[CH3:23])=[CH:18][CH:17]=1>O1CCCC1>[OH:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:23][C:22]([C:19]2[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[CH:17][CH:18]=2)=[O:24])[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10]
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Reactant: COc1ccc(C(C)=O)cc1
Solvent: C1CCOC1
Product: COc1ccc(C(=O)C=Cc2cc(O)c(O)c([N+](=O)[O-])c2)cc1

Procedure:
The procedure described in Example 8 was repeated using 1.8 g of 3,4-dihydroxy-5-nitrobenzaldehyde and 1.5 g of 4'-methoxyacetophenone in 20 ml of tetrahydrofuran. Yield 1.88 g (60%), m.p. 222°-228° C.
Reaction SMILES: Cl[C:2]1[C:21]([C:22]2[CH:23]=[N:24][CH:25]=[N:26][CH:27]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[CH3:37][N:38]([CH3:45])[C@H:39]1[CH2:43][NH:42][CH2:41][C@@H:40]1[OH:44].C([O-])([O-])=O.[Na+].[Na+]>CC(O)C>[CH3:37][N:38]([CH3:45])[C@@H:39]1[C@@H:40]([OH:44])[CH2:41][N:42]([C:2]2[C:21]([C:22]3[CH:27]=[N:26][CH:25]=[N:24][CH:23]=3)=[CH:20][C:5]([C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]([F:18])([F:19])[F:17])=[CH:11][CH:10]=3)=[O:7])=[CH:4][N:3]=2)[CH2:43]1
Reactant: CN(C)[C@H]1CNC[C@@H]1O
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(-c2cncnc2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)[C@H]1CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2-c2cncnc2)C[C@@H]1O
Temperature: 110 °C
Reaction time: 16 h

Procedure:
6-Chloro-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 223.1, 60 mg, 0.149 mmol) and DIPEA (0.182 mL, 1.043 mmol) were added to a vial containing iPrOH (1 mL). (3S,4S)-4-(Dimethylamino)pyrrolidin-3-ol (50 mg, 0.246 mmol) was added. The mixture was stirred at 110° C. for 16 h. The RM was treated with sat. aq. Na2CO3 (20 mL) and was extracted with EtOAc. The combined extracts were washed with brine (10 mL), dried over Na2SO4, filtered and the filtrate was evaporated off under reduced pressure to give a crude product that was purified by preparative SFC (Column DEAP, from 13% to 18% in 6 min) to afford the title product as a white solid. HPLC (Condition 10) tR=5.62 min, UPLC-MS (Condition 3) tR=0.73 min, m/z=489.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.15 (s, 6H) 2.52-2.59 (m, 1H) 2.87 (dd, J=10.95, 5.08 Hz, 1H) 3.19 (dd, J=11.34, 5.90 Hz, 1H) 3.28 (m, J=11.30, 6.30 Hz, 1H) 3.45 (dd, J=11.34, 6.65 Hz, 1H) 4.08 (quin, J=5.08 Hz, 1H) 5.09 (d, J=5.08 Hz, 1H) 7.36 (d, J=8.60 Hz, 2H) 7.85 (m, J=9.00 Hz, 2H) 8.11 (d, J=2.35 Hz, 1H) 8.80 (d, J=2.35 Hz, 1H) 8.90 (s, 2H) 9.20 (s, 1H) 10.19 (s, 1H).
Reaction SMILES: C(O)C.C1(C)C=CC=CC=1.[CH2:11]([C:14]1[CH:19]=[CH:18][C:17]([CH:20]=[CH:21][CH:22]2[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH2:23]2)=[CH:16][CH:15]=1)[CH2:12][CH3:13]>[H][H].[Pd]>[CH2:11]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH:22]2[CH2:23][CH2:24][C:25](=[O:28])[CH2:26][CH2:27]2)=[CH:16][CH:15]=1)[CH2:12][CH3:13]
Reactant: [H][H]
Reactant: CCCc1ccc(C=CC2CCC(=O)CC2)cc1
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCc1ccc(CCC2CCC(=O)CC2)cc1
Yield: 94 %

Procedure:
In a liquid mixture comprising 200 ml of ethanol and 200 ml of toluene was dissolved 42 g of the 4-(2-(4-n-propylphenyl)ethenyl)cyclohexanone mentioned above, 4 g of palladium/carbon (5%) was added as catalyst, and they were subjected to a catalytic reduction in hydrogen gas atmosphere. After finishing of the reaction, the catalyst was filtered off and the solvent was distilled off under a reduced pressure to obtain 39.8 g of 4-(2-(4-n-propylphenyl)ethyl)cyclohexanone.
Reaction SMILES: CS(O[C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]2[S:13][C:14]3[CH:20]=[C:19]([Br:21])[CH:18]=[CH:17][C:15]=3[N:16]=2)[CH2:7]1)(=O)=O.[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[N:22]1([C@H:6]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]3[S:13][C:14]4[CH:20]=[C:19]([Br:21])[CH:18]=[CH:17][C:15]=4[N:16]=3)[CH2:7]2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CS(=O)(=O)O[C@@H]1CCCN(c2nc3ccc(Br)cc3s2)C1
Reactant: C1CCNCC1
Product: Brc1ccc2nc(N3CCC[C@H](N4CCCCC4)C3)sc2c1
Yield: 24 %

Procedure:
The title compound was prepared by the method of Example 34, substituting (R)-1-(6-bromobenzo[d]thiazol-2-yl)piperidin-3-yl methanesulfonate (Reference Example 12) in place of (S)-1-(6-bromobenzo[d]thiazol-2-yl)piperidin-3-yl methanesulfonate (Reference Example 10) and substituting piperidine in place of azetidine to give (S)-2-(1,3′-bipiperidin-1′-yl)-6-bromobenzo[d]thiazole (0.018 g, 24% yield). 1H NMR (300 MHz, CD3OD) δ ppm 1.45-1.55 (m, 2H), 1.56-1.73 (m, 6H), 1.82-1.95 (m, 1H), 2.04-2.12 (m, 1H), 2.46-2.57 (m, 1H), 2.59-2.74 (m, 4H), 3.04-3.18 (m, 2H), 3.96-4.05 (m, 1H), 4.22-4.30 (m, 1H), 7.33 (d, J=9 Hz, 1H), 7.39 (dd, J=2, 9 Hz, 1H), 7.79 (d, J=2 Hz, 1H); MS (DCI/NH3) m/z 380 (M+H)+.
Reaction SMILES: [O:1]=[S:2]1(=[O:27])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]2[CH:7]=[C:6]([CH:16]([CH2:20][CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[C:17]([OH:19])=O)[CH:5]=[CH:4][C:3]1=2.[CH3:28][N:29]1[CH:33]=[CH:32][C:31]([NH2:34])=[N:30]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1>CN(C)C=O.C(OCC)(=O)C>[O:1]=[S:2]1(=[O:27])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]2[CH:7]=[C:6]([CH:16]([CH2:20][CH:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)[C:17]([NH:34][C:31]3[CH:32]=[CH:33][N:29]([CH3:28])[N:30]=3)=[O:19])[CH:5]=[CH:4][C:3]1=2
Reactant: Cn1ccc(N)n1
Reactant: O=C(O)C(CC1CCOCC1)c1ccc2c(c1)Nc1ccccc1S2(=O)=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1ccc(NC(=O)C(CC2CCOCC2)c2ccc3c(c2)Nc2ccccc2S3(=O)=O)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
600 mg of 2-(5,5-dioxo-5,10-dihydrophenothiazin-2-yl)-3-(tetrahydropyran-4-yl)propionic acid, 120 mg of commercially available 1-methyl-1H-pyrazole-3-amine and 729 μl of N,N-diisopropylethylamine are dissolved in 5 ml of dimethylformamide. 561 mg of HATU and 200 mg of HOAT are added, and the mixture is stirred at room temperature for two hours. The reaction mixture is then diluted by addition of 200 ml of ethyl acetate and washed three times with in each case 50 ml of water and saturated sodium chloride solution. The organic phase is dried over MgSO4, and the solvent is then removed under reduced pressure. The residue is purified by RP-HPLC. This gives 200 mg of 2-(5,5-dioxo-5,10-dihydrophenothiazin-2-yl)-N-(11-methyl-1H-pyrazol-3-yl)-3-(tetrahydropyran-4-yl)propionamide as a colorless lyophilisate.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][Si](C(C)(C)C)(C)C)[C@H:9]1[C@@H:21](O)[C:22]([F:25])([F:24])[F:23])=[O:7])(C)(C)C.[N:27]([C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[C:32]([Cl:38])[C:31]=1[F:39])=C=O>>[Cl:38][C:32]1[C:31]([F:39])=[C:30]([N:27]2[C@H:21]([C:22]([F:23])([F:24])[F:25])[C@@H:9]3[C@H:10]([OH:13])[CH2:11][CH2:12][N:8]3[C:6]2=[O:7])[CH:37]=[CH:36][C:33]=1[C:34]#[N:35]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1[C@@H](O)C(F)(F)F
Reactant: N#Cc1ccc(N=C=O)c(F)c1Cl
Product: N#Cc1ccc(N2C(=O)N3CC[C@@H](O)[C@H]3[C@H]2C(F)(F)F)c(F)c1Cl

Procedure:
The title compound was prepared from (2R,3R)-3-(tert-butyl-dimethylsilanyloxy)-2-[(1R)-(2,2,2-trifluoro-1-hydroxyethyl)]pyrrolidine-1-carboxylic acid tert-butyl ester (66A) and 2-chloro-4-isocyanato-3-fluorobenzonitrile (73C) following procedures analogous to those found in Example 72. LCMS: m/z 364[M+H]+
Reaction SMILES: [C:1]([O:4][CH3:5])(=[O:3])[CH3:2].[C]=O.[H][H]>>[C:1]([O:4][CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH3:5])(=[O:3])[CH3:2]
Reactant: COC(C)=O
Reactant: [H][H]
Agent: [C]=O
Product: CC(=O)OC(C)OC(C)=O

Procedure:
There are few literature or patent references regarding methods for producing ethylidene diacetate. Several of these references disclose methods wherein methyl acetate, carbon monoxide and hydrogen are reacted in the presence of a homogeneous catalyst to produce ethylidene diacetate. While these methods which employ a homogeneous catalyst produce good selectivity and yield, all suffer from several significant disadvantages, including difficulties associated with separating and purifying the reaction products from the catalyst. Conventional homogeneous catalysts employed in these methods include complexes of group VIII transition metals, preferably rhodium, ruthenium, iridium, palladium and platinum. Japanese Patent No. 51-115409 and European Patent No. 0028474 disclose methods for producing ethylidene diacetate using a homogeneous rhodium catalyst. Japanese Patent No. 54-98713 and British Patent No. 1,112,555 disclose methods for producing ethylidene diacetate using homogeneous palladium catalysts. All of these methods suffer from difficulties in separating and purifying the reaction products from the homogeneous catalyst. These prior methods require the use of a distillation process to separate the homogeneous catalyst from the reaction products. For example, the '474 European patent, which discloses a method having a yield of 75.3% ethylidene diacetate based on dimethyl acetate starting material, requires a distillation step to separate the homogeneous catalyst from the reaction products.
Reaction SMILES: Br.Br[CH2:3][C:4]1[C:9]([Cl:10])=[CH:8][N:7]=[CH:6][C:5]=1[Cl:11].[NH2:12][C:13]1[CH:18]=[C:17]([CH3:19])[N:16]=[C:15]([SH:20])[N:14]=1.C(N(CC)CC)C>CCO>[Cl:11][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([Cl:10])[C:4]=1[CH2:3][S:20][C:15]1[N:14]=[C:13]([NH2:12])[CH:18]=[C:17]([CH3:19])[N:16]=1
Reactant: Clc1cncc(Cl)c1CBr
Reactant: Cc1cc(N)nc(S)n1
Agent: Br
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(N)nc(SCc2c(Cl)cncc2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.8 %

Procedure:
A mixture of 4-(bromomethyl)-3,5-dichloropyridine hydrobromide (2.9 g, 10.5 mmol), 4-amino-6-methylpyrimidine-2-thiol (1.0 g, 7.1 mmol), and triethylamine (3 mL, 21.5 mmol) in absolute EtOH (80 mL) was stirred at room temperature overnight. The mixture was evaporated, co-evaporated with EtOAc (20 mL), and dried in vacuo. The solid residue was treated with water (150 mL). The solid product was recovered by filtration, washed with water (2×25 mL), diethyl ether (2×25 mL), and hexanes (2×25 mL), and dried in vacuo, affording the title compound (1.9 g, 92% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.29 (s, 3H), 4.78 (s, 2H), 6.29 (s, 1H), 8.45 (s (br), 2H), 8.69 (s, 2H); M+302.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[C:9]#[N:10])[CH:6]=1.[CH3:15][N+:16]([CH3:18])=[CH2:17].[I-]>CN(C=O)C>[CH3:15][N:16]([CH2:18][C:6]1[N:5]([C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[C:9]#[N:10])[CH:4]=[N:3][C:2]=1[CH3:1])[CH3:17]
Reactant: C=[N+](C)C
Reactant: Cc1cn(-c2ccccc2C#N)cn1
Agent: [I-]
Solvent: CN(C)C=O
Product: Cc1ncn(-c2ccccc2C#N)c1CN(C)C
Yield: 57 %

Procedure:
As described for example 84b, 2-(4-methyl-imidazol-1-yl)-benzonitrile was reacted with Eschenmoser's salt in DMF for 5 h at 90° C. Evaporation of the solvent, aqueous workup and chromatography (SiO2, dichloromethane:methanol=100:0 to 96:4) afforded the title compound as a light yellow oil (yield: 57%). MS: m/e=241.4 [M+H]+.