Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]([C:16]1[C:21](=[O:22])[C:20]([CH3:23])=[C:19]([CH3:24])[C:18](=[O:25])[C:17]=1[CH3:26])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([OH:3])=[O:2].[N+](=[CH2:29])=[N-].CCOCC>CCOCC>[CH3:29][O:2][C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]([C:16]1[C:21](=[O:22])[C:20]([CH3:23])=[C:19]([CH3:24])[C:18](=[O:25])[C:17]=1[CH3:26])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:3]
Reactant: C=[N+]=[N-]
Reactant: CC1=C(C)C(=O)C(C(CCCCCC(=O)O)c2ccccc2)=C(C)C1=O
Solvent: CCOCC
Product: COC(=O)CCCCCC(C1=C(C)C(=O)C(C)=C(C)C1=O)c1ccccc1

Procedure:
6-(6-Carboxy-1-phenylhexyl)-2,3,5-trimethylbenzoquinone (29 g) was suspended in ether (500 ml). Diazomethane/ether solution was added until the raw material was disappeared on thin-layer chromatography. Then the ether layer was washed with water, dried over anhydrous sodium sulfate and concentrated. The concentrate was subjected to short column chromatography using silica gel (500 ml) and eluted with hexane/dichloromethane (1:1) to obtain 6-(6-methoxycarbonyl-1-phenylhexyl)-2,3,5-trimethylbenzoquinone (25.5 g) as an orange oil. This oil was dissolved in ether (200 ml) and stirred at room temperature for 1.5 hours with a solution containing sodium hydrosulfite (52 g) in water (200 ml). The ether layer was separated and washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to obtain 6-(6-methoxycarbonyl-1-phenylhexyl)-2,3,5-trimethylhydroquinone (25.5 g). Then this compound was dissolved in dichloromethane (35 ml), imidazole (9.37 g, 2 eq.) was added, tert-butyldiphenylsilyl chloride (28.36 g, 1.5 eq.) was added dropwise with stirring at room temperature and the mixture was allowed to react overnight. The deposited imidazole hydrochloride was filtered off, and the filtrate was concentrated. The concentrate was subjected to column chromatography on silica gel (800 ml) and eluted with dichloromethane/hexane (2:1) to obtain the desired compound as a pale yellow viscous oil (46 g).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([S:12](=[O:17])(=[O:16])[N:13]([CH3:15])[CH3:14])[CH:6]=1)=[O:4].[OH:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][CH3:29])=[S:27])=[CH:21][CH:20]=1>CC(C)=O.C(O)C.C(OCC)(=O)C>[BrH:1].[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2([OH:4])[CH2:2][S:27][C:26](=[N:25][C:22]3[CH:23]=[CH:24][C:19]([OH:18])=[CH:20][CH:21]=3)[N:28]2[CH3:29])=[CH:6][C:7]=1[S:12](=[O:17])(=[O:16])[N:13]([CH3:15])[CH3:14]
Reactant: CN(C)S(=O)(=O)c1cc(C(=O)CBr)ccc1Cl
Reactant: CNC(=S)Nc1ccc(O)cc1
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: CCO
Product: Br
Product: CN1C(=Nc2ccc(O)cc2)SCC1(O)c1ccc(Cl)c(S(=O)(=O)N(C)C)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
6.8 g (0.02 mole) of 2-bromo-4'-chloro-3'-dimethylsulfamoylacetophenone are dissolved in 60 ml of acetone or 150 ml of ethanol or 50 ml of ethyl acetate and, after addition of a solution of 3.7 g (0.022 mole) of 1-(4-hydroxyphenyl)-3-methyl-thiourea in 60 ml of acetone or 50 ml of ethanol or 100 ml of ethyl acetate, the solution is stirred at room temperature for 1 to 4 hours, the crystals are filtered off and, after washing with a little acetone and ether, dried in a cool stream of air or in vacuo over paraffin shavings. Colorless crystals, m.p. 255°-264° C. with decomposition, by slow heating; m.p. 178°-180° C., by rapid heating.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[CH2:13][CH2:12][NH:11][CH2:10][C:9]=3[C:14](=[O:16])[O:15][C:4]=2[CH:3]=1.C(N(CC)CC)C.Cl[CH2:25][C:26](=[O:28])[CH3:27]>C(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[CH2:13][CH2:12][N:11]([CH2:25][C:26](=[O:28])[CH3:27])[CH2:10][C:9]=3[C:14](=[O:16])[O:15][C:4]=2[CH:3]=1
Reactant: CC(=O)CCl
Reactant: Cc1ccc2c3c(c(=O)oc2c1)CNCC3
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(=O)CN1CCc2c(c(=O)oc3cc(C)ccc23)C1
Yield: 77.8 %

Procedure:
A mixture of 1,2,3,4-tetrahydro-8-methyl-5H-[1]benzopyrano[3,4-c]pyridin-5-one (2.0 g, 0.009 moles), triethylamine (1.4 ml, 0.010 moles), and 1-chloro-2-propanone (0.8 g, 0.009 moles) in ethanol (50 ml) is stirred and heated to reflux. After 20 hours the mixture is cooled and the precipitate filtered off, rinsed with ethanol, and dried to give the product (1.9 g), mp 128°-129° C.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([N:28]1[C:37]2[C:32](=[CH:33][C:34]([NH2:38])=[CH:35][CH:36]=2)[C:31]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([CH3:39])[CH2:30][C:29]1([CH3:47])[CH3:46])(=[O:27])[CH3:26].[Br:48][C:49]1[CH:50]=[C:51]([CH:55]=[C:56]([Br:58])[CH:57]=1)[C:52](O)=[O:53].C(N(CC)C(C)C)(C)C>O1CCCC1>[C:25]([N:28]1[C:37]2[C:32](=[CH:33][C:34]([NH:38][C:52](=[O:53])[C:51]3[CH:50]=[C:49]([Br:48])[CH:57]=[C:56]([Br:58])[CH:55]=3)=[CH:35][CH:36]=2)[C:31]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([CH3:39])[CH2:30][C:29]1([CH3:47])[CH3:46])(=[O:27])[CH3:26]
Reactant: O=C(O)c1cc(Br)cc(Br)c1
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)N1c2ccc(NC(=O)c3cc(Br)cc(Br)c3)cc2C(C)(c2ccccc2)CC1(C)C

Procedure:
HATU condensation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) with 3,5-dibromobenzoic acid (10 mg) and N,N-diisopropylethylamine (22 μl) in tetrahydrofuran (1 ml) was performed according to the method described in example 11.
Reaction SMILES: Cl.N1C=CC=CC=1.C[O:9][C:10]1[CH:11]=[C:12]([C:16]2[N:20]=[C:19]([S:21]([NH2:24])(=[O:23])=[O:22])[S:18][N:17]=2)[CH:13]=[CH:14][CH:15]=1>>[OH:9][C:10]1[CH:11]=[C:12]([C:16]2[N:20]=[C:19]([S:21]([NH2:24])(=[O:23])=[O:22])[S:18][N:17]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: COc1cccc(-c2nsc(S(N)(=O)=O)n2)c1
Agent: Cl
Solvent: c1ccncc1
Product: NS(=O)(=O)c1nc(-c2cccc(O)c2)ns1
Temperature: 0 °C

Procedure:
Pyridine hydrochloride (160 g) was preheated to 205° and 8 g of finely ground 3-(3-methoxyphenyl)-1,2,4-thiadiazole-5-sulfonamide was added. Said temperature was maintained for 15 minutes. The mixture was then poured into ice water (1000 ml) and extracted with ethyl acetate (3×500 ml), and the extracts were washed with saturated sodium chloride solution (500 ml) and dried over anhydrous magnesium sulfate. Concentration gave 5.3 g of product. Flash chromatography using 10% ethyl acetate/dichloromethane as an eluent gave 2.3 g of product. This was combined with 0.7 g of product from a previous reaction and recrystallized in hot water to give 2.2 g of solid, m.p. 191°-192°.
Reaction SMILES: [O-:1][C:2]#[N:3].[Na+].O.[NH2:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([NH2:12])=[O:11]>C(O)(=O)C>[NH:6]([C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([NH2:12])=[O:11])[C:2]([NH2:3])=[O:1]
Reactant: N#C[O-]
Reactant: NC(=O)c1cccc(N)c1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: NC(=O)Nc1cccc(C(N)=O)c1
Reaction time: 0.25 h
Yield: 78.1 %

Procedure:
Sodium cyanate (1.3 gm, 20 mMole) in 9.0 ml or water was added over a 15 minute period to a solution of 3-aminobenzamide (1.36 gm, 10 mMole) in acetic acid at 35° C. The mixture was stirred for a further 15 minutes during which time a white precipitate formed. This was filtered off, washed with cold water and crystallized from 25% ethanol to give 1.4 gm (78%) of shiny crystals. m.p. >300° C.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][C:24](=[O:28])[NH:25][CH2:26][CH3:27])[CH:21]=4)[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][N:8]2[CH2:9][CH2:10][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][C:24](=[O:28])[NH:25][CH2:26][CH3:27])[CH:21]=4)[CH:16]=[CH:15]3)[CH2:12][CH2:13]2)=[CH:29][CH:30]=1
Reactant: CCNC(=O)Cc1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CCNC(=O)Cc1ccc2ccn(C3CCN(CCc4ccc(F)cc4)CC3)c2c1
Temperature: 50 °C
Reaction time: 6 h
Yield: 80.9 %

Procedure:
A suspension of 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(ethylcarbamoylmethyl)indoline (0.41 g) obtained in Example 149 and active manganese dioxide (0.40 g) in chloroform (30 ml) was vigorously stirred at 50° C. for 6 hr. Then the reaction mixtures were filtered through celite and the residue was washed with chloroform. After concentrating the filtrate under reduced pressure, the residue was recrystallized from chloroform/hexane to give the title compound (0.33 g) as white needles (yield: 89.5%).
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[CH2:21][C:22]1[CH:23]=[C:24]([Cl:29])[C:25]([Cl:28])=[N:26][CH:27]=1>C(Cl)(Cl)Cl>[Cl:28][C:25]1[C:24]([Cl:29])=[CH:23][C:22]([CH:21]=[CH2:1])=[CH:27][N:26]=1
Reactant: Clc1cc(CBr)cnc1Cl
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: C=Cc1cnc(Cl)c(Cl)c1
Reaction time: 2 h
Yield: 129.9 %

Procedure:
2.9 g of triphenylphosphine was added to 3.6 g of compound (7) (14.9 mmol) prepared in Example 4 dissolved in 20 mL of chloroform and the mixture was reacted at 120° C. for 10 minutes by radiating with microwave radiation. And the mixture concentrated under reduced pressure to remove chloroform, and then crystallized from diethyl ether. The crystal was added to 5 mL of 40% formaldehyde, and 50% NaOH was slowly added dropwise to be a concentration of 1.7 N. After stirring for 2 hours, the resultant was extracted with ether, and concentrated under reduced pressure. The residue was separated by column chromatography (eluting solvent: chloroform/methanol=30/1) to obtain 2.5 g of 2,3-dichloro-5-vinylpyridine (yield 97%).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]2[C@H:15]3[C@H:25]([CH2:26][CH2:27][C@:10]12[CH3:11])[C@:23]1([CH3:24])[C@H:18]([CH2:19][C:20](=[O:28])[CH2:21][CH2:22]1)[CH2:17][C@H:16]3[CH2:29][CH2:30][CH2:31][C:32]1[CH:37]=[C:36]([OH:38])[CH:35]=[C:34]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:33]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].[CH2:49]([O:56][C:57](=[O:62])[CH2:58][CH2:59][CH2:60]Br)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1.O>CN(C=O)C>[Si:1]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]2[C@H:15]3[C@H:25]([CH2:26][CH2:27][C@:10]12[CH3:11])[C@:23]1([CH3:24])[C@H:18]([CH2:19][C:20](=[O:28])[CH2:21][CH2:22]1)[CH2:17][C@H:16]3[CH2:29][CH2:30][CH2:31][C:32]1[CH:37]=[C:36]([O:38][CH2:60][CH2:59][CH2:58][C:57]([O:56][CH2:49][C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)=[O:62])[CH:35]=[C:34]([O:39][CH2:40][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:33]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: O=C(CCCBr)OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H]2[C@@H]3[C@H](CCCc4cc(O)cc(OCc5ccccc5)c4)C[C@H]4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H]2[C@@H]3[C@H](CCCc4cc(OCCCC(=O)OCc5ccccc5)cc(OCc5ccccc5)c4)C[C@H]4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 0.5 h

Procedure:
A solution of 17β-(tert-butyldimethylsilyloxy)-7α-(3-(3-benzyloxy-5-hydroxyphenyl)propyl)-5α-androstan-3-one (21.0 mg) in DMF (0.3 ml) was cooled on ice, followed by addition of sodium hydride (1.6 mg) and 15-crown-5-ether (7.8 μl). After the reaction mixture was stirred for 30 minutes, 4-bromo-n-butyric acid benzyl ester (10 mg) was added and stirred on ice for 1 hour. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and then filtered. After evaporation under reduced pressure to remove the solvent, the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/4) to give 17β-(tert-butyldimethylsilyloxy)-7α-(3-(3-benzyloxy-5-(3-(benzyloxycarbonyl)propoxy)phenyl)propyl)-5α-androstan-3-one.
Reaction SMILES: Cl[C:2]1[S:10][C:9]2[S:8](=[O:12])(=[O:11])[NH:7][N:6]=[C:5]([CH3:13])[C:4]=2[CH:3]=1.C([Li])CCC.[S:19](=[O:21])=[O:20].O.O.O.C([O-])(=O)C.[Na+].[NH2:30]OS(O)(=O)=O>C1COCC1.O>[CH3:13][C:5]1[C:4]2[CH:3]=[C:2]([S:19]([NH2:30])(=[O:21])=[O:20])[S:10][C:9]=2[S:8](=[O:12])(=[O:11])[NH:7][N:6]=1
Reactant: CC1=NNS(=O)(=O)c2sc(Cl)cc21
Reactant: NOS(=O)(=O)O
Reactant: O=S=O
Agent: CC(=O)[O-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC1=NNS(=O)(=O)c2sc(S(N)(=O)=O)cc21
Temperature: -78 °C
Reaction time: 18 h

Procedure:
The product from step A (1.5 g, 6.30 mmol) was dissolved in dry THF (60 mL) and cooled to -78° C. under nitrogen. n-Butyllithium (5.33 mL of a 2.5 M solution in hexanes, 13.3 mmol) was added dropwise and the mixture was stirred for 1h at -78° C. A stream of sulfur dioxide gas was passed through the surface of the mixture for 15 min and then the mixture was allowed to warm to room temperature. Evaporation of the volatiles provided a residue which was dissolved in water (60 mL) to which was added sodium acetate trihydrate (2.59 g, 19.06 mmol). This solution was cooled to 0° C. and hydroxylamine-O-sulfonic acid (2.15 g, 19.06 mmol) was added followed by stirring for 18h. The reaction mixture was extracted with ethyl acetate (2×50 mL). The combined extracts were dried over MgSO4 and concentrated to a crude oil which was purified by flash column chromatography (silica, hexane-ethyl acetate gradient) to lead to a white solid (1 g, 50%). decomposition: >163° C. 1H NMR (DMSO-d6): δ:2.48 (3H, 1s, CH3); 8.17 (2H, s, NH2 exchangeable).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[S:5](Cl)([CH3:8])(=[O:7])=[O:6].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>N1C=CC=CC=1>[CH3:8][S:5]([NH:4][CH2:3][CH2:1][O:2][S:5]([CH3:8])(=[O:7])=[O:6])(=[O:7])=[O:6]
Reactant: CS(=O)(=O)Cl
Reactant: NCCO
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: c1ccncc1
Product: CS(=O)(=O)NCCOS(C)(=O)=O
Reaction time: 0.5 h

Procedure:
A stirred solution of ethanolamine (9.15 g) in pyridine (40 ml) was cooled to 0° C. in an ice-salt bath, and mesylchloride (23 ml) was added dropwise at such a rate that the temperature did not rise above 5° C. When the addition was complete the mixture was allowed to rise to room temperature for 1/2 hour. The mixture was poured into citric acid solution and continuously extracted with ehtylacetate for 11/2 hours. The solution was dried over magnesium sulphate and evaporated to give 23.7 g of the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]([C:22]1C=C(O)C(=C[CH:28]=1)O)(C)(C)[CH3:19].[C:30]1(C)[CH:35]=CC=[CH:32][CH:31]=1>>[CH2:30]([CH:12]1[CH:11]2[C:10]([C:13]([OH:15])=[O:14])([CH2:19][CH:18]=[CH:22][CH2:28]2)[CH2:9][N:8]1[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH3:31].[CH2:1]([N:8]1[CH2:9][C:10]2([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]([CH2:35][CH:30]=[CH:31][CH2:32]2)[CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccccc1
Reactant: CC(C)(C)c1ccc(O)c(O)c1
Reactant: CCOC(=O)C1=CCN(Cc2ccccc2)C1
Product: CCC1C2CC=CCC2(C(=O)O)CN1Cc1ccccc1
Product: CCOC(=O)C12CC=CCC1CN(Cc1ccccc1)C2
Temperature: 120 °C

Procedure:
231 g (1 mol) of ethyl 1-benzyl-2,5-dihydropyrrole-3-carboxylate and 10 g of 4-tert-butylpyrocatechol are dissolved in 1500 ml of toluene, 20 bar of nitrogen are injected and 350 g of 1,3-betadiene are then blown into the autoclave. The mixture is heated at 120° C. for three days and cooled, the pressure is released, and the solution is concentrated and distilled. Yield: 264.9 g (87.6% of theory), boiling point: 127°-140° C./0.1 mbar. The product is 94% pure according to gas-chromatographic detemination.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13](Br)[CH:12]=1)[CH2:9][OH:10])(C)(C)C.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21](B(O)O)[CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].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(OCC)(=O)C>[NH2:7][CH:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:21]2[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=2)[CH:12]=1)[CH2:9][OH:10]
Reactant: OB(O)c1cccnc1
Reactant: CC(C)(C)OC(=O)NC(CO)c1cccc(Br)c1
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: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Product: NC(CO)c1cccc(-c2cccnc2)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 100.7 %

Procedure:
To a solution of [1-(3-bromo-phenyl)-2-hydroxy-ethyl]-carbamic acid tert-butyl ester (160 mg, 0.51 mmol) in ethyleneglycoldimethylether (10 mL) in a sealed tube were added pyridine-3-boronic acid (82 mg, 0.66 mmol), cesium carbonate (500 mg, 1.53 mmol) and water (2 mL). Argon was bubbled through the solution for 10 min, and Pd(PPh3)4 (30 mg, 0.025 mmol) was added. The reaction mixture was heated at 100° C. for 6 h. The reaction mixture was cooled down to room temperature, and ethyl acetate (20 mL) was added. The reaction mixture was washed with saturated NH4Cl (2×10 mL), and the organic layer was dried over anhydrous magnesium sulfate, filtered. The filtrate was concentrated in vacuo, and the crude product was diluted in CH2Cl2 (8 mL) and trifluoroacetic acid (2 mL). The reaction mixture was agitated for 1 h and concentrated in vacuo. The residue was purified by solid phase extraction (SCX cartridge, silca gel benzene sulfonic acid linked) to give the title product (110 mg, 100% yield) as brown oil.
Reaction SMILES: [ClH:1].C([NH:9][CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][C:14]([O:20][CH:21]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH2:23][CH2:24][CH3:25])=[CH:15][CH:16]=2)[CH2:11]1)C1C=CC=CC=1>C(O)C.[Pd]>[ClH:1].[NH2:9][CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][C:14]([O:20][CH:21]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH2:23][CH2:24][CH3:25])=[CH:15][CH:16]=2)[CH2:11]1
Reactant: CCCCC(Oc1ccc2c(c1)CC(NCc1ccccc1)CC2)C(=O)OCC
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCCCC(Oc1ccc2c(c1)CC(N)CC2)C(=O)OCC
Yield: 78.1 %

Procedure:
A solution of 2-benzylamino-7-(ethoxycarbonylpentan-5-yloxy) tetralin hydrochloride (8.9 g), prepared as described in Example 1, in 95% ethanol (150 ml) is hydrogenated at atmospheric pressure and 60° C. in the presence of 10% Pd/C (1 g) as the hydrogenation catalyst. After 3 hours the catalyst is filtered off, the filtrate is concentrated to dryness and the residue is twice taken up in absolute ethanol (100 ml) and concentrated to dryness. The obtained product is then triturated with acetone (100 ml), filtered and crystallized from isopropanol (50 ml) affording 5.5 g of the compound indicated in the title. M.p. 114°-117° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:14]([NH:16][C:17]2[CH:21]=[CH:20][N:19](C(OC(C)(C)C)=O)[N:18]=2)=[O:15])[CH:5]=[C:6]([O:8][C@@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:7]=1.F[C:30]1[CH:35]=[C:34](F)[C:33]([F:37])=[CH:32][C:31]=1[S:38]([CH:41]1[CH2:45][CH2:44][O:43]C1=O)(=[O:40])=[O:39].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[F:37][C:33]1[C:34]([O:1][C:2]2[CH:3]=[C:4]([CH:5]=[C:6]([O:8][C@@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:7]=2)[C:14]([NH:16][C:17]2[CH:21]=[CH:20][NH:19][N:18]=2)=[O:15])=[CH:35][C:30]2[O:43][CH2:44][CH2:45][CH2:41][S:38](=[O:40])(=[O:39])[C:31]=2[CH:32]=1
Reactant: COC[C@H](C)Oc1cc(O)cc(C(=O)Nc2ccn(C(=O)OC(C)(C)C)n2)c1
Reactant: O=C1OCCC1S(=O)(=O)c1cc(F)c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COC[C@H](C)Oc1cc(Oc2cc3c(cc2F)S(=O)(=O)CCCO3)cc(C(=O)Nc2cc[nH]n2)c1
Reaction time: 1 h
Yield: 22.9 %

Procedure:
1,1-Dimethylethyl 3-{[(3-hydroxy-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}phenyl) carbonyl]amino}-1H-pyrazole-1-carboxylate (145 mg, 0.5 mmol), 3-[(2,4,5-trifluorophenyl)sulfonyl]dihydrofuran-2(3H)-one (140 mg, 0.5 mmol) and potassium carbonate (138 mg, 2 mmol) in acetonitrile (4 mL) were heated at 130° C. for 1 hour then 160° C. for a further 1 hour in a microwave reactor. Water was added to the reaction mixture and the phases separated. The aqueous phase was extracted with ethyl acetate (3×20 mL), and the combined organics washed with 1M hydrochloric acid, a saturated sodium bicarbonate solution, brine, dried (MgSO4), filtered and evaporated. The residue was chromatographed on alumina, eluting with 0-10% methanol in DCM, to give the desired compound as a white solid (58 mg).
Reaction SMILES: [CH:1]([C:3]1[S:11][C:10]2[C:9](=[O:12])[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][N:6]([CH3:18])[C:5]=2[CH:4]=1)=[O:2].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+].C(Cl)Cl>ClCCCl>[OH:2][CH2:1][C:3]1[S:11][C:10]2[C:9](=[O:12])[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][N:6]([CH3:18])[C:5]=2[CH:4]=1
Reactant: CCOC(=O)c1cn(C)c2cc(C=O)sc2c1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: CCOC(=O)c1cn(C)c2cc(CO)sc2c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 35.4 %

Procedure:
To a solution of ethyl 2-formyl-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxylate (1.0 g, 3.8 mmol) in 1,2-dichloroethane (23 mL) was added sodium triacetoxyborohydride (1.6 g, 7.5 mmol). The reaction was stirred at room temperature for 24 hours. The reaction was poured into sat. aq. sodium bicarbonate (50 mL) and methylene chloride (30 mL), before it was quenched with water (50 mL). The mixture was allowed to stand at 0° C. overnight. The solid ppt. was collected by vacuum filtration and washed with water. Drying in vacuo yielded an off-white solid (0.36 g, 36%). The filtrate was concentrated to near dryness and diluted with water (20 mL). Filtration followed by treatment with high vacuum gave a second crop of product (0.45 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]=[O:12])[CH:10]=1)[NH:7][N:6]=[CH:5]2.CN(C1CCCCC1)C1CCCCC1.Cl[CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33]>O1CCCC1>[Cl:1][C:2]1[CH:10]=[C:9]([CH:11]=[O:12])[C:8]2[C:4](=[CH:5][N:6]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[N:7]=2)[CH:3]=1
Reactant: O=Cc1cc(Cl)cc2cn[nH]c12
Reactant: C[Si](C)(C)CCOCCl
Agent: CN(C1CCCCC1)C1CCCCC1
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cc2cc(Cl)cc(C=O)c2n1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
5-Chloro-1H-indazole-7-carbaldehyde (5.6 g, 31.0 mmol) and N-methyldicyclohexylamine (9 mL, 41.9 mmol) were suspended in tetrahydrofuran (100 mL), cooled to 0° C., and treated with (2-(chloromethoxy)ethyl)trimethylsilane (8.3 mL, 46.5 mmol). Cooling was removed and stirring continued for 4 h. The reaction was poured into ethyl acetate, washed with water (3×), 1 M potassium bisulfate (2×), brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (25% ethyl acetate/hexanes) gave 5.6 g (58%) as a faint yellow oil. 1H-NMR (CDCl3, 300 MHz) δ 10.50 (s, 1H), 8.21 (s, 1H), 7.94 (d, J=2.2 Hz, 1H), 7.82 (d, J=1.8 Hz, 1H), 5.78 (s, 2H), 3.62-3.67 (m, 2H), 0.90-0.96 (m, 2H), 0.05 (s, 9H). Mass spec.: 332.98 (MNa)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C:8]23[CH2:15][CH:14]2[CH2:13][O:12][CH2:11][C:10](=[S:16])[NH:9]3)[CH:7]=1.[F:18][C:19]([F:32])([F:31])[CH2:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([C:28](O)=[O:29])=[N:26][CH:27]=1>>[F:17][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:28]([C:25]2[CH:24]=[CH:23][C:22]([O:21][CH2:20][C:19]([F:32])([F:31])[F:18])=[CH:27][N:26]=2)=[O:29])=[CH:7][C:6]=1[C:8]12[CH2:15][CH:14]1[CH2:13][O:12][CH2:11][C:10](=[S:16])[NH:9]2
Reactant: O=C(O)c1ccc(OCC(F)(F)F)cn1
Reactant: Nc1ccc(F)c(C23CC2COCC(=S)N3)c1
Product: O=C(Nc1ccc(F)c(C23CC2COCC(=S)N3)c1)c1ccc(OCC(F)(F)F)cn1

Procedure:
Prepared in an analogous manner as described for intermediate B14A from (1SR,7RS)-1-(5-amino-2-fluoro-phenyl)-5-oxa-2-aza-bicyclo[5.1.0]octane-3-thione (intermediate B13A) (87 mg, 0.34 mmol) and 5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid [CAS-no 881409-53-6; described in example 49] (80 mg, 0.36 mmol). The title compound was obtained as a light yellow solid (143 mg, 87%). MS (ISP): m/z=456.1 [(M+H)+].