Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(C[O:8][C:9]([C:11]2[CH:57]=[CH:56][C:14]([C:15]([S:17][CH:18]3[N:21]([C:22]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=4)=[O:23])[C:20](=[O:35])[CH:19]3[CH:36]=[P:37]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:16])=[CH:13][CH:12]=2)=[O:10])=CC=1>FC(F)(F)C(O)=O.C(OCC)(=O)C>[C:9]([C:11]1[CH:12]=[CH:13][C:14]([C:15]([S:17][CH:18]2[N:21]([C:22]([O:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([N+:32]([O-:34])=[O:33])=[CH:30][CH:31]=3)=[O:23])[C:20](=[O:35])[CH:19]2[CH:36]=[P:37]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)([C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[O:16])=[CH:56][CH:57]=1)([OH:10])=[O:8]
Reactant: COc1ccc(COC(=O)c2ccc(C(=O)SC3C(C=P(c4ccccc4)(c4ccccc4)c4ccccc4)C(=O)N3C(=O)OCc3ccc([N+](=O)[O-])cc3)cc2)cc1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(C(=O)SC2C(C=P(c3ccccc3)(c3ccccc3)c3ccccc3)C(=O)N2C(=O)OCc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-(4-p-methoxybenzyloxycarbonylbenzoylthio)-1-p-nitrobenzyloxycarbonyltriphenylphosphoranylidenemethyl-2-azetidinone (1.65 g) and anizole (0.54 g) in trifluoroacetic acid (4.1 ml) was stirred for 0.5 hour at 0° C. Evaporation of trifluoroacetic acid gave an oily residue which was dissolved in ethyl acetate. The ethyl acetate solution was extracted with aqueous potassium carbonate. The aqueous layer was washed with ether, acidified with hydrochloric acid and extracted with ethyl acetate. The ethyl acetate extract was washed with water, dried over anhydrous sodium sulfate and evaporated to give 4-(4-carboxybenzoylthio)-1-p-nitrobenzyloxycarbonyltriphenylphosphoranylidenemethyl-2-azetidinone.
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[O:12]1[CH2:17][CH2:16][CH:15]([CH2:18][OH:19])[CH2:14][CH2:13]1.CCN(CC)CC>CN(C1C=CN=CC=1)C.C(Cl)Cl.O>[CH3:8][C:7]1[CH:9]=[CH:10][C:4]([S:1]([O:19][CH2:18][CH:15]2[CH2:16][CH2:17][O:12][CH2:13][CH2:14]2)(=[O:3])=[O:2])=[CH:5][CH:6]=1
Reactant: OCC1CCOCC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCC2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
TsCl (7.22 g, 37.9 mmol) was added portionwise to a solution of alcohol (9) (4.0 g, 34.44 mmol), Et3N (7.0 g, 69 mmol) and DMAP (0.05 g, 0.35 mmol) in dry DCM (50 mL) at 0° C. The reaction mixture was allowed to warm to room temperature and further stirred for 1 h. The reaction mixture was diluted with water, extracted with EtOAc, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give (tetrahydro-2H-pyran-4-yl)methyl 4-methylbenzene-sulfonate (10) as white solid. Yield (8.5 g, 91%); 1H NMR (400 MHz, DMSO-d6) δ 7.78 (d, J=8.0 Hz, 2H), 7.48 (d, J=8.0 Hz, 2H), 3.87 (d, J=6.4 Hz, 2H), 3.78 (dd, J=11.2, 4.2 Hz, 2H), 3.22 (dt, J=11.6, 1.6 Hz, 2H), 2.42 (s, 3H), 1.88-1.79 (m, 1H), 1.46 (dd, J=12.8, 1.6 Hz, 2H), 1.18-1.07 (m, 2H).
Reaction SMILES: [CH:1]1([C:4]2[C:13]([CH:14]=[CH:15][C:16]#N)=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH2:3][CH2:2]1.C(O)=[O:26].Cl>[Ni].O>[CH:1]1([C:4]2[C:13]([CH:14]=[CH:15][CH:16]=[O:26])=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH2:3][CH2:2]1
Reactant: O=CO
Reactant: N#CC=Cc1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Agent: [Ni]
Agent: Cl
Solvent: O
Product: O=CC=Cc1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Temperature: 25 °C
Yield: 96.7 %

Procedure:
In a 5 mL-volume glass flask equipped with a stirrer, a thermometer and a dropping funnel were placed under nitrogen atmosphere 314 mg (1.0 mmol) of 3-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]prop-2-enenitrile (prepared in Reference Example 1), 2.25 mL of formic acid (60 mmol, mol calculated as 100% formic acid), 0.75 mL of water, and 620 mg (5.3 mmol as nickel atom) of water-containing developed Raney-nickel (NDHT-90, nickel content 50 wt. %, available from Kawaken Fine Chemical Co., Ltd.). The content was reacted at 80° C. for hours. After the reaction was complete, the content was cooled to room temperature. After addition of 9 mL of water and 9 mL of hydrochloric acid (1 mol/L), the catalyst was removed by filtration using a celite. The celite was washed with two portions of 2-butanol (1 mL) and two portions of toluene (9 mL). The organic portion was dried over anhydrous magnesium sulfate. The dried organic portion was filtered and the filtrate was concentrated under reduced pressure to give 307 mg (yield 91%) of 3-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]prop-2-enal as yellow solid (purity 97%, in terms of an area percent according to high performance liquid chromatography).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Br.Br[CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[CH:4][CH:3]=1
Reactant: Sc1ccc(Br)cc1
Reactant: BrCc1cccnc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Brc1ccc(SCc2cccnc2)cc1
Yield: 85.9 %

Procedure:
Following method of example 9a, reaction of 4-bromo-benzenethiol (4.8 g, 24.1 mmol) with hydrobromic acid salt of 3-bromomethyl-pyridine (6.9 g, 26.5 mmol) and potassium carbonate (7.3 g, 53 mmol) in 91 ml acetone gives the title compound as a yellow solid (5.8 g). MS (m/e): 281 (M+H).
Reaction SMILES: [NH:1]1[C:12]2[C:4](=[CH:5][CH:6]=[C:7]3[C:11]=2[C:10](=[O:13])[C:9](=[O:14])[NH:8]3)[N:3]=[N:2]1.[CH:15]1[C:20]([NH:21][NH2:22])=[CH:19][CH:18]=[C:17]([S:23]([NH2:26])(=[O:25])=[O:24])[CH:16]=1.Cl>>[NH:1]1[C:12]2[C:4](=[CH:5][CH:6]=[C:7]3[C:11]=2[C:10](=[O:13])[C:9](=[O:14])[NH:8]3)[N:3]=[N:2]1.[O:14]=[C:9]1[C:10](=[N:22][NH:21][C:20]2[CH:19]=[CH:18][C:17]([S:23]([NH2:26])(=[O:24])=[O:25])=[CH:16][CH:15]=2)[C:11]2[C:7](=[CH:6][CH:5]=[C:4]3[C:12]=2[N:1]=[N:2][NH:3]3)[NH:8]1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Agent: O=C1Nc2ccc3nn[nH]c3c2C1=O
Product: NS(=O)(=O)c1ccc(NN=C2C(=O)Nc3ccc4[nH]nnc4c32)cc1

Procedure:
1,6-Dihydro-1,2,3,6-tetraaza-as-indacene-7,8-dione was prepared according to Procedure A in 56% yield: 1H NMR (DMSO-d6): δ6.93 (d, J=8.6 Hz, 1H), 8.32 (d, J=8.6 Hz, 1H), 11.14 (s, 1H); APCI−MS m/z 189 (M+1)+. Condensation of 1,6-dihydro-1,2,3,6-tetraaza-as-indacene-7,8-dione with 4-sulfonamidophenylhydrazine hydrochloride according to Procedure G gave the title compound in 15% yield: 1H NMR (DMSO-d6): δ7.06 Z (d, J=8.4 Hz, 1H), 7.24 E (d, J=8.4 Hz, 1H), 7.30 Z (s, 2H), 7.30 E (s, 2H), 7.55 E (d, J=8.5 Hz, 2H), 7.82 Z (d, J=8.5 Hz, 2H), 7.82 E (d, J=8.5 Hz,1H), 7.90 E (d, J=8.7 Hz, 2H), 7.90 Z (d, J=8.8 Hz, 2H), 7.98 Z (d, J=8.4 Hz,1H), 10.86 E (s,1H), 11.35 Z (s, 1H), 12.87 Z (s, 1H), 12.95 E (s, 1H), 16.00 Z (s, 1H), 16.25 E (s, 1H); APCI−MS m/z 356 (M−H)−. Anal. Calcd for C14H11N7O3S.H2O: C, 44.80, H, 3.49; N, 26.12; S, 8.54. Found C, 44.72, H, 3.46; N, 26.05; S, 8.48.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=O)[CH2:10][N:9]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1.C(=O)([O-])O.[Na+].O>CN(C)P(=O)(N(C)C)N(C)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[S:32])[CH2:10][N:9]=1
Reactant: O=C1CN=C(c2ccccc2F)c2cc([N+](=O)[O-])ccc2N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1F)=NCC(=S)N2
Temperature: 105 °C
Reaction time: 1.17 h
Yield: 183.2 %

Procedure:
A solution of 20.0 g of 5-(2-fluorophenyl)-7-nitro-3H-1,4-benzodiazepin-2(1H)-one (G. M. Clarke, J. B. Lee, F. J. Swinbourne & B. Williamson, J. Chem. Res. Synop. 1980, 400) in 100 ml of hexamethylphosphoric acid triamide was treated with 14 g of Lawesson reagent and the mixture was stirred at 105° C. for 70 min. The reaction mixture was poured into 800 ml of saturated aqueous sodium hydrogen carbonate solution and 800 ml of water. After stirring at room temperature for 15 min. the precipitate was filtered off, washed with water and dried. There were obtained 20 g of crude 5-(2-fluorophenyl)-7-nitro-3H-1,4-benzodiazepine-2(1H)-thione, which was used in this form for the next step.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]#[N:10])[CH:4]=1)=O.Br.Br.Br.[CH2:14]([C:16]1[C:17]([C:24]2[CH:32]=[C:31]3[C:27]([C:28]([C:33]4[NH:34][C:35]5[CH2:40][CH2:39][NH:38][CH2:37][C:36]=5[N:41]=4)=[N:29][NH:30]3)=[CH:26][CH:25]=2)=[CH:18][C:19]([F:23])=[C:20]([OH:22])[CH:21]=1)[CH3:15]>>[CH2:14]([C:16]1[CH:21]=[C:20]([OH:22])[C:19]([F:23])=[CH:18][C:17]=1[C:24]1[CH:32]=[C:31]2[C:27]([C:28]([C:33]3[NH:34][C:35]4[CH2:40][CH2:39][N:38]([CH2:1][C:3]5[CH:8]=[CH:7][N:6]=[C:5]([C:9]#[N:10])[CH:4]=5)[CH2:37][C:36]=4[N:41]=3)=[N:29][NH:30]2)=[CH:26][CH:25]=1)[CH3:15]
Reactant: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCNC4)n[nH]c2c1
Reactant: N#Cc1cc(C=O)ccn1
Agent: Br
Product: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(Cc3ccnc(C#N)c3)C4)n[nH]c2c1
Yield: 24.6 %

Procedure:
The title compound was prepared from 4-formyl-pyridine-2-carbonitrile (26 mg, 198 μmol) and 5-ethyl-2-fluoro-4-[3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-6-yl]-phenol trihydrobromide salt (Preparation 25, 50 mg, 132 μmol) using the method of Example 18. The crude material was purified by HPLC Method B to afford 16 mg of the title compound.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[N:8]=1)=O.[Cl:21][C:22]1[N:27]=[C:26]([NH:28]N)[CH:25]=[CH:24][CH:23]=1.C(O)(=O)C>CCO>[Cl:21][C:22]1[N:27]=[C:26]([N:28]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:25]=[CH:24][CH:23]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccncc2)ccc1=O
Reactant: NNc1cccc(Cl)n1
Solvent: CC(=O)O
Solvent: CCO
Product: O=c1ccn(-c2ccncc2)nc1-c1ccnn1-c1cccc(Cl)n1
Yield: 11.6 %

Procedure:
A solution of 3-((E)-3-dimethylamino-acryloyl)-1-pyridin-4-yl-1H-pyridazin-4-one (A-1; 0.075 g; 0.3 mmol) in EtOH (2 ml) was treated with (6-chloropyridin-2-yl)-hydrazine (0.048 g; 0.3 mmol) in a sealed tube and irradiated at 100° C. for 30 min. Acetic acid (0.5 ml) was added and the mixture again irradiated at 100° C. for 15 min. The solvent of the reaction mixture was removed and the crude product purified by preparative HPLC yielding 0.0122 g (12%) of the final product. MS: M=351.1 (M+H)−
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].[CH3:16][O:17][C:18](=[O:25])[CH:19](Cl)[C:20]([O:22][CH3:23])=[O:21]>CC(C)=O>[CH3:16][O:17][C:18](=[O:25])[CH:19]([O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)C(Cl)C(=O)OC
Reactant: COc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)C(Oc1ccccc1OC)C(=O)OC
Temperature: 45 °C

Procedure:
2-Methoxy-phenol (guaiacol) (48 ml) was slowly added to a stirred suspension of potassium carbonate (70.8 g) in acetone (480 ml) followed by heating to 45° C. Then, dimethylchloromalonate (63.2 ml) in acetone (50 ml) was added within 20 min. The reaction mixture was heated to reflux for 16 h. The solvent was evaporated under reduced pressure, the residue taken into water and extracted with DCM. The combined organic layers were dried over sodium sulfate and evaporated. The oily product was crystallized from tert.-butyl-methyl-ether. Dimethyl-(o-methoxyphenoxy)malonate (86 g) was obtained.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]2[CH:23]=[N:22][CH:21]=[N:20]2)=[CH:11][CH:10]=1)C1C=CC=CC=1>[C].[Pd].C(O)C>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]2[CH:23]=[N:22][CH:21]=[N:20]2)=[CH:11][CH:10]=1
Reactant: c1ccc(COc2ccc(CCCCn3cncn3)cc2)cc1
Agent: [Pd]
Solvent: CCO
Product: Oc1ccc(CCCCn2cncn2)cc1
Yield: 54.8 %

Procedure:
A mixture of 1-[4-(4-benzyloxyphenyl)butyl]-1,2,4-triazole (3.15 g), palladium-carbon (5%, 3.0 g) and ethanol (50 ml) was subjected to catalytic hydrogenation under atmospheric pressure at room temperature. The catalyst was filtered off, and the filtrate was concentrated. The residue was subjected to a silica gel column chromatography. The crystalline product obtained from the fraction eluted with tetrahydrofuran-hexane (1:1, v/v) was recrystallized from ethyl acetate-hexane to give 1-[4-(4-hydroxyphenyl)butyl]-1,2,4-triazole (1.22 g, 55%) as colorless prisms, mp 135-136° C.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]2[CH:7]=[C:8](Br)[S:9][C:4]=2[CH:3]=1.[C:11]([O:15][C:16]([N:18]1[C:22]([Sn](CCCC)(CCCC)CCCC)=[CH:21][N:20]=[C:19]1[C@@H:36]1[CH2:40][CH2:39][CH2:38][N:37]1[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[O:17])([CH3:14])([CH3:13])[CH3:12].C(OC(N1CCC[C@H]1C1NC(C2SC3C=C(C4C=CC(C5NC([C@@H]6CCCN6C(=O)[C@@H](NC(OC)=O)C(C)C)=NC=5)=CC=4)SC=3C=2)=CN=1)=O)(C)(C)C>>[C:11]([O:15][C:16]([N:18]1[CH:22]=[C:21]([C:8]2[S:9][C:4]3[CH:3]=[C:2]([Br:1])[O:6][C:5]=3[CH:7]=2)[N:20]=[C:19]1[C@@H:36]1[CH2:40][CH2:39][CH2:38][N:37]1[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: Brc1cc2sc(Br)cc2o1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc([C@@H]2CCCN2C(=O)OC(C)(C)C)n1C(=O)OC(C)(C)C
Agent: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3cc4sc(-c5cnc([C@@H]6CCCN6C(=O)OC(C)(C)C)[nH]5)cc4s3)cc2)[nH]1)C(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc(-c2cc3oc(Br)cc3s2)cn1C(=O)OC(C)(C)C
Yield: 16 %

Procedure:
Intermediate E81 was synthesized from 2,5-dibromo-thieno[3,2-b]furan (8.9 mmol) (Roowin) and intermediate 61 (9.35 mmol) following the procedure as described for the intermediate 63 (reaction time=6 hours and chromatography eluent: petroleum ether/AcOEt) to give intermediate E81 in 16% yield. MS (ESI, EI+) m/z=539 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]([NH:8][NH2:9])[N:4]([C:10]([O:12]CC)=O)[N:3]=1.[Na]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[N:4]([C:10](=[O:12])[NH:9][N:8]=2)[N:3]=1
Reactant: CCOC(=O)N1N=C(Cl)C=CC1NN
Agent: [Na]
Solvent: CCO
Product: O=c1[nH]nc2ccc(Cl)nn12

Procedure:
39 g. of 3-chloro-6-hydrazino-1(6H)pyridazinecarboxylic acid, ethyl ester (0.18 mol.) are added to a solution of 4.9 g. of sodium (0.216 mol.) in 400 ml. of absolute ethanol and the mixture is then refluxed for 4 hours with stirring. After cooling, the sodium salt of 6-chloro-1,2,4,-triazolo[4,3-b]pyridazin-3(2H)-one is filtered off, washed with ether and, after drying, dissolved in water. Acidification with acetic acid (25%) precipitates the free compound which then is filtered off, washed with water and dried, yielding 26 g. (85%) of 6-chloro-1,2,4-triazolo[4,3-b]pyridazin-3(2H)one, which is recrystallized from ethanol, m.p. 273°-274° .
Reaction SMILES: N#N.[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)=[CH2:4].N1C=CC=CC=1.Cl[C:19]([O:21][CH:22]=[CH2:23])=[O:20]>C(Cl)(Cl)Cl>[C:19](=[O:20])([O:21][CH:22]=[CH2:23])[O:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]=[CH2:4])=[CH:6][CH:7]=1
Reactant: C=COC(=O)Cl
Reactant: C=Cc1ccc(O)cc1
Agent: N#N
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: C=COC(=O)Oc1ccc(C=C)cc1
Temperature: 5 °C

Procedure:
A 500 ml round bottom flask equipped with a reflux condenser, a mechanical stirrer , a thermometer, a dropping funnel and an efficient N2 blanket, is charged with 30.0 g (0.25 mole) of 4-vinylphenol, 21.8 g of pyridine and 300 ml of chloroform. The contents are then cooled down to 5 degrees C., and 25,3 g of vinyl chloroformate is added dropwise via the dropping funnel with constant stirring and the temperature maintained at 5 degrees or below. The temperature is then allowed to rise to ambient temperature and the mixture stirred overnight. The reaction mixture is then passed through a silica gel column and dried over magnesium sulfate and filtered. After the solvent is removed under pressure, the named product is recovered.
Reaction SMILES: [Cl-].[Na+].C(O)(=O)C.[F:7][C:8]([C@H:17]1[C@H:21]([OH:22])[CH2:20][CH:19]=[CH:18]1)(C(OC)=O)[C:9]([O:11][CH3:12])=[O:10].FC([C@@H]1[C@@H](O)CC=C1)(C(OC)=O)C(OC)=O.FC([C@H]1[C@H](O)CC=C1)C(OC)=O>CS(C)=O>[F:7][CH:8]([C@@H:17]1[C@@H:21]([OH:22])[CH2:20][CH:19]=[CH:18]1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)C(F)(C(=O)OC)[C@@H]1C=CC[C@H]1O
Agent: COC(=O)C(F)(C(=O)OC)[C@H]1C=CC[C@@H]1O
Agent: COC(=O)C(F)[C@@H]1C=CC[C@H]1O
Agent: [Cl-]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: COC(=O)C(F)[C@H]1C=CC[C@@H]1O
Temperature: 115 °C
Reaction time: 5 h

Procedure:
1 mL of dimethyl sulfoxide, 0.073 g (1.25 mmol) of sodium chloride, and 0.061 g (1.00 mmol) of acetic acid were added to 0.232 g (1.00 mmol) of a mixture of the compound of the formula 8a and the compound of the formula 8b, and the mixture was heated and stirred at 110 to 120° C. for 5 hours. After allowing it to cool, analysis was carried out using a high-performance liquid chromatography, and it was found that 0.146 g (the value quantitatively determined by high performance liquid chromatography) of a mixture of the compound of the formula 9a and the compound of the formula 9b was obtained.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:8]=[C:9]3[C:14](=[C:15]([CH3:17])[CH:16]=2)[NH:13][C:12](=[O:18])[CH:11]=[CH:10]3)[CH:4]=[CH:5][N:6]=1.[Cl:19]N1C(=O)CCC1=O>ClCCl>[Cl:19][C:4]1[N:3]([C:7]2[CH:8]=[C:9]3[C:14](=[C:15]([CH3:17])[CH:16]=2)[NH:13][C:12](=[O:18])[CH:11]=[CH:10]3)[C:2]([CH3:1])=[N:6][CH:5]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cc(-n2ccnc2C)cc2ccc(=O)[nH]c12
Solvent: ClCCl
Product: Cc1cc(-n2c(Cl)cnc2C)cc2ccc(=O)[nH]c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 6-(2-methylimidazol-1-yl)-8-methyl-2-(1H)-quinolone (0.24 g) and N-chlorosuccinimide (0.14 g) in dichloromethane (10 cm3) was stirred at room temperature for 2 hours. The mixture was then chromatographed directly on silica (Merck "MK 60.9385" [Trade Mark]) eluting with methanol:dichloromethane, 1:20 by volume. Combination and evaporation of the appropriate fractions afforded the title compound, m.p. 258°-61°, (0.18 g).
Reaction SMILES: [O:1]([CH2:9][P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[Li]CCCC.[CH2:23](Br)[CH:24]=[C:25]([CH2:27][CH2:28][CH:29]=[C:30]([CH2:32][CH2:33][CH:34]=[C:35]([CH3:37])[CH3:36])[CH3:31])[CH3:26].C([O-])(O)=O.[Na+]>C1COCC1>[O:1]([CH:9]([P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])[CH2:23]/[CH:24]=[C:25](\[CH3:26])/[CH2:27][CH2:28]/[CH:29]=[C:30](\[CH3:31])/[CH2:32][CH2:33][CH:34]=[C:35]([CH3:37])[CH3:36])[Si:2]([C:5]([CH3:7])([CH3:6])[CH3:8])([CH3:3])[CH3:4]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCBr
Reactant: CCOP(=O)(CO[Si](C)(C)C(C)(C)C)OCC
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C(C/C=C(\C)CC/C=C(\C)CCC=C(C)C)O[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of the diethyl (t-butyldimethylsiloxy)methylphosphonate (562 mg, 2.0 mmol) in THF (5 ml) under argon at -78° C. was added n-BuLi (0.84 ml of a 2.5M solution in hexanes, 2.1 mmol) and the resulting mixture stirred at -78° C. for 15 min. Farnesyl bromide (0.542 ml, 2.0 mmol) was added to the mixture over 5 min and the solution stirred a further 1 hr at -78° C. and then allowed to warm to r.t. The reaction mixture was poured into saturated NaHCO3 solution and the organic solvent evaporated in vacuo, the residue was extracted into ethylacetate and washed with brine, dried (MgSO4) and concentrated in vacuo and the resulting oil chromatographed on silica gel eluted with ethylacetate:hexanes (3:7, v:v). to afford the title compound as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH2:15][CH2:16][OH:17])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O.Br[CH:35]=[C:36]([C:38]1[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=1)[CH3:37]>CN(C=O)C.[Cu]I>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:35]=[C:36](/[C:38]3[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=3)\[CH3:37])[C:6]3[CH2:11][CH2:12][N:13]([CH2:15][CH2:16][OH:17])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(CCO)CC3
Reactant: CC(=CBr)c1ccncc1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C/C(=C\n1c2c(c3cc(C)ccc31)CN(CCO)CC2)c1ccncc1
Temperature: 85 °C

Procedure:
2-(3,4-Dihydro-8-methyl-1H-pyrido[4,3-b]indol-2(5H)-yl)ethanol (232 mg, 1 mmol) was dissolved in DMF (3 mL). potassium phosphate (424 mg, 2 mmol), copper (I) iodide (19 mg, 0.1 mmol) and L-proline (23 mg, 0.2 mmol) were added. 4-(1-bromoprop-1-en-2-yl)pyridine (294 mg, 1.5 mmol) dissolved in DMF (2 mL) was added dropwise to the reaction mixture. Nitrogen was purged for 2 min in the reaction mixture which was heated at 85° C. overnight (prolonged heating was required in some cases). DMF was evaporated and water added to the reaction mixture. The precipitate obtained was filtered and purified by silica gel chromatography (100-200 mesh) using 0-8% MeOH:DCM as eluent. The compound was further purified through reverse phase purification. Yield: 115 mg. 1H NMR (CD3OD, oxalate salt) δ (ppm): 8.70 (d, 2H), 7.68 (d, 2H), 7.38 (m, 2H), 7.10 (m, 2H), 4.60 (m, 2H), 4.0 (m, 2H), 3.78 (m, 2H), 3.50 (m, 2H), 3.15 (m, 2H), 2.42 (s, 3H), 2.05 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:7][CH:6]=1)=[O:4].[F:16][C:17]([F:29])([F:28])[C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.C(N(CC)CC)C.O>ClCCl>[CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:11][CH2:12][N:13]([S:24]([C:21]3[CH:20]=[CH:19][C:18]([C:17]([F:16])([F:28])[F:29])=[CH:23][CH:22]=3)(=[O:26])=[O:25])[CH2:14][CH2:15]2)=[N:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1cnc(N2CCNCC2)s1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)c1cnc(N2CCN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)CC2)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.3 %

Procedure:
To a solution of compound 11 (200 mg, 0.886 mmol) in dichloromethane (7.5 mL) were added 4-trifluoromethyl benzenesulfonyl chloride (322 mg, 1.320 mmol) and triethylamine (220 mg, 2.169 mmol) under a N2 atmosphere. The reaction mixture was stirred at room temperature for 4 h. Water (10 mL) followed by dichloromethane (10 mL) were added to the reaction mixture and the organic layer was separated, dried on sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using silica gel to give the compound 12f as a solid (333 mg, 86.9%). HPLC: 99.42% (Rt=11.936 min).
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:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:22][CH3:23])=[CH:15][CH:16]=2)[CH2:11]1)C1C=CC=CC=1>C(O)C.O.[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:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:22][CH3:23])=[CH:15][CH:16]=2)[CH2:11]1
Reactant: CCOC(=O)C(CC)Oc1ccc2c(c1)CC(NCc1ccccc1)CC2
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(CC)Oc1ccc2c(c1)CC(N)CC2

Procedure:
A solution of 2-benzylamino-7-(ethoxycarbonylpropan-3-yloxy) tetralin hydrochloride (14 g), prepared as described in Example 3, in a mixture of 95% ethanol (250 ml) and water (10 ml) is hydrogenated at atmospheric pressure and 60° C. in the presence of 10% Pd/C (2 g) as the hydrogenation catalyst. After 5 hours the catalyst is filtered off, the filtrate is concentrated to dryness and the residue is taken up in absolute ethanol (100 ml) and concentrated to dryness a few times. The obtained product is then triturated with acetone, filtered and crystallized from isopropanol affording 8.8 g of the compound of the title. M.p. 134°-136° C.