Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][CH2:9][C:10]1[NH:11][C:12]([CH3:15])=[CH:13][CH:14]=1>C(Cl)Cl>[C:5]([NH:8][CH2:9][C:10]1[NH:11][C:12]([CH3:15])=[CH:13][CH:14]=1)(=[O:7])[CH3:6]
Reactant: Cc1ccc(CN)[nH]1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)NCc1ccc(C)[nH]1

Procedure:
6.0 g (0.06 mol) of acetic anhydride in 20 ml of methylene chloride are added dropwise to 6.4 g (0.06 mol) of 2-(amino-methyl)-5-methyl-pyrrole (compare Example 11) in 20 ml of methylene chloride at 10° C. After a reaction time of 2 hours at room temperature, the mixture is concentrated and the residue is chromatographed over a silica gel column.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[C:22]3[C:17](=[CH:18][C:19]([O:25][CH2:26][CH3:27])=[C:20]([O:23][CH3:24])[CH:21]=3)[C@@H:16]3[C@@H:11]([CH2:12][CH2:13][C@@H:14]([OH:28])[CH2:15]3)[N:10]=2)=[CH:7][CH:6]=[C:5]([O:29][CH3:30])[N:4]=1.[CH3:31][S:32](O)(=[O:34])=[O:33]>O1CCCC1>[S:32]([O:28][C@@H:14]1[CH2:13][CH2:12][C@@H:11]2[C@@H:16]([C:17]3[C:22]([C:9]([C:8]4[C:3]([O:2][CH3:1])=[N:4][C:5]([O:29][CH3:30])=[CH:6][CH:7]=4)=[N:10]2)=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH2:26][CH3:27])[CH:18]=3)[CH2:15]1)(=[O:34])(=[O:33])[CH3:31]
Reactant: CS(=O)(=O)O
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(OC)nc1OC)=N[C@@H]1CC[C@@H](O)C[C@H]21
Solvent: C1CCOC1
Product: CCOc1cc2c(cc1OC)C(c1ccc(OC)nc1OC)=N[C@@H]1CC[C@@H](OS(C)(=O)=O)C[C@H]21
Temperature: 60 °C
Yield: 98 %

Procedure:
(2R,4aR,10bR)-6-(2,6-Dimethoxy-pyridin-3-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol (1.5 g; 3.6 mmol) is dissolved in 9 ml of tetrahydrofuran. The solution is heated up to 60° C. 247 μg (3.8 mmol) of methanesulfonic acid are added. After crystallisation the suspension is stirred over night. The crystals are filtered off and dried to obtain 1.73 g (95%) of the title compound (m.p.: 193° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:16][CH:17]=3)[N:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[S:32])=[CH:26][C:25]=1[C:33]([F:36])([F:35])[F:34]>>[F:20][C:19]([F:22])([F:21])[C:15]1[CH:14]=[C:13]2[C:18]([C:9]([S:8][C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:31]([NH:30][C:27]4[CH:28]=[CH:29][C:24]([Cl:23])=[C:25]([C:33]([F:36])([F:34])[F:35])[CH:26]=4)=[S:32])=[CH:3][CH:4]=3)=[CH:10][CH:11]=[N:12]2)=[CH:17][CH:16]=1
Reactant: FC(F)(F)c1cc(N=C=S)ccc1Cl
Reactant: Nc1ccc(Sc2ccnc3cc(C(F)(F)F)ccc23)cc1
Product: FC(F)(F)c1ccc2c(Sc3ccc(NC(=S)Nc4ccc(Cl)c(C(F)(F)F)c4)cc3)ccnc2c1
Yield: 62.7 %

Procedure:
4-(4-aminophenylthio)-7-trifluoromethylquinoline (0.01 mole, 3.2 g) and 4-chloro-3-trifluoromethylphenylisothiocyanate (0.01 mole, 2.4 g) were reacted according to procedure C to yield the title compound 3.5 g, 63%. Mass Spec (FD) 557. Calculated for C24H14ClF6N3S2 : C, 51.66; H, 2.53; N, 7.53. Found: C, 51.92; H, 2.53; N, 7.46.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10]N)[CH:5]=[C:6]([Br:9])[C:7]=1[Br:8].[CH3:12][CH:13]([CH3:17])[C:14](=O)[CH3:15].Cl.C(=O)([O-])[O-].[Na+].[Na+]>>[Br:1][C:2]1[C:7]([Br:8])=[C:6]([Br:9])[CH:5]=[C:4]2[C:3]=1[C:13]([CH3:17])([CH3:12])[C:14]([CH3:15])=[N:10]2
Reactant: CC(=O)C(C)C
Reactant: NNc1cc(Br)c(Br)c(Br)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC1=Nc2cc(Br)c(Br)c(Br)c2C1(C)C
Yield: 56.4 %

Procedure:
1.73 g of 3,4,5-tribromophenylhydrazine and 2 mL (18.5 mmol) of 3-methyl-2-butanone were refluxed for an hour. Next, 15 mL of concentrated HCl were added and refluxed for another 3.5 h. The reaction mixture was neutralized with concentrated aqueous solution of sodium carbonate, and the product was extracted with benzene. The organic layer was dried with MgSO4 and benzene was removed under reduced pressure by a rotary evaporator to yield 1.12 g of 4,5,6-tribromo-2,3,3-trimethyl-3H-indole. 1H-NMR (200 MHz, DMSO-d6), δ, ppm: 7.16 (1H, s, arom.), 2.22 (3H, s, CH3), 1.35 (6H, s, C(CH3)2).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][O:23][C:24]3[C:29]([Cl:30])=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=3[Cl:32])=[CH:16][CH:15]=2)[C@@H:10]([C:33]([OH:35])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Si:36]([O:43][C:44]1[CH:45]=[C:46]([CH:52]=[C:53]([CH2:55][CH2:56][CH2:57][O:58][CH3:59])[CH:54]=1)[CH2:47][NH:48][CH:49]1[CH2:51][CH2:50]1)([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CCOCC>[Si:36]([O:43][C:44]1[CH:45]=[C:46]([CH:52]=[C:53]([CH2:55][CH2:56][CH2:57][O:58][CH3:59])[CH:54]=1)[CH2:47][N:48]([CH:49]1[CH2:51][CH2:50]1)[C:33]([C@@H:10]1[C@@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][O:23][C:24]3[C:29]([Cl:30])=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=3[Cl:32])=[CH:16][CH:15]=2)[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]1)=[O:35])([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:37])[CH3:38]
Reactant: COCCCc1cc(CNC2CC2)cc(O[Si](C)(C)C(C)(C)C)c1
Reactant: Cc1cc(Cl)c(OCCOc2ccc([C@H]3CCN(C(=O)OC(C)(C)C)C[C@@H]3C(=O)O)cc2)c(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCCc1cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(O[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (3R,4S)-1-(tert-butoxycarbonyl)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-3-carboxylic acid (piperidine acid 1) (1 eq) and N-[3-{[tert-Butyl(dimethyl)silyl]oxy}-5-(3-methoxypropyl)benzyl]cyclo-propanamine (amine 1) (1.8 eq.) in DCM (0.15 M) was added HATU (1.5 eq.) and Hunig's base (3 eq.). After stirring for 18 hr at rt, the reaction was diluted with ether. The organic extract was washed three times with 1 N aqueous HCl, water, brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, 20% EtOAc in Hex) to afford the title compound as an oil.
Reaction SMILES: Br[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[N+:10]([C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16])([O-:12])=[O:11].C(=O)([O-])[O-].[Cs+].[Cs+].Cl>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClCCl>[N+:10]([C:13]1[CH:14]=[C:15]([NH:16][C:2]2[N:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])[CH:17]=[CH:18][CH:19]=1)([O-:12])=[O:11]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: O=Cc1cccnc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O
Product: O=Cc1cccnc1Nc1cccc([N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 83.1 %

Procedure:
A suspension of 2-bromonicotinaldehyde (2.54 g, 13.6 mmol; synthesized according to SYNTHETIC COMMUNICATIONS, 23(19): 2727–2730 (1993)), 3-nitroaniline (2.26 g, 1.2 eq.), palladium acetate (123 mg, 0.04 eq.), 1,3-bis(diphenyl-phosphino)propane (341 mg, 0.06 eq.), and cesium carbonate (6.22 g, 1.4 eq.) in toluene (30 ml) was stirred at 100° C. for 4 hours under nitrogen atmosphere, and cooled to room temperature, followed by addition of 10% hydrochloric acid (50 ml) and dichloromethane. The mixture was stirred for 1 hr, then diluted with water (50 ml), and extracted with dichloromethane. The extract was dried, and then evaporated. To the residue was added hexane to precipitate crystals, filtered off, washed with hexane, and dried under reduced pressure to afford 2-(3-nitrophenylamino)-nicotinaldehyde as a yellow powder (2.75 g, 74%).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([NH:11][C:12]([NH2:14])=[NH:13])[S:9][CH:10]=1)=O)C.O.[NH2:16][NH2:17]>C(O)C>[NH:11]([C:8]1[S:9][CH:10]=[C:6]([C:4]([NH:16][NH2:17])=[O:3])[N:7]=1)[C:12]([NH2:14])=[NH:13]
Reactant: NN
Reactant: CCOC(=O)c1csc(NC(=N)N)n1
Solvent: O
Solvent: CCO
Product: N=C(N)Nc1nc(C(=O)NN)cs1
Yield: 82.1 %

Procedure:
16.7 g (0.0779 mol) of 2-guanidino-4-thiazole carboxylic acid ethyl ester was combined with 25 ml (0.514 mol) of hydrazine hydrate in 200 ml absolute ethanol. The slurry was heated to reflux. After 1.5 hour reflux a solid began to form from the clear solution. After 2 hours reflux the reaction slurry was cooled and the resulting solid was collected by filtration and was washed with isopropyl alcohol and ether to give 12.8 g (82%) 2-guanidino-4-thiazole carboxylic acid hydrazide, mp 247° (dec.).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[OH:24])(=[O:5])[CH:2]([CH3:4])[CH3:3].CC(C)([O-])C.[K+].[CH3:31][O:32][CH2:33][CH2:34]Cl>O1CCCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[O:24][CH2:34][CH2:33][O:32][CH3:31])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: Cc1ccccc1Nc1c(C(=O)C(C)C)cnc2c(O)cccc12
Reactant: COCCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COCCOc1cccc2c(Nc3ccccc3C)c(C(=O)C(C)C)cnc12
Yield: 11.3 %

Procedure:
A mixture of 3-isobutyryl-4-(2-methylphenylamino) 8-hydroxyquinoline (5.0 g, 15.6 mmol), potassium t-butoxide (2.63 g, 23.4 mmol) and 2-chloroethyl methyl ether (2.85 ml, 31.2 mmol) in tetrahydrofuran (250 ml) was heated at reflux for 3 days, then the solvent evaporated. Water was added, the product extracted into dichloromethane, and the organic extracts dried and evaporated. Chromatography (silica gel, ethyl acetate/2% acetic acid/0%-5% methanol) removed unchanged starting material, then further chromatography (silica gel, 1%-1.5% methanol in dichloromethane) and crystallization from petroleum ether (40-60) gave 3-isobutyryl-4-(2-methylphenylamino)-8-(2-methoxyethoxy)quinoline (0.67 g), m.p. 68°-70°.
Reaction SMILES: C[O-].[Na+].[C:4]([CH2:6][C:7]([O:9][CH3:10])=[O:8])#[N:5].Cl[C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20].Cl>O.C(OC(=O)C)C.CS(C)=O>[Cl:18][C:16]1[CH:15]=[CH:14][C:13]([N+:19]([O-:21])=[O:20])=[C:12]([CH:6]([C:4]#[N:5])[C:7]([O:9][CH3:10])=[O:8])[CH:17]=1
Reactant: COC(=O)CC#N
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Cl
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)C(C#N)c1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 93 %

Procedure:
In a flask made of glass equipped with a stirrer, a thermometer, a reflux condenser and a dropping funnel and having an inner volume of 200 ml were charged 2.79 g (51.6 mmol) of sodium methoxide and 15 ml of dimethyl sulfoxide under argon atmosphere, and then, while stirring at room temperature, 5.16 g (51.6 mmol) of methyl cyanoacetate with a purity of 99% was gradually added dropwise over 5 minutes. Moreover, at room temperature, to the mixture was gradually added dropwise 5.00 g (25.8 mmol) of 2,4-dichloronitrobenzene with a purity of 98%, and the resulting mixture was reacted at 40 to 48° C. for 10 minutes and at 65° C. for 2 hours. After completion of the reaction, the mixture was cooled to room temperature, 100 ml of ethylacetate was added to the mixture, and 4.30 ml (25.7 mmol) of 6 mol/l hydrochloric acid and 20 ml water were gradually added dropwise while stirring. Then, the organic layer was separated, washed with 50 ml of a saturated saline solution, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting concentrate was purified by silica gel column chromatography (filler: Daisogel 1002W, eluent: hexane:ethyl acetate=9:1 (volume ratio)) to obtain 6.11 g (isolation yield: 92%) of methyl 2-(5-chloro-2-nitrophenyl)-2-cyanoacetate as yellowish crystals with a purity of 99% (areal percentage by high performance liquid chromatography).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:28][C@H:29]1[CH2:34][C:33]2[C:35]([N:39]3[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]3)=[CH:36][CH:37]=[CH:38][C:32]=2[O:31][CH2:30]1>CN(C)C=O>[CH3:45][N:42]1[CH2:43][CH2:44][N:39]([C:35]2[C:33]3[CH2:34][C@H:29]([NH:28][C:11](=[O:13])[C:10]4[CH:9]=[CH:8][C:7]([N:4]5[CH2:3][CH2:2][O:1][CH2:6][CH2:5]5)=[CH:15][CH:14]=4)[CH2:30][O:31][C:32]=3[CH:38]=[CH:37][CH:36]=2)[CH2:40][CH2:41]1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CO3)CC1
Reactant: O=C(O)c1ccc(N2CCOCC2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(N4CCOCC4)cc2)CO3)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 68 %

Procedure:
A solution of 4-morpholinobenzoic acid (380 mg, 1.83 mmol, described in: Degutis, J.; Rasteikiene, L.; Degutiene, A. Zh. Org. Khim. 1978, 14(10), 2060-2064) and 1,1'-carbonyldiimidazole (310 mg, 1.92 mmol) in anhydrous N,N-dimethylformamide (12 mL) was stirred at 75° C. for 30 min. The mixture was allowed to cool after which a solution of (S)-3-amino-5-(4-methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran (430 mg, 1.74 mmol) in N,N-dimethylformamide (8 mL) was added. The reaction mixture was stirred at room temperature for 3 days. Another portion of 1,1 '-carbonyldiimidazole (57 mg, 0.35 mmol) was added, and the mixture was stirred for an additional 3.5 h. The solvent was removed in vacuo, and the residue was purified by column chromatography on silica (eluent: chloroform/ethanol; 93:7+0.5% NH3) affording 513 mg (68% yield) of the title compound as a white solid: mp 210-212° C.; [α]22D -145° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 436 (65, M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[N:10]=[C:11]([CH3:24])[NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.I[CH3:26].[H-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[N:10]([CH3:26])[C:11]([CH3:24])=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1
Reactant: Cc1nc(Sc2ccc(Cl)cc2)c(-c2ccc(S(C)(=O)=O)cc2)[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(S(C)(=O)=O)cc2)c(Sc2ccc(Cl)cc2)n1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To the product of Step 4 (0.38 g, 0.96 mmol) and iodomethane (1.0 mL, 1M solution in THF, 1.0 mmol) in THF (5 mL) at 5° C. under argon was added NaH (60% in mineral oil, 0.040 g, 1.0 mmol). After stirring at RT for 16 h, the reaction was partitioned between CH2Cl2 (10 mL) and H2O (20 mL). The organic layer was separated, washed with H2O, brine, dried with anhydrous Na2SO4 and concentrated. The residue was purified by crystallization from EtOAc/hexane to give the title compound. 1H NMR (400 MHz, CDCl3): 2.52 (3H, s), 3.03 (3H, s), 3.51 (3H, s), 6.91-6.99 (2H, m), 7.21-7.29 (2H, m), 7.88-7.94 (2H, m), 8.21-8.27 (2H, m). LC-MS: m/z 393.0 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:10][CH:11](C)[CH2:12][OH:13])=[N:4][C:5]([F:9])=[C:6]([Cl:8])[CH:7]=1.ClC1C(OCC(O)C)=NC(F)=C(Cl)C=1>>[Cl:1][C:2]1[C:3]([O:10][CH2:11][CH2:12][OH:13])=[N:4][C:5]([F:9])=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(CO)Oc1nc(F)c(Cl)cc1Cl
Agent: CC(O)COc1nc(F)c(Cl)cc1Cl
Product: OCCOc1nc(F)c(Cl)cc1Cl

Procedure:
Mixture of 2-(3,5-Dichloro-6-fluoro-2-pyridyloxy)-1-propanol and 1-(3,5-dichloro-6-fluoro-2-pyridyloxy)-2-propanol;
Reaction SMILES: I[C:2]1[C:6]2[C:7]([NH:11][CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:8][CH:9]=[CH:10][C:5]=2[N:4]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[N:3]=1.[C:27]1([OH:33])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)CC(O)=O>O1CCOCC1>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][N:4]2[C:5]3[CH:10]=[CH:9][N:8]=[C:7]([NH:11][CH:12]4[CH2:17][CH2:16][O:15][CH2:14][CH2:13]4)[C:6]=3[C:2]([O:33][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:3]2)=[CH:20][CH:21]=1
Reactant: Oc1ccccc1
Reactant: COc1ccc(Cn2nc(I)c3c(NC4CCOCC4)nccc32)cc1
Agent: CN(C)CC(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: COc1ccc(Cn2nc(Oc3ccccc3)c3c(NC4CCOCC4)nccc32)cc1
Temperature: 120 °C
Reaction time: 24 h

Procedure:
To a pressure tube was added 3-iodo-1-(4-methoxybenzyl)-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-c]pyridin-4-amine (0.60 g, 1.3 mmol), phenol (0.36 g, 3.9 mmol), Cu(I) iodide (25 mg, 0.13 mmol), caesium carbonate (1.3 g, 0.39 mol), N,N-dimethylglycine (33 mg, 0.32 mmol) and 1,4-dioxane (3.0 mL). The tube was flushed with nitrogen, sealed, and stirred at 120° C. for 24 hours. The reaction mixture was cooled, filtered and concentrated under reduced pressure. The residue was re-dissolved in ethyl acetate, filtered through a pad of silica gel, and concentrated to give crude 1-(4-methoxybenzyl)-3-phenoxy-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-c]pyridin-4-amine which was used directly in the following step.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31]>C(#N)C.C(O)C>[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31].[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31].[F:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][N:18]4[CH2:4][C:3]5[C:28](=[CH:29][CH:30]=[CH:20][CH:2]=5)[CH2:27]4)[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: NCCCN1CCC(c2noc3cc(F)ccc23)CC1
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC#N
Product: Fc1ccc2c(C3CCN(CCCN4Cc5ccccc5C4)CC3)noc2c1

Procedure:
A stirred mixture of 3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propyl amine (3.46 g, 12.5 mmol), K2CO3 (4 g, 29 mmol) and αα'-dibromo-o-xylene (3.3 g, 12.5 mmol) in acetonitrile (300 ml) was heated at reflux for 3.5 hours. The mixture was cooled and the insolubles were filtered. The dark red solution was concentrated down to a dark oil. This oil was purified by flash chromatography over a silica gel column (SiO2, 45 g; eluted with dichloromethane and MeOH in dichloromethane). The product thus obtained weighed 1.95 g as an oil. This oil was dissolved in ethanol and was treated with a solution of fumaric acid (600 mg) in ethanol. The resulting crystals were collected as an off white solid and weighed 1.44 gm, m.p. 206°-209° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([NH2:11])[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:7]=1)=[O:5])[CH3:2].Br[CH2:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([NH:11][CH2:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CC(C)(C)C(=O)CBr
Reactant: CCOC(=O)c1cc(N)n(-c2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(NCC(=O)C(C)(C)C)n(-c2ccccc2)n1
Temperature: 100 °C
Yield: 23.4 %

Procedure:
6 g (25.9 mmol) of 5-Amino-1-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester are dissolved in 50 ml DMF, 4.65 g (25.9 mmol) 1-bromopinacolone and 16 g (49.1 mmol, 1.9 eq) of Cs2CO3 are added and the resulting mixture is heated to 100° C. for 4 hours. The reaction mixture is filtrated and the solvent removed in vacuo, the residue is subjected to preparative HPLC chromatography to obtain 2 g (23%) of the product.
Reaction SMILES: CO[C:3]([C:5]1[C:10]([CH2:11][S:12]([CH2:15][C:16]2[C:21]([F:22])=[CH:20][CH:19]=[C:18]([Cl:23])[C:17]=2[Cl:24])(=[O:14])=[O:13])=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Cl:24][C:17]1[C:18]([Cl:23])=[CH:19][CH:20]=[C:21]([F:22])[C:16]=1[C:15]1[S:12](=[O:14])(=[O:13])[CH2:11][C:10]2[N:9]=[CH:8][CH:7]=[N:6][C:5]=2[C:3]=1[OH:4]
Reactant: COC(=O)c1nccnc1CS(=O)(=O)Cc1c(F)ccc(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=S1(=O)Cc2nccnc2C(O)=C1c1c(F)ccc(Cl)c1Cl
Temperature: 100 °C

Procedure:
A mixture of 3-(2,3-dichloro-6-fluoro-phenylmethanesulfonylmethyl)-pyrazine-2-carboxylic acid methyl ester (0.261 g) and potassium carbonate (0.182 g) in N,N-dimethylformamide (6 ml) was heated to 100° C. for 2 hours. The reaction mixture was cooled to ambient temperature, diluted with water and washed with diethyl ether. The aqueous layer was acidified with aqueous hydrochloric acid (2M) and the resulting precipitate isolated by filtration. The precipitate was washed with water and diethyl ether and dried to give Compound No. C1 of Table C (0.106 g). MH+=361, RT=1.35 min.
Reaction SMILES: [Sn](Cl)Cl.[CH2:4]([Si:6]([CH2:40][CH3:41])([CH2:38][CH3:39])[C:7]1(O)[C:18]2[C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[S:15][C:14]=2[C:13]([Si:24]([CH2:29][CH3:30])([CH2:27][CH3:28])[CH2:25][CH3:26])(O)[C:12]2[C:11]3[C:31]([C:35]#[CH:36])=[CH:32][CH:33]=[CH:34][C:10]=3[S:9][C:8]1=2)[CH3:5]>C(O)(=O)C.CC(C)=O>[CH2:40]([Si:6]([CH2:4][CH3:5])([CH2:38][CH3:39])[C:7]1[C:18]2[C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[S:15][C:14]=2[C:13]([Si:24]([CH2:27][CH3:28])([CH2:25][CH3:26])[CH2:29][CH3:30])=[C:12]2[C:8]=1[S:9][C:10]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]#[CH:36])[C:11]=12)[CH3:41]
Reactant: C#Cc1cccc2sc3c(c12)C(O)([Si](CC)(CC)CC)c1sc2ccccc2c1C3(O)[Si](CC)(CC)CC
Agent: Cl[Sn]Cl
Solvent: CC(=O)O
Solvent: CC(C)=O
Product: C#Cc1cccc2sc3c([Si](CC)(CC)CC)c4c(sc5ccccc54)c([Si](CC)(CC)CC)c3c12
Temperature: 2.5 °C

Procedure:
A solution of tin(II)chloride dehydrate (2.08 g, 9.2 mmol) in 50% acetic acid (35 ml) is added within ten minutes to a solution of 6,12-bis-triethylsilanylethynyl-6,12-dihydro-dibenzo[d,d′]benzo[1,2-b;4,5-b′]dithiophene-6,12-diol (educt 4) (2.40 g, 6 mmol) in acetone (30 ml). There is a slight temperature increase (2-3° C.), and formation of a yellow suspension takes place. This suspension is stirred over night at ambient temperature, and then the solid is filtered off. The solid is then washed with 50% acetic acid (30 ml), water (twice with 40 ml), and acetone (2*40 ml). The residue is then dried to give crude product which is filtered over a pad of silica (60 g) with chloroform to give product which is recrystallised from ethyl acetate (40 ml). The product is filtered off, washed with ethyl acetate (2*10 ml), and hexane (10 ml). After drying, the title product is obtained as yellow crystals. Mp. (DSC) 82° C. and 204° C. 1H-NMR (CDCl3, 300 MHz) δ 0.92 (q, 6H, SiCH2); 1.26 (tr, 9H, CH3); 7.48 (m, 1H, H-2), 7.51 (m, 1H, H-3), 7.91 (d, 1H, H-4); 9.29 (d, 1H, H-1). 13C-NMR (CDCl3, 75 MHz) δ 4.95 (CH2); 8.10 (CH3); 102.69, 107.26 (C≡C); 112.46 (C-6); 122.74 (C-4); 124.39 (C-2); 125.05 (C-1); 127.47 (C-3); 132.72 (C-6a); 135.49 (C-6b); 140.53 (C-4-a); 143.08 (C-5a).
Reaction SMILES: [C:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]=[CH:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([O:30]CC)=[O:29])=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)([O:3]C(C)(C)C)=[O:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:1]([C:8]1[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]\[C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([OH:30])=[O:29])=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)([OH:3])=[O:2]
Reactant: CCOC(=O)c1ccc(-c2ccc(C=Cc3ccc(C(=O)OC(C)(C)C)cc3)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=C(O)c1ccc(/C=C\c2ccc(-c3ccc(C(=O)O)cc3)cc2)cc1
Reaction time: 4 h

Procedure:
31.2 g of 1-(4-Carbo-tert.-butoxyphenyl)-2-(4'-carbethoxybiphenyl-4-yl)-ethene in 150 ml of absolute toluene are boiled under reflux for 3 hours with 1 g of p-toluene sulphonic acid. The reaction mixture is then evaporated to dryness, 8.68 g of NaOH in 100 ml of H2O and 100 ml of ethanol are added, and the mixture is boiled for 4 hours. It is then filtered hot after the addition of active charcoal, diluted with 200 ml of H2O and extracted twice with CH2Cl2, and the product is precipitated from the aqueous phase with conc. HCl.