Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][C:14]([C:16](=[O:30])[NH:17][C:18]3[CH:23]=[C:22]([C:24]4[S:25][CH:26]=[CH:27][CH:28]=4)[CH:21]=[CH:20][C:19]=3[NH2:29])=[CH:15][C:10]=2[N:9]=[C:8]1[CH3:31])(=O)C.C(N(CC)CC)C>CO>[NH2:29][C:19]1[CH:20]=[CH:21][C:22]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)=[CH:23][C:18]=1[NH:17][C:16]([C:14]1[CH:13]=[CH:12][C:11]2[N:7]([CH2:6][CH2:5][OH:4])[C:8]([CH3:31])=[N:9][C:10]=2[CH:15]=1)=[O:30]
Reactant: CC(=O)OCCn1c(C)nc2cc(C(=O)Nc3cc(-c4cccs4)ccc3N)ccc21
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1nc2cc(C(=O)Nc3cc(-c4cccs4)ccc3N)ccc2n1CCO

Procedure:
A solution of acetate 308 (18 mg; 41 μmol) and triethylamine (0.5 mL) in dry methanol (2.0 mL) was stirred at room temperature for 16 h and then concentrated in vacuo to give the title compound 309 in quantitative yield. 1H NMR: (400.2 MHz, DMSO) δ (ppm): 9.70 (s, 1H), 8.22 (s, 1H), 7.84 (dd; J=1.4, 8.2 Hz; 1H); 7.57 (d, J=8.4 Hz, 1H), 7.49 (d; J=2.2 Hz; 1H); 7.34 (dd; J=1.4, 5.1 Hz; 1H); 7.28 (dd; J=2.2, 8.2 Hz; 1H); 7.23 (dd; J=1.1, 3.5 Hz; 1H); 7.04 (dd; J=3.5, 5.1 Hz; 1H); 6.80 (d; J=8.4 Hz; 1H); 5.14 (bs, 2H); 5.00 (bs, 1H); 4.28 (t; J=5.4 Hz; 2H); 3.72 (t; J=5.4 Hz; 2H); 2.59 (s, 3H). MS: calc: 392.5; found: 393.2 (M+H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:3]=1.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:3]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1cc(O)c2ccccc2c1
Product: CCOC(=O)c1cc(OCc2ccccc2)c2ccccc2c1

Procedure:
In an analogous manner to that described in Example 14(a), by alkylating ethyl 4-hydroxy-naphthalene-2-carboxylate [J. Agric. Chem Soc. Japan 24, 313 (1950)] with benzyl bromide there was obtained ethyl 4-benzyloxy-naphthalene-2-carboxylate as an almost colourless solid, Rf : 0.53 (SiO2, hexane:ethyl acetate=4:1).
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=O)[NH:14][CH:13]=[C:12]2[C:20]#[N:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:22]CCCl.O=P(Cl)(Cl)Cl>C(OCC)(=O)C>[CH2:1]([S:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([Cl:22])=[N:14][CH:13]=[C:12]2[C:20]#[N:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1c[nH]c(=O)c2ccc(SCc3ccccc3)cc12
Reactant: ClCCCl
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1cnc(Cl)c2ccc(SCc3ccccc3)cc12
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A vial was charged with 6-(benzylthio)-1-oxo-1,2-dihydroisoquinoline-4-carbonitrile (0.492 g, 1.683 mmol) and DCE (8.41 ml). POCl3 (0.314 ml, 3.37 mmol) was added and the reaction was stirred overnight at 90° C. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (40 g silica gel column, gradient elution 0 to 100% EtOAc:Heptane) to afford 6-(benzylthio)-1-chloroisoquinoline-4-carbonitrile as a brown solid. m/z (ESI) 311.1 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][S:11](Cl)(=[O:13])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[NH4+:19].[NH4+]>C(#N)C.N>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][S:11]([NH2:19])(=[O:13])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: [NH4+]
Reactant: O=[N+]([O-])c1ccc(CS(=O)(=O)Cl)cc1
Agent: N
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: NS(=O)(=O)Cc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 92.5 %

Procedure:
To a solution of (4-nitrophenyl)methanesulfonyl chloride (4 g, 17 mmol) in acetonitrile (100 mL) was added a solution of ammonium carbonate (3 g, 31.3 mmol) in ammonia (50 mL). The reaction mixture was stirred for 1 h, and TLC indicated the starting material consumed completely. The organic solvent was removed under reduced pressure. Addition of water (10 mL) led to precipitate formation. The solid was collected, washed with water (2×5 mL), and dried to give (4-nitrophenyl)methanesulfonamide (3.4 g, 93%) as a white solid. MS (ES+) C7H8N2O4S requires: 216, found: 217 [M+H]+.
Reaction SMILES: [CH2:1]([OH:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[CH:9](Br)([CH3:11])[CH3:10]>>[CH:9]([O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:8])([CH3:11])[CH3:10]
Reactant: OCCCCCCO
Reactant: CC(C)Br
Product: CC(C)OCCCCCCO

Procedure:
The above compound is produced in analogous manner to that described in Example 32, but using 1,6-hexandiol in the place of 1,4-butanol and isopropylbromide in the place of isopentylbromide. B.P.: 73°-75° /0.22 mm Hg.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>[I-].[K+].C(#N)C>[CH2:10]([O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1ccc(OCc2ccccc2)cc1
Yield: 100.3 %

Procedure:
Add 4-cyanophenol (1.191 g, 10 mmol), benzyl bromide (1.881 g, 11 mmol), potassium carbonate (3.455 g, 25 mmol) and potassium iodide (166 mg, 1 mmol) to acetonitrile (80 mL) and heat at reflux for 12 h. Cool, partition between EtOAc and water, separate he organic layer, and extract the aqueous layer with EtOAc. Combine the organic extracts, wash with brine, dry over Na2SO4, filter and concentrate. Purify by chromatography on silica gel eluting with EtOAc/hexane (1:6) to give the desired intermediate as a white solid (2.098 g, 100%). MS (ES+) m/z: 227 (M+NH4)+.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:15][C:14]=3I)=[O:9])=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:38][C@@H:39]([OH:42])[C:40]#[CH:41]>C(Cl)(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13]4=[C:14]([CH:41]=[C:40]([C@H:39]([OH:42])[CH3:38])[N:12]4[CH:11]=2)[CH:15]=[C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:17]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(I)cc(CN3CCOCC3)cc2c1O
Reactant: C#C[C@@H](C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: C[C@@H](O)c1cc2cc(CN3CCOCC3)cc3c(=O)c(C(=O)NCc4ccc(Cl)cc4)cn1c23
Temperature: 25 °C
Reaction time: 48 h
Yield: 13 %

Procedure:
To a suspension of N-(4-chlorobenzyl)-4-hydroxy-8-iodo-6-(4-morpholinylmethyl)-3-quinolinecarboxamide (300 mg), PdCl2(PPh3)2 (39.2 mg), CuI (12.8 mg), and Et3N (0.16 mL) in CHCl3 (5.6 mL) is added (R)-(+)-3-butyn-2-ol (0.053 mL). The reaction is stirred at room temperature for 2 days. The reaction is condensed to remove CHCl3. The solvent is replaced with ETOH (5.6 mL) and additional Et3N (0.16 mL) is added to the reaction mixture. N2 is passed over the surface and the reaction is heated at 60° C. overnight, then allowed to cool to room temperature. The reaction mixture is condensed, adsorbed onto silica, and chromatographed eluting with 1% MeOH in CH2Cl2 to 3% MeOH in CH2Cl2. Product-containing fractions are combined, condensed, and recrystallized from hot acetonitrile to afford 33.8 mg (13%) of N-(4-chlorobenzyl)-2-[(1R)-1-hydroxyethyl]-8-(4-morpholinylmethyl)-6-oxo-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxamide as a tan solid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([C:13]([F:16])([F:15])[F:14])[CH:7]=2.C(=O)([O-])[O-].[K+].[K+].Cl.[N+:24]([C:27]1[CH:32]=[CH:31][C:30]([NH:33][CH:34]2[CH2:39][CH2:38][CH:37]([O:40][CH2:41][C:42]([N:44]3[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]3)=[O:43])[CH2:36][CH2:35]2)=[CH:29][C:28]=1[C:50]([F:53])([F:52])[F:51])([O-:26])=[O:25]>CN(C=O)C.CCOC(C)=O>[N+:24]([C:27]1[CH:32]=[CH:31][C:30]([NH:33][CH:34]2[CH2:35][CH2:36][CH:37]([O:40][CH2:41][C:42]([N:44]3[CH2:49][CH2:48][N:47]([CH2:2][C:3]4[CH:4]=[N:5][C:6]5[C:11]([CH:12]=4)=[CH:10][CH:9]=[C:8]([C:13]([F:16])([F:15])[F:14])[CH:7]=5)[CH2:46][CH2:45]3)=[O:43])[CH2:38][CH2:39]2)=[CH:29][C:28]=1[C:50]([F:53])([F:52])[F:51])([O-:26])=[O:25]
Reactant: O=C(COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1)N1CCNCC1
Reactant: FC(F)(F)c1ccc2cc(CCl)cnc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1)N1CCN(Cc2cnc3cc(C(F)(F)F)ccc3c2)CC1
Temperature: 70 °C
Reaction time: 8 h
Yield: 34.8 %

Procedure:
To a solution of 3-chloromethyl-7-trifluoromethyl-quinoline (140 mg, 0.57 mmol, 1.1 eq.) in DMF (10 ml) was added potassium carbonate (345 mg, 2.5 mmol, 5 eq.) then 2-[4-(4-Nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-1-piperazin-1-yl-ethanone hydrochloride (233 mg, 0.5 mmol, 1 eq.) was added. The solution was stirred overnight at 70° C. and diluted with EtOAc (25 ml) and washed with water (25 ml), saturated aqueous lithium chloride (25 ml) and brine (25 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a residue, which was applied onto a silica gel column and eluted with methanol in dichloromethane. The semi-purified material was further purified by HPLC to afford 2-[4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-1-[4-(7-trifluoromethyl-quinolin-3-ylmethyl)-piperazin-1-yl]-ethanone as a yellow solid (111.2 mg, 30%). (CI, m/z): [M+H]+ 640; 1H NMR (400 MHz, CDCl3): δ 1.20-1.36 (m, 2H), 1.40-1.54 (m, 2H), 2.08-2.21 (m, 4H), 2.46-2.61 (m, 4H), 3.32-3.49 (m, 2H), 3.53-3.62 (m, 2H), 3.63-3.71 (m, 2H), 3.76 (s, 2H), 4.20 (s, 2H), 4.46 (d, J=7.6 Hz, 1H), 6.63 (dd, J=9.1, 2.6 Hz, 1H), 6.85 (d, J=2.5 Hz, 1H), 7.75 (dd, J=8.5, 1.6 Hz, 1H) 7.94 (d, J=8.5 Hz, 1H), 8.02 (d, J=9.0 Hz, 1H), 8.13 (d, J=1.2 Hz, 1H), 8.43 (s, 1H), 9.03 (d, J=2.1 Hz, 1H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[N+:13]([O-:15])=[O:14].[Br:16]N1C(=O)CCC1=O.C(=O)([O-])O.[Na+]>C(#N)C>[Br:16][C:8]1[CH:7]=[C:6]([C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([N+:13]([O-:15])=[O:14])[C:3]=1[NH:2][CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: CNc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CNc1c(Br)cc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 5 h
Yield: 69 %

Procedure:
To a mixture of methyl-(2-nitro-4-trifluoromethyl-phenyl)-amine (16 g) and acetonitrile (200 ml) was added N-bromosuccinimide (15 g) while ice-cooling. The reaction mixture was stirred at room temperature for 5 hours. To the resulting reaction mixture was poured saturated aqueous sodium hydrogen carbonate solution, and then the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give (2-bromo-6-nitro-4-trifluoromethyl-phenyl)-methyl-amine (15 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:20]=[CH:19][C:13]([O:14][Si](C)(C)C)=[CH:12][CH:11]=2)=[CH2:9])=[CH:4][CH:3]=1.Br[C:22]1C=CC(C(C2C=CC(O)=CC=2)=C)=CC=1.C[Si](C)(C)N[Si](C)(C)C.C(I)I>CCOCC.[Zn].Cl[Cu]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:10]3[CH:20]=[CH:19][C:13]([OH:14])=[CH:12][CH:11]=3)[CH2:22][CH2:9]2)=[CH:4][CH:3]=1
Reactant: C=C(c1ccc(Br)cc1)c1ccc(O[Si](C)(C)C)cc1
Reactant: C=C(c1ccc(O)cc1)c1ccc(Br)cc1
Agent: Cl[Cu]
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Zn]
Solvent: CCOCC
Solvent: ICI
Product: Oc1ccc(C2(c3ccc(Br)cc3)CC2)cc1

Procedure:
Eg) A mixture of 457 mg of zinc dust and 692 mg of CuCl in 15 ml of ether is heated under reflux under argon. Subsequently, a solution of 934 mg of [4-[1-(4-bromo-phenyl)-vinyl]-phenoxy]-trimethyl-silane in 15 ml of ether, prepared from 748 mg of 4-[1-(4-bromo-phenyl)-vinyl]-phenol (Ex. Ef) and 14 ml of hexamethyldisilazane under reflux, is added dropwise and thereafter 0.56 ml of methylene iodide is added. The reaction mixture is heated under reflux and diluted with ether. The residue is washed with ether and the filtrate is washed with water, dried and concentrated. The crude product is purified over silica gel with ethyl acetate-hexane as the eluent. 4-(1-(4-Bromo-phenyl)cyclopropyl)-phenol is obtained as a brown oil, MS: m/e 288 (M+H+, 1 Br).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]=[C:11]([NH:13][NH2:14])[CH2:10][N:9]=[C:8]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])[C:7]=2[CH:22]=1.O=[C:26]([CH2:30][CH2:31][N:32]([CH2:36][CH2:37][CH3:38])[CH2:33][CH2:34][CH3:35])[C:27]([OH:29])=[O:28]>>[F:24][C:2]([F:1])([F:23])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]=[C:11]([NH:13][N:14]=[C:26]([C:27]([OH:29])=[O:28])[CH2:30][CH2:31][N:32]([CH2:36][CH2:37][CH3:38])[CH2:33][CH2:34][CH3:35])[CH2:10][N:9]=[C:8]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])[C:7]=2[CH:22]=1
Reactant: CCCN(CCC)CCC(=O)C(=O)O
Reactant: NNC1=Nc2ccc(C(F)(F)F)cc2C(c2ccccc2F)=NC1
Product: CCCN(CCC)CCC(=NNC1=Nc2ccc(C(F)(F)F)cc2C(c2ccccc2F)=NC1)C(=O)O

Procedure:
In the manner given in Example 13, 7-(trifluoromethyl)-2-hydrazino-5-(o-fluorophenyl)-3H-1,4-benzodiazepine can be stirred with 2-oxo-4-(dipropylamino)-butyric acid at room temperature to give 7-(trifluoromethyl)-2-[[1-carboxy-3-(dipropylamino)propylidene]-hydrazino]-5-(o-fluorophenyl)-3H-1,4-benzodiazepine.
Reaction SMILES: CO[CH:3](OC)[CH2:4][NH:5][C:6](=[O:19])[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=[O:8].C(O)(C(F)(F)F)=O>CC(O)=O>[OH:19][C:6]1[C:7](=[O:8])[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)[CH:3]=[CH:4][N:5]=1
Reactant: COc1ccc(CNC(=O)C(=O)NCC(OC)OC)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: COc1ccc(Cn2ccnc(O)c2=O)cc1
Temperature: 25 °C
Yield: 85.7 %

Procedure:
A solution of N1-(2,2-dimethoxyethyl)-N2-(4-methoxybenzyl)oxalamide (7.5 g, 25.3 mmol) and TFA (2.340 mL, 30.4 mmol) in AcOH (160 mL) was stirred at 135° C. in a seal tube for 1.5 hours. After cooling to RT and removal of the volatiles under vacuum, ethyl ether (150 ml) and sat. aq. NaHCO3 solution (150 ml) were added. The resulting precipitate was collected by filtration, washed with H2O (50 ml) and ether (50 ml) prior to drying under high vacuum to yield 3-hydroxy-1-(4-methoxybenzyl)pyrazin-2(1H)-one (5.30 g, 21.68 mmol, 86% yield) as brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.17 (1H, br. s.), 7.18 (2H, d), 6.81 (2H, d), 6.46 (1H, d, J=5.77 Hz), 6.23 (1H, br. s.), 4.74 (2H, s), 3.24 (1H, s).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:17][CH2:18][CH2:19]Br>CN(C=O)C>[Br:17][CH2:18][CH2:19][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(OCCBr)cc1
Reaction time: 8 h
Yield: 84.8 %

Procedure:
1-(4-hydroxyphenyl)ethanone (8.2 g, 60.2 mmol), potassium carbonate (15.2 g, 110.1 mmol), and KI (1.0 g, 6.0 mmol) in 100 DMF was stirred for 5 min, then 1,2-dibromoethane (60 ml, 696.2 mmol)was added. The mixture was stirred overnight, evaporated, diluted with EtAc/Hexane (1:1), washed with 0.1 M HCl/NaCl (conc), dried over MgSO4, filtered, evaporated and purified by SiO2 chrmatography eluted with EtAc/Hexane (1:3 to 2:3) to afford 12.41 g (85.2%) of the title compound. 1H NMR (CDCl3) 7.87 (ddd, 2H, J=2.8, 4.9, 9.7 Hz), 6.88 (ddd, 2H, J=2.8, 4.9, 9.6 Hz), 4.29 (t, 2H, J=6.2 Hz), 3.59 (t, 2H, J=6.2 Hz); 13C NMR 196.88, 162.11, 131.15, 130.54, 113.80, 68.06, 29.50, 26.62; MS m/z+ 264.80 (M+Na), 266.80 (M+2+Na).
Reaction SMILES: Br[C:2]1[C:3]([NH2:18])=[N:4][C:5]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)=[N:6][C:7]=1[N:8]1[CH:12]=[CH:11][CH:10]=[N:9]1.[C-:19]#[N:20].C(OCC)(=O)C>N1C=CC=CC=1>[NH2:18][C:3]1[C:2]([C:19]#[N:20])=[C:7]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)[N:6]=[C:5]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:4]=1
Reactant: Nc1nc(-n2cccn2)nc(-n2cccn2)c1Br
Reactant: [C-]#N
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: N#Cc1c(N)nc(-n2cccn2)nc1-n1cccn1
Yield: 39.6 %

Procedure:
A mixture of 0.2 g (0.65 mmol) of 5-bromo-2,6-di(1H-pyrazol-1-yl)pyrimidin-4-amine and 0.06 g (0.72 mmol) of cupper (I) cyanide in 3 ml of pyridine was irradiated with microwaves at 250° C. for 20 min. After nearly complete conversion to the corresponding carbonitrile as was indicated by TLC, ethyl acetate was added and filtered throw celite. The solution was extracted two times with 10 ml of saturated solution of NaHCO3 and Brine. The organic layer was separated, dried with MgSO4 and concentrated to give 0.065 g (39.6%) of the desired product.
Reaction SMILES: [C:1]1([N:7]2[C:15](=[O:16])[C:14]3[C:9]([C:10]4[C:11](=[CH:17][NH:18][CH:19]=4)[NH:12][CH:13]=3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[CH3:29][N:30]=[C:31]=[O:32]>CN(C=O)C>[CH3:29][NH:30][C:31]([N:18]1[CH:19]=[C:10]2[C:11]([NH:12][CH:13]=[C:14]3[C:15](=[O:16])[N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:8]=[C:9]32)=[CH:17]1)=[O:32]
Reactant: CN=C=O
Reactant: O=c1c2c[nH]c3c[nH]cc3c-2nn1-c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)n1cc2[nH]cc3c(=O)n(-c4ccccc4)nc-3c2c1
Reaction time: 8 h

Procedure:
One equivalent of pyrrolo-pyridine 12a was dissolved in DMF (0.1 M) under an atmosphere of nitrogen. 3 equivalents of di-iso-propylethylamine was added, followed by 1.5 equivalents of methylisocyanate and stirred overnight. The crude reaction mixture was concentrated to dryness and purification by column chromatography afforded the compound 13a. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.84 (d, J=3.52 Hz, 3H) 7.02-7.18 (m, 1H) 7.30-7.47 (m, 2H) 7.57-7.78 (m, 1H) 7.90-8.04 (m, 1H) 8.05-8.20 (m, 2H) 8.32-8.50 (m, 1H) 8.52-8.68 (m, 1H) 12.28-12.49 (m, 1H)
Reaction SMILES: [C:1]1([N:7]=[N+:8]=[N-:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OCC)C.[CH2:15]([OH:18])[C:16]#[CH:17]>>[C:1]1([N:7]2[CH:17]=[C:16]([CH2:15][OH:18])[N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#CCO
Reactant: [N-]=[N+]=Nc1ccccc1
Solvent: CCOCC
Product: OCc1cn(-c2ccccc2)nn1
Temperature: 90 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
Phenyl azide (2.02 g, 17.0 mmol) was dissolved in neat propargyl alcohol (3 mL) and the mixture was heated to 90° C. for 2 h. The reaction mixture was cooled to room temperature and the reaction mixture was diluted into diethyl ether and left overnight during which time 7 precipitated as a crystalline solid to afford 1.03 g (35%) of the desired product 7 while the mother liquor contained primarily the regioisomer 9: 1H NMR (400 MHz, CDCl3) δ 7.97, (s, 1H), 7.70, (d, J=8.40 Hz, 2H), 7.50, (m, 2H), 7.41 (m, 1H), 4.88, (d, J=6.00 Hz, 2H), 2.70, (bs, 1H). Step b: Preparation of 1-phenyl-1H-1,2,3-triazole-4-carbaldehyde (9). To a solution of (1-phenyl-1H-1,2,3-triazol-4-yl)methanol, 7, (1.03 g, 5.87 mmol) in CH2Cl2 (50 mL) was added MnO2 (2.05 g, 23.5 mmol). The reaction mixture was stirred for 3 days at room temperature. The reaction mixture was then filtered through Celite© and the resulting filtrate was concentrated in vacuo. The crude material was purified by silica gel chromatography (0-5% methanol/dichloromethane) yielding 0.83 g (82%) of 9: 1H NMR (400 MHz, CDCl3) δ 10.22 (s, 1H), 8.51 (s, 1H), 7.53, (d, J=9.6 Hz, 2H), 7.58-7.49, (m, 3H). Step c: Preparation of N-methyl-N-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)-5,6,7,8-tetrahydroquinolin-8-amine (Y). To a solution of 1-phenyl-1H-1,2,3-triazole-4-carbaldehyde, 9, (0.23 g, 1.35 mmol) in 1,2-dichloroethane (2 mL) was added N-methyl-5,6,7,8-tetrahydroquinolin-8-amine, 5, (0.20 g, 1.23 mmol), sodium triacetoxyborohydride (0.10 g, 1.60 mmol), and 3 drops of acetic acid. The reaction mixture was stirred for 16 h at room temperature. The reaction mixture was then poured into aqueous saturated NaCl (10 mL) and was extracted with ethyl acetate (10 mL). The organic phase was dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (0-5% methanol/dichloromethane) yielding 35 mg (9%) of Y: 1H NMR (400 MHz, CDCl3) δ 8.74 (s, 1H), 8.47 (s, 1H), 7.78, (d, J=8.4 Hz, 2H), 7.50-7.39, (m, 4H), 7.20, (m, 1H), 4.72, (d, J=13.6 Hz, 1H), 4.63-4.58 (m, 2H), 2.90-2.60 (m, 6H), 2.22-2.17 (m, 1H), 2.10-1.95, (m, 1H), 1.90-1.78, (m, 1H).
Reaction SMILES: ClCC1C=CC(O[CH2:10][O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])=CC=1.O[C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1>>[CH3:15][Si:14]([CH3:17])([CH3:16])[CH2:13][CH2:12][O:11][CH2:10][C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: C[Si](C)(C)CCOCOc1ccc(CCl)cc1
Product: COC(=O)c1ccc(COCC[Si](C)(C)C)cc1

Procedure:
The 1-chloromethyl-4-(2-trimethylsilanyl-ethoxymethoxy)-benzene used at the alkylating agent was prepared in analogy to Example 5(a)-(c) from methyl 4-hydroxybenzoate by introducing the SEM group to give methyl 4-(2-trimethylsilanylethoxymethyl)-benzoate. Subsequent reduction with lithium aluminium hydride gave [4-(2-trimethylsilanylethoxy-methoxy)-phenyl]-methanol and chlorination of this gave 1-chlormethyl-4-(2-trimethylsilanyl-ethoxymethoxy)-benzene as a colourless oil; MS: 272 (M)+.
Reaction SMILES: [C:1](=[O:3])=[O:2].C1COCC1.[Li][C:10]1[S:20][C:13]2[C:14]3[CH:19]=[CH:18][S:17][C:15]=3[S:16][C:12]=2[CH:11]=1>O>[S:20]1[C:13]2[C:14]3[CH:19]=[CH:18][S:17][C:15]=3[S:16][C:12]=2[CH:11]=[C:10]1[C:1]([OH:3])=[O:2]
Reactant: [Li]c1cc2sc3sccc3c2s1
Reactant: O=C=O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc2sc3sccc3c2s1
Temperature: -78 °C
Yield: 61 %

Procedure:
Carbon dioxide was added in small lumps to a flask against a fast flow of nitrogen. The flask was then sealed under a nitrogen bubbler and cooled to the −78° C. THF was added to cover the CO2 and the mixture stirred. The cooled lithiodithienothiophene was added dropwise via syringe and a violent reaction was observed resulting in the formation of a yellow suspension. Once addition was complete the mixture was allowed to warm to r.t. during which time the mixture turned to an off white colour. After stirring for a further 30 min. water (30 cm3) was added and the mixture turned to a light green/brown solution. This was washed with ether (2×20 cm3) and the organics discarded. The aqueous layer was acidified by the addition of HCl (10 cm3, 5 M) which precipitated out a fine yellow solid. Recrystallisation was attempted in 33% acetic acid. A fine, insoluble suspension remained after heating and this was left to further crystallise overnight to give the title compound as a fine yellow/green powder (286 mg, 61%); δH 7.31, (1H, d, J5.1), 7.56 (2H, d, J5.1), 7.94 (1H, s); v max/cm−1 (KBr) 3090 m, 2823 m, 2559 m, 1652 s, 1504 s, 1470 w, 1428 s, 1311 s, 1265 m, 1164 m, 928 s, 750 s, 716 s and 602 s; m.p. 276° C. (sublimes) m.p.(lit.reference 29) 275-277° C.)