Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:9]=[CH:8][C:7](Br)=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CC#N.O>[NH2:1][C:2]1[N:9]=[CH:8][C:7]([C:16]2[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: COc1ccc(B(O)O)cc1
Reactant: Nc1ncc(Br)cc1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1ccc(-c2cnc(N)c(C=O)c2)cc1
Yield: 46.6 %

Procedure:
2-amino-5-bromonicotinaldehyde (1.61 g, 8 mmol), 4-methoxyphenylboronic acid (2.43 g, 16 mmol) and anhydrous potassium carbonate (2.21 g, 16 mmol) were dissolved in 50 ml of CH3CN/H2O (8:2), and 1 mol % of dichlorobis(triphenylphopsine)palladium(II) (56 mg, 0.08 mmol) was added while stirring. The reaction mixture was heated to reflux and stirred for 2 h. The reaction mixture was allowed to cool, and then partitioned between diethyl ether and water. The aqueous layer was extracted with another portion of diethyl ether. The combined organics were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The compound was purified by chromatography on silica gel eluting with with 30% EtOAc/hexanes to yield 2-amino-5-(4-methoxyphenyl)nicotinaldehyde (0.85 g, 47%).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[F:15][C:16]([F:25])([F:24])[C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1>>[F:15][C:16]([F:24])([F:25])[C:17]1[CH:18]=[CH:19][C:20]([NH:21][CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]2)=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Nc1ccc(C(F)(F)F)cc1
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(C(F)(F)F)cc2)CC1

Procedure:
The title compound was prepared from 1,1-dimethylethyl 4-oxo-1-piperidinecarboxylate and 4-trifluoromethylaniline using a method similar to that described for D20
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]4[S:23][C:24]([CH3:27])=[N:25][N:26]=4)=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Br[CH2:29][CH3:30].[OH-].[Na+].CN(C)C=O>O>[CH2:29]([N:26]1[N:25]=[C:24]([CH3:27])[S:23][C:22]1=[N:21][C:18]1[CH:19]=[CH:20][C:15]([N:12]2[CH2:11][CH2:10][N:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH2:14][CH2:13]2)=[CH:16][CH:17]=1)[CH3:30]
Reactant: COc1ccc(N2CCN(c3ccc(Nc4nnc(C)s4)cc3)CC2)cc1
Reactant: CCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1nc(C)sc1=Nc1ccc(N2CCN(c3ccc(OC)cc3)CC2)cc1
Reaction time: 4 h
Yield: 25.3 %

Procedure:
A mixture of 10.6 parts of N-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-5-methyl-1,3,4-thiadiazol-2-amine, 0.5 parts of bromoethane, 4 parts of sodium hydroxide pellets and 188 parts of N,N-dimethylformamide was stirred for 4 hours at 40°-50° C. After the addition of water, the crystallized product was filtered off and purified by column chromatography over silica gel using a mixture of trichloromethane, methanol, ethyl acetate and hexane (48:2:30:20 by volume) as eluent. The first fraction was collected and the eluent was evaporated. The residue was crystallized from 4-methyl-2-pentanone. The product was filtered off and dried, yielding 2.9 parts (25.3%) of N-(3-ethyl-5-methyl-1,3,4-thiadiazol-2(3H)-ylidene)-4-[4-(4-methoxyphenyl)-1-piperazinyl]benzenamine; mp. 175.4° C. (int. 14). The second fraction was collected and the eluent was evaporated. The residue was crystallized from 4-methyl-2-pentanone. The product was filtered off and dried, yielding 6.5 parts (56.7%) of N-ethyl-N-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-5-methyl-1,3,4-thiadiazol-2-amine; mp. 186.8° C. (int. 15).
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]2[CH:29]=[CH:28][CH:27]=[CH:26][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:31][C:32](=[O:36])[C@H:33]([CH3:35])O>>[CH2:1]([C:8]1[O:9][C:10]2[CH:29]=[CH:28][CH:27]=[CH:26][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C@H:33]([CH3:35])[C:32]([OH:36])=[O:31])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H](C)O
Reactant: Oc1ccc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1
Product: C[C@@H](Oc1ccc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from 4′-(2-benzyl-benzofuran-3-yl)-biphenyl-4-ol, and (S)-(+)- lactic acid methyl ester, in substantially the same manner, as described in Example 1, steps g-h, and was obtained as a white solid, mp 112-114° C.; MS m/e 448 (M+);
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][O:17][CH3:18])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:24](=[O:40])[CH2:25][C:26](=O)[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)[CH:28]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:18][O:17][CH2:16][CH2:15][O:14][C:12]1[C:11]([C:19]([F:20])([F:22])[F:21])=[CH:10][C:9]2[NH:23][C:24](=[O:40])[CH2:25][C:26]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]4[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=4)[CH:28]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: COCCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cccnc3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cccnc3)c1)=N2

Procedure:
The title compound was prepared from {5-(2-methoxy-ethoxy)-2-[3-oxo-3-(3-pyridin-3-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M188) (278 mg, 0.49 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (153 mg, 69%).
Reaction SMILES: [CH3:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17](Cl)=[O:18].N1C=CC=CC=1>C(OCC)C>[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[C:8]([N+:9]([O-:11])=[O:10])[C:2]=1[CH3:1])=[O:18]
Reactant: Cc1c(N)cccc1[N+](=O)[O-]
Reactant: O=C(Cl)c1ccco1
Solvent: CCOCC
Solvent: c1ccncc1
Product: Cc1c(NC(=O)c2ccco2)cccc1[N+](=O)[O-]

Procedure:
A solution of 2-methyl-3-nitroaniline (1 mmol) in anhydrous diethyl ether was treated with 2-furoyl chloride (1.1 mmol) and pyridine (3.0 mmol) at 25° C. for 12 h. Extraction and chromatography afforded N-(2-furoyl)-2-methyl-3-nitroaniline as a white solid. TLC: Rf =0.41, 50% EtOAc-hexane.
Reaction SMILES: C([NH:5][C:6]([NH:8][CH2:9][CH2:10][N:11]1[CH2:17][CH2:16][CH2:15][CH2:14][C:13]([CH2:26][CH3:27])([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=2)[C:12]1=[O:28])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:26]([C:13]1([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=2)[CH2:14][CH2:15][CH2:16][CH2:17][N:11]([CH2:10][CH2:9][NH:8][C:6]([NH2:5])=[O:7])[C:12]1=[O:28])[CH3:27]
Reactant: CCC1(c2cccc(OC)c2)CCCCN(CCNC(=O)NC(C)(C)C)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC1(c2cccc(OC)c2)CCCCN(CCNC(N)=O)C1=O
Reaction time: 72 h

Procedure:
To a solution of 1-tert-butyl-3-{2-[3-ethyl-3-(3-methoxy-phenyl)-2-oxo-azepan-1-yl]-ethyl}-urea (as described above in Step A) (0.35 g, 0.93 mmol) in CH2Cl2 (2.0 mL) was added TFA (6.0 mL) and the solution was stirred for 72 hr. The solvents were removed in vacuo to obtain the title compound.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][C@@H:5]([N:7]2[CH:15]=[N:14][C:13]3[C:8]2=[N:9][C:10]([N:31]2[CH2:35][CH2:34][C@@H:33]([NH:36][C:37]([NH:39][C:40]4[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=4)=[O:38])[CH2:32]2)=[N:11][C:12]=3[NH:16][CH2:17][CH:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:4]([OH:46])[C@@H:3]1[OH:47].O=C1CCC(=O)N1[O:55][C:56](=O)[CH2:57][NH:58]C(OC(C)(C)C)=O.[ClH:67]>C1COCC1.CCO>[ClH:67].[ClH:67].[NH2:58][CH2:57][C:56]([NH:1][C@H:2]1[CH2:6][C@@H:5]([N:7]2[CH:15]=[N:14][C:13]3[C:8]2=[N:9][C:10]([N:31]2[CH2:35][CH2:34][C@@H:33]([NH:36][C:37]([NH:39][C:40]4[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=4)=[O:38])[CH2:32]2)=[N:11][C:12]=3[NH:16][CH2:17][CH:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@H:4]([OH:46])[C@@H:3]1[OH:47])=[O:55]
Reactant: CC(C)(C)OC(=O)NCC(=O)ON1C(=O)CCC1=O
Reactant: N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)Nc5cccnc5)C4)nc32)[C@H](O)[C@@H]1O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Product: NCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)Nc5cccnc5)C4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-{(R)-1-[9-((1R,2S,3R,4S)-4-amino-2,3-dihydroxy-cyclopentyl)-6-(2,2-diphenyl-ethylamino)-9H-purin-2-yl]-pyrrolidin-3-yl}-3-pyridin-3-yl-urea (Example 26 step 2) (17 mg, 26 μmol) in THF (1 ml) is treated with tert-butoxycarbonylamino-acetic acid 2,5-dioxo-pyrrolidin-1-yl ester (9 mg, 29 μmol) and stirred at room temperature overnight. The resulting solution is treated with 1.25 M HCl in EtOH (1 ml) and stirred at room temperature for 2 days. Purification by C-18 reverse phase column chromatography eluting with acetonitrile:water:HCl (0.1%) (gradient of 0 to 100% acetonitrile) yields the title compound. (MH+ 691.99)
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:16]=[C:15]([O:17]C)[CH:14]=[C:13]([O:19][CH3:20])[CH:12]=1.[Al+3].[Cl-].[Cl-].[Cl-].Cl>C1(C)C=CC=CC=1>[OH:17][C:15]1[CH:14]=[C:13]([O:19][CH3:20])[CH:12]=[C:11]([Cl:10])[C:16]=1[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:8]
Reactant: COc1cc(Cl)cc(OC)c1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: COc1cc(O)c(C(=O)c2ccccc2)c(Cl)c1
Reaction time: 5 h
Yield: 52.9 %

Procedure:
14.1 g (100 mmol) of benzoyl chloride are added dropwise with stirring at room temperature to a solution of 19 g (110 mmol) of 1-chloro-3,5-dimethoxybenzene and 14.7 g (110 mmol) of AlCl3 in 100 ml of toluene. The mixture is held at 70° C. with stirring for 5 h. The reaction mixture is cooled, then treated with 10% HCl and extracted with toluene. The resulting solution is washed with water and subsequently with saturated sodium chloride solution. The residue which remains after drying over MgSO4, filtering and concentrating by evaporation is purified by chromatography over silica gel (ethyl acetate/hexane 1:5). The product is recrystallized from hexane. 13.9 g of the compound are obtained as pale yellow crystals having a melting point of 92°-94° C.
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].CC(C)N=C=NC(C)C.[C:19]([O:23][C:24]([N:26]1[CH2:39][CH2:38][C:37]2[C:36]3[CH:35]=[C:34]([Cl:40])[C:33]([Cl:41])=[CH:32][C:31]=3[N:30]([CH2:42][C:43](O)=[O:44])[C:29]=2[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>CN(C1C=CN=CC=1)C.C1COCC1.CCOC(C)=O>[Cl:41][C:33]1[C:34]([Cl:40])=[CH:35][C:36]2[C:37]3[CH2:38][CH2:39][N:26]([C:24]([O:23][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:25])[CH2:27][CH2:28][C:29]=3[N:30]([CH2:42][C:43]([NH:4][C:3]3[CH:5]=[CH:6][CH:7]=[C:8]([CH3:9])[C:2]=3[CH3:1])=[O:44])[C:31]=2[CH:32]=1
Reactant: Cc1cccc(N)c1C
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(CC(=O)O)c3cc(Cl)c(Cl)cc23)CC1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cccc(NC(=O)Cn2c3c(c4cc(Cl)c(Cl)cc42)CCN(C(=O)OC(C)(C)C)CC3)c1C
Reaction time: 18 h
Yield: 52.4 %

Procedure:
DMAP (60 mg, 0.49 mmol), 2,3-dimethylaniline (0.065 mL, 0.53 mmol) and DIC (0.084 mL, 0.54 mmol) were added to the solution of crude [3-(tert-butoxycarbonyl)-8,9-dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl]acetic acid (0.20 g, 0.48 mmol) in dry THF (2.5 mL). After 18 h, the reaction was diluted with EtOAc followed by washing with 10% aqueous citric acid, saturated aqueous NaHCO3, and brine. The organic layer was then dried over Na2SO4, decanted, and concentrated. The crude product was first purified by column chromatography (Biotage, 40S, SIM) with CH2Cl2/EtOAc (98:2) to give 0.13 g of impure product. Then, crystallization from EtOAc/heptane gave 96 mg (38%) of a white solid: mp 186-187.5° C.; IR (diffuse reflectance) 3290, 2977, 2939, 1692, 1681, 1662, 1538, 1471, 1450, 1412, 1366, 1338, 1282, 1235, 1163 cm−1; MS (El) m/z 515 (M+), 375, 373, 226, 225, 223, 120, 84, 76, 56, 51; Anal. Calcd for C27H31Cl2N3O3: C, 62.79; H, 6.05; N, 8.14; found: C, 62.60; H, 6.04; N, 8.07.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:17]=[CH:16][C:15]([O:18]C)=[CH:14][CH:13]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:20]C.Cl.[NH+]1C=CC=CC=1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:20]
Reactant: COc1ccc(-c2ccc3c(Cl)c(OC)ccc3c2)cc1
Agent: Cl
Agent: c1cc[nH+]cc1
Product: Oc1ccc(-c2ccc3c(Cl)c(O)ccc3c2)cc1

Procedure:
The title compound was prepared by reacting 1-chloro-2-methoxy-6-(4-methoxyphenyl)naphthalene (0.32 g, 1.07 mmol) with pyridinium HCl (7g) at 190° C. according to method B to yield 0.12 g (41%) of an off white solid: mp 222–224° C. (dec.); 1H NMR (DMSO-d6): δ 6.88 (2H, d, J=8.46 Hz), 7.29 (1H, d, J=8.88 Hz), 7.63 (2H d, J=8.50 Hz), 7.81–7.88 (2H, m), 8.02–8.08 (2H, m), 9.59 (1H, s), 10.43(1H, s); MS (ESI) m/z 269/271(M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]([C:10]([O:12]C)=[O:11])=[N:8][N:7]([CH3:14])[N:6]=1)=[O:4].[OH-].[K+]>CO>[CH3:1][O:2][C:3]([C:5]1[C:9]([C:10]([OH:12])=[O:11])=[N:8][N:7]([CH3:14])[N:6]=1)=[O:4]
Reactant: COC(=O)c1nn(C)nc1C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1nn(C)nc1C(=O)O
Yield: 72.3 %

Procedure:
To a solution of 2-methyl-2H-1,2,3-triazole-4,5-dicarboxylic acid dimethylester (1.2 g; 6 mmol) in 30 ml methanol was added 358 mg KOH (assay 86%; 5.5 mmol). The mixture was heated at reflux temperature for 48 hours. The solvent was evaporated and the residue was then taken into water and extracted with ethyl acetate (3 times). The combined organic phases contained non-reacted starting material. The aqueous phase was acidified with 2N HCl (pH2-3) and extracted with ethyl acetate (3 times). The extracts were combined, dried (anhydrous MgSO4) and evaporated to dryness to give 803 mg (72%) of the desired compound (m.p. 125-126° C.; 1H-NMR (300 MHz, DMSO-d6), δ (ppm): 13.7 (br.s, 1H, exchangable with D2O), 4.24 (s, 3H), 3.84 (s, 3H).
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([Li])CCC.[C:33]([O:37][C:38]([CH:40]1[CH:46]([CH:47]=O)[CH2:45][CH2:44][CH2:43][CH2:42][N:41]1[S:49]([C:52]1[CH:57]=[CH:56][C:55]([O:58][CH3:59])=[CH:54][CH:53]=1)(=[O:51])=[O:50])=[O:39])([CH3:36])([CH3:35])[CH3:34]>C1COCC1.CCCCC>[C:33]([O:37][C:38]([CH:40]1[CH:46]([CH:47]=[CH:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:45][CH2:44][CH2:43][CH2:42][N:41]1[S:49]([C:52]1[CH:57]=[CH:56][C:55]([O:58][CH3:59])=[CH:54][CH:53]=1)(=[O:51])=[O:50])=[O:39])([CH3:36])([CH3:34])[CH3:35]
Reactant: c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: COc1ccc(S(=O)(=O)N2CCCCC(C=O)C2C(=O)OC(C)(C)C)cc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCC
Product: COc1ccc(S(=O)(=O)N2CCCCC(C=Cc3ccccc3)C2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of Benzyl triphenylphosphonium bromide (229 mg, 0.528 mmoL) in 2 mL of THF at 0° C. was added 2.0M butyl lithium solution (0.272 mL) in pentane. After five minutes the solution was warmed to ambient temperature, and kept at that temperature for 30 minutes before adding in the 3-Formyl-1-(4-methoxy-benzene sulfonyl)-azepane-2-carboxylic acid tert-butyl ester (200 mg, 0.503 mmoL) dissolved in 1.52 mL of THF. After 20 hours the reaction was quenched by adding water dropwise, the reaction was diluted with ethyl acetate and washed twice with brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent evaporated under reduced pressure. The residue was purified by column chromatography (silica: 20% to 25% ethyl acetate in hexanes) to yield 1-(4-Methoxy-benzenesulfonyl)-3-styryl-azepane-2-carboxylic acid tert-butyl ester; MS: (M+H)+ =472, (M+NH4)+ =489.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:7]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:8]=2[S:9][CH:10]=1)=[O:5].[CH3:18][Li].[NH4+].[Cl-]>C1COCC1>[C:4]([C:6]1[C:7]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:8]=2[S:9][CH:10]=1)(=[O:5])[CH3:18]
Reactant: [Li]C
Reactant: COc1ccc2c(C(=O)N(C)OC)csc2c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc2c(C(C)=O)csc2c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 48.3 %

Procedure:
6-Methoxy-benzo[b]thiophene-3-carboxylic acid methoxy-methyl amide (800 mg, 3.19 mmol) was stirred in dry THF (20 mL) under argon at −78° C. under argon. Methyl lithium (5.0 mL, 1.5 M in hexanes, 2.35 mmol) was added dropwise, and the reaction stirred 1 h at −78° C. and then 1 h while warning to −20° C. The reaction was poured over saturated NH4Cl (40 mL) and extracted with EtOAc (2×30 mL). Organics were washed with brine (25 mL), dried (Na2SO4), and concentrated in vacuo. Purification by silica gel chromatography gave 234 mg (36%) of 3-acetyl-6-methoxy-benzo[b]thiophene as an orange solid. 1H NMR (300 MHz, CDCl3) δ8.64 (d, 1H, J=9.0Hz), 8.11 (s, 1H), 7.30 (d, 1H, J=2.4Hz), 7.10 (dd, 1H, J=9.0, 2.4Hz), 3.89 (s, 3H), 2.63 (s, 3H) (C11H10O2S) C, H. S. Calculated C=64.06, H=4.89, S=15.54; found C=64.31, H=4.82, S=15.50.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:15][CH3:16])[C:10]=2[Br:14])[CH:5]=1)(=[O:3])[CH3:2].[C:17](OCCCC)(=[O:19])[CH3:18].C[O-].[Na+].Cl>O>[Br:14][C:10]1[C:9]([O:15][CH3:16])=[CH:8][CH:7]=[C:6]2[C:11]=1[CH:12]=[CH:13][C:4]([C:1]([OH:3])=[CH:2][C:17](=[O:19])[CH3:18])=[CH:5]2
Reactant: CCCCOC(C)=O
Reactant: COc1ccc2cc(C(C)=O)ccc2c1Br
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COc1ccc2cc(C(O)=CC(C)=O)ccc2c1Br
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
50 Grams (0.179 moles) of 2-acetyl-5-bromo-6-methoxynaphthalene and 200 ml of n-butyl acetate are placed in a flask equipped with refrigerator and stirrer and, under stirring and at the temperature of 15° C., 14.5 g (0.268 moles) of sodium methoxide are added. The temperature of the reaction mixture goes up to 25° C. and is kept at this value for 30 minutes, then the mixture is warmed at 65° C. for one hour, is added with 100 ml of water and is brought to pH 4 by adding a concentrated aqueous solution of hydrochloric acid. The reaction mixture is then cooled to 0°÷5° C. and kept at this temperature for one hour. The solid is filtered, abundantly washed with water on the filter, then washed with butyl acetate and dried in oven under vacuum obtaining 53 g of product with a yield equal to 92%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH:9]=[C:10]([C:12]([OH:14])=O)[O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl.Cl.Cl.[N:18]1([CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][CH:30]([NH2:33])[CH2:29][CH2:28]2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[N:18]1([CH2:25][CH2:26][N:27]2[CH2:28][CH2:29][CH:30]([NH:33][C:12]([C:10]3[O:11][C:7]4[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=4[CH:9]=3)=[O:14])[CH2:31][CH2:32]2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: COc1cccc2oc(C(=O)O)cc12
Reactant: NC1CCN(CCN2CCCCCC2)CC1
Agent: Cl
Product: COc1cccc2oc(C(=O)NC3CCN(CCN4CCCCCC4)CC3)cc12

Procedure:
This compound is synthesized analogously to Example 1 from 4-Methoxy-benzofuran-2-carboxylic acid and amine 5.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.[O:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[O:26][CH2:27][CH2:28][CH2:29][C:30]#[CH:31]>C(N(CC)CC)C.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>[C:8]1([C:5]2[N:6]=[CH:7][C:2]([C:31]#[C:30][CH2:29][CH2:28][CH2:27][O:26][CH:21]3[CH2:22][CH2:23][CH2:24][CH2:25][O:20]3)=[N:3][C:4]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Clc1cnc(-c2ccccc2)c(-c2ccccc2)n1
Reactant: C#CCCCOC1CCCCO1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: C(#Cc1cnc(-c2ccccc2)c(-c2ccccc2)n1)CCCOC1CCCCO1
Temperature: 80 °C
Reaction time: 8 h
Yield: 75.8 %

Procedure:
To a solution of 1.58 g of 2-chloro-5,6-diphenylpyrazine in 10 ml of triethylamine, 1.20 g of 5-(2-tetrahydropyranyloxy)-1-pentyne, 208 mg of dichlorobis(triphenylphosphine)palladium (II) and 56 mg of copper (I) iodide were added, followed by stirring under an argon atmosphere at 80° C. for 8 hours. The solvent was evaporated under reduced pressure and the residue was dissolved in diethyl ether, and then the insoluble matter was removed by filtration through celite. After the solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography to obtain 1.79 g of the desired compound as a brown oily substance.
Reaction SMILES: S(OC)(OC)(=O)=O.[CH3:8][S:9][C:10]1[C:11]2[C:12]3[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=O)[C:13]=3[CH:20]=[CH:21][CH:22]=2.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:24]>N1C=CC=CC=1>[CH3:8][S:9][C:10]1[C:11]2[C:12]3[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([SH:24])[C:13]=3[CH:20]=[CH:21][CH:22]=2
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CSc1ccc2c3c(cccc13)C(=O)N2
Solvent: COS(=O)(=O)OC
Solvent: c1ccncc1
Product: CSc1ccc2c3c(cccc13)C(S)=N2

Procedure:
Chlorosulfonation of benz(cd)indol-2-(1H-one yields the 6-sulfonylchloride derivative, which upon treatment with zinc dust in acetic acid-hydrochloric acid solution, yields 6-mercaptobenz(cd)indol-2-(1H)-one. Treatment with dimethyl sulfate in alkaline solution leads to 6-methylthiobenz(cd)indol-2-(1H)-one, which on heating with P2S5 in pyridine yields 6-methylthiobenz(CD)indol-2-thiol. The reaction of the latter compound with molar equivalents of 3-(4-pyridinyl)propanamine and mercuric acetate in ethanol, under the conditions of Example 55, leads to the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[S:11][N:10]=[C:9]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[N:8]=1)=[O:5])[CH3:2].[Br:17]Br>CO>[CH2:1]([O:3][C:4]([NH:6][C:7]1[S:11][N:10]=[C:9]([CH:12]([Br:17])[C:13]([O:15][CH3:16])=[O:14])[N:8]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)Nc1nc(CC(=O)OC)ns1
Reactant: BrBr
Solvent: CO
Product: CCOC(=O)Nc1nc(C(Br)C(=O)OC)ns1
Temperature: 0 °C
Reaction time: 2 h
Yield: 86.7 %

Procedure:
Into a 1 L round bottom flask was charged methyl 2-(5-ethoxycarbonylamino-1,2,4-thiadiazol-3-yl)acetate (50.0 g, 0.204 mol, 1.0 eq) followed by methanol (500 mL). The resulting slurry was cooled to 0° C. To the cooled slurry was charged a pre-made solution of bromine (9.9 mL, 0.194 mol, 0.95 eq) in methanol (100 mL) dropwise over 30 minutes maintaining the temperature between 0-5° C. The cold bath was removed and the solution was allowed to warm to room temperature and stirred for two hours. Proton NMR analysis of the reaction mixture showed reaction completion. The orange solution was evaporated to an orange oil. The orange oil was taken up in diethyl ether (400 mL) and the organic was washed with water (2×100 mL), saturated 1:1 NaHCO3/Na2S2O4 (2×100 mL) and then brine (100 mL). The clear colorless ether layer was dried with sodium sulfate, filtered and evaporated in vacuo to give 54.5 grams of the title compound as a clear colourless oil. 1H NMR (CDCl3) δ 1.38 (t, 3H); 3.98 (s, 3H); 4.55 (q, 2H); 5.81 (s, 1H).