Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+](=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[N-].[CH:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:3]1([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:12][CH:11]=[CH:10][CH:9]=[CH:14][CH:13]=1
Reactant: c1ccccc1
Reactant: CCOC(=O)C=[N+]=[N-]
Product: CCOC(=O)C1=CC=CC=CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.8 %

Procedure:
Ethyl diazoacetate (43.4 g, 0.38 mol) was added slowly (syringe pump) over a period of 7 hours to a mixture of benzene (594.32 g, 7.61 mol) and tetrakis(perfluorobenzoato) dirhodium(II) (0.84 g, 00.16 mol). After stirring at room temperature for 16 hours, the solvent was removed and the oily residue distilled in vacuo to give 50.44 g (81%) of ethyl 1,3,5-cycloheptatriene-1-carboxylate: bp 90°-96° C. 2 4-3.0 mm Hg); 1H NMR (CDCl3) δ6.6 (m, 2H), 6.2 (m, 2H), 5.3 (m, 2H), 4.2 (q, 2H OCH2CH3), 2.5 (t, 1H), 1.3 (t, 3H CH2CH3)
Reaction SMILES: CC(C)(OC(N[C@H](C(N[C@H](C([NH:26][C@@H:27]([CH2:38][CH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1)[CH:28]([P:30]([O:35][CH2:36][CH3:37])([O:32][CH2:33][CH3:34])=[O:31])[OH:29])=O)CC(C)C)=O)CC1C=CC=CC=1)=O)C.[CH3:46][C:47]([CH3:72])([O:49][C:50]([NH:52][C@H:53]([C:69](O)=[O:70])[CH2:54][C:55]1[N:59]([CH2:60][O:61][CH2:62][C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[CH:58]=[N:57][CH:56]=1)=[O:51])[CH3:48].O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[CH3:46][C:47]([CH3:48])([O:49][C:50]([NH:52][C@H:53]([C:69]([NH:26][C@@H:27]([CH2:38][CH:39]1[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]1)[CH:28]([P:30]([O:35][CH2:36][CH3:37])([O:32][CH2:33][CH3:34])=[O:31])[OH:29])=[O:70])[CH2:54][C:55]1[N:59]([CH2:60][O:61][CH2:62][C:63]2[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=2)[CH:58]=[N:57][CH:56]=1)=[O:51])[CH3:72]
Reactant: CCOP(=O)(OCC)C(O)[C@H](CC1CCCCC1)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cncn1COCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOP(=O)(OCC)C(O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cncn1COCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Compound B from Example 2 (1.47 g, 4.46 mmol) was added to a solution of [(1,1-dimethylethoxy)carbonyl]-3-[(phenylmethoxy)methyl]-L-histidine (T. Brown and J. H. Jones, Journal of Chemical Society, Chemical Communications (1981), 648) in tetrahydrofuran (22 mL) and cooled to 0° C. 1-Hydroxybenzotriazole hydrate (682 mg, 4.46 mmol), N,N-diisopropylethylamine (854.5 μl, 4.9 mmol) and dicyclohexylcarbodiimide (920 mg, 4.46 mmol) were added sequentially. After 16 hours at 25° C., the reaction mixture was filtered and concentrated. The residue was dissolved in ethyl acetate (60 mL), washed sequentially with saturated aqueous sodium hydrogen carbonate (2×40 mL), saturated aqueous sodium chloride (40 mL), dried (Na2HSO4) and concentrated. Repeated purifications by column chromatography of the crude product (2.9 g) yielded 2.03 g (70.2%) of pure title A compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[C:12]([O:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:26]1([S:32]([N:35]2[C:43]3[CH:42]=[C:41]([Cl:44])[CH:40]=[C:39]4[CH2:45][CH2:46][CH:47]([CH2:48][C:49](O)=[O:50])[C:37]([C:38]=34)=[C:36]2[C:52]([O:54][CH3:55])=[O:53])(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[C:26]1([S:32]([N:35]2[C:43]3[CH:42]=[C:41]([Cl:44])[CH:40]=[C:39]4[CH2:45][CH2:46][CH:47]([CH2:48][C:49](=[O:50])[NH:14][C:13]5[CH:15]=[CH:16][C:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:11][C:12]=5[O:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:37]([C:38]=34)=[C:36]2[C:52]([O:54][CH3:55])=[O:53])(=[O:34])=[O:33])[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COC(=O)c1c2c3c(cc(Cl)cc3n1S(=O)(=O)c1ccccc1)CCC2CC(=O)O
Reactant: CC(C)(C)OC(=O)COc1cc(CNC(=O)OC(C)(C)C)ccc1N
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1c2c3c(cc(Cl)cc3n1S(=O)(=O)c1ccccc1)CCC2CC(=O)Nc1ccc(CNC(=O)OC(C)(C)C)cc1OCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 103.1 %

Procedure:
A mixture of 4-tert-butoxycarbonylaminomethyl-2-tert-butoxycarbonylmethoxyaniline (202 mg, 0.574 mmol), methyl 1-benzenesulfonyl-7-chloro-3-carboxymethyl-1,3,4,5-tetrahydrobenz[cd]indole-2-carboxylate (250 mg, 0.574 mmol), triethylamine (0.2 mL, 1.43 mmol), and N,N-bis(2-oxo-3-oxazolidinyl)-phosphinic chloride (Bop-Cl, 161 mg, 0.631 mmol) in dichloromethane (5 mL) was stirred for 15 h at room temperature and diluted with ethyl acetate. The mixture was washed successively with 5% potassium hydrogen sulfate, water, saturated sodium bicarbonate, water, and brine, dried over magnesium sulfate, and concentrated to give 463 mg of the title compound (quant): 1H NMR (CDCl3) δ8.63 (s, 1H), 8.33 (d, 1H, J=8.6 Hz), 8.03 (d, 2H, J=6.9 Hz), 7.92 (s, 1H), 7.58 (t, 1H, J=6.9 Hz); 7.52 (t, 2H, J=6.9 Hz), 7.06 (s, 1H), 6.94 (d, 1H, J=Hz), 6.80 (s, 1H), 4.82 (br, 1H), 4.35 (s, 2H), 4.12 (d, 2H, J=7.3 Hz), 3.89 (s, 3H), 3.86 (m, 1H), 3.03 (mt, 1H, J=14.7 Hz), 2.81 (m, 1H), 2.81 (dd, 1H, J=14.7, 4.3 Hz), 2.53 (dd, 1H, J=14.7, 10.4 Hz), 2.22 (m, 1H), 1.72 (m, 1H), 1.46 (s, 9H), 1.45 (s, 9H).
Reaction SMILES: [C:1]([C:4]1[CH:13]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=2[C:22]([F:25])([F:24])[F:23])[C:12]2[C:11](=[O:26])[NH:10][CH:9]=[CH:8][C:7]=2[NH:6][C:5]=1[CH3:27])(=[O:3])[CH3:2].ClCCl.F[B-](F)(F)F.[CH2:36]([O+](CC)CC)[CH3:37].CO>O>[C:1]([C:4]1[CH:13]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=2[C:22]([F:25])([F:24])[F:23])[C:12]2[C:7](=[CH:8][CH:9]=[N:10][C:11]=2[O:26][CH2:36][CH3:37])[NH:6][C:5]=1[CH3:27])(=[O:3])[CH3:2]
Reactant: CC(=O)C1=C(C)Nc2cc[nH]c(=O)c2C1c1ccc(C#N)cc1C(F)(F)F
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CCOc1nccc2c1C(c1ccc(C#N)cc1C(F)(F)F)C(C(C)=O)=C(C)N2
Reaction time: 2 h

Procedure:
50 mg (0.134 mmol) of 4-(3-acetyl-2-methyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridin-4-yl)-3-(trifluoromethyl)benzonitrile are dissolved under an argon atmosphere in 5 ml of abs. dichloromethane, and 50.9 mg (0.268 mmol) of triethyloxonium tetrafluoroborate are added. After a reaction time of two hours at room temperature (reaction checked by HPLC), the mixture is mixed with 5 ml of methanol and 0.5 ml of water and again stirred for 2 h. It is then diluted with 20 ml of water and extracted three times with dichloromethane. The combined organic phases are dried with sodium sulfate, and the solvent is removed in a rotary evaporator. The residue is purified by preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→95:5). 23 mg (42.8% of theory) of the title compound are obtained.
Reaction SMILES: Cl.[CH:2]1([N:5]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:6](=[O:18])[C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:17][CH:16]=[N:15][CH:14]=3)=[CH:9][CH:8]=2)[CH2:4][CH2:3]1.Cl[C:26]1[N:31]=[CH:30][C:29]([O:32][CH:33]([CH3:35])[CH3:34])=[CH:28][N:27]=1>CN1CCCC1=O>[CH:2]1([N:5]([CH:19]2[CH2:24][CH2:23][N:22]([C:26]3[N:31]=[CH:30][C:29]([O:32][CH:33]([CH3:35])[CH3:34])=[CH:28][N:27]=3)[CH2:21][CH2:20]2)[C:6](=[O:18])[C:7]2[CH:8]=[CH:9][C:10]([C:13]3[O:17][CH:16]=[N:15][CH:14]=3)=[CH:11][CH:12]=2)[CH2:4][CH2:3]1
Reactant: CC(C)Oc1cnc(Cl)nc1
Reactant: O=C(c1ccc(-c2cnco2)cc1)N(C1CCNCC1)C1CC1
Agent: Cl
Solvent: CN1CCCC1=O
Product: CC(C)Oc1cnc(N2CCC(N(C(=O)c3ccc(-c4cnco4)cc3)C3CC3)CC2)nc1

Procedure:
The title compound is prepared from N-cyclopropyl-4-oxazol-5-yl-N-piperidin-4-yl-benzamide hydrochloride and 2-chloro-5-isopropoxy-pyrimidine following a procedure analogous to that described in Example 19 using N-methylpyrrolidinone as solvent. LC (method 16): tR=0.48 min; Mass spectrum (ESI+): m/z=448 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.ClC1C=C(C=CC=1)C(OO)=[O:14]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N+:6]([O-:14])[CH:7]=1
Reactant: Cc1ccc(Br)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(Br)c[n+]1[O-]

Procedure:
A solution of 5-bromo-2-methylpyridine (2.0 g, 12 mmol, 1.0 eq) and m-chloroperoxybenzoic acid (70%, 2.89 g, 12.9 mmol, 1.1 eq) in 30 mL chloroform was stirred at room temperature for 4 hours. The reaction mixture was then partitioned between dichloromethane and 2 M aqueous sodium carbonate. The aqueous layer was extracted once more with dichloromethane, and the combined organic portions dried over magnesium sulfate and concentrated to give 5-bromo-2-methylpyridine 1-oxide. LCMS (ESI) m+H=189.0; 1H NMR (400 MHz, DMSO-d6) δ: 8.57 (s, 1H), 7.50 (d, 1H), 7.45 (d, 1H), 2.30 (s, 3H).
Reaction SMILES: [CH2:1]1[N:6]([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]3[CH:18]=[CH:19][C:20]([NH:22][C:14]=3[CH:13]=2)=[O:21])[CH2:5][CH2:4][N:3]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=2[Cl:30])[CH2:2]1.CC(C)([O-])C.[K+].CC1CCCO1.Cl[C:44]([O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])=[O:45]>O>[C:44](=[O:45])([O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[O:21][C:20]1[CH:19]=[CH:18][C:15]2[C:14](=[CH:13][C:12]([O:11][CH2:10][CH2:9][CH2:8][CH2:7][N:6]3[CH2:5][CH2:4][N:3]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=4[Cl:30])[CH2:2][CH2:1]3)=[CH:17][CH:16]=2)[N:22]=1
Reactant: O=c1ccc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2[nH]1
Reactant: CCCCCCOC(=O)Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC1CCCO1
Solvent: O
Product: CCCCCCOC(=O)Oc1ccc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of dehydro-aripiprazole (1.5 g, 3.4 mmol), potassium tert-butoxide (0.75 g, 6.7 mmol) and 2-methyltetrahydrofuran (30 mL) at 0° C. was added hexyl chloroformate (1.32 mL, 8.1 mmol). The reaction mixture was stirred for 2 h, allowed to self warm to room temperature and stirred for a further 4 h. The reaction mixture was then diluted with water and extracted with ethyl acetate. The organic phase was dried over MgSO4, filtered and evaporated. The residue was further purified on silica eluting with ethyl acetate/tetrahydrofuran and the major product containing fractions evaporated to give a yellow solid. This was triturated in heptane (30 mL) for 2.5 h, filtered and dried to give Compound-328 (1.55 g) as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[CH2:12][CH2:11][N:10](CCCN)[CH2:9][CH2:8]1.C(N1CCC(C2C=CC=CN=2)CC1)C1C=CC=CC=1>CO.[OH-].[Pd+2].[OH-]>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1
Reactant: NCCCN1CCC(c2ccccn2)CC1
Agent: [Pd+2]
Agent: [OH-]
Agent: c1ccc(CN2CCC(c3ccccn3)CC2)cc1
Solvent: CO
Product: c1ccc(C2CCNCC2)nc1
Reaction time: 24 h
Yield: 99 %

Procedure:
3-[4-(2-Pyridyl)-piperidine-1-yl]propylamine (Scheme 6). To 1-Benzyl -4-(2-pyridyl)-piperidine (3. 2 6 g, 12.9 mmol) in dry methanol (25 ml), 10% palladium hydroxide (1.9 g) was added and the solution was hydrogenated at 200 psi for 24 hours. The solution was filtered over celite, concentrated to give 2.1 g (99%) of 4-(2-pyridyl)-piperidine which was used as such for the subsequent step. A mixture of 3-bromopropylamine hydrobromide (20 g, 91.3 mmol), potassium carbonate (37.85 g, 273.9 mmol) and di-tert-butyldicarbonate (21.90 g, 100 mmol) in methanol was stirred at room temperature for 24 hours. The reaction mixture was concentrated and partitioned between 250 ml EtOAc and 50 ml water, dried over sodium sulfate, filtered and concentrated. Purification of the crude product by column chromatography (Hexane: EtOAc, 4.5:0.5) gave 17.5 g (80%) of the product as a pale yellow oil. To a stirred solution of the 4-(2-pyridyl)-piperidine (1.86 g, 11.4 mmol) in dioxane (20 ml), N-(tert-butoxycarbonyl)-3-bromopropylamine (2.82 g, 11.4 mmol) and potassium carbonate (3.16 g, 22.9 mmol) were added and the solution refluxed for 24 hours. The reaction mixture was cooled to room temperature, concentrated and partitioned between 40 ml chloroform and 5 ml water. The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (ethyl acetate: methanol, 4:1) to yield 1.86 g (49%) of the required product as a colorless oil; 1H-NMR (CDCl3): δ 1.45 (s, 9H),1.54-1.69 (m, 8H), 2.21-2.68 (m, 2H), 2.74-2.80 (m, 1H), 3.02-3.22 (m, 4H), 5.41 (s, 1H), 7.13-7.17 (m, 1H), 7.33 (d, J=7.93 Hz, 1H).7.63 (t, J=7.6 Hz, 1H), 8.54 (d, J=4.6 Hz, 1H). To N-(tert-butoxycarbonyl)-3-[4-(2-pyridyl)-piperidin-1-yl]propylamine (0.15 g, 0.45 mmol) in 5 ml of dichloromethane, 1 ml of trifluoroacetic acid was added and the solution stirred at room temperature for 1 hour. The solution was concentrated, neutralized with 10% KOH solution and extracted into 25 ml of dichloromethane. The organic layer was dried over sodium sulfate, filtered and concentrated to give 0.098 g (100%) of 3-[4-(2-pyridyl)-piperidin-1-yl]propylamine which was used as such for the subsequent step (step h).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[C:9]2[CH:10]=[CH:11][N:12]=[CH:13][C:14]=2[CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:17]=1)(=[O:7])=[O:6].[C:24]1([CH2:34][CH2:35][CH:36]=O)[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:52]CCCl>CO>[ClH:52].[ClH:52].[C:24]1([CH2:34][CH2:35][CH2:36][NH:1][CH2:2][CH2:3][NH:4][S:5]([C:8]2[C:9]3[CH:10]=[CH:11][N:12]=[CH:13][C:14]=3[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:17]=2)(=[O:7])=[O:6])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: ClCCCl
Reactant: O=CCCc1cccc2ccccc12
Reactant: NCCNS(=O)(=O)c1cc(-c2ccccc2)cc2cnccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: Cl
Product: O=S(=O)(NCCNCCCc1cccc2ccccc12)c1cc(-c2ccccc2)cc2cnccc12

Procedure:
Stir a mixture of 7-phenyl-isoquinoline-5-sulfonic acid (2-amino-ethyl)-amide (0.25 mmol, 1.0 eq) and 3-naphthalen-1-yl-propionaldehyde (0.25 mmol, 1.0 eq) in 1,2-dichloroethane (DCE) (2.0 mL) at room temperature for six (6) hours, and then add sodium triacetoxyborohydride (0.6 mmol, 2.4 eq). Stir overnight, then dilute the mixture with CH3OH, and apply to a cation exchange column (10 g), wash with a mixture of, CH3OH and CH2Cl2 (1:1), then NH3 (2.0 M in CH3OH). Purify the residue on silica gel (gradient 10% CH3OH in CH2Cl2) to give 100 mg the free amine product as oil. Dissolve the free amine in CH3OH (15 mL) and treat dropwise with 37% HCl aqueous solution (1.0 mL) with stirring. Concentrate the resultant solution and dried under vacuum at 37° C. to give the title compound as a white powder. 1H NMR (DMSO-d6, 400 MHz): 9.65 (1H, s), 8.85 (2H, br), 8.75 (1H, s), 8.69 (1H, d, J=6.0 Hz), 8.64 (1H,s), 8.53 (1H, t, J=6.0 Hz), 8.07 (1H, d, J=8.0 Hz), 7.91 (2H, d, J=7.6 Hz), 7.78 (1H, d, J=8.0 Hz), 7.49-7.61(4H, s), 7.46 (1H, d, J=7.6 Hz), 7.35 (1H, d, J=7.2 Hz), 3.12-3.15 (2H, m), 3.07 (2H, t, J=7.6 Hz), 2.95-3.02 (4H, m), 1.93-1.99 (2H, m). IS-MS, m/e 582.58 (m+1)
Reaction SMILES: Cl[C:2]1[S:3][C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([C:7](=[O:12])[NH:8][CH:9]([CH3:11])[CH3:10])[N:6]=1.[CH2:18]([NH:20][C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][N:25]=1)=[O:22])[CH3:19].C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1.C(OCC)(=O)C.C1(P([Pd-4](P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:18]([NH:20][C:21](=[O:22])[NH:23][C:24]1[N:25]=[CH:26][C:27]([C:2]2[S:3][C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([C:7](=[O:12])[NH:8][CH:9]([CH3:11])[CH3:10])[N:6]=2)=[CH:28][CH:29]=1)[CH3:19]
Reactant: CCOC(=O)c1sc(Cl)nc1C(=O)NC(C)C
Reactant: CCNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCNC(=O)Nc1ccc(-c2nc(C(=O)NC(C)C)c(C(=O)OCC)s2)cn1
Temperature: 100 °C
Yield: 12.1 %

Procedure:
In a 10 mL of microwave vial, ethyl 2-chloro-4-isopropylcarbamoyl-thiazole-5-carboxylate (Intermediate 28, 1.1 g, 3.97 mmol), N-ethyl-N′-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-urea (Intermediate 1, 1.15 g, 3.97 mmol), cesium carbonate (1.29 g, 3.97 mmol), Tetrakis (triphenylphosphino) palladium (0) (0.458 g, 0.397 mmol) in 15 mL of 4:1 dioxane:H2O was degassed for 30 min, then heated to 100° C. for 30 min. The reaction mixture was diluted with ethyl acetate (25 mL), then washed with water (10 mL). The organic layer was dried, then concentrated under reduced pressure to yield crude a residue which was purified by column chromatography over silica gel to afford 0.195 g (17.72%) of the title compound as solid. MS (APCI): 406 (M+H−) for C18H23N5O4S; NMR: 1.13 (t, 3H), δ 1.16 (d, 6H), 1.28 (t, 3H), δ 3.2 (q, 2H), 4.04 (m, 1H), 4.29 (q, 2H), 7.63 (d, 1H), 7.70 (br s, 1H), 8.27 (dd, 1H), δ 8.45 (d, 1H), 8.83 (d, 1H), 9.56 (s, 1H).
Reaction SMILES: Br[CH:2](Br)[C:3]1[CH:7]=[C:6]([C:8]([O:10]CC)=[O:9])[N:5]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[N:4]=1.[OH-:22].[Li+]>C1COCC1.O>[CH:2]([C:3]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[N:4]=1)=[O:22]
Reactant: [OH-]
Reactant: CCOC(=O)c1cc(C(Br)Br)nn1-c1ccc(OC)cc1
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-n2nc(C=O)cc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 33 %

Procedure:
Ethyl 3-(dibromomethyl)-1-(4-methoxyphenyl)-1H-pyrazole-5-carboxylate (0.34 g, 0.813 mmol) was dissolved in 2 mL THF and lithium hydroxide (34 mg, 0.816 mmol) was dissolved in 0.5 mL water and added to the methanolic solution. After stirring at room temperature for 16 hours the solvent was evaporated, the residue was dissolved in 10 mL of water, acidified with 1N HCl and extracted with EtOAc to give 66 mg (33%) of the desired product after evaporation. 1H NMR (CDCl3): δ10.06 (s, 1H); 7.56 (s, 1H); 7.40 (d, J=9.1, 2H); 7.01 (d, J=9.1, 2H); 4.54 (s, 2H); 3.88 (s, 3H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([C:6]1[O:7][CH2:8][C:9](=[O:16])[C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:5].C(N(C(C)C)CC)(C)C.[CH3:26][O:27][CH2:28][CH2:29][O:30][CH2:31]Cl>ClCCl.O>[CH3:26][O:27][CH2:28][CH2:29][O:30][CH2:31][O:1][CH2:2][CH2:3][N:4]([C:6]1[O:7][CH2:8][C:9](=[O:16])[C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:5]
Reactant: CCOC(=O)C1=C(N(C)CCO)OCC1=O
Reactant: COCCOCCl
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1=C(N(C)CCOCOCCOC)OCC1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of ethyl 2-[(2-hydroxyethyl)-N-methylamino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.5 g, 2.18 mmol) which similarly prepared according to the procedure described in the Example 74, Fourth step in dichloromethane (6.0 mL) that cooled with ice bath, diisopropylethylamine (0.75 mL, 4.36 mmol) then 2-methoxyethoxymethyl chloride (0.5 mL, 4.36 mmol) were added. The reaction mixture was allowed to warm to ambient temperature and stirred for 16 h. The reaction mixture was diluted with water, extracted with ethyl acetate for 3 times. The organic layer was dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel(hexane/ethyl acetate) to afford ethyl 2-({2-[(2-methoxyethoxy)methoxy]ethyl}-N-methylamino)-4-oxo-4,5-dihydrofuran-3-carboxylate as oil (0.31 g, y. 46%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]#[N:8].[N+:9]([C:12]1[S:16][C:15]([CH:17]=O)=[CH:14][CH:13]=1)([O-:11])=[O:10].C(O)(C(F)(F)F)=O>C(O)(C)C>[N+:9]([C:12]1[S:16][C:15]([CH:17]=[N:1][C:2]2[S:3][CH:4]=[CH:5][C:6]=2[C:7]#[N:8])=[CH:14][CH:13]=1)([O-:11])=[O:10]
Reactant: O=Cc1ccc([N+](=O)[O-])s1
Reactant: N#Cc1ccsc1N
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccsc1N=Cc1ccc([N+](=O)[O-])s1
Yield: 70.7 %

Procedure:
2-Amino-thiophene-3-carbonitrile (30 mg) and 5-nitro-thiophene-2-carboxaldehyde (41 mg) were mixed in isopropanol with TFA and refluxed for 28 hours. The reaction was then purified by flash chromatography, resulting in 45 mg (71%) of the title compound as an orange powder. M.p.: 192°-194° C. 1H-NMR (300 MHz, [D]acetone): δ=8.98 (s, 1H), 8.12 (d, 1H, 3J=4.3 Hz), 7.85 (d, 1H, 3J=4.3 Hz), 7.61 (d, 1H, 3J=5.7 Hz), 7.38 (d, 1H, 3J=5.7 Hz). 13C-NMR (300 MHz, [D] acetone): δ=161.2, 154.3, 147.3, 133.7, 130.0, 128.6, 125.9, 125.1, 109.5, 108.5.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C:14]([CH2:15][C@@H:16]([OH:24])[CH2:17][CH2:18]1)=[CH:13][CH2:12]3)([O:3][CH3:4])=[O:2].[C:25](OC(=O)C)(=[O:27])[CH3:26]>N1C=CC=CC=1>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C:14]([CH2:15][C@@H:16]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][CH2:18]1)=[CH:13][CH2:12]3)([O:3][CH3:4])=[O:2]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: c1ccncc1
Product: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(C)=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mechanically stirred solution of 17β-carbomethoxy-3β-hydroxy-5-androstene (100 g, 0.30 mol), prepared as described in Rasmusson et al., Journal of Medicinal Chemistry 1984, 27, 1690, incorporated herein by reference, in pyridine (750 mL) in a 2 L 4-necked round bottom flask equipped with an addition funnel at ambient temperature is added acetic anhydride (130 mL, 1.38 mol). The resulting dark solution is stirred at ambient temperature for 18 h, transferred to an addition funnel, and added drop wise to 3 L of ice-water. The resulting precipitate is collected by filtration, washed with 2×1 L H2O, and dried under vacuum to afford 17β-carbomethoxy-3β-acetoxy-5-androstene; 1H NMR (400 MHz, CDCl3) δ5.36 (br d, J=5.1 Hz, 1H), 4.59 (m, 1H), 3.67 (s, 3H), 2.37-2.29 (m, 3H), 2.20-2.08 (m, 1H), 2.03 (s, 3H), 2.02-1.97 (m, 2H), 1.90-1.38 (m, 10H), 1.34-1.21 (m, 2H), 1.18-1.05 m, 2H), 1.02 (s, 3H), 1.00-0.96 (m, 1H), 0.66 (s, 3H).
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[C:5]2[C:10](=[C:11]3[C:16]=1[CH:15]=[CH:14][CH:13]=[CH:12]3)[CH2:9][CH2:8][CH2:7][CH2:6]2.S(Cl)([Cl:19])=O>C(Cl)Cl>[ClH:19].[Cl:19][CH2:2][C:3]1[N:4]=[C:5]2[C:10](=[C:11]3[C:16]=1[CH:15]=[CH:14][CH:13]=[CH:12]3)[CH2:9][CH2:8][CH2:7][CH2:6]2
Reactant: OCc1nc2c(c3ccccc13)CCCC2
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cl
Product: ClCc1nc2c(c3ccccc13)CCCC2

Procedure:
Prepared by treating 110 mg of 6-hydroxymethyl-1,2,3,4-tetrahydro-phenanthridine with 60 μl of thionyl chloride in 2.5 ml methylene chloride at 0° C. to ambient temperature.
Reaction SMILES: [F:1][B-:2]([F:5])([F:4])[F:3].[CH3:6][N:7]([CH3:23])[C:8]1[CH:22]=[CH:21][C:11]([CH:12]=[N:13][N+:14]2[CH:18]=[CH:17][N:16]([CH3:19])[C:15]=2[CH3:20])=[CH:10][CH:9]=1.[CH3:24][N:25]([CH3:34])[C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=1.N1CCCCC1.O>C1(C)C=CC=CC=1>[F:1][B-:2]([F:5])([F:4])[F:3].[CH3:23][N:7]([CH3:6])[C:8]1[CH:9]=[CH:10][C:11]([CH:12]=[N:13][N+:14]2[CH:18]=[CH:17][N:16]([CH3:19])[C:15]=2[CH:20]=[CH:30][C:29]2[CH:32]=[CH:33][C:26]([N:25]([CH3:34])[CH3:24])=[CH:27][CH:28]=2)=[CH:21][CH:22]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: Cc1n(C)cc[n+]1N=Cc1ccc(N(C)C)cc1
Agent: F[B-](F)(F)F
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: CN(C)c1ccc(C=Cc2n(C)cc[n+]2N=Cc2ccc(N(C)C)cc2)cc1

Procedure:
0.66 g of 1-[[p-(dimethylamino)benzylidene]-amino]-2,3-dimethylimidazolium tetrafluoroborate, 0.45 g of p-(dimethylamino)benzaldehyde and 0.34 g of piperidine are suspended in 30 ml of toluene, whereupon the suspension is heated to boiling under reflux for about 70 hours on a water separator filled with toluene which contains 5% piperidine. The precipitated material is removed by filtration under suction, washed with toluene, twice with diethyl ether and twice with water and recrystallized from methanol. There is obtained colorless 1-[[p-(dimethylamino)benzylidene]amino]-2-[p-(dimethylamino)styryl]-3-methylimidazolium tetrafluoroborate of melting point 235°-238°.