Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([O:10][CH3:11])(=[O:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6].CS(O[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[F:25])(=O)=O>CN(C=O)C>[F:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][CH2:17][CH:4]([C:3]([O:10][CH3:11])=[O:9])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)CC(=O)OC
Reactant: CS(=O)(=O)OCCc1ccccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(CCc1ccccc1F)C(=O)OC
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 60% sodium hydride (8.24 g) in DMF (200 ml) was added dropwise dimethyl malonate (24.9 g) under ice-cooling, and the suspension was stirred at 50° C. for 30 min. After cooling to room temperature, a solution of 2-(2-fluorophenyl)ethyl methanesulfonate in DMF (30 ml) was added dropwise, and the mixture was stirred at 150° C. for 1 hr. After cooling to room temperature, the reaction mixture was poured into ice water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give dimethyl 2-[2-(2-fluorophenyl)ethyl]malonate.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.[H-].[Na+].Cl[CH2:9][CH2:10][CH2:11][C:12]#[C:13][C:14]1[CH:15]=[C:16]([CH:20]([O:30][CH:31]2[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]2)[C:21]2[NH:25][C:24]3[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=3[N:22]=2)[CH:17]=[CH:18][CH:19]=1>CN(C=O)C>[CH3:37][N:34]1[CH2:35][CH2:36][CH:31]([O:30][CH:20]([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([C:13]#[C:12][CH2:11][CH2:10][CH2:9][N:2]3[N:3]=[CH:4][CH:5]=[N:1]3)[CH:15]=2)[C:21]2[NH:22][C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=3[N:25]=2)[CH2:32][CH2:33]1
Reactant: c1c[nH]nn1
Reactant: CN1CCC(OC(c2cccc(C#CCCCCl)c2)c2nc3ccccc3[nH]2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCC(OC(c2cccc(C#CCCCn3nccn3)c2)c2nc3ccccc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1,2,3-triazole (66 mg) in DMF (0.6 mL) is added sodium hydride (25 mg). After gas evolution ceased, 2-[[3-(5-chloropent-1-ynyl)phenyl](1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole (50 mg) and a catalytic quantity of n-tetrabutylammonium iodide are added. After stirring overnight at room temperature, the solvent is removed under reduced pressure to dryness. The residue is purified by chromatography (dichloromethane/methanol/ammonia 90/10/1) to afford 2-{(1-methylpiperidin-4-yloxy)[3-(5-[1,2,3]triazol-2-yl-pent-1-ynyl)phenyl]methyl}-1H-benzimidazole.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[CH3:15][C:16]1[O:20][C:19]([CH2:21][NH2:22])=[CH:18][CH:17]=1.[CH3:23][N:24]1[C:29]2[CH:30]=[CH:31][C:32]([CH:34]=O)=[CH:33][C:28]=2[O:27][CH2:26][CH2:25]1>>[CH3:23][N:24]1[C:29]2[CH:30]=[CH:31][C:32]([CH2:34][NH:1][C:4]3[C:5]4[CH:6]=[CH:7][C:8]([NH:22][CH2:21][C:19]5[O:20][C:16]([CH3:15])=[CH:17][CH:18]=5)=[N:9][C:10]=4[CH:11]=[CH:12][CH:13]=3)=[CH:33][C:28]=2[O:27][CH2:26][CH2:25]1
Reactant: Cc1ccc(CN)o1
Reactant: CN1CCOc2cc(C=O)ccc21
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Product: Cc1ccc(CNc2ccc3c(NCc4ccc5c(c4)OCCN5C)cccc3n2)o1

Procedure:
The title compound, MS: m/e=388.4 (M+H+), was prepared from 5-nitro-2-chloroquinoline, 5-methyl-2-furanmethanamine and 4-methyl-3,4-dihydro-2H-1,4-benzoxazine-7-carbaldehyde as described in example 26.
Reaction SMILES: N1CCCCC1.FC(F)OC1C=CC(C=O)=CC=1OC.C(CC(N[C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30]([OH:32])=[O:31])=O)(O)=O>C1(C)C=CC=CC=1>[C:30]([OH:32])(=[O:31])[C:29]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:28]=1
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Agent: COc1cc(C=O)ccc1OC(F)F
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: O=C(O)c1ccccc1
Temperature: 25 °C
Yield: 81.6 %

Procedure:
Piperidine (0.25 mL, 2.6 mmol) was added to a suspension of 4-(difluoromethoxy)-3-methoxybenzaldehyde (0.52 g, 2.6 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (0.52 mg, 2.6 mmol) in toluene (5.0 mL). The reaction flask was fitted with a Dean-Stark apparatus and heated to reflux for 30 min. The reaction was then cooled to rt and the resulting suspension was filtered and washed with toluene. The piperidinium salt was dissolved in MeOH (5 mL) and water (2 mL) and the solution was acidified with 50% aqueous AcOH. The crude product was collected by filtration and recrystallised from EtOH/water, filtered and washed with water to afford (E)-2-[[3-methoxy-4-(difluoromethoxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid (259 mg, 71%) as a colourless crystalline solid; mp 172-174° C.; δH (500 MHz, DMSO-d6) 3.90 (s, 3H, OCH3), 6.94 (d, J=15.6 Hz, 1H, CH═CHCO), 7.12 (t, J=75 Hz, 1H, OCHF2), 7.17 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.20 (d, J5′,6′=8.0 Hz, 1H, H5′), 7.32 (dd, J5′,6′=8.0, J2′,6′=2.0 Hz, 1H, H6′), 7.56 (d, J2′,6′=2.0 Hz, 1H, H2′), 7.61 (d, J=15.6 Hz, 1H, CH═CHCO), 7.62 (dt, J4,5=J5,6=8.0, J3,5=1.5 Hz, 1H, H5), 8.00 (dd, J3,4=8.0, J3,5=1.5 Hz, 1H, H3), 8.61 (d, J5,6=8.0 Hz, 1H, H6), 11.33 (s, 1H, NH), 13.60 (br s, 1H, CO2H); δC (125 MHz, DMSO-d6) 56.1, 112.3, 114.5, 116.5 (t, J=256 Hz), 116.8, 120.4, 120.8, 121.4, 122.7, 122.9, 131.1, 132.9, 134.0, 140.6, 140.8, 150.7, 163.7, 169.4; HRMS (ESI−) calculated for C18H15F2NO5 [M-H ]− 362.0835, found 362.0839; νmax 1032, 1260, 1586, 1604, 1661, 2988, 3509 cm−1.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][CH:4]=1.Br[C:11]1[CH:20]=[CH:19][C:14]([CH2:15][N:16]([CH3:18])[CH3:17])=[CH:13][CH:12]=1>O1CCCC1.C1C=CC([P]([Pd]([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)=CC=1>[Br:9][C:6]1[CH:7]=[CH:8][C:3]([C:13]2[C:14]([CH2:15][N:16]([CH3:18])[CH3:17])=[CH:19][CH:20]=[CH:11][CH:12]=2)=[CH:4][CH:5]=1
Reactant: CN(C)Cc1ccc(Br)cc1
Reactant: Brc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: CN(C)Cc1ccccc1-c1ccc(Br)cc1
Reaction time: 5 h

Procedure:
A solution of the Grignard reagent prepared from 344 mg of magnesium and 2.27 g of 1,4-dibromobenzene in 15 ml of THF (tetrahydrofuran) is added dropwise to a suspension of 2 g of 4-bromo-N,N-dimethylbenzylamine and 158 mg of tetrakistriphenylphosphinepalladium in 10 ml of THF. The addition is carried out at room temperature and under an argon atmosphere. After completion of the addition, the mixture is heated to boiling for an additional 5 hours and then evaporated under reduced pressure. The residue is then treated with ether and saturated ammonium chloride solution and the aqueous phase is separated. This is extracted with ether. The organic extracts are washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated. The residue is purified by chromatography on silica gel while eluting with methylene chloride/methanol 9:1. 4'-Bromo-N,N-dimethylbiphenylmethanamine, m.p. 60°-62°C., is obtained.
Reaction SMILES: Br[CH:2]([CH2:18][CH2:19][CH3:20])[CH2:3][N:4]([N:13]1[CH:17]=[N:16][N:15]=[CH:14]1)[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1.[OH:21][C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C.O>[OH:21][C:22]1[CH:27]=[CH:26][C:25]([S:28][CH2:20][CH2:19][CH2:18][CH2:2][CH2:3][N:4]([N:13]2[CH:17]=[N:16][N:15]=[CH:14]2)[C:5]2[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=2)=[CH:24][CH:23]=1
Reactant: CCCC(Br)CN(c1ccc(C#N)cc1)n1cnnc1
Reactant: Oc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccc(N(CCCCCSc2ccc(O)cc2)n2cnnc2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 4-[(2-Bromo-pentyl)-[1,2,4]triazol-4-yl-amino]-benzonitrile (CAB03005, 500 mg, 1.5 mmol), 4-hydroxy-thiophenol (378 mg, 3.0 mmol) and potassium carbonate (414 mg, 3.0 mmol) in DMF (10 mL) was stirred for 12 hours at room temperature. The mixture was transferred into a separation funnel and ethyl acetate (50 mL) and water (50 mL) were added. The organic layer was separated, washed with brine (30 mL), dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: ethyl acetate, Rf: 0.43). The resulting yellow oil was dissolved in ethyl acetate and precipitated by addition of hexane to give an light yellow powder. Yield: 338 mg (59%). 1H-NMR (400 MHz, d6-DMSO) δ=1.40-1.54 (m, 6H), 2.77 (t, J=6.8 Hz, 2H), 3.79 (t, J=6.6 Hz, 2H), 6.61 (d, J=9.0 Hz, 2H), 6.72 (d, J=9.0 Hz, 2H), 7.20 (d, J=9.0 Hz, 2H), 7.72 (d, J=9.0 Hz, 2H), 8.96 (s, 2H), 9.55 (s, 1H. —OH). 13C-NMR (100 MHz, d6-DMSO) δ=25.66, 26.67, 29.35, 35.56, 53.86, 103.06, 113.89, 116.80, 119.84, 124.54, 133.39, 134.47, 144.09, 151.89, 157.26. LRMS (FAB+): 380.0 (100, [M+H]+). LRMS (FAB+) 380.15355 C20H22N5OS requires 380.154507.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([N:9]2[CH2:14][CH2:13][C:12]3([O:19][C:18]4[C:20]5[C:25]([C:26](=[O:29])[C:27](=[O:28])[C:17]=4[S:16][CH2:15]3)=[CH:24][CH:23]=[CH:22][CH:21]=5)[CH2:11][CH2:10]2)[CH2:5][CH2:4]1.[C:30]([C:34]1[CH:44]=[CH:43][C:37]([O:38][CH2:39][C@@H:40]2[CH2:42][O:41]2)=[CH:36][CH:35]=1)([CH3:33])([CH3:32])[CH3:31].CCN(C(C)C)C(C)C>>[C:30]([C:34]1[CH:44]=[CH:43][C:37]([O:38][CH2:39][C@@H:40]([OH:41])[CH2:42][N:3]2[CH2:4][CH2:5][CH:6]([N:9]3[CH2:14][CH2:13][C:12]4([O:19][C:18]5[C:20]6[C:25]([C:26](=[O:29])[C:27](=[O:28])[C:17]=5[S:16][CH2:15]4)=[CH:24][CH:23]=[CH:22][CH:21]=6)[CH2:11][CH2:10]3)[CH2:7][CH2:8]2)=[CH:36][CH:35]=1)([CH3:31])([CH3:32])[CH3:33]
Reactant: CC(C)(C)c1ccc(OC[C@@H]2CO2)cc1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(C3CCNCC3)CC1)O2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(OC[C@@H](O)CN2CCC(N3CCC4(CC3)CSC3=C(O4)c4ccccc4C(=O)C3=O)CC2)cc1

Procedure:
Compound 198 was synthesized using 1′-piperidin-4-ylspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione bis-hydrochloride, (2S)-2-[(4-tert-butylphenoxy)methyl]oxirane, hunig's base and conditions outlined in procedure Y. M.p.=190-193° C.; 400 MHz 1H NMR (CDCl3) δ: 8.04-8.02 (m, 1 H), 7.74-7.67 (m, 2 H), 7.51-7.47 (m, 1 H), 7.30-7.28 (m, 2 H), 6.85-6.83 (m, 2 H), 4.30 (t, 1 H), 4.02-3.94 (m, 2 H), 3.46-3.1 (m, 3 H), 2.95-2.92 (m, 4 H), 2.82 (d, 2 H), 2.72 (t, 2 H), 2.65 (bs, 2 H), 2.45 (t, 1 H), 2.19 (d, 2 H), 1.98-1.93 (m, 6 H), 1.29 (s, 9 H); LCMS: 591 [M+H].
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O.C1(C)C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(=O)([O-])O.[Na+]>CCOC(C)=O>[O:12]=[C:10]1[C:3]2[CH:4]=[CH:5][S:1][C:2]=2[CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: O=C(O)CCCCc1cccs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C1CCCCc2sccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.5 %

Procedure:
To a mixture of 5-(2-thienyl)pentanoic acid (5.04 g) and toluene (50 ml) was dropwise added trifluoroacetic anhydride (6.95 ml) over 1 minute with ice-water cooling. The reaction mixture was stirred at room temperature (r.t.) overnight, and was poured into a mixture of a saturated aqueous solution of sodium hydrogen carbonate (NaHCO3) and AcOEt. The organic layer was washed with water and brine, and dried over MgSO4, and evaporated. The resulting oil was purified by chromatography on silica gel (SiO2) (20% AcOEt in n-hexane as eluent). The fractions including the object compound were combined and evaporated to give 4-oxo-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene (1.57 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH2:11]OS(C)(=O)=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH:17]([NH2:20])([CH3:19])[CH3:18]>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH2:11][NH:20][CH:17]([CH3:19])[CH3:18])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)N
Reactant: CS(=O)(=O)OCCSc1ccc(Cl)c(Cl)c1
Product: CC(C)NCCSc1ccc(Cl)c(Cl)c1
Product: Cl

Procedure:
A solution of 151.46 g (0.548 mole) of methane-sulfonic acid [2-[(3,4-dichlorophenyl)thio]ethyl]ester in 100 ml of isopropylamine was heated overnight in a bomb at 100° C. The isopropylamine was removed in a rotary evaporator and the residue partitioned between chloroform and 5% sodium hydroxide. The chloroform was removed by rotary evaporator to give an oil, the free base of the title compound. The oil was dissolved in methanol and converted to the hydrochloride salt with ethereal hydrogen chloride. Recrystallization of the salt from methanol-diethyl ether gave 101.53 g (61.6%) of white crystalline product, m.p. 132°-133.5° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([CH2:11][CH2:12][C@H:13]([OH:27])[CH2:14]OS(CC2C=CC(C)=CC=2)(=O)=O)=[CH:9][CH:10]=1)=[O:5])[CH3:2].[N-:28]=[N+:29]=[N-:30].[Na+].[Na+].[Cl-]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([CH2:11][CH2:12][C@H:13]([OH:27])[CH2:14][N:28]=[N+:29]=[N-:30])=[CH:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(CC[C@H](O)COS(=O)(=O)Cc2ccc(C)cc2)s1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(CC[C@H](O)CN=[N+]=[N-])s1
Temperature: 80 °C
Yield: 113.5 %

Procedure:
To a stirred solution of 42.94 g (108 mmol) of the tosylate (4) in 250 ml of DMF (N,N-dimethylformamide) was added 31.52 g (485 mmol) of sodium azide. The solution was heated under argon for 4 hours at 80° C. The reaction mixture was cooled and poured into 600 ml of saturated NaCl, and the resulting oil was separated. The aqueous solution was extracted three times with Et2O. The Et2O extracts were combined with the oil and washed once with saturated NaCl, dried (MgSO4), and concentrated, yielding 33.0 g of the azide (5) as a crude product that was sufficiently pure to use in the next step (f). An analytical sample of the azide (5) was obtained by flash chromatography on silica gel, eluting CH2Cl2 -EtOAc (20:1) to produce a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[OH-].[K+].[CH3:12][CH2:13][C:14](=[O:17])[CH2:15][CH3:16].Cl>O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[C:13]([CH3:12])[C:14](=[O:17])[CH2:15][CH3:16])=[CH:4][CH:3]=1
Reactant: CCC(=O)CC
Reactant: O=Cc1ccc(Cl)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCC(=O)C(C)=Cc1ccc(Cl)cc1
Temperature: 65 °C
Reaction time: 8 h
Yield: 41.3 %

Procedure:
To 4-chlorobenzaldehyde 46a (99.6 mmol, 14 g) in water (44 mL) was added KOH (44.6 mmol, 2.5 g). The mixture was heated at 65° C. and 3-pentanone (99.6 mmol, 8.58 g) was added dropwise over 10 min. After refluxing for 8 h, the reaction mixture was cooled to room temperature and stirred overnight. Following addition of 260 mL 1N aqueous HCl, the mixture was extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated. The crude product was purified by flash column chromatography (silica gel, 5% EtOAc/heptane) to give 8.59 g of 46b.
Reaction SMILES: Cl/[C:2](=[N:8]/[OH:9])/[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(N([CH2:15][CH3:16])CC)C.[Cl-].[Na+].[O:19]1CC[CH2:21][CH2:20]1>>[OH:19][CH:20]([C:15]1[O:9][N:8]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:16]=1)[CH3:21]
Reactant: CCN(CC)CC
Reactant: C1CCOC1
Reactant: CCOC(=O)/C(Cl)=N\O
Agent: [Cl-]
Agent: [Na+]
Product: CCOC(=O)c1cc(C(C)O)on1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
14.02 g of 1-butyn-2-ol and 7.58 g of ethyl (2E)-chloro(hydroxyimino)acetate were dissolved in 50 ml of tetrahydrofuran, and a solution of 6.06 g of triethylamine in 25 ml of tetrahydrofuran was then added dropwise at 0° C. over 30 minutes. The mixture was stirred at room temperature overnight. After aqueous saturated sodium chloride was added, the reaction mixture was separated into layers. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 5.67 g of ethyl 5-(1-hydroxyethyl)-isoxazole-3-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:27][CH2:28][CH2:29][NH2:30])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[CH:32]1([N:38]=[C:39]=[O:40])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:27][CH2:28][CH2:29][NH:30][C:39]([NH:38][CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)=[O:40])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: O=C=NC1CCCCC1
Reactant: Cc1cc(F)ccc1-c1nc(NCCN)nc2c1ccc(=O)n2-c1c(F)cccc1F
Product: Cc1cc(F)ccc1-c1nc(NCCNC(=O)NC2CCCCC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Yield: 78.1 %

Procedure:
The title compound from Example 157 (42.3 mg, 0.0001 mol) was treated with cyclohexylisocyanate (12.5 mg, 0.00011 mol) in the same manner as described in Example 158. Purification afforded 43 mg (78%) of the title compound as a red solid (m.p. 178°-183°) LC MS (m/e)=551 (MH+). Rt=2.38 min.
Reaction SMILES: Cl[C:2]1[S:6][CH:5]=[CH:4][C:3]=1[CH2:7]Br.[Cl-].C[N+](C(=O)CCCCCCC)(C(=O)CCCCCCC)[C:12](=O)[CH2:13][CH2:14]CCCCC.C(Cl)(Cl)Cl>O1CCCC1.[OH-].[Na+]>[S:6]1[CH:5]=[CH:4][C:3]2[CH:7]=[CH:12][CH:13]=[CH:14][C:2]1=2
Reactant: CCCCCCCC(=O)[N+](C)(C(=O)CCCCCCC)C(=O)CCCCCCC
Reactant: Clc1sccc1CBr
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: c1ccc2sccc2c1

Procedure:
Stir cis-6-chloro-2,3-dihydro-3-hydroxy-2-[(1', 2', 4'-triazolyl)-1'-methyl]benzo(b)thiophene (1.17 gms., 4.37 mmols), 2-chloro-3-thenylbromide (1.06 gms., 5.0 mmol) and methyl tricaprylyl ammonium chloride (0.1 gm.) in tetrahydrofuran (25 ml) and 50% sodium hydroxide (10 ml) at room temperature for one hour. Pour the reaction mixture into chloroform (500 ml.) and extract with two 500 ml. portions of water. Dry the chloroform solution over anhydrous magnesium sulfate, filter and evaporate in vacuo. Chromatograph the resultant residue on silica gel eluting with chloroform. Combine the like eluates as determined by thin layer chromatography and evaporate in vacuo to obtain cis-6-chloro-3-(2'-chloro-3'-thenyloxy)-2,3-dihydro-2-[(1", 2", 4"-triazolyl)-1"-methyl]benzo(b)thiophene, a gum.
Reaction SMILES: [CH3:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([NH:8][C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[C:11]([N:19]3[CH:23]=[CH:22][N:21]=[C:20]3[CH3:24])[CH:10]=2)=[O:7])=[CH:4][C:3]=1[N+:27]([O-])=O.O.O.Cl[Sn]Cl>C(O)C.C(OCC)(=O)C>[NH2:27][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][C:2]=1[CH3:1])[C:6]([NH:8][C:9]1[CH:14]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:12]=[C:11]([N:19]2[CH:23]=[CH:22][N:21]=[C:20]2[CH3:24])[CH:10]=1)=[O:7]
Reactant: Cc1ccc(C(=O)Nc2cc(-n3ccnc3C)cc(C(F)(F)F)c2)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)Nc2cc(-n3ccnc3C)cc(C(F)(F)F)c2)cc1N
Temperature: 80 °C
Reaction time: 3 h

Procedure:
The compound (27 g, 72.1 mmol) obtained in Step 2 of Preparation Example 6 was dissolved in ethanol (300 mL), SnCl2.2H2O (81 g, 360 mmol) was added thereto and stirred at 80° C. for 3 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The organic layer was washed with sat. NaHCO3 solution several times. The organic layer was dried with anhydrous MgSO4, filtered and concentrated to obtain the title compound without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([CH3:16])=[N:4][C:3]=1[OH:17].CC(CC(O)=O)=O.C(N(CC)CC)C.[C:32](Cl)(=[O:36])[CH:33]([CH3:35])[CH3:34]>C(Cl)Cl>[OH:17][C:3]1[N:4]=[C:5]([CH3:16])[C:6]2[C:11]([C:2]=1[NH:1][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=2
Reactant: CC(C)C(=O)Cl
Reactant: COc1cc2c(C)nc(O)c(N)c2cc1OC
Agent: CC(=O)CC(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2c(C)nc(O)c(NC(=O)C(C)C)c2cc1OC
Reaction time: 1 h
Yield: 39.4 %

Procedure:
4-Amino-3-hydroxy-6,7-dimethoxy-1-methylisoquinoline (BBQ) (1.772 grams, 5 mmol) as the diacetate solvate in 50 ml methylene chloride was treated with 2.5 ml triethylamine (16.5 mmol) for 5 minutes and subsequently with 0.63 ml isobutyryl chloride (6 mmol) with stirring under a nitrogen atmosphere. After 1 hour, the slurry was evaporated to dryness in vacuo and boiled in 50 ml methanol and 5 ml water for 15 minutes. The solid was isolated by filtration, washed successively with methanol and acetone, and then dried in vacuo at 50° C. to provide 0.6 grams of Compound BO (39.4% yield) having a melting point of 292°-294° C. (with decomposition).
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6]([CH3:8])=[C:5]([C:9]([O:11][CH3:12])=[O:10])[CH:4]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[Cl:20])[C:3]=1[C:21]#[N:22].[C:23](OC(=O)C)(=[O:25])[CH3:24].C(OC)(=O)C>CO>[C:23]([NH:1][C:2]1[NH:7][C:6]([CH3:8])=[C:5]([C:9]([O:11][CH3:12])=[O:10])[CH:4]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[Cl:20])[C:3]=1[C:21]#[N:22])(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)C1=C(C)NC(N)=C(C#N)C1c1cccc(Cl)c1Cl
Solvent: CO
Solvent: COC(C)=O
Product: COC(=O)C1=C(C)NC(NC(C)=O)=C(C#N)C1c1cccc(Cl)c1Cl

Procedure:
6.7 g (20 mmol) of methyl 6-amino-5-cyano-4-(2,3-dichlorophenyl)-2-methyl-1,4-dihydropyridine-3-carboxylate and 33.5 ml (350 mmol) of acetic anhydride are heated under reflux for 30 minutes. Excess acetic anhydride is then converted into methyl acetate by addition of methanol at 25° C., while stirring. The reaction solution is evaporated in vacuo and toluene is then shipped off from the residue twice in vacuo. The residue is then boiled up with 50 ml of toluene. The crystals which have separated out are filtered off and washed with toluene.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][CH:15]3[CH2:20][C:19]([CH3:22])([CH3:21])[NH:18][C:17]([CH3:24])([CH3:23])[CH2:16]3)[N:9]=2)=[CH:4][CH:3]=1.[CH3:25][C:26]([NH2:30])([CH3:29])[C:27]#[CH:28]>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>[NH2:30][C:26]([CH3:29])([CH3:25])[C:27]#[C:28][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][CH:15]3[CH2:20][C:19]([CH3:22])([CH3:21])[NH:18][C:17]([CH3:24])([CH3:23])[CH2:16]3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: CC1(C)CC(Nc2nccc(-c3ccc(Br)cc3)n2)CC(C)(C)N1
Reactant: C#CC(C)(C)N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CC(C)(N)C#Cc1ccc(-c2ccnc(NC3CC(C)(C)NC(C)(C)C3)n2)cc1
Temperature: 95 °C
Reaction time: 16 h

Procedure:
To a solution of [4-(4-bromo-phenyl)-pyrimidin-2-yl]-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine (62 mg, 0.16 mmol) (Example 180) in 10 ml triethylamine were added bis(triphenylphosphine)palladium dichloride (22 mg, 0.03 mmol), 1,1-dimethyl-prop-2-ynylamine (166 μl, 1.43 mmol) and CuI (9.5 mg, 0.05 mmol). The mixture was stirred at 95° C. for 16 hours. The reaction mixture was concentrated, the residue taken up in EtOAc and the organic phase was washed with water. The organic layer was dried and concentrated. Purification using preparative HPLC gave the title compound. Yield: 26 mg (42%).