Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:24]=[C:25]([O:27][CH3:28])[CH:26]=1)[NH2:23]>>[CH3:28][O:27][C:25]1[CH:24]=[C:22]([CH:21]=[C:20]([O:19][CH3:18])[CH:26]=1)[NH:23][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccncc2)n1
Reactant: COc1cc(N)cc(OC)c1
Product: COc1cc(Nc2cc(C(F)(F)F)nc(-c3ccncc3)n2)cc(OC)c1

Procedure:
The title compound was prepared from 4-chloro-2-(4-pyridinyl)-6-trifluoromethyl-pyrimidine (150 mg, 0.578 mmol) and 3,5-dimethoxyaniline (95 mg, 0.621 mmol) similar to Example 160 and was isolated as off-white solid (119 mg, 0.316 mmol, 55%). 1H NMR (DMSO-d6): 10.31 (s, br, 1H), 8.80 (m, 2H), 8.17 (m, 2H), 7.17 (s, 1H), 7.04 (s, 2H), 6.32 (m, 1H), 3.80 (s, 6H), 3.53 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:11])=[N:7][NH:8]2)=[CH:4][C:3]=1[F:12].[H-].[Na+].Cl[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([NH2:22])[N:17]=1>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:11])=[N:7][N:8]2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH2:22])[N:17]=2)=[CH:4][C:3]=1[F:12]
Reactant: Nc1nccc(Cl)n1
Reactant: Cc1n[nH]c2cc(Br)c(F)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nn(-c2ccnc(N)n2)c2cc(Br)c(F)cc12
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To a solution of 6-bromo-5-fluoro-3-methyl-1H-indazole (130 mg, 0.284 mmol, 50% purity) in DMF (2 ml) was added NaH (60% oil dispersion, 18.16 mg, 0.454 mmol) at 0° C. The reaction mixture stirred for 15 minutes before the slow addition of a solution of 4-chloropyrimidin-2-amine (73.53 mg, 0.568 mmol) in DMF (2 mL). The resulting mixture was stirred at 60° C. for 16 hr. The reaction mixture was cooled and partitioned between water (15 ml) and EtOAc (15 ml). A precipitate formed and was collected by suction filtration. The filtrate was concentrated in vacuo and purified by flash chromatography (Isolute column, 1-2% methanol in DCM) to give the title intermediate as a yellow oil: 1H NMR (500 MHz, DMSO) delta 2.56 (3H, s), 7.00 (1H, s), 7.04-7.14 (2H, m), 7.92 (1H, d, J=8.35 Hz), 8.26 (1H, d, J=5.52 Hz), 9.22 (1H, d, J=5.99 Hz); LC-MS: m/z=+321.90, 323.80 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[C:11]([O:15][C:16](=[O:38])[CH2:17][N:18]1[C:22]2[CH:23]=[CH:24][C:25]([NH:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:26][C:21]=2[N:20]=[C:19]1[CH2:35][CH2:36][CH3:37])([CH3:14])([CH3:13])[CH3:12].CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl.Cl>[C:11]([O:15][C:16](=[O:38])[CH2:17][N:18]1[C:22]2[CH:23]=[CH:24][C:25]([N:27]([CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:6](=[O:7])[C:5]3[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:26][C:21]=2[N:20]=[C:19]1[CH2:35][CH2:36][CH3:37])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCCc1nc2cc(NCc3ccccc3)ccc2n1CC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1nc2cc(N(Cc3ccccc3)C(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Fluoro-benzoyl chloride (42 μL, 0.36 mmol) was added to a solution of (5-benzylamino-2-propyl-benzoimidazol-1-yl)-acetic acid tert-butyl ester (45 mg, 0.12 mmol), DIEA (41 μL, 0.24 mmol) and DMAP (15 mg, 0.12 mmol) in CH2Cl2 (1 mL), and stirred overnight at room temperature. The reaction solution was diluted with aqueous HCl (1.0 M) and filtered through an Extrelut column. The Extrelut column was washed with CH2Cl2, and the filtrate was concentrated to afford the subtitle compound that was used without further purification. MS calculated for C30H32FN3O3+H: 502, observed: 502.
Reaction SMILES: C([O:3][C:4](=[O:30])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:15]([Br:16])[C:14]([C:21]3[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=3)([C:17]([F:20])([F:19])[F:18])[O:13][N:12]=2)=[CH:7][C:6]=1[CH3:29])C.O.[OH-].[Li+].CO>O>[Br:16][CH:15]1[C:14]([C:21]2[CH:22]=[C:23]([Cl:28])[CH:24]=[C:25]([Cl:27])[CH:26]=2)([C:17]([F:18])([F:19])[F:20])[O:13][N:12]=[C:11]1[C:8]1[CH:9]=[CH:10][C:5]([C:4]([OH:30])=[O:3])=[C:6]([CH3:29])[CH:7]=1
Reactant: CCOC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2Br)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2Br)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 60 h
Yield: 87.9 %

Procedure:
A mixture of 4-[4-bromo-5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid ethyl ester (0.71 g, 1.35 mmol) (Example 1.6), lithium hydroxide monohydrate (0.17 g, 4 mmol), methanol (25 ml) and water (5 ml) was stirred at ambient temperature for 60 hours. The mixture was concentrated and the residue dissolved in water. The solution was acidified by addition of aqueous hydrochloric acid (1N). The precipitate was isolated by filtration and dried under vacuum to afford 4-[4-bromo-5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methyl-benzoic acid (0.59 g, 88% yield) as a white powder. 1H-NMR (CDCl3, 400 MHz): 8.05-7.45 (m, 6H), 5.87 (s, 1H), 2.65 (s, 3H) ppm.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([N:25]2[CH2:29][CH2:28][CH2:27][S:26]2(=[O:31])=[O:30])[CH:3]=1.[O:32]1[CH2:36][CH:35]=[N:34][C:33]1=[O:37]>>[O:30]=[S:26]1(=[O:31])[CH2:27][CH2:28][CH2:29][N:25]1[C:4]1[CH:3]=[C:2]([N:34]2[CH2:35][CH2:36][O:32][C:33]2=[O:37])[CH:7]=[CH:6][C:5]=1[C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=2)[CH2:12][CH2:11]1)=[O:9]
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(Br)cc3N3CCCS3(=O)=O)CC2)c(C)c1
Reactant: O=C1N=CCO1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCOC4=O)cc3N3CCCS3(=O)=O)CC2)c(C)c1
Yield: 81.7 %

Procedure:
By reaction and treatment in the same manner as in Example 149 and using [4-bromo-2-(1,1-dioxoisothiazolidin-2-yl)phenyl][4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (507 mg) described in Preparation Example 180 and oxazolin-2-one (104 mg), the title compound (419 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1([O:25][CH3:26])[CH2:8][CH2:7][C:6]([C:23]#N)([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH:10]=2)[CH2:5][CH2:4]1.[H-].S(=O)(O)[O-:29].[Na+]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1([O:25][CH3:26])[CH2:8][CH2:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH:10]=2)([CH:23]=[O:29])[CH2:5][CH2:4]1
Reactant: O=S([O-])O
Reactant: COc1ccc(C2(C#N)CCC(OC)(OC)CC2)cc1OC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccc(C2(C=O)CCC(OC)(OC)CC2)cc1OC1CCCC1
Reaction time: 2 h
Yield: 96 %

Procedure:
A solution of 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one dimethyl ketal (0.57 g, 1.6 mmol) in toluene (20 mL) at room temperature under an argon atmosphere was treated with a solution of dissobutylaluminium hydride (1.5M in toluene, 2.7 mL, 4 mmol). After 2 h, a solution of saturated aqueous sodium bisulfite was added and the mixture was extracted twice with ethyl acetate. The organic extract was washed with 5% aqueous sodium carbonate,was dried (potassium carbonate) and the solvent was removed in vacuo to provide an oil (0.55 g, 96%).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([NH:18]C(=O)OC(C)(C)C)[CH2:14][CH2:13]3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.Cl.C(OCC)(=O)C>C(OCC)(=O)C>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([NH2:18])[CH2:14][CH2:13]3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)NC1CCN(Cc2ccc3c(c2)OCCO3)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: NC1CCN(Cc2ccc3c(c2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To 100 mL of an ethyl acetate solution containing 3.62 g of tert-butyl (1-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)piperidin-4-yl)carbamate, 30 mL of 4 mol/L hydrogen chloride/ethyl acetate was added, and the mixture was stirred at room temperature for 6 hours. The solvent was removed under reduced pressure, the residue thus obtained was added with ethyl acetate, and a solid substance was collected by filtration. The solid substance thus obtained was purified by silica gel column chromatography [silica gel; Chromatorex-NH, manufactured by Fuji Silysia Chemical Ltd., eluent; chloroform:methanol=5:1] to obtain 1.35 g of a pale yellow oily substance, 1-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)piperidin-4-ylamine.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[OH:27][CH2:28][C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=3)[N:10]=2)=[C:2]([O:27][CH2:28][C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[CH:7]=1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Reactant: OCc1cccnc1
Product: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3OCc3cccnc3)n2)c1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (50 mg; 0.129 mmol), intermediate 42.1, and 3-(hydroxymethyl)-pyridine (57 mg; 0.515 mmol), example 74 was prepared analogously to the procedure for the preparation of example 42.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([C:14](=[O:16])[CH3:15])[CH:11]=[CH:12][CH:13]=1.[NH:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:24]=[C:25]([NH:29][C:30]([CH:32]3[CH2:34][CH2:33]3)=[O:31])[CH:26]=[CH:27][CH:28]=2)[CH2:19][CH2:18]1>>[C:14]([C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=1)[O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:24]=[C:25]([NH:29][C:30]([CH:32]3[CH2:33][CH2:34]3)=[O:31])[CH:26]=[CH:27][CH:28]=2)[CH2:19][CH2:18]1)(=[O:16])[CH3:15]
Reactant: CC(=O)c1cccc(OCCCCCCl)c1
Reactant: O=C(Nc1cccc(C2CCNCC2)c1)C1CC1
Product: CC(=O)c1cccc(OCCCCCN2CCC(c3cccc(NC(=O)C4CC4)c3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 1-{3-[(5-chloropentyl)oxy]phenyl}ethanone and N-[3-(4-piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e: 449.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]([NH2:7])=[NH:6])=[NH:3].Br[CH2:9][C:10](=O)[CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25].C(O)(=O)C>CN(C)C=O>[NH:4]([C:5]1[NH:7][CH:9]=[C:10]([CH2:11][CH2:12][CH2:13][CH2:14][N:15]2[C:16](=[O:25])[C:17]3=[CH:24][CH:23]=[CH:22][CH:21]=[C:18]3[C:19]2=[O:20])[N:6]=1)[C:2]([NH2:1])=[NH:3]
Reactant: N=C(N)NC(=N)N
Reactant: O=C(CBr)CCCCN1C(=O)c2ccccc2C1=O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: N=C(N)Nc1nc(CCCCN2C(=O)c3ccccc3C2=O)c[nH]1
Reaction time: 3 h

Procedure:
Biguanide (1.01 g.) was stirred in dry dimethylformamide (15 ml.) and N-(6-bromo-5-oxohexyl)phthalimide (1.5 g.) added. The mixture was stirred for 3 hours, acetic acid (5 ml.) was then added and the total reaction mixture evaporated to dryness. The residue was dissolved in water (10 ml.) and extracted with ethyl acetate (5×20 ml.). The combined ethyl acetate extracts were evaporated to give a brown foam which was purified by column chromatography on silica gel using chloroform/methanol/ammonia (s.g. 0.880) 80:20:0.5 v/v/v. The appropriate fractions were evaporated to give 2-guanidino-4-(4-phthalimidobutyl)imidazole as a brown foam (0.3 g.).
Reaction SMILES: Cl[CH2:2][S:3][C:4]1[CH:5]=[C:6]([CH3:10])[CH:7]=[CH:8][CH:9]=1.[F:11][C:12]1[CH:13]=[N:14][C:15](=[O:18])[NH:16][CH:17]=1.C(N(CC)CC)C.[K+].[Br-]>ClCCl>[CH3:10][C:6]1[CH:5]=[C:4]([S:3][CH2:2][N:16]2[CH:17]=[C:12]([F:11])[CH:13]=[N:14][C:15]2=[O:18])[CH:9]=[CH:8][CH:7]=1
Reactant: O=c1ncc(F)c[nH]1
Reactant: Cc1cccc(SCCl)c1
Agent: [Br-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(SCn2cc(F)cnc2=O)c1

Procedure:
3-(Chloromethylthio)toluene (6.5 mmol) was added to a solution of 5-fluoropyrimidin-2-one (6.5 mmol) and triethylamine (6.5 mmol) in dichloromethane (75 ml) and the resultant mixture heated under reflux for 2 days. The solvent was then distilled off, the residue triturated with water and the residual material extracted with CCl4. Evaporation of the extracts and crystallisation of the residue from ethyl acetate gave the pure product; 0.40 g (25%), m.p. 124° C. (Found: C57.42; H4.63. Calc. for C12H11FN2OS: C57.59; H4.43) 1H NMR (DMSO d6); δ 2.28 (Me), 5.17(CH2), 7.2 (Ph), 8.05 (H-4), 8.70 (H-6). IR (KBr): 1670 cm-1 (CO), MS [70 eV, m/z (% rel. int.)]: 250 (8,M), 137(11), 136(36), 135(10), 128(7), 127(100), 100(34), 91(9).
Reaction SMILES: O.[CH3:2][O:3][C:4](=[O:15])[C:5](=[N:10][O:11][CH2:12][CH2:13][CH3:14])[C:6]([CH2:8]Cl)=O.[NH2:16][C:17]([NH2:19])=[S:18].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:2][O:3][C:4](=[O:15])/[C:5](/[C:6]1[N:16]=[C:17]([NH2:19])[S:18][CH:8]=1)=[N:10]\[O:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCON=C(C(=O)CCl)C(=O)OC
Reactant: NC(N)=S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCCO/N=C(\C(=O)OC)c1csc(N)n1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a mixture solution of 20 ml of water and 25 ml of ethanol are added 7.0 g of 4-chloro-2-(n-propoxyimino)-acetoacetic acid methyl ester, 2.4 g of thiourea and 4.3 g of sodium acetate(trihydrate). The mixture is stirred for one hour at 40° C. The reaction mixture is, under cooling, adjusted to pH 6.5 with a saturated aqueous solution of potassium carbonate, followed by stirring for 30 minutes. The resulting crystals are collected by filtration, washed with water and isopropyl ether in this order, and dried to yield 2-(2-amino-4-thiazolyl)-(Z)-2-(n-propoxyimino)acetic acid methyl ester as crystals, m.p. 115°-116° C.
Reaction SMILES: [NH:1]([CH2:8][C:9]1[CH:10]=[C:11]([CH:24]=[CH:25][CH:26]=1)[O:12][CH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:28](Cl)(=[O:38])[O:29][C@@H:30]1[CH:35]2[CH2:36][CH2:37][N:32]([CH2:33][CH2:34]2)[CH2:31]1>CC#N.CCOC(C)=O>[N:32]12[CH2:37][CH2:36][CH:35]([CH2:34][CH2:33]1)[C@@H:30]([O:29][C:28]([N:1]([CH2:8][C:9]1[CH:10]=[C:11]([CH:24]=[CH:25][CH:26]=1)[O:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:22][CH:23]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:38])[CH2:31]2
Reactant: COC(=O)c1ccc(COc2cccc(CNc3ccccc3)c2)cc1
Reactant: O=C(Cl)O[C@H]1CN2CCC1CC2
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)c1ccc(COc2cccc(CN(C(=O)O[C@H]3CN4CCC3CC4)c3ccccc3)c2)cc1
Temperature: 25 °C
Yield: 76 %

Procedure:
A suspension of methyl 4-[[3-(anilinomethyl)phenoxy]methyl]benzoate (380 mg, 1.1 mmol) and (R)-quinuclidin-3-yl carbonochloridate hydrochloride (described in the co-pending International Patent Application No. PCT/EP2013/075529 (published as WO 2014/086855) as Intermediate 16) (300 mg, 1.33 mmol) in anhydrous CH3CN (5 mL) was heated to 100° C. for 15 min under microwave irradiation. After cooling to room temperature, the mixture was diluted with EtOAc (50 mL) and washed with saturated aqueous NaHCO3 (20 mL) The layers were separated and the organic phase was dried over Na2SO4, filtered and the solvent was removed in vacuo to yield the title compound (419 mg, 76% yield) which was used directly in the next step without any further purification.
Reaction SMILES: [CH:1]([C:3]1[CH:7]=[CH:6][S:5][N:4]=1)=[CH2:2].C([Li])CCC.[CH2:13]([Sn:17]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:19][CH2:20][CH2:21][CH3:22])Cl)[CH2:14][CH2:15][CH3:16].C(=O)(O)[O-].[Na+]>C1COCC1>[CH2:23]([Sn:17]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:19][CH2:20][CH2:21][CH3:22])[C:6]1[S:5][N:4]=[C:3]([CH:1]=[CH2:2])[CH:7]=1)[CH2:24][CH2:25][CH3:26]
Reactant: C=Cc1ccsn1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: C=Cc1cc([Sn](CCCC)(CCCC)CCCC)sn1
Temperature: -78 °C
Reaction time: 1 h
Yield: 43.8 %

Procedure:
To a cold (−78° C.) solution of 3-vinylisothiazole (300 mg, 2.70 mmol) in anhydrous THF (6.0 mL) was added n-butyllithium (1.855 mL, 2.97 mmol) dropwise. After stirring the reaction mixture for 60 minutes at −78° C., a solution of tributylchlorostannane (0.873 mL, 3.24 mmol) in anhydrous THF (1.5 mL) was added. The reaction mixture was stirred for 30 minutes at −78° C. and then allowed to warm to room temperature over a 1 hour period. Saturated aqueous sodium bicarbonate was added and the aqueous phase was extracted with EtOAc. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo. The residue was purified by silica gel chromatography (Flash 60 column) eluting with hexane/EtOAc (19:1) to give the title compound as a pale yellow oil (472.8 mg, 44%). 1H NMR (500 MHz, CDCl3) δ ppm 0.90 (t, J=7.32 Hz, 9H), 1.13-1.18 (m, 6H), 1.34 (sextet, J=7.42 Hz, 6H), 1.52-1.61 (m, 6H), 5.50 (dd, J=11.23, 0.98 Hz, 1H), 6.00 (dd, J=17.60, 0.98 Hz, 1H), 6.96 (dd, J=17.57, 11.23 Hz, 1H), 7.33 (s, 1H).
Reaction SMILES: C(O[C:5]1[C:8](=[O:9])[C:7](=[O:10])[C:6]=1[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21]#[N:22])[CH:19]=2)[O:14][C:13]([CH3:24])([CH3:23])[CH:12]=1)(C)C.[CH3:25][NH2:26]>CC#N.CCO>[CH3:24][C:13]1([CH3:23])[CH:12]=[C:11]([C:6]2[C:7](=[O:10])[C:8](=[O:9])[C:5]=2[NH:26][CH3:25])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21]#[N:22])[CH:19]=2)[O:14]1
Reactant: CC(C)Oc1c(C2=CC(C)(C)Oc3ccc(C#N)cc32)c(=O)c1=O
Reactant: CN
Solvent: CC#N
Solvent: CCO
Product: CNc1c(C2=CC(C)(C)Oc3ccc(C#N)cc32)c(=O)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
To a solution of 437 mg (1.35 mmol) of 4-(2-isopropoxy-3,4-dioxo-cyclobut-1-enyl)-2,2-dimethyl-2H-chromene-6-carbonitrile in CH3CN 14 mL) was added dropwise 8.03M methylamine in EtOH. The reaction mixture was stirred at ambient temperature for 1 h. The reaction mixture was quenched with H2O (50 mL) and then was extracted into 20% THF-CH2Cl2. The combined organic extracts were dried (Na2SO4) and purified by flash chromatography (4% MeOH--CHCl3) and crystallization from CH2Cl2 -petroleum ether to give 210 mg (53% yield) of the title compound, mp 193°-194° C., as a white solid: 1H-NMR (DMSO-d6 ; 400 MHz; major rotamer) δ8.7-8.8 (br q, 1H), 7.78 (d, 1H), 7.67 (dd, 1H), 7.01 (d, 1H), 6.22 (s, 1H), 3.25 (d, 3H), and 1.46 ppm (s, 3H); IR (KBr) 2220, 1775, 1735, 1620 cm-1 ; mass spectrum (DCI+), m/e 2.95.
Reaction SMILES: [C:1]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:28])[O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]([CH3:27])[C:19](=[O:26])[CH2:20][O:21][CH2:22][CH2:23][CH:24]=O)[CH2:12][CH2:11]1.[NH2:35][C:36]1[CH:48]=[CH:47][C:39]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])=[CH:38][CH:37]=1>>[C:1]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]([CH3:27])[C:19](=[O:26])[CH2:20][O:21][CH2:22][CH2:23][CH2:24][NH:35][C:36]2[CH:48]=[CH:47][C:39]([C:40]([O:42][C:43]([CH3:44])([CH3:45])[CH3:46])=[O:41])=[CH:38][CH:37]=2)[CH2:12][CH2:11]1)=[O:28]
Reactant: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)COCCC=O
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Product: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)COCCCNc1ccc(C(=O)OC(C)(C)C)cc1
Yield: 62.7 %

Procedure:
The compound (222 mg, 0.475 mmol) obtained in Example 26c and tert-butyl 4-aminobenzoate (92 mg, 0.475 mmol) were used according to the method described in Example 18b to give the title compound (192 mg; yield, 63%) as a white solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:25])([CH3:24])[C@@H:11]([O:14]CC1C=CC(OC)=CC=1)[CH:12]=[CH2:13])(=[O:7])=[O:6].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>ClCCl.O>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:25])([CH3:24])[C@@H:11]([OH:14])[CH:12]=[CH2:13])(=[O:7])=[O:6]
Reactant: C=C[C@H](OCc1ccc(OC)cc1)C(C)(C)COS(=O)(=O)CCCCl
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Solvent: O
Product: C=C[C@H](O)C(C)(C)COS(=O)(=O)CCCCl
Yield: 90.9 %

Procedure:
Following the general procedure for the oxidative cleavage of (4-methoxy)benzyl ethers of Description 19, (3S)-3-[(4-methoxyphenyl)methoxy]-2,2-dimethylpent-4-enyl (3-chloropropyl)sulfonate (13a) (0.50 g, 1.3 mmol), dissolved in a mixture of dichloromethane (DCM) and water (10:1) (10 mL) was treated with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (0.35 g, 1.5 mmol). After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) to provide 0.32 g (91% yield) of the title compound (16a) as a colorless oil. Rf=0.48 (EtOAc/Hxn=1:2). 1H NMR (400 MHz, CDCl3): δ=0.95 (s, 3H), 1.00 (s, 3H), 1.75 (d, J=3.6 Hz, 1H), 2.32-2.39 (m, 2H), 3.31-3.35 (m, 2H), 3.70-3.73 (m, 2H), 3.97 (d, J=9.2 Hz, 1H), 4.02-4.04 (m, 1H), 4.26 (d, J=9.2 Hz, 1H), 5.25-5.33 (m, 2H), 5.87-5.96 (m, 1H) ppm. MS (ESI) m/z: 271.08 (M+H)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH2:17])[C:14]([NH2:18])=[C:13]([NH2:19])[N:12]=1.[CH2:20]([O:22][C:23]([N:25]=[C:26]=S)=[O:24])[CH3:21].C(N=C=NC(C)C)(C)C>C(#N)C.C(N(CC)CC)C>[NH2:19][C:13]1[N:12]=[C:11]([S:10][CH2:9][C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[F:1])[N:16]=[C:15]2[C:14]=1[N:18]=[C:26]([NH:25][C:23](=[O:24])[O:22][CH2:20][CH3:21])[NH:17]2
Reactant: Nc1nc(SCc2cccc(F)c2F)nc(N)c1N
Reactant: CCOC(=O)N=C=S
Agent: CC(C)N=C=NC(C)C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)Nc1nc2c(N)nc(SCc3cccc(F)c3F)nc2[nH]1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of the product of example 5, step (c) (10.5 g) in acetonitrile (50 ml) and triethylamine (17 ml) was added to an ice cold stirred solution of ethoxycarbonylisothiocyanate (3 ml) in acetonitrile (50 ml). This mixture was then stirred at room temperature for 20 min. Diisopropylcarbodiimide (4.5 ml) was then added and the reaction mixture was stirred at reflux for 2 hr and allowed to cool. The reaction mixture was evaporated to dryness and purified by flash chromatography on silica gel (ethyl acetate:dichloromethane, 1:1) to yield the sub-titled compound as a yellow solid (3.0 g).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[F:12][C:13]1[C:18](F)=[CH:17][C:16]([NH2:20])=[C:15]([N+:21]([O-:23])=[O:22])[CH:14]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[F:12][C:13]1[C:18]([O:9][CH2:8][CH2:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:17][C:16]([NH2:20])=[C:15]([N+:21]([O-:23])=[O:22])[CH:14]=1
Reactant: Nc1cc(F)c(F)cc1[N+](=O)[O-]
Reactant: OCCN1CCCCC1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1cc(OCCN2CCCCC2)c(F)cc1[N+](=O)[O-]
Temperature: 22 °C
Reaction time: 2 h
Yield: 54.5 %

Procedure:
A solution of 1.11 g of 2-piperidin-1-ylethanol in 20 mL of N,N-dimethylformamide (DMF) is cooled to 0° C. with an ice bath. 689 mg of sodium hydride (60% in suspension in oil) are added in small portions. The suspension obtained is added dropwise to a suspension containing 500 mg of 4,5-difluoro-2-nitrophenylamine and 724 mg of sodium bicarbonate in 15 mL of DMF. The reaction medium is stirred at ambient temperature (22° C.) for 2 hours and then heated at 90° C. for 1 hour. The solvent is concentrated to dryness, then the reaction crude is taken up in 30 mL of ethyl acetate and the organic phase is washed with 2×30 mL of distilled water and 1×30 mL of a saturated aqueous solution of sodium chloride. The organic phase is dried over magnesium sulfate and the solvent is evaporated off under vacuum in a rotary evaporator. The crude is triturated in ethyl ether and the solid is filtered through sintered glass and rinsed with ethyl ether. 443 mg of 4-fluoro-2-nitro-5-(2-piperidin-1-ylethoxy)-phenylamine in the form of a red solid are isolated. 1H NMR (300 MHz, DMSO-d6, δ in ppm): 1.37 (m, 2H); 1.48 (m, 4H); 2.43 (m, 4H); 2.69 (t, J=6.5 Hz, 2H); 4.13 (t, J=6.5 Hz, 2H); 6.65 (d, J=8.0 Hz, 1H); 7.48 (broad s, 2H); 7.75 (d, J=12.0 Hz, 1H).