Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:36]=[CH:35][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([CH2:17][O:18][C:19]4[CH:32]=[CH:31][C:22]([CH2:23][CH:24]5[S:28][C:27](=[O:29])[NH:26][C:25]5=[O:30])=[CH:21][CH:20]=4)[N:14]([CH3:33])[C:13]=3[CH:34]=2)=[CH:6][CH:5]=1.[CH2:37]([N:44]=[C:45]=[S:46])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(N(CC)CC)C>CN(C)C=O>[CH2:37]([NH:44][C:45]([NH:3][C:4]1[CH:36]=[CH:35][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([CH2:17][O:18][C:19]4[CH:32]=[CH:31][C:22]([CH2:23][CH:24]5[S:28][C:27](=[O:29])[NH:26][C:25]5=[O:30])=[CH:21][CH:20]=4)[N:14]([CH3:33])[C:13]=3[CH:34]=2)=[CH:6][CH:5]=1)=[S:46])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(N)cc3)cc21
Reactant: S=C=NCc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(NC(=S)NCc4ccccc4)cc3)cc21
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 63.9 %

Procedure:
A mixture of 5-[4-[6-(4-aminophenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione dihydrochloride (400 mg), benzyl isothiocyanate (248 mg), triethylamine (153 mg) and anhydrous N,N-dimethylformamide (8 ml) was stirred at room temperature for 3.5 hours. The reaction mixture was concentrated and partitioned between ethyl acetate and water. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated. The residue was chromatographed on a silica gel column using ethyl acetate:n-hexane=2:1→3:1→4:1 as the eluant to afford the title compound (291 mg, mp 174.8-177.2° C.).
Reaction SMILES: O1CCC[CH2:2]1.[C:6]([O:9][N:10]([C:17]([O:19][C:20]([CH3:30])([CH3:29])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:18])[CH2:11][CH2:12][O:13][CH2:14][CH2:15][OH:16])(=[O:8])[CH3:7].[H-].[Na+].IC>O>[C:6]([O:9][N:10]([C:17]([O:19][C:20]([CH3:30])([CH3:29])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:18])[CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:2])(=[O:8])[CH3:7]
Reactant: C1CCOC1
Reactant: CC(=O)ON(CCOCCO)C(=O)OC(C)(C)CCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: COCCOCCN(OC(C)=O)C(=O)OC(C)(C)CCc1ccccc1
Reaction time: 0.33 h
Yield: 50 %

Procedure:
Under an argon gas atmosphere, a tetrahydrofuran (20 mL) solution of benzyl{tert-butoxycarbonyl-[2-(2-hydroxyethoxy)ethyl]amino} acetate (5.83 g, 16.5 mmol) was added dropwise to a tetrahydrofuran (10 mL) solution of sodium hydride (1.2 g, 24.8 mmol, 50% in mineral oil) at 0° C. After stirring at the same temperature for 20 minutes, iodomethane (1.6 mL, 24.8 mmol) was added at 0° C. The reaction mixed liquid was stirred at room temperature for 20 hours and then water was added while cooling in an ice bath, thereby terminating the reaction. The reaction liquid was extracted three times with ether and the organic layer was dried, and then the residue was concentrated under reduced pressure and purified by silica gel flash column chromatography (eluent: hexane/ethyl acetate=5/1, 3/1) to obtain benzyl{tert-butoxycarbonyl-[2-(2-methoxyethoxy)ethyl]amino} acetate (3.02 g, 8.21 mmol) as a colorless oily product with a yield of 50%.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([SH:11])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:26][N:27]([CH3:31])[CH2:28][CH2:29]Cl>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:29][CH2:28][N:27]([CH3:31])[CH3:26])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CN(C)CCCl
Reactant: Nc1nc(S)nc2c1nc(O)n2Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)CCSc1nc(N)c2nc(O)n(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 11 h
Yield: 3.6 %

Procedure:
Crude 6-amino-9-benzyl-8-hydroxy-2-mercaptopurine (200 mg, 0.73 mmol) was suspended in dimethylformamide (80 ml). To the suspension were added potassium carbonate (300 mg, 2.2 mmol) and 2-dimethylaminoethylchloride (160 mg, 1.1 mmol) in order. The mixture was stirred at room temperature for 11 hours. The solvent was removed in vacuo, and the residue was purified by silica gel chromatography (10% methanol/chloroform) to give the subject compound (9 mg, yield 4%).
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:5][N:4]([C:6]2([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:23][CH2:22][C:9]3([CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]3)[CH2:8][CH2:7]2)[CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:30][C:2]1([F:1])[CH2:5][N:4]([C:6]2([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:7][CH2:8][C:9]3([CH2:10][CH2:11][NH:12][CH2:13][CH2:14]3)[CH2:22][CH2:23]2)[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CCC(c1ccccc1)(N1CC(F)(F)C1)CC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC1(F)CN(C2(c3ccccc3)CCC3(CCNCC3)CC2)C1
Reaction time: 3 h

Procedure:
tert-Butyl 9-(3,3-difluoroazetidin-1-yl)-9-phenyl-3-azaspiro[5.5]undecane-3-carboxylate (300 mg, 0.714 mmol) was taken up in DCM (24 ml) and TFA (6 ml) was added. The resulting mixture was stirred for 3 h. The TLC revealed completion of the reaction and the solvent was removed under reduced pressure. The compound was azeotroped (2-3×) with DCM and used in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[Cl:12][C:13]1[C:14]([F:23])=[C:15]([S:19](Cl)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1>CN(C1C=CN=CC=1)C>[Cl:12][C:13]1[C:14]([F:23])=[C:15]([S:19]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[N:10]=[CH:9][CH:8]=[CH:7]3)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1F
Reactant: Nc1cccc2cccnc12
Agent: CN(C)c1ccncc1
Product: O=S(=O)(Nc1cccc2cccnc12)c1cccc(Cl)c1F
Yield: 33.9 %

Procedure:
In a similar fashion using route 14 general procedure 27, 8-aminoquinoline (100 mg, 0.70 mmol), 3-chloro-2-fluorobenzenesulfonyl chloride (180 mg, 0.83 mmol) and DMAP (cat.) gave the title compound (80 mg, 35%) after purification by column chromatography with DCM as the eluent followed by trituration from EtOAc/n-hexane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.[F:19][C:20]([F:39])([F:38])[C:21]1[CH:22]=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][C:25]=2[N:31]1[CH2:36][CH2:35][C:34](=O)[CH2:33][CH2:32]1.C([BH3-])#N.[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([N:13]3[CH2:14][CH2:15][N:16]([CH:34]4[CH2:35][CH2:36][N:31]([C:25]5[CH:26]=[CH:27][CH:28]=[C:29]6[C:24]=5[N:23]=[CH:22][C:21]([C:20]([F:39])([F:38])[F:19])=[CH:30]6)[CH2:32][CH2:33]4)[CH2:17][CH2:18]3)[CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2
Reactant: COc1cc(N2CCNCC2)c2ncccc2c1
Reactant: O=C1CCN(c2cccc3cc(C(F)(F)F)cnc23)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COc1cc(N2CCN(C3CCN(c4cccc5cc(C(F)(F)F)cnc45)CC3)CC2)c2ncccc2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 6-methoxy-8-piperazinoquinoline (Example A, Step 4; 0.0825 g) and 1-[3-(trifluoromethyl)quinolin-8-yl]piperidin-4-one (0.1 g) in methanol (5 mL) was treated with sodium cyanoborohydride (Step 4, 0.032 g). The resulting mixture was stirred at room temperature for 18 hours and then concentrated on a rotary evaporator. The residue was taken up in CH2C2, washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated on a rotary evaporator. The crude product was purified by flash chromatography on silica gel using hexane/ethyl acetate to give the desired product, which was converted to its dihydrochloride salt in using 1N HCl/Et2O to yield 0.035 g as a yellow solid; MS (ES) m/z (relative intensity): 522 (M+H)+ (100).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([OH:15])([C:9]#[C:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[CH2:6][C:7]#[CH:8].N1C=CN=C1.Cl[Si:22]([CH3:25])([CH3:24])[CH3:23].CCCCCC>CN(C)C=O>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([O:15][Si:22]([CH3:25])([CH3:24])[CH3:23])([C:9]#[C:10][Si:11]([CH3:12])([CH3:13])[CH3:14])[CH2:6][C:7]#[CH:8]
Reactant: C[Si](C)(C)Cl
Reactant: C#CCC(O)(C#C[Si](C)(C)C)CCCCl
Agent: c1c[nH]cn1
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: C#CCC(C#C[Si](C)(C)C)(CCCCl)O[Si](C)(C)C
Reaction time: 1 h

Procedure:
To a stirred mixture of 8.5 grams of 7-chloro-4-hydroxy-4-trimethylsilylethynyl-1-heptyne and 6.2 grams of imidazole in 24 ml of dry dimethylformamide is added, under nitrogen, 5.7 ml of chloro-trimethylsilane, in a slow stream, via a syringe. The mixture is stirred in an ice bath for one hour and then at room temperature overnight. The mixture is poured into hexane, washed with saturated sodium bicarbonate solution, water and then brine and dried over sodium sulfate. The solvents are evaporated to dryness yielding the desired product.
Reaction SMILES: CO[C:3]1[C:6](=[O:7])[C:5](=[O:8])[C:4]=1[NH:9][C:10]1[CH:11]=[C:12]([NH:17][C:18]([C:20]2[S:21][CH:22]=[CH:23][C:24]=2[NH:25][CH2:26][C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]=[CH:29][CH:28]=2)=[O:19])[CH:13]=[CH:14][C:15]=1[CH3:16].[NH3:37]>>[NH2:37][C:3]1[C:6](=[O:7])[C:5](=[O:8])[C:4]=1[NH:9][C:10]1[CH:11]=[C:12]([NH:17][C:18]([C:20]2[S:21][CH:22]=[CH:23][C:24]=2[NH:25][CH2:26][C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]=[CH:29][CH:28]=2)=[O:19])[CH:13]=[CH:14][C:15]=1[CH3:16]
Reactant: COc1c(Nc2cc(NC(=O)c3sccc3NCc3ccnc4ccccc34)ccc2C)c(=O)c1=O
Reactant: N
Product: Cc1ccc(NC(=O)c2sccc2NCc2ccnc3ccccc23)cc1Nc1c(N)c(=O)c1=O

Procedure:
EXAMPLE 45 was prepared according to the procedure described in EXAMPLE 3 using N-{3-[(2-methoxy-3,4-dioxocyclobut-1-en-1-yl)amino]4-methylphenyl}-3-[(quinolin-4-ylmethyl)amino]thiophene-2-carboxamide (EXAMPLE 44) and ammonia instead of dimethylamine. MS (ES+): m/z 483.9 [M+1]
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:21][C:22]2[CH:23]=[N:24][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:27]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18](O)=[O:19])[CH2:15][N:16]=1)=[CH:8]2.Cl.[CH2:33]([N:35]=C=NCCCN(C)C)[CH3:34].ON1C2C=CC=CC=2N=N1.C(N)C>O.CN(C)C=O>[CH2:33]([NH:35][C:18](=[O:19])[CH2:17][CH:14]1[S:13][C:12]([C:9]2[NH:10][C:11]3[C:7]([CH:8]=2)=[CH:6][C:5]([O:21][C:22]2[CH:23]=[N:24][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:27]=2)=[CH:4][C:3]=3[O:2][CH3:1])=[N:16][CH2:15]1)[CH3:34]
Reactant: CCN=C=NCCCN(C)C
Reactant: COc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Agent: CCN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCNC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)nc4)cc(OC)c3[nH]2)S1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.4 %

Procedure:
A mixture of [2-(7-methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetic acid (200 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (120 mg), 1-hydroxybenzotriazole (90 mg) and N,N-dimethylformamide (3 mL) was stirred at room temperature for 30 min, and then ethylamine (2M solution in tetrahydrofuran, 0.43 mL) was added to the mixture. The whole was stirred at room temperature for 15 h. Water was added to the mixture and the resultant was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and brine, dried (MgSO4), filtered, and concentrated in vacuo. The residual crystals were washed with ethyl acetate-hexane and collected by filtration to give pale yellow crystals. The crystals were recrystallized from acetone-methanol to give the title compound (130 mg, 62%) as colorless prisms. MS 489 (MH+). mp 236-237° C.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[C:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])([CH3:8])([CH3:7])[CH3:6].C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH3:7][C:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH:1]=[CH:2][CH3:3])([CH3:8])[CH3:6]
Reactant: CC(C)(C)c1ccccc1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC=COc1ccccc1C(C)(C)C
Temperature: 35 °C

Procedure:
Allyl bromide (69.2 ml), 2-t-butylphenol (122.9 ml) and potassium carbonate (121.6 g) were stirred in 265 ml of acetone at reflux temperature for 50 hours and then cooled to 35° C. Water (600 ml) was added and the resulting layers were separated. The aqueous layer was extracted with 600 ml of diethyl ether. The organic layer was combined with the aqueous layer's ether extract and the resulting solution was dried over sodium sulfate overnight. After sodium sulfate removal, the solvent was evaporated to provide, after further workup, 147 g of the subtitled intermediate.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.[CH3:12][O-:13].[Na+].Cl>CO>[CH3:12][O:13][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1
Reactant: C[O-]
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1ccc([N+](=O)[O-])c(O)c1
Temperature: 60 °C
Yield: 93 %

Procedure:
Part A: 5-Fluoro-2-nitrophenol (5.00 g, 31.8 mmol) and methanol (120 mL) were combined and the mixture was treated with sodium methoxide (4.6 mL, 190.8 mmol, 25% w/w solution in MeOH). The reaction mixture was heated at 60° C. for 40 h. The mixture was transferred to a separatory funnel containing cold 1 N HCl and the aqueous layer was extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated to afford 5-methoxy-2-nitrophenol (5.0 g, 93% yield) as a yellow solid: mp 93.0-94.0° C., 1H NMR (300 MHz, CDCl3): δ 11.05 (s, 1H), 8.03 (d, J=10.3 Hz, 1H), 6.55-6.51 (m, 2H), 3.89 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[CH:11]=[N:12][C:13]([N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:14][CH:15]=2)=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Br[C:23]1[N:28]=[C:27]([CH:29]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH2:30][OH:31])[CH:26]=[CH:25][CH:24]=1>>[OH:31][CH2:30][CH:29]([C:27]1[N:28]=[C:23]([NH:1][C:2]2[S:3][C:4]([C:10]3[CH:11]=[N:12][C:13]([N:16]4[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]4)=[CH:14][CH:15]=3)=[CH:5][C:6]=2[C:7]([NH2:9])=[O:8])[CH:24]=[CH:25][CH:26]=1)[N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1
Reactant: NC(=O)c1cc(-c2ccc(N3CCCCC3)nc2)sc1N
Reactant: OCC(c1cccc(Br)n1)N1CCOCC1
Product: NC(=O)c1cc(-c2ccc(N3CCCCC3)nc2)sc1Nc1cccc(C(CO)N2CCOCC2)n1

Procedure:
The title compound was prepared by using the procedure listed in Example 1 with 2-amino-5-(6-piperidin-1-ylpyridin-3-yl)thiophene-3-carboxamide (70 mg, 0.23 mmol) and 2-(6-bromopyridin-2-yl)-2-morpholin-4-ylethanol (Example 141, Step 1) (66 mg, 0.23 mmol) as the starting materials.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]([CH3:16])[C:5]([O:6][C:7]2[N:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[C:4]([Cl:17])[CH:3]=1.[O:18]1[CH:23]=[CH:22][CH2:21][CH2:20][CH2:19]1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>C(Cl)Cl.C1COCC1>[Br:1][C:2]1[CH:15]=[C:14]([CH3:16])[C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([O:13][CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23][O:18]3)=[CH:11][N:12]=2)=[C:4]([Cl:17])[CH:3]=1
Reactant: C1=COCCC1
Reactant: Cc1cc(Br)cc(Cl)c1Oc1ccc(O)cn1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1cc(Br)cc(Cl)c1Oc1ccc(OC2CCCCO2)cn1
Temperature: 25 °C
Reaction time: 95 h

Procedure:
To a solution of 6-(4-bromo-2-chloro-6-methylphenoxy)pyridin-3-ol (5.00 g) in CH2Cl2-THF (70 mL, 5:2) were added 3,4-dihydro-2H-pyran (4.35 mL) and PPTS (200 mg) at room temperature. After stirring at room temperature for 95 hours, the solvent was removed under reduced pressure. To the residue was added saturated aqueous NaHCO3, and extracted with AcOEt. The organic layer was washed with saturated aqueous NaCl, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=4/1 to 1/1) to give 2-(4-bromo-2-chloro-6-methyl-phenoxy)-5-(tetrahydro-2H-pyran-2-yloxy)pyridine as a yellow oil (6.30 g).
Reaction SMILES: Cl[CH2:2][C@@:3]([CH3:7])([OH:6])[CH2:4][OH:5].[H-].[Na+].[CH3:10][CH:11]([CH2:16][CH2:17][CH2:18][CH:19]([CH3:26])[CH2:20][CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:12][CH2:13][Mg]Br>O>[CH3:7][C@@:3]([OH:6])([CH2:2][CH2:13][CH2:12][CH:11]([CH3:10])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:26])[CH2:20][CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:4][OH:5]
Reactant: CC(C)CCCC(C)CCCC(C)CC[Mg]Br
Reactant: C[C@](O)(CO)CCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC(C)CCCC(C)CCCC(C)CCC[C@@](C)(O)CO
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.9 %

Procedure:
367 mg (3 mmol) of (2S)-3-chloro-2-methyl-1,2-propanediol were dissolved in 5 ml of dry tetrayhydrofuran and left to react at room temperature with 100 mg (7.2 mmol) of sodium hydride (55-60%) until the evolution of gas had finished. 350 mg of potassium tert.-butylate were added to the resulting thick suspension. Thereupon, 2.9 mmol of (3RS,7RS)-3,7,11-trimethyldodecylmagnesium bromide were added and the mixture was stirred at room temperature for 16 hours. 50 ml of water were subsequently added and the mixture was extracted with ether. The organic phases were dried over sodium sulphate and concentrated. There was obtained 0.81 g (96%) of (2R,6RS,10RS)-2,6,10,14-tetramethyl-1,2-pentadecanediol with [α]D20 =+1.35° (c=1.5% in CHCl3).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[H][H]>[Pd].C(O)C>[F:1][C:2]([F:20])([F:21])[CH:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCC(Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCCCCC(Oc1ccc(N)cc1)C(F)(F)F
Temperature: 25 °C

Procedure:
To 100 ml of dry ethanol containing 77.7 g of oa p-(1-trifluoromethyl-heptyloxy)-nitrobenzene, was added 0.5 g of 5% Pd/C (5% palladium carbon) followed by carrying out reduction within an atmosphere of hydrogen at normal pressure under stirring at room temperature. After it was confirmed that no absorption of hydrogen was observed, the catalyst was removed by filtration and then the ethanol was distilled off to obtain 6.7 g of oily oa p-(1-trifluoromethylheptyloxy)-aniline.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[N+:14]([O-])([OH:16])=[O:15]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:3]=[C:4]([N+:14]([O-:16])=[O:15])[C:5]([CH2:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: CCc1ccc(Cl)cc1C(=O)OC
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCc1c(C(=O)OC)cc(Cl)cc1[N+](=O)[O-]
Temperature: -5 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
A solution of methyl 5-chloro-2-ethylbenzoate (1.08 g, 5.4 mmol) in concentrated sulphuric acid (7.0 ml) was cooled to −5° C. in an acetone/ice bath. A mixture of 70% nitric acid (0.45 ml, 7.1 mmol) and concentrated sulphuric acid (0.5 ml) was added dropwise to the reaction mixture at −5° C. over 15 minutes. The resulting pale yellow reaction mixture was stirred at −5° C. for 1 hour before being poured onto ice (100 ml) and extracted with CH2Cl2 (3×20 ml). The combined organic phases were washed with deionized water (20 ml), brine (20 ml), dried over Na2SO4, filtered and concentrated in-vacuo. The resulting oil was added to a solution containing methanol (25 ml) and thionyl chloride (0.75 ml) at 0° C. Following addition, the mixture was heated under gentle reflux for 6 hours, before cooling to room temperature and concentrating in-vacuo to give the title compound (1.2 g) as an orange oil which was used without further purification in the next step.
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[C:9](=[O:10])[CH:8]=[CH:7][NH:6][C:5]1=[O:11].S(Cl)([Cl:14])=O>ClC(Cl)Cl>[Cl:14][CH2:2][CH2:3][N:4]1[C:9](=[O:10])[CH:8]=[CH:7][NH:6][C:5]1=[O:11]
Reactant: O=S(Cl)Cl
Reactant: O=c1cc[nH]c(=O)n1CCO
Solvent: ClC(Cl)Cl
Product: O=c1cc[nH]c(=O)n1CCCl
Reaction time: 1 h

Procedure:
To a stirred solution of 3 parts of 3-(2-hydroxyethyl)-2,4(1H,3H)-pyrimidinedione and 45 parts of trichloromethane were added dropwise 8 parts of thionyl chloride. Upon completion, stirring was continued for 1 hour at reflux temperature. The reaction mixture was cooled. The precipitated product was filtered off and crystallized from 2-propanol, yielding 3.1 parts of 3-(2-chloroethyl)-2,4(1H,3H)-pyrimidinedione; mp. 170° C. (60).
Reaction SMILES: Cl[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)[N:5]=[CH:4][CH:3]=1.[C:16]([O:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30][CH3:31])(=[O:24])[C:17]1[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[OH:19]>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:19][C:18]1[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=1[C:16]([O:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30][CH3:31])=[O:24]
Reactant: CC/C=C\CCOC(=O)c1ccccc1O
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: CC/C=C\CCOC(=O)c1ccccc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: 120 °C
Reaction time: 8 h
Yield: 63.7 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (112 mg), (Z)-3-hexenyl salicylate (440 mg), and 4-dimethylaminopyridine (244 mg) were suspended in o-dichlorobenzene (1 ml), and the suspension was stirred at 120° C. overnight. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (130 mg, yield 64%).
Reaction SMILES: [CH2:1]([O:9][N:10]1[C:15]([CH3:17])([CH3:16])[CH2:14][CH:13]([OH:18])[CH2:12][C:11]1([CH3:20])[CH3:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:21](OC)(=[O:24])[CH2:22][SH:23].[NH2-].[Li+]>C1(C)C=CC=CC=1>[C:21]([O:18][CH:13]1[CH2:14][C:15]([CH3:17])([CH3:16])[N:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:11]([CH3:19])([CH3:20])[CH2:12]1)(=[O:24])[CH2:22][SH:23]
Reactant: CCCCCCCCON1C(C)(C)CC(O)CC1(C)C
Reactant: COC(=O)CS
Agent: [Li+]
Agent: [NH2-]
Solvent: Cc1ccccc1
Product: CCCCCCCCON1C(C)(C)CC(OC(=O)CS)CC1(C)C

Procedure:
The general procedure of Example 1 is followed using 2.09 grams (7.0 mmol) of 1-octyloxy-4-hydroxy-2,2,6,6-tetramethylpiperidine, 0.74 gram (7.0 mmol) of methyl thioglycolate and 0.17 gram of lithium amide in 50 ml of toluene to afford the title compound after purification by silica gel chromatography.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=1)(=[O:4])=[O:3].[CH:16]([NH:19][CH2:20][CH2:21][NH2:22])([CH3:18])[CH3:17].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:22][CH2:21][CH2:20][NH:19][CH:16]([CH3:18])[CH3:17])(=[O:14])=[O:13])=[CH:8][CH:7]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)NCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)NCCNS(=O)(=O)c1ccc(NS(C)(=O)=O)cc1

Procedure:
4-methylsulfonamidobenzenesulfonyl chloride (2.70 g) was added portionwise to a 0.01 mole portion of N-isopropylethylenediamine and triethylamine (0.01 mole) in methylene chloride (250 ml) to obtain a white solid which precipitated from the methylene chloride reaction mixture 2.62 g, m.r. 180°-182° C. This solid was washed well with methylene chloride, dissolved in isopropanol/HCl/methanol and the methanol boiled away. The product was precipitated and filtered to yield 1.65 g, m.r. 158°-160° C.(d).