Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[NH:3]1[CH:7]=[N:6][CH:5]=[N:4]1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[C:16](\[CH2:22]OS(C2C=CC(C)=CC=2)(=O)=O)/[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:11][CH:10]=1.O>CN1CCCC1=O>[Cl:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[C:16](\[CH2:22][N:3]2[CH:7]=[N:6][CH:5]=[N:4]2)/[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:11][CH:10]=1
Reactant: c1nc[nH]n1
Reactant: Cc1ccc(S(=O)(=O)OC/C(=C\c2ccc(Cl)cc2)CC(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)(C)C/C(=C/c1ccc(Cl)cc1)Cn1cncn1
Temperature: 50 °C
Reaction time: 12 h
Yield: 70.5 %

Procedure:
9.2 g of sodium hydroxide are added to a solution of 16.8 g of 1,2,4-triazole in 150 ml of N-methylpyrrolidone and the mixture is heated at 50° C. for 30 minutes. After the reaction mixture has been cooled to room temperature, 73.1 g of Z-1-(4-chlorophenyl)-2-(4-methylphenylsulfonyloxymethyl)-4,4-dimethylpent-1-ene, dissolved in 100 ml of N-methylpyrrolidone, are slowly added dropwise to the solution and stirring is carried out for 12 hours at room temperature. Thereafter, 200 ml of water are added and the mixture is extracted several times with methyl tert-butyl ether, and the organic phase is washed twice with water, dried over sodium sulfate and evaporated down. The remaining residue is chromatographed over silica gel using 9:1 n-hexane/ethyl acetate to give 38 g (71%) of Z-1-(4-chlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-4,4-dimethylpent-1-ene, which can be crystallized from methyl tert-butyl ether/n-hexane (mp.: 81°-84° C., compound No. A1).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[S:12]([CH2:15][CH2:16][NH:17][CH2:18][C:19]1[O:20][CH:21]=[CH:22][CH:23]=1)(=[O:14])=[O:13].Cl[C:25]1C2C(=CC=CC=2)C=CC=1SCCNCC1OC(C)=CC=1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[S:12]([CH2:15][CH2:16][NH:17][CH2:18][C:19]1[O:20][C:21]([CH3:25])=[CH:22][CH:23]=1)(=[O:14])=[O:13]
Reactant: Cc1ccc(CNCCSc2ccc3ccccc3c2Cl)o1
Reactant: O=S(=O)(CCNCc1ccco1)c1ccc2ccccc2c1Cl
Product: Cc1ccc(CNCCS(=O)(=O)c2ccc3ccccc3c2Cl)o1
Yield: 59 %

Procedure:
Prepared as described for compound 25, from 2-[(1-chloronaphthalen-2-yl)sulfanyl]-N-[(5-methylfuran-2-yl)methyl]ethanamine in 59% yield as white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15]O)=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:17]N1C(=O)CCC1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][Br:17])=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: OCc1ccc(OCc2ccccc2)cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCc1ccc(OCc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 540 mg (2.51 mmol) 5-benzyloxy-2-pyridinemethanol (prepared according to J. Med. Chem. 1977, 20, 1258-1262), 536 mg N-bromo succinimide (3.01 mmol), and 1.2 g polymer bound triphenylphosphine (loading approx. 3 mmol/g, approx. 3.3 mmol) in dichloromethane (40 mL) was stirred overnight at room temperature. All solids were removed by filtration, and the filtrate was washed with aqueous sodium bicarbonate and water, and than concentrated in vacuo. The crude product (540 mg of a slightly pink solid, 79% crude yield) was used without further purification.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH3:11][NH:12][CH3:13].C(Cl)(Cl)Cl>C(N(CC)CC)C>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:12]([CH3:13])[CH3:11])=[O:7])=[CH:4][CH:3]=1
Reactant: CNC
Reactant: O=C(Cl)c1ccc(I)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CN(C)C(=O)c1ccc(I)cc1
Reaction time: 1 h
Yield: 94 %

Procedure:
4-Iodobenzoyl chloride (10.0 g) was added portionwise to dimethylamine (1.8 g) in triethylamine (40 ml) at 0°. The suspension was stirred at 0° for 1 h, treated with chloroform (200 ml), washed with aqueous sodium bicarbonate (1 M; 100 ml), dried and evaporated to give the title compound (9.7 g) m.p. 103°-106°.
Reaction SMILES: [CH:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][C:17]([CH:18]=[CH:19][C:20]([O:22]CC)=[O:21])=[CH:16][C:15]=3[C:31]([F:34])([F:33])[F:32])[CH:11]=2)[NH:6][CH:5]=1)([CH3:3])[CH3:2].[OH-].[Na+].Cl.C(OCC)(=O)C>O1CCOCC1>[CH:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[C:26]([C:27]([F:28])([F:29])[F:30])=[CH:25][C:17]([CH:18]=[CH:19][C:20]([OH:22])=[O:21])=[CH:16][C:15]=3[C:31]([F:34])([F:32])[F:33])[CH:11]=2)[NH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)C=Cc1cc(C(F)(F)F)c(Oc2ccc3[nH]cc(C(C)C)c3c2)c(C(F)(F)F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)c1c[nH]c2ccc(Oc3c(C(F)(F)F)cc(C=CC(=O)O)cc3C(F)(F)F)cc12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
0.23 g (0.46 mmol) of ethyl cinnamate derivative from Example 13 are dissolved in 10 ml of dioxane, 4 ml of 1 molar sodium hydroxide solution are added and the mixture is stirred for 5 hours at room temperature. The reaction solution is acidified to pH 4 using 1N hydrochloric acid, treated with ethyl acetate and the aqueous phase is extracted a further two times with ethyl acetate. The combined organic phases are washed with sodium chloride solution, dried over sodium sulphate, filtered, concentrated and dried overnight in a high vacuum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:4]=1[CH2:5][CH:6]1[NH:11][C:10](=O)[CH2:9][O:8][CH:7]1[CH2:13]2.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:1][O:2][C:3]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:4]=1[CH2:5][CH:6]1[NH:11][CH2:10][CH2:9][O:8][CH:7]1[CH2:13]2
Reactant: COc1cccc2c1CC1NC(=O)COC1C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cccc2c1CC1NCCOC1C2
Reaction time: 2 h
Yield: 91.2 %

Procedure:
To a solution of 6-methoxy-4a,5,10,10a-tetrahydro-4H-naphto[2,3-b][1,41oxazin-3-one (1.4 g, 6.0 mmol) in 100 ml of THF was added 10 ml of LiAlH4 solution in THF (10 mmol). The resulting solution was stirred for 2 h at reflux. The reaction was quenched with ice and the reaction mixture was then diluted with EtOAc. Filtration of the reaction mixture provided a clean organic layer which was concentrated in vacuo to yield 1.2 g (92%) of the desired product as a colorless oil. 1H NMR (300 MHz, CDCl3): δ 1.85 (s, 1H), 2.34 (dd, 1H, J=12.0, 17.0 Hz), 2.78-3.16 (m, 6H), 3.50 (ddd, 1H, J=5.2, 6.8, 10.5 Hz), 3.74 (m, 1H), 3.81 (s, 3H), 3.94 (m, 1H), 6.70 (m, 2H), 7.16 (t, 1H, J=7.6 Hz).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=O.[CH3:8][C:9]([S:12]([NH2:14])=[O:13])([CH3:11])[CH3:10]>C1COCC1.C(OCC)(=O)C.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[O:1]1[CH:5]=[CH:4][N:3]=[C:2]1/[CH:6]=[N:14]/[S:12]([C:9]([CH3:11])([CH3:10])[CH3:8])=[O:13]
Reactant: O=Cc1ncco1
Reactant: CC(C)(C)S(N)=O
Agent: [Ti+4]
Agent: CC[O-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)S(=O)/N=C/c1ncco1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.7 %

Procedure:
In a round-bottomed flask, oxazole-2-carbaldehyde (300 mg, 3.09 mmol) was dissolved in THF (7 ml) and 2-methylpropane-2-sulfinamide (450 mg, 3.71 mmol) and titanium(IV) ethoxide (1.3 ml, 6.18 mmol) were added. The reaction mixture was stirred at room temperature overnight then slowly quenched by dropwise addition of brine (2 ml) which resulted in the formation of a thick yellow precipitate. The reaction mixture was diluted with ethyl acetate and stirred vigorously at room temperature for 10 min. The suspension was filtered over Celite and rinsed with ethyl acetate. The filtrate was concentrated and the residue was chromatographed over silica gel with EtOAc/hexanes (gradient 0-30% EtOAc) to afford 419 mg (68%) of 2-methyl-propane-2-sulfinic acid 1-oxazol-2-yl-meth-(E)-ylideneamide as a light yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(#N)C>[CH2:18]([N:6]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:5]1[CH:7]=[C:8]([F:9])[C:2]([Br:1])=[CH:3][C:4]=1[F:10])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Nc1cc(F)c(Br)cc1F
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Fc1cc(N(Cc2ccccc2)Cc2ccccc2)c(F)cc1Br

Procedure:
To a mixture of 4-bromo-2,5-difluoroaniline (8 g, 39 mmol) and potassium carbonate (16 g, 116 mmol) in acetonitrile (200 mL) was added (bromomethyl)benzene (14.5 g, 85 mmol). After refluxing for 20 hours, the mixture was filtered and the filtrate was concentrated. The residue was purified by flash chromatography on silica gel (200-300 mesh) eluting with 5/1 petroleum ether/ethyl acetate to give the title compound. MS: 388 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH2:9][CH3:10])[C:6](=[O:11])[NH:5][C:4](=[O:12])[C:3]=1[NH:13][C:14]([C:16]12[CH2:23][CH:22]3[CH2:24][CH:18]([CH2:19][CH:20]1[CH2:21]3)[CH2:17]2)=[O:15].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:32][C:33](=[O:35])[CH3:34].O>CN(C)C=O>[NH2:1][C:2]1[N:7]([CH2:8][CH2:9][CH3:10])[C:6](=[O:11])[N:5]([CH2:32][C:33](=[O:35])[CH3:34])[C:4](=[O:12])[C:3]=1[NH:13][C:14]([C:16]12[CH2:17][CH:18]3[CH2:24][CH:22]([CH2:21][CH:20]1[CH2:19]3)[CH2:23]2)=[O:15]
Reactant: CCCn1c(N)c(NC(=O)C23CC4CC(CC2C4)C3)c(=O)[nH]c1=O
Reactant: CC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCn1c(N)c(NC(=O)C23CC4CC(CC2C4)C3)c(=O)n(CC(C)=O)c1=O
Yield: 66 %

Procedure:
To a solution of 2.20 g (6.63 mmol) of 6-amino-5-(3-tricyclo[3.3.1.03,7 ]nonylcarbonylamino)-1-propyluracil (Japanese Published Unexamined Patent Application No. 173889/91) in 35 ml of dimethylformamide, 3.24 g (9.95 mmol) of cesium carbonate, 1.23 ml (13.3 mmol) of bromoacetone were added with stirring. The reaction mixture was stirred at 60° C. for 3.5 hours. The mixture was cooled, poured into 100 ml of water and extracted three times with 30 ml of chloroform. The organic layer was washed with 0.2M sodium thiosulfate aqueous solution, with water, with a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluate: 2% methanol/chloroform) to give 1.70 g (yield 66%) of Compound I as a pale yellow powder.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[CH2:8]([N:14]1[C:23]2[C:18](=[CH:19][C:20]([CH3:24])=[CH:21][CH:22]=2)[C:17]([O:25][CH3:26])=[C:16]([CH2:27]Br)[C:15]1=[O:29])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>CN(C)C=O.C(OCC)(=O)C>[CH2:8]([N:14]1[C:23]2[C:18](=[CH:19][C:20]([CH3:24])=[CH:21][CH:22]=2)[C:17]([O:25][CH3:26])=[C:16]([CH2:27][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[C:15]1=[O:29])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: c1c[nH]cn1
Reactant: CCCCCCn1c(=O)c(CBr)c(OC)c2cc(C)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCn1c(=O)c(Cn2ccnc2)c(OC)c2cc(C)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of imidazole (0.07 g) in dimethylformamide (1.5 ml) was stirred with 60% sodium hydride (0.04 g) at ice-bath temperature under nitrogen until the reaction was complete. The reaction mixture was then treated with a solution of 1-hexyl-3-bromomethyl-4-methoxy-6-methyl-2(1H)-quinolinone (Example 14, 0.27 g) in dimethylformamide (3 ml) and stirred at room temperature for 2 hours. The solution was then diluted with ethyl acetate and washed several times with water. The organic layer was then dried and evaporated under reduced pressure. The crude reaction product was chromatographed on silica-gel (44 g). Elution with 2% methanoldichloromethane gave 1-hexyl-3-(1H-imidazol-1-ylmethyl)-4-methoxy-6-methyl-2(1H)-quinolinone which crystallized as a white solid. That the expected product was obtained was confirmed by the spectral data: MS: m/e 353 (M.+); NMR (CDCl3): δ3.90 (s, 3H, OCH3), 5,18 (s, 2H, CH2 -Im), 6.99, 7.14, 7.72 (s, 3H, CH=) wherein Im represents imidazole.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:25]#[N:26])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1)=[O:4].[NH2:27][CH2:28][C:29]([OH:31])=[O:30]>>[C:25]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:27][CH2:28][C:29]([OH:31])=[O:30])=[O:4])[N:6]=1)#[N:26]
Reactant: NCC(=O)O
Reactant: COC(=O)c1nc(C#N)c2c(Oc3cccc(OC)c3)cccc2c1O
Product: COc1cccc(Oc2cccc3c(O)c(C(=O)NCC(=O)O)nc(C#N)c23)c1

Procedure:
The title compound was synthesized from 1-cyano-4-hydroxy-8-(3-methoxy-phenoxy)-isoquinoline-3-carboxylic acid methyl ester and glycine in analogy to example 1b; MS-(−)-ion: M−1=392.4.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH:18]([CH3:20])[CH3:19])[C:9]([N:11]2[C:15](=[O:16])[NH:14][C:13](=[O:17])[O:12]2)=[O:10])=[CH:4][CH:3]=1.[CH:21](OC(OC(C)C)OC(C)C)([CH3:23])[CH3:22]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH:18]([CH3:20])[CH3:19])[C:9]([N:11]2[C:15](=[O:16])[N:14]([CH:21]([CH3:23])[CH3:22])[C:13](=[O:17])[O:12]2)=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C)OC(OC(C)C)OC(C)C
Reactant: CC(C)N(C(=O)n1oc(=O)[nH]c1=O)c1ccc(F)cc1
Product: CC(C)N(C(=O)n1oc(=O)n(C(C)C)c1=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
A solution of the compound of Step A (1.0 g, 3.6 mmol) in 20 mL of triisopropylorthoformate was heated at 145° C. for 2 h and then allowed to stir at ambient temperature overnight. The volatiles were removed under reduced pressure, and the residue recrystallized from methanol to give 0.99 g (86%) of the title compound, a compound of this invention, as a solid melting at 78-80° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8](Cl)=[O:9])([CH3:4])([CH3:3])[CH3:2].[OH:19][CH2:20][C:21]1[CH:32]=[CH:31][C:24]([C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26])=[CH:23][CH:22]=1>>[C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26])=[CH:31][CH:32]=1)=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1O
Reactant: C=CCOC(=O)c1ccc(CO)cc1
Product: C=CCOC(=O)c1ccc(COC(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc1

Procedure:
In a manner similar to Example 1(d), by reaction of 7.7 g (28.6 mmol) of 3,5-di-tert-butyl-4-hydroxybenzoyl chloride with 5.5 g (28.6 mmol) of allyl 4-hydroxymethylbenzoate, 4.1 g (34%) of the expected allyl ester, melting point 100°-1° C., are obtained.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=2)[CH2:9][OH:10])[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH3:14][S:15](Cl)(=[O:17])=[O:16].C(N(CC)CC)C>C(Cl)Cl>[CH3:14][S:15]([O:10][CH2:9][C:8]1[CH:11]=[CH:12][CH:13]=[C:6]([N:1]2[CH:5]=[CH:4][CH:3]=[CH:2]2)[CH:7]=1)(=[O:17])=[O:16]
Reactant: OCc1cccc(-n2cccc2)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1cccc(-n2cccc2)c1
Reaction time: 1 h
Yield: 93.3 %

Procedure:
170 mg of the resulting alcohol compound was dissolved in 10 ml of methylene chloride, and 120 mg of methanesulfonyl chloride and 150 mg of triethylamine were added. The mixture was stirred for 1 hour under ice cooling. The reaction mixture was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated to give 230 mg (yield 92%) of the captioned compound as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][CH2:6][CH2:7]Br)[CH3:2].[Cl:10][C:11]1[CH:21]=[CH:20][C:14]([CH2:15][NH:16][C:17](=[S:19])[S-:18])=[CH:13][CH:12]=1.[NH4+]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:9])[CH2:5][CH2:6][CH2:7][S:19][C:17](=[S:18])[NH:16][CH2:15][C:14]1[CH:20]=[CH:21][C:11]([Cl:10])=[CH:12][CH:13]=1)[CH3:2]
Reactant: S=C([S-])NCc1ccc(Cl)cc1
Reactant: CCOC(=O)CCCBr
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCSC(=S)NCc1ccc(Cl)cc1

Procedure:
To a solution of 160 g. of 4-bromobutyric acid ethyl ester in 1125 ml. of absolute dimethylformamide were added gradually under an atmosphere of argon at 0° C. while stirring well and cooling, 172.3 g. of ammonium (N-4-chlorobenzyl)dithiocarbamate, the temperature was maintained constant. The slightly yellow solution was stirred overnight at room temperature, diluted with 1500 ml. of water and extracted four times with 500 ml. of ethyl acetate each time. The combined organic phases were washed three times with 200 ml of saturated sodium chloride solution each time and dried over 80 g. of magnesium sulfate with the addition of carbon, filtered and evaporated under reduced pressure. The resulting crystalline residue was recrystallized from 700 ml. of diisopropyl ether, and 218 g. of 4-{[(p-chlorobenzyl)thiocarbamoyl]thio}-butyric acid ethyl ester having a melting point of 61°-62° C. was obtained.
Reaction SMILES: [F:1][CH2:2][C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[O:18][N:17]=[C:16]([CH2:19]OS(C)(=O)=O)[CH:15]=3)=[CH:10][CH:9]=2)[O:6][C:5]([CH3:26])([CH3:25])[N:4]1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].[OH-].[NH4+:35]>O1CCOCC1>[NH2:35][CH2:19][C:16]1[CH:15]=[C:14]([C:11]2[CH:10]=[CH:9][C:8]([C@H:7]3[O:6][C:5]([CH3:26])([CH3:25])[N:4]([C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])[C@@H:3]3[CH2:2][F:1])=[CH:13][CH:12]=2)[O:18][N:17]=1
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(-c3cc(COS(C)(=O)=O)no3)cc2)OC1(C)C
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(-c3cc(CN)no3)cc2)OC1(C)C
Temperature: 35 °C
Reaction time: 12 h

Procedure:
To a dioxane (10 ml) solution of (4S,5R)-tert-butyl 4-(fluoromethyl)-2,2-dimethyl-5-(4-(3-((methylsulfonyloxy)methyl)isoxazol-5-yl)phenyl)oxazolidine-3-carboxylate (1.0 g, 2.1 mmol) is added 30% aqueous ammonium hydroxide solution (5 ml). The mixture is stirred at 35° C. for 12 hours. The product is partitioned between water (50 ml) and methylene chloride (25 ml). The organic phase is dried (sodium sulfate) and concentrated to give the title compound (685 mg): m/z (Cl) 406 ([M+H]+.
Reaction SMILES: [C:1]([C:3](=[C:7](SC)[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][NH2:27])=[CH:22][CH:21]=1.[OH-].[Na+]>>[NH2:2][C:1]1[N:26]([C:23]2[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)[N:27]=[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: CSC(=C(C#N)C(N)=O)c1ccc(C)cc1
Reactant: COc1ccc(NN)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(-n2nc(-c3ccc(C)cc3)c(C(N)=O)c2N)cc1
Yield: 31.3 %

Procedure:
The title compound was prepared from 2-cyano-3-methylthio-3-(4-tolyl) acrylamide (232 mg, 1.0 mmol), 4-methoxyphenylhydrazine hydrochloride (192 mg, 1.1 mmol) and sodium hydroxide (44 mg, 1.1 mmol) following the procedure used for the compound of Example 12. The crude product was purified by chromatography (SiO2, 75% ethyl acetate in hexane) and recrystallisation from ethyl acetate-hexane to give the title compound as white crystals (101 mg) m.p. 174-175°. δH (d6DMSO) 7.49-7.43 (4H, m), 7.28 (2H, d, J 7.8 Hz), 7.07 (2H, d, J 8.9 Hz), 6.32 (2H, br s), 3.81 (3H, s) and 2.29 (3H, s), one set of amino protons not observed. MS (ES+) 323 (MH+, 100%).
Reaction SMILES: C[Al](C)C.[CH2:5]([N:7]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[N:19]=[CH:18][C:17]([C:20]([O:22]C)=O)=[CH:16][N:15]=2)[CH2:9][CH2:8]1)[CH3:6].[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH2:34][CH2:35][C:36]2[CH:37]=[C:38]([NH2:41])[NH:39][N:40]=2)[CH:29]=[C:30]([O:32][CH3:33])[CH:31]=1>C1(C)C=CC=CC=1>[CH3:33][O:32][C:30]1[CH:29]=[C:28]([CH2:34][CH2:35][C:36]2[CH:37]=[C:38]([NH:41][C:20]([C:17]3[CH:18]=[N:19][C:14]([N:10]4[CH2:11][CH2:12][CH2:13][N:7]([CH2:5][CH3:6])[CH2:8][CH2:9]4)=[N:15][CH:16]=3)=[O:22])[NH:39][N:40]=2)[CH:27]=[C:26]([O:25][CH3:24])[CH:31]=1
Reactant: CCN1CCCN(c2ncc(C(=O)OC)cn2)CC1
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CCN1CCCN(c2ncc(C(=O)Nc3cc(CCc4cc(OC)cc(OC)c4)n[nH]3)cn2)CC1
Temperature: 60 °C
Reaction time: 18 h
Yield: 21.7 %

Procedure:
Trimethylaluminium (1.25 ml, 2.50 mmol) was added dropwise to a stirred suspension of methyl 2-(4-ethyl-1,4-diazepan-1-yl)pyrimidine-5-carboxylate (265 mg, 1.00 mmol) and 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (248 mg, 1.00 mmol) in toluene (5.01 ml) at 25° C. The resulting solution was stirred at 60° C. for 18 h. The cooled reaction mixture was quenched into methanol (50 mL) and treated with HCl (2M aqueous solution, to pH7 or lower) and purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH and evaporated to dryness to afford impure product. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing desired product still contained an impurity, so they were concentrated to dryness and purified by crystallisation from MeCN to afford the title compound (104 mg, 22%) as a cream solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([CH2:10][O:11][CH:12]3[CH:17]([C:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH2:29][C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=5[O:36][CH3:37])=[CH:20][CH:19]=4)[CH2:16][CH2:15][N:14]([C:38]([O:40][CH2:41][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)=[O:39])[CH2:13]3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Cl[CH2:49][CH2:50][CH2:51][O:52][CH3:53]>>[CH3:37][O:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[CH2:29][O:28][CH2:27][CH2:26][CH2:25][O:24][C:21]1[CH:20]=[CH:19][C:18]([CH:17]2[CH2:16][CH2:15][N:14]([C:38]([O:40][CH2:41][C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)=[O:39])[CH2:13][CH:12]2[O:11][CH2:10][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH:3]=[CH:2][N:1]3[CH2:49][CH2:50][CH2:51][O:52][CH3:53])=[CH:23][CH:22]=1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCc2cccc3[nH]ccc23)cc1
Reactant: COCCCCl
Product: COCCCn1ccc2c(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCCCOCc4ccccc4OC)cc3)cccc21

Procedure:
Analogously to Example 10a, 0.148 g of benzyl 3-(1H-indol-4-ylmethoxy)-4-{4-[3-(2-methoxy-benzyloxy)propoxy]phenyl}piperidine-1-carboxylate (Example 10b2) and 0.110 ml of 1-chloro-3-methoxypropane are reacted. The title compound is obtained as a slightly yellowish oil. Rf=0.25 (1:1 EtOAc-heptane); Rt=27.24 min (II).
Reaction SMILES: C(C1[O:6][C:7]2[C:13]([S:14]([N:17]3[CH2:23][CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)(=[O:16])=[O:15])=[C:12]([Cl:24])[CH:11]=[CH:10][C:8]=2[N:9]=1)(C)(C)C.O.OS(O)(=O)=O.[OH-].[Na+]>O1CCOCC1>[NH2:9][C:8]1[C:7]([OH:6])=[C:13]([S:14]([N:17]2[CH2:23][CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)(=[O:16])=[O:15])[C:12]([Cl:24])=[CH:11][CH:10]=1
Reactant: CC(C)(C)c1nc2ccc(Cl)c(S(=O)(=O)N3CCCNCC3)c2o1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Nc1ccc(Cl)c(S(=O)(=O)N2CCCNCC2)c1O
Temperature: 100 °C
Yield: 80.2 %

Procedure:
To a solution of 2-tert-Butyl-6-chloro-7-(homopiperazine-1-sulfonyl)-benzooxazole (2.0 g, 4.24 mmol) in 1,4-dioxane (56 mL) was treated with water (3.5 mL) and conc. H2SO4 (3.5 mL). The mixture was heated to 100° C. for 16 h. The reaction was cooled to room temperature, and then basified to pH=14 with 25% aq NaOH. washed. The mixture was extracted with ethyl acetate (3 times), dried with MgSO4, filtered, and concentrated to afford the title compound (1.04 g, 80%). EI-MS m/z 306.2(M+).