Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH2:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:17][O:18][C:19](Cl)=[O:20]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:19](=[O:20])[O:18][CH3:17])=[CH:4][CH:3]=1
Reactant: NCc1ccc(Br)cc1
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)NCc1ccc(Br)cc1
Temperature: 0 °C

Procedure:
1-(4-bromophenyl)methanamine (300 mg, 1.612 mmol) was taken up in dichloromethane (8062 μl) and triethylamine (225 μl, 1.612 mmol) was added. The solution was cooled to 0° C. and methyl chloridocarbonate (118 μl, 1.612 mmol) was added dropwise. The reaction was allowed to warm to room temperature overnight. It was quenched with aqueous sodium bicarbonate and extracted using ethyl acetate (3×). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification was performed via silica gel chromatography (50-100% ethyl acetate in hexanes) to yield the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:14]([OH:16])=O)[CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:18][N:19](C)[OH:20].[CH3:22]N1CCOCC1.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CCOC(C)=O>[CH3:22][O:20][N:19]([CH3:18])[C:14]([C:9]1([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10][CH2:11][CH2:12][CH2:13]1)=[O:16]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCCC1
Reactant: CN(C)O
Reactant: CN1CCOCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CON(C)C(=O)C1(NC(=O)OC(C)(C)C)CCCC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 1-[(tert-butoxycarbonyl)amino)cyclopentanecarboxylic acid (5.89 g, 25.68 mmol) in CH2Cl2 (25 mL) were added dimethylhydroxylamine hydrochloride (2.51 g, 25.68 mmol) and N-methylmorpholine (2.82 mL, 25.68 mmol), sequentially. The mixture was cooled to 0° C., treated with 1.0M DCC in CH2Cl2, and stirred under an atmosphere of nitrogen while warning to room temperature overnight. The mixture was filtered, washing with CH2Cl2, and the resulting filtrate was concentrated in vacuo to afford an oil. The oil was re-suspended in EtOAc, and the mixture was filtered once more. The resulting filtered was subjected to column chromatography eluting with a gradient of 0-100% EtOAc/hexanes. Collection and concentration of the appropriate fractions afforded the product as an opaque white solid.
Reaction SMILES: [N:1]([CH:4]([CH3:6])[CH3:5])=[C:2]=[O:3].Cl.[CH3:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[C:19]([C:21]3[CH:30]=[C:29]4[C:24]([CH2:25][CH2:26][NH:27][CH2:28]4)=[CH:23][CH:22]=3)[N:18]=[C:17]([NH2:31])[N:16]=2)[CH2:11][CH2:10]1>>[NH2:31][C:17]1[N:18]=[C:19]([C:21]2[CH:30]=[C:29]3[C:24]([CH2:25][CH2:26][N:27]([C:2]([NH:1][CH:4]([CH3:6])[CH3:5])=[O:3])[CH2:28]3)=[CH:23][CH:22]=2)[CH:20]=[C:15]([N:12]2[CH2:11][CH2:10][N:9]([CH3:8])[CH2:14][CH2:13]2)[N:16]=1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Reactant: CC(C)N=C=O
Agent: Cl
Product: CC(C)NC(=O)N1CCc2ccc(-c3cc(N4CCN(C)CC4)nc(N)n3)cc2C1

Procedure:
This compound was prepared from 2-isocyanatopropane and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt using procedures analogous to those for Example 5. Analytic LCMS (M+H)+: m/z=410.4.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C(=O)([O-])[O-].[K+].[K+].Br[CH:20]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].CS(C)=O>O>[C:24]([O:23][C:21]([CH:20]([O:1][N:2]1[C:3](=[O:12])[C:4]2=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]2[C:6]1=[O:7])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC(C)(C)OC(=O)C(Br)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)C(ON1C(=O)c2ccccc2C1=O)c1ccccc1
Reaction time: 18 h
Yield: 77.3 %

Procedure:
(a)(i) A mixture of N-hydroxyphthalimide (24.5 g), anhydrous potassium carbonate (16.5 g), t-butyl α-bromophenylacetate (41 g) and dimethylsulphoxide (225 ml) was stirred for 18 hours and was then poured into water (1.2 liters). The precipitated solid was filtered off, washed well with water, dried, and crystallised from industrial methylated spirits to give N-[α-(t-butoxycarbonyl) benzyloxy] phthalimide (41 g, 78%); m.p. 120.6°-121.5°.
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][CH2:5][C@@H:6]([NH2:8])[CH3:7].C(N(CC)CC)C.[C:16](N1C=CN=C1)(N1C=CN=C1)=[S:17].Cl>C1COCC1.C(OCC)(=O)C>[N:8]([C@@H:6]([CH3:7])[CH2:5][CH2:4][O:3][CH3:2])=[C:16]=[S:17]
Reactant: COCC[C@H](C)N
Reactant: S=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COCC[C@H](C)N=C=S
Reaction time: 8 h
Yield: 95.8 %

Procedure:
(S)-4-Methoxybutan-2-amine hydrochloride (25.4 g, 181.92 mmol) is suspended in THF (609 mL) and triethylamine (TEA, 32.17 mL, 230.78 mmol) is added. 1,1′-Thiocarbonyldiimidazole (46.74 g, 251.76 mmol) is added to the white suspension (slightly exothermic reaction) and the resulting yellow suspension is stirred under a nitrogen atmosphere overnight. Ethyl acetate (500 mL) is added to the yellow suspension, followed by 1 N HCl (500 mL). The organic phase is separated and washed with 1 N HCl (3×200 mL), water (200 mL), and brine (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the title compound (25.3 g, 83%) as a yellow oil. 1H NMR (400 MHz, CDCl3); δ 1.37 (3H, d, J=6.6 Hz), 1.83 (2H, q, J=6.6 Hz), 3.35 (3H, s), 3.6-3.4 (2H, m), 3.99 (1H, six, J=6.6 Hz).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[N:10]=[CH:9][N:8]([CH2:12][CH3:13])[C:7]=2[C:6](=[O:14])[NH:5][C:4]1=[O:15])[CH3:2].Cl[CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:24])([CH3:23])[CH3:22]>>[CH2:1]([N:3]1[C:11]2[N:10]=[CH:9][N:8]([CH2:12][CH3:13])[C:7]=2[C:6](=[O:14])[N:5]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:24])([CH3:23])[CH3:22])[C:4]1=[O:15])[CH3:2]
Reactant: CC(C)(O)CCCCCl
Reactant: CCn1cnc2c1c(=O)[nH]c(=O)n2CC
Product: CCn1cnc2c1c(=O)n(CCCCC(C)(C)O)c(=O)n2CC

Procedure:
This compound was obtained according to the method described in Example 1 starting from 3,7-diethylxanthine and 1-chloro-5-hydroxy-5-methylhexane and recrystallizing the final product from diisopropylether.
Reaction SMILES: COC(OC)C=O.[F:8]/[C:9](=[C:13](/[CH3:19])\[CH:14]([O:17][CH3:18])[O:15][CH3:16])/[C:10]([O-])=[O:11].[H-].C([Al+]CC(C)C)C(C)C>>[F:8]/[C:9](=[C:13](/[CH3:19])\[CH:14]([O:15][CH3:16])[O:17][CH3:18])/[CH:10]=[O:11]
Reactant: COC(OC)/C(C)=C(\F)C(=O)[O-]
Agent: CC(C)C[Al+]CC(C)C
Agent: COC(C=O)OC
Agent: [H-]
Product: COC(OC)/C(C)=C(\F)C=O

Procedure:
The 6-fluoro octatrienoate is prepared by reacting triethyl phosphono fluoroacetate with glyoxal dimethyl acetal and the resulting reaction product, a mixture of ethyl E and Z-2-fluoro-4,4-dimethoxy-3-methyl-2-butenoate, is reduced with di-isobutyl aluminum hydride in the cold to form Z-2-fluoro-3-methyl-4,4-dimethoxy-2-buten-1-al. The latter compound is then reacted via a Horner reaction with a compound of the formula ##STR38## or via a Wittig reaction with ##STR39## wherein X is halogen to form a compound of the formula ##STR40## The latter compound is then treated with hydrochloric acid and diethyl ether to form the 6-fluoro octatrienoate depicted.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][O:10][N:9]=2)=[CH:4][CH:3]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17].C(N(CC)CC)C>ClCCl>[C:16]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][O:10][N:9]=2)=[CH:6][CH:7]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1conc1-c1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Oc1ccc(-c2nocc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.6 %

Procedure:
To a solution (120 ml) of 3-(4-hydroxyphenyl)isoxazole-4-carboxylic acid (1.39 g, 6.77 mmol) in dichloromethane were added acetic anhydride (2.07 g, 20.28 mmol), triethylamine (3.43 g, 33.90 mmol), and 4-N,N-dimethylaminopyridine (84 mg, 0.676 mmol), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and water was added. The mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (ethyl acetate) to give the title compound (1.50 g, 78%).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:13]([NH:15][C@H:16]([C:20]([NH:22][C@H:23]([C:34]([OH:36])=[O:35])[CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27][CH:26]=1)=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[CH:10]([CH3:12])[CH3:11])=O)(C)(C)C.C(O)(=O)C.[ClH:41].O>O1CCOCC1>[ClH:41].[NH2:8][C@H:9]([C:13]([NH:15][C@H:16]([C:20]([NH:22][C@H:23]([C:34]([OH:36])=[O:35])[CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27][CH:26]=1)=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[CH:10]([CH3:11])[CH3:12]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)C(C)C
Agent: Cl
Solvent: CC(=O)O
Solvent: C1COCCO1
Solvent: O
Product: CC(C)[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)C(C)C

Procedure:
The title compound was prepared using the previously described process using the following reagants: 0.85 grams (1.7 mmoles) t-butyloxycarbonyl-Valyl-valyl-tryptophan, 6 ml glacial acetic acid and 3 ml 5.68 N HCl in dioxane Total yield was 0.75 grams (100 percent). Anaylsis calculated for C21H30N4O4.HCl.1/3 H2O: C, 56.69; H, 7.17; N, 12.59. Found: C, 57.06; H, 7.3; N, 12.17.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.C(O)(=O)[CH2:15][C:16]([OH:18])=[O:17]>>[F:1][C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[CH:15][C:16]([OH:18])=[O:17]
Reactant: O=Cc1ccc(C(F)(F)F)cc1F
Reactant: O=C(O)CC(=O)O
Product: O=C(O)C=Cc1ccc(C(F)(F)F)cc1F

Procedure:
According to the previously described general procedure (GP1), Knoevenagel condensation (75° C.; 3h20) between 2-fluoro-4-(trifluoromethyl)benzaldehyde (5.000 g; 26.027 mmol) and malonic acid (5.145 g; 49.451 mmol) gave the product 3-(2-fluoro-4-trifluoromethyl-phenyl)-acrylic acid as a colorless solid (5.030 g; 82.5%). LC-MS: tR=0.89 min; [M+H]+: no ionisation.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:11]=[N:12][CH:13]=[C:14]([O:16][CH3:17])[CH:15]=2)=[CH:4][C:3]=1[NH2:18].N1C=CC=CC=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:11]=[N:12][CH:13]=[C:14]([O:16][CH3:17])[CH:15]=2)=[CH:4][C:3]=1[NH:18][S:26]([CH3:25])(=[O:28])=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cncc(C#Cc2ccc(F)c(N)c2)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cncc(C#Cc2ccc(F)c(NS(C)(=O)=O)c2)c1
Temperature: 0 °C
Reaction time: 14 h
Yield: 57.4 %

Procedure:
Dissolve 2-fluoro-5-(5-methoxypyridin-3-ylethynyl)-phenylamine, (prepared as described in EXAMPLE 111), (330 mg, 1.36 mmol) in dichloromethane (10 mL) under nitrogen and cool to 0° C. Add pyridine (0.240 ml, 2.99 mmol) followed by methanesulfonyl chloride (0.106 mL, 1.36 mmol) dropwise via syringe. Stir 14 h while allowing to warn to room temperature. Concentrate and purify by silica gel chromatography, eluting with 80:20 ethyl acetate:hexanes to 100% ethyl acetate, to give the title compound as a white solid (250 mg, 57%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][CH2:14][CH3:15])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([Cl:12])=[CH:7]2.[C:16](OCC)(OCC)(OCC)[CH3:17]>>[CH3:15][C:14]1[N:13]([CH2:16][CH3:17])[C:3]2[CH:4]=[CH:5][C:6]3[CH:7]=[C:8]([Cl:12])[CH:9]=[N:10][C:11]=3[C:2]=2[N:1]=1
Reactant: CCNc1ccc2cc(Cl)cnc2c1N
Reactant: CCOC(C)(OCC)OCC
Product: CCn1c(C)nc2c3ncc(Cl)cc3ccc21
Temperature: 25 °C

Procedure:
14 g (64 mmol) of 8-amino-3-chloro-7-ethylaminoquinoline and 42 g (0.26 mol) of triethyl orthoacetate are stirred at 100° C. for 1 hour. The mixture is allowed to cool to room temperature, excess orthoester is evaporated off, and the residue is recrystallized from ethyl acetate.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:14]([CH2:20][CH2:21][CH2:22][CH3:23])=[N:13][C:7]=3[C:8]([NH2:12])=[N:9][C:10]=2[CH:11]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:20]([C:14]1[N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:6]2[C:5]3[CH:4]=[CH:3][C:2]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:11][C:10]=3[N:9]=[C:8]([NH2:12])[C:7]=2[N:13]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCCc1nc2c(N)nc3cc(Br)ccc3c2n1CC(C)C
Reactant: OB(O)c1ccccc1
Product: CCCCc1nc2c(N)nc3cc(-c4ccccc4)ccc3c2n1CC(C)C

Procedure:
7-Bromo-2-butyl-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine and benzeneboronic acid were coupled according to the general procedure described in Part J of Example 1. Purification by chromatography on silica gel (20% acetone in toluene to 60% acetone in toluene gradient) afforded 2-butyl-1-isobutyl-7-phenyl-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, m.p.>250° C.
Reaction SMILES: [CH3:1][O:2][C:3]([OH:6])([OH:5])[CH3:4].C(O)(=O)[C:8]1[CH:13]=[CH:12][CH:11]=CC=1>>[CH3:1][O:2][C:3]1([CH3:4])[O:6][CH:12]2[CH:11]([CH2:8][CH2:13]2)[O:5]1
Reactant: COC(C)(O)O
Reactant: O=C(O)c1ccccc1
Product: COC1(C)OC2CCC2O1
Yield: 965.7 %

Procedure:
88.0 g (1.0 mol) of cyclobutane-cis-1,2-diol, 120.0 g (1.0 mol) of orthoacetic acid methyl ester and 10.0 g of benzoic acid are heated from 80° to 120° C. in the course of 3 hours. Methanol which forms is distilled off continuously. Fractional distillation gives 114.0 g (79%) of 3-methoxy-3-methyl-2,4-dioxa-bicyclo[3,2,0]heptane (stereoisomer mixture) of boiling point12 52°-53°.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[O:10].[Br:11]N1C(C)(C)C(=O)N(Br)C1=O.FC(F)(F)S(O)(=O)=O>ClCCl>[Br:11][C:7]1[CH:8]=[CH:9][C:4]2[NH:3][C:2](=[O:10])[O:1][C:5]=2[CH:6]=1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: O=c1[nH]c2ccccc2o1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1[nH]c2ccc(Br)cc2o1
Reaction time: 1 h

Procedure:
A mixture of 2-benzoxazolinone (3.00 g, 22.2 mmol), 1,3-dibromo-5,5-dimethylhydantoin (3.49 g, 12.2 mmol), and trifluoromethanesulfonic acid (5.00 g, 33.3 mmol) in dichloromethane (100 mL) at room temperature was protected from light, stirred for 1 hour, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 50% ethyl acetate/hexanes to provide the desired product.
Reaction SMILES: FC(F)(F)C(O)=O.CSC.C([O:18][C:19]1[CH:34]=[CH:33][CH:32]=[CH:31][C:20]=1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]#[N:30])=[CH:24][CH:23]=1)C1C=CC=CC=1>O>[OH:18][C:19]1[CH:34]=[CH:33][CH:32]=[CH:31][C:20]=1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]#[N:30])=[CH:24][CH:23]=1
Reactant: N#CCc1ccc(Cc2ccccc2OCc2ccccc2)cc1
Solvent: CSC
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: N#CCc1ccc(Cc2ccccc2O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
Trifluoroacetic acid (17 mL), water (1 mL) and dimethyl sulfide (2 mL) were added to [4-(2-benzyloxybenzyl)-phenyl]acetonitrile (0.41 g), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=3/1) to give [4-(2-hydroxybenzyl)phenyl]acetonitrile (0.26 g).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][CH:22]=1)[O:6][CH2:7][C:8]1[N:9]=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:11][C:12]=1[CH3:13].[OH:23][N:24]1[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]2[C:25]1=[O:34].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:13][C:12]1[O:11][C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:9][C:8]=1[CH2:7][O:6][C:5]1[CH:4]=[C:3]([CH:22]=[CH:21][CH:20]=1)[CH2:2][O:23][N:24]1[C:25](=[O:34])[C:26]2=[CH:33][CH:32]=[CH:31][CH:30]=[C:27]2[C:28]1=[O:29]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: Cc1oc(-c2ccccc2)nc1COc1cccc(CCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccccc2)nc1COc1cccc(CON2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 90.6 %

Procedure:
A mixture of 4-(3-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (8.00 g), N-hydroxyphthalimide (4.13 g), potassium carbonate (7.05 g) and N,N-dimethylformamide (80 ml) was stirred at room temperature for 20 hours and water (800 ml) was added. The resultant crystals were filtered and washed with water to obtain N-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]phthalimide (10.1 g, yield 90%) as pale-brown crystals. m.p. 146-147° C.
Reaction SMILES: [CH3:1][CH:2]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:8]=1)[CH2:3][NH2:4].C1(O[C:27](=[O:35])OC2C=CC=CC=2)C=CC=CC=1.O.[NH2:37][NH2:38]>C(O)C>[CH3:1][CH:2]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:8]=1)[CH2:3][NH:4][C:27]([NH:37][NH2:38])=[O:35]
Reactant: NN
Reactant: CC(CN)COc1cccc(CN2CCCCC2)c1
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Solvent: O
Solvent: CCO
Product: CC(CNC(=O)NN)COc1cccc(CN2CCCCC2)c1

Procedure:
2.2 g (8 mmol) of 2-methyl-3-[3-(1-piperidinylmethyl)phenoxy]-1-propanamine in 20 ml of ethanol are stirred together with 1.9 g (8 mmol) of diphenylcarbonate at room temperature for 12 hours. 4 g of hydrazine hydrate is then added to the solution and the reaction mixture is heated under reflux for one hour. Isolation of the product is carried out as described in Example 1.
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:7]=[C:8]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4].C(O)(=O)C.[CH3:22][C:23](=O)[CH2:24][CH3:25].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH:23]([N:15]1[CH2:16][CH2:17][CH:12]([C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([S:3]([CH3:2])(=[O:5])=[O:4])[CH:7]=2)[CH2:13][CH2:14]1)([CH2:24][CH3:25])[CH3:22]
Reactant: CS(=O)(=O)c1cccc(C2CCNCC2)c1
Reactant: CCC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCC(C)N1CCC(c2cccc(S(C)(=O)=O)c2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
4-(3-methanesulfonyl-phenyl)-piperidine hydrochloride (20 mg), glacial acetic acid (4.4 mg) and 2-butanone (5.1 mg) were mixed in 1,2-dichloroethane (5 mL). Sodium triacetoxyborohydride (23.5 mg) was added to the solution and the reaction mixture was stirred at room temperature under a nitrogen atmosphere for 5 h (G.L.C. analysis indicated a complete reaction). The reaction was quenched with saturated aqueous NaHCO3 and the product was extracted with CH2Cl2. The combined organic phases were dried (MgSO4), filtered, and the solvent was evaporated to afford 1-sec-butyl-4-(3-methanesulfonyl-phenyl)-piperidine as an oily residue. The product was chromatographed on a silica column with CH2Cl2:MeOH (9:1 (v/v)) as eluent. Collection of the fractions containing pure product and evaporation of the solvent afforded pure amine (15 mg, 71%); MS m/z (relative intensity, 70 eV) 295 (M+, 1), 280 (7), 266 (bp), 187 (4), 129 (4).
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)(=[O:4])[CH2:2][CH3:3].[C:11](=[O:16])([O:14][CH3:15])OC.C[O-].[Na+].Cl>O.C(OCC)(=O)C>[O:8]1[CH2:9][CH2:10][CH:5]([C:1](=[O:4])[CH:2]([CH3:3])[C:11]([O:14][CH3:15])=[O:16])[CH2:6][CH2:7]1
Reactant: COC(=O)OC
Reactant: CCC(=O)C1CCOCC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)C(C)C(=O)C1CCOCC1
Temperature: 7.5 °C
Yield: 33.3 %

Procedure:
In a flask made of glass having an inner volume of 100 ml and equipped with a stirring device, a thermometer, a dropping funnel and a distillation device were charged 1.28 g (9 mmol) of 4-propionyltetrahydropyran synthesized in the same manner as in Example 5, 16.0 g (180 mmol) of dimethyl carbonate and 1.2 g (22 mmol) of sodium methoxide, and the mixture was reacted at 80 to 85° C. for 2 hours with distilling by-producing methanol off. After completion of the reaction, the reaction mixture was cooled to 5 to 10° C., to the reaction mixture were added 50 ml of ethyl acetate, 3.4 g (24 mmol) of 6 mol/l hydrochloric acid and 15 ml of water in this order. After the organic layer was separated, the aqueous layer was extracted twice with 50 ml of ethyl acetate. The organic layer was concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (Eluent; hexane/ethyl acetate=3/1 (volume ratio)) to give 0.60 g (Isolation yield: 33%) of methyl 3-(4-tetrahydropyranyl)-2-methyl-3-oxopropanoate as a colorless liquid.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]([C:6]1[C:11]2[S:12][C:13]([CH3:15])=[CH:14][C:10]=2[CH:9]=[CH:8][CH:7]=1)=[O:5].[CH2:16]=O>C(Cl)(Cl)Cl.[Cl-].[Zn+2].[Cl-]>[CH3:2][O:3][C:4]([C:6]1[C:11]2[S:12][C:13]([CH3:15])=[C:14]([CH2:16][Cl:1])[C:10]=2[CH:9]=[CH:8][CH:7]=1)=[O:5]
Reactant: Cl
Reactant: C=O
Reactant: COC(=O)c1cccc2cc(C)sc12
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cccc2c(CCl)c(C)sc12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Hydrogen chloride gas was passed for 30 minutes through a stirred mixture of 2-methylbenzo[b]thiophene-7-carboxylic acid methyl ester (4.50 g), paraformaldehyde (1.23 g) and anhydrous zinc chloride (1.03 g) in chloroform (50 ml). The mixture was stirred at room temperature for 5 hours and then allowed to stand for 18 hours. The mixture was then washed several times with water and the organic layer was dried (Na2SO4) and evaporated. The residue was crystallised from chloroform/petrol (b.p. 60°-80°) to give 3-chloromethyl-2-methylbenzo[b]thiophene-7-carboxylic acid methyl ester (4.10 g), m.p. 125°-126°.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([OH:11])[CH:3]=1.[Br:12]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[Br:12][C:10]1[C:2]([F:1])=[CH:3][C:4]([OH:11])=[C:5]([CH:9]=1)[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1ccc(F)cc1O
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(O)c1cc(Br)c(F)cc1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 96.5 %

Procedure:
To a stirring solution of 4-fluoro-2-hydroxy-benzoic acid (5.58 g, 35.7 mmol) in dimethyl formamide (72 mL, 0.5 M) was added N-bromosuccinimide (7.08 g, 39.3 mmol). The mixture was allowed to stir for 24 h at room temperature. Next, the mixture was diluted with 300 mL of ethyl acetate and washed successively with water (3 x 330 mL) and saturated aq LiCl (4×200 mL). The organic layer was dried over Na2SO4, filtered and concentrated to afford 5-bromo-4-fluoro-2-hydroxy-benzoic acid (8.1 g, 96%) as a beige powder. Please note, the product may contain up to 20% of a dibrominated impurity which may be separated from the desired product after coupling with a benzylamine or upon methylation (Example 50): Rf 0.32 (20% methanol in dichloromethane); 1H NMR (DMSO-d6, 300 mHz) δ 8.00 (d, J=8.1 Hz, 1H), 7.05 (d, J=10.5 Hz, 1H).
Reaction SMILES: Cl[C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[C:6]([Cl:13])[C:3]=1[C:4]#[N:5].[NH3:14]>CCO>[NH2:14][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[C:6]([Cl:13])[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(Cl)ccc([N+](=O)[O-])c1Cl
Reactant: N
Solvent: CCO
Product: N#Cc1c(Cl)ccc([N+](=O)[O-])c1N
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 68 %

Procedure:
A 500 mL pressure flask was charged with 2,6-dichloro-3-nitrobenzonitrile (30.0 g, 138 mmol) and a 5.1M solution of ammonia in EtOH (170 mL). The flask was sealed and heated in an oil bath at 80° C. with stirring for 1.5 h. The cooled solution was filtered, the crystals washed with water and dried to yield 2-amino-6-chloro-3-nitrobenzonitrile (18.4 g, 68%), mp 181-184° C.; MS (ES−) 196, 198 (M−H−).