Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH3:24])[C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[C:14]1[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]1=[O:23])[O:9][CH2:8]2.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.O>CN(C=O)C>[CH3:24][N:4]([CH2:3][CH2:2][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)[C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[C:14]1[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]1=[O:23])[O:9][CH2:8]2
Reactant: CN(CCCl)c1ccc2c(c1)COC2=C1C(=O)Nc2ccccc21
Reactant: C1COCCN1
Solvent: CN(C)C=O
Solvent: O
Product: CN(CCN1CCOCC1)c1ccc2c(c1)COC2=C1C(=O)Nc2ccccc21
Temperature: 110 °C

Procedure:
A mixture of 3-{5-[(2-chloro-ethyl)-methyl-amino]-3H-isobenzofuran-1-ylidene}-1,3-dihydro-indol-2-one (1.20 g, 3.52 mmol) and morpholine (3 ml, 34.4 mmol) in DMF (5 ml) was heated at 110° C. under nitrogen for 16 hours. The mixture was cooled to room temperature and was then poured into water (100 ml). The solid was filtered, washed with water and dried under vacuum to give a crude product. Purification of the crude product by silica gel column chromatography, eluted with a gradient of MeOH in CHCl3, resulted in 3-{5-[methyl-(2-morpholin-4-yl-ethyl)-amino]-3H-isobenzofuran-1-ylidene}-1,3-dihydro-indol-2-one as a yellow solid (0.57 g, 41%).
Reaction SMILES: [NH2:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(O[C:14]([S-])=[S:15])C.[K+]>N1C=CC=CC=1>[SH:15][C:14]1[O:10][C:9]2[C:2](=[C:3]([C:4]#[N:5])[CH:6]=[CH:7][CH:8]=2)[N:1]=1
Reactant: N#Cc1cccc(O)c1N
Reactant: CCOC(=S)[S-]
Agent: [K+]
Solvent: c1ccncc1
Product: N#Cc1cccc2oc(S)nc12
Yield: 45.5 %

Procedure:
A solution of 2-amino-3-hydroxybenzonitrile (298 mg) and potassium ethylxanthate (427 mg) in pyridine (7.4 ml) was heated under reflux for 3 hr. To the reaction mixture was added distilled water, the mixture was acidified with 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with distilled water and brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (178 mg).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(O[CH:16]([C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[F:34])[C:17]1[N:21]([CH3:22])[C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[N:18]=1)=O)(C)(C)C.[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([SH:42])=[CH:38][CH:37]=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([S:42][CH:16]([C:27]2[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=2[F:34])[C:17]2[N:21]([CH3:22])[C:20]3[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=3[N:18]=2)=[CH:38][CH:37]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: Cn1c(C(OC(=O)OC(C)(C)C)c2cc(F)ccc2F)nc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(C(Sc2ccc(Cl)cc2)c2cc(F)ccc2F)nc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.3 %

Procedure:
Trifluoroacetic acid (2.0 ml) was added to the 2-[(t-butoxycarbonyloxy)-(2,5-difluorophenyl)methyl]-1-methyl-1H-benzimidazole (204 mg, 0.545 mmol) obtained in Referential Example 13. The resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. Dioxane was added to the residue, followed by further concentration under reduced pressure. The residue was dissolved in thionyl chloride (1.0 ml). One drop of dimethylformamide was added to the resulting solution. The resulting mixture was stirred for 16 hours at room temperature. The reaction mixture was concentrated under reduced pressure. Dioxane was added to the residue and the resulting mixture was concentrated further under reduced pressure. The residue was dissolved in dimethylformamide (5.0 ml). After addition of 4-chlorobenzenethiol (118 mg, 0.82 mmol) and potassium carbonate (451 mg, 3.27 mmol), the resulting mixture was stirred at 50° C. for 2 hours. The reaction mixture was then allowed to stand at room temperature and ethyl acetate (60 ml) was added thereto. The resulting mixture was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography (hexane:ethyl acetate=10:1 to 5:1) to give the title compound (195 mg, 89%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:10]([F:13])=[C:4]2[C:5]([O:7][C:8](=O)[C:3]=12)=[O:6].O.O.O.C([O-])(=O)C.[Na+].O.[NH2:23][NH2:24]>C(O)(=O)C>[F:1][C:2]1[CH:12]=[CH:11][C:10]([F:13])=[C:4]2[C:3]=1[C:8](=[O:7])[N:23]=[N:24][C:5]2=[O:6]
Reactant: NN
Reactant: O=C1OC(=O)c2c(F)ccc(F)c21
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C1N=NC(=O)c2c(F)ccc(F)c21
Yield: 99.2 %

Procedure:
3,6-Difluorophthalic anhydride (10 g, 54 mmol) was added to a mixture of sodium acetate trihydrate (10 g, 73 mmol) and hydrazine hydrate (5 ml, 156 mmol) in 40% aqueous acetic acid. The reaction was heated under reflux conditions for 16 h and the reaction was filtered to give the title-compound as a white solid (10.5 g, 98%), 1H NMR (250 MHz, d6-DMSO) δ 8.01 (2H, t, J=9 Hz), 11.50-11.80 (2H, br s).
Reaction SMILES: [Cl-].[CH2:2]([O:9][C:10]([CH2:12][C@@H:13]([NH3+:25])[CH2:14][O:15][C:16]1[CH:21]=[C:20]([C:22]#[N:23])[CH:19]=[CH:18][C:17]=1[I:24])=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:26]([C:28]1[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=1)#[N:27].ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>ClCCl.O>[C:22]([C:20]1[CH:19]=[CH:18][C:17]([I:24])=[C:16]([CH:21]=1)[O:15][CH2:14][C@H:13]([NH:25][C:32](=[O:33])[C:31]1[CH:35]=[CH:36][C:28]([C:26]#[N:27])=[CH:29][CH:30]=1)[CH2:12][C:10]([O:9][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)=[O:11])#[N:23]
Reactant: N#Cc1ccc(I)c(OC[C@H]([NH3+])CC(=O)OCc2ccccc2)c1
Reactant: N#Cc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: N#Cc1ccc(C(=O)N[C@@H](COc2cc(C#N)ccc2I)CC(=O)OCc2ccccc2)cc1
Reaction time: 0.17 h

Procedure:
4.73 g (10 mmol) of (1R)-1-benzyloxycarbonylmethyl-2-(5-cyano-2-iodophenoxy)ethylammonium chloride, 2.9 g (20 mmol) of 4-cyanobenzoic acid, 3.0 g (22 mmol) of 1-hydroxybenzotriazole and 6.1 ml (44 mmol) of triethylamine were dissolved in 50 ml of dichloromethane. 4.2 g (22 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride was added to the solution under cooling with ice, and they were stirred for 10 minutes and then at room temperature for one hour. Water is added to the reaction mixture to terminate the reaction. The mixture was treated with dichloromethane as the extractant in an ordinary manner to obtain the crude product, which was purified by the silica gel column chromatography (volume ratio of hexane:ethyl acetate=3:1) to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[NH:10][CH2:11][C:12]([OH:14])=O)[CH:5]=[CH:6][CH:7]=1.[NH:16]([CH:23]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([Br:37])[CH:32]=1)[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.S(Cl)(Cl)=O>>[Br:37][C:33]1[CH:32]=[C:31]([CH:23]([N:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12](=[O:14])[CH2:11][NH:10][C:9]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=2)=[O:15])[C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)C(Nc1ccccc1)c1cccc(Br)c1
Reactant: Cc1cccc(NC(=O)NCC(=O)O)c1
Solvent: O=S(Cl)Cl
Product: Cc1cccc(NC(=O)NCC(=O)N(c2ccccc2)C(C(=O)OC(C)(C)C)c2cccc(Br)c2)c1
Yield: 51 %

Procedure:
The procedure is as in Example 1, but using 1.04 g of 2-[3-(3-methylphenyl)ureido]acetic acid, 1.8 g of tert-butyl (RS)-2-anilino-2-(3-bromophenyl)acetate and 0.36 cm3 of thionyl chloride as starting materials The product obtained is purified by chromatography on 100 g of silica (0.04-0.063 mm) contained in a column 3 cm in diameter [eluent: methanol/dichloromethane (1/99 by volume)], using an excess pressure of 40 kPa of nitrogen and collecting 10-cm3 fractions. Fractions 11 to 17 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. and the residue obtained is recrystallized from cyclohexane. 1.4 g of tert-butyl (RS)-2-(3-bromophenyl)-2-{2-[3-(3-methylphenyl)ureido]-N-phenylacetamido}acetate melting at 103° C. are then obtained.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][OH:19])[CH:13]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>O1CCCC1.C(OCC)(=O)C>[F:8][C:5]1[CH:6]=[CH:7][C:2]([O:19][CH2:18][C:14]2[CH:13]=[N:12][CH:17]=[CH:16][CH:15]=2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Reactant: OCc1cccnc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(F)ccc1OCc1cccnc1
Reaction time: 12 h

Procedure:
To a stirred, cooled (about 0° C.) solution of 1,4-Difluoro-2-nitro-benzene (3.0 mmol) and 3-pyridylcarbinol (3.1 mmol) in tetrahydrofuran (8 mL) was added lithium bis(trimethylsilyl)amide (3.2 mmol; 3.2 mL of a 1.0 M solution in tetrahydrofuran). After stirring for 12 hours, the reaction was diluted with 30 mL of ethyl acetate and washed with 30 mL of 10% aqueous sodium carbonate (2×30 mL), brine (1×30 mL), then dried (MgSO4) and filtered. The filtered solution was concentrated under reduced pressure to provide the desired crude product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[Cl:24])[O:5][C:6]1[N:11]=[C:10]2[S:12][C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])=[N:14][C:9]2=[CH:8][CH:7]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[CH:28][C:27]=1[C:35]([F:38])([F:37])[F:36]>CN(C)C=O.C(OCC)(=O)C>[Cl:24][C:23]1[CH:22]=[CH:21][C:4]([O:5][C:6]2[N:11]=[C:10]3[S:12][C:13]([NH:15][C:16]([CH:18]4[CH2:20][CH2:19]4)=[O:17])=[N:14][C:9]3=[CH:8][CH:7]=2)=[CH:3][C:2]=1[NH:1][C:33](=[O:34])[NH:32][C:29]1[CH:30]=[CH:31][C:26]([Cl:25])=[C:27]([C:35]([F:36])([F:37])[F:38])[CH:28]=1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1Cl
Temperature: 25 °C
Reaction time: 10 h
Yield: 32.8 %

Procedure:
N-[5-(3-Amino-4-chlorophenoxy)[1,3]thiazolo[5,4-b]pyridin-2-yl]cyclopropanecarboxamide (120 mg, 0.33 mmol) was dissolved in N,N-dimethylformamide (2.0 ml), 1-chloro-4-isocyanato-2-(trifluoromethyl)benzene (89 mg, 0.40 mmol) was added, and the mixture was stirred at room temperature for 10 hr. The reaction mixture was diluted with ethyl acetate (10 mL), and washed with saturated brine (10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/hexane=50/50→100/0), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give the title compound (63 mg, 33%) as a colorless powder.
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][N:13]=[C:12]3[C:18]2[N:19]=[N:20][N:21]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][CH:24]=3)[CH:22]=2)[N:6]=[C:5]([C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)[CH:4]=[CH:3]1.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>>[N:38]1([C:27]([C:26]2[CH:30]=[CH:31][C:23]([N:21]3[CH:22]=[C:18]([C:12]4[C:11]5[C:15](=[CH:16][CH:17]=[C:9]([CH2:8][N:7]6[C:2](=[O:1])[CH:3]=[CH:4][C:5]([C:32]7[CH:33]=[CH:34][N:35]=[CH:36][CH:37]=7)=[N:6]6)[CH:10]=5)[NH:14][N:13]=4)[N:19]=[N:20]3)=[CH:24][CH:25]=2)=[O:29])[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1
Reactant: O=C(O)c1ccc(-n2cc(-c3n[nH]c4ccc(Cn5nc(-c6ccncc6)ccc5=O)cc34)nn2)cc1
Reactant: C1COCCN1
Product: O=C(c1ccc(-n2cc(-c3n[nH]c4ccc(Cn5nc(-c6ccncc6)ccc5=O)cc34)nn2)cc1)N1CCOCC1

Procedure:
The title compound was obtained following procedure described for example 94, step b), but starting from 4-(4-{5-[(6-oxo-3-pyridin-4-ylpyridazin-1(6H)-yl)methyl]-1H-indazol-3-yl}-1H-1,2,3-triazol-1-yl)benzoic acid (65 mg; 0.12 mmol; 1.0 eq.) and morpholine (4 mL; 46 mmol; 372 eq.) to give the title compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 13.42 (s, 1H), 9.38 (s, 1H), 8.70 (dd, J=1.6, 4.6 Hz, 2H), 8.50 (s, 1H), 8.16 (d, J=6.0 Hz, 1H), 8.14 (d, J=3.0 Hz, 1H), 7.92 (dd, J=1.6, 4.6 Hz, 2H), 7.69 (d, J=8.6 Hz, 2H), 7.61 (d, J=8.7 Hz, 1H), 7.54 (d, J=8.7 Hz, 1H), 7.17 (d, J=9.8 Hz, 1H), 5.53 (s, 2H), 3.64 (s, 8H). HPLC (Condition A): Rt 2.24 min (purity 98.8%). MS (ESI+): 560.3, MS (ESI−): 558.2.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][C:3]=1[F:10].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=1[C:19]([F:22])([F:21])[F:20]>>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:2]2[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][C:3]=2[F:10])=[CH:14][C:13]=1[C:19]([F:20])([F:21])[F:22]
Reactant: O=Cc1cnc(Cl)c(F)c1
Reactant: Oc1ccc(Cl)c(C(F)(F)F)c1
Product: O=Cc1cnc(Oc2ccc(Cl)c(C(F)(F)F)c2)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D1 starting from 6-chloro-5-fluoro-3-pyridinecarbaldehyde and 4-chloro-3-(trifluoromethyl)phenol. LC-MS (ESI): m/z 320 [M+H]+; 3.62 min (ret time).
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[Cl:6][C:7]1[CH:20]=[CH:19][C:10]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[O:12])=[CH:9][CH:8]=1.S(=O)(=O)(O)O.[OH-].[NH4+]>>[N+:1]([C:8]1[CH:9]=[C:10]([CH:19]=[CH:20][C:7]=1[Cl:6])[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)=[O:12])([O-:4])=[O:2]
Reactant: O=C(c1ccc(Cl)cc1)c1ccccn1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [NH4+]
Product: O=C(c1ccc(Cl)c([N+](=O)[O-])c1)c1ccccn1
Temperature: 0 °C

Procedure:
15.5 g. (0.153 mol) of potassium nitrate was added portionwise to a stirred solution of 33 g. (0.152 mol) of 2-(4-chlorobenzoyl)pyridine in 200 ml. of sulfuric acid, while maintaining the temperature below 40° C. After 1 hour the mixture was cautiously poured into 2 liters of ice water and neutralized with ammonium hydroxide. The resulting product 2-(3-nitro-4-chlorobenzoyl)pyridine was collected as white microneedles, mp. 98° -99° C. (cyclohexane).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:6][C:7]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[CH:8][CH:9]=1)[CH3:3].[N+](N[C:19]1[NH:24][C:23](=[O:25])[C:22]([CH2:26][C:27]2[CH:32]=[CH:31][N:30]([CH2:33][CH2:34][CH2:35][CH3:36])[C:29](=[O:37])[CH:28]=2)=[CH:21][N:20]=1)([O-])=O>N1C=CC=CC=1>[CH3:3][N:2]([CH2:4][C:5]1[O:6][C:7]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:19]2[NH:24][C:23](=[O:25])[C:22]([CH2:26][C:27]3[CH:32]=[CH:31][N:30]([CH2:33][CH2:34][CH2:35][CH3:36])[C:29](=[O:37])[CH:28]=3)=[CH:21][N:20]=2)=[CH:8][CH:9]=1)[CH3:1]
Reactant: CCCCn1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cc1=O
Reactant: CN(C)Cc1ccc(CSCCN)o1
Solvent: c1ccncc1
Product: CCCCn1ccc(Cc2cnc(NCCSCc3ccc(CN(C)C)o3)[nH]c2=O)cc1=O

Procedure:
2-(2-Dimethylaminomethyl-5-furylmethylthio)ethylamine (1.44 g) and 2-nitroamino-5-(1-n-butyl-2-oxopyridin-4-ylmethyl)pyrimidin-4-one (1.76 g) were refluxed in pyridine (10 ml) for 24 hours. The reaction mixture was evaporated under reduced pressure to afford an oil which was washed with hot water. The mixture was allowed to cool overnight and the water was decanted to give the title compound as a residue. Ethanolic HCl (3 ml) and isopropanol were added with warming to give a solution which was evaporated under reduced pressure to give a residue which was recrystallised from isopropanolethanolic HCl to give 2-[2-(2-dimethylaminomethyl-5-furylmethylthio)ethylamino]-5-(1-n-butyl-2-oxopyridin-4-ylmethyl)pyrimidin-4-one as a trihydrochloride salt (2.67 g), m.p. 169°-171.5° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][S:26]([C:23]2[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=2)(=[O:28])=[O:27])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCCCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCCCCc2ccccc2)cc1
Temperature: 25 °C
Yield: 102.8 %

Procedure:
To a solution of 5-phenyl-1-pentanol (3.28 g, 20 mmoles) and triethylamine (6.13 ml, 44 mmoles) in CH2Cl2 (35 ml) under N2, p-toluen-sulphonyl chloride (4.19 g, 22 mmoles) was added and then put under stirring up to room temperature for 1 night. The mixture was washed with water, NaHCO3 and 5% HCl, anhydrified and brought to dryness to give 6.55 g of the title compound (yield: 100%).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.[C:14]1([OH:21])[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[OH:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[O:21][CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: Oc1cccc(O)c1
Reactant: ClCc1ccc2ccccc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Oc1cccc(OCc2ccc3ccccc3n2)c1

Procedure:
A mixture (0.06 moles) of 2-chloromethylquinoline hydrochloride, (0.06 moles) of 1,3-benzenediol and 18 g of potassium carbonate in 50 ml of dimethylformamide is heated at 70° C. overnight. The reaction mixture is poured into water, and the precipitated product is collected, filtered and dried to give 2-(3-hydroxyphenoxy)methylquinoline having an m.p. of 151°-53° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH2:7][C:8]1([C:19](O)=[O:20])[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1>O1CCCC1>[NH2:7][C:8]1([CH2:19][OH:20])[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1
Reactant: COc1ccc2c(c1)CCC2(N)C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCC2(N)CO
Temperature: 2.5 °C
Reaction time: 0.5 h

Procedure:
A suspension of 168 mmol of lithium aluminium hydride in 300 ml of tetrahydrofuran is cooled to 0-5° C. 80.0 mmol of 1-amino-5-methoxyindane-1-carboxylic acid are added in portions, and the reaction mixture is then heated to reflux for 1 hour. The reaction mixture is cooled to room temperature and quenched with 7.8 ml of water, 36.2 ml of 1M sodium hydroxide solution and a further 21.0 ml of water. The reaction mixture is stirred at room temperature for 30 minutes and then filtered through Hyflo. The filtrate is evaporated. The title compound is obtained as a beige solid which is employed without further purification for the next stage. Rt=2.36 (gradient III).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([NH:6][C:7]1[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:8]=1[C:14](=[O:16])[CH3:15])=[O:5].[CH2:17]([NH:19][CH2:20][CH3:21])[CH3:18].[ClH:22]>C1C=CC=CC=1.CCOCC>[ClH:22].[CH2:17]([N:19]([CH2:20][CH3:21])[CH2:2][CH2:3][C:4]([NH:6][C:7]1[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:8]=1[C:14](=[O:16])[CH3:15])=[O:5])[CH3:18]
Reactant: CC(=O)c1cccc(C)c1NC(=O)CCBr
Reactant: CCNCC
Agent: Cl
Solvent: c1ccccc1
Solvent: CCOCC
Product: CCN(CC)CCC(=O)Nc1c(C)cccc1C(C)=O

Procedure:
To a solution of 1.5 g of 3-bromo-2'-acetyl-6'-methylpropionanilide in 20 ml of benzene was added 0.8 g of diethylamine at room temperature. The resultant mixture was stirred at room temperature for 24 hours. The reaction mixture was washed with water, dried over anhydrous sodium sulfate and evaporated to give an oily residue. The residue was dissolved in ether and hydrogen chloride was added to the solution to give crystals. Recrystallization from ethanol gave 3-(diethylamino)-2'-acetyl-6'-methylpropionanilide hydrochloride having a melting point of 124° to 126° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9]Br)([CH3:4])([CH3:3])[CH3:2].[CH2:12]([O:14][C:15](=[O:29])[CH2:16][CH:17]1[CH2:23][CH2:22][CH2:21][C:20]2[CH:24]=[C:25]([OH:28])[CH:26]=[CH:27][C:19]=2[CH2:18]1)[CH3:13]>>[CH2:12]([O:14][C:15](=[O:29])[CH2:16][CH:17]1[CH2:23][CH2:22][CH2:21][C:20]2[CH:24]=[C:25]([O:28][CH2:9][CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:11])[CH:26]=[CH:27][C:19]=2[CH2:18]1)[CH3:13]
Reactant: CCOC(=O)CC1CCCc2cc(O)ccc2C1
Reactant: CC(C)(C)OC(=O)NCCBr
Product: CCOC(=O)CC1CCCc2cc(OCCNC(=O)OC(C)(C)C)ccc2C1

Procedure:
The title compound was prepared according to the procedure of Example 19 except that (2-bromo-ethyl)-carbamic acid tert-butyl ester was used in place of (3-bromo-propyl)-carbamic acid tert-butyl ester and (2-hydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-acetic acid ethyl ester was used in place of (7-hydroxy-1,2,3,4-tetrahydro-napthalen-2-yl)-acetic acid ethyl ester and the title compound was isolated as a pale yellow oil.
Reaction SMILES: CNC.CC(C)([O-])C.[K+].Cl.[Cl:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[CH2:18][NH:17][CH2:16][CH2:15]2.Br[C:23]1[CH:28]=[C:27]([CH3:29])[C:26]([NH:30][C:31](=[O:37])[CH2:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[C:25]([CH3:38])[CH:24]=1>C1(C)C=CC=CC=1>[Cl:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[CH2:18][N:17]([C:23]1[CH:28]=[C:27]([CH3:29])[C:26]([NH:30][C:31](=[O:37])[CH2:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[C:25]([CH3:38])[CH:24]=1)[CH2:16][CH2:15]2
Reactant: Clc1ccc2c(c1)CCNC2
Reactant: Cc1cc(Br)cc(C)c1NC(=O)CC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: CNC
Agent: Cl
Solvent: Cc1ccccc1
Product: Cc1cc(N2CCc3cc(Cl)ccc3C2)cc(C)c1NC(=O)CC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Bis(dibenzylidineacetone)palladium (2 mg, 0.0035 mmol) and 2′-dicyclohexylphosphanyl-biphenyl-2-yl)-dimethylamine (3.3 mg, 0.0084 mmol) were added to dry toluene (5 mL purged with argon) and stirred for 15 minutes under argon. Potassium tert-butoxide (188 mg, 1.7 mmol), 6-chloro-1,2,3,4-tetrahydro isoquinoline hydrochloride salt (165 mg, 0.8 mmol), and N-(4-bromo-2,6-dimethylphenyl)-3,3-dimethylbutanamide (200 mg, 0.67 mmol) were then added, and the reaction mixture was stirred at 80° C. overnight. The reaction mixture was then cooled to room temperature and filtered through silica gel. Purification by preparative thin layer chromatography afforded the title compound as a solid.
Reaction SMILES: C([O:4][CH:5]1[CH2:10][CH:9]2[CH2:11][C:6]1([CH3:12])[CH2:7][CH2:8]2)(=O)C>[OH-].[Na+]>[CH3:12][C:6]12[CH2:11][CH:9]([CH2:8][CH2:7]1)[CH2:10][CH:5]2[OH:4]
Reactant: CC(=O)OC1CC2CCC1(C)C2
Agent: [Na+]
Agent: [OH-]
Product: CC12CCC(CC1O)C2
Temperature: 25 °C
Yield: 98.2 %

Procedure:
A mixture of 1-methylbicyclo[2.2.1]heptan-2-yl acetate (31 g, 0.17 mol) and aqueous sodium hydroxide solution (5%, 250 mL) was refluxed for 2 h. After being cooled to room temperature, the reaction mixture was extracted with diethyl ether (3×100 mL) and the combined organic layers were dried over magnesium sulfate and concentrated to afford the desired compound (21 g, 0.167 mol, yield: 82%), which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ ppm 3.47-3.46 (m, 1H), 2.16-2.14 (m, 1H), 1.81-1.75 (m, 1H), 1.57-1.52 (m, 1H), 1.43-1.30 (m, 3H), 1.15 (brs, 3H), 1.01-0.97 (m, 2H).
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH2:12][C:13]([OH:15])=O.[CH:16]1([NH2:19])[CH2:18][CH2:17]1.Cl>CS(C)=O>[CH:16]1([N:19]2[C:2]3[C:3](=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[CH:6][C:7]=3[F:8])[CH2:12][C:13]2=[O:15])[CH2:18][CH2:17]1
Reactant: O=C(O)Cc1cc([N+](=O)[O-])cc(F)c1F
Reactant: NC1CC1
Agent: Cl
Solvent: CS(C)=O
Product: O=C1Cc2cc([N+](=O)[O-])cc(F)c2N1C1CC1
Temperature: 50 °C
Reaction time: 20 h

Procedure:
Crude (2,3-difluoro-5-nitrophenyl) acetic acid (2.50 g, 11.5 mmol) and cyclopropylamine (6 eq., 4.78 ml, 0.0691 mol) are mixed in DMSO (10 ml) and stirred at 50 ° C. for 20 hours. 2N Hydrochloric acid (40 ml) is added in one portion and the mixture stirred at room temperature for 2 hours. The resulting light yellow precipitate is filtered, washed with water and dried under vacuum. The residue is purified by flash column chromatography (20% Ethyl acetate/hexane) to give the title compound as a yellow solid. HPLC r.t. 4.90 min; MS for C11H9FN2O3 m/z 235.0 (M−H)−.