Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:8][C:9]1[CH:18]=[CH:17][C:12]([CH2:13][N:14]=[C:15]=[S:16])=[CH:11][CH:10]=1.Cl.[N:20]1([CH2:26][CH2:27][CH2:28]Cl)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.[I-].[K+]>CCOCC.C(O)C>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][N:14]([CH2:28][CH2:27][CH2:26][N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[C:15](=[N:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[SH:16])=[CH:17][CH:18]=1
Reactant: NC1CCCCC1
Reactant: ClCCCN1CCCCC1
Reactant: S=C=NCc1ccc(Cl)cc1
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: CCOCC
Solvent: CCO
Product: SC(=NC1CCCCC1)N(CCCN1CCCCC1)Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Cyclohexylamine (10 mmol) was added dropwise to 4-chlorobenzylisothio-cyanate (10 mmol) dissolved in 20 ml of dry ether. The solution was stirred for 2 hours at room temperature. The precipitated product was filtered off and crystallized from ethyl acetate. 3-Piperidinopropyl chloride hydrochloride (3 mmol), the product (3 mmol), and ca-talytic amounts of potassium iodide were refluxed in ethanol for 6 days. Sub-sequently, ethanol was evaporated, and the residue was purified by column chromato-graphy (eluent: methylene chloride/methanol (95/5)). After evaporation of the solvent the product was crystallized with hydrochloric acid from diethyl ether/ethanol.
Reaction SMILES: IC1[C:3]([O:22]C)=[CH:4][C:5]([O:20]C)=[C:6]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=3)[N:11]=[CH:10][CH:9]=2)[CH:7]=1.[CH3:24][C:25]([CH2:27][CH3:28])=[CH2:26].[CH3:29]COCC>>[CH3:26][CH:25]([CH2:24][CH3:29])[CH2:27][C:28]1[C:3]([OH:22])=[CH:4][C:5]([OH:20])=[C:6]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=3)[N:11]=[CH:10][CH:9]=2)[CH:7]=1
Reactant: C=C(C)CC
Reactant: COc1cc(OC)c(-c2ccnn2-c2cccc(C)c2)cc1I
Reactant: CCOCC
Product: CCC(C)Cc1cc(-c2ccnn2-c2cccc(C)c2)c(O)cc1O

Procedure:
12.4 Analogous reaction of 5-[5-iodo-2,4-dimethoxyphenyl]1-(3-methylphenyl)-1H-pyrazole with 2-methyl-1-butene, hydrogenation and ether cleavage gives the compound 5-{5-(2-methylbutyl)-2,4-dihydroxyphenyl}-1-(3-methylphenyl)-1H-pyrazole.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:3]=1[CH2:4][C:5]1[N:6]([CH3:12])[C:7]([CH2:10][OH:11])=[N:8][N:9]=1.O.[C-]#[N:20].[Na+]>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[F:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:2]([F:1])[C:3]=1[CH2:4][C:5]1[N:6]([CH3:12])[C:7]([C:10]([NH2:20])=[O:11])=[N:8][N:9]=1
Reactant: Cn1c(CO)nnc1Cc1c(F)cccc1F
Reactant: [C-]#N
Agent: [Mn+4]
Agent: [Na+]
Agent: [O-2]
Solvent: O
Solvent: Cc1ccccc1
Product: Cn1c(Cc2c(F)cccc2F)nnc1C(N)=O
Reaction time: 4 h

Procedure:
1.43 g (6 mmol) of 5-(2,6-difluorobenzyl)-3-hydroxymethyl-4-methyl-4H-1,2,4-triazole and 5.22 g (60 mmol) of manganese dioxide are heated under reflux in 40 ml of toluene for 3 hours using a water separator. The reaction mixture is then cooled and filtered over Hyflo, and the filtrate is concentrated by evaporation. The residue is added to 90 ml of isopropanol saturated with ammonia. At 0°, 1.47 g (30 mmol) of sodium cyanide and 10.44 g (120 mmol) of manganese dioxide are added. The reaction mixture is stirred for 4 hours at 0° and filtered over Hyflo. The filtrate is concentrated by evaporation. Recrystallisation of the residue from ethanol yields the pure 5-(2,6-difluorobenzyl)-4-methyl-4H-1,2,4-triazole-3-carboxamide.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[OH:14])=[O:6])[CH3:2].C(N(CC)CC)C.[C:23]([Si:27]([CH3:30])([CH3:29])Cl)([CH3:26])([CH3:25])[CH3:24].O>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:15])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][Si:27]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:30])[CH3:29])=[CH:9][C:8]=1[OH:14])=[O:6])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)C(=O)c1ccc(O)cc1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C(=O)c1ccc(O[Si](C)(C)C(C)(C)C)cc1O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 40 %

Procedure:
To a solution of (2,4-Dihydroxy-phenyl)-oxo-acetic acid ethyl ester (from step 1, 2.71 g, 12.9 mmol, 1 eq) in anhydrous DCM (40 mL) solution was added triethylamine (1.97 mL, 14.2 mmol, 1.1 eq), followed by addition of tert-butyldimethylchlorosilane (1.89 g, 14.2 mmol, 1.1 eq)/DCM (10 mL) solution dropwise at 0° C. under argon. The reaction mixture was stirred at 0° C. for 5 min. Water (30 mL) was added to the reaction mixture to quench the reaction. The organic layer was washed with water (2×30 mL), dried over Na2SO4, filtrated, and concentrated under reduced pressure to afford a light yellow solid (4.1 g, contains 40% mono-substituted product) as crude product. This material was used in step 3 without further purification.
Reaction SMILES: [C:1](=[O:8])([O:5][CH2:6][CH3:7])OCC.CN(C)P(=O)(N(C)C)N(C)C.[CH3:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23].Cl>O>[CH2:6]([O:5][C:1](=[O:8])[CH2:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH3:7]
Reactant: CCOC(=O)OCC
Reactant: CC(=O)C(C)(C)C
Agent: Cl
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCOC(=O)CC(=O)C(C)(C)C
Temperature: 45 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
250 g of potassium-tert.-butylate were suspended in a solution of 480 cc of diethyl carbonate and 100 cc of hexamethyl phosphoric acid triamide, followed by the gradual dropwise addition of 100 g pinacolone at 45° C/normal pressure. On completion of the addition, the mixture was stirred for 1 hour at 45° C and, after cooling, alcohol, water and finally hydrochloric acid carefully added one after the other to the reaction mixture. The reaction mixture was then treated and purified in the same way as described in 1 above. The yield was 67% of pivaloyl acetic acid ethyl ester.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=O)=O.[CH:18]1[C:23]([NH:24][NH2:25])=[CH:22][CH:21]=[C:20]([S:26]([NH2:29])(=[O:28])=[O:27])[CH:19]=1.Cl>C(O)C>[F:1][C:2]([F:17])([F:16])[C:3]1[C:5]2[CH2:14][CH2:13][C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[C:6]=2[N:24]([C:23]2[CH:18]=[CH:19][C:20]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:21][CH:22]=2)[N:25]=1
Reactant: O=C1c2ccccc2CCC1C(=O)C(F)(F)F
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Solvent: CCO
Product: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)c3c2-c2ccccc2CC3)cc1
Yield: 71.2 %

Procedure:
A 100 mL one necked round bottomed flask equipped with reflux condenser, nitrogen inlet and provisions for magnetic stirring was charged with 2-trifluoroacetyl-1-tetralone from Step 1 (1.21 g, 5.0 mmol), 4-sulfonamidophenylhydrazine hydrochloride (1.12 g, 5.0 mmol) and 25 mL or absolute ethanol. The solution was warmed to reflux for 15 hours and concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with water, and with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was recrystallized from a mixture of ethyl acetate and isooctane to give 1.40 g, 71% of pure product: mp 257-258° C.; 1H NMR (CDCl3/CD3OD, 4:1) δ 2.7 (m, 2H), 2.9 (m, 2H), 6.6 (m, 1H), 6.9 (m, 1H), 7.1 (m, 1H), 7.16 (m, 1H), 7.53 (m, 2H), 7.92 (m, 2H); 19F NMR (CDCl3) δ −62.5. FAB-MS M+H=394.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH:11][CH2:12][CH2:13][CH3:14])[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH:21]1(Br)[CH2:25][CH2:24][CH2:23][CH2:22]1>O>[CH:21]1([N:11]([CH2:12][CH2:13][CH3:14])[CH2:10][CH2:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CCCNCCc1cccc(OC)c1
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCCN(CCc1cccc(OC)c1)C1CCCC1

Procedure:
A stirred mixture of 3.4 g of 3-methoxy-N-propyl-benzeneethanamine, 4 g of potassium carbonate and 15 ml of cyclopentyl bromide was refluxed for one hour after which 5 g of potassium carbonate were added thereto and the mixture was refluxed for another 3 hours. The mixture was poured into 50 ml of water and the mixture was extracted 3 times with 50 ml of ether. The organic phase was dried and filtered and the filtrate was evaporated to dryness to obtain 4.5 g of N-cyclopentyl-3-methoxy-N-propylbenzeneethanamine in the form of a red oil which was used as is for the next step.
Reaction SMILES: [CH2:1]([NH:6][NH:7][C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]([CH3:5])([CH3:4])[CH3:3].[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-].[Na+]>C1(C)C=CC=CC=1.CCCCCC>[CH2:1]([N:6]([C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[NH:7][C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)CNNC(=O)c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CC(C)(C)CN(NC(=O)c1ccccc1)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of the 2-neopentyl-1-benzoylhydrazine in toluene (40 ml) at 5° C., were added dropwise and simultaneously solutions of benzoyl chloride (1.4 g, 10 mmoles) in toluene (5 ml) and aqueous 50% sodium hydroxide solution (0.8 g) while maintaining the temperature below 10° C. After the addition, the reaction mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was diluted with hexane and the precipitated product isolated by filtration. The product was washed with water and hexane and dried. The crude product was recrystallized from methanol to afford N'-neopentyl-N,N'-dibenzoylhydrazine as a white powder: m.p. 237°-239° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([B:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]2)[CH:5]=[CH:4][C:3]=1[NH2:17].[Cl:18][C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[S:26](Cl)(=[O:28])=[O:27].N1C=CC=CC=1>C(Cl)Cl>[Cl:18][C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[S:26]([NH:17][C:3]1[CH:4]=[CH:5][C:6]([B:8]2[O:12][C:11]([CH3:13])([CH3:14])[C:10]([CH3:16])([CH3:15])[O:9]2)=[CH:7][C:2]=1[F:1])(=[O:28])=[O:27]
Reactant: CC1(C)OB(c2ccc(N)c(F)c2)OC1(C)C
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)OB(c2ccc(NS(=O)(=O)c3cccc(Cl)c3Cl)c(F)c2)OC1(C)C

Procedure:
Intermediate 25 was prepared in analogy to GP 4 from 1.78 g 2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (7.5 mmol) and 2.03 g 2,3-dichloro-benzenesulfonyl chloride (8.25 mmol, 1.1 eq.) in 20 mL DCM and in the presence of 0.66 mL pyridine (8.25 mmol, 1.1. eq.) yielding after trituration 2.42 g of the target compound (72% yield).
Reaction SMILES: [C:1]([S:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:13]=2)[N:8]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:31]=[N:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=3)=[CH:26][CH:25]=2)[C:7]=1[CH2:38][C:39]([CH3:44])([CH3:43])[C:40]([OH:42])=[O:41])([CH3:4])([CH3:3])[CH3:2].C(SC1C2C(=CC=C([O:59]CC3C=CC=CN=3)C=2)N(CC2C=CC(C3C=NC(O)=CC=3)=CC=2)C=1CC(C)(C)C(O)=O)(C)(C)C>>[CH3:37][O:36][C:33]1[N:32]=[CH:31][C:30]([C:27]2[CH:28]=[CH:29][C:24]([CH2:23][N:8]3[C:9]4[C:14](=[CH:13][C:12]([O:15][CH2:16][C:17]5[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=5)=[CH:11][CH:10]=4)[C:6]([S:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[O:59])=[C:7]3[CH2:38][C:39]([CH3:44])([CH3:43])[C:40]([OH:42])=[O:41])=[CH:25][CH:26]=2)=[CH:35][CH:34]=1
Reactant: COc1ccc(-c2ccc(Cn3c(CC(C)(C)C(=O)O)c(SC(C)(C)C)c4cc(OCc5ccccn5)ccc43)cc2)cn1
Reactant: CC(C)(C)Sc1c(CC(C)(C)C(=O)O)n(Cc2ccc(-c3ccc(O)nc3)cc2)c2ccc(OCc3ccccn3)cc12
Product: COc1ccc(-c2ccc(Cn3c(CC(C)(C)C(=O)O)c(S(=O)C(C)(C)C)c4cc(OCc5ccccn5)ccc43)cc2)cn1

Procedure:
3-[3-tert-butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-(1-oxy-pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid (M3); the acyl gluconuride of 3-[3-tert-butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-(pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid (M4); and 3-[3-tert-butylsulfanyl-1-[4-(6-hydroxy-pyridin-3-yl)-benzyl]-5-(pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid (M5; which exists also as a pyridon-5-yl tautomer).
Reaction SMILES: CCCCCC.CCOC(C)=O.[CH3:13][O:14][C:15](=[O:25])[C:16]([CH3:24])([CH3:23])[CH2:17][CH2:18][C:19]([O:21]C)=[O:20].[OH-].[K+]>CO>[CH3:13][O:14][C:15](=[O:25])[C:16]([CH3:23])([CH3:24])[CH2:17][CH2:18][C:19]([OH:21])=[O:20]
Reactant: COC(=O)CCC(C)(C)C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)C(C)(C)CCC(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.4 %

Procedure:
To a solution of 2,2-dimethyl-pentanedioic acid (3.0 g, 19 mmol) is added K2CO3 (6.49 g, 47 mmol) and iodomethane (2.5 ml, 39 mmol) at room temperature. The mixture is stirred at room temperature for 18 hours. To the mixture, H2O is added and the solution is extracted with AcOEt. The organic layer is washed with H2O, saturated aqueous NaHCO3 and brine, and dried over MgSO4. Solvent is removed under reduced pressure to give 2,2-dimethyl-pentanedioic acid dimethyl ester (2.49 g, 70%); TLC (hexane/AcOEt, 3:1) Rf 0.50, 1H NMR (400 MHz, chloroform-d) δ ppm 1.19 (s, 6H), 1.88 (m, 2H), 2.29 (m, 2H), 3.67 (s, 6H). To a solution of 2,2-dimethyl-pentanedioic acid dimethyl ester (2.40 g, 12.8 mmol) in MeOH (15 ml) is added potassium hydroxide (0.788 g, 14.0 mmol). The mixture is stirred at room temperature for 16 hours and refluxed for 2 hours. The mixture is cooled to room temperature and concentrated under reduced pressure. To the obtained residue, 1M aqueous HCl (14 ml) is added and the solution is extracted with ether. The organic layer is washed with H2O, dried over Na2SO4, and concentrated under reduced pressure to give 2,2-dimethyl-pentanedioic acid 1-methyl ester (1.97 g, 88%); 1H NMR (400 MHz, chloroform-d) ppm 1.20 (s, 6H), 1.87-1.91 (m, 2H), 2.32-2.36 (m, 2H), 3.67 (s, 3H). To a suspension of 2,2-dimethyl-pentanedioic acid 1-methyl ester (1.00 g, 5.75 mmol) in THF (3 mL), 1M LiBHEt3 in THF (38.0 ml, 38.0 mmol) is added dropwise maintaining the temperature below 10° C. under nitrogen. The mixture is stirred at 10° C. for 1 hour. To the mixture, 50% AcOH (4.6 mL) and H2O are added. The solution is extracted with AcOEt, and the organic layer is washed with H2O, dried over MgSO4, and concentrated under reduced pressure to give 5-hydroxy-4,4-dimethyl-pentanoic acid (850 mg, quant.); 1H NMR (400 MHz, chloroform-d) ppm 1.06 (s, 6H), 1.70 (t, 2H), 2.56 (t, 2H), 3.98 (s, 2H). To a solution of 5-hydroxy-4,4-dimethyl-pentanoic acid (300 mg, 2.05 mmol) in DMF (5 ml), K2CO3 (369 mg, 2.87 mmol) and iodomethane (154 ul, 2.47 mmol) are added at room temperature. The mixture is stirred at room temperature for 15 hours. To the mixture, H2O is added and the solution is extracted with AcOEt. The organic layer is washed with H2O, and brine, and dried over MgSO4, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography to give 5,5-dimethyl-tetrahydro-pyran-2-one (150 mg, 47%); TLC (hexane/AcOEt, 2:1) Rf 0.40, 1H NMR (400 MHz, chloroform-d) δ ppm 1.06 (s, 6H), 1.70 (t, 2H), 2.56 (t, 2H), 3.97 (s, 2H).
Reaction SMILES: COC[O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH:37]4[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]4)=[CH:28][CH:27]=3)[C:10]([C:16]3[CH:21]=[CH:20][C:19]([O:22]COC)=[CH:18][CH:17]=3)([CH3:15])[CH2:11][O:12]2)=[CH:7][CH:6]=1.C(Cl)Cl>CO>[OH:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH:37]4[CH2:38][CH2:39][NH:40][CH2:41][CH2:42]4)=[CH:28][CH:27]=3)[C:10]([C:16]3[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=3)([CH3:15])[CH2:11][O:12]2)=[CH:7][CH:6]=1
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2c2ccc(OCCCCC3CCNCC3)cc2)cc1
Solvent: ClCCl
Solvent: CO
Product: CC1(c2ccc(O)cc2)COc2cc(O)ccc2C1c1ccc(OCCCCC2CCNCC2)cc1

Procedure:
A mixture of (3RS,4RS)-7-methoxymethoxy-3-(4-(methoxymethoxy)phenyl)-3-methyl-4-[4-(4-piperidylbutyloxy)phenyl]chroman (325 mg, 0.56 mmol) p-toluenesulfonic acid (1.42 g, 5.6 mmol) and methanol was stirred at reflux for 12 h. After cooling, the mixture was extracted with ethyl acetate, dried over MgSO4, and filtered. The filtrate was evaporated under reduced pressure, and the concentrate thus obtained was subjected to silica gel column chromatography (CH2Cl2:methanol=10:1) to give 160 mg (yield. 58%) of a white foamy solid.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[Br:12]Br.O>C(Cl)Cl.CC(O)=O>[Br:12][C:7]1[CH:8]=[C:2]([F:1])[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]=1[NH2:6]
Reactant: BrBr
Reactant: Nc1ccc(F)cc1[N+](=O)[O-]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O
Product: Nc1c(Br)cc(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 140 %

Procedure:
To a mixture of 4-fluoro-2-nitroaniline (10.0 g, 42.55 mmol) in DCM (150 mL) and HOAc (75 mL) at 0° C. was added dropwise Br2 (9.9 ml, 130 mmol) at a rate to maintain the internal reaction temperature below 10° C. The reaction mixture was stirred at RT overnight and then poured into water (500 mL), followed by separation of the organic phase. The pH of the aqueous phase was adjusted to about 7 by adding NH4OH, and the mixture was extracted with DCM (100 mL×3). The combined extracts were dried (MgSO4), filtered, and concentrated in vacuo to afford 2-bromo-4-fluoro-6-nitroaniline as a yellow solid (14 g, 93%). MS (ESI): m/z=233 [M−1]−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7](=O)[CH2:6][CH2:5]2.[OH-].[K+].Cl.Cl[CH2:17][CH2:18][CH2:19][NH2:20].[C:21](Cl)(=[O:23])[CH3:22]>C1(C)C=CC=CC=1.C(N(CC)CC)C.O>[C:21]([N:20]1[C:7]2[CH2:6][CH2:5][C:4]3[CH:3]=[C:2]([Cl:1])[CH:11]=[CH:10][C:9]=3[C:8]=2[CH2:17][CH2:18][CH2:19]1)(=[O:23])[CH3:22]
Reactant: CC(=O)Cl
Reactant: O=C1CCc2cc(Cl)ccc2C1
Reactant: NCCCCl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)N1CCCC2=C1CCc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
100 g (0.55 mol) of 6-chloro-3,4-dihydro-2(1H)-naphthalenone are dissolved under argon in 2 l of toluene, treated with 64.0 g of powdered potassium hydroxide, heated to boiling temperature, 165 g of 3-chloropropylamine hydrochloride are added portionwise thereto during 30 minutes and the mixture is boiled on a water separator until educt can no longer be detected in the thin-layer chromatogram. After cooling to room temperature, the mixture is treated with 155 ml of triethylamine. While cooling with ice so that an internal temperature of 25° is not exceeded, the mixture is treated dropwise with 60 ml of acetyl chloride dissolved in 450 ml of toluene. The mixture is stirred at room temperature for 1 hour, extracted with water/methylene chloride and dried with magnesium sulfate. The solvent is distilled in a vacuum and there is obtained 4-acetyl-8-chloro-1,2,3,4,5,6-hexahydrobenzo[f]quinoline in the form of brown crystals which can be used as the crude product for the reaction described hereinafter.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[N:23]=[CH:22][CH:21]=[N:20]1)=[O:11].Cl[C:25]1[N:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][N:26]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[N:19]2[N:23]=[CH:22][CH:21]=[N:20]2)=[O:11])[C@@H:3]1[CH2:2][NH:1][C:25]1[N:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][N:26]=1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2nccc(C(F)(F)F)n2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 2-chloro-4-(trifluoromethyl)pyrimidine. ESI-MS (m/z): 460 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][C:8]([N:10]2[CH2:15][C@H:14]([CH3:16])[NH:13][C@H:12]([CH3:17])[CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1.C(N(C(C)C)CC)(C)C.[I-].[Na+]>C1COCC1.CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]([N:10]2[CH2:11][C@H:12]([CH3:17])[N:13]([CH2:25][C:24]3[CH:27]=[CH:28][C:21]([F:20])=[CH:22][CH:23]=3)[C@H:14]([CH3:16])[CH2:15]2)=[O:9])=[CH:18][CH:19]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: C[C@@H]1CN(C(=O)COc2ccc(Cl)cc2)C[C@H](C)N1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[C@@H]1CN(C(=O)COc2ccc(Cl)cc2)C[C@H](C)N1Cc1ccc(F)cc1
Yield: 61.3 %

Procedure:
To a solution of (cis)-1-((4-chlorophenoxy)methyl)carbonyl-3,5-dimethylpiperazine (0.20 g, 0.71 mmol) in anhydrous THF (2 mL) was added 4-fluorobenzyl-bromide (0.11 mL, 0.85 mmol), diisopropylethylamine (0.15 mL, 0.85 mmol) and sodium iodide (0.042 g, 0.28 mmol). The resultant mixture was stirred at ambient temperature for 2 days. At that time the mixture was poured into ether and washed with 5% aqueous NaHCO3 solution, then brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to afford a yellow oil. Purification by flash column chromatography on silica gel afforded 0.17 g of (cis)-1-((4-chlorophenoxy)methyl)carbonyl-3,5-dimethyl-4-(4-fluorobenzyl)piperazine as a pink oil; which was converted to its hydrochoride salt; NMR (CDCl3) 7.6 (m, 2), 7.3 (m, 4), 7.0-6.8 (m, 2), 5.0-2.8 (m, 10), 1.5-1.3 (m, 6) ppm.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:14][C:13]([F:16])([F:15])[CH2:12][CH2:11][N:10]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=2[O:26][CH3:27])[C:9]1=[O:28])(C)(C)C.Cl.O1CCOCC1.CCN(C(C)C)C(C)C.[Cl:46][C:47]1[CH:48]=[CH:49][C:50]([S:53](Cl)(=[O:55])=[O:54])=[N:51][CH:52]=1>ClCCl>[CH3:27][O:26][C:19]1[CH:20]=[C:21]([O:24][CH3:25])[CH:22]=[CH:23][C:18]=1[CH2:17][N:10]1[CH2:11][CH2:12][C:13]([F:15])([F:16])[CH2:14][C@@H:8]([NH:7][S:53]([C:50]2[CH:49]=[CH:48][C:47]([Cl:46])=[CH:52][N:51]=2)(=[O:55])=[O:54])[C:9]1=[O:28]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cn1
Reactant: COc1ccc(CN2CCC(F)(F)C[C@@H](NC(=O)OC(C)(C)C)C2=O)c(OC)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(CN2CCC(F)(F)C[C@@H](NS(=O)(=O)c3ccc(Cl)cn3)C2=O)c(OC)c1

Procedure:
[(R)-1-(2,4-Dimethoxy-benzyl)-5,5-difluoro-2-oxo-azepan-3-yl]-carbamic acid tert-butyl ester (0.46 g, 1.0 mmol) was dissolved in 20 ml dichloromethane. 4 M HCl/1,4-dioxan (20 ml) were added dropwise and the mixture was allowed to react for 1 h. The reaction mixture was concentrated under reduced pressure and concentrated once from acetonitrile. To the resultant hydrochloride salt was added CH2Cl2 (15 ml) followed by the dropwise addition of Hünig's base (0.44 ml, 2.5 mmol). A solution of 5-chloropyridine-2-sulfonyl chloride (0.33 g, 1.1 mmol) in CH2Cl2 (5 ml) was added and the reaction mixture (pH 8) was stirred for a further 1.5 h. The reaction mixture was purified over silica gel (heptane-ethylacetate, 95:5-0:100): white solid 0.37 g (76%);
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1)=[O:19].O>C1COCC1>[N:1]1([C:18]([O:20][C:21]2[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=2)=[O:19])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: c1ccc2c(c1)CCCN2
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 108.1 %

Procedure:
1,2,3,4-Tetrahydroquinoline (1 ml, 7.97 mmol) was dissolved in THF (20 ml), and pyridine (1.58 ml, 15.93 mmol) was added thereto and cooled on ice. p-Nitrophenyl chloroformate (1.61 g, 7.97 mmol) was added to the reaction solution and stirred at room temperature for 4 hours, then water and a saturated saline solution were added, and the reaction solution was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated under reduced pressure, whereby 2.57 g 4-nitrophenyl 3,4-dihydroquinoline-1(2H)-carboxylate was obtained as pale yellow solution.