Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][N:3]=1.C(N(CC)CC)C.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>CN(C=O)C.CCOCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])=[CH:4][N:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1ccc(Br)nc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1ccc(Br)nc1
Reaction time: 1 h
Yield: 97 %

Procedure:
To a stirred mixture of 2-bromo-5-hydroxymethylpyridine (4.7 g, 0.023 mol) and triethylamine (3.4 mL, 0.024 mol) in DMF (30 mL) was added tert-butyldimethylsilyl chloride. After 1 h, the mixture was diluted with ether and washed with water. The ether phase was dried (MgSO4) and concentrated to give 6.8 g (97%) of product as a colorless oil.
Reaction SMILES: N[C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[I:21].N([Cl:24])=O>C(#N)C.ClCCl>[Cl:24][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[I:21]
Reactant: O=NCl
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1I
Solvent: ClCCl
Solvent: CC#N
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(Cl)c1I

Procedure:
To a stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-iodopyrazole (1 g) in acetonitrile (15 ml) at 0° C. was added dropwise nitrosyl chloride (2.7 ml of a ˜1M solution in dichloromethane). The reaction mixture was heated under reflux for 10 minutes. The reaction mixture was then evaporated and the residue was purified by column chromatography on silica gel eluted with hexane: toluene (2:1) and then toluene. Combination and evaporation of suitable fractions gave the title compound as a pale orange solid, m.p. 115.7-116.3° C.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([N:17]2[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]2)=[O:16])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:31]([O:33][C:34]1[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][CH:35]=1)=[O:32]>C(Cl)Cl>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([O:14][C:15]([N:17]2[CH2:18][CH2:19][CH:20]([O:23][C:31]([O:33][C:34]3[CH:35]=[CH:36][C:37]([N+:40]([O-:42])=[O:41])=[CH:38][CH:39]=3)=[O:32])[CH2:21][CH2:22]2)=[O:16])=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Oc1ccc(Oc2ccccc2)cc1)N1CCC(O)CC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1CCN(C(=O)Oc2ccc(Oc3ccccc3)cc2)CC1
Reaction time: 2 h
Yield: 97.4 %

Procedure:
A solution of the alcohol (25 g, 80 mmol) produced in Example 2 and pyridine (6.4 mL, 80 mmol) in 300 mL of methylene chloride was added under nitrogen dropwise over one hour to a solution of 4-nitrophenyl chloroformate (16.1 g, 80 mmol) in 200 mL of methylene chloride at ice bath temperature. The reaction was stirred at ice bath temperature for two hours and then overnight at room temperature. The reaction was extracted one time with 1N HCl, two times with saturated Na2CO3, dried (MgSO4) and the solvent removed under reduced pressure to give 37.3 g of an off-white solid. Recrystallization from 1:1 ethyl acetate: hexane gave 26.4 g (69%) of the title compound as an off-white solid, mp 108-109° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[C@H:7]([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[NH2:8])([CH3:4])([CH3:3])[CH3:2].[C:18](N1C=CN=C1)([N:20]1[CH:24]=[CH:23][N:22]=[CH:21]1)=[O:19]>CN(C)C=O>[C:1]([O:5][C:6](=[O:17])[C@H:7]([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[NH:8][C:18]([N:20]1[CH:24]=[CH:23][N:22]=[CH:21]1)=[O:19])([CH3:3])([CH3:4])[CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)C[C@H](N)C(=O)OC(C)(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C[C@H](NC(=O)n1ccnc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
L-aspartic acid di-tert-butyl ester (0.84 g, 3.0 mmol) and 1,1′-carbonyldiimidazole (2.4 g, 15 mmol) were dissolved in N,N-dimethylformamide (10 ml), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added, and the mixture was washed with 1N hydrochloric acid (15 mL) and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (0.72 g, 2.1 mmol).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:7]([O:11][C:12]([N:14]1[CH2:17][CH:16](OS(C)(=O)=O)[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]>>[C:7]([O:11][C:12]([N:14]1[CH2:17][CH:16]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[CH2:15]1)=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Reactant: C1CNCCN1
Product: CC(C)(C)OC(=O)N1CC(N2CCNCC2)C1
Temperature: 120 °C

Procedure:
Piperazine (23.69 g, 8 mol. equiv.) was melted and 1-(t-butoxycarbonyl)-3-methanesulphonyloxyazetidine (see International Patent Application Publication no. WO93/19059) (8.64 g, 34.4 mmol) added. The mixture was heated at 120° C. for 15 hours under nitrogen. The reaction was cooled to room temperature and the excess piperazine removed under reduced pressure. The residue was then chromatographed on silica gel using gradient elution (methanol:dichloromethane 1:19 changing to 1:4, by volume) to give the title compound (6.32 g). LRMS m/z=242 (m+1)+.
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][C:17]([C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)=[CH:18][N:19]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH-].[K+].[CH2:29](I)[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].O>CN(C)C=O>[CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][C:17]([C:20]3[CH:21]=[CH:22][C:23]([O:26][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:24][CH:25]=3)=[CH:18][N:19]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCc1ccc(-c2ncc(-c3ccc(O)cc3)s2)cc1
Reactant: CCCCCCI
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCc1ccc(-c2ncc(-c3ccc(OCCCCCC)cc3)s2)cc1
Temperature: 100 °C
Reaction time: 0.75 h
Yield: 32.5 %

Procedure:
To a solution of 0.40 g (1.10 mM) of 2-(4-octylphenyl)-5-(4-hydroxyphenyl)thiazole in 20 ml of N,N-dimethylformamide (DMF), 0.40 g (1.10 mM) of potassium hydroxide was added, followed by stirring for 45 minutes at 100° C. To the mixture, 0.36 g (1.70 mM) of hexyl iodide was added at 100° C. under stirring, followed by further stirring for 6 hours and 16 minutes at 120° C. After the reaction, the reaction mixture was poured into 100 ml of water and extracted with ethyl acetate. The organic layer was washed with water, followed by drying with anhydrous sodium sulfate and distilling-off of the solvent under reduced pressure. The residue was purified by silica gel column chromatography (eluent: toluene) and recrystallized from ethanol to obtain 0.16 g of 2-(4-octylphenyl)-5-(4-hexyloxyphenyl)thiazole (Yield: 32.3%). ##STR43##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[N:12]=[CH:11][C:10]=1[NH2:20].NC1C=CC(C)=CC=1[C:24](O)=[O:25]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:9]2[C:18]3[CH:17]=[C:16]([CH3:19])[CH:15]=[CH:14][C:13]=3[N:12]=[CH:11][C:10]=2[NH:20][C:24]1=[O:25]
Reactant: Cc1ccc2ncc(N)c(Nc3ccccc3Cl)c2c1
Reactant: Cc1ccc(N)c(C(=O)O)c1
Product: Cc1ccc2ncc3[nH]c(=O)n(-c4ccccc4Cl)c3c2c1

Procedure:
The title compound os obtained as described for Example 92 using N4-(2-chloro-phenyl)-6-methyl-quinoline-3,4-diamine, which is obtained as described for Example 92, steps a=to e) using 2-amino-5-methyl-benzoic acid (Fluka, Buchs, Switzerland) as starting material. Title compound: Analytical HPLC: tret=5.80 min (Grad. 2); ES-MS: m/e0=310.1, 312.1.
Reaction SMILES: [NH2:1][C:2]([N:4]1[CH2:9][CH2:8][CH:7]([NH:10]C(=O)OC(C)(C)C)[CH2:6][CH2:5]1)=[S:3].[Cl:18][CH:19]([C:25](=O)[CH2:26][N:27]1[C:35](=[O:36])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]1=[O:37])[C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[ClH:18].[NH2:10][CH:7]1[CH2:6][CH2:5][N:4]([C:2]2[S:3][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:25]([CH2:26][N:27]3[C:35](=[O:36])[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:28]3=[O:37])[N:1]=2)[CH2:9][CH2:8]1
Reactant: CCOC(=O)C(Cl)C(=O)CN1C(=O)c2ccccc2C1=O
Reactant: CC(C)(C)OC(=O)NC1CCN(C(N)=S)CC1
Product: CCOC(=O)c1sc(N2CCC(N)CC2)nc1CN1C(=O)c2ccccc2C1=O
Product: Cl

Procedure:
The title compound was prepared in a manner analogous to Intermediate 126 starting from tert-butyl [1-(aminocarbonothioyl)piperidin-4-yl]carbamate (Intermediate 125) and ethyl 2-chloro-4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-oxobutanoate (Intermediate 35).
Reaction SMILES: [C:1]([O:5][C:6]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([O:50][Si:51]([C:54]([CH3:57])([CH3:56])[CH3:55])([CH3:53])[CH3:52])[CH2:21][N:22]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]2[CH:46]=[CH:45][C:44]([N+:47]([O-])=O)=[CH:43][CH:42]=2)[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[NH2:47][C:44]1[CH:43]=[CH:42][C:41]([CH2:40][CH2:39][CH2:38][CH2:37][O:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][N:22]([CH2:21][C@@H:20]([C:12]2[CH:11]=[CH:10][C:9]([O:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[C:18]3[C:13]=2[CH:14]=[CH:15][C:16](=[O:19])[NH:17]3)[O:50][Si:51]([C:54]([CH3:57])([CH3:56])[CH3:55])([CH3:53])[CH3:52])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:46][CH:45]=1
Reactant: CC(C)(C)OC(=O)Oc1ccc([C@H](CN(CCCCCCOCCCCc2ccc([N+](=O)[O-])cc2)C(=O)OC(C)(C)C)O[Si](C)(C)C(C)(C)C)c2ccc(=O)[nH]c12
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)Oc1ccc([C@H](CN(CCCCCCOCCCCc2ccc(N)cc2)C(=O)OC(C)(C)C)O[Si](C)(C)C(C)(C)C)c2ccc(=O)[nH]c12

Procedure:
A suspension of Pd/C (10% w/w, 15 mg) and Intermediate 107 (0.25 g, 0.31 mmol) in MeOH (4 mL) was stirred under a balloon of hydrogen gas for 30 minutes, followed by filtration of the mixture through a pad of Celite diatomaceous earth, and concentration under reduced pressure. The title compound was provided as a white foam (0.13 g, 54%). ES/MS calcd. for C43H68N3O8Si+ 782.5. Found m/z=782.6 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]([CH:5]1[CH2:10][CH2:9][N:8](C(OCC2C=CC=CC=2)=O)[CH2:7][CH2:6]1)=[O:4].CO.[H][H]>[Pd]>[CH3:1][N:2]([CH3:21])[C:3]([CH:5]1[CH2:6][CH2:7][NH:8][CH2:9][CH2:10]1)=[O:4]
Reactant: [H][H]
Reactant: CN(C)C(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CN(C)C(=O)C1CCNCC1

Procedure:
Palladium (10.0 mg, 9.40E-6 mol) was added to a solution of benzyl 4-[(dimethylamino)carbonyl]piperidine-1-carboxylate (190.0 mg, 0.0006544 mol) in methanol (5.0 mL, 0.12 mol) under nitrogen. The mixture was hydrogenised with a balloon filled with hydrogen for 3 h. The mixture was filtered and the filtrate was concentrated to give the desired product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH:11]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:12])[C:5]([OH:7])=O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[NH2:49][CH2:50][C:51]1[C:52]([OH:59])=[N:53][C:54]([CH3:58])=[CH:55][C:56]=1[CH3:57]>ClCCl.O>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH:11]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:12])[C:5]([NH:49][CH2:50][C:51]1[C:52]([OH:59])=[N:53][C:54]([CH3:58])=[CH:55][C:56]=1[CH3:57])=[O:7]
Reactant: CC(Oc1ccccc1)c1ccc(C(=O)O)cc1F
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)Oc3ccccc3)c(F)c2)c(O)n1
Reaction time: 0.5 h
Yield: 45.8 %

Procedure:
A solution of 3-fluoro-4-(1-phenoxyethyl)benzoic acid (300 mg, 1.2 mmol) in dichloromethane (15.0 mL) was added N-hydroxybenzotriazole (270 mg, 2 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (384 mg, 2 mmol), triethylamine (202 mg, 2 mmol). The mixture was stirred for 30 minutes. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (270 mg, 1.8 mmol) was added and the mixture was stirred at room temperature for 12 hours. To the mixture, water (50 mL) was added. The mixture was extracted with dichloromethane (2*50 mL). The combined organic phase was separated, dried over sodium sulfate, filtered and concentrated to give a residue. The residue was purified by preparative-TLC (silica gel, methanol/dichloromethane=1:20, 1% NH3) to give 3-fluoro-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(1-phenoxyethyl)benzamide as white solid (217 mg, 46%). LRMS (M+H+) m/z: calcd 394.17. found 394. HPLC purity (214 nm): 96%. 1H NMR (300 MHz, CD3OD): δ 7.57-7.49 (m, 3H), 7.16 (t, J=8.4 Hz, 2H), 6.85-6.82 (m, 3H), 6.09 (s, 1H), 5.68 (q, J=6.6 Hz, 1H), 4.45 (s, 2H), 2.34 (s, 3H), 2.23 (s, 3H), 1.62 (d, J=8.4 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:36])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:26][C:25]=3[O:33][CH2:34][CH3:35])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[CH3:39][S:40]([CH2:43][CH2:44][CH2:45][N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1)(=[O:42])=[O:41]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:36])[C@:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[N:11]([C:21]([N:49]3[CH2:48][CH2:47][N:46]([CH2:45][CH2:44][CH2:43][S:40]([CH3:39])(=[O:41])=[O:42])[CH2:51][CH2:50]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([CH:30]([CH3:31])[CH3:32])=[CH:26][C:25]=3[O:33][CH2:34][CH3:35])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)CCCN1CCNCC1
Reactant: CCOc1cc(C(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Product: CCOc1cc(C(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCS(C)(=O)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-isopropyl-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-(3-methanesulfonyl-propyl)-piperazine dihydrochloride (prepared as described in Fotouhi, N. et al. WO 2005110996) to give the title compound as a racemic mixture. The enantiomers were separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OJ-H 3×25 cm, 35° C. at 100 bar, eluting with 15% of 1:1 ethanol/acetonitrile in carbon dioxide) gave the title compound. HR-MS (ES, m/z) calculated for C37H47N4O4SCl2 [(M+H)+] 713.2690, observed 713.2692.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6](=O)[CH2:5][CH2:4][N:3]1[C:9]([O:11][CH3:12])=[O:10].C1(C[NH2:20])C=CC=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1.[H][H]>[Pd].C(O)C>[NH2:20][CH:6]1[CH2:5][CH2:4][N:3]([C:9]([O:11][CH3:12])=[O:10])[CH:2]([CH3:1])[CH2:7]1
Reactant: [H][H]
Reactant: NCc1ccccc1
Reactant: COC(=O)N1CCC(=O)CC1C
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: COC(=O)N1CCC(N)CC1C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 56 parts of methyl 2-methyl-4-oxo-1-piperidinecarboxylate 35.4 parts of benzenemethanamine, 0.1 parts of 4-methylbenzenesulfonic acid and 240 parts of ethanol is stirred for 15 minutes at room temperature. The whole is hydrogenated at normal pressure and at room temperature with 7 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is distilled, yielding methyl 4-amino-2-methyl-1-piperidine carboxylate; bp. 99°-102° C. at 0.2 mm. pressure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-])=O.[Al].S(=O)(=O)(O)[OH:13].C(=O)([O-])O.[Na+]>O>[F:1][C:2]1[CH:7]=[C:6]([OH:13])[CH:5]=[CH:4][C:3]=1[NH2:8]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: O=S(=O)(O)O
Agent: O=C([O-])O
Agent: [Al]
Agent: [Na+]
Solvent: O
Product: Nc1ccc(O)cc1F
Reaction time: 0.67 h
Yield: 86 %

Procedure:
2.03 Grams of o-fluoronitrobenzene, 0.70 g of aluminum powder, 43 ml of water and 4.4 g of conc. sulfuric acid were added to a reactor and stirred at an inner temperature of from 90° to 95° C. for 40 minutes. After cooling the reaction solution, a 5% aqueous sodium hydrogencarbonate solution was added to make the reaction solution weakly alkaline. The reaction solution was then extracted with three 100-ml portions of diethyl ether. The ether layers were combined, dried and concentrated to obtain a crude product. This crude product was subjected to chromatography on silica gel to obtain 1.58 g of 3-fluoro-4-aminophenol.
Reaction SMILES: [C:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[N:7]=[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:5]=1)(=[O:3])[CH3:2].CO[CH:25](OC)[N:26]([CH3:28])[CH3:27]>C1(C)C=CC=CC=1>[CH3:25][N:26]([CH3:28])/[CH:27]=[CH:2]/[C:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[N:7]=[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:5]=1)=[O:3]
Reactant: CCOC(=O)c1cc(C(C)=O)n(Cc2cccc(OC)c2)n1
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(C(=O)/C=C/N(C)C)n(Cc2cccc(OC)c2)n1
Temperature: 140 °C
Reaction time: 18 h

Procedure:
To a solution of ethyl 5-acetyl-1-(3-methoxy-benzyl)-1H-pyrazole-3-carboxylate (300 mg, 1 mmol) in 2 mL toluene, 240 mg (2 mmol) of N,N-dimethylformamide dimethyl acetal were added. The mixture was stirred for 18 h at 140° C. The volatiles were removed under vacuum to afford the title compound in quantitative yield.
Reaction SMILES: [Br:1][C:2]1[NH:6][CH:5]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[C:3]=1[CH:11]([CH3:13])[CH3:12].[H-].[Na+].[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[Br:1][C:2]1[N:6]([S:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:24])=[O:23])[CH:5]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[C:3]=1[CH:11]([CH3:13])[CH3:12]
Reactant: COC(=O)c1c[nH]c(Br)c1C(C)C
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1cn(S(=O)(=O)c2ccccc2)c(Br)c1C(C)C
Yield: 93 %

Procedure:
Using methyl 5-bromo-4-isopropyl-1H-pyrrole-3-carboxylate (3.29 g), sodium hydride (60% in oil, 708 mg), and benzenesulfonyl chloride (2.60 g), a procedure as in Reference Example 41 was performed to give the title compound as a pale-yellow oil (yield 4.8 g, 93%).
Reaction SMILES: [CH:1]1([NH:5][C@H:6]2[CH2:11][CH2:10][CH2:9][CH2:8][C@H:7]2[NH:12][C:13](=[O:30])[C:14]2[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][C:17]([C:24]([F:27])([F:26])[F:25])=[CH:16][C:15]=2[O:28][CH3:29])[CH2:4][CH2:3][CH2:2]1.C=O.[C:33](=O)([O-])[O-].[Na+].[Na+]>C(O)=O>[CH:1]1([N:5]([CH3:33])[CH:6]2[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]2[NH:12][C:13](=[O:30])[C:14]2[C:19]([C:20]([F:21])([F:22])[F:23])=[CH:18][C:17]([C:24]([F:25])([F:26])[F:27])=[CH:16][C:15]=2[O:28][CH3:29])[CH2:4][CH2:3][CH2:2]1
Reactant: O=C([O-])[O-]
Reactant: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)N[C@@H]1CCCC[C@@H]1NC1CCC1
Agent: C=O
Agent: [Na+]
Solvent: O=CO
Product: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)NC1CCCCC1N(C)C1CCC1
Temperature: 110 °C
Yield: 38 %

Procedure:
cis-N-(2-Cyclobutylamino-cyclohexyl)-2-methoxy-4,6-bis-trifluoromethyl-benzamide (example 16, 118 mg, 0.27 mmol) was dissolved in 2 mL formic acid. Formaldehyde (36% in water, 0.06 mL, 0.81 mmol) was added and the reaction mixture was stirred at 110° C. over night. The reaction mixture was basified by slow addition of 10 ml 1N sodium carbonate solution. The mixture was extracted three times with ethyl acetate. The combined organic phases were dried on sodium sulfate, filtered and evaporated. Purification of the residue by flash chromatography on silica gel (dichloromethane/methanol/ammonia 100:0:0→110:10:1) yielded the title compound as a white solid (46 mg, 38%), MS: m/e=453.2 [(M+H)+].
Reaction SMILES: Cl[C:2]1[C:3]2[C:4]3[C:5]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:6]=4[N:7]=[C:8]([NH:16][CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:9]=3[C:10](=[O:15])[C:11]=2[CH:12]=[CH:13][N:14]=1>CN(C)CCN.ClCCl>[CH3:21][N:19]([CH3:20])[CH2:18][CH2:17][NH:16][C:8]1[C:9]2[C:10](=[O:15])[C:11]3[CH:12]=[CH:13][N:14]=[C:2]([NH:16][CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:3]=3[C:4]=2[C:5]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:6]=2[N:7]=1
Reactant: COc1ccc2c3c(c(NCCN(C)C)nc2c1)C(=O)c1ccnc(Cl)c1-3
Agent: CN(C)CCN
Solvent: ClCCl
Product: COc1ccc2c3c(c(NCCN(C)C)nc2c1)C(=O)c1ccnc(NCCN(C)C)c1-3
Temperature: 60 °C
Reaction time: 8 h

Procedure:
23 mg. of 11-chloro-6-(2-dimethylamino-ethylamino)-3-methoxy-5,10-diaza-benzo[c]fluoren-7-one (Example 27e) was suspended in N,N-dimethylethylenediamine (2.0 ml) and the mixture was stirred at 60° C. overnight under nitrogen. The solution was diluted with dichloromethane and washed with saturated ammonium chloride aqueous solution and dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified by silica gel thin layer chromatography developed by dichloromethane-methanol-25% ammonia solution=100:5:1. The desired product was obtained as a dark red powder (17 mg). ESI−MS: m/z 435 (MH+); 1H-NMR (CDCl3): δ2.27 (6H, s), 2.34 (6H, s), 2.60-2.66 (4H, m), 3.60 (2H, q-like, J=6.6 Hz), 3.75 (2H, q-like, J=6.3 Hz), 3.96 (3H, s), 5.76 (1H, brt, J=ca 6 Hz), 6.84 (1H, dd, J=2.6 Hz, 9.6 Hz), 6.92 (1H, d, J=4.6 Hz), 7.04 (1H, d, J=2.6 Hz), 7.36 (1H, brt, J=ca 6 Hz), 8.27 (1H, d, J=4.6 Hz), 8.49 (1H, d, 9.6 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)[CH3:2].CC(C)([O-])C.[K+].[C:20]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])(=[O:23])[CH:21]=[CH2:22]>C1COCC1>[CH2:1]([O:3][C:4](=[O:13])[CH:5]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)[CH2:22][CH2:21][C:20]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH3:2]
Reactant: CCOC(=O)Cc1ccc(Cl)cc1
Reactant: C=CC(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CCC(=O)OC(C)(C)C)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
The (4-chlorophenyl)-acetic acid ethyl ester (9.52 g, 47.9 mmol) was dissolved in 80 mL of THF, cooled to 0° C., and treated with potassium tert-butoxide (538 mg, 4.79 mmol). The resulting orange solution was allowed to stir for 15 minutes at 0° C., then cooled to −78° C. The tert-butyl acrylate (7.72 mL, 52.7 mmol) was added in three equal portions over ten minutes. The solution was allowed to stir overnight warming slowly to room temperature. The reaction solution was concentrated in vacuo, and the residue was partitioned between ethyl acetate and saturated NH4Cl solution. The aqueous was extracted with ethyl acetate, and the organics were combined. The organic was washed with brine, separated, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by chromatography (silica gel eluted with 9:1 hexanes:EtOAc) to afford the 2-(4-chlorophenyl)-pentanedioic acid 5-tert-butyl ester 1-ethyl ester in greater than 80% purity (9.00 g, 57%). 1H NMR (CDCl3, 400 MHz) δ 7.31-7.21 (m, 4H), 4.13 (q, J=7.6 Hz, 2H), 3.58 (t, J=8.0 Hz, 1H), 2.27 (m, 1H), 2.16 (t, J=7.2 Hz, 2H), 2.04 (m, 1H), 1.43 (s, 9H), 1.21 (t, J=7.6 Hz, 3H).