Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:17]=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=2)[CH2:3]1.N1C=CC=CC=1.[N:30]1[CH:35]=[CH:34][CH:33]=[C:32]([S:36](Cl)(=[O:38])=[O:37])[CH:31]=1.CC1(C)C2C(=CC=C(C)C=2)NC(C2C=C(N)C=CC=2)C1>ClCCl>[CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:13])[F:14])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:17]=[C:18]([NH:22][S:36]([C:32]3[CH:31]=[N:30][CH:35]=[CH:34][CH:33]=3)(=[O:38])=[O:37])[CH:19]=[CH:20][CH:21]=2)[CH2:3]1
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: CC1(C)CC(c2cccc(N)c2)Nc2ccc(C(F)(F)F)cc21
Agent: Cc1ccc2c(c1)C(C)(C)CC(c1cccc(N)c1)N2
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)CC(c2cccc(NS(=O)(=O)c3cccnc3)c2)Nc2ccc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.4 %

Procedure:
To a stirred solution of 3-(4,4-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamine (150 mg, 0.47 mmol) in pyridine (0.74 mg, 0.94 mmol) and dichloromethane (3 mL) at 0° C. was added dropwise a solution of pyridine-3-sulfonyl chloride (100 mg, 0.56 mmol) in dichloromethane (1 mL). The mixture was stirred at room temperature overnight. Thin layer chromatography and LC-MS indicated that 3-(4,4,6-trimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamine was consumed completely. The mixture was quenched with water (5 mL) and extracted with dichloromethane (5 mL×2). The combined organic layers were dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography on silica gel to afford pyridine-3-sulfonic acid [3-(4,4-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-amide (170 mg, 78.7%) as a white solid. MS (ESI+APCI) M+1=442.3.
Reaction SMILES: CO[CH:3](OC)[CH2:4][C:5]1[CH:30]=[CH:29][C:8]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([S:16]([C:19]3[S:23][C:22]([NH:24][C:25](=[O:27])[CH3:26])=[N:21][C:20]=3[CH3:28])(=[O:18])=[O:17])[CH2:12][CH2:11]2)=[CH:7][CH:6]=1.[I-].[Na+].Cl[Si](Cl)(Cl)C.C(O)(=O)C.[NH2:44][CH2:45][C@@H:46]([C:48]1[CH:49]=[CH:50][C:51]([OH:59])=[C:52]([NH:54][S:55]([CH3:58])(=[O:57])=[O:56])[CH:53]=1)[OH:47].C([BH3-])#N.[Na+]>C(#N)C.CO.ClCCl>[OH:47][C@H:46]([C:48]1[CH:49]=[CH:50][C:51]([OH:59])=[C:52]([NH:54][S:55]([CH3:58])(=[O:57])=[O:56])[CH:53]=1)[CH2:45][NH:44][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([S:16]([C:19]3[S:23][C:22]([NH:24][C:25](=[O:27])[CH3:26])=[N:21][C:20]=3[CH3:28])(=[O:17])=[O:18])[CH2:12][CH2:11]2)=[CH:29][CH:30]=1
Reactant: COC(Cc1ccc(NC2CCN(S(=O)(=O)c3sc(NC(C)=O)nc3C)CC2)cc1)OC
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Agent: C[Si](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [I-]
Solvent: ClCCl
Solvent: CC#N
Solvent: CC(=O)O
Product: CC(=O)Nc1nc(C)c(S(=O)(=O)N2CCC(Nc3ccc(CCNC[C@H](O)c4ccc(O)c(NS(C)(=O)=O)c4)cc3)CC2)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 7 %

Procedure:
N-[5-({4-[4-(2,2-dimethoxyethyl)anilino]-1-piperidinyl}sulfonyl)-4-methyl-1,3-thiazol-2-yl]acetamide (0.46 g, 0.953 mmol) was added to a pre-prepared mixture of sodium iodide (0.357 g, 2.38 mmol) and trichloro(methyl)silane (0.224 mL, 1.91 mmol) in anhydrous acetonitrile. The reaction was stirred at ambient temperature for 10 minutes. Dichloromethane was added and the reaction washed with 10% sodium thiosulfate solution, water and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and the solvent partially removed in vacuo. The aldehyde solution was used directly and treated with methanol, acetic acid (0.146 mL, 2.43 mmol), N-{5-[(1R)-2-amino-1-hydroxyethyl]-2-hydroxyphenyl}methanesulfonamide (0.235 g, 0.953 mmol) followed by sodium cyanoborohydride (0.06 g, 0.953 mmol). The reaction was stirred at ambient temperature for 24 hours. The reaction was taken to dryness in vacuo, adsorbed onto silica and purified by flash chromatography on silica gel Merck-60 (eluant: 5:1 chloroform-methanol containing 1% ammonium hydroxide) to yield the title compound (0.045 g, 0.067 mmol).
Reaction SMILES: [C:1]1([NH:7][C:8]([NH:10][C:11]2[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][N:13](C(OC(C)(C)C)=O)[N:12]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>FC(F)(F)C(O)=O.ClCCl>[C:1]1([NH:7][C:8]([NH:10][C:11]2[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][NH:13][N:12]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1cn(C(=O)OC(C)(C)C)nc1NC(=O)Nc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1c[nH]nc1NC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
To a solution of 3-amino-4-ethoxycarbonylpyrazole (1.0 g) in THF (10 ml), was added di-tert-butyl dicarbonate (2.2 g), and the mixture was stirred overnight at room temperature. The reaction mixture was evaporated under reduced pressure followed by silica-gel column chromatography (toluene/ethyl acetate=15/1) to give 3-amino-1(tert-butoxycarbonyl)-4-ethoxycarbonylpyrazole (0.59 g). This intermediate was derived to N-phenyl-N'-(1-tert-butoxycarbonyl-4-ethoxycarbonylpyrazol-3-yl)urea by the similar method to Reference Example 1 (yield 75%). N-phenyl-N'-(1-tertbutoxycarbonyl-4-ethoxycarbonylpyrazol-3-yl)urea (0.5 g) was dissolved in a solution of 10% trifluoroacetic acid in dichloromethane (7 ml), and the resulted solution was stirred overnight at room temperature. The reaction mixture was evaporated under reduced pressure followed by addition of ether to give the title compound (0.304 g, yield 83%).
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH:20]([OH:22])[CH3:21]>C(C(C)=O)C>[N:1]1([C:6]2[CH:7]=[C:8]([CH:9]=[CH:10][CH:11]=2)[O:12][CH2:21][CH2:20][OH:22])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Oc1cccc(-n2ccnc2)c1
Reactant: CC(O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: OCCOc1cccc(-n2ccnc2)c1
Yield: 49.9 %

Procedure:
A slurry of 16.0 g (0.10 mole) of 3-(imidazol-1-yl)phenol and 42 g (0.3 mole) of potassium carbonate in 100 ml of methyl ethyl ketone was heated to reflux with stirring. The mixture was treated with 25.5 g (0.3 mole) of chloroethanol by dropwise addition over a 2 hr period. The mixture was heated at reflux for an additional 18 hr then treated with an additional 16.1 g (0.2 mole) of chloroethanol and 27.6 (0.2 mol) of potassium carbonate. After an additional 22 hr heating at reflux all starting material was consumed. The reaction mixture was filtered and the filtrate was concentrated. The residue was partitioned between methylene chloride and 0.1N sodium hydroxide solution. The organic layer was concentrated and the residue was crystallized from ethyl acetate to give 10.2 g (50%) of the title compound as tan crystals, mp 81.0°-83.0° C.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([O:34][CH3:35])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[NH2:38][CH2:39][C:40]1[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=1.CS(C)=O>C(#N)C>[CH3:35][O:34][C:23]1[CH:22]=[C:21]([C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:38][CH2:39][C:40]4[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=4)=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:20])[CH:26]=[CH:25][C:24]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33]
Reactant: NCc1cccnc1
Reactant: COc1cc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)ccc1-c1ccccc1C
Solvent: CS(C)=O
Solvent: CC#N
Product: COc1cc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)ccc1-c1ccccc1C

Procedure:
A solution of 2,2,2-trichloro-1-{10-[(2-methoxy-2′-methyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Step F (2 mmol), and 3-aminomethylpyridine (4.2 mmol), in dimethylsulfoxide (7 mmol) and acetonitrile (15 mL) was stirred at 80° C. for 18 hours. The solvents were evaporated and the residue was dissolved in dichloromethane, washed with water, dried over anhydrous sodium sulfate, and evaporated. The product crystallized from ethyl acetate and hexane (0.96g; 89%), m.p. 165-167° C.
Reaction SMILES: OS(O)(=O)=O.[CH2:6]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([OH:13])=[O:12])[CH3:7].[CH3:17]O>O>[CH2:6]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([O:13][CH3:17])=[O:12])[CH3:7]
Reactant: CO
Reactant: CCc1cccc(C(=O)O)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: CCc1cccc(C(=O)OC)c1
Temperature: 25 °C
Yield: 91 %

Procedure:
Concentrated H2SO4 (1.0 mL) was added to a solution of 3-ethylbenzoic acid (500 mg, 3.33 mmol) in MeOH (10 mL). The mixture was heated at reflux for 18 h then cooled to room temperature. The mixture was diluted with water (50 mL) and extracted with Et2O (3×100 mL). The combined organic phase was dried (Na2SO4), filtered and concentrated in vacuo. Purification of the crude residue by chromatography on silica gel (hexanes→20% EtOAc/hexanes, gradient) afforded 500 mg (91%) of methyl 3-ethylbenzoate.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)([OH:3])=[O:2].[NH2:20][CH2:21][CH:22]1[CH2:26][CH2:25][CH2:24][N:23]1[CH2:27]C>>[C:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[O:7][C:8]1[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=1)([OH:3])=[O:2].[CH3:27][N:23]1[CH2:24][CH2:25][CH2:26][CH:22]1[CH2:21][NH:20][C:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:3]
Reactant: CCN1CCCC1CN
Agent: O=C(O)c1cccc(Oc2ccc([N+](=O)[O-])cc2)c1
Product: CN1CCCC1CNC(=O)c1cccc(Oc2ccc([N+](=O)[O-])cc2)c1

Procedure:
Entry 64: 4-(3-Carboxyphenoxy)-1-nitrobenzene was synthesized according to Method A13, Step 2. 4-(3-Carboxyphenoxy)-1-nitrobenzene was coupled with 2-aminomethyl-1-ethylpyrrolidine according to Method A13, Step 3 to give 4-(3-(N-((1-methylpyrrolidinyl)methyl)carbamoyl)phenoxy)-1-nitrobenzene. According to Method A 13 Step 4, 4-(3-(N-((1-methylpyrrolidinyl)methyl)carbamoyl)phenoxy)-t-nitrobenzene was reduced to 4-(3-(N-((1-methylpyrrolidinyl)methyl)carbamoyl)phenoxy)aniline. According to Method C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(N-((1-methylpyrrolidinyl)methyl)carbamoyl)phenoxy)aniline to afford the urea.
Reaction SMILES: [C:1]([CH2:4][CH:5]([CH3:19])[CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH:12]=[CH:11]2)([OH:3])=O.C(=O)([O-])[O-].[K+].[K+].ClC(OCC(C)C)=O.[CH3:34][NH:35][CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH:37]1[CH3:42].[Na+].[Cl-]>CN(C)C=O>[CH3:34][N:35]([CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH:37]1[CH3:42])[C:1]([CH2:4][CH:5]([CH3:19])[CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH:12]=[CH:11]2)=[O:3]
Reactant: CC(COc1ccc2[nH]c(=O)ccc2c1)CC(=O)O
Reactant: CNC1CCCCC1C
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CC(COc1ccc2[nH]c(=O)ccc2c1)CC(=O)N(C)C1CCCCC1C
Reaction time: 2 h

Procedure:
2.6 Grams of 6-(3-carboxy-2-methylpropoxy)-carbostyril and 1.4 g of potassium carbonate are added to 50 ml of dimethylformamide, followed by dropwise addition of 1.1 ml of isobutyl chloroformate under external ice cooling and agitation while maintaining the internal temperature at 10° to 20° C. After this dropwise addition, the mixture is agitated at 30° to 40° C. for 2 hours and then added with 1.6 ml of N-methyl-2-methylcyclohexylamine, followed by additional 2-hour agitation at the same temperature. The reaction solution is poured into 200 ml of saturated NaCl solution and the precipitated crystals are filtered out and washed with water. The obtained crude crystals are recrystallized from benzene-ligroin to obtain 0.9 g of 6-{3-[N-methyl-N-(2-methylcyclohexyl)-aminocarbonyl]-2-methylpropoxy}carbostyril in the form of colorless needle-like crystals. m.p., 146°-149° C.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([F:22])[CH:16]=1)(OC(C)(C)C)=O.C=O.[ClH:25]>C(O)=O>[ClH:25].[F:22][C:17]1[CH:16]=[C:15]([CH:20]=[C:19]([F:21])[CH:18]=1)[O:14][CH2:13][C@@H:9]1[CH2:10][CH2:11][CH2:12][N:8]1[CH3:1]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cc(F)cc(F)c1
Agent: C=O
Agent: Cl
Solvent: O=CO
Product: CN1CCC[C@H]1COc1cc(F)cc(F)c1

Procedure:
A 0.25 g (0.8 mmol) sample of (S)-N-BOC-2-(3,5-difluorophenoxymethyl)pyrrolidine, from Example 7b above, was dissolved in 10 mL of a 2:1 mixture of formic acid:formaldehyde and stirred for 16 hr at reflux. To this solution was added excess 10% HCl, and the mixture was extracted twice with ethyl acetate. The aqueous layer was adjusted to pH 12 with K2CO3 and then extracted with methylene chloride. The solvent was dried over MgSO4 and removed under vacuum to yield the crude product, which was then triturated with ether as ethanolic HCl was added. Repeated drying and washing with ether gave 0.118 g of title product. MS: 228 (M+H)+. NMR (D2O) δ: 2.01-2.24 (m, 2H), 2.34-2.43 (m, 1H), 3.02 (s, 3H), 3.27 (br s, 1H), 3,78 (br s, 1H), 3.92 (br s, 1H), 4.27 (dd, 1H, J=6, 11 Hz), 4.44 (dd, 1H, J=3, 11 Hz), 6.63-6.71 (m, 3H). Anal. Calcd for C12H16ClF2NO.0.8 H2O: C, 51.82; H, 6.38; N, 5.04; Found: C, 51.77; H, 6.06; N, 4.82.
Reaction SMILES: [CH:1]([Mg]Cl)([CH3:3])[CH3:2].[Br:6][C:7]1[CH:15]=[C:14]2[C:10]([C:11](=[O:17])[C:12](=[O:16])[NH:13]2)=[CH:9][CH:8]=1>C1COCC1>[Br:6][C:7]1[CH:15]=[C:14]2[C:10]([C:11]([OH:17])([CH:1]([CH3:3])[CH3:2])[C:12](=[O:16])[NH:13]2)=[CH:9][CH:8]=1
Reactant: CC(C)[Mg]Cl
Reactant: O=C1Nc2cc(Br)ccc2C1=O
Solvent: C1CCOC1
Product: CC(C)C1(O)C(=O)Nc2cc(Br)ccc21

Procedure:
Addition of isopropylmagnesiumchloride to 6-bromoisatin at −78° C. in THF gives after usual workup 6-bromo-3-hydroxy-3-isopropyl-1,3-dihydro-indol-2-one which is reacted with 8-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-ylamine using general procedure 2 to give the title compound as a solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][C:12]([OH:14])=O)=[CH:2]1.[CH:15]([NH:18][NH:19][C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH3:17])[CH3:16].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][C:12]([N:18]([CH:15]([CH3:17])[CH3:16])[NH:19][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:14])=[CH:2]1
Reactant: CC(C)NNC(=O)c1ccccc1
Reactant: O=C(O)CCc1c[nH]c2ccccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To solution containing 3-(1H-indol-3-yl)propanoic acid (200 mg, 1.06 mmol), N′-isopropylbenzohydrazide (283.4 mg, 1.59 mmol) and HATU (604.6 mg, 1.59 mmol) dissolved in DMF (7.0 ml), N,N-diisopropylethylamine (DIPEA)(0.277 ml, 1.59 mmol) was slowly drop-wise added and stirred at room temperature for 12 hr. The reaction mixture was diluted with EtOAc, washed with water and brine, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was separated through silica gel chromatography (n-hexane:EtOAc:methanol=20:3:1) and dried so that white solid form of N′-(3-(1H-indol-3-yl)propanoyl)-N′-isopropylbenzohydrazide was obtained (327 mg, 88%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:30])=[C:24]([N+:27]([O-])=O)[CH:25]=2)[NH:20][C:19](=[O:31])[C:18]=1[C:32]1[CH:37]=[C:36]([CH3:38])[CH:35]=[C:34]([CH3:39])[CH:33]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].NN>O.O.O.O.O.O.[Fe](Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:30])=[C:24]([NH2:27])[CH:25]=2)[NH:20][C:19](=[O:31])[C:18]=1[C:32]1[CH:33]=[C:34]([CH3:39])[CH:35]=[C:36]([CH3:38])[CH:37]=1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1cc(C)cc(-c2c(OCC[C@@H]3CCCCN3C(=O)OC(C)(C)C)c3cc([N+](=O)[O-])c(Cl)cc3[nH]c2=O)c1
Agent: Cl[Fe](Cl)Cl
Agent: NN
Solvent: O
Product: Cc1cc(C)cc(-c2c(OCC[C@@H]3CCCCN3C(=O)OC(C)(C)C)c3cc(N)c(Cl)cc3[nH]c2=O)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 100.1 %

Procedure:
To a solution of (S)-2-{2-[7-chloro-3-(3,5-dimethylphenyl)-6-nitro-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester (Example 5, Step 5A: 750 mg in 13 mL dry methanol) was added 18 mg iron(III)chloride hexahydrate followed by 100 mg activated carbon and the mixture heated to reflux on an oil bath. After 15 minutes, hydrazine (0.169 mL) was added dropwise and the reaction allowed to proceed at reflux for 12 hours. At this time, the mixture was cooled to room temperature, filtered through diatomaceous earth and the solvent removed in vacuo. The concentrate was solvated in 400 mL methylene chloride, washed successively with water (100 mL) and brine (100 mL), dried over sodium sulfate and concentrated in vacuo to give the title compound (crude: 710 mg).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([N:8]2[CH:13]=[CH:12][C:11](=[O:14])[CH:10]=[CH:9]2)[CH2:4][CH2:3]1.[NH:15]1[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)=[O:21])[CH2:16]1>>[O:14]=[C:11]1[CH:12]=[CH:13][N:8]([CH:5]2[CH2:6][CH2:7][CH:2]([N:15]3[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[CH:26]=4)=[O:21])[CH2:16]3)[CH2:3][CH2:4]2)[CH:9]=[CH:10]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: O=C1CCC(n2ccc(=O)cc2)CC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(n3ccc(=O)cc3)CC2)C1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 1-(4-oxo-cyclohexyl)-1H-pyridin-4-one (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in Example 2 Step C) using the procedure described in Step D of Example 1.
Reaction SMILES: [C:1]([NH:8][C@H:9]1[CH2:12][C@H:11]([CH2:13][OH:14])[CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O[N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[C:1]([NH:8][C@H:9]1[CH2:12][C@H:11]([CH2:13][O:14][N:16]2[C:20](=[O:21])[C:19]3[C:18](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:17]2=[O:26])[CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](CO)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)N[C@H]1C[C@H](CON2C(=O)c3ccccc3C2=O)C1

Procedure:
Analogously to Example 6a, starting from 5.6 g (0.02782 mol) of trans-3-(N-BOC-amino)-cyclobutanemethanol, 4.54 g (0.02783 mol) of N-hydroxyphthalimide, 7.3 g (0.02783 mol) of triphenylphosphine and 5.12 ml (0.0306 mol) of diethyl azodicarboxylate (93%), the title compound is obtained, m.p. 120°-122° C.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[C:20]([F:23])([F:22])[F:21])[C:12]2=[O:24])[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:25][O:26][CH2:27][CH2:28][N:29]1[CH:33]=[CH:32][C:31]([NH2:34])=[N:30]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[C:20]([F:23])([F:22])[F:21])[C:12]2=[O:24])[C:8]([NH:34][C:31]2[CH:32]=[CH:33][N:29]([CH2:28][CH2:27][O:26][CH3:25])[N:30]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COCCn1ccc(N)n1
Reactant: O=C(O)[C@H](CC1CCCC1)N1Cc2c(cccc2C(F)(F)F)C1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCn1ccc(NC(=O)[C@H](CC2CCCC2)N2Cc3c(cccc3C(F)(F)F)C2=O)n1
Temperature: 25 °C
Yield: 43.1 %

Procedure:
To a solution of (S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionic acid (prepared as in Example 1, 71 mg, 0.21 mmol) and 1-(2-methoxy-ethyl)-1H-pyrazol-3-ylamine (prepared as in US 20080021032, Example 72, 32 mg, 0.23 mmol) and benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (Chemimpex, 0.11 g, 0.25 mmol) in methylene chloride (5 mL) was added N,N-diisopropylethylamine (0.11 mL, 0.62 mmol) dropwise and the resulting solution stirred at room temperature over night. The solution was diluted with methylene chloride, washed with a 1 N hydrochloric acid solution (15 mL), a saturated sodium bicarbonate solution (20 mL) dried over magnesium sulfate. The mixture was filtered and evaporated and the resulting material purified via automated flash chromatography (Analogix, SF4-12 g column, 50-80% ethyl acetate/hexanes) to give (S)-3-cyclopentyl-N-[1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide (42 mg, 43%) as an off white solid: HR-ES(+) m/e calcd for C23H27N4O3F3 [M+H]+ 465.2108, observed 465.2107; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.04-2.18 (m, 10H), 3.20 (s, 3H), 3.51-4.28 (m, 4H), 4.60-5.34 (m, 3H), 6.40 (d, J=1.81 Hz, 1H), 7.41-8.28 (m, 5H), 10.93 (s, 1H).
Reaction SMILES: C(O[C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[N:16]2[CH:17]=[N:18][CH:19]=[C:15]2[CH:14]=[CH:13][CH:12]=1)=[O:5])C.[CH3:20][NH2:21]>C(O)CCC>[CH3:20][NH:21][C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[N:16]2[CH:17]=[N:18][CH:19]=[C:15]2[CH:14]=[CH:13][CH:12]=1)=[O:5]
Reactant: CN
Reactant: CCOC(=O)CCCCCc1cccc2cncn12
Solvent: CCCCO
Product: CNC(=O)CCCCCc1cccc2cncn12

Procedure:
A solution of 3.9 g of 5-(5-ethoxycarbonylpentyl)-imidazo[1,5-a]pyridine in 40 ml of n-butanol is saturated with methylamine and heated on a steam bath for 56 hours in a pressure bottle. The reaction mixture is evaporated to dryness; the resulting product is first crystallized from ether and then recrystallized from 1:1 ethyl acetate-ether to yield the 5-[5-(N-methylcarbamoyl)pentyl]-imidazo[1,5-a]pyridine melting at 118°-22°.
Reaction SMILES: [CH3:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=O.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O.O>C(Cl)Cl>[C:4]([C:3]1[C:2]([CH3:1])=[N:10][CH:9]=[CH:8][CH:7]=1)#[N:6]
Reactant: Cc1ncccc1C(N)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Cc1ncccc1C#N
Yield: 75.2 %

Procedure:
To a suspension of 2-methylnicotinamide from step 1 (11.1 g, 0.081 mol) in triethylamine (24.8 g, 0.243 mol) and 400 mL of methylene chloride was added trifluoroacetic anhydride (21.0 g, 0.100 mol) rapidly at 0° C. The reaction was complete after a few minutes at this temperature. Water was added and the aqueous layer was extracted with methylene chloride. The combined organic layers were washed with water, brine and dried over magnesium sulfate. After filtration, the filtrate was concentrated and the residue was purified by chromatography on silica gel (ethyl acetate/hexane, 1:1) to give 7.2 g of 3-cyano-2-methylpyridine as a pale yellow solid (75%): mp(DSC) 56-58° C.