Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[C:7](Cl)=[O:8].[Cl:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=1)[NH2:14]>N1C=CC=CC=1>[Cl:10][C:11]1[CH:12]=[C:13]([NH:14][C:7]([C:3]2[N:4]=[CH:5][NH:6][C:2]=2[CH3:1])=[O:8])[CH:15]=[CH:16][CH:17]=1
Reactant: Cc1[nH]cnc1C(=O)Cl
Reactant: Nc1cccc(Cl)c1
Solvent: c1ccncc1
Product: Cc1[nH]cnc1C(=O)Nc1cccc(Cl)c1

Procedure:
Under a dry nitrogen atmosphere a solution of 5-methyl-1H-imidazole-4-carboxylic acid chloride (1.5 g, 0.01 mole) and 3-chloroaniline (1.3 g, 0.01 mole) in 25 ml of pyridine was stirred at ambient temperature for two days. The reaction mixture was then concentrated under reduced pressure, and the residue was slurried with aqueous saturated sodium bicarbonate. The resultant solid was collected by filtration, washed with water, and recrystallized, yielding N-(3-chlorophenyl)-5-methyl-1H-imidazole-4-carboxamide; (0.5 g; mp, 199°-202°).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=[N:5]1)[CH3:3].[Cl:13]N1C(=O)CCC1=O>CN(C=O)C>[Cl:13][C:7]1[CH:6]=[N:5][N:4]([CH:2]([CH3:1])[CH3:3])[C:8]=1[C:9]([O:11][CH3:12])=[O:10]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1ccnn1C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1c(Cl)cnn1C(C)C
Temperature: 60 °C
Yield: 93.6 %

Procedure:
A solution of methyl 1-(1-methylethyl)-1H-pyrazole-5-carboxylate (120 mg) in DMF (3 ml) was treated with N-chlorosuccinimide (95 mg) and heated to 60° C. for 18 h under nitrogen. The cooled mixture was partitioned between diethyl ether (20 ml) and water (20 ml), separated and dried over sodium sulphate then evaporated to give the title compound as a pale yellow oil (135 mg).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1)[CH3:2].[CH3:16][Li].O>CCOCC>[CH2:14]([O:13][CH:4]([O:3][CH2:1][CH3:2])[C:5]1[CH:12]=[CH:11][C:8]([CH:9]([OH:10])[CH3:16])=[CH:7][CH:6]=1)[CH3:15]
Reactant: [Li]C
Reactant: CCOC(OCC)c1ccc(C=O)cc1
Solvent: CCOCC
Solvent: O
Product: CCOC(OCC)c1ccc(C(C)O)cc1
Temperature: -75 °C
Reaction time: 2 h

Procedure:
4-(Diethoxymethyl)benzaldehyde (104 g, 0.5 mol) was dissolved in 300 ml of ether and the resulting solution cooled to -75° C. in an acetone-dry ice bath. With vigorous stirring, methyllithium (390 mL of 1.4M in ether, 0.55 mol) was added at a rate which maintained the temperature at less than -60° C. The reaction mixture was allowed to warm to room temperature, stirred for two hours at that temperature, poured into 500 mL of ice and water, stirred 10 minutes and the layers separated. The aqueous layer was extracted with 500 mL ether. The organic layers were combined, washed with 500 mL each of H2O and then brine dried (MgSO4) and stripped in vacuo to yield 110-111.5 (98-100%) of present title product as a viscous, light yellow oil.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[NH:7][C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:9]([C:11]([OH:14])([CH3:13])[CH3:12])[N:10]=1)(=[O:3])[CH3:2].CC(C)([O-])C.[K+].[C:26]([N:45]1[C:49]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=2[C:56]2[CH:63]=[CH:62][C:59]([CH2:60]Br)=[CH:58][CH:57]=2)=[N:48][N:47]=[N:46]1)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:1]([O:4][CH2:5][C:6]1[N:7]([CH2:60][C:59]2[CH:58]=[CH:57][C:56]([C:51]3[CH:52]=[CH:53][CH:54]=[CH:55][C:50]=3[C:49]3[N:45]([C:26]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:46]=[N:47][N:48]=3)=[CH:63][CH:62]=2)[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:9]([C:11]([OH:14])([CH3:12])[CH3:13])[N:10]=1)(=[O:3])[CH3:2]
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCOC(=O)c1[nH]c(COC(C)=O)nc1C(C)(C)O
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCOC(=O)c1c(C(C)(C)O)nc(COC(C)=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 61 %

Procedure:
Following a procedure similar Example described in Example 82(a), but using 730 mg of ethyl 2-acetoxymethyl-4-(1-hydroxy-1-methylethyl)imidazole-5-carboxylate [prepared as described in Preparation 48(iii)], 320 mg of potassium t-butoxide and 2.11 g of 4-[2-(trityltetrazol-5-yl)phenyl]benzyl bromide and then purifying the product by column chromatography through silica gel using a 2:1 by volume mixture of hexane and ethyl acetate, 1.23 g of the title compound were obtained as a foam-like solid.
Reaction SMILES: C(OC(=O)[NH:5][C:6]1[C:15]([Cl:16])=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1[F:17])C.O[Li].O>CCO.O>[F:17][C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:14]=[C:15]([Cl:16])[C:6]=1[NH2:5]
Reactant: CCOC(=O)Nc1c(Cl)cc2ccccc2c1F
Agent: [Li]O
Solvent: CCO
Solvent: O
Product: Nc1c(Cl)cc2ccccc2c1F
Temperature: 25 °C

Procedure:
A mixture of 1.43 g (5.34 mmol) of N-(1-fluoro-3-chloro-2-naphthyl)carbamic acid ethyl ester, and 4.48 g (106.8 mmol) LiOH.H2O in 30 mL of EtOH and 70 mL of H2O is heated to reflux for 16 hours under an atmosphere of nitrogen. After cooling to room temperature, the mixture is concentrated in vacuo to give a residue that is extracted 3 times with 30 mL CH2Cl2. The combined organic layers are washed with 30 mL of saturated aqueous NaHCO3, 30 mL of saturated brine, dried over MgSO4 and the solvents evaporated to give 1-fluoro-3-chloro-2-aminonaphthalene as a brown solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:21][C@@H:22]1[C@@H:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:25][N:24]([C:33](=[O:39])[CH2:34][CH2:35][C:36](O)=[O:37])[CH2:23]1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:41]([O:43][C:44](=[O:47])[CH2:45][NH2:46])[CH3:42].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>ClCCl.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]([CH2:21][C@@H:22]1[C@@H:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:25][N:24]([C:33](=[O:39])[CH2:34][CH2:35][C:36]([NH:46][CH2:45][C:44]([O:43][CH2:41][CH3:42])=[O:47])=[O:37])[CH2:23]1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: C[C@H](c1cccc2ccccc12)N(C[C@H]1CN(C(=O)CCC(=O)O)C[C@@H]1c1ccccc1)C(=O)OC(C)(C)C
Reactant: CCOC(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CNC(=O)CCC(=O)N1C[C@H](CN(C(=O)OC(C)(C)C)[C@H](C)c2cccc3ccccc23)[C@@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 77.6 %

Procedure:
A mixture of 350 mg of the crude 4-[(3R,4S)-3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]-4-oxobutanoic acid obtained in Example 9 (1), 101 mg of glycine ethyl ester hydrochloride, 45 mg of HOBt, 73 mg of triethylamine and 5 ml of dichloromethane was mixed with 190 mg of WSC hydrochloride and stirred at room temperature for 2 days. The reaction solution was concentrated under a reduced pressure, and the thus obtained residue was purified by a silica gel column chromatography (chloroform-ethyl acetate) to obtain 315 mg of ethyl ({4-[(3R,4S)-3-({(tert-butoxycarbonyl) [(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]-4-oxobutanoyl}amino)acetate as a colorless oily substance.
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:8][C:9](=[O:11])[CH3:10])=[C:5]([Br:7])[N:6]=1.C(NCC)C>C(O)C.[Ni]>[Br:7][C:5]1[N:6]=[CH:2][S:3][C:4]=1[NH:8][C:9](=[O:11])[CH3:10]
Reactant: CC(=O)Nc1sc(Br)nc1Br
Agent: [Ni]
Solvent: CCNCC
Solvent: CCO
Product: CC(=O)Nc1scnc1Br
Temperature: 25 °C
Reaction time: 12 h
Yield: 77.8 %

Procedure:
A mixture of N-(2,4-dibromothiazol-5-yl)acetamide from example 1.4 (0.35 g, 1.17 mmol), diethylamine (0.085 g, 1.17 mmol) and Raney Ni (0.14 g, 2.33 mmol) in ethanol (50 mL) was stirred at room temperature for 12 h in a 100 mL round-bottomed flask to give a black solution. The reaction mixture was filtered and concentrated to give the title compound (0.20 g, 0.91 mmol, 78%) as a yellow solid which was directly used for the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][C:7]2=[O:13].[Br:14]N1C(=O)CCC1=O>S(=O)(=O)(O)O>[Br:14][C:10]1[C:9]([Cl:12])=[C:8]2[C:3]([CH2:4][CH2:5][NH:6][C:7]2=[O:13])=[C:2]([Cl:1])[CH:11]=1
Reactant: O=C1NCCc2c(Cl)ccc(Cl)c21
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Product: O=C1NCCc2c(Cl)cc(Br)c(Cl)c21
Reaction time: 2 h
Yield: 74.7 %

Procedure:
To a solution of 5,8-dichloro-3,4-dihydroisoquinolin-1(2H)-one (253e, 40 g, 0.186 mol) in concentrated sulfuric acid (200 mL) at 60° C. was added N-bromosuccinimide (49.7 g, 0.279 mol) in portions. Stirring was continued at 60° C. for 2 hours, then more N-bromosuccinimide (5 g. 28 mmol) was added. After stirring at 60° C. for 1 hour more, the mixture was poured onto ice water (500 mL), then extracted with dichloromethane (3×500 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (800 mL), dried over sodium sulfate, and concentrated in vacuo. The residue was stirred in ethyl acetate (40 mL) and petroleum ether (20 mL), and the resulting solids collected by filtration and dried under vacuum to give 7-bromo-5,8-dichloro-3,4-dihydroisoquinolin-1(2H)-one (253f, 41 g, 75% yield) as an off-white solid.
Reaction SMILES: Cl.[N:2]1([C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:17]=2[NH:16][C:15](=[O:18])[CH:14]=[CH:13]3)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[O:19]=[C:20]1[NH:29][C:28]2[N:27]=[C:26]([O:30][CH2:31][CH2:32][CH2:33][CH:34]=O)[CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21]1>>[O:18]=[C:15]1[CH:14]=[CH:13][C:12]2[C:17](=[C:8]([N:2]3[CH2:7][CH2:6][N:5]([CH2:34][CH2:33][CH2:32][CH2:31][O:30][C:26]4[N:27]=[C:28]5[C:23]([CH2:22][CH2:21][C:20](=[O:19])[NH:29]5)=[CH:24][CH:25]=4)[CH2:4][CH2:3]3)[CH:9]=[CH:10][CH:11]=2)[NH:16]1
Reactant: O=CCCCOc1ccc2c(n1)NC(=O)CC2
Reactant: O=c1ccc2cccc(N3CCNCC3)c2[nH]1
Agent: Cl
Product: O=C1CCc2ccc(OCCCCN3CCN(c4cccc5ccc(=O)[nH]c45)CC3)nc2N1

Procedure:
In a manner similar to that of other examples above, 8-piperazin-1-yl-1H-quinolin-2-one hydrochloride (Chem. Pharm. Bull. 1984, 32, 2100–2110) was coupled by reductive amination to 4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde followed by typical workup and purification to give the title compound. MS: APCI: M+1: 448.2 (Exact Mass: 447.23).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[N+:10]([O-])([O-:12])=[O:11].[K+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:4]([CH:3]=1)[CH:5]=[O:6]
Reactant: O=[N+]([O-])[O-]
Reactant: O=Cc1cccc(Cl)c1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=Cc1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.4 %

Procedure:
3-Chlorobenzaldehyde (15 g, 107 mmol) was added to concentrated sulfuric acid (150 mL) at −20° C., followed by addition of potassium nitrate (11.9 g, 117 mmol) in portions, keeping the temperature below −10° C. After addition, the mixture was stirred for 30 minutes and then poured into ice-water. The aqueous phase was extracted with ethyl acetate, and the organic phases were combined, washed by brine, dried over anhydrous sodium sulfate, evaporated and purified by silica gel chromatography to afford the product 5-chloro-2-nitrobenzaldehyde (12.0 g, yield 60.6%).
Reaction SMILES: O1CCOCC1.[C:7]([C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][C:25]=1[O:26][CH2:27][CH:28]([CH3:30])[CH3:29])[C:12]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1)=[S:13])#[N:8].[OH-].[K+]>[Fe-3](C#N)(C#N)(C#N)(C#N)(C#N)C#N.[K+].[K+].[K+].O>[C:7]([C:9]1[CH:10]=[C:11]([C:12]2[S:13][C:16]3[C:17]([O:21][CH3:22])=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]=2)[CH:23]=[CH:24][C:25]=1[O:26][CH2:27][CH:28]([CH3:30])[CH3:29])#[N:8]
Reactant: COc1cccc(NC(=S)c2ccc(OCC(C)C)c(C#N)c2)c1
Agent: N#C[Fe-3](C#N)(C#N)(C#N)(C#N)C#N
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1cccc2nc(-c3ccc(OCC(C)C)c(C#N)c3)sc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 36 %

Procedure:
Dioxane (70 mL) and water (70 mL) were added to a mixture of 3-cyano-4-isobutyloxy-N-(3-methoxyphenyl)thiobenzamide (900 mg, 2.64 mmol), potassium ferricyanide (2.61 g, 7.93 mmol), and potassium hydroxide (892 mg, 15.9 mmol). The resulting mixture was stirred for 20 hours at room temperature. The mixture was then placed under reduced pressure to distill the solvent off, and extracted with ethyl acetate (50 mL). The ethyl acetate portion was washed with water, dried over anhydrous magnesium sulfate, and placed under reduced pressure to distill the solvent off. The residue was purified by silica gel column chromatography (ethyl acetate/toluene=1/20-1/10), to give 322 mg (yield 36%) of the desired compound in the form of a pale yellow crystalline product.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[S:16][CH:17]=2)=[CH:9][CH:8]=1.N1C=CC=CC=1>C(Cl)Cl.CCOC(C)=O>[Br:1][CH2:2][C:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])[S:16][CH:17]=2)=[CH:9][CH:8]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)Nc1nc(-c2ccc(N)cc2)cs1
Reactant: O=C(Br)CBr
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1nc(-c2ccc(NC(=O)CBr)cc2)cs1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 63.5 %

Procedure:
To an ice-cold solution of 2-bromoacetyl bromide (10.1 g, 50.0 mmol), in CH2Cl2 (200 mL) was added (30 min) a solution of tert-butyl N-{4-(4-aminophenyl)-2-thiazolyl}carbamate (14.6 g, 50.0 mmol, described in example 1) and pyridine (4.04 mL, 50.0 mmol) in CH2Cl2 (50 mL). The reaction mixture was stirred at 0° for 30 min and then at room temperature for 30 min. The reaction mixture then was diluted with in EtOAc (1.5 L). The resulting mixture was washed successively with H2O (500 mL), 10% (w/v) aqueous citric acid (2×500 mL), brine (500 mL), saturated aqueous NaHCO3 (500 mL) and brine (500 mL), then dried (MgSO4) and filtered. The organic solution was concentrated under reduced pressure to a volume of 500 mL. The resulting suspension was filtered and the collected solid was washed with EtOAc (2×10 mL) to yield 13.1 g of the title compound. An additional 2.4 g was obtained by concentration of the filtrate to a volume of 25 mL giving a total of 15.5 g (75% yield) of the tert-butyl N-{4-{4-{(2-bromo-1-oxoethyl)amino}phenyl}-2-thiazolyl}carbamate as a white solid: 1H NMR (400 MHz, DMSO-d6) δ11.54 (s, 1H), 10.44 (s, 1H), 7.82 (d, J=8.7 Hz, 2H), 7.62 (d, J=8.7 Hz, 2H), 7.46 (s, 1H), 4.04 (s, 2H), 1.49 (s, 9H); MS (FAB) m/z412/414 (MH)+.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Br:12])[CH:7]=1.[Br:13][CH:14]([CH3:18])[C:15](Br)=[O:16]>C(=S)=S>[Br:13][CH:14]([CH3:18])[C:15]([C:9]1[CH:10]=[CH:11][C:6]([Br:5])=[CH:7][C:8]=1[Br:12])=[O:16]
Reactant: CC(Br)C(=O)Br
Reactant: Brc1cccc(Br)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(Br)C(=O)c1ccc(Br)cc1Br
Yield: 76 %

Procedure:
15 g of aluminium chloride are added with caution, at 0° C., to 25 g of 1,3-dibromobenzene in 250 ml of carbon disulphide, and 22.86 g of 2-bromopropionyl bromide are then run in slowly. The mixture is maintained at reflux for 8 hours, then the carbon disulphide is evaporated off under vacuum and the reaction medium is poured onto crushed ice. The product is extracted twice with heptane, dried, evaporated to dryness and then is purified on a column of silica, using a mixture of cyclohexane and ethyl acetate (10:1 v/v) as eluent, to give the expected product.
Reaction SMILES: Cl.[F:2][C:3]([F:23])([F:22])[C:4]1[CH:21]=[CH:20][CH:19]=[CH:18][C:5]=1[CH:6]([O:13][CH:14]1[CH2:17][NH:16][CH2:15]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N-:24]=[C:25]=[O:26]>>[F:23][C:3]([F:2])([F:22])[C:4]1[CH:21]=[CH:20][CH:19]=[CH:18][C:5]=1[CH:6]([O:13][CH:14]1[CH2:17][N:16]([C:25]([NH:24][CH2:3][C:4]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:5]=2)=[O:26])[CH2:15]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: [N-]=C=O
Reactant: FC(F)(F)c1ccccc1C(OC1CNC1)c1ccccc1
Agent: Cl
Product: O=C(NCc1ccccc1)N1CC(OC(c2ccccc2)c2ccccc2C(F)(F)F)C1

Procedure:
This material was prepared 3-[2-(trifluoromethyl)benzhydryloxy]azetidine hydrochloride (133) and the corresponding isocyanate using the procedure described for compound (10).
Reaction SMILES: [C:1]1([CH2:7][C:8]2[C:9]([C:14]([OH:16])=O)=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[C:21]([NH2:25])([CH3:24])([CH3:23])[CH3:22]>C(OCC)C.N1C=CC=CC=1>[C:21]([NH:25][C:14]([C:9]1[C:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:16])([CH3:24])([CH3:23])[CH3:22]
Reactant: O=C(O)c1ccccc1Cc1ccccc1
Reactant: CC(C)(C)N
Solvent: c1ccncc1
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Product: CC(C)(C)NC(=O)c1ccccc1Cc1ccccc1

Procedure:
To a mixture of 49.8 g. (0.235 mole) α-phenyl-o-toluic acid, 300 ml. ether and 10 ml. pyridine, add dropwise with stirring 25 ml. (0.35 mole) of thionyl chloride. The resulting mixture is stirred 21 hours at room temperature then filtered and the solvent removed in vacuo. The resulting acid chloride is dissolved in 150 ml. ether and added dropwise to 35.7 g (0.48 mole) of tert.butylamine in 500 ml. of ethyl ether, and the mixture cooled to 0° C. After addition is complete the resulting mixture is stirred 1 hour at room temperature, the layers separated, the ether washed with 100 ml. of water, 100 ml. of 2N sodium hydroxide and then with water again, dried over magnesium sulfate, filtered and evaporated to give N-tert.butyl-α-phenyl-o-toluamide; m.p. 91°- 92° C.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.[OH-].[Na+].[F:10][C:11]([F:24])([F:23])[O:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>O1CCCC1>[CH3:1][C@@H:2]1[NH:3][CH2:4][CH2:5][N:6]([S:19]([C:16]2[CH:15]=[CH:14][C:13]([O:12][C:11]([F:10])([F:23])[F:24])=[CH:18][CH:17]=2)(=[O:21])=[O:20])[CH2:7]1
Reactant: C[C@H]1CNCCN1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@H]1CN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)CCN1
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.7 %

Procedure:
A mixture of (2S)-2-methylpiperazine (1 g, 9.98 mmol, supplier Aldrich) in tetrahydrofuran (8 mL) and 3M aqueous sodium hydroxide (6.66 mL, 19.97 mmol) was cooled to 0° C. before addition of 4-[(trifluoromethyl)oxy]benzenesulfonyl chloride (2.86 g, 10.98 mmol, supplier Aldrich) dropwise via a dropping funnel. After addition, the cool bath was removed and the reaction stirred at room temperature for 4 h before standing at room temperature for 17 h. The mixture was concentrated in vacuo and then the residue was taken up in water (15 mL) and DCM (20 mL) and the mixture stirred for 1 h. The layers were separated and then the organic phase extracted with 1M HCl (40 mL). The acidic aqueous phase was then basified to pH12 with solid NaOH and the mixture extracted with DCM (2×30 mL). The combined organic phase was dried (phase separator) and concentrated under vacuum to give the title compound (2.58 g) as a colourless oil.
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5](=[O:9])[O:6][C:7]=1[CH3:8].[Cl:10][C:11]1[S:15][C:14]([C:16]2[O:20][N:19]=[C:18]([CH2:21][N:22]3[C:30]4[C:25](=[CH:26][C:27]([C:31]([OH:33])=[O:32])=[CH:28][CH:29]=4)[CH:24]=[C:23]3[C:34](=[O:45])[NH:35][CH:36]3[CH2:41][CH2:40][N:39]([CH:42]([CH3:44])[CH3:43])[CH2:38][CH2:37]3)[CH:17]=2)=[CH:13][CH:12]=1.ClC1C=CC(NC(CN2C3C=CC=C(C(O)=O)C=3C=C2C(=O)NC2CCN(C(C)C)CC2)=O)=NC=1>>[CH3:8][C:7]1[O:6][C:5](=[O:9])[O:4][C:3]=1[CH2:2][O:33][C:31]([C:27]1[CH:26]=[C:25]2[C:30](=[CH:29][CH:28]=1)[N:22]([CH2:21][C:18]1[CH:17]=[C:16]([C:14]3[S:15][C:11]([Cl:10])=[CH:12][CH:13]=3)[O:20][N:19]=1)[C:23]([C:34](=[O:45])[NH:35][CH:36]1[CH2:37][CH2:38][N:39]([CH:42]([CH3:43])[CH3:44])[CH2:40][CH2:41]1)=[CH:24]2)=[O:32]
Reactant: CC(C)N1CCC(NC(=O)c2cc3cc(C(=O)O)ccc3n2Cc2cc(-c3ccc(Cl)s3)on2)CC1
Reactant: Cc1oc(=O)oc1CCl
Agent: CC(C)N1CCC(NC(=O)c2cc3c(C(=O)O)cccc3n2CC(=O)Nc2ccc(Cl)cn2)CC1
Product: Cc1oc(=O)oc1COC(=O)c1ccc2c(c1)cc(C(=O)NC1CCN(C(C)C)CC1)n2Cc1cc(-c2ccc(Cl)s2)on1

Procedure:
The title compound was prepared analogously to example 5 with the difference that 4-Chloromethyl-5-methyl-[1,3]dioxol-2-one and 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-indole-5-carboxylic acid was used instead of Carbonic acid 1-chloro-ethyl ester 2-methoxy-ethyl ester and 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-indole-4-carboxylic acid. MS (ES+): m/e=639, chloro pattern.
Reaction SMILES: [F:1][C:2]1([F:16])[CH:7]([OH:8])[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.CC([O-])(C)C.[K+].C1COCC1.[N:28]1[N:29]=[C:30]([C:37]2[CH:46]=[CH:45][C:44]3[C:39](=[C:40](F)[CH:41]=[C:42]([F:47])[CH:43]=3)[N:38]=2)[N:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=12>CN(C=O)C>[N:28]1[N:29]=[C:30]([C:37]2[CH:46]=[CH:45][C:44]3[C:39](=[C:40]([O:8][CH:7]4[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[CH2:3][C:2]4([F:1])[F:16])[CH:41]=[C:42]([F:47])[CH:43]=3)[N:38]=2)[N:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=12
Reactant: Fc1cc(F)c2nc(-c3nnc4ccccn34)ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(O)C(F)(F)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(F)cc3ccc(-c4nnc5ccccn45)nc23)C(F)(F)C1
Reaction time: 0.25 h

Procedure:
tert-Butyl 3,3-difluoro-4-hydroxypiperidine-1-carboxylate (0.0706 g, 0.298 mmol) was treated with 1 M KOtBu in THF (0.283 mL, 0.283 mmol) and stirred for 15 minutes. The solution was treated with 2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6,8-difluoroquinoline (0.042 g, 0.149 mmol) and DMF (0.80 mL) then the mixture was stirred at ambient temperature for 16 hours. The mixture was directly chromatographed on SiO2 eluting with a gradient of 2% NH4OH in isopropanol/ethyl acetate. The desired product was collected and concentrated to a colorless oil, (72 mg). MS APCI (+) m/z 500.0 (M+1) detected.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:30][N:31]1[CH:35]=[CH:34][CH:33]=[C:32]1[C:36](O)=[O:37]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:36]([C:32]4[N:31]([CH3:30])[CH:35]=[CH:34][CH:33]=4)=[O:37])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cn1cccc1C(=O)O
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)c2cccn2C)c1

Procedure:
Prepared as described in Example 105 using (1R,2S)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-(3-methoxyphenyl)propan-2-amine (6a, 39 mg, 100 mmol) and 1-methyl-2-pyrrolecarboxylic acid (25 mg, 200 μmol). Yield 35 mg (70%).
Reaction SMILES: O=[C:2]([CH3:12])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]CC)=[O:8].BrC(C)CCCCC(OCC)=O.[CH3:25][CH2:26][CH2:27][C:28]1[C:33]([OH:34])=[C:32]([C:35]([CH3:37])=[O:36])[CH:31]=[CH:30][C:29]=1[OH:38]>>[C:35]([C:32]1[CH:31]=[CH:30][C:29]([O:38][CH:2]([CH3:12])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])=[C:28]([CH2:27][CH2:26][CH3:25])[C:33]=1[OH:34])(=[O:36])[CH3:37]
Reactant: CCOC(=O)CCCCC(C)=O
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: CCOC(=O)CCCCC(C)Br
Product: CCCc1c(OC(C)CCCCC(=O)O)ccc(C(C)=O)c1O

Procedure:
Following the procedure of Example 15, ethyl 6-oxo-heptanoate was transformed into ethyl 6-bromoheptanoate. The reaction of 4.74 g. of ethyl 6bromoheptanoate and 3.88 g. of 2,4-dihydroxy-3-propylacetophenone followed by hydrolysis in the usual manner gave 300 mg. of the title product as an oil.