Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.C(Cl)(Cl)Cl.[N+:10]([O-:13])(O)=[O:11].C(=O)([O-])[O-].[K+].[K+].[CH:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[N+:10]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([O-:13])=[O:11]
Reactant: O=[N+]([O-])O
Reactant: c1ccccc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1ccccc1

Procedure:
Sulfuric acid was added to a chloroform solution containing the benzene. To the solution was then added nitric acid, and the mixture was heated at a temperature of 50° C. for five hours. After completion of the reaction, the organic layer was neutralized with a 5% aqueous potassium carbonate solution, washed with water, and dried on magnesium sulfate. The solvent was evaporated to give a white solid. The white solid was recrystallized in petroleum-derived ethanol to give nitrobenzene. The obtained nitrobenzene was allowed to react with hydrogen gas at a temperature of 200° C. in the presence of a nickel catalyst so that aniline was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:23]([N:28]([CH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=2[S:54](=[O:57])(=[O:56])[NH2:55])=[CH:44][CH:43]=1)[C:29]([N:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33][CH2:32]1)=[O:30])[CH2:24][CH2:25][CH2:26][CH3:27].C1CCN2C(=NCCC2)CC1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:55][S:54]([C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][C:48]=1[C:45]1[CH:44]=[CH:43][C:42]([CH2:41][N:28]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:29]([N:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:34][CH2:33][CH2:32]2)=[O:30])=[CH:47][CH:46]=1)(=[O:57])=[O:56])=[O:6]
Reactant: CCCCCN(Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1)C(=O)N1CCCc2ccccc21
Reactant: O=C(O)c1ccccc1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCCN(Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2Cl)cc1)C(=O)N1CCCc2ccccc21

Procedure:
The title compound was prepared from 2-chlorobenzoic acid (2.0 equivalents), CDI (2.0 equiv), 1-[N-pentyl-N-[(2'-sulfamoylbiphenyl-4-yl)methyl]carbamoyl]-1,2,3,4-tetrahydroquinoline (from Step B) (1.0 equiv), and DBU (2.0 equiv), according to the procedure of Example 3, Step C, to give a 78% yield of the desired material after flash chromatography as an off-white solid, mp 71°-74° C.; homogeneous by TLC in 9:1 CH2Cl2 --MeOH; FAB-MS m/e 630 (M+1)+.
Reaction SMILES: C([Li])CCC.[CH3:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9].[CH2:13]([O:20][C@@H:21]1[C@@H:27]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@H:26]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C@@H:25]([CH2:44][O:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[O:24][C:22]1=[O:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CCCCCC.O1CCCC1>[CH2:13]([O:20][C@@H:21]1[C@@H:27]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@H:26]([O:36][CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C@@H:25]([CH2:44][O:45][CH2:46][C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[O:24][C:22]1([OH:23])[CH2:6][P:7]([O:10][CH3:11])([O:8][CH3:9])=[O:12])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COP(=O)(CC1(O)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1)OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.9 %

Procedure:
A solution of n-butyllithium in n-hexane (1.6M solution, 68.8 ml) was added to a solution of dimethyl methylphosphonate (13.65 g) in tetrahydrofuran (200 ml) in a stream of argon at -70° to -78° C., and then stirred for 30 min. To the solution was added a solution of 2,3,4,6-tetra-O-benzyl-D-glucono-1,5-lactone (29.6 g) in tetrahydrofuran (150 ml) at -70° to -78° C. The mixture was stirred for 1 hour at the same temperature. The cooling bath was removed and the mixture was allowed to warm to 0° C. with stirring. Ice-cold 10% ammonium chloride solution (400 ml) was added to the reaction mixture and the resulting oily substances were extracted with ethyl acetate (1.2 l). The ethyl acetate solution was washed with 2N hydrochloric acid and saturated aqueous sodium hydrogen-carbonate, dried with anhydrous sodium sulfate and then evaporated in vacuo. Ethyl ether-petroleum ether (1:3; 400 ml) was added to the residue and the mixture was refrigerated to give 3,4,5,7-tetra-O-benzyl-1-deoxy-1-(dimethoxyphosphoryl)-D-gluco-2-heptulopyranose (33.1 g) as white crystals; m.p. 112°-113° C.;
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][O-:16])[N:10]=[CH:9]2)C=CC=CC=1.[Na+].F[C:31]1[CH:36]=[CH:35][C:34]([S:37]([C:40]2[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=2)(=[O:39])=[O:38])=[CH:33][CH:32]=1>>[NH:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][O:16][C:31]2[CH:32]=[CH:33][C:34]([S:37]([C:40]3[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=3)(=[O:39])=[O:38])=[CH:35][CH:36]=2)[N:10]=[CH:9]1
Reactant: [O-]CCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: O=S(=O)(c1ccc(F)cc1)c1ccc(F)cc1
Agent: [Na+]
Product: O=S(=O)(c1ccc(F)cc1)c1ccc(OCCCc2c[nH]cn2)cc1

Procedure:
5 mmol of sodium 3-(1-triphenylmethyl-1H-imidazol-4-yl)propanolate and 10 mmol of bis(4-fluorophenyl) sulphone are treated as described in Example 61 (method A).
Reaction SMILES: [C:1]([Si:5]([CH3:25])([CH3:24])[O:6][CH:7]([C:9]([CH3:23])([CH:21]=[CH2:22])[C:10](N1[C@@H](C(C)C)COC1=O)=[O:11])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[OH:26]O.O.[OH-].[Li+]>O1CCCC1.O>[C:1]([Si:5]([CH3:25])([CH3:24])[O:6][CH:7]([C:9]([CH3:23])([CH:21]=[CH2:22])[C:10]([OH:11])=[O:26])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: OO
Reactant: C=CC(C)(C(=O)N1C(=O)OC[C@@H]1C(C)C)C(C)O[Si](C)(C)C(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C=CC(C)(C(=O)O)C(C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 40.4 %

Procedure:
A cooled (0° C.) solution of (S)-3-{2-[1-(tert-butyl-dimethyl-silanyloxy)-ethyl]-2-methyl-but-3-enoyl}-4-isopropyl-oxazolidin-2-one (1.729 g, 4.677 mmol) in tetrahydrofuran/water (60 mL, 2:1) was subsequently treated with hydrogen peroxide (30% aqueous, 2.4 mL, 23.385 mmol) and lithium hydroxide monohydrate (392.4 mg, 9.355 mmol). After stirring for 2 days at room temperature, hydrogen peroxide (30% aqueous, 2.4 mL, 23.385 mmol) and lithium hydroxide monohydrate (400 mg, 9.535 mmol) were added at 0° C. After stirring at room temperature for 4 days, the reaction was quenched with solid sodium metabisulfite (18 g). After stirring for 1 h at room temperature, the pH was adjusted with hydrochloric acid (1 M) to pH 2 at 0° C. The aqueous layer was extracted with ethyl acetate (2×). The organics were combined, dried over anhydrous sodium sulfate, filtered and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography using a 100 g Isolute cartridge eluted with a continuous gradient of iso-hexanes/diethyl ether 1:0 to 7:3 to afford the title compound (488.0 mg, 40%) as a yellow solid and as a single pair of enantiomers along with unreacted (S)-3-{2-[1-(tert-butyl-dimethyl-silanyloxy)-ethyl]-2-methyl-but-3-enoyl}-4-isopropyl-oxazolidin-2-one (431.5 mg, 25%, LCMS (m/z) 370.1 [M+H], Tr=3.93 min) as the other single pair of enantiomers as a colourless oil. 1H NMR (300 MHz, CDCl3) δ 0.12 (s, 6H), 0.92 (s, 9H), 1.18 (d, J=6.0 Hz, 3H), 1.34 (s, 3H), 3.99 (q, J=6.2 Hz, 1H), 5.18 (d, J=17.8 Hz, 1H), 5.28 (d, J=10.5 Hz, 1H), 6.22 (dd, J=17.6, 11.2 Hz, 1H).
Reaction SMILES: Cl.[F:2][C@@H:3]1[CH2:7][NH:6][C@H:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:4]1.CCN(C(C)C)C(C)C.Br[CH2:22][CH2:23][CH:24]=[CH2:25]>C(#N)C>[CH3:11][O:10][C:8]([C@@H:5]1[CH2:4][C@H:3]([F:2])[CH2:7][N:6]1[CH2:25][CH2:24][CH:23]=[CH2:22])=[O:9]
Reactant: C=CCCBr
Reactant: COC(=O)[C@@H]1C[C@H](F)CN1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C=CCCN1C[C@@H](F)C[C@H]1C(=O)OC
Temperature: 70 °C
Reaction time: 48 h

Procedure:
In a 25 mL round-bottomed flask, (2S,4S)-methyl 4-fluoropyrrolidine-2-carboxylate hydrochloride (160 mg, 871 μmol, Eq: 1.00) was combined with acetonitrile (3 mL) to give a white suspension. Hunig's base (282 mg, 380 μL, 2.18 mmol, Eq: 2.50) and 4-bromobut-1-ene (144 mg, 108 μL, 1.05 mmol, Eq: 1.20) were added sequentially. The reaction mixture was stirred at 70° C. for 2 days. The crude reaction mixture was concentrated in vacuo. The reaction mixture was poured into an aqueous 5% Na2CO3 solution and extracted with DCM (2×). The organic layers were combined, washed with brine (1×), the organic layers were dried over Na2SO4 and concentrated in vacuo to yield a yellow liquid (160 mg; 91%). m/z=202.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[CH2:12][S:11][C@H:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])[N:9]1[C:20](=[O:38])[CH2:21][NH:22][C:23](=[O:37])[NH:24][C:25]1[CH:26]=[C:27]([CH:34]=[CH:35][CH:36]=1)[CH:28]([OH:33])[C:29]([O:31]C)=[O:30])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+]>O.CO.[OH-].[Na+]>[C:1]([O:5][C:6]([C@@H:8]1[CH2:12][S:11][C@H:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])[N:9]1[C:20](=[O:38])[CH2:21][NH:22][C:23](=[O:37])[NH:24][C:25]1[CH:26]=[C:27]([CH:34]=[CH:35][CH:36]=1)[CH:28]([OH:33])[C:29]([OH:31])=[O:30])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(O)c1cccc(NC(=O)NCC(=O)N2[C@@H](c3ccccc3F)SC[C@H]2C(=O)OC(C)(C)C)c1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)[C@@H]1CS[C@H](c2ccccc2F)N1C(=O)CNC(=O)Nc1cccc(C(O)C(=O)O)c1
Yield: 22 %

Procedure:
The operation is carried out in a fashion similar to that described in Example 77, but starting from 0.70 g of methyl (RS)-3-{3-{2-[(2R,4R)-4-tert-butoxycarbonyl-2-(2-fluorophenyl)-3-thiazolidinyl]-2-oxoethyl}ureido}mandelate in 7 cm3 of a water/methanol (30/70 by volume) mixture and 0.08 g of potassium hydroxide. The crude product (0.45 g) is dissolved in 8.5 cm3 of a 0.1N aqueous sodium hydroxide solution. The solution thus obtained is washed with 2 times 25 cm3 of ethyl acetate, filtered and acidified to a pH of 2 by addition of a 1N aqueous hydrochloric acid solution. The product precipitated is separated by filtration, washed with 2 times 10 cm3 of water and dried in air. 0.15 g of (RS)-3-{3-{2-[(2R,4R)-4-tert-butoxycarbonyl-2-(2-fluorophenyl)-3-thiazolidinyl]-2-oxoethyl}ureido}mandelic acid is thus obtained in the form of a white product, melting at 135° C. [proton NMR (200 MHz, DMSO D6 plus several drops of CD3COOD, δ in ppm, J in Hz), 2 rotamers at room temperature, peak coalescence at 110° C.: characteristic chemical shifts at 110° C. 1.55 (s, 9H, --C(CH3)3); 3.32 and 3.53 (2dd, J=12.5 and 6.5, 2H, S--CH2 --); 3.8 (bd, 1H of N--COCH2 --N); 4.08 (d, J=17.5, 1H, the other H of N--COCH2 --N); 5 (m and s, 2H in total respectively N--CH--COO and Ar--CH--); 6.2 (broad, 1H, --NHCO--); 6.54 (s, 1H, S--CH--N); 7.02 (bd, J=7.5, 1H, in position 4 on CO--NH--Ph); 7.1 to 7.5 (m, 6H, aromatic); 7.94 (dd, J=7.5 and 9, 1H, in position 6 on S--CH--Ph--); 8.5 (broad, --CONH--Ar)], [infrared spectrum (KBr), characteristic bands in cm-1 : 3390, 2980, 2930, 2840, 2700 to 2250 (broad band), 1735, 1650, 1610, 1560, 1490, 1455, 1370, 1230, 1150, 1060, 790, 760, 700].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:21])[CH2:9][NH:10][CH2:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:13])[CH:5]=[CH:6][CH:7]=1.C(N(CC)C(C)C)(C)C.[C:31]1([S:37](Cl)(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.OS([O-])(=O)=O.[K+]>C(Cl)Cl>[C:31]1([S:37]([N:10]([CH2:9][CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[OH:21])[CH2:11][C:12]([NH:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:13])(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(CNCC(O)c1cccc(Br)c1)Nc1ccccc1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CN(CC(O)c1cccc(Br)c1)S(=O)(=O)c1ccccc1)Nc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To a cooled suspension of 2-[2-(3-bromo-phenyl)-2-hydroxy-ethylamino]-N-phenyl-acetamide (840 mg) and N,N-diisopropylethylamine (760 mL) in methylene chloride (20 mL) was added benzenesulfonyl chloride (0.31 mL). The mixture was stirred at 0° C. for 1 hour and at room temperature overnight. A 1M aqueous solution of KHSO4 was added, the phases were separated, and the inorganic one was extracted with ethyl acetate (×2). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (SiO2, n-heptanelethyl acetate 1:1) to yield 2-{benzenesulfonyl-[2-(3-bromo-phenyl)-2-hydroxy-ethyl]-amino}-N-phenyl-acetamide (1.17 g, 99%) as a white foam, MS: 489.0 (M+H, 1Br)+.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7](O)=[O:8])=[C:4]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:3]=1.OC1C2N=N[NH:24]C=2C=CC=1.Cl.CN(C)CCCN=C=NCC.N>C(#N)C>[Br:1][C:2]1[S:6][C:5]([C:7]([NH2:24])=[O:8])=[C:4]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:3]=1
Reactant: Oc1cccc2[nH]nnc12
Reactant: CC(C)(C)OC(=O)Nc1cc(Br)sc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CC#N
Product: CC(C)(C)OC(=O)Nc1cc(Br)sc1C(N)=O
Reaction time: 0.17 h

Procedure:
5-Bromo-3-[(t-butyloxycarbonyl)amino]thiophene-2-carboxylic acid (0.80 g) was stirred in acetonitrile (80 ml). Hydroxybenztriazole (1.41 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.62 g) were added and stirring continued at room temperature for 10 minutes. Concentrated aqueous ammonia solution (8 ml) was added and the reaction mixture was heated to reflux for 1 h. The acetonitrile was removed by evaporation. Water (100 ml) was added and the mixture was sonicated and triturated. The resultant off-white solid was then collected by filtration, washed with water and dried under vacuum (0.763 g).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[O:15]=[C:16]1[CH:20]([C:21]([OH:23])=O)[CH2:19][CH2:18][N:17]1[C:24]1[CH:25]=[C:26](C)[CH:27]=[CH:28][CH:29]=1.O=[C:32]1C(C(O)=O)CCN1C1C=C(C)C=CC=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:21]([CH:20]1[CH2:19][CH2:18][N:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:32])[C:16]1=[O:15])=[O:23]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: Cc1cccc(N2CCC(C(=O)O)C2=O)c1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1N1CCC(C(=O)NCCc2c[nH]c3ccc(Cl)cc23)C1=O
Yield: 44.3 %

Procedure:
This compound was prepared according to method E with 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g; 0.433 mmol), 2-oxo-1-o-tolylpyrrolidine-3-carboxylic acid 2-oxo-1-o-tolylpyrrolidine-3-carboxylic acid (0.095; 0.433 mmol), PyBOP (0.225 g; 0.433 mmol), N,N diisopropylethylamine (0.186 mL; 1.08 mmol) in DMF (3 mL). The crude mixture was purified flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.076 g (44%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-oxo-1-o-tolylpyrrolidine-3-carboxamide as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:26])[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1.[CH:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(OCC)C>[CH2:27]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:26])[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1ccc(NC(=O)C(=O)N2CCC(Cc3ccc(F)cc3)CC2)cc1
Solvent: CCOCC
Product: O=C(Nc1ccc(NCc2ccccc2)cc1)C(=O)N1CCC(Cc2ccc(F)cc2)CC1

Procedure:
The title compound is prepared from N-(4-amino-phenyl)-2-[4-(4-fluoro-benzyl)-piperidin-1-yl]-2-oxo-acetamide (Example 104) and benzaldehyde according to the method described in Example 82. Melting Point: 145-148° C. (diethylether)
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][CH2:15][CH3:16])[CH2:10][C:11]([OH:13])=O)=[CH:5][C:4]=1[C:17]([F:20])([F:19])[F:18])#[N:2].[CH2:21]([NH2:24])[CH2:22][CH3:23]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][CH2:15][CH3:16])[CH2:10][C:11]([NH:24][CH2:21][CH2:22][CH3:23])=[O:13])=[CH:5][C:4]=1[C:17]([F:20])([F:19])[F:18])#[N:2]
Reactant: CCCN(CC(=O)O)c1ccc(C#N)c(C(F)(F)F)c1
Reactant: CCCN
Product: CCCNC(=O)CN(CCC)c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Synthesized as described in example 3 using N-[4-cyano-3-(trifluoromethyl)phenyl]-N-propylglycine and propylamine: 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J=8.6 Hz, 1H), 6.92 (d, J=2.5 Hz, 1H), 6.76 (dd, J=8.8, 2.5 Hz, 1H), 5.94 (bs, 1H), 3.98 (s, 2H), 3.41 (t, J=7.9 Hz, 2H), 3.22 (q, J=6.8 Hz, 2H), 1.68 (m, 2H), 1.45 (m, 2H), 0.99 (t, J=7.3 Hz, 3H), 0.82 (t, J=7.5 Hz, 3H).
Reaction SMILES: [N:1]1([S:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C1C(=O)N([Br:25])C(=O)C1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:25][C:15]1[CH:16]=[C:11]([CH2:10][S:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)(=[O:9])=[O:8])[CH:12]=[CH:13][C:14]=1[NH2:17]
Reactant: Nc1ccc(CS(=O)(=O)N2CCOCC2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Nc1ccc(CS(=O)(=O)N2CCOCC2)cc1Br
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99 %

Procedure:
To a solution of 4-(morpholine-4-sulfonylmethyl)-phenylamine (437 mg, 1.70 mmol, WO 9720822) in DCM (10 mL) was added NBS (304 mg, 1.70 mmol) at 0° C. The solution was allowed to stir at RT for 15 min. Satd aq NaHCO3 (20 mL) was then added and the organic layer was separated, dried (Na2SO4) and concentrated to afford the title compound (564 mg, 98%). 1H-NMR (CDCl3; 400 MHz): δ 7.47 (d, 1H, J=1.9 Hz), 7.15 (dd, 1H, J=8.2, 1.9 Hz), 6.77 (d, 1H, J=8.2 Hz), 4.23 (br s, 2H), 4.12 (s, 2H), 3.65-3.68 (m, 4H), 3.14-3.17 (m, 4H).
Reaction SMILES: Br[C:2]([Br:5])(Br)Br.[CH:6]12[O:14][CH:9]([CH:10](CO)[CH2:11]1)[CH:8]=[CH:7]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[CH:9]12[O:14][CH:6]([CH:11]([CH2:2][Br:5])[CH2:10]1)[CH:7]=[CH:8]2
Reactant: BrC(Br)(Br)Br
Reactant: OCC1CC2C=CC1O2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCC1CC2C=CC1O2
Temperature: 0 °C
Reaction time: 12 h

Procedure:
Tetrabromomethane (1.161 g, 3.50 mmol) was added to a solution of 7-oxanorborn-2-en-5-ylmethanol (0.305 g, 2.50 mmol, from Example 2) in CH2Cl2 (12.5 ml). The solution was cooled to 0° C. and admixed with triphenylphosphine (1.836 g, 7 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 12 h. The solvent was removed under reduced pressure and the remaining solid was taken up in cyclohexane. The crude product was purified by flash chromatography (using a 98:2 mixture of cyclohexane and ethyl acetate). 0.3 g (59% of theory) of the pure product were obtained. The product was stored under cool conditions with the exclusion of light.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[CH:10]1[CH2:15][CH:14]([C:16]([O:18][CH3:19])=[O:17])[CH2:13][CH2:12][NH:11]1.CCN(C(C)C)C(C)C.[C:29](Cl)(=[O:32])[O:30][CH3:31]>C(Cl)Cl>[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[CH:10]1[CH2:15][CH:14]([C:16]([O:18][CH3:19])=[O:17])[CH2:13][CH2:12][N:11]1[C:29]([O:30][CH3:31])=[O:32]
Reactant: COC(=O)Cl
Reactant: COC(=O)C1CCNC(c2ccc(F)cc2F)C1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCN(C(=O)OC)C(c2ccc(F)cc2F)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.7 %

Procedure:
Methyl 2-(2,4-difluorophenyl)piperidine-4-carboxylate hydrochloride (2.34 g, 8.02 mmol) was dissolved in DCM (50 mL), then DIPEA (3.50 mL, 20.05 mmol) was added. Methyl carbonochloridate (0.884 mL, 11.23 mmol) was added dropwise to the solution. The mixture was stirred at room temperature for 4 h, washed with 0.1 M HCl (100 mL) and satd NaHCO3 (100 mL), then dried through a phase-separator and evaporated yielding dimethyl 2-(2,4-difluorophenyl)piperidine-1,4-dicarboxylate (2.38 g, 95%) as an orange oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([C:23]2([OH:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[CH:5]=[CH:6][CH:7]=1.[Cl:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][C:36]=1[Cl:37].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:30][C:31]1[CH:32]=[C:33]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([C:23]3([OH:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:9][N:10]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:12][CH2:11]3)[CH:3]=2)[CH:34]=[CH:35][C:36]=1[Cl:37]
Reactant: CC(C)(C)OC(=O)N1CCN(CC(c2cccc(Br)c2)C2(O)CCCCC2)CC1
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCN(CC(c2cccc(-c3ccc(Cl)c(Cl)c3)c2)C2(O)CCCCC2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 66.5 %

Procedure:
A mixture of tert-butyl 4-[2-(3-bromophenyl)-2-(1-hydroxycyclohexyl)ethyl]piperazine-1-carboxylate (0.72 g, 1.55 mmol) and tetrakis(triphenylphosphine)palladium (37 mg, 0.032 mmol, 10 mol %) in 1,2-dimethoxyethane (30 mL) was stirred for 10 min at room temperature. To this mixture was added sequentially 3,4-dichlorophenyl boronic acid (0.44 g, 2.32 mmol) and a 2M aqueous solution of sodium carbonate (0.8 mL, 1.6 mmol, 5 equivalent), and the mixture was heated at reflux until all starting material was consumed and precipitation of black palladium occurred (3 h). After cooling, water was added and the reaction mixture was extracted with ethyl acetate (30 mL). The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated to give a crude solid, which was purified via flash column chromatography (silica, gradient from 0% ethyl acetate/hexane to 30% ethyl acetate/hexane) to yield 0.55 g (67%) of tert-butyl 4-[2-(3′,4′-dichloro-biphenyl-3-yl)-2-(1-hydroxycyclohexyl)ethyl]piperazine-1-carboxylate as a foam, which was used as such in the next step.
Reaction SMILES: OCCCN1C=C(C2C=CC(N[C:22]3[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]4[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=4[O:48][CH3:49])[N:23]=3)=C3C=2CN(C)C3=O)C=N1.[NH2:50][C:51]1[CH:60]=[C:59]([F:61])[C:58]([Br:62])=[CH:57][C:52]=1[C:53]([NH:55][CH3:56])=[O:54]>>[Br:62][C:58]1[C:59]([F:61])=[CH:60][C:51]([NH:50][C:26]2[C:27]([C:28]([F:29])([F:30])[F:31])=[CH:22][N:23]=[C:24]([NH:32][C:33]3[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=3[O:48][CH3:49])[N:25]=2)=[C:52]([C:53](=[O:54])[NH:55][CH3:56])[CH:57]=1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Reactant: CNC(=O)c1cc(Br)c(F)cc1N
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3cc(F)c(Br)cc3C(=O)NC)n2)c(OC)c1)OCC

Procedure:
Prepared analogously to Compound 1B replacing Compound 1C with 2-amino-5-bromo-4-fluoro-N-methylbenzamide (Compound 7D, 0.327 g, 1.32 mmol) to afford the title compound as 642 mg of a white solid (88% yield). 1H NMR (DMSO-d6, 400 MHz): δ 11.94 (br. s., 1H), 9.15 (br. s., 1H), 8.88 (d, J=4.6 Hz, 1H), 8.53 (br. s., 1H), 8.42 (s, 1H), 8.08 (d, J=7.8 Hz, 1H), 7.47 (d, J=7.6 Hz, 1H), 7.02 (s, 1H), 6.82-6.90 (m, 1H), 3.93-4.02 (m, 4H), 3.77 (s, 3H), 3.18-3.27 (m, 2H), 2.77 (d, J=4.3 Hz, 3H), 1.19 (t, J=7.1 Hz, 6H). MS (ESI): m/z 664.09 [M+H]+. UPLC: tR=1.60 min (UPLC-TOF: polar—3 min).