Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[NH:5][C:4]([CH3:11])([CH3:10])[CH2:3]1.[CH2:12]=[C:13]1[O:17][C:15](=[O:16])[CH2:14]1>>[C:15]([NH:1][CH:2]1[CH2:3][C:4]([CH3:11])([CH3:10])[NH:5][C:6]([CH3:9])([CH3:8])[CH2:7]1)(=[O:16])[CH2:14][C:13]([CH3:12])=[O:17]
Reactant: C=C1CC(=O)O1
Reactant: CC1(C)CC(N)CC(C)(C)N1
Product: CC(=O)CC(=O)NC1CC(C)(C)NC(C)(C)C1

Procedure:
The procedure of Example (1a) was repeated using 4- amino-2,2,6,6-tetramethylpiperidine, without introducing catalyst and performing the addition of diketene at a temperature of 0° C. to 10° C.; 4-acetoacetamido-2,2,6,6-tetramethyl-piperidine was obtained in the form of a white solid which had a melting point of 115° C.
Reaction SMILES: C([O:5][C:6](=[O:19])[CH:7]([CH3:18])[C:8]([C:10]1[C:15]([F:16])=[CH:14][C:13]([Cl:17])=[CH:12][N:11]=1)=[O:9])(C)(C)C.Br>C(O)(=O)C>[Cl:17][C:13]1[CH:14]=[C:15]([F:16])[C:10]([C:8](=[O:9])[CH:7]([CH3:18])[C:6]([OH:19])=[O:5])=[N:11][CH:12]=1
Reactant: CC(C(=O)OC(C)(C)C)C(=O)c1ncc(Cl)cc1F
Agent: Br
Solvent: CC(=O)O
Product: CC(C(=O)O)C(=O)c1ncc(Cl)cc1F
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 77.5 %

Procedure:
25.5 g of 3- (5-chloro-3-fluoropyridin-2-yl)-2-methyl-3-oxopropionic acid tert-but yl ester (Example P34) are added dropwise to 30 ml of a 33% solution of hydrogen bromide (HBr) in glacial acetic acid to form a suspension. The mixture is subsequently stirred for 90 minutes and then introduced into 300 ml of ice-water. The resulting precipitate is filtered off, washed with water and dried. 15.9 g of the desired title compound are obtained in the form of a solid having a melting point of 101-102° C.
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15](O)=[O:16])=[CH:14][C:9]=2[N:8]=[C:7]1[CH2:18][C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)[CH2:4][CH3:5])[CH3:2].C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[CH3:44][CH:45]([CH3:58])[CH2:46][C@H:47]([NH2:57])[CH2:48][S:49]([C:52]1[NH:56][CH:55]=[N:54][N:53]=1)(=[O:51])=[O:50].Cl>CN(C=O)C.O.C(Cl)CCl>[CH3:44][CH:45]([CH3:58])[CH2:46][C@H:47]([NH:57][C:15]([C:13]1[CH:12]=[CH:11][C:10]2[N:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[C:7]([CH2:18][C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)=[N:8][C:9]=2[CH:14]=1)=[O:16])[CH2:48][S:49]([C:52]1[NH:56][CH:55]=[N:54][N:53]=1)(=[O:51])=[O:50]
Reactant: CCC(CC)n1c(Cc2cccs2)nc2cc(C(=O)O)ccc21
Reactant: CC(C)C[C@H](N)CS(=O)(=O)c1nnc[nH]1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: O
Product: CCC(CC)n1c(Cc2cccs2)nc2cc(C(=O)N[C@@H](CC(C)C)CS(=O)(=O)c3nnc[nH]3)ccc21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 120 mg of 1-(1-ethyl-propyl)-2-thiophen-2-ylmethyl-1H-benzoimidazole-5-carboxylic acid in 1 ml of dry DMF 25 mg of HOAT, 85 mg of EDC and 0.36 ml of DIPEA were added at 0° C. After 15 min 108 mg of (S)-3-Methyl-1-(4H-[1,2,4]triazole-3-sulfonylmethyl)-butylamine-hydrochloride were added and the reaction was stirred at rt for 20 h. The reaction was then poured into water and the pH was adjusted to 3 by the addition of 2 M aqueous hydrochloric acid. The reaction was extracted with ethyl acetate three times. The combined organic phases were washed with 2 M aqueous hydrochloric acid, saturated sodium bicarbonate solution and brine, dried over magnesium sulphate and concentrated. After purification by HPLC 163 mg (82%) of 1-(1-Ethyl-propyl)-2-thiophen-2-ylmethyl-1H-benzoimidazole-5-carboxylic acid [(S)-3-methyl-1-(4H-[1,2,4]-triazole-3-sulfonylmethyl)-butyl]-amide were obtained.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH:10]([N:13]2[CH:17]=[CH:16][N:15]=[N:14]2)[CH2:9]1)C1C=CC=CC=1.[ClH:18]>CO.[Pd]>[ClH:18].[N:13]1([CH:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)[CH:17]=[CH:16][N:15]=[N:14]1
Reactant: c1ccc(CN2CCC(n3ccnn3)C2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: c1cn(C2CCNC2)nn1
Reaction time: 20 h

Procedure:
To a solution of N-benzyl-3-(1,2,3-triazol-1-yl) pyrrolidine (1 g, 0. 0044 mol), in methanol (50 ml) was added 10 % Pd/C (100 mg ) and conc. HCl (1 ml). The suspension was hydrogenated at r.t. and 50 psi pressure for 20 h. The Pd/C was removed by filtration and the solution was concentrated. The residue was recrystallized from methanol/ether to obtain white crystalline title compound. Yield: 680 mg (89.45%). 1H NMR (D20) δ: 2.40-2.80 (m, 2H), 3.58-3.66 (m, 2H), 3.90-3.92 (d, 2H), 5.58-5.67 (m, 1H), 8.02 (d, 1H), 8.26 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=2[C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:4][C:3]=1[N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24].[O:29]=[C:30]1[NH:34][C:33](=[O:35])[CH:32]([CH2:36][C:37]2[CH:47]=[CH:46][C:40]([O:41][CH2:42][C:43](O)=[O:44])=[CH:39][CH:38]=2)[S:31]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCCC1>[O:29]=[C:30]1[NH:34][C:33](=[O:35])[CH:32]([CH2:36][C:37]2[CH:38]=[CH:39][C:40]([O:41][CH2:42][C:43]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([O:8][C:9]4[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=4[C:16]([CH3:19])([CH3:17])[CH3:18])=[CH:4][C:3]=3[N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:44])=[CH:46][CH:47]=2)[S:31]1
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(O)cc2C(C)(C)C)ccc1N
Agent: CCOP(=O)(C#N)OCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(O)cc2C(C)(C)C)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Yield: 77.6 %

Procedure:
In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-[2-amino-5-(2-t-butyl-4-hydroxyphenoxy)phenyl]-N-methyl-carbamate (0.95 g), 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid (0.76 g), diethyl cyanophosphonate (0.44 g), triethylamine (0.27 g) and anhydrous tetrahydrofuran (20 ml) and the reaction mixture was purified to give the desired product (1.24 g).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]2[C:5]([O:6][C:7]3[C:8]([F:19])=[CH:9][C:10]([O:17][CH3:18])=[CH:11][C:12]=3[C:13]2=[O:16])=[CH:4][CH:3]=1.[BH4-].[Na+]>C1COCC1.CO>[Br:1][C:2]1[CH:15]=[C:14]2[C:5]([O:6][C:7]3[C:8]([F:19])=[CH:9][C:10]([O:17][CH3:18])=[CH:11][C:12]=3[CH:13]2[OH:16])=[CH:4][CH:3]=1
Reactant: COc1cc(F)c2oc3ccc(Br)cc3c(=O)c2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(F)c2c(c1)C(O)c1cc(Br)ccc1O2
Yield: 88.5 %

Procedure:
To a mixture of 7-bromo-4-fluoro-2-methoxy-9H-xanthen-9-one (45 g, 139 mmol) in THF (400 ml) and MeOH (400 ml) at RT was added NaBH4 (10.54 g, 279 mmol) slowly over the course of one hour. The solution was stirred vigorously for 30 additional minutes, then quenched slowly with a saturated ammonium chloride solution (200 ml). Additional water was added and the mixture was filtered, then washed with water and dried under vacuum to afford 7-bromo-4-fluoro-2-methoxy-9H-xanthen-9-ol (40 g, 123 mmol) as a light yellow solid that was advanced without further purification.
Reaction SMILES: Cl[C:2]1[C:3]2[S:10][C:9]([I:11])=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:12]([O:16][C:17](=[O:36])[NH:18][CH:19]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[C:20](=[O:27])[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)([CH3:15])([CH3:14])[CH3:13]>ClCCCl>[C:12]([O:16][C:17](=[O:36])[NH:18][CH:19]([CH2:28][C:29]1[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=1)[C:20]([N:21]1[CH2:26][CH2:25][N:24]([C:2]2[C:3]3[S:10][C:9]([I:11])=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:23][CH2:22]1)=[O:27])([CH3:15])([CH3:13])[CH3:14]
Reactant: Clc1ncnc2cc(I)sc12
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(Cl)cc1)C(=O)N1CCNCC1
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NC(Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ncnc3cc(I)sc23)CC1
Yield: 10.3 %

Procedure:
To a solution of 4-chloro-6-iodothieno[3,2-d]pyrimidine (0.22 g, 0.742 mmol) in DCE (5 mL)/TEA (2 mL) was added [1-(4-chlorobenzyl)-2-oxo-2-piperazin-1-yl-ethyl]-carbamic acid tert-butyl ester (25 mg, 0.68 mmol). The mixture was refluxed for 2 hours. The solvent was removed and the residue was subject to chromatography on silica gel to afford the product {1-(4-chlorobenzyl)-2-[4-(6-iodothieno[3,2-d]pyrimidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-carbamic acid tert-butyl ester (44 mg, 95%). 1H NMR (CDCl3, 400 Hz) δ 8.47 (s, 1H), 7.64 (s, 1H), 7.27-7.25 (d, J=8.4 Hz, 2H), 7.17-7.15 (d, J=8.0 Hz, 2H), 5.44 (d, J=8.8 Hz, 1H), 4.85-4.81 (m, 1H), 3.86-3.50 (m, 7H), 3.24-3.19 (m, 1H), 2.99-2.97 (d, J=7.2 Hz, 2H), 1.43 (s, 9H). MS (ESI+) [M+H]+ 628.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[N+:12]([C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][C:21]=1[F:22])[NH2:18])([O-:14])=[O:13]>>[N+:12]([C:15]1[CH:16]=[C:17]([NH:18][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])[CH:19]=[CH:20][C:21]=1[F:22])([O-:14])=[O:13]
Reactant: O=C(O)Cc1ccccc1Br
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Product: O=C(O)Cc1ccccc1Nc1ccc(F)c([N+](=O)[O-])c1

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 3-nitro-4-fluoroaniline to yield 2-[(3-nitro-4-fluorophenyl)amino]phenylacetic acid.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].IC>C(#N)C.CN(C)C=O>[C:1]1([C@@H:7]2[CH2:9][C@H:8]2[NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CN[C@@H]2C[C@H]2c2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: CI
Product: c1ccc([C@@H]2C[C@H]2NCC2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 13.5 %

Procedure:
To a solution of tert-butyl 4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylate (Example 1, 100 mg, 0.303 mmol) in acetonitrile (2 ml) and N,N-dimethylformamide (DMF) (0.5 ml) was added potassium carbonate (125 mg, 0.908 mmol) followed by iodomethane (0.038 ml, 0.605 mmol). The reaction mixture was stirred for 4 hours at room temperature. The reaction mixture was evaporated. The oil was purified on preparative HPLC (5 to 70% AcCN: H2O gradient with 0.1% formic acid modifier). The fractions were collected. The combined fractions were neutralized with aq. NH4OH, concentrated and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and evaporated. The oil was dissolved in 2 mL of dioxane and 1 mL of HCl. The reaction mixture was heated under reflux for 15 min, and then evaporated to dryness. 4-(((trans-2-Phenylcyclopropyl)amino)methyl)piperidine (12 mg, 0.041 mmol, 13.41% yield) was isolated as a white solid. 1H NMR (400 MHz, METHANOL-d4) δ 7.35 (d, J=4.29 Hz, 2H), 7.14-7.30 (m, 3H), 3.47 (d, J=13.14 Hz, 2H), 3.35-3.42 (m, 2H), 3.12-3.27 (m, 2H), 3.09 (d, J=8.34 Hz, 3H), 2.89-3.05 (m, 1H), 2.77-2.89 (m, 1H), 2.04-2.52 (m, 3H), 1.83 (d, J=5.56 Hz, 1H), 1.37-1.73 (m, 3H); LC-MS Rt=0.38 min; MS (ESI): 245.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH:18]=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:21]([F:26])([F:25])C([O-])=O.[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C)C=O.CCOCC>[CH2:1]([O:8][C:9]([CH:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH:18]=[C:21]([F:26])[F:25])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CCC1CCC(C(=O)OCc2ccccc2)CC1
Reactant: O=C([O-])C(F)(F)Cl
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)C1CCC(CC=C(F)F)CC1
Temperature: 130 °C
Reaction time: 4 h
Yield: 58 %

Procedure:
A solution of 4-(2-oxo-ethyl)-cyclohexanecarboxylic acid benzyl ester (trans:cis=4:1) (21.4 mg, 0.082 mmol) in dimethylformamide (0.3 ml) was added to a solution of sodium chlorodifluoroacetate (34.1 mg, 0.224 mmol) and triphenylphosphine (59.9 mg, 0.228 mmol) in dimethylformamide (0.41 ml) at 90 to 95° C. over five minutes, and the mixture was stirred at 130° C. for four hours. Sodium chlorodifluoroacetate (34.0 mg, 0.22 mmol) was then added to the reaction mixture at the same temperature, and the mixture was further stirred for two hours. The reaction mixture was diluted with ether, and the organic layer was washed with water, dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 4-(3,3-difluoro-allyl)-cyclohexanecarboxylic acid benzyl ester (trans:cis=4:1) (14.1 m, 58%).
Reaction SMILES: C([O:3][C:4]([C:6]1([S:28]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)(=[O:30])=[O:29])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C>C1COCC1.CO.[OH-].[Na+]>[CH3:38][O:37][C:34]1[CH:35]=[CH:36][C:31]([S:28]([C:6]2([C:4]([OH:5])=[O:3])[CH2:11][CH2:10][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:15][CH:14]=3)[CH2:8][CH2:7]2)(=[O:29])=[O:30])=[CH:32][CH:33]=1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OC)cc2)CCN(Cc2ccc(OCCN3CCCCC3)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3ccc(OCCN4CCCCC4)cc3)CC2)cc1

Procedure:
4(4-Methoxy-benzenesulfonyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylic acid was prepared starting from 4-(4-Methoxy-benzenesulfonyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylic acid ethyl ester (5.4 g, 10 mmol) dissolved in THF:methanol 3:1 and 10 N NaOH (40 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 4.0 g (77%); off white powder; mp 174° C.; MS: 517.6 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:15]([C:17]3[C:18]([O:36][CH2:37][CH3:38])=[C:19]([C:25]4[CH:26]=[CH:27][C:28]([C:31]([N:33]([CH3:35])[CH3:34])=[O:32])=[N:29][CH:30]=4)[C:20]([CH3:24])=[C:21]([Cl:23])[CH:22]=3)[CH3:16])[N:9]=[C:10]([CH:11]([OH:14])CO)[C:3]=12.C(O)(=O)C.I([O-])(=O)(=O)=O.[Na+]>O1CCCC1.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:15]([C:17]3[C:18]([O:36][CH2:37][CH3:38])=[C:19]([C:25]4[CH:26]=[CH:27][C:28]([C:31]([N:33]([CH3:35])[CH3:34])=[O:32])=[N:29][CH:30]=4)[C:20]([CH3:24])=[C:21]([Cl:23])[CH:22]=3)[CH3:16])[N:9]=[C:10]([CH:11]=[O:14])[C:3]=12
Reactant: CCOc1c(C(C)n2nc(C(O)CO)c3c(N)ncnc32)cc(Cl)c(C)c1-c1ccc(C(=O)N(C)C)nc1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: CCOc1c(C(C)n2nc(C=O)c3c(N)ncnc32)cc(Cl)c(C)c1-c1ccc(C(=O)N(C)C)nc1
Reaction time: 2 h
Yield: 89.3 %

Procedure:
To a solution of 5-(3-{1-[4-amino-3-(1,2-dihydroxyethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2-ethoxy-6-methylphenyl)-N,N-dimethylpyridine-2-carboxamide (70 mg, 0.13 mmol) in tetrahydrofuran (0.98 mL) and water (0.59 mL) was added acetic acid (1.9 μL, 0.034 mmol) and sodium periodate (83 mg, 0.39 mmol) at 0° C. After stirring for 2 h, the reaction mixture was diluted with water, and extracted with dichloromethane. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated to give the desired product (0.059 g, 90%). LCMS calculated for C25H27ClN7O3 (M+H)+: m/z=508.2; Found: 508.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([C:12]1[CH:17]=[N:16][CH:15]=[C:14]([CH:18]3[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]3)[N:13]=1)[C:5]2([CH3:25])[CH3:24].CCN(CC)CC.[C:33](Cl)(=[O:35])[CH3:34]>C(Cl)Cl>[C:33]([N:20]1[CH2:21][CH2:22][CH2:23][CH:18]([C:14]2[N:13]=[C:12]([N:6]3[C:5]([CH3:25])([CH3:24])[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=4)[C:7]3=[O:11])[CH:17]=[N:16][CH:15]=2)[CH2:19]1)(=[O:35])[CH3:34]
Reactant: CC(=O)Cl
Reactant: CC1(C)c2cc(Cl)ccc2C(=O)N1c1cncc(C2CCCNC2)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCCC(c2cncc(N3C(=O)c4ccc(Cl)cc4C3(C)C)n2)C1
Yield: 34.9 %

Procedure:
To a mixture of 5-chloro-3,3-dimethyl-2-(6-piperidin-3-yl-pyrazin-2-yl)-2,3-dihydro-isoindol-1-one (80 mg, 0.22 mmol) and Et3N (44.4 mg, 0.44 mmol) in DCM (2 mL) was added acetyl chloride (26.4 mg, 0.34 mmol) at 0° C. After removal of solvent, the residue was purified by prep-HPLC to yield the title compound (30.6 mg, 35%) as a white solid. MS: 399.2 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH:14][CH2:15][C:16]2[CH:20]=[C:19]([CH3:21])[O:18][N:17]=2)=[C:4]([O:22][CH3:23])[CH:3]=1.[CH3:24][S:25]([C:28]1[CH:29]=[C:30]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[C:31](O)=[O:32])(=[O:27])=[O:26]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH2:15][C:16]2[CH:20]=[C:19]([CH3:21])[O:18][N:17]=2)[C:31](=[O:32])[C:30]2[CH:34]=[C:35]([C:37]([F:40])([F:38])[F:39])[CH:36]=[C:28]([S:25]([CH3:24])(=[O:27])=[O:26])[CH:29]=2)=[C:4]([O:22][CH3:23])[CH:3]=1
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Reactant: COc1cc(F)ccc1-c1ccncc1NCc1cc(C)on1
Product: COc1cc(F)ccc1-c1ccncc1N(Cc1cc(C)on1)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1

Procedure:
The title compound was prepared in analogy to example 90, from [4-(4-fluoro-2-methoxy-phenyl)-pyridin-3-yl]-(5-methyl-isoxazol-3-ylmethyl)-amine and 3-(methylsulfonyl)-5-(trifluoromethyl)benzoic acid (example 114, intermediate a) after a reaction time of 18 hours at room temperature. The compound was purified by silica gel chromatography on a 20 g column using an MPLC (Flashmaster) system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Light brown solid (53%). MS (ESI): m/z=564.121 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([CH3:19])[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]2[CH2:11][CH2:10][O:9][C:8](=[O:12])[C:7]=12.C([O-])(=O)C.[Na+].[H][H]>CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:19][C:4]1[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]2[CH2:11][CH2:10][O:9][C:8](=[O:12])[C:7]2=[CH:2][N:3]=1
Reactant: [H][H]
Reactant: Cc1nc(Cl)c2c(c1-c1ccccc1)CCOC2=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1ncc2c(c1-c1ccccc1)CCOC2=O
Yield: 96.4 %

Procedure:
8-chloro-6-methyl-5-phenyl-3,4-dihydro-pyrano[3,4-c]pyridine-1-on (120 mg, 0.438 mmol), palladium acetate (5.0 mg, 0.022 mmol) and sodium acetate (72 mg, 0.877 mmol) were suspended in 5 mL of anhydrous methanol and then stirred at room temperature for about 2 hours under the hydrogen atmosphere. The mixture was filtered and then concentrated under reduced pressure, added with 15 mL of a saturated solution of sodium hydrogen carbonate and then extracted twice with 20 mL of methylene chloride. The resulting organic layer was dried with anhydrous sodium sulfate, filtered and then concentrated. A silica gel column chromatography (2% MeOH/MC) was performed on the resulting residue and 101 mg (96%) of 6-methyl-5-phenyl-3,4-dihydro-pyrano[3,4-c]pyridine-1-on was obtained in white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH3:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11]1>C(COC)OC>[Cl:1][C:2]1[N:7]=[C:6]([C:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]([CH3:9])[CH:11]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: Cn1ccc2ccccc21
Solvent: COCCOC
Product: Cn1cc(-c2ccnc(Cl)n2)c2ccccc21
Temperature: 60 °C
Reaction time: 8 h
Yield: 122.7 %

Procedure:
To a stirred solution 2,4-dichloropyrimidine (70.5 g, 463.76 mmol) in dimethoxyethane (900 mL) was added FeCl3 (77.16 g, 459.12 mmol) and 1-methyl indole (68.28 g) at 60° C. The resulting mixture was stirred overnight at 60° C. After cooling, a solid was precipitated by adding methanol (345 mL) and water (900 mL). The resulting slurry was stirred for 3 h. The solid was collected by filtration, washed with CH3OH (1.38 L) and dried at 50° C. overnight to give the title compound (138.7 g, 81.5%) as a purple solid; 1H NMR (CDCl3) 3.89 (3H, s), 7.36-7.41 (3H, m), 7.49 (1H, s), 7.96 (1H, s), 8.34 (1H, s), 8.45 (1H, s); m/z: ES+ MH+ 244.05.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH2:20]C)=[O:18])=[C:15]([O:22][CH2:23][CH2:24][NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:14]([C:33]3C=CO[CH:34]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(S(CC2C(C(OC)=O)=C(O)C(CC)=CC=2)(=O)=O)C=CC=CC=1.C(OC(NCCBr)=O)(C)(C)C>>[C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([O:22][CH2:23][CH2:24][NH:25][C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[C:14]([CH2:33][CH3:34])=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1OCCNC(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)NCCBr
Agent: CCc1ccc(CS(=O)(=O)c2ccccc2)c(C(=O)OC)c1O
Product: CCc1ccc(CS(=O)(=O)c2ccccc2)c(C(=O)OC)c1OCCNC(=O)OC(C)(C)C

Procedure:
Prepared by proceeding in a similar manner to Intermediate 10, starting from methyl 6-(benzenesulphonylmethyl)-3-ethyl-2-hydroxybenzoate (Intermediate 110) and 2-(t-butoxycarbonylamino)ethyl bromide
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:13]=[CH:12][C:11]([CH2:14][C@H:15]([NH:20]C(OC(C)(C)C)=O)[C:16]([O:18][CH3:19])=[O:17])=[CH:10][CH:9]=1>C(Cl)Cl>[NH2:20][C@@H:15]([CH2:14][C:11]1[CH:12]=[CH:13][C:8]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:9][CH:10]=1)[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@@H](N)Cc1ccc(-c2ccccc2)cc1
Reaction time: 1 h
Yield: 139.2 %

Procedure:
Trifluoroacetic acid (1 mL, 10 mmol) was added to a solution of (S)-methyl 3-(biphenyl-4-yl)-2-(tert-butoxycarbonylamino)propanoate (30 mg) in methylene chloride (2 mL). The reaction was stirred for 1 h, and was concentrated under reduced pressure to give the crude product methyl (2S)-2-amino-3-biphenyl-4-ylpropanoate (30 mg, 100%). Analytical LCMS (M+H)+: m/z=256.1.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[Br:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[F:19])[CH:14]=[O:15]>O>[Br:10][C:11]1[C:18]([F:19])=[CH:17][C:16]([N+:6]([O-:9])=[O:7])=[C:13]([CH:12]=1)[CH:14]=[O:15]
Reactant: O=Cc1ccc(F)c(Br)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=Cc1cc(Br)c(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 0° C. solution of concentrated sulfuric acid (125 mL, 2340 mmol) and nitric acid (11.79 mL, 185 mmol) was added 3-bromo-4-fluorobenzaldehyde (25.0 g, 123 mmol). The reaction was warmed to ambient temperature, during which time the solids dissolved. After 2 h, the reaction mixture was poured into a mixture of ice (500 mL) and water (250 mL). The resulting suspension was filtered through a medium frit affording 5-bromo-4-fluoro-2-nitrobenzaldehyde as a yellow solid.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[C:20]12([CH2:30][C:31](O)=[O:32])[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]3)[CH2:21]1)[CH2:27]2>>[C:20]12([CH2:30][C:31]([NH:1][N:2]3[N:11]=[C:10]([C:12]4[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=4)[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[C:3]3=[O:19])=[O:32])[CH2:27][CH:26]3[CH2:25][CH:24]([CH2:23][CH:22]([CH2:28]3)[CH2:21]1)[CH2:29]2
Reactant: Cc1ccc(-c2nn(N)c(=O)c3ccccc23)cc1
Reactant: O=C(O)CC12CC3CC(CC(C3)C1)C2
Product: Cc1ccc(-c2nn(NC(=O)CC34CC5CC(CC(C5)C3)C4)c(=O)c3ccccc23)cc1

Procedure:
The product of Example 135A and 2-(adamantan-1-yl)acetic acid were treated using a method similar to that described in Example 17C to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.24 (s, 1H), 8.39-8.42 (m, 1H), 7.88-8.02 (m, 2H), 7.73-7.76 (m, 1H), 7.47-7.50 (m, 2H), 7.37-7.40 (m, 2H), 2.42 (s, 3H), 2.05 (s, 2H), 1.94-1.99 (m, 3H), 1.65-1.73 (m, 9H), 1.57-1.64 (m, 3H); MS (APCI+) M/Z 428 (M+H)+.