Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[C:6]3[CH2:13][CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1.[Mg]>>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[CH:6]3[CH2:13][CH2:14][CH2:15][CH:5]3[C:4]=2[CH:3]=1
Reactant: Cc1ccc2[nH]c(=O)c3c(c2c1)CCC3
Agent: [Mg]
Product: Cc1ccc2c(c1)C1CCCC1C(=O)N2

Procedure:
8-Methyl-1,2,3,5-tetrahydrocyclopenta[c]quinolin-4-one (R. J. Brown, F. W. S. Carver, B. L. Hollingsworth, J. Chem. Soc. 1961, 4295) (1.20 g, 6.0 mmol) and magnesium (1.46 g, 60 mmol) are converted into 0.48 g (40%) of product analogously to Example 7.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[O:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].C1(C)C(S(O[CH2:31][CH2:32][CH:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)(=O)=O)=CC=CC=1>>[CH2:34]1[CH2:35][CH2:36][CH2:37][CH:33]1[CH:32]([N:8]1[C:9]([O:10][C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]1=[O:19])[CH3:31]
Reactant: Cc1ccccc1S(=O)(=O)OCCC1CCCC1
Reactant: Cc1cc(C)cc(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Product: Cc1cc(C)cc(Oc2c(C(C)C)c(=O)[nH]c(=O)n2C(C)C2CCCC2)c1
Yield: 28.3 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and (2-cyclopentyl)ethyl toluenesulfonate were reacted by the same method with example 44 to obtain the titled compound (105 mg).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.NC1C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl[C:32]1[C:41]2[C:40](=[O:42])[NH:39][CH:38]=[N:37][C:36]=2[CH:35]=[C:34]([Cl:43])[N:33]=1>C1COCC1>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[CH:11][C:10]([NH:13][C:32]3[C:41]4[C:40](=[O:42])[NH:39][CH:38]=[N:37][C:36]=4[CH:35]=[C:34]([Cl:43])[N:33]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=c1[nH]cnc2cc(Cl)nc(Cl)c12
Reactant: Nc1ccc(N2CCOCC2)nc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: Nc1ccccc1
Solvent: C1CCOC1
Product: O=c1[nH]cnc2cc(Cl)nc(Nc3ccc(N4CCOCC4)nc3)c12
Reaction time: 0.17 h

Procedure:
At 0° C., to a solution of aniline 6-morpholinopyridin-3-amine (II) (125 mg, 0.7 mmol) in THF (3 mL) was added NaHMDS (2 mL, 1M/THF). After 10 minutes, compound 5,7-dichloropyrido[4,3-d]pyrimidin-4(3H)-one (I) (108 mg, 0.5 mmol) was added. The resulting mixture was stirred for 4 hours. The mixture was subjected to HPLC-MS, and the product 5-(6-morpholinopyridin-3-ylamino)-7-chloropyrido[4,3-d]pyrimidin-4(3H)-one was obtained as a purple solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:3]=1.C([Li])CCC.[O:20]1[CH2:22][CH2:21]1>O1CCCC1>[Cl:8][C:6]1[CH:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:3]=[C:2]([CH2:1][CH2:22][CH2:21][OH:20])[CH:7]=1
Reactant: C1CO1
Reactant: Cc1cc(Cl)cc(N2CCOCC2)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OCCCc1cc(Cl)cc(N2CCOCC2)n1
Temperature: -78 °C

Procedure:
2-Methyl-4-chloro-6-morpholino-pyridine (50 mmol) is dissolved in tetrahydrofuran (200 mL). The reaction is chilled to −78° C. under an inert atmosphere. A solution of n-butyllithium in hexanes (24 mL, 2.5M, 60 mmol) is added, and the reaction mixture is stirred for thirty minutes. A solution of oxirane dissolved in tetrahydrofuran (40 mL, 41.5M, 60 mmol) is added, and the reaction is allowed to warm to room temperature while stirring overnight. The solvent is removed under reduced pressure, and the crude material is dissolved in methylene chloride (200 mL) and washed with saturated ammonium chloride (2×50 mL), dried with sodium sulfate, and evaporated to dryness. The compound is purified by column chromatography to give 3-(4-chloro-6-morpholin-4-yl-pyrid-2-yl)-propan-1-ol.
Reaction SMILES: [NH2:1][C:2]1[C:3](Br)=[N:4][CH:5]=[CH:6][CH:7]=1.C(O[C:12]([S-:14])=[S:13])C.[K+].CN(C)C=O.Cl>O>[N:1]1[C:2]2[C:3](=[N:4][CH:5]=[CH:6][CH:7]=2)[S:13][C:12]=1[SH:14]
Reactant: CCOC(=S)[S-]
Reactant: Nc1cccnc1Br
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Sc1nc2cccnc2s1
Temperature: 130 °C
Reaction time: 0.17 h
Yield: 96.5 %

Procedure:
In a round-bottomed flask, 3-amino-2-bromopyridine (1.14 g, 6.59 mmol), potassium ethylxanthate (2.32 g, 14.5 mmol) and dry dimethylformamide (4 mL) were mixed. The reaction mixture was heated to 130° C. overnight. After cooling to room temperature, the reaction mixture was diluted with water (150 mL). 5 N Hydrochloric acid (4 mL) was added and the mixture was stirred for 10 minutes. The precipitate formed was collected by filtration and dried in a vacuum oven at 80° C. overnight to give thiazolo[5,4-b]pyridine-2-thiol (1.07 g, 6.36 mmol, 97% yield) as tan solid. 1H NMR (300 MHz, DMSO-d) δ ppm 7.43 (dd, J=8.18, 4.82 Hz, 1 H) 7.63 (dd, J=8.18, 1.32 Hz, 1 H) 8.34-8.47 (m, 1 H). ESI (M+1) 168.9.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][NH2:7].Cl[CH2:9][C:10]1[N:11]=[C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][N:13]2[CH:22]=1>C(Cl)Cl>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][NH:7][CH2:9][C:10]1[N:11]=[C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:19])[F:20])[CH:15]=[CH:14][N:13]2[CH:22]=1
Reactant: FC(F)(F)c1ccn2cc(CCl)nc2c1
Reactant: NCC1OCCO1
Solvent: ClCCl
Product: FC(F)(F)c1ccn2cc(CNCC3OCCO3)nc2c1
Temperature: 25 °C
Yield: 56.8 %

Procedure:
To a DCM 5 mL solution of 1-(1,3-dioxolan-2-yl)methanamine (814 mg, 7.89 mmol) was added 2-(chloromethyl)-7-(trifluoromethyl)imidazo[1,2-a]pyridine (Intermediate 19) (620 mg, 2.63 mmol). After heating to reflux for 1.5 hr, the reaction mixture (suspension) was cooled to room temperature and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with a gradient solvent mixture (5% MeOH-DCM to 15% MeOH-DCM) to give the title compound as solid (450 mg). LC/MS: m/z 302(M+H).
Reaction SMILES: [CH3:1][C:2]([OH:11])([CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])[CH:3]=[CH2:4].[OH-].[K+].Cl[CH2:15][C:16]([C:18]1[CH:23]=[C:22]([CH:24]([CH3:26])[CH3:25])[C:21]([OH:27])=[C:20]([CH:28]([CH3:30])[CH3:29])[CH:19]=1)=[O:17].Cl>CN1CCCC1=O>[CH3:1][C:2]([CH:3]=[CH2:4])([O:11][CH2:15][C:16]([C:18]1[CH:19]=[C:20]([CH:28]([CH3:30])[CH3:29])[C:21]([OH:27])=[C:22]([CH:24]([CH3:26])[CH3:25])[CH:23]=1)=[O:17])[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9]
Reactant: C=CC(C)(O)CCC=C(C)C
Reactant: CC(C)c1cc(C(=O)CCl)cc(C(C)C)c1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: C=CC(C)(CCC=C(C)C)OCC(=O)c1cc(C(C)C)c(O)c(C(C)C)c1
Reaction time: 16 h
Yield: 2.2 %

Procedure:
To a solution of 12.7 g (79 mmol) of 3,7-dimethyl-octa-1,6-dien-3-ol and 10.9 g (195 mmol) of potassium hydroxide in 80 ml of N-methylpyrrolidone a solution of 10.0 g (39 mmol) of 2-chloro-1-(4-hydroxy-3,5-di-isopropylphenyl)-ethanone in 120 ml of N-methylpyrrolidone is added dropwise at room temperature and under inert atmosphere. After the addition is completed stirring is continued for additional 16 hours. Then the reaction mixture is acidified with 1N HCl and extracted with ethyl acetate. The collected organic phases are washed with water and brine, dried and evaporated. Crystallization of the crude product from hexane gives 0.32 g of compound III, m.p. 71-72° C.
Reaction SMILES: [CH2:1]1[N:6]([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]3[CH:18]=[CH:19][C:20]([NH:22][C:14]=3[CH:13]=2)=[O:21])[CH2:5][CH2:4][N:3]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=2[Cl:30])[CH2:2]1.N1C=CC=CC=1.[C:37](Cl)(=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39]>ClCCl>[C:37]([O:21][C:20]1[CH:19]=[CH:18][C:15]2[C:14](=[CH:13][C:12]([O:11][CH2:10][CH2:9][CH2:8][CH2:7][N:6]3[CH2:5][CH2:4][N:3]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=4[Cl:30])[CH2:2][CH2:1]3)=[CH:17][CH:16]=2)[N:22]=1)(=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39]
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=c1ccc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2[nH]1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Oc1ccc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2n1
Reaction time: 20 h

Procedure:
To a solution of dehydro-aripiprazole (1.2 g, 2.7 mmol) in dichloromethane (30 mL) was added pyridine (1 mL), followed by pivaloyl chloride (0.66 mL, 5.4 mmol). The reaction mixture was stirred for 20 hours, then washed with water and dried over MgSO4. After evaporation the residue was co-evaporated with toluene and then further purified on silica eluting with ethyl acetate. After evaporation of the product containing fraction, Compound-316 (0.53 g) was obtained as a colourless oil.
Reaction SMILES: O[CH:2]1[O:21][C@H:20]([CH2:22][OH:23])[C@@H:7]([O:8][C@@H:9]2[O:17][C@H:16]([CH2:18][OH:19])[C@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]2[OH:11])[C@H:5]([OH:6])[C@H:3]1[OH:4].[CH2:24]([NH2:34])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>>[CH3:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][NH:34][CH:2]1[O:21][C@H:20]([CH2:22][OH:23])[C@@H:7]([O:8][C@@H:9]2[O:17][C@H:16]([CH2:18][OH:19])[C@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]2[OH:11])[C@H:5]([OH:6])[C@H:3]1[OH:4]
Reactant: OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O
Reactant: CCCCCCCCCCN
Product: CCCCCCCCCCNC1O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@H]1O

Procedure:
The process was carried out in essentially the same manner as in Step (a) of Example 5, using 21 g of lactose and 15.2 g of decylamine.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[N:14]([C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:15]1[CH:20]=[N:19][CH:18]=[C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[N:22]=2)[N:16]=1)(C)(C)C.[OH-].[NH4+]>ClCCl>[Cl:34][C:31]1[CH:30]=[CH:29][C:28]([NH:14][C:15]2[CH:20]=[N:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[N:22]=3)[N:16]=2)=[CH:33][CH:32]=1
Reactant: Cc1cccc(-c2cncc(N(C(=O)OC(C)(C)C)c3ccc(Cl)cc3)n2)n1
Agent: [NH4+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cccc(-c2cncc(Nc3ccc(Cl)cc3)n2)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 95.5 %

Procedure:
Trifluoroacetic acid (1.0 mL, 13.4 mmol) in dichloromethane (3 mL) was added to an ice cooled solution of (4-chloro-phenyl)-[6-(6-methyl-pyridin-2-yl)-pyrazin-2-yl]-carbamic acid tert-butyl ester (70 mg, 0.18 mmol) in dichloromethane (4 mL) and stirred for 2.5 hour at room temperature. The reaction mixture was cooled on an ice bath and aqueous ammonium hydroxide was added followed by evaporation of dichloromethane. The formed precipitate was filtered off. The crude product was purified by flash chromatography (ethyl acetate/heptane as eluent) to give (4-chloro-phenyl)-[6-(6-methyl-pyridin-2-yl)-pyrazin-2-yl]-amine (51 mg, 98%).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][C:26]1[CH:38]=[C:37]([C:39]([N:41]2[CH2:50][C:49]3[CH:48]=[N:47][N:46]([CH3:51])[C:45]=3[NH:44][C:43]3[CH:52]=[CH:53][CH:54]=[CH:55][C:42]2=3)=[O:40])[CH:36]=[CH:35][C:27]=1[O:28][CH2:29][CH2:30][CH2:31][C:32](O)=[O:33].Cl.Cl.[CH3:58][C:59]([CH3:69])([CH3:68])[CH2:60][CH2:61][N:62]1[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]1.CCN(C(C)C)C(C)C>ClCCl>[CH3:58][C:59]([CH3:69])([CH3:68])[CH2:60][CH2:61][N:62]1[CH2:63][CH2:64][N:65]([C:32](=[O:33])[CH2:31][CH2:30][CH2:29][O:28][C:27]2[CH:35]=[CH:36][C:37]([C:39]([N:41]3[CH2:50][C:49]4[CH:48]=[N:47][N:46]([CH3:51])[C:45]=4[NH:44][C:43]4[CH:52]=[CH:53][CH:54]=[CH:55][C:42]3=4)=[O:40])=[CH:38][C:26]=2[CH3:25])[CH2:66][CH2:67]1
Reactant: CC(C)(C)CCN1CCNCC1
Reactant: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1OCCCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1OCCCC(=O)N1CCN(CCC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 53 %

Procedure:
HBTU (101 mg, 0.27 mmol) was added to a solution of 4-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenoxy]-butyric acid from E76.2 (71 mg, 0.17 mmol) and 1-(3,3-dimethyl-butyl)-piperazine dihydrochloride from Example E4 (54 mg, 0.22 mmol) in dichloromethane (10 ml) and DIEA (0.15 ml, 0.86 mmol). The mixture was stirred for 20 h at room temperature, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 6% methanol:94% dichloromethane) to give a white powder identified as the title compound (52 mg, 53%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([C@H:13]3[CH2:18][CH2:17][C@H:16]([C:19]([OH:21])=O)[CH2:15][CH2:14]3)[NH:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.[OH:22][CH:23]([CH3:26])[CH2:24][NH2:25].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.O>[OH:22][CH:23]([CH3:26])[CH2:24][NH:25][C:19]([C@H:16]1[CH2:15][CH2:14][C@H:13]([C:10]2[NH:11][CH:12]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[N:9]=2)[CH2:18][CH2:17]1)=[O:21]
Reactant: O=C(O)[C@H]1CC[C@H](c2nc(-c3cccc(Br)c3)c[nH]2)CC1
Reactant: CC(O)CN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CC(O)CNC(=O)[C@H]1CC[C@H](c2nc(-c3cccc(Br)c3)c[nH]2)CC1

Procedure:
The solution of trans-4-[4-(3-bromo-phenyl)-1H-imidazol-2-yl]-cyclohexyl-carboxylic acid (1.22 mmol), 2-hydroxy-propylamine(3.65 mmol) and BOP (1.22 mmol) in DMF (6 mL) was stirred overnight at room temperature. The mixture was diluted with water, extracted with EtOAc, washed with saturated NaHCO3, dried over Na2SO4, and concentrated under vacuum. The residue was purified with flash chromatography (90:10:1 CH2Cl2/MeOH/NH4OH) to give trans-4-[4-(3-bromo-phenyl)-1H-imidazol-2-yl]-cyclohexane-carboxylic acid (2-hydroxy-propyl) amide.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:29])=[C:4]([NH:10][C@H:11]([C@@H:26]([OH:28])[CH3:27])[C:12]([NH:14][NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH3:30][C:31]([Si:34](Cl)([CH3:36])[CH3:35])([CH3:33])[CH3:32].N1C=CN=C1>>[Si:34]([O:28][C@@H:26]([CH3:27])[C@@H:11]([NH:10][C:4]1[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[C:3]=1[CH3:29])[C:12]([NH:14][NH:15][C:16](=[O:25])[C:17]1[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=1)=[O:13])([C:31]([CH3:33])([CH3:32])[CH3:30])([CH3:36])[CH3:35]
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(C#N)cc2)[C@H](C)O)ccc(C#N)c1Cl
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(C#N)cc2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Yield: 83.8 %

Procedure:
N′-((2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoyl)-4-cyano benzohydrazide (12.1 g, 29.3 mmol) was reacted with TBDMSCl (13.2 g, 88.0 mmol) and imidazole (68.1 g, 146.0 mmol) in a manner analogous to that described for the preparation of intermediate 7b. Purification of the compound was accomplished by pouring the reaction mixture into ice-cold water and filtering off the solid precipitate. This was taken up in methylene chloride (400 mL) and sequentially washed with water (2×100 mL) and brine (100 mL). This was dried over sodium sulfate, tittered and concentrated down to roughly 100 mL. Hexanes were then added producing a white solid. This was filtered out and washed with hexanes to give the product as a white solid (12.92 g, 84%). 1H NMR (400 MHz, CDCl3, δ in ppm) 9.32 (m, 2H), 7.89 (AA′XX′, J=8.4 Hz, 2H), 7.71 (AA′XX′, J=8.6 Hz, 2H), 7.37 (d, J=8.4 Hz, 1H), 6.47 (d, J=8.8 Hz, 1H), 5.37 (d, J=6.2 Hz, 1H), 4.49 (m, 1H), 3.99 (m, 1H), 2.33 (s, 3H), 1.25 (d, J=6.2 Hz, 3H), 0.92 (s, 9H), 0.14 (s, 3H), 0.09 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-])=O)([CH3:6])[C:3]([OH:5])=[O:4]>CO.[Pd]>[CH3:6][C:2]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:14])([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: CC(C)(Nc1ccccc1[N+](=O)[O-])C(=O)O
Agent: [Pd]
Solvent: CO
Product: CC(C)(Nc1ccccc1N)C(=O)O
Yield: 84.6 %

Procedure:
30 g (mol/7.45) of 2-methyl-(2'-nitroanilino)-propionic acid in solution in 320 ml of methanol are hydrogenated in the presence of 3 g of palladium on carbon to 10% in an autoclave with a capacity of 500 ml. H2 pressure in the cold = 105 kg/cm2. Temperature = 25°-35° C. (exothermic). Duration: 5 minutes. Pressure drop (calculated): 53 kg (actual): 43 kg. After filtration of the catalyst and evaporation of the filtrate to dryness, 22 g of a pink-coloured solid of melting point 130°-132° C. are isolated. Yield 84.6% (theoretical yield = 26 g).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:31]([O-:33])=[O:32])=[C:6]([CH:30]=1)[C:7]([NH:9][CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)=[O:8].[CH2:34]([NH:36][CH2:37][CH3:38])[CH3:35]>CN(C=O)C>[CH2:34]([N:36]([CH2:37][CH3:38])[C:2]1[CH:3]=[CH:4][C:5]([N+:31]([O-:33])=[O:32])=[C:6]([CH:30]=1)[C:7]([NH:9][CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)=[O:8])[CH3:35]
Reactant: O=C(NCC1CCN(C(c2ccccc2)c2ccccc2)CC1)c1cc(F)ccc1[N+](=O)[O-]
Reactant: CCNCC
Solvent: CN(C)C=O
Product: CCN(CC)c1ccc([N+](=O)[O-])c(C(=O)NCC2CCN(C(c3ccccc3)c3ccccc3)CC2)c1
Yield: 97.3 %

Procedure:
Step 1): To a solution of 5-fluoro-2-nitro-N-[(1-diphenylmethylpiperidin-4-yl)methyl]benzamide (prepared according to Preparation 24) (2.1 g, 4.68 mmol) in DMF (30 ml) was added diethylamine (1.46 ml, 14.06 mmol). The solution was refluxed overnight and evaporated under reduced pressure to give 5-diethylamino-2-nitro-N-[(1-diphenylmethylpiperidin-4-yl)methyl]benzamide (2.28 g, 97.5%): mp 167°-168° C.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:25]([C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[O:36])=[CH:30][CH:29]=1)(=[O:27])[CH3:26]>O1CCCC1>[C:25]([C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35]([N:15]2[CH2:16][CH2:17][N:12]([C:10]3[S:9][N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:11]=3)[CH2:13][CH2:14]2)=[O:36])=[CH:30][CH:29]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)c1ccc(N=C=O)cc1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc(NC(=O)N2CCN(c3nc(-c4ccccc4)ns3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added 4-acetylphenyl isocyanate (196 mg, 1.22 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and ethyl acetate to give 278 mg (84.0%) of the desired product as a solid.
Reaction SMILES: [Br:1]N1C(=O)NC(=O)N(Br)C1=O.[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]([O:28][CH3:29])=[O:27])=[C:22]([O:30][CH:31]([CH3:33])[CH3:32])[CH:21]=1.CN(C=O)C>O>[Br:1][C:25]1[CH:24]=[C:23]([C:26]([O:28][CH3:29])=[O:27])[C:22]([O:30][CH:31]([CH3:33])[CH3:32])=[CH:21][C:20]=1[C:14]1[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=1[F:12]
Reactant: COC(=O)c1ccc(-c2ccc(F)cc2F)cc1OC(C)C
Reactant: O=c1[nH]c(=O)n(Br)c(=O)n1Br
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)c(-c2ccc(F)cc2F)cc1OC(C)C
Yield: 166.6 %

Procedure:
Dibromoisocyanuric acid (2.19 g) was added to a mixture of methyl 2′,4′-difluoro-3-isopropoxybiphenyl-4-carboxylate (3.90 g) and DMF (40 mL), and the resultant mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The obtained organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (4.90 g).
Reaction SMILES: CCN=C=NCCCN(C)C.OC(C(F)(F)F)=O.[NH2:19][CH2:20][C:21]([NH:23][CH:24]1[CH2:27][N:26]([CH:28]2[CH2:33][CH2:32][CH:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:30][CH2:29]2)[CH2:25]1)=[O:22].[N+:40]([C:43]1[CH:51]=[CH:50][C:46]([C:47](O)=[O:48])=[CH:45][C:44]=1[C:52]([F:55])([F:54])[F:53])([O-:42])=[O:41]>>[N+:40]([C:43]1[CH:51]=[CH:50][C:46]([C:47]([NH:19][CH2:20][C:21](=[O:22])[NH:23][CH:24]2[CH2:27][N:26]([CH:28]3[CH2:33][CH2:32][CH:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH2:30][CH2:29]3)[CH2:25]2)=[O:48])=[CH:45][C:44]=1[C:52]([F:53])([F:54])[F:55])([O-:42])=[O:41]
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Reactant: NCC(=O)NC1CN(C2CCC(c3ccccc3)CC2)C1
Agent: CCN=C=NCCCN(C)C
Solvent: O=C(O)C(F)(F)F
Product: O=C(CNC(=O)c1ccc([N+](=O)[O-])c(C(F)(F)F)c1)NC1CN(C2CCC(c3ccccc3)CC2)C1

Procedure:
The title compound was prepared as a white solid from EDCI coupling of 2-amino-N-[1-(4-phenyl-cyclohexyl)-azetidin-3-yl]-acetamide TFA salt (as prepared in Step D of Example 66) and 4-nitro-3-trifluoromethyl-benzoic acid (Aldrich) using the procedure described in Step F of Example 1.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Br[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][O:30][CH:31]2[CH2:36][CH2:35][S:34](=[O:38])(=[O:37])[CH2:33][CH2:32]2)[N:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][O:30][CH:31]3[CH2:36][CH2:35][S:34](=[O:37])(=[O:38])[CH2:33][CH2:32]3)[N:24]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: O=S1(=O)CCC(OCc2cccc(Br)n2)CC1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3cccc(COC4CCS(=O)(=O)CC4)n3)s2)c(F)c1

Procedure:
The title compound was prepared as described in Example 1 with 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (0.10 g, 0.32 mmol) and 2-bromo-6-{[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy]methyl}pyridine (0.10 g, 0.32 mmol) as the starting materials.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:12][C:13]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[CH:17][N:16]=2)=[O:14])[CH:5]=[C:6]([Cl:11])[C:7]=1[O:8][CH2:9][CH3:10]>CO>[Cl:11][C:6]1[CH:5]=[C:4]([NH:12][C:13]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([OH:21])=[O:20])=[CH:17][N:16]=2)=[O:14])[CH:3]=[C:2]([Cl:1])[C:7]=1[O:8][CH2:9][CH3:10]
Reactant: CCOc1c(Cl)cc(NC(=O)c2ccc(C(=O)OC)cn2)cc1Cl
Solvent: CO
Product: CCOc1c(Cl)cc(NC(=O)c2ccc(C(=O)O)cn2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 109.2 %

Procedure:
6-(3,5-Dichloro-4-ethoxyphenylcarbamoyl)nicotinic acid (AAA-020) (19 mg, 109%) was prepared from methyl 6-(3,5-dichloro-4-ethoxyphenylcarbamoyl)nicotinate (3) (18 mg, 49 μmol) using a procedure essentially the same as in Step (iii) for AAA-013, except methanol (0.5 mL) was also added and the reaction mixture was stirred at RT overnight: m/z 353 [M−H]− (ES−). 1H NMR (400 MHz, DMSO-d6) δ: 11.12 (1H, s), 9.18 (1H, dd), 8.55 (1H, dd), 8.29 (1H, dd), 8.13 (2H, s), 4.06 (2H, q), 1.37 (3H, t).
Reaction SMILES: O.NN.[CH3:4][C:5]([CH3:28])([CH3:27])[CH2:6][C:7]([C:9]1[CH:26]=[CH:25][C:12]([CH2:13][N:14]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:11][CH:10]=1)=[O:8]>CO>[CH3:4][C:5]([CH3:28])([CH3:27])[CH2:6][C:7]([C:9]1[CH:10]=[CH:11][C:12]([CH2:13][NH2:14])=[CH:25][CH:26]=1)=[O:8]
Reactant: CC(C)(C)CC(=O)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Agent: NN
Solvent: CO
Solvent: O
Product: CC(C)(C)CC(=O)c1ccc(CN)cc1
Temperature: 25 °C
Yield: 76.7 %

Procedure:
Add hydrazine hydrate (0.189 mL, 3.913 mmol) to a stirred suspension of 2-[4-(3,3-dimethyl-butyryl)-benzyl]-isoindole-1,3-dione (875 mg, 2.609 mmol) in methanol (15 mL). Heat the mixture to reflux overnight. Cool the mixture to room temperature and concentrate in vacuo. Partition the residue between EtOAc and 5N aqueous HCl and wash the acidic aqueous phase again with 5N aqueous HCl. Basify with 5N aqueous NaOH to pH 12. Extract the basic aqueous solution three times with chloroform. Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo to give the title compound as a yellow oil (411 mg, 77%) that was used without any further purification.