Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:9][C:8]([CH3:11])([CH3:10])[CH2:7][N:6]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)(=[O:14])=[O:13])[CH2:5][CH:4]1[OH:21].[NH:22]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C@H:23]([C:28](O)=[O:29])[CH2:24][CH:25]([CH3:27])[CH3:26].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[C:34]([O:33][C:31](=[O:32])[NH:22][C@H:23]([C:28](=[O:29])[NH:2][CH:3]1[CH2:9][C:8]([CH3:11])([CH3:10])[CH2:7][N:6]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)(=[O:14])=[O:13])[CH2:5][CH:4]1[OH:21])[CH2:24][CH:25]([CH3:26])[CH3:27])([CH3:35])([CH3:37])[CH3:36]
Reactant: CC1(C)CC(N)C(O)CN(S(=O)(=O)c2ccccn2)C1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)NC1CC(C)(C)CN(S(=O)(=O)c2ccccn2)CC1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
4-Amino-6,6-dimethyl-1-(pyridine-2-sulfonyl)-azepan-3-ol HCl salt from Example 92g (0.22 g, 0.6 mmol) was dissolved in 5 ml DMF. To this solution, was added Boc-Leu-OH (0.22 g, 0.9 mmol) and HBTU (0.34 g, 0.9 mmol) and then NMM (0.24 g, 2.4 mmol). The mixture was stirred at r.t. overnight. DMF was removed under high vacuum. The residue was diluted with EtOAc and washed with H2O, 10% NaHCO3 and brine. Purification by column chromatography gave 0.22 g of the title compound (72% yield); MS (M+H+): 512.9; 1H-NMR (400 MHz, CDCl3): •8.68-8.67(d, 1H), 7.97-7.88(m, 2H), 7.69-7.64(m, 1H), 6.62-6.53(m, 1H), 5.06-5.00(m, 1H), 4.03-3.18(m, 7H), 1.80-1.42(m, 15H), 1.04-0.92(m, 12H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][OH:9])[CH2:4][CH2:3]1.[C:10](O)(=[O:17])[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1>>[OH:9][CH2:8][CH:5]1[CH2:6][CH2:7][CH:2]([NH:1][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[CH2:3][CH2:4]1
Reactant: NC1CCC(CO)CC1
Reactant: O=C(O)c1ccncc1
Product: O=C(NC1CCC(CO)CC1)c1ccncc1

Procedure:
Prepared as in Example 24a from (4-Aminocyclohexyl)methanol and isonicotinic acid as a yellow oil (100%). MS 235 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[NH2:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][N:31]=1)[C:26](O)=[O:27]>>[NH2:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][N:31]=1)[C:26]([NH:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[O:15])=[CH:10][CH:9]=2)[C:5]([CH3:21])=[CH:4][CH:3]=1)=[O:27]
Reactant: Cc1ccc(N)cc1-c1ccc(C(=O)NCC2CC2)cc1
Reactant: Nc1cc(C(=O)O)ccn1
Product: Cc1ccc(NC(=O)c2ccnc(N)c2)cc1-c1ccc(C(=O)NCC2CC2)cc1

Procedure:
2-Amino-N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)isonicotinamide was prepared from 5′-amino-N-(cyclopropylmethyl)-2′-methyl-1,1′-biphenyl-4-carboxamide and 2-aminoisonicotinic acid using method B. NMR; δH CDCl3 8.20,(1H, d), 7.93,(1H, s), 7.82,(2H, d), 7.60,(1H, d), 7.46,(1H, s), 7.39,(2H,d), 7.30-7.26,(2H, m), 6.96,(1H, s), 6.29,(1H, b), 4.67,(2H, s), 3.34,(2H, m), 2.24,(3H, s), 1.08,(1H, m), 0.59,(2H, m), 0.30,(2H, m). LCMS: retention time 2.75 min, MH+401.
Reaction SMILES: C([NH:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1)(=O)C.[N+:13]([O-])([O-:15])=[O:14].[K+]>S(=O)(=O)(O)O>[NH2:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=1[N+:13]([O-:15])=[O:14]
Reactant: CC(=O)Nc1ccc(C#N)cc1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: N#Cc1ccc(N)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-acetamidobenzonitrile (9.40 g) in concentrated sulfuric acid (80 ml) was added potassium nitrate in small portions at a temperature not exceeding 10° C. The reaction mixture was stirred at 5°-10° C. for 2 hours and poured into ice-water and the separated crystals were collected by suction. To the crystals was added 4N hydrochloric acid (100 ml) and the mixture was refluxed for 2 hours. After cooling to room temperature, the crystals were recovered by filtration, washed with water and dried under reduced pressure to give 7.22 g of 4-amino-3-nitrobenzonitrile.
Reaction SMILES: [NH2:1][C@@:2]1([C:19]2[CH:24]=[C:23]([Br:25])[C:22]([F:26])=[CH:21][C:20]=2[F:27])[CH2:7][O:6][C@@H:5]([CH2:8][O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:4][C@H:3]1[CH2:17][OH:18].[C:28]([N:36]=[C:37]=[S:38])(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>ClCCl>[CH2:10]([O:9][CH2:8][C@@H:5]1[O:6][CH2:7][C@@:2]([NH:1][C:37]([NH:36][C:28](=[O:35])[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[S:38])([C:19]2[CH:24]=[C:23]([Br:25])[C:22]([F:26])=[CH:21][C:20]=2[F:27])[C@H:3]([CH2:17][OH:18])[CH2:4]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N[C@@]1(c2cc(Br)c(F)cc2F)CO[C@@H](COCc2ccccc2)C[C@H]1CO
Reactant: O=C(N=C=S)c1ccccc1
Solvent: ClCCl
Product: O=C(NC(=S)N[C@@]1(c2cc(Br)c(F)cc2F)CO[C@@H](COCc2ccccc2)C[C@H]1CO)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To C7 (0.946 g, 2.14 mmol) in dichloromethane (22 mL) was added benzoyl isothiocyanate (0.273 mL, 2.04 mmol) and the resulting solution was allowed to stir at room temperature for 18 hours. The reaction mixture was concentrated in vacuo, providing the product as an orange oily residue, which was carried forward into the next step without further purification. Yield: 964 mg, 1.59 mmol, 74%. LCMS m/z 607.6 [M+H+], Br isotopic pattern. 1H NMR (400 MHz, CD3OD), characteristic peaks: δ 7.89-7.90 (m, 2H), 7.62-7.66 (m, 2H), 7.50-7.54 (m, 2H), 7.31 (d, J=6.6 Hz, 2H), 7.18-7.25 (m, 2H), 7.06 (dd, J=11.9, 8.8 Hz, 2H), 4.52-4.59 (m, 2H), 3.84-3.90 (m, 3H), 3.55-3.64 (m, 3H), 3.45-4.51 (m, 1H) 1.90-1.99 (m, 3H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[Cl:16][C:17]1[CH:18]=[CH:19][C:20]2[C:21]3[N:39]=[C:38]4[C:33]([CH:34]=[CH:35][CH:36]=[CH:37]4)=[C:23]4[CH:24]=[C:25](O)[CH:26]=[C:27]([N:28]([CH3:31])[C:29]=2[CH:30]=1)[C:22]=34>C(Cl)Cl>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]2[C:21]3[N:39]=[C:38]4[C:33]([CH:34]=[CH:35][CH:36]=[CH:37]4)=[C:23]4[CH:24]=[C:25]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[CH:26]=[C:27]([N:28]([CH3:31])[C:29]=2[CH:30]=1)[C:22]=34
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CN1c2cc(Cl)ccc2-c2nc3ccccc3c3cc(O)cc1c23
Solvent: ClCCl
Product: CN1c2cc(Cl)ccc2-c2nc3ccccc3c3cc(OS(=O)(=O)C(F)(F)F)cc1c23
Yield: 81 %

Procedure:
The general procedure (Method L) applied to trifluoromethanesulphonic acid anhydride (0.05 ml, 0.3 mmol, 1 eq), 10-chloro-6-hydroxy-8-methyl-8H-quino[4,3,2-kl]acridine, 37 (100 mg, 0.3 mmol) in DCM (50 mL) gave the title compound as a yellow solid, (114 mg, 0.25 mmol, 81%).
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[C:23]([F:25])[C:22]([F:26])=[CH:21][C:20]=3[O:27][CH3:28])=[CH:15][CH:14]=2)[CH:5]=1.[OH-].[Li+].CO>C1COCC1>[F:26][C:22]1[C:23]([F:25])=[CH:24][C:19]([C:16]2[CH:15]=[CH:14][C:13]([O:12][CH2:11][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=3[F:10])[C:3]([OH:29])=[O:2])=[CH:18][CH:17]=2)=[C:20]([O:27][CH3:28])[CH:21]=1
Reactant: COC(=O)c1ccc(F)c(COc2ccc(-c3cc(F)c(F)cc3OC)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(F)c(F)cc1-c1ccc(OCc2cc(C(=O)O)ccc2F)cc1
Yield: 94.9 %

Procedure:
3-(4′,5′-Difluoro-2′-methoxybiphenyl-4-yloxymethyl)-4-fluorobenzoic acid methyl ester (0.76 g, 1.9 mmol) was dissolved in THF (10 mL) and lithium hydroxide solution (0.5N, 8 mL) was added followed by addition of methanol (2 mL). The mixture was refluxed for 2 hrs and solvents were evaporated. The mixture was extracted with ether and water. The aqueous layer was treated with hydrochloric acid (1N, 5 mL) and extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. Solvents were evaporated to give a white solid as 3-(4′,5′-difluoro-2′-methoxybiphenyl-4-yloxymethyl)-4-fluorobenzoic acid (0.7 g, 96%). HRMS-ES calculated for C21, H15, F3, O4, 411.0814; found m/z 411.0815 [M+Na]+; 1H-NMR (DMSO-d6) δ ppm 13.15 (br, s, 1H), 8.16 (dd, J=7.2, 1.8 Hz, 1H), 7.96-8.04 (m, 1H), 7.32-7.45 (m, 4H), 7.24 (dd, J=13.0, 6.9 Hz, 1H), 7.08 (d, J=8.5 Hz, 2H), 5.24 (s, 2H), 3.76 (s, 3H).
Reaction SMILES: [OH:1][C@H:2]1[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[C:6](=[O:13])[CH2:5][CH2:4][CH2:3]1.[Si:14](OS(C(F)(F)F)(=O)=O)([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16].CCN(CC)CC>C(Cl)Cl>[CH:15]([Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[O:1][C@H:2]1[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[C:6](=[O:13])[CH2:5][CH2:4][CH2:3]1)([CH3:17])[CH3:16]
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: O=C1CCC[C@@H](O)c2ncccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[Si](O[C@@H]1CCCC(=O)c2cccnc21)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
In a 1L round-bottomed flask was (R)-9-hydroxy-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-one (19.14 g, 108 mmol) (azeotroped with dry benzene) in CH2Cl2 (300 mL) to give a tan solution. After cooling to 0° C., TIPS-OTf (29.3 mL, 108 mmol) and Et3N (30.1 mL, 216 mmol) were added via syringe, and the mixture was stirred at 0° C. for 1h. LCMS indicated complete conversion. Volatiles were stripped off and the residue was partitioned between NaHCO3 solution and EtOAc. The layers were separated and the organic layer was washed with brine, dried and concentrated to a tan oil (37 g). It was purified by FCC up to 20% EtOAc/hexane to afford the product as a white solid (26.3 g, 73% for two steps). MS(ESI)[M+H+]=334.37.
Reaction SMILES: [C:1]([C:4]1[CH:23]=[CH:22][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16](O)=[O:17])=[C:6]([CH2:24][CH2:25][CH3:26])[C:5]=1[OH:27])(=[O:3])[CH3:2].[N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][CH2:35][CH2:36][CH2:37][NH2:38])[CH:29]=1>>[C:1]([C:4]1[CH:23]=[CH:22][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([NH:38][CH2:37][CH2:36][CH2:35][CH2:34][C:30]2[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=2)=[O:17])=[C:6]([CH2:24][CH2:25][CH3:26])[C:5]=1[OH:27])(=[O:3])[CH3:2]
Reactant: NCCCCc1cccnc1
Reactant: CCCc1c(OCCCOc2cccc(C(=O)O)c2)ccc(C(C)=O)c1O
Product: CCCc1c(OCCCOc2cccc(C(=O)NCCCCc3cccnc3)c2)ccc(C(C)=O)c1O
Yield: 88 %

Procedure:
The reaction of 0.80 g of 3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]benzoic acid with 0.35 g of 3-pyridine butanamine according to Example 40 gave 0.95 g, mp 84°-86°, (88% yield) of 3-[3-(4-Acetyl-3-hydroxy-2-propylphenoxy)propoxy]-N-[4-(3-pyridinyl)butyl]benzamide, the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6]CC)=O.[Cl:13][C:14]1[N:19]=[C:18]([CH3:20])[CH:17]=[CH:16][CH:15]=1>>[Br:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4](=[O:6])[CH2:20][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:13])[N:19]=1
Reactant: Cc1cccc(Cl)n1
Reactant: CCOC(=O)c1ccccc1Br
Product: O=C(Cc1cccc(Cl)n1)c1ccccc1Br
Yield: 77 %

Procedure:
In a similar manner as described in Example 1 from ethyl 2-bromobenzoate (50.0 g, 218 mmol) and 6-chloro-2-picoline (24 mL, 218 mmol), 1-(2-bromophenyl)-2-(6-chloro-2-pyridinyl)ethanone (52.4 9, 77%) was obtained as a yellow solid. 1H NMR (CDCl3): δ 7.53 (d, 1 H), 7.45 (d, 1 H), 7.25 (d, 1 H), 7.05 (d, 1 H), 6.97 (d, 1 H), 6.67 (d, 1H), 6.53 (d, 1H), 5.28 (s, 1H); MS m/z 310 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[Li+].CC([N-]C(C)C)C.[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1>CO>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH2:22][C:21]1[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=1
Reactant: COc1ccc(C=O)cc1
Reactant: Clc1ccncc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CO
Product: COc1ccc(Cc2cnccc2Cl)cc1

Procedure:
4-Chloropyridine is treated sequentially with LDA (1.1 molar equivalents) and 4-methoxybenzaldehyde (1 molar equivalent). The resulting carbinol is isolated and deoxygenated with triethylsilane (10 molar equivalents) and 50% trifluoroacetic acid in methylene chloride to provide the title compound.
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([CH3:13])[CH:10]=[C:9]([C:14]3[CH:15]=[N:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=3)[N:8]=2)[CH:6]=1.[NH2:24][C:25]1[CH:30]=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][N:26]=1>>[CH3:13][C:11]1[CH:10]=[C:9]([C:14]2[CH:15]=[N:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=2)[N:8]=[C:7]([N:5]2[CH:6]=[C:2]([C:28]3[CH:29]=[CH:30][C:25]([NH2:24])=[N:26][CH:27]=3)[N:3]=[CH:4]2)[N:12]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Cc1cc(-c2ccc(C(F)(F)F)nc2)nc(-n2cnc(I)c2)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)nc2)nc(-n2cnc(-c3ccc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 2-(4-iodo-imidazol-1-yl)-4-methyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidine (example B.9) (0.35 g, 0.81 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.214 g, 0.97 mmol) according to the general procedure III. Obtained as a yellow solid (0.19 g, 59%). MS (ISP) 398.2 [(M+H)+]; mp 220° C.
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:17][CH2:16][C@@H:15]([C:18](=[O:22])[N:19]([CH3:21])[CH3:20])[CH2:14][C@@H:13]1[NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=O)C1C=CC=CC=1.[H][H]>O1CCCC1.[Pd]>[C:27]([O:26][C:24]([NH:23][C@@H:13]1[CH2:14][C@@H:15]([C:18](=[O:22])[N:19]([CH3:20])[CH3:21])[CH2:16][CH2:17][C@@H:12]1[NH2:11])=[O:25])([CH3:30])([CH3:28])[CH3:29]
Reactant: [H][H]
Reactant: CN(C)C(=O)[C@@H]1CC[C@H](NC(=O)OCc2ccccc2)[C@@H](NC(=O)OC(C)(C)C)C1
Agent: [Pd]
Solvent: C1CCOC1
Product: CN(C)C(=O)[C@H]1CC[C@H](N)[C@H](NC(=O)OC(C)(C)C)C1
Yield: 97.1 %

Procedure:
(1S,2S,4R)—N1-Benzyloxycarbonyl-N2-(tert-butoxycarbonyl)-4-(N,N-dimethylcarbamoyl)-1,2-cyclohexanediamine (560 mg) was dissolved in tetrahydrofuran (100 ml), and 10% palladium on carbon (220 mg) was added to stir the mixture for 17 hours in a hydrogen atmosphere. After the catalyst was removed by filtration, the filtrate was concentrated to obtain the title compound (370 mg) as a colorless oil.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:25]=[C:26]([O:28][CH:29]([CH3:31])[CH3:30])[CH:27]=1)[C:12]([NH:14][C:15]1[N:20]=[CH:19][C:18]([C:21]([O:23][CH3:24])=[O:22])=[CH:17][CH:16]=1)=[O:13])C1C=CC=CC=1.C(O)C>C1COCC1.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([CH:25]=[C:26]([O:28][CH:29]([CH3:31])[CH3:30])[CH:27]=1)[C:12]([NH:14][C:15]1[N:20]=[CH:19][C:18]([C:21]([O:23][CH3:24])=[O:22])=[CH:17][CH:16]=1)=[O:13]
Reactant: COC(=O)c1ccc(NC(=O)c2cc(OCc3ccccc3)cc(OC(C)C)c2)nc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: COC(=O)c1ccc(NC(=O)c2cc(O)cc(OC(C)C)c2)nc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 94.1 %

Procedure:
Methyl 6-[(3-benzyloxy-5-isopropoxybenzoyl)amino]-3-pyridinecarboxylate (1.92 g, 4.57 mM) was dissolved in THF (100 ml) and then ethanol (100 ml) and 10% palladium on carbon (250 mg) were added. The reaction was stirred at ambient temperature under an atmosphere of hydrogen (balloon) for 20 hours and was then filtered through diatomaceous earth. The filtrates were concentrated under reduced pressure to give methyl 6-[(3-hydroxy-5-isopropoxybenzoyl)amino]-3-pyridinecarboxylate as a colourless solid (1.42 g); H1 NMR δ (d6-DMSO) 1.24 (6H d) 3.85 (3H s) 4.62 (1H sept) 6.49 (1H s) 6.97 (1H s) 7.04 (1H s) 8.30 (2H s) 8.89 (1H s) 9.67 (1H s) 11.01 (1H s br); [M+H]-331; [M−H] 329.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[C:21]([CH3:23])[C:20]([OH:24])=[C:19]([CH2:25][CH3:26])[CH:18]=3)[N:13]=2)=[CH:9][C:8]=1[CH3:27])[CH2:4][CH3:5])[CH3:2].C([NH:35][CH2:36][CH2:37][CH2:38]Br)(OC(C)(C)C)=O>>[CH2:1]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[C:21]([CH3:23])[C:20]([O:24][CH2:38][CH2:37][CH2:36][NH2:35])=[C:19]([CH2:25][CH3:26])[CH:18]=3)[N:13]=2)=[CH:9][C:8]=1[CH3:27])[CH2:4][CH3:5])[CH3:2]
Reactant: CCc1cc(-c2noc(-c3cc(C)c(CN(CC)CC)s3)n2)cc(C)c1O
Reactant: CC(C)(C)OC(=O)NCCCBr
Product: CCc1cc(-c2noc(-c3cc(C)c(CN(CC)CC)s3)n2)cc(C)c1OCCCN
Yield: 38.4 %

Procedure:
The title compound (309 mg) is prepared in analogy to Example 201 starting from 4-[5-(5-diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenol (700 mg, 1.82 mmol) and 3-(Boc-amino)-propylbromide (900 mg, 3.63 mmol); LC-MS: tR=0.46 min; [M+1]+=443.10.
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:9]([O:11][CH:12]([OH:17])[C:13]([F:16])([F:15])[F:14])[CH3:10]>>[CH2:9]([O:11][CH:12]([O:17][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1)[C:13]([F:16])([F:15])[F:14])[CH3:10]
Reactant: CCOC(O)C(F)(F)F
Reactant: Nc1cccnc1Cl
Product: CCOC(Oc1ncccc1N)C(F)(F)F

Procedure:
Was prepared in a similar manner as intermediate III.1 from 2-chloropyridin-3-amine and 1-ethoxy-2,2,2-trifluoro-ethanol.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]([OH:13])=O)[CH2:4][CH2:3][CH2:2]1.[CH2:14]([O:16][C:17]([C:19]1([NH2:28])[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1)=[O:18])[CH3:15].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:14]([O:16][C:17]([C:19]1([NH:28][C:11]([C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[C:10]=2[NH:1][CH2:2][CH2:3][CH2:4]3)=[O:13])[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1)=[O:18])[CH3:15]
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Reactant: O=C(O)c1cccc2c1NCCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(NC(=O)c2cccc3c2NCCC3)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.9 %

Procedure:
To a solution of 1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (173 mg, 0.97 mmol), 2-amino-indan-2-carboxylic acid ethyl ester (200 mg, 0.97 mmol), HATU (553 mg, 1.46 mmol) in anhydrous DMF (20 mL) is added DIPEA (241 μL, 1.46 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (40 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by HPLC to give a pure product (63) as white solid (300 mg, 85%).
Reaction SMILES: I.I.[N:3]1([C:10]2[N:14]([CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:13]3[CH:22]=[CH:23][CH:24]=[CH:25][C:12]=3[N:11]=2)[CH2:9][CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH:38]=[N:37][N:36]=[N:35]2)=[CH:30][C:29]=1[C:39]([N:41]1[CH2:45][CH2:44][C@:43]([CH2:52][CH2:53]OS(C)(=O)=O)([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH2:42]1)=[O:40].C(N(CC)CC)C>C(#N)C>[CH3:21][O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][N:14]1[C:13]2[CH:22]=[CH:23][CH:24]=[CH:25][C:12]=2[N:11]=[C:10]1[N:3]1[CH2:9][CH2:8][CH2:7][N:6]([CH2:53][CH2:52][C@:43]2([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH2:44][CH2:45][N:41]([C:39]([C:29]3[CH:30]=[C:31]([N:34]4[CH:38]=[N:37][N:36]=[N:35]4)[CH:32]=[CH:33][C:28]=3[O:27][CH3:26])=[O:40])[CH2:42]2)[CH2:5][CH2:4]1
Reactant: COCCOCCn1c(N2CCCNCC2)nc2ccccc21
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)N1CC[C@](CCOS(C)(=O)=O)(c2ccccc2)C1
Agent: I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COCCOCCn1c(N2CCCN(CC[C@]3(c4ccccc4)CCN(C(=O)c4cc(-n5cnnn5)ccc4OC)C3)CC2)nc2ccccc21
Yield: 59.3 %

Procedure:
Heat a mixture of 2-[1,4]diazepan-1-yl-1-[2-(2-methoxy-ethoxy)-ethyl]-1H-benzoimidazole dihydroiodide (0.71 g, 1.24 mmol), methanesulfonic acid 2-{(S)-1-[1-(2-methoxy-5-tetrazol-1-yl-phenyl)-methanoyl]-3-phenyl-pyrrolidin-3-yl}-ethyl ester (0.60 g, 1.27 mmol, example 47.2) and acetonitrile (10 mL), triethylamine (1.2 mL, 8.61 mmol) and acetonitrile (15 mL) at 85° C. for 18 hours. Quench the reaction and purify the crude product as described in Example 113 to afford 0.51 g of the title compound, Rf=0.40 (silica gel, dichloromethane:methanol:30% ammonium hydroxide, 90:10:0.1). The compound may be converted to the dihydrochloride salt by methods well known in the art.
Reaction SMILES: [C:1]([C:4]1[CH:22]=[CH:21][C:7]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14](O)=[O:15])=[C:6]([CH2:23][CH2:24][CH3:25])[C:5]=1[OH:26])(=[O:3])[CH3:2].[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][CH2:34][CH2:35][CH2:36][NH2:37])[CH:28]=1>>[C:1]([C:4]1[CH:22]=[CH:21][C:7]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14]([NH:37][CH2:36][CH2:35][CH2:34][CH2:33][C:29]2[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=2)=[O:15])=[C:6]([CH2:23][CH2:24][CH3:25])[C:5]=1[OH:26])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCOc2ccccc2C(=O)O)ccc(C(C)=O)c1O
Reactant: NCCCCc1cccnc1
Product: CCCc1c(OCCOc2ccccc2C(=O)NCCCCc2cccnc2)ccc(C(C)=O)c1O
Yield: 77 %

Procedure:
The reaction of 0.83 g of 2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]benzoic acid with 0.38 g (0.0026 mol) of 3-pyridine butanamine according to Example 40 gave 0.88 g, mp 77°-80°, (77% yield) of 2-[2-(4-Acetyl-3-hydroxy-2-propylphenoxy)ethoxy]-N-[4-(3-pyridinyl)butyl]benzamide, the title compound.
Reaction SMILES: [Na].C(O)C.[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][NH2:13])[N:7]=1.[C:14](#[N:18])/[CH:15]=[CH:16]/[CH3:17]>CCOCC>[NH2:18][C:14]1[CH2:15][CH:16]([CH3:17])[N:12]([C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([Cl:5])[N:7]=2)[N:13]=1
Reactant: C/C=C/C#N
Reactant: NNc1cccc(Cl)n1
Agent: [Na]
Solvent: CCO
Solvent: CCOCC
Product: CC1CC(N)=NN1c1cccc(Cl)n1

Procedure:
A 0.23 g. amount of sodium metal is dissolved in 75 ml. of absolute ethanol, then 7.2 g of 2-chloro-6-hydrazinopyridine is added followed by 3.4 g. of distilled crotononitrile. The reaction mixture is refluxed for 18 hours and the procedure of Example 5 is followed through the anhydrous magnesium silicate filtration step. The filtrate is evaporated to give a dark orange gum which crystallizes on standing. The residue is dissolved in ether, treated with activated charcoal and filtered through diatomaceous earth. The filtrate is concentrated while adding hexane at reflux to yield an oil. The oil is seeded and cooled. Ether is added and continued cooling provides light yellow crystals. The mixture is filtered to give 5.2 g. of the desired product as pale yellow crystals, m.p. 105°-107° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[O:6][CH2:7][C:8]([OH:10])=O.CCN(C(C)C)C(C)C.[NH2:23][CH2:24][CH:25]([OH:37])[CH2:26][N:27]1[CH2:36][CH2:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28]1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>C(Cl)Cl>[CH2:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:35][CH2:36][N:27]1[CH2:26][CH:25]([OH:37])[CH2:24][NH:23][C:8](=[O:10])[CH2:7][O:6][C:5]1[CH:11]=[CH:12][CH:13]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cccc(OCC(=O)O)c1
Reactant: NCC(O)CN1CCc2ccccc2C1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cccc(OCC(=O)NCC(O)CN2CCc3ccccc3C2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 30 %

Procedure:
To a stirred mixture of 2-(3-methoxyphenoxy)acetic acid (100 mg, 0.549 mmol) in DCM (5 mL) was added DIEA (106 mg, 0.824 mmol), 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (113 mg, 0.549 mmol) and Bop-Cl (168 mg, 0.66 mmol). The mixture was stirred at 25° C. for 16 hours then the reaction mixture was quenched with water (20 mL), extracted with DCM (3×20 mL). The combined extracts were washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep-HPLC to afford the desired product (61 mg, Yield 32%). 1H NMR (400 MHz, MeOD) δ 7.21 (dd, J1=J2=8.0 Hz, 1H), 7.17-7.03 (m, 4H), 6.59-6.51 (m, 3H), 4.52 (s, 2H), 4.05-4.01 (m, 1H), 3.77 (s, 3H), 3.73 (d, J=2.8 Hz, 2H), 3.47-3.37 (m, 2H), 2.92 (d, J=5.2 Hz, 2H), 2.87 (d, J=5.2 Hz, 2H), 2.61 (d, J=6.0 Hz, 2H). LCMS (m/z): 371.1 (M+1).