Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[N:4]=[C:3]1[C:10]1[CH:11]=[N:12][N:13]([CH3:15])[CH:14]=1.[NH2:16][C@@H:17]([CH3:33])[CH2:18][N:19]1[CH:23]=[CH:22][C:21]([C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[C:26]([Cl:32])[CH:25]=2)=[N:20]1>>[Cl:32][C:26]1[CH:25]=[C:24]([C:21]2[CH:22]=[CH:23][N:19]([CH2:18][C@@H:17]([NH:16][C:7]([C:5]3[N:4]=[C:3]([C:10]4[CH:11]=[N:12][N:13]([CH3:15])[CH:14]=4)[N:2]([CH3:1])[CH:6]=3)=[O:9])[CH3:33])[N:20]=2)[CH:31]=[CH:30][C:27]=1[C:28]#[N:29]
Reactant: Cn1cc(-c2nc(C(=O)O)cn2C)cn1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cn(C)c(-c2cnn(C)c2)n1

Procedure:
The title compound was prepared using the procedure described in Example 32(e) starting from 1-methyl-2-(1-methyl-1H-pyrazol-4-yl)-1H-imidazole-4-carboxylic acid (0.3 g, 1.44 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.377 g, 1.44 mmol). The product was purified by flash chromatography. Yield 200 mg. 1H-NMR (400 MHz; DMSO-d6): δ 1.10 (d, 3H), 3.72 (s, 3H), 3.91 (s, 3H), 4.23-4.45 (m, 3H), 6.95 (d, 1H), 7.63 (d, 1H), 7.83 (t, 2H), 7.99 (d, 1H), 8.03 (d, 1H), 8.07 (s, 1H), 8.17 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[CH:23]1[CH:24]=[CH:25][C:26]2N(O)N=[N:29][C:27]=2[CH:28]=1.Cl.CN(C)CCCN=C=NCC.C1(N)CCCCC1>CN(C=O)C>[CH:27]1([NH:29][C:20]([C:17]2[CH:16]=[CH:15][C:14]([C:3]3[CH:4]=[C:5]([C:8]4[O:9][C:10]([CH3:13])=[N:11][N:12]=4)[CH:6]=[CH:7][C:2]=3[CH3:1])=[CH:19][CH:18]=2)=[O:21])[CH2:28][CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: NC1CCCCC1
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NC4CCCCC4)cc3)c2)o1
Reaction time: 18 h

Procedure:
2′-Methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid (11.3 mg, 0.034 mmol), HOBT (6.0 mg, 0.044 mmol), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (8.0 mg, 0.042 mmol) and cyclohexylamine (0.34 mmol) were mixed in DMF (0.7 ml) and the reaction left at room temperature for 18 h. The DMF was evaporated under vacuum and the residue partitioned between DCM (0.4 ml) and water (0.4 ml). The organic phase was washed with aqueous sodium hydroxide (0.5M, 0.2 ml) and the DCM evaporated under vacuum. The residue was purified by mass directed HPLC to give N-cyclohexyl-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide.
Reaction SMILES: [F:1][CH:2]([F:16])[C@@H:3]1[C@@H:13]([OH:14])[C@H:12]([OH:15])[C@H:6]2[N:7]=[C:8](SC)[O:9][C@H:5]2[CH2:4]1.Cl.[NH:18]1[CH2:21][CH2:20][CH2:19]1.C([O-])(O)=O.[Na+]>CCO>[N:18]1([C:8]2[O:9][C@H:5]3[CH2:4][C@H:3]([CH:2]([F:16])[F:1])[C@@H:13]([OH:14])[C@H:12]([OH:15])[C@H:6]3[N:7]=2)[CH2:21][CH2:20][CH2:19]1
Reactant: C1CNC1
Reactant: CSC1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](C(F)F)C[C@@H]2O1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: O[C@H]1[C@H](O)[C@@H](C(F)F)C[C@@H]2OC(N3CCC3)=N[C@H]12
Reaction time: 0.17 h
Yield: 84.7 %

Procedure:
To a solution of (3 aR,4R,5R,6S,7aS)-6-(difluoromethyl)-2-(methylthio)-3a,4,5,6,7,7a-hexahydrobenzo[d]oxazole-4,5-diol (52.6 mg, 0.208 mmol) in EtOH (5 mL) was added azetidine hydrochloride (97 mg, 1.04 mmol). The mixture was heated at reflux for 5 h. After cooling, solid NaHCO3 (200 mg, 2.38 mmol) was added and stirred for 10 min Solvent was evaporated and the residue was purified by silica gel column chromatography, eluted with 5% 2 M NH3 MeOH solution in DCM to give the product (3aR,4R,5R,6S,7aS)-2-(azetidin-1-yl)-6-(difluoromethyl)-3a,4,5,6,7,7a-hexahydrobenzo[d]oxazole-4,5-diol (46.2 mg, 85%) as a white solid. MS m/z 263.1 (M+1, 100%); 1H NMR (400 MHz, MeOD) δ 6.14 (td, J=56.8 Hz, 1.8 Hz, 1H), 4.66-4.69 (m, 1H), 4.00 (t, J=7.6 Hz, 4H), 3.62 (t, J=7.2 Hz, 1H), 3.34 (t, J=9.2 Hz, 1H), 3.24 (t, J=7.9 Hz, 1H), 2.29-2.36 (m, 2H), 2.21 (dt, J=15.1 Hz, 3.6 Hz, 1H), 1.95-2.10 (m, 1H), 1.82-1.90 (m, 1H); 13C NMR (100 MHz, MeOD) δ 164.62, 117.96 (t, J=238.5 Hz), 81.20, 79.89 (d, J=1.6 Hz), 71.36 (dd, J=7.2 Hz, 1.0 Hz), 68.72, 51.91, 42.25 (t, J=19.8 Hz), 22.61 (t, J=4.7 Hz), 17.75.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:11][C:12]1[O:13][C:14]2[CH:30]=[CH:29][CH:28]=[CH:27][C:15]=2[C:16]=1[C:17](=O)[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1>CCOCC>[CH3:11][C:12]1[O:13][C:14]2[CH:30]=[CH:29][CH:28]=[CH:27][C:15]=2[C:16]=1[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1
Reactant: COc1ccc(C(=O)c2c(C)oc3ccccc23)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Product: COc1ccc(Cc2c(C)oc3ccccc23)cc1

Procedure:
Aluminiumchloride, 1.75 g (13.16 mmol), in 5 ml ether was added to a suspension of lithiumaluminiumhydride, 0.25 g (6.58 mmol), in 3 ml ether during 20 min. 2-methyl-3-(4-methoxybenzoyl)benzofuran, 1.0 g (3.76 mmol), in 10 ml ether was added during 30 min, and the mixture then heated for 45 min. Excess of the reagent was destroyed by adding 0.35 ml H2O, 0.35 ml 1M NaOH and 3 ml H2O to the mixture. Ether, 200 ml, was added, and the organic layer was extracted with 2×100 ml H2O, 2×100 ml 1M sulphuric acid, 100 ml H2O and dried (MgSO4), evaporating gave 0.95 g of 2-methyl-3-(4-methoxybenzyl)benzofuran which was purified on silica.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[F:7][C:8]([F:22])([F:21])[C:9]([NH:11][CH2:12][CH2:13][NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10].CN1CCOCC1>C(OCC)(=O)C>[CH2:5]([O:4][C:2](=[O:3])[N:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:13][CH2:12][NH:11][C:9](=[O:10])[C:8]([F:7])([F:21])[F:22])[CH3:6]
Reactant: CCOC(=O)Cl
Reactant: O=C(NCCNc1ccccc1)C(F)(F)F
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: CCOC(=O)N(CCNC(=O)C(F)(F)F)c1ccccc1
Reaction time: 17 h

Procedure:
Ethyl chloroformate [541-41-3] (1.4 mL, 14.7 mmol) was added to an ambient temperature solution of 2,2,2-trifluoro-N-(2-phenylamino-ethyl)-acetamide (3.4 g, 14.6 mmol) and N-methyl morpholine [109-02-4] (2.0 mL, 17.7 mmol) in ethyl acetate (145 mL) and stirred under N2 blanket for 17 h. The reaction suspension was then washed with dilute aqueous hydrochloric acid, brine, dried (MgSO4), evaporated and carried on to the next synthetic step without further isolation.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9](O)[CH2:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1.P([N:34]=[N+:35]=[N-:36])(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1.C1CCN2C(=NCCC2)CC1.ClC1C(Cl)=CC=CC=1C=CC1C=CN=CC=1>C1COCC1>[N:34]([CH:9]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=1[Cl:1])[CH2:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[N+:35]=[N-:36]
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: OC(Cc1ccncc1)c1cccc(Cl)c1Cl
Agent: Clc1cccc(C=Cc2ccncc2)c1Cl
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: [N-]=[N+]=NC(Cc1ccncc1)c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.7 %

Procedure:
1-(2,3-dichlorophenyl)-2-(pyridin-4-yl)ethanol (7) (6.20 g, 23.2 mmol) in THF (100 mL) was added diphenyl phosphorazidate (6.00 mL, 27.8 mmol), and DBU (4.20 mL, 23.1 mmol) at 0° C. The mixture was stirred at room temperature overnight. The mixture was heated at 50° C. for 1.5 hour. The solvents were evaporated under reduced pressure. The residue was diluted with water, and extracted with ethyl acetate (3×). The pooled organic layer was dried over magnesium sulfate. The mixture was filtered. Silica gel was added to the filtrate, and the solvents were evaporated under reduce pressure. Purification by chromatography on silica gel (60% hexane, 40% ethyl acetate) gave a 4:1 mixture of products: 4-(2-azido-2-(2,3-dichlorophenyl)ethyl)pyridine (8) (4 parts, 3.82 g, 10.6 mmol, 46% yield), and 4-(2,3-dichlorostyryl)pyridine (9) (1 part).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=[O:12])=[C:5]2[CH2:14][CH2:15][CH2:16][NH:17]C(OC(C)(C)C)=O.[ClH:25].C(OCC)C>C(Cl)Cl.O1CCOCC1>[ClH:25].[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=[O:12])=[C:5]2[CH2:14][CH2:15][CH2:16][NH2:17]
Reactant: CC(C)(C)OC(=O)NCCCc1c(C(=O)O)[nH]c2ccc(Br)cc12
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCOCC
Product: NCCCc1c(C(=O)O)[nH]c2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 5-bromo-3-[3-(t-butoxycarbonylamino)-propyl]-1H-indole-2-carboxylic acid (55 mg, 0.14 mmol, 1.0 equiv) in methylene chloride (5 mL) at 0° C. was added 0.2 mL of 4M HCl in dioxane. The reaction was stirred at ambient temperature for 1 h. Then 10 mL of diethyl ether was added to the reaction and the reaction concentrated. To this residue was added 10 mL diethyl ether and the solid was filtered off and washed with diethyl ether several times and air dried for 15 min to provide the title compound (32 mg); MS, electrospray, 298 (M+H).
Reaction SMILES: [C:1]1([C:11]2[N:12]=[C:13]([CH2:18][CH2:19][CH3:20])[NH:14][C:15]=2[CH:16]=[O:17])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]2[N:39]([C:40]([C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[N:38]=[N:37][N:36]=2)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]1([C:11]2[N:12]=[C:13]([CH2:18][CH2:19][CH3:20])[N:14]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[C:35]4[N:39]([C:40]([C:53]5[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=5)([C:47]5[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=5)[C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=5)[N:38]=[N:37][N:36]=4)=[CH:27][CH:28]=3)[C:15]=2[CH:16]=[O:17])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCc1nc(-c2cccc3ccccc23)c(C=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1nc(-c2cccc3ccccc23)c(C=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A suspension of 4-(naphth-1-yl)-2-n-propylimidazole-5-carboxaldehyde (0.90 g, 39.7 mmol, 1 eq), 4-bromomethyl-2'-(N-triphenylmethyl-(1H-tetrazol-5-yl))biphenyl (2.03 g, 43.7 mmol), 1.1 eq), dry DMF (20 mL), and 3.0 g of potassium carbonate was stirred at room temperature for 18 h. The reaction mixture was filtered, the precipitate was washed with methylene chloride and evaporated under reduced pressure. The residue was chromatographed in 98:2 methylene chloride/ethyl acetate over silica gel to yield a yellow foam. Yield: 1.50 g. NMR (CDCl3) δ 9.45 (s, 1H); 7.85 (m, 1H); 6.86-7.45 (m, 29H); 5.55 (s, 2H); 2.60 (t, 2H); 1.80 (m, 2H); 0.95 (t, 3H). ##STR78##
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:14][C:15]2[CH:19]=[CH:18][N:17]([CH:20]([CH3:22])[CH3:21])[N:16]=2)[N:3]=1.[CH:23]1(B(O)O)[CH2:25][CH2:24]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O>[CH:23]1([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][C:9]=3[N+:11]([O-:13])=[O:12])[N:4]([CH2:14][C:15]3[CH:19]=[CH:18][N:17]([CH:20]([CH3:22])[CH3:21])[N:16]=3)[N:3]=2)[CH2:25][CH2:24]1
Reactant: CC(C)n1ccc(Cn2nc(Br)c3c([N+](=O)[O-])cccc32)n1
Reactant: OB(O)C1CC1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)n1ccc(Cn2nc(C3CC3)c3c([N+](=O)[O-])cccc32)n1
Temperature: 105 °C
Yield: 67.2 %

Procedure:
A flask was charged with 3-bromo-1-((1-isopropyl-1H-pyrazol-3-yl)methyl)-4-nitro-1H-indazole (1.8 g, 4.94 mmol), cyclopropylboronic acid (0.849 g, 9.88 mmol), potassium phosphate (3.15 g, 14.8 mmol) and 20:1 toluene/water (10.5 mL). The mixture was degassed for 30 minutes with an argon filled balloon. Palladium acetate was added (55.5 mg, 0.247 mmol) followed by tricyclohexyl phosphine (0.139 g, 0.494 mmol). The mixture was further degassed with argon and heated at 100-110° C. for 16 hours. The mixture was filtered through GF/F paper, rinsing with EtOAc, concentrated under vacuum and the residue was purified by silica gel chromatography (1-20% EtOAc in hexanes) to provide 3-cyclopropyl-1-((1-isopropyl-1H-pyrazol-3-yl)methyl)-4-nitro-1H-indazole (1.08 g, 67% yield) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH2:25][C:26](=[O:28])[NH2:27])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[C:30](Cl)(=[O:32])[CH3:31]>>[CH3:1][O:2][C:3](=[O:29])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][C:14]=2[CH2:23][N:24]([C:30](=[O:32])[CH3:31])[CH2:25][C:26](=[O:28])[NH2:27])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: CC(=O)Cl
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CNCC(N)=O)c1
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC(N)=O)C(C)=O)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: {2′-[(carbamoylmethyl-amino)-methyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid methyl ester and acetyl chloride.
Reaction SMILES: [Si]([O:18][C:19]1[CH:58]=[CH:57][C:22]([O:23][CH2:24][C@@H:25]([OH:56])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([S:36]([CH:39]3[CH2:44][CH2:43][N:42]([C:45]([NH:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])=[O:46])[CH2:41][CH2:40]3)(=[O:38])=[O:37])=[CH:32][CH:31]=2)=[CH:21][C:20]=1[CH3:59])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[CH2:48]([NH:47][C:45]([N:42]1[CH2:43][CH2:44][CH:39]([S:36]([C:33]2[CH:32]=[CH:31][C:30]([CH2:29][CH2:28][NH:27][CH2:26][C@H:25]([OH:56])[CH2:24][O:23][C:22]3[CH:57]=[CH:58][C:19]([OH:18])=[C:20]([CH3:59])[CH:21]=3)=[CH:35][CH:34]=2)(=[O:38])=[O:37])[CH2:40][CH2:41]1)=[O:46])[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55]
Reactant: CCCCCCCCNC(=O)N1CCC(S(=O)(=O)c2ccc(CCNC[C@H](O)COc3ccc(O[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)c(C)c3)cc2)CC1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCCCCCCNC(=O)N1CCC(S(=O)(=O)c2ccc(CCNC[C@H](O)COc3ccc(O)c(C)c3)cc2)CC1

Procedure:
4-{[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}3-methyl-phenoxy)-2-hydroxypropyl]amino}ethyl)phenyl]sulfonyl}-N-octyl-1-piperidinecarboxamide (0.395 g, 0.520 mmol) was reacted according to Procedure H to give the title compound (eluant: 20/3(v/v) chloroform/methanol) (0.225 g, 0.373 mmol).
Reaction SMILES: [CH2:1]([O:8][C@H:9]([C@H:11]([N:24]1[CH:28]=[C:27]([C:29](O)=[O:30])[N:26]=[CH:25]1)[CH2:12][CH2:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][S:33]([NH2:36])(=[O:35])=[O:34].Cl.C(N=C=NCCCN(C)C)C.Cl>CN(C)C1C=CN=CC=1.CN(C)C=O.O.C(OCC)(=O)C>[CH3:32][S:33]([NH:36][C:29]([C:27]1[N:26]=[CH:25][N:24]([C@H:11]([CH2:12][CH2:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][CH:15]=2)[C@@H:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH3:10])[CH:28]=1)=[O:30])(=[O:35])=[O:34]
Reactant: CS(N)(=O)=O
Reactant: C[C@H](OCc1ccccc1)[C@@H](CCc1cccc2ccccc12)n1cnc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H](OCc1ccccc1)[C@@H](CCc1cccc2ccccc12)n1cnc(C(=O)NS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 27.6 %

Procedure:
A mixture of 1-[(2S,3R)-2-benzyloxy-5-(1-naphthyl)-3-pentyl]imidazole-4-carboxylic acid (obtained in Example 30)(55 mg), methanesulfonamide (12.7 mg), 4-dimethylaminopyridine (24.3 mg), and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (51.2 mg) in N,N-dimethylformamide (2 ml) was stirred at room temperature for three days. Ethyl acetate and water were added, and the whole was acidified to pH 3 with hydrochloric acid. The organic layer was dried and evaporated. The residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (20:1) to give a pale yellow gummy oil of N-methylsulfonyl-1-[(2S,3R)-2-benzyloxy-5-(1-naphthyl)-3-pentyl]imidazole-4-carboxamide (18 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[N:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:35]4[CH:36]=[CH:37][N:32]=[CH:33][CH:34]=4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(Br)cc3)oc2C)cc1
Reactant: OB(O)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4ccncc4)cc3)oc2C)cc1

Procedure:
To a 25 mL round-bottomed flask equipped for magnetic stirring and fitted with a reflux condenser was added 2-(4-{2-[2-(4-bromophenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methyl propionic acid ethyl ester (0.410 mmoles, 200 mg) (see Ex. 2, Part B), 4-pyridyl boronic acid (0.451 mmoles), toluene (5 mL), ethanol (5 mL), and sodium carbonate (0.819 mmoles, 0.410 mL of a 2M solution). This mixture was vacuum degassed and nitrogen was added in at a positive pressure. Pd(PPh3)4 (catalytic, spatula tip) was added and the reaction was heated to reflux for 3 h. Distilled water was added to the mixture. Subsequently, this was extracted with ethyl acetate and washed with brine. The organic layer was collected, filtered over a thin pad of silica gel, and concentrated in-vacuo. The crude mixture was then purified by chromatography on silica gel affording 2-(4-{2-[2-(4-pyrid-4-yl-phenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid ethyl ester.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.Br[C:20]1[C:21]2[C:22]3[CH:36]=[CH:35][S:34][C:23]=3[C:24](=[O:33])[NH:25][C:26]=2[C:27]([CH3:32])=[CH:28][C:29]=1[O:30][CH3:31]>>[CH3:31][O:30][C:29]1[CH:28]=[C:27]([CH3:32])[C:26]2[NH:25][C:24](=[O:33])[C:23]3[S:34][CH:35]=[CH:36][C:22]=3[C:21]=2[C:20]=1[C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NC(C)(C)c1ccc(Br)cc1
Reactant: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1Br
Product: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1-c1ccc(C(C)(C)NC(=O)OC(C)(C)C)cc1
Yield: 79.1 %

Procedure:
Following General Procedure E, tert-butyl 2-(4-bromophenyl)propan-2-ylcarbamate (0.44 g, 1.4 mmol) was reacted with 9-bromo-8-methoxy-6-methylthieno[2,3-c]quinolin-4(5H)-one (0.45 g, 1.4 mmol) to afford the desired product (0.53 g, 79%) as a brown solid: ESI MS m/z 479 [C27H30N2O4S+H]+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:7]([O:24]COC)=[C:8]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[O:18][CH2:17]4)[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1.Cl>CO>[CH:1]1([CH2:4][O:5][C:6]2[C:7]([OH:24])=[C:8]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[O:18][CH2:17]4)[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1
Reactant: COCOc1c(-c2ccc3c(c2)COC3=O)ccc(OC)c1OCC1CC1
Agent: Cl
Solvent: CO
Product: COc1ccc(-c2ccc3c(c2)COC3=O)c(O)c1OCC1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.7 %

Procedure:
To a stirring solution of 5-(3-(cyclopropylmethoxy)-4-methoxy-2-(methoxymethoxy)phenyl)isobenzofuran-1(3H)-one (1.5 g, 4.05 mmol) in methanol (25 mL) was added concentrated hydrochloride (5 mL) and the reaction mixture was stirred for 2 h at RT. The reaction mixture was concentrated under reduced pressure and the obtained residue was basified with sodium bicarbonate solution and then extracted with dichloromethane (3×). The combined dichloromethane layers were washed with brine, dried over sodium sulphate and concentrated under reduced pressure to afford the title compound as a solid (1 g, 76%).
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14]C(=O)OC(C)(C)C)[CH2:10][CH2:9]1)(=[O:7])=[O:6]>CO.Cl>[Br:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)(=[O:6])=[O:7]
Reactant: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)Cc2ccccc2Br)CC1
Agent: Cl
Solvent: CO
Product: NC1CCN(S(=O)(=O)Cc2ccccc2Br)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of tert-butyl (1-((2-bromobenzyl)sulfonyl)piperidin-4-yl)carbamate (500 mg, 1.15 mmol) in HCl methanol (6 N, 20 mL) was stirred at rt for 24 hours, and then concentrated to dryness to give 1-(2-bromobenzylsulfonyl)piperidin-4-amine.HCl (400 mg, 94%), which was directly used for next step without any further purification. MS (ESI): mass calcd. for C14H19BrN2O3S, 332.02; m/z found, 332.9 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][NH:7][CH2:6][CH2:5]2.[N:12]1([C:18]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:19]=2[C:20](O)=[O:21])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([C:20]([C:19]1[CH:23]=[C:24]([N+:27]([O-:29])=[O:28])[CH:25]=[CH:26][C:18]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[O:21])[CH2:6][CH2:5]2
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1N1CCOCC1
Reactant: Clc1ccc2c(c1)CCNC2
Product: O=C(c1cc([N+](=O)[O-])ccc1N1CCOCC1)N1CCc2cc(Cl)ccc2C1

Procedure:
Prepared in analogy to example 1.1 from 6-chloro-1,2,3,4-tetrahydro-isoquinoline (CA [33537-99-4]) and 2-morpholin-4-yl-5-nitro-benzoic acid (example 2.8).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([NH:14][C:15]3[CH:16]=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[C:11]([C:23]3[N:28]=[C:27]([CH3:29])[N:26]=[C:25](SC)[N:24]=3)=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[NH3:32]>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([NH:14][C:15]3[CH:16]=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[C:11]([C:23]3[N:28]=[C:27]([CH3:29])[N:26]=[C:25]([NH2:32])[N:24]=3)=[CH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: N
Reactant: COc1ccc(Nc2nc(-c3ccc(F)cc3)ncc2-c2nc(C)nc(SC)n2)cn1
Solvent: C1COCCO1
Product: COc1ccc(Nc2nc(-c3ccc(F)cc3)ncc2-c2nc(C)nc(N)n2)cn1
Temperature: 100 °C

Procedure:
A glass microwave reaction vessel was charged with 2-(4-fluorophenyl)-N-(6-methoxypyridin-3-yl)-5-(4-methyl-6-(methylthio)-1,3,5-triazin-2-yl)pyrimidin-4-amine (12 mg, 0.028 mmol), ammonia (0.5 mL, 30% in water) and dioxane (1 mL). The reaction mixture was stirred and heated in a oil bath at 100° C. for 17 h. The solvent was removed in vacuo and the residue was purified by silica gel chromatography eluting with 80% EtOAc/hexanes to give 4-(2-(4-fluorophenyl)-4-(6-methoxypyridin-3-ylamino)pyrimidin-5-yl)-6-methyl-1,3,5-triazin-2-amine 1H NMR (300 MHz, CDCl3) δ 9.60 (s, 1H); 8.35-8.54 (m, 3H); 8.12 (dd, J=8.84, 2.41 Hz, 1H); 7.15 (t, J=8.62 Hz, 2H); 6.86 (d, J=8.92 Hz, 1H); 5.44 (s, 2H); 3.99 (s, 3H); 2.56 (s, 3H). m/z (ESI, +ve ion) 405.0 (M+H)+.
Reaction SMILES: [OH:1][N:2]1[C:6]([I:7])=[CH:5][CH:4]=[N:3]1.[CH3:8][N:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10](Cl)=[O:11]>>[I:7][C:6]1[N:2]([O:1][C:10](=[O:11])[N:9]([CH3:8])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=[CH:4][CH:5]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: On1nccc1I
Product: CN(C(=O)On1nccc1I)c1ccccc1

Procedure:
The title compound was prepared from 1-hydroxy-5-iodopyrazole and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (64%, oil).