Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([C:43]2([S:46]([CH3:49])(=[O:48])=[O:47])[CH2:45][CH2:44]2)[N:38]=1>>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([C:43]4([S:46]([CH3:49])(=[O:48])=[O:47])[CH2:45][CH2:44]4)[N:38]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: CS(=O)(=O)C1(c2cccc(Br)n2)CC1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2cccc(C3(S(C)(=O)=O)CC3)n2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Yield: 76 %

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-ethyl}-1,3-oxazinan-2-one and 2-bromo-6-(1-methanesulfonyl-cyclopropyl)-pyridine following a procedure analogous to that described in Example 1. Yield: 76% of theory; LC (method 1): tR=1.93 min; Mass spectrum (ESI+): m/z=549 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]2[CH:10]([C:11]2([CH3:23])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-])=O)[CH:15]=2)[C:9]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[Cl-].[Ca+2].[Cl-]>C(O)C.[Fe]>[NH2:20][C:16]1[CH:15]=[C:14]([C:11]2([CH3:23])[CH:10]3[CH:12]2[CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]3=[O:24])[CH:19]=[CH:18][CH:17]=1
Reactant: CC1(c2cccc([N+](=O)[O-])c2)C2CN(Cc3ccccc3)C(=O)C21
Agent: [Fe]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: CC1(c2cccc(N)c2)C2CN(Cc3ccccc3)C(=O)C21
Yield: 95.4 %

Procedure:
To a solution of 3-benzyl-6-methyl-6-(3-nitrophenyl)-3-azabicyclo[3.1.0]hexan-2-one (Preparation 28, 2 g, 6.2 mmol) in absolute ethanol (170 ml) was added water (30 ml), calcium chloride (344 mg, 3.1 mmol) and iron powder (3.02 g, 53.8 mmol). The mixture was heated to reflux under nitrogen for 4 h, then cooled. The solution was filtered through silica (10 g) eluting with methanol, then concentrated in vacuo to give the title compound as a white solid (1.73 g, 95%).
Reaction SMILES: Cl.CN(C)[CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1)=O.[CH2:19]([O:21][C:22](=[O:29])[CH:23]=[C:24]([NH2:28])[CH:25]1[CH2:27][CH2:26]1)[CH3:20]>CC(O)=O>[CH2:19]([O:21][C:22](=[O:29])[C:23]1[CH:4]=[CH:5][C:6]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:15])([F:16])[F:17])=[CH:12][CH:13]=2)=[N:28][C:24]=1[CH:25]1[CH2:27][CH2:26]1)[CH3:20]
Reactant: CN(C)CCC(=O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)C=C(N)C1CC1
Agent: Cl
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1

Procedure:
0.657 g (2.33 mmol) of the above prepared (example 1L]) 3-dimethylamino-1-(4-trifluoromethyl-phenyl)-propan-1-one hydrochloride and 0.362 g (1.0 eq., not corrected for impurities) of the above synthesised 3-amino-3-cyclopropyl-acrylic acid ethyl ester was dissolved in 7 ml of AcOH and heated to reflux for 3 h. After cooling, the bulk of the solvent was evaporated i. V. Ensuing flash chromatography (SiO2, hexane/AcOEt=93/7) yielded 0.101 g of the title compound as light yellow solid.
Reaction SMILES: [CH:1]([CH:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1)=O.[CH3:15][NH2:16]>CO.C(Cl)Cl>[CH3:15][NH:16][CH2:1][CH:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1
Reactant: CN
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)C1
Solvent: CO
Solvent: ClCCl
Product: CNCC1CCN(C(=O)OC(C)(C)C)C1
Reaction time: 12 h
Yield: 95.2 %

Procedure:
To a solution of 1,1-dimethylethyl 3-formyl-1-pyrrolidinecarboxylate (500 mg, 2.51 mmol) in MeOH/DCM (6 mL, 1:1) were added NaHCO (1.05 g, 12.6 mmol) followed by methylamine (2.51 mL, 5.02 mmol, 2.0 M in MeOH). After 12 h at 25° C., NaBH (1.05 g, 12.6 mmol) was added. After 1 h, the reaction was concentrated and the residue was partitioned between DCM and H O. The aqueous phase was extracted several times with DCM and the combined organic fractions were dried over MgSO4, concentrated and purified via column chromatography (silica, 4% MeOH in DCM (1% NH OH)) yielding the title compound (512 mg, 95%) as a brown oil: LC/MS (ES) m/e 215 (M+H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH2:30][O:31][CH3:32])[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1.[CH3:33][O:34][CH2:35][C:36](Cl)=[O:37]>>[CH3:33][O:34][CH2:35][C:36]([N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH2:30][O:31][CH3:32])[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:5][CH2:6]1)=[O:37]
Reactant: COCC(=O)Cl
Reactant: COCCOc1ccc2c(c1-c1ncnc3c(C(=O)NC4CCNCC4)c[nH]c13)OCO2
Product: COCCOc1ccc2c(c1-c1ncnc3c(C(=O)NC4CCN(C(=O)COC)CC4)c[nH]c13)OCO2

Procedure:
Starting from 4-[5-(2-methoxy-ethoxy)-benzo[1,3]dioxol-4-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide (example A187) and methoxy-acetyl chloride the title compound was obtained as colorless solid.
Reaction SMILES: Cl[C:2]1([CH:8]=[CH:7][CH:6]=[CH:5][CH:4]1[N+:9]([O-:11])=[O:10])[NH2:3].[CH:12]1(N)[CH2:14][CH2:13]1>C(OCC)(=O)C>[CH:12]1([NH:3][C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N+:9]([O-:11])=[O:10])[CH2:14][CH2:13]1
Reactant: NC1CC1
Reactant: NC1(Cl)C=CC=CC1[N+](=O)[O-]
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccccc1NC1CC1

Procedure:
1-Chloro-2-nitroaniline (13 g, 0.082 mole) and 17.15 ml of cyclopropylamine were heated together at reflux temperature for 24 hours, cooled and poured into ethyl acetate. The organic solution was washed with a saturated brine solution (3×100 ml), dried with magnesium sulfate and concentrated to dryness. The residue was chromatographed on silica gel using 60% hexane in chloroform to give 2.04 g of the desired intermediate.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][CH2:5][NH2:6].[N:7]1[CH:12]=[CH:11][C:10]([CH:13]=O)=[CH:9][CH:8]=1.C([O-])([O-])=O.[K+].[K+]>O>[Cl:2][CH2:3][CH2:4][CH2:5][N:6]=[CH:13][C:10]1[CH:11]=[CH:12][N:7]=[CH:8][CH:9]=1
Reactant: O=Cc1ccncc1
Reactant: NCCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: ClCCCN=Cc1ccncc1

Procedure:
To 3-chloropropylamine HCl (15.1 g, 0.120 moles (hereinafter mol)) and H2O (100 mL) was added pyridine-4-carboxaldehyde (9.55 mL, 0.100 mol), then K2CO3 (8.28 g, 0.060 mol) then CH2CL2 (100 mL) and the mixture was stirred for 40 min. The phases were separated and the aq phase was extracted with additional CH2Cl2 (2×50 mL), dried (Na2SO4) and concentrated to afford 17.1 g (94%) 1H NMR (CD3Cl): d 8.69 (d, J=4.5 Hz, 2H, 8.32 (s, 1H), 8.28 (s, 1H), 7.58 (d, J=4.5 Hz, 2H), 3.71 (m, 2H), 3.63 (t, J=6Hz, 2H), 2.24 (t, J=6Hz, 2H). The presence of 9% of the aldehyde was evident by 1H NMR.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][C:3]=1[C:13]([OH:15])=[O:14].[C:16]([O-])(O)=O.[Na+].CI.O>CN(C)C=O>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][C:3]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: O=C([O-])O
Reactant: O=C(O)c1cc(O)c2ccccc2c1O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc(O)c2ccccc2c1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.3 %

Procedure:
1,4-Dihydroxy-2-naphthoic acid (10 g, 49 mmol) and NaHCO3 (4.12 g, 49 mmol) was dissolved in DMF (dimethylformamide) (50 mL). Methyl iodide (6.96 g, 49 mmol) was added and the solution stirred at room temperature for 24 h, poured into water (1 L), filtered and washed with water to give the title compound (8.80 g, 82%) as a green powder.
Reaction SMILES: [C:1]1([CH:7]([CH2:10][CH:11]([CH3:13])[CH3:12])[CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:14][C:15]1[C:33]([C:34]([F:37])([F:36])[F:35])=[CH:32][CH:31]=[CH:30][C:16]=1[CH2:17]NCC(C1C=CC(OC)=CC=1)C>>[Cl:14][C:15]1[C:33]([C:34]([F:35])([F:36])[F:37])=[CH:32][CH:31]=[CH:30][C:16]=1[CH2:17][NH:9][CH2:8][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:10][CH:11]([CH3:13])[CH3:12]
Reactant: COc1ccc(C(C)CNCc2cccc(C(F)(F)F)c2Cl)cc1
Reactant: CC(C)CC(CN)c1ccccc1
Product: CC(C)CC(CNCc1cccc(C(F)(F)F)c1Cl)c1ccccc1
Yield: 77 %

Procedure:
The titled compound was prepared from 2-Phenyl-4-methylpentylamine in 77% yield in the same manner as the preparation of N-(2-Chloro-3-trifluoromethylbenzyl)-2-(4-methoxyphenyl)propylamine in Example 188d. MS (ESI) 370 (MH+)
Reaction SMILES: S(=O)(=O)(O)[OH:2].ON=[CH:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]([CH3:20])[CH3:19])=[O:10]>>[CH:18]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:12]=1[NH:11][C:9](=[O:10])[C:8]2=[O:2])([CH3:20])[CH3:19]
Reactant: CC(C)c1ccccc1NC(=O)C=NO
Reactant: O=S(=O)(O)O
Product: CC(C)c1cccc2c1NC(=O)C2=O
Temperature: 80 °C
Yield: 84 %

Procedure:
To concentrated sulfuric acid at 80° C. was added 2-hydroxyimino-N-(2-isopropyl-phenyl)-acetamide in several small portions over 10 minutes. After addition it was heated at 80° C. for 30 minutes., then poured into ice. Filtration, washing with water, and drying under vacuum over P2O5 provided 2.974 g (84%) of the title compound as a solid. ESI (−) MS m/e=188 (MH−).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([C:28]([C:30]2[CH:31]=[C:32]([CH3:39])[C:33]3[O:37][CH2:36][CH2:35][C:34]=3[CH:38]=2)=[O:29])[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C.Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:22]4[CH:23]=[C:24]([C:28]([C:30]5[CH:31]=[C:32]([CH3:39])[C:33]6[O:37][CH2:36][CH2:35][C:34]=6[CH:38]=5)=[O:29])[N:25]=[CH:26][N:27]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1
Reactant: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2c1OCC2
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c5c(c4)CCO5)ncn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
100 mg (0.363 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 90.0 mg (0.229 mmol) (6-chloro-pyrimidin-4-yl)-(7-methyl-2,3-dihydro-benzofuran-5-yl)-methanone and 0.200 mL (1.16 mmol) DIPEA were combined in 1.5 mL DMF and stirred for 48 h at RT. Then the reaction mixture was combined with a few drops of hydrochloric acid and purified by preparative HPLC-MS. The fractions containing the product were combined and freeze-dried.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1.CC(=CC)C.Cl([O-])=[O:27].[Na+].P([O-])(O)(O)=O.[Na+]>C(#N)C.C(O)(C)(C)C.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:27])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1
Reactant: COc1cccc(-c2cc3c(C=O)c[nH]c3cc2Cl)c1
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: CC#N
Solvent: O
Product: COc1cccc(-c2cc3c(C(=O)O)c[nH]c3cc2Cl)c1
Reaction time: 0.17 h
Yield: 37.9 %

Procedure:
To a solution of 6-chloro-5-(3-methoxyphenyl)-1H-indole-3-carbaldehyde (100 mg, 0.35 mmol) in ACN/t-butanol=1/1(4 mL) was added 2-methyl-2-butene (1 mL) at 0° C. and stirred 10 min. Then an aqueous solution of sodium chlorite (315 mg, 3.5 mmol) and sodium dihydrogen phosphate (480 mg, 3.5 mmol) in water (1 mL) was added to the system dropwise. The reaction was stirred at room temperature for 10 h. The reaction was quenched with sodium sulfite. The mixture was partitioned between DCM and water. The combined organics were dried and concentrated to give a residue, which was purified by reverse phase HPLC to give the title compound (40 mg, 38%) as a white solid. MS (AP−) 300.1 (M−1)−. 1H NMR (400 MHz, CD3OD) δ 8.01 (s, 1H), 8.00 (s, 1H), 7.58 (s, 1H), 7.33 (t, 1H), 7.01-6.97 (m, 2H), 6.93 (dd, 1H), 3.84 (m, 1H).
Reaction SMILES: [C:1]([NH:5][C:6]([C@@H:8]1[CH2:17][C@H:16]2[C@H:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:10][N:9]1[CH2:18][C@@H:19]([OH:43])[C@@H:20]([NH:29][C:30](=[O:42])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([O:37]C(=O)C)[C:32]=1[CH3:41])[CH2:21][S:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N>CO>[C:1]([NH:5][C:6]([C@@H:8]1[CH2:17][C@H:16]2[C@H:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:10][N:9]1[CH2:18][C@@H:19]([OH:43])[C@@H:20]([NH:29][C:30](=[O:42])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([OH:37])[C:32]=1[CH3:41])[CH2:21][S:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)Oc1cccc(C(=O)N[C@@H](CSc2ccccc2)[C@H](O)CN2C[C@H]3CCCC[C@H]3C[C@H]2C(=O)NC(C)(C)C)c1C
Agent: N
Solvent: CO
Product: Cc1c(O)cccc1C(=O)N[C@@H](CSc1ccccc1)[C@H](O)CN1C[C@H]2CCCC[C@H]2C[C@H]1C(=O)NC(C)(C)C
Reaction time: 1.5 h
Yield: 54 %

Procedure:
The obtained (3S, 4aS, 8aS)-2-[(2R, 3R)-3-(3-acetoxy-2-methyl-benzoylamino)-2-hydroxy-4-phenylthiobutyl]decahydroisoquinoline-3-carboxylic acid t-butylamide (12.7 g) was dissolved in methanol (96 ml) and 28% aqueous ammonia (24 ml) was added, which was followed by stirring for 1.5 hours. The resulting precipitate was collected by filtration and washed with a mixed solution of methanol (75 ml)/water (25 ml). The residue was dried at 50° C. under reduced pressure to give (3S, 4aS, 8aS)-2-[(2R, 3R)-2-hydroxy-3-(3-hydroxy-2-methylbenzoylamino)-4-phenylthiobutyl]decahydroisoquinoline-3-carboxylic acid t-butylamide (compound [15], 8.00 g, yield 54%, from (2R, 3R-benzyloxycarbonylamino-4-phenylthio-2-methanesulfonyloxy-1-(4-nitrobenzoyloxy)butane) as colorless crystals. 1H-NMR (CD3OD, 300 MHz) δ: 7.49 (m,2H), 7.27 (m,2H), 7.17 (m,1H), 7.01 (m,1H), 6.90 (m,1H), 6.79 (m,1H), 4.43 (m,1H), 4.06 (m,1H), 3.54 (dd,J=10.1,3.5Hz,1H), 3.37 (m,1H), 3.04 (dd,J=8.7,1.7Hz,1H), 2.60 (m,2H), 2.24 (s,3H), 2.17 (m,2H), 2.01 (m,1H), 1.9-1.1 (m,11H), 1.17 (s,9H)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([F:22])=[C:12]([C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=O)[CH:13]=2)=[CH:4][C:3]=1[C:23]1[N:24]=[N:25][N:26]([CH:28]([CH3:30])[CH3:29])[CH:27]=1.B(F)(F)F.CCOCC.[BH4-].[Na+]>C1COCC1>[F:22][C:11]1[CH:10]=[CH:9][C:8]([C:5]2[CH:4]=[C:3]([C:23]3[N:24]=[N:25][N:26]([CH:28]([CH3:29])[CH3:30])[CH:27]=3)[C:2]([NH2:1])=[N:7][CH:6]=2)=[CH:13][C:12]=1[CH2:14][N:16]1[CH2:17][CH2:18][O:19][CH2:20][CH2:21]1
Reactant: CC(C)n1cc(-c2cc(-c3ccc(F)c(C(=O)N4CCOCC4)c3)cnc2N)nn1
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)n1cc(-c2cc(-c3ccc(F)c(CN4CCOCC4)c3)cnc2N)nn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 41.5 %

Procedure:
To a solution of [5-[6-amino-5-(1-isopropyltriazol-4-yl)-3-pyridyl]-2-fluoro-phenyl]-morpholino-methanone (150 mg, 0.365 mmol) in THF (10.0 mL) was added BF3.Et2O (0.25 mL, 1.827 mmol) at 0° C. and stirred for 30 min. After 30 min, NaBH4 (69 mg, 1.827 mmol) was added at 0° C. and stirred at room temperature for 18 h. After cooling to 0° C., quenched with MeOH (2 mL) and heated to reflux for 6 h. The reaction mixture was diluted with EtOAc (20 mL), washed with water (20 mL), dried over anhydrous Na2SO4 and solvent was evaporated under reduced pressure. Crude compound was purified by column using 100-200 mesh silica gel. The column was eluted with 5% MeOH in DCM to afford 60 mg (yield: 41.66%) of the title compound as white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH2:11][CH2:12][CH2:13][CH:14]1[O:18][CH:17]2[O:19][CH:20](C3C=CC(F)=CC=3)[CH2:21][CH:16]2[CH2:15]1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[N+:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[NH:11][CH2:12][CH2:13][CH:14]1[O:18][CH:17]2[O:19][CH2:20][CH2:21][CH:16]2[CH2:15]1)([O-:10])=[O:9]
Reactant: NCCC1CC2CC(c3ccc(F)cc3)OC2O1
Reactant: O=[N+]([O-])c1cnccc1Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1cnccc1NCCC1CC2CCOC2O1
Reaction time: 8 h
Yield: 78.3 %

Procedure:
4Chloro-3-nitropyridine (160 mg, 1.0 mmol) is added to a stirred solution of 5-(2-aminoethyl)-2-(4-fluorophenyl)hexahydrofuro[2,3-b]furan (200 mg, 0.8 mmol) and triethylamine (1.0 ml) in chloroform (15 ml) at ambient temperature. The reaction mixture is stirred overnight, then washed with water, dried over anhydrous magnesium sulphate, filtered and the solvent removed under reduced pressure to leave an orange oil. This is purified by chromatography over silica (1:1 ethyl acetate/hexane) to give 2-(4-fluorophenyl)-5-(2-(N-3-nitropyrid-4-ylaminoethyl)hexahydrofuro[2,3-b]furan (175 mg, 59%) as a yellow amorphous solid.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH2:16][CH2:17][N:18]([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])[C:14]#[N:15])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[K+].Br[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1.O>C1(C)C=CC=CC=1>[C:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)([CH2:16][CH2:17][N:18]([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:20])[CH3:21])[C:14]#[N:15])=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)N(CCC(C#N)c1ccc(-c2ccccc2)cc1)C(C)C
Reactant: Brc1ccccn1
Agent: [H-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)N(CCC(C#N)(c1ccc(-c2ccccc2)cc1)c1ccccn1)C(C)C
Reaction time: 0.5 h
Yield: 88.8 %

Procedure:
A mixture of 50.0 g (0.16 mole) of 2-(4-phenylphenyl)-4-[N,N-bis(1-methylethyl)amino]butanenitrile and 29.7 g of potassium hydride (about 0.26 mole as a 35% dispersion in oil) in 1000 ml of toluene was heated at 65°. A solution of 32 g (0.20 mole) of 2-bromopyridine in 450 ml of toluene was added slowly. After addition was complete, the mixture was stirred an additional 30 minutes, cooled in an ice bath, and treated with 750 ml of water. The toluene layer was separated and extracted with 10% aqueous hydrochloric acid. The acidic aqueous layer was neutralized with a slight excess of aqueous sodium hydroxide and extracted wih dichloromethane. The organic phase was washed with brine, dried over magnesium sulfate, filtered, and concentrated to dryness, giving 56.5 g of the title compound as an oil having the expected NMR spectrum. The intermediate nitrile was used without further purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[NH:15]1[CH:16]=[CH:17][C:13]([NH:12][C:4]2[N:3]=[C:2]([C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([C:19]([F:30])([F:29])[F:18])[CH:21]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)=[N:14]1
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: FC(F)(F)c1cccc(-c2nc(Nc3cc[nH]n3)cc3ccccc23)c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 4-trifluoromethyl-phenylboronic acid to give (1H-pyrazol-3-yl)-[1-(3-trifluoromethyl-phenyl)-isoquinolin-3-yl]-amine. LC-MS m/e 355(MH+).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[C:22]([CH:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:26][CH2:25]1)=[O:23].[OH-].[Na+]>C(#N)C.N1C=CC=CC=1>[C:1]1([CH2:7][CH2:8][N:9]2[CH:13]=[CH:12][N:11]=[C:10]2[C:22]([CH:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:26][CH2:25]2)=[O:23])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)N1CCC(C(=O)Cl)CC1
Reactant: c1ccc(CCn2ccnc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: CC#N
Product: CCOC(=O)N1CCC(C(=O)c2nccn2CCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 34 %

Procedure:
To a cooled mixture of 54.2 g of 1-(2-phenylethyl)-1H-imidazole, 34.7 g of N,N-diethylethanamine and 50 ml of pyridine there were added dropwise 69.2 g of ethyl 4-chlorocarbonyl-1-piperidinecarboxylate(temp.≤0.20° C.) and then 30 ml of acetonitrile. The whole was stirred for 2 hours at room temperature and for 4 hours at reflux temperature. After cooling, there were added 30 ml NaOH 50% and refluxing was continued for 1/2 hour. The cooled reaction mixture was evaporated and the residue was taken up in water. The product was extracted with dichloromethane and the extract was dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CH2Cl2 /CH3OH 97:3). The eluent of the desired fraction was evaporated and the residue was dried, yielding 38 g (33.9%) of ethyl 4-[[1-(2-phenylethyl)-1H-imidazol-2-yl]carbonyl]-1-piperidinecarboxylate (interm. 1).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[C:7]([CH3:9])[CH:8]=1.B(Br)(Br)Br.O>ClCCl>[OH:2][C:3]1[CH:4]=[C:5]([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[C:7]([CH3:9])[CH:8]=1
Reactant: CCOC(=O)CCc1cc(C)cc(OC)c1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)CCc1cc(C)cc(O)c1
Temperature: -5 °C
Reaction time: 2 h
Yield: 53.4 %

Procedure:
To a solution of ethyl 3-(3-methoxy-5-methylphenyl)propanoate (2.00 g) in dichloromethane (30 mL) was added a 1.0 M solution (13.5 mL) of boron tribromide in dichloromethane at −5° C., and the mixture was stirred at −5° C. for 2 hr. Water (20 mL) was added dropwise to the reaction mixture over 30 min, and the mixture was extracted with dichloromethane. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.00 g) as a yellow oil.
Reaction SMILES: ClC1C=CC(N2[C:16]([C:17]([NH:19][CH3:20])=[O:18])=[C:15]3[C:10]([CH:11]=[C:12]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[C:13]([CH:21]4[CH2:23][CH2:22]4)=[CH:14]3)=[N:9]2)=CC=1.[Br:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][C:31]=1[F:37]>>[Br:29][C:30]1[CH:36]=[CH:35][C:33]([N:34]2[C:16]([C:17]([NH:19][CH3:20])=[O:18])=[C:15]3[C:10]([CH:11]=[C:12]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[C:13]([CH:21]4[CH2:22][CH2:23]4)=[CH:14]3)=[N:9]2)=[CH:32][C:31]=1[F:37]
Reactant: CNC(=O)c1c2cc(C3CC3)c(NS(C)(=O)=O)cc2nn1-c1ccc(Cl)cc1
Reactant: Nc1ccc(Br)c(F)c1
Product: CNC(=O)c1c2cc(C3CC3)c(NS(C)(=O)=O)cc2nn1-c1ccc(Br)c(F)c1

Procedure:
Compound (46) was prepared in a similar manner to the synthesis of Compound (44) with the following variation: 4-bromo-3-fluoroaniline was used instead of 4-chloroaniline at Step d. ESI-MS m/z [M+H]+: 481.1. 1H NMR (400 MHz, DMSO) δ 9.21 (brs, 1H), 8.67 (brs, 1H), 7.96-7.83 (m, 2H), 7.76-7.62 (m, 2H), 7.45-7.30 (m, 2H), 3.10 (s, 3H), 2.90-2.76 (m, 3H), 2.31-2.20 (m, 1H), 1.07-0.92 (m, 2H), 0.80-0.66 (m, 2H).