Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH3:18])[CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[C:9]([C:15]([OH:17])=O)[NH:10]2.[ClH:20].Cl.Cl.[NH2:23][CH:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][N:32]2[CH2:37][CH2:36][CH:35]([OH:38])[CH2:34][CH2:33]2)[CH2:26][CH2:25]1>>[ClH:20].[ClH:20].[OH:38][CH:35]1[CH2:34][CH2:33][N:32]([CH2:31][CH2:30][N:27]2[CH2:26][CH2:25][CH:24]([NH:23][C:15]([C:9]3[NH:10][C:11]4[C:7]([CH:8]=3)=[C:6]([O:5][CH2:4][CH2:3][C:2]([CH3:1])([CH3:19])[CH3:18])[CH:14]=[CH:13][CH:12]=4)=[O:17])[CH2:29][CH2:28]2)[CH2:37][CH2:36]1
Reactant: CC(C)(C)CCOc1cccc2[nH]c(C(=O)O)cc12
Reactant: NC1CCN(CCN2CCC(O)CC2)CC1
Agent: Cl
Product: CC(C)(C)CCOc1cccc2[nH]c(C(=O)NC3CCN(CCN4CCC(O)CC4)CC3)cc12

Procedure:
This compound is synthesized analogously to Example 1 from 4-(3,3-dimethyl-butoxy)-1H-indole-2-carboxylic acid (92) (preparation see below) and amine 21.
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[C:8](=[O:24])[N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[C:10]([CH3:13])=[CH:11][CH:12]=1)=[O:6])[C:2]#[CH:3].[OH:25][N:26]=[C:27](Cl)[CH3:28].O>CCOC(C)=O>[CH3:28][C:27]1[CH:3]=[C:2]([CH2:1][NH:4][C:5]([C:7]2[C:8](=[O:24])[N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:21])([F:22])[F:23])[CH:15]=3)[C:10]([CH3:13])=[CH:11][CH:12]=2)=[O:6])[O:25][N:26]=1
Reactant: C#CCNC(=O)c1ccc(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Reactant: CC(Cl)=NO
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(CNC(=O)c2ccc(C)n(-c3cccc(C(F)(F)F)c3)c2=O)on1
Reaction time: 48 h
Yield: 52.8 %

Procedure:
The compound obtained in step (a) (0.050 g, 0.15 mmol) was dissolved in EtOAc (15 ml) under magnetic stirring. To this solution was added N-hydroxyacetimidoyl chloride (0.15 g, 1.6 mmol), water (0.3 ml) and KHCO3 (0.16 g, 1.6 mmol). The mixture was stirred for 2 days at which time LC-MS showed 90% conversion. The reaction was stopped and the mixture was partitioned between EtOAc (25 ml) and water (25 ml). The organic phase was washed (water, brine) and dried. Filtration and evaporation gave a crude mixture which was purified by chromatography on silica. Freeze-drying the pure fractions afforded the subtitle compound (0.031 g, 53%) as a white powder.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][C:8]([CH3:11])([CH3:10])[NH:7][C:6]([CH3:13])([CH3:12])[C:5]1=[O:14].[CH2:15]1[O:17][CH2:16]1>CO.Cl>[OH:1][CH2:2][CH2:3][N:4]1[CH2:9][C:8]([CH3:10])([CH3:11])[N:7]([CH2:15][CH2:16][OH:17])[C:6]([CH3:13])([CH3:12])[C:5]1=[O:14]
Reactant: C1CO1
Reactant: CC1(C)CN(CCO)C(=O)C(C)(C)N1
Agent: Cl
Solvent: CO
Product: CC1(C)CN(CCO)C(=O)C(C)(C)N1CCO
Temperature: 130 °C

Procedure:
45.3 g (0.22 moles) of 1-(2-hydroxyethy)-3,3,5,5-tetramethyl-piperazin-2-one are dissolved in 450 ml of methanol in the presence of 2 ml of HCl 37% (% wiw). The solution is poured into an autoclave and 19.4 g (0.44 moles) of ethylene oxide are added. The solution is heated to 130° C. and maintained at 130° C. for 60 hours under stirring.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[N:7]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[H][H].C(OC(C)C)(C)C>[Pd].CCOC(C)=O>[C:1]([O:5][C:6](=[O:19])[N:7]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(Cc1ccc([N+](=O)[O-])cc1)C(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(C)OC(C)C
Solvent: CCOC(C)=O
Product: CN(Cc1ccc(N)cc1)C(=O)OC(C)(C)C
Yield: 66.4 %

Procedure:
A Parr bottle was charged with (4-nitrobenzyl)-methy-carbarnic acid tert-butyl ester (30.0 g, 113 mmol), 150 mL EtOAc, and 10% Pd/C (3.0 g, 10 wt %), and shaken under 40 psi hydrogen for 90 min. When hydrogen uptake ceased, the reaction vessel was purged with nitrogen, filtered through celite, and concentrated to provide a tan solid, which was granulated with 300 mL of isopropyl ether to provide the title compound as an off-white solid (17.7 g in two crops, 75 mmol, 66% yield):
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:8]=1)([O-:3])=[O:2].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[I:27]I>C1COCC1>[I:27][C:8]1[N:7]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[N:6]=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: II
Reactant: C[Si](C)(C)CCOCn1cc([N+](=O)[O-])cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ncc([N+](=O)[O-])c1I
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 97 %

Procedure:
In an oven-dried flask, 4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (1.5192 g, 6.2432 mmol) was dissolved in 20 mL THF and cooled at −78° C. To this solution was slowly added 1.0M lithium hexamethyldisilazide in tetrahydrofuran (7.5 mL, 7.5 mmol). After stirring for 40 minutes at −78° C., a solution of iodine (1.7602 g, 6.9351 mmol) in 8 mL THF was slowly added. The reaction mixture was kept at −78° C. for an additional 1.5 hours, and then quenched with saturated aqueous ammonium chloride and warmed to room temperature. The reaction mixture was partitioned between ethyl acetate and half-saturated aqueous Na2S2O3. The organic layer was dried with magnesium sulfate, filtered, and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (0 to 15% ethyl acetate in heptanes) to yield 2.2349 g (97%) of 5-iodo-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole. 1H NMR (400 MHz, DMSO-d6) δ: 8.48 (s, 1H), 5.59 (s, 2H), 3.61 (t, J=8.0, 2H), 0.86 (t, J=8.0, 2H), −0.04 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:10])=[C:6]([CH:9]=1)[CH:7]=O.[BH4-].[Na+].CO.[ClH:15]>C1COCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:10])=[C:6]([CH:9]=1)[CH2:7][Cl:15]
Reactant: Cl
Reactant: Cc1ccc(Br)cc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1ccc(Br)cc1CCl
Temperature: 2.5 °C
Reaction time: 5 h

Procedure:
To a mixture of 80.9 g (0.406 mol) of 5-bromo-2-methylbenzaldehyde and 7.80 g (0.206 mol) of NaBH4 in 300 ml of THF 200 ml of methanol was added dropwise by vigorous stirring for 5 h at 0-5° C. This mixture was stirred overnight at room temperature and then added to 1 liter of cold water. The resulting mixture was acidified by 2 M HCl to pH˜1, and the formed (5-bromo-2-methylphenyl)methanol was extracted with 3×250 ml of dichloromethane. The combined organic extract was dried over Na2SO4 and evaporated to dryness. To the residue dissolved in 450 ml of dichloromethane 37 ml of SOCl2 was added dropwise at +5° C. The resulting solution was stirred overnight at room temperature, evaporated to dryness, the residue was dissolved in 500 ml CH2Cl2, and the obtained solution was washed with 500 ml of water. The organic layer was separated, the aqueous layer was additionally extracted with 2×100 ml of dichloromethane. The combined organic extract was passed through a short pad of silica gel 60 (40-63 um), the filtrate was evaporated to dryness, and the residue was dried in vacuum to yield 5-bromo-2-methylbenzyl chloride as a slightly yellowish liquid which was further used without an additional purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](Cl)=[O:9])[CH:5]=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([NH:19][C:20]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:23]=2)=[O:21])[CH:15]=[CH:16][C:17]=1[CH3:18].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([NH:11][C:12]2[CH:13]=[C:14]([NH:19][C:20]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)[CH:23]=3)=[O:21])[CH:15]=[CH:16][C:17]=2[CH3:18])=[O:9])[CH:5]=[CH:4][N:3]=1
Reactant: O=C(Cl)c1ccnc(Cl)c1
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1NC(=O)c1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.4 %

Procedure:
2-Chloropyridine-4-carbonyl chloride (0.143 g) was added to a stirred mixture of N-(3-amino-4-methylphenyl)-2-morpholinopyridine-4-carboxamide (0.211 g), triethylamine (0.164 g) and methylene chloride (10 ml) and the mixture was stirred at ambient temperature for 16 hours. The precipitate was isolated, washed with a saturated aqueous sodium bicarbonate solution and with methylene chloride and dried under vacuum at 40° C. There was thus obtained the title compound (0.276 g); NMR Spectrum: (DMSOd6) 2.2 (s, 3H), 3.50-3.53 (m, 4H), 3.69-3.73 (m, 4H), 7.08 (d, 1H), 7.24 (d, 2H), 7.34 (d, 1H) 7.81 (s, 1H), 7.88 (d, 1H), 7.98 (s, 1H), 8.26 (d, 1H), 8.6 (d, 1H); Mass Spectrum M+H+ 452 and 454.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][N:14]([S:34]([CH3:37])(=[O:36])=[O:35])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH:21]1[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]1.[ClH:38]>CCOC(C)=O>[ClH:38].[CH3:37][S:34]([N:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[CH2:13][CH2:12][N:3]1[C:4](=[O:11])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]1=[O:1])(=[O:35])=[O:36]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccccc2N(CCN2C(=O)c3ccccc3C2=O)S(C)(=O)=O)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CS(=O)(=O)N(CCN1C(=O)c2ccccc2C1=O)c1ccccc1C1CCNCC1
Temperature: 25 °C

Procedure:
To a 150 mL round-bottomed flask equipped with stirring was added tert-butyl 4-(2-{[2-(1,3-dioxo-isoindolin-2-yl)ethyl](methylsulfonyl)-amino}-phenyl)-piperidinecarboxylate (Step a) (1.58 g, 3 mmol) and EtOAc (5 mL). The mixture was treated with a satd solution of anhydrous HCl in EtOAc (70 mL) at 0° C. The reaction mixture was warmed to RT and stirred for 3 h. The solvent was removed in vacuo to provide the title compound as a white foam (1.38 g). MS (ESI, pos. ion) m/z: 428 (M+1); MS (ESI, neg. ion) m/z: 426 (M−1). Calc'd for C22H25N3O4S: 427.16.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][CH2:13][CH3:14])[CH:8]=[C:7]2[O:15][CH:16]1[CH2:20][N:19]([C:21](=[O:39])[CH:22]([NH:27][C:28]([O:30][C:31]2([C:35]([F:38])([F:37])[F:36])[CH2:34][CH2:33][CH2:32]2)=[O:29])[C:23]([CH3:26])([CH3:25])[CH3:24])[CH:18]([C:40]([NH:42][C:43]2([C:48]([OH:50])=O)[CH2:45][CH:44]2[CH2:46][CH3:47])=[O:41])[CH2:17]1.C(N([CH:57]([CH3:59])[CH3:58])C(C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1([O:87][S:88](=[O:91])(=[O:90])[NH2:89])CC1.C1CCN2C(=NCCC2)CC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[F:38][C:35]([F:36])([F:37])[C:31]1([O:30][C:28](=[O:29])[NH:27][CH:22]([C:21]([N:19]2[CH2:20][CH:16]([O:15][C:7]3[C:6]4[C:11](=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=4)[N:10]=[C:9]([O:12][CH2:13][CH3:14])[CH:8]=3)[CH2:17][CH:18]2[C:40](=[O:41])[NH:42][C:43]2([C:48]([NH:89][S:88]([O:91][CH:57]3[CH2:59][CH2:58]3)(=[O:90])=[O:87])=[O:50])[CH2:45][CH:44]2[CH2:46][CH3:47])=[O:39])[C:23]([CH3:25])([CH3:26])[CH3:24])[CH2:34][CH2:33][CH2:32]1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOc1cc(OC2CC(C(=O)NC3(C(=O)O)CC3CC)N(C(=O)C(NC(=O)OC3(C(F)(F)F)CCC3)C(C)(C)C)C2)c2cccc(Cl)c2n1
Reactant: NS(=O)(=O)OC1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CCOc1cc(OC2CC(C(=O)NC3(C(=O)NS(=O)(=O)OC4CC4)CC3CC)N(C(=O)C(NC(=O)OC3(C(F)(F)F)CCC3)C(C)(C)C)C2)c2cccc(Cl)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.8 %

Procedure:
To 1-({4-(8-chloro-2-ethoxy-quinolin-4-yloxy)-1-[3,3-dimethyl-2-(1-trifluoromethyl-cyclobutoxycarbonylamino)-butyryl]-pyrrolidine-2-carbonyl}-amino)-2-ethyl-cyclopropanecarboxylic acid (110 mg, 0.15 mmol) in DMF (3 mL, 0.05 M) was added i-Pr2EtN (90 μL, 0.38 mmol) and HATU (86 mg, 0.23 mmol) and stirred 1 h at rt. To the reaction mixture at it was added sulfamic acid cyclopropyl ester (46 mg, 0.30 mmol) and DBU (90 μL, 0.60 mmol). The reaction was stirred 17 h at it, and then added to 5% aq citric acid and extracted with ethyl acetate. The combined organic extracts were washed water, and brine, and subsequently dried over magnesium sulfate. Concentration, followed by purification by reverse phase HPLC and lyophilization gave {1-[4-(8-chloro-2-ethoxy-quinolin-4-yloxy)-2-(1-cyclopropoxysulfonylaminocarbonyl-2-ethyl-cyclopropylcarbamoyl)-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl}-carbamic acid 1-trifluoromethyl-cyclobutyl ester (20 mg, 16% yield) as a white powder. NMR (CD3OD, 500 MHz) δ 9.18 (s, 1H), 7.95 (d, 1H), 7.70 (d, 1H), 7.20 (dd, 1H), 6.48 (s, 1H), 5.4 (br s, 1H), 4.45-4.6 (m, 4H), 4.2-4.3 (m, 2H), 2.58-2.62 (m, 1H), 2.2-2.4 (m, 4H), 1.5-1.7 (m, 4H), 1.43 (t, 3H), 1.2-1.3 (m, 3H) 1.2 (dd, 2H), 1.1-0.9 (m, 13H), 0.85 (m, 2H). LCMS found 846.00 [M+H]+.
Reaction SMILES: C([NH:11][CH2:12][C:13](=[O:31])[CH2:14][CH2:15][C:16]([O:18][CH:19]([C:21]([O:23][CH2:24][C:25]1C=CC=CC=1)=[O:22])[CH3:20])=[O:17])(OCC1C=CC=CC=1)=O.[H][H].[ClH:34].[CH2:35](OCC)C>[Pd].CC(O)C.O1CCOCC1>[ClH:34].[NH2:11][CH2:12][C:13](=[O:31])[CH2:14][CH2:15][C:16]([O:18][CH:19]([C:21]([O:23][CH:24]([CH3:25])[CH3:35])=[O:22])[CH3:20])=[O:17]
Reactant: CC(OC(=O)CCC(=O)CNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reactant: CCOCC
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: CC(C)OC(=O)C(C)OC(=O)CCC(=O)CN
Yield: 71 %

Procedure:
A stirred mixture of the product of 2b (4.92 g; 11.5 mmol), 10% palladium on activated carbon (100 mg), hydrogen gas and 2.0 M hydrogen chloride in diethyl ether (10 mL; 20 mmol) in 2-propanol (15 mL) and dioxane (15 mL) was hydrogenated at ca. 6 bar for 2 days at ambient temperature. The mixture was filtered through a Celite® 545 pad and the residue was washed with 2-propanol (2×5 mL). The combined filtrates were evaporated and the resulting oil was triturated with diethyl ether (4×10 mL), then stored in a freezer. The oil did not solidify. After vacuum-drying (at 0.005 mm Hg) overnight, 1.97 g (71%) product was obtained (tan, viscous oil).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[C:4]([CH3:10])[CH:3]=1.[OH:11][C:12]([CH3:27])([CH3:26])[CH2:13][CH2:14]OS(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH2:14][CH2:13][C:12]([CH3:27])([OH:11])[CH3:26])=[C:4]([CH3:10])[CH:3]=1
Reactant: Cc1cc(Br)cc(C)c1O
Reactant: Cc1ccc(S(=O)(=O)OCCC(C)(C)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Br)cc(C)c1OCCC(C)(C)O
Temperature: 80 °C
Yield: 70 %

Procedure:
4-Bromo-2,6-dimethylphenol (2.00 g, 9.95 mmol), toluene-4-sulfonic acid 3-hydroxy-3-methyl-butyl ester (Intermediate 10, 2.83 g, 10.9 mmol) and potassium carbonate (1.01 g, 10.9 mmol) are combined in N,N-dimethylformamide (50 mL) and heated at 80° C. for 24 hours. The mixture is cooled, poured into water and extracted with diethyl ether. The organic phase is dried and the solvent removed. The residue is purified by flash chromatography (0-50% ethyl acetate in cyclohexane) to give the title compound (Yield 2.00 g). GC (METHOD 1): tR=11.26 min; Mass spectrum (EI+): m/z=286/288 [M]+.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([N:25]3[CH2:29][CH2:28][CH2:27][C@@H:26]3[CH3:30])=[N:23][N:24]=2)[CH:21]=1>CN(C=O)C>[CH3:30][C@H:26]1[CH2:27][CH2:28][CH2:29][N:25]1[C:22]1[N:20]2[CH:21]=[C:16]([O:12][C@H:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[C@@H:2]([NH2:1])[CH2:3][CH2:4]3)[CH:17]=[CH:18][C:19]2=[N:24][N:23]=1
Reactant: C[C@H]1CCCN1c1nnc2ccc(F)cn12
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H]1CCCN1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 38.4 %

Procedure:
Intermediate A (318 mg, 1.95 mmol) was dissolved in DMF (1 mL) and sodium hydride (60% dispersion in oil, 125 mg, 3.25 mmol) was added portionwise. The mixture was stirred at RT for 10 min. A solution of Intermediate 78a (357 mg, 1.62 mmol) in DMF (1 mL) was added and the reaction mixture was heated at 60° C. for 1.5 h. The mixture was cooled to RT and partitioned between EtOAc (10 mL) and water (10 mL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by FCC, using 0-10% [2M NH3 in MeOH] in DCM, to afford the title compound as an orange gum (226 mg, 38%). LCMS (Method 3): Rt 0.42, 2.06 min, m/z 364 [MH+].
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[Br:17][C:18]1[N:19]=[CH:20][C:21](N)=[N:22][CH:23]=1>>[Br:17][C:18]1[N:19]=[CH:20][C:21]([O:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH:1]4[CH2:4][CH2:3][CH2:2]4)[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:22][CH:23]=1
Reactant: Oc1ccc2c(c1)CCN(C1CCC1)CC2
Reactant: Nc1cnc(Br)cn1
Product: Brc1cnc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)cn1

Procedure:
The title compound was prepared from 3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) and 2,5-dibromopyrazine (D48) using the method of Example 257 (E257); MS (ES+) m/e 375 [M+H]+.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:24])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20]Cl)=[C:14]([O:22][CH3:23])[CH:13]=2)[CH2:4][CH2:3]1.[CH3:25][NH:26][CH3:27]>CC(CC(C)C)=O>[CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:24])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:26]([CH3:27])[CH3:25])=[C:14]([O:22][CH3:23])[CH:13]=2)[CH2:4][CH2:3]1
Reactant: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCCl
Reactant: CNC
Solvent: CC(=O)CC(C)C
Product: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCN(C)C

Procedure:
Using 5 g of N-(trans-4-methylcyclohexyl)-4-(2-chloroethoxy)-3-methoxycinnamamide (Example 138), 100 ml of methylisobutylketone, and 150 ml of a 50% aqueous dimethylamine solution, a reaction similar to that conducted in Example 107 was carried out. As a result, 3.59 g of N-(trans-4-methylcyclohexyl)-4-(2-dimethylaminoethoxy)-3-methoxycinnamamide (a compound of the present invention) was obtained as white crystal, which had the following physiochemical properties:
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([OH:11])[CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1.[CH3:12]I>>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:5]2[O:4][CH:3]=[C:2]([CH3:1])[C:6]=2[CH:7]=1
Reactant: Cc1coc2ccc(O)cc12
Reactant: CI
Product: COc1ccc2occ(C)c2c1

Procedure:
5-Methoxy-3-methyl-benzofuran was prepared via methylation of 3-methyl-benzofuran-5-ol (Structure I) (prepared as above in EXAMPLEs I-III) using methyl iodide (MeI).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][NH:10][CH:11]([CH3:13])[CH3:12])[C:5]2[C:14](I)=[N:15][N:16]([C:17]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:4]=2[CH:3]=1.CC([O-])(C)C.[Na+].C1COCC1>CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C.C1(C)C=CC=CC=1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[N:16]([C:17]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:15]=[C:14]3[C:5]2=[C:6]([CH2:8][CH2:9][N:10]3[CH:11]([CH3:12])[CH3:13])[N:7]=1
Reactant: CC(C)NCCc1nc(Cl)cc2c1c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)N1CCc2nc(Cl)cc3c2c1nn3C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 55 °C

Procedure:
N-(2-(6-chloro-3-iodo-1-trityl-1H-pyrazolo[4,3-c]pyridin-4-yl)ethyl)propan-2-amine (554 mg, 0.913 mmol) and RuPhos pre-catalyst (66.5 mg, 0.091 mmol) were charged in a 2 dram vial, evacuated and backfilled with nitrogen and taken in toluene (4 mL) before the addition of a solution of 2M NaOtBu in THF (1.15 mL, 2.3 mmol). The reaction mixture was heated at 55° C. for 1 hour before it was diluted with EtOAc and washed with water, brine, dried with sodium sulfate and concentrated. Purification of the residue by flash column (0-50% EtOAc-hexanes) gave 7-chloro-3-isopropyl-1-trityl-1,3,4,5-tetrahydropyrazolo[3,4,5-de][1,6]naphthyridine. MS ESI calc'd. for C30H27ClN4 [M+H]+ 480. found 480.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](Cl)=[N:7]2.[CH3:13][O:14][C:15]1[CH:23]=[C:22]2[C:18]([CH2:19][CH2:20][CH:21]2[NH2:24])=[CH:17][CH:16]=1.[CH3:25][S:26][CH2:27][CH2:28][CH2:29][NH2:30]>>[CH3:13][O:14][C:15]1[CH:23]=[C:22]2[C:18]([CH2:19][CH2:20][CH:21]2[NH:24][C:6]2[CH:5]=[CH:4][C:3]3[C:2]([NH:30][CH2:29][CH2:28][CH2:27][S:26][CH3:25])=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=2)=[CH:17][CH:16]=1
Reactant: COc1ccc2c(c1)C(N)CC2
Reactant: CSCCCN
Reactant: Clc1ccc2c(I)cccc2n1
Product: COc1ccc2c(c1)C(Nc1ccc3c(NCCCSC)cccc3n1)CC2

Procedure:
The title compound, MS: m/e=394.3 (M+H+), was prepared in accordance with the general method of example 1 from 5-iodo-2-chloroquinoline, 6-methoxyindan-1-ylamine (CAS 103028-81-5) and 3-(methylthio)propylamine.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][C:13]1([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]1.O.NN.O.O.[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31]>CO>[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].[NH2:3][CH2:12][C:13]1([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[CH2:14][CH2:15]1
Reactant: CC(C)(C)OC(=O)NC1(CN2C(=O)c3ccccc3C2=O)CC1
Agent: NN
Agent: O=C(O)C(=O)O
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NC1(CN)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of tert-butyl {1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]cyclopropyl}carbamate (80.0 g, 253 mmol) in methanol (1600 mL) was added hydrazine hydrate (80% solution in water, 15.9 g, 320 mmol). The reaction mixture was heated to reflux. After 4 hours, the reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was washed with DCM (3×500 mL) and then the combined organic layers were concentrated under reduced pressure. This residue was dissolved in diethyl ether (1000 mL) and diluted with oxalic acid dihydrate (solution in ethanol, 35.2 g, 279 mmol), which was added dropwise. After 1 hour, the precipitated solids were collected by filtration, washed with diethyl ether (4×200 mL), and dried to give tert-butyl [1-(aminomethyl)cyclopropyl]carbamate oxalate salt. MS ESI calc'd. for C9H19N2O2 [M+H]+ 187. found 187. 1H NMR (400 MHz, D2O) δ 2.98 (s, 2H), 1.36-1.30 (m, 9H), 0.81 (s, 4H).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C@@H:5]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:6][CH2:7][CH2:8][CH3:9])[OH:4].NC[C@H]([C@@H](NC(=O)OC(C)(C)C)CCCC)O.C(N(CC)C(C)C)(C)C.[N:44]1([C:50](Cl)=[O:51])[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1>ClCCl>[OH:4][C@H:3]([C@@H:5]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][NH:1][C:50]([N:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1)=[O:51]
Reactant: CCCC[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CN
Reactant: O=C(Cl)N1CCOCC1
Agent: CCCC[C@H](NC(=O)OC(C)(C)C)[C@H](O)CN
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCC[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CNC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.2 %

Procedure:
To a solution of 100 mg (0.41 mmol) of tert-butyl (1S)-1-[(1S)-2-amino-1-hydroxyethyl]pentylcarbamate & tert-butyl (1S)-1-[(1R)-2-amino-1-hydroxyethyl]pentylcarbamate and 0.070 mL (0.41 mmol) of N,N-diisopropylethylamine in 2 mL dichloromethane was added 0.050 mL (0.41 mmol) 4-morpholinecarbonyl chloride. The reaction mixture was stirred at room temperature for 18 h, diluted with dichloromethane, and washed with 1N hydrochloric acid and brine. After drying over anhydrous magnesium sulfate, the solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography eluting with ethyl acetate to afford 130 mg (89%) of tert-butyl (1S)-1-{(1S)-1-hydroxy-2-[(4-morpholinylcarbonyl)amino]ethyl}pentylcarbamate & tert-butyl (1S)-1-{(1R)-1-hydroxy-2-[(4-morpholinylcarbonyl)amino]ethyl}pentylcarbamate. 1H-NMR (300 MHz, DMSO-d6): δ 6.55–6.36 (m, 2H), 5.00–4.65 (m, 1H), 3.60-3.23 (m, 9H), 3.10–2.80 (m, 2H), 1.40–1.05 (m, 15 H), 0.87 (m, 1H); ES-LCMS m/z 382 (M+Na).