Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH2:46])[CH:43]=[CH:44][CH:45]=2)=[N:8]1.[CH3:47][O:48][C:49]1[CH:57]=[CH:56][C:52]([C:53](Cl)=[O:54])=[CH:51][CH:50]=1.O>N1C=CC=CC=1>[NH:18]1[CH:19]=[N:20][C:16]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[NH:7][N:8]=[C:9]3[C:40]2[CH:41]=[C:42]([NH:46][C:53]([C:52]3[CH:56]=[CH:57][C:49]([O:48][CH3:47])=[CH:50][CH:51]=3)=[O:54])[CH:43]=[CH:44][CH:45]=2)=[N:17]1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Nc2cccc(-c3n[nH]c4ccc(-c5nc[nH]n5)cc34)c2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 66.4 %

Procedure:
To a solution of 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.200 g, 0.33 mmol) in pyridine (2 mL) was added 4-methoxybenzoyl chloride (0.068 g, 0.40 mmol). The reaction was stirred at room temperature for 15 h. Water (10 mL) was added and the solid collected by suction filtration. The solid was dried in a vacuum oven for 3 h. The residue was dissolved in 4 N hydrochloric acid in 1,4-dioxane (10 mL) and the mixture was stirred at room temperature for 2 h. After neutralization with aqueous sodium bicarbonate, the reaction mixture was extracted with ethyl acetate. The combined organic fractions were dried over anhydrous sodium sulfate, filtered and evaporated. Addition of dichloromethane (10 mL) to the residue gave the title compound (0.090 g, 66% yield) which was isolated by filtration: 1H NMR (DMSO-d6) δ 10.33 (s, 1H), 8.73 (s, 1H), 8.44 (s, 1H), 8.30 (s, 1H), 8.11 (d, 1H), 8.03 (d, 2H), 7.93 (d, 1H), 7.10 (m, 2H), 7.53 (t, 1H), 7.09 (d, 2H), 3.85 (s, 3H); ES-MS (m/z) 411 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[N:14]([CH2:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][OH:29])=[CH:22][CH:21]=4)[CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1.C(N(C(C)C)CC)(C)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:40][S:41]([O:29][CH2:28][CH2:27][O:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][CH2:18][N:14]2[CH2:13][C@@H:12]([C:10]3[CH:9]=[CH:8][C:6]4[O:7][C:2]([CH3:30])([CH3:1])[O:3][CH2:4][C:5]=4[CH:11]=3)[O:16][C:15]2=[O:17])=[CH:25][CH:24]=1)(=[O:43])=[O:42]
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCc4ccc(OCCO)cc4)C(=O)O3)ccc2O1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)OCc2cc([C@@H]3CN(CCc4ccc(OCCOS(C)(=O)=O)cc4)C(=O)O3)ccc2O1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-3-{2-[4-(2-hydroxyethoxy)phenyl]ethyl}-1,3-oxazolidin-2-one (450 mg) in DCM (20 ml) at 0° C. under nitrogen was treated with diisopropylethylamine (0.23 ml) followed by methanesulphonyl chloride (0.09 ml) and the mixture was stirred at 0° C. for 1 h. Saturated NaHCO3 solution was added and the mixture was vigorously stirred for 5 min. The layers were separated and the organic phase washed with saturated NaHCO3 solution, dried (Na2SO4) and the solvent evaporated in vacuo to give the title compound (528 mg). LCMS RT=3.15 min.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([N:12]2[CH2:15][CH:14]([F:16])[CH2:13]2)[CH2:9]1)=O)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[F:16][CH:14]1[CH2:15][N:12]([CH:10]2[CH2:11][NH:8][CH2:9]2)[CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CC(N2CC(F)C2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC1CN(C2CNC2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94.8 %

Procedure:
A 25 mL round-bottomed flask was charged with a solution of 3-fluoro-[1,3′]biazetidinyl-1′-carboxylic acid tert-butyl ester (0.109 g, 0.47 mmol) in DCM/TFA (2 mL/2 mL). The reaction mixture was stirred for 90 min at room temperature. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the desired product was eluted using 2 M NH3 in MeOH to give 3-Fluoro-[1,3′]biazetidinyl as a colourless oil (0.058 g, 94%). 1H NMR (CDCl3, 400 MHz) δ 5.14 (dp, J=57.2, 5.3 Hz, 1H); 3.75-3.46 (m, 8H); 3.34-3.24 (m, 1H); 3.27-3.10 (m, 1H).
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:36][CH2:35][C:12]2([C:16](=[O:17])[N:15]([C:18]3[CH:23]=[CH:22][C:21]([CH:24]4[CH2:29][CH2:28][CH:27]([N:30]5[CH2:33][CH2:32][CH2:31]5)[CH2:26][CH2:25]4)=[CH:20][C:19]=3[F:34])[CH2:14][CH2:13]2)[CH2:11][CH2:10]1)=O)(C)(C)C>O1CCOCC1>[ClH:1].[N:30]1([CH:27]2[CH2:26][CH2:25][CH:24]([C:21]3[CH:22]=[CH:23][C:18]([N:15]4[CH2:14][CH2:13][C:12]5([CH2:35][CH2:36][NH:9][CH2:10][CH2:11]5)[C:16]4=[O:17])=[C:19]([F:34])[CH:20]=3)[CH2:29][CH2:28]2)[CH2:33][CH2:32][CH2:31]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(c1ccc(C3CCC(N4CCC4)CC3)cc1F)C2=O
Agent: Cl
Solvent: C1COCCO1
Product: O=C1N(c2ccc(C3CCC(N4CCC4)CC3)cc2F)CCC12CCNCC2

Procedure:
The title compound was prepared in the same manner as Example 17 by using hydrochloric acid in dioxane to hydrolyze 2-[4-(4-azetidin-1-yl-cyclohexyl)-2-fluoro-phenyl]-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([Cl:13])=[CH:9][CH:10]=2)[C:5]1=O.O.[NH2:16][CH2:17][CH:18]([OH:20])[CH3:19]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:13][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:12]1[N:16]([CH2:17][CH:18]([OH:20])[CH3:19])[CH:2]=[CH:3][C:4]=1[CH2:5]2
Reactant: O=CCC1Cc2ccc(Cl)cc2C1=O
Reactant: CC(O)CN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(O)Cn1ccc2c1-c1ccc(Cl)cc1C2
Reaction time: 0.58 h
Yield: 80 %

Procedure:
A solution of 2 g of (RS)-2-(2-oxoethyl)-6-chlor-1-indanone and 100 mg of p-toluenesulfonic acid in 90 ml of anhydrous toluene was heated on a water separator. A solution of 2.88 g of (RS)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 35 minutes, during which the solvent was reduced to a volume of 30 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/toluene 1:1). There were obtained 1.9 g (80%) of (RS)-1-(6-chloro-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol as a brown oil which was used directly in the next reaction.
Reaction SMILES: [CH2:1]=[C:2]([CH2:6][C:7]([N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[O:8])[C:3]([OH:5])=[O:4].[CH2:15]([S:19]([OH:21])=[O:20])[CH:16]([CH3:18])[CH3:17].C(#N)C>C1(C)C=CC=CC=1>[CH3:17][CH:16]([CH3:18])[CH2:15][S:19]([CH2:1][CH:2]([CH2:6][C:7]([N:9]1[CH2:10][CH2:11][O:12][CH2:13][CH2:14]1)=[O:8])[C:3]([OH:5])=[O:4])(=[O:21])=[O:20]
Reactant: C=C(CC(=O)N1CCOCC1)C(=O)O
Reactant: CC(C)CS(=O)O
Solvent: Cc1ccccc1
Solvent: CC#N
Product: CC(C)CS(=O)(=O)CC(CC(=O)N1CCOCC1)C(=O)O
Temperature: 85 °C
Reaction time: 4.5 h
Yield: 28 %

Procedure:
A mixture of 2-Methylene-4-morpholin-4-yl-4-oxo-butyric acid (3.98 g, 20 mmol) and isobutyl-sulphinic acid (2.44 g, 20 mmol) were suspended in anhydrous toluene (80 mL) and anhydrous acetonitrile (20 mL). This mixture was warmed to 85° C. and stirred vigorously for 4.5 h. The reaction mixture was allowed to cool to room temperature and concentrated under vacuum. The residue was purified by flash chromatography using a 90 g silica gel column eluting with 10% methanol/CH2Cl2. Recovered 3.7 g of product as an oil. Triturated residue with isopropanol (5 mL)/ether (100 mL). Product began to precipitate out. Cooled this to 5° C. for 17 hrs(overnight). Product was collected by filtration, washed with ether and dried under vacuum to give 2-(2-Methyl-propane-1-sulfonylmethyl)-4-morpholin-4-yl-4-oxo-butyric acid as a white solid (1.8 g).
Reaction SMILES: [N+:1]([C:4]1[CH:28]=[CH:27][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16](=[O:26])[N:17]([CH3:25])[CH:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH:10]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>O1CCCC1.CO.[C].[Pd]>[NH2:1][C:4]1[CH:28]=[CH:27][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16](=[O:26])[N:17]([CH3:25])[CH:18]3[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]3)[CH:10]=2)=[CH:6][CH:5]=1
Reactant: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc([N+](=O)[O-])cc3)ccn2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(N)cc3)ccn2)CC1
Reaction time: 8 h

Procedure:
3-[4-(4-Nitrophenoxy)pyridin-2-yl]-1-methyl-1-(1-methylpiperidin-4-yl)urea was dissolved in tetrahydrofuran (4 ml)-methanol (4 ml), and then 10% palladium carbon (65 mg) was added thereto under a nitrogen atmosphere, followed by replacing with hydrogen inside the system and stirring overnight. After replacing with nitrogen inside the system, the reaction mixture was filtered to remove the catalyst, which was washed with methanol. The filtrate was concentrated under a reduced pressure to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate). Fractions containing the target compound were concentrated under a reduced pressure to provide the titled compound (113.5 mg, quantitatively) as colorless powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH:4]([C:9]1[CH:14]=[C:13]([O:15][S:16]([C:19]([F:22])([F:21])[F:20])(=[O:18])=[O:17])[CH:12]=[C:11](OCC2C=CC=CC=2)[CH:10]=1)[CH2:5][C:6]([CH3:8])=[CH2:7].[F:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1>>[CH3:1][O:2][C:3](=[O:31])[CH:4]([C:9]1[CH:10]=[C:11]([C:35]2[CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=[C:33]([F:32])[CH:34]=2)[CH:12]=[C:13]([O:15][S:16]([C:19]([F:22])([F:21])[F:20])(=[O:17])=[O:18])[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: C=C(C)CC(C(=O)OC)c1cc(OCc2ccccc2)cc(OS(=O)(=O)C(F)(F)F)c1
Reactant: OB(O)c1cc(F)cc(C(F)(F)F)c1
Product: COC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2cc(F)cc(C(F)(F)F)c2)c1
Yield: 66 %

Procedure:
The title compound was prepared in 66% yield from 2-(3-benzyloxy-5-trifluoromethanesulfonyloxy-phenyl)-4-methyl-pent-4-enoic acid methyl ester (prepared in Example 26, step (c)) under the conditions described in Example 26, step (d-f)) using 3-fluoro-5-trifluoromethylphenylboronic acid in step (d).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH2:10][C:11]2[C:16]([F:17])=[CH:15][CH:14]=[C:13]([F:18])[C:12]=2[Cl:19])[C:5]([NH2:8])=[N:6][CH:7]=1.[C:20]([C:23]1[S:27][C:26](B(O)O)=[CH:25][CH:24]=1)([OH:22])=[O:21]>>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([C:26]2[S:27][C:23]([C:20]([OH:22])=[O:21])=[CH:24][CH:25]=2)=[CH:3][C:4]=1[O:9][CH2:10][C:11]1[C:16]([F:17])=[CH:15][CH:14]=[C:13]([F:18])[C:12]=1[Cl:19]
Reactant: O=C(O)c1ccc(B(O)O)s1
Reactant: Nc1ncc(Br)cc1OCc1c(F)ccc(F)c1Cl
Product: Nc1ncc(-c2ccc(C(=O)O)s2)cc1OCc1c(F)ccc(F)c1Cl

Procedure:
5-[6-Amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-thiophene-2-carboxylic acid was prepared following procedure 3 starting from 5-bromo-3-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-2-ylamine and 5-carboxythiophene-2-boronic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:5]=[O:6].[CH2:21](O)[CH2:22][OH:23].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[O:6]1[CH2:21][CH2:22][O:23][CH:5]1[C:4]1[CH:7]=[CH:8][C:9]([O:10][Si:11]([CH:15]([CH3:17])[CH3:16])([CH:18]([CH3:20])[CH3:19])[CH:12]([CH3:13])[CH3:14])=[C:2]([F:1])[CH:3]=1
Reactant: OCCO
Reactant: CC(C)[Si](Oc1ccc(C=O)cc1F)(C(C)C)C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)[Si](Oc1ccc(C2OCCO2)cc1F)(C(C)C)C(C)C
Temperature: 25 °C

Procedure:
Into a 5 L 3-neck flask equipped with a condenser and a Dean-Stark trap add 3-fluoro-4-triisopropylsilanyloxybenzaldehyde (Example 737, Part A) (90.14 g, 0.3041 mol), ethylene glycol (188.75 g, 3.041 mol), and p-toluenesulfonic acid (0.58 g, 0.003041 mol) in toluene (3.155 L). Beat to boil and reflux until 130 mL of H2O (lower layer) is collected in the Dean-Stark trap (5 hrs). Cool to room temperature, wash with 10% aqueous potassium carbonate solution (2×1 L) and brine (2×1 L), and dry over sodium sulfate. Filter and concentrate to give the crude product.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:15])[CH:13]=2)/[C:8](=[CH:16]/[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)/[C:7]1=[O:24])=[O:5])[CH3:2].[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH:32]=[N:33][C:34]([O:36][Si](C)(C)C)=[CH2:35]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:15])[CH:13]=2)[C:8]2([CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=3)[CH2:35][C:34](=[O:36])[NH:33][CH:32]2[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[Cl:25])[C:7]1=[O:24])=[O:5])[CH3:2]
Reactant: C=C(N=Cc1ccccc1Cl)O[Si](C)(C)C
Reactant: CCOC(=O)N1C(=O)/C(=C\c2cccc(Cl)c2)c2ccc(Cl)cc21
Solvent: Cc1ccccc1
Product: CCOC(=O)N1C(=O)C2(c3ccc(Cl)cc31)C(c1cccc(Cl)c1)CC(=O)NC2c1ccccc1Cl
Yield: 67.1 %

Procedure:
In a manner similar to the method described in example 4c, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester (0.31 g, 0.85 mmol) prepared in example 4b was reacted with 1-(2-chlorophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (2.1 g, 8.27 mmol) prepared in example 16a, in toluene to give racemic (2′R,3R,4′S)-6-chloro-2′-(2-chlorophenyl)-4′-(3-chlorophenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester as a yellow gum (Yield 0.31 g, 67%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[CH2:19]([O:26][CH2:27][CH2:28][NH2:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1C=CC=CC=1>[CH2:19]([O:26][CH2:27][CH2:28][NH:29][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Clc1ncnc2ccccc12
Reactant: NCCOCc1ccccc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: c1ccc(COCCNc2ncnc3ccccc23)cc1
Reaction time: 5 h
Yield: 66.2 %

Procedure:
To a solution of 3.3 g (0.02 mol) of 4-chloroquinazoline in 50 ml of benzene were added 2.0 g (0.02 mol) of triethylamine and 3.0 g (0.02 mol) of 2-benzyloxyethylamine, and the mixture was heated, with stirring, at 60°~70° C. for 5 hours. After completion of the reaction, the benzene was evaporated under reduced pressure, and the resulting crystals were washed with water, collected by filtration, dried and recrystallized from benzene/n-hexane, affording 3.7 g of 4-[2-(benzyloxy)ethyl]aminoquinazoline in the form of colorless needles.
Reaction SMILES: Cl.[F:2][CH:3]([F:25])[CH2:4][NH:5][C:6](=[O:24])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]3[O:22][CH2:21][CH2:20][NH:19][CH2:18][C:17]=3[CH:23]=2)=[CH:9][CH:8]=1.CCN(C(C)C)C(C)C.[F:35][C:36]1[CH:37]=[C:38]([CH:42]2[CH2:47][C:46](=[O:48])[CH2:45][CH2:44][N:43]2[C:49](Cl)=[O:50])[CH:39]=[CH:40][CH:41]=1>O1CCCC1>[F:25][CH:3]([F:2])[CH2:4][NH:5][C:6](=[O:24])[C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:14]=[CH:15][C:16]3[O:22][CH2:21][CH2:20][N:19]([C:49]([N:43]4[CH2:44][CH2:45][C:46](=[O:48])[CH2:47][CH:42]4[C:38]4[CH:39]=[CH:40][CH:41]=[C:36]([F:35])[CH:37]=4)=[O:50])[CH2:18][C:17]=3[CH:23]=2)=[CH:11][CH:12]=1
Reactant: O=C1CCN(C(=O)Cl)C(c2cccc(F)c2)C1
Reactant: O=C(NCC(F)F)c1ccc(-c2ccc3c(c2)CNCCO3)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCN(C(=O)N2CCOc3ccc(-c4ccc(C(=O)NCC(F)F)cc4)cc3C2)C(c2cccc(F)c2)C1
Temperature: 50 °C
Yield: 13.2 %

Procedure:
To a slurry of N-(2,2-difluoroethyl)-4-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)benzamide hydrochloride (0.19 g, 0.51 mmol), DIPEA (0.45 mL, 2.6 mL) and tetrahydrofuran (3 mL) was added 2-(3-fluorophenyl)-4-oxopiperidine-1-carbonyl chloride (reagent preparation 37) (0.13 g, 0.51 mmol). The reaction mixture was heated (50° C.) for 3 h and then concentrated. Purification by preparative reverse phase HPLC provided N-(2,2-difluoroethyl)-4-(4-{[2-(3-fluorophenyl)-4-oxopiperidin-1-yl]carbonyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)benzamide (37 mg, 13% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): 7.82 (d, 2H), 7.55 (d, 2H), 7.47 (dd, 1H), 7.20-7.34 (m, 3H), 7.13 (d, 1H), 6.93-7.06 (m, 3H), 6.43 (t, 1H), 5.99 (tt, 1H), 5.34-5.40 (m, 1H), 4.54 (s, 2H), 4.20-4.30 (m, 2H), 3.73-3.93 (m, 5H), 3.20-3.30 (m, 1H), 2.84-3.06 (m, 2H), 2.54-2.64 (m, 1H), 2.32 (d, 1H); MS (EI) for C30H28F3N3O4: 552 (MH+).
Reaction SMILES: [CH3:1][C:2]([CH3:34])([CH2:32][CH3:33])[C:3](=[O:31])[C:4]([N:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[C:11](=[O:30])[CH2:12][CH2:13][CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22]CC2C=CC=CC=2)=[CH:18][CH:17]=1)=[O:5]>C(OCC)(=O)C.[Pd]>[OH:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][CH2:14][CH2:13][CH2:12][C:11]([CH:7]2[CH2:8][CH2:9][CH2:10][N:6]2[C:4](=[O:5])[C:3](=[O:31])[C:2]([CH3:1])([CH3:34])[CH2:32][CH3:33])=[O:30])=[CH:21][CH:20]=1
Reactant: CCC(C)(C)C(=O)C(=O)N1CCCC1C(=O)CCC=Cc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCC(C)(C)C(=O)C(=O)N1CCCC1C(=O)CCCCc1ccc(O)cc1
Yield: 60.7 %

Procedure:
A mixture of 1.63 g (3.53 mmol) of 3,3-dimethyl-1-(2-{5-[4-(phenylmethoxy)phenyl]pent-4-enoyl}pyrrolidinyl)pentane-1,2-dione and 400 mg of 10% Pd/C in 100 ml of ethyl acetate was hydrogenated at 50 psi overnight. The mixture was filtered through Celite, concentrated, and chromatographed (25% ethyl acetate/hexane) to obtain 800 mg (61%) of 1-{2-[5-(4-hydroxyphenyl)pentanoyl]pyrrolidinyl}-3,3-dimethylpentane-1,2-dione (68). 1H NMR (CDCl3, 400 MHz): δ0.87 (t, 3H, J=7.50); 1.21 (s, 6H); 1.63 (m, 4H); 1.67 (m, 2H); 1.93 (m, 3H); 2.04 (m, 1H); 2.52 (m, 4H); 3.47 (m, 2H); 4.57 (m, 1H); 6.72 (d, 2H, J=8.40); 7.03 (d, 2H, J=8.40). Anal. Calcd. for C22H31NO4: C, 70.75; H, 8.37; N, 3.75. Found: C, 70.64; H, 8.44; N, 3.65. TLC: Rf=0.45 (25% ethyl acetate/hexane).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][C@@H:24]2[OH:27])[C@:20]2([CH3:21])[C@@H:15]([CH2:16][C@@H:17]([O:28][CH2:29][CH2:30][OH:31])[CH2:18][CH2:19]2)[CH2:14][C@H:13]3[OH:32])[CH2:10][CH2:9]1)[CH3:7].[CH3:34][S:35](Cl)(=[O:37])=[O:36].C(N(CC)CC)C.[NH4+].[Cl-]>C1COCC1>[OH:32][C@@H:13]1[CH2:14][CH:15]2[C@:20]([CH3:21])([CH2:19][CH2:18][C@H:17]([O:28][CH2:29][CH2:30][O:31][S:35]([CH3:34])(=[O:37])=[O:36])[CH2:16]2)[C@@H:22]2[C@@H:12]1[C@H:11]1[C@:25]([CH3:26])([C@@H:24]([OH:27])[CH2:23]2)[C@@H:8]([C@H:6]([CH3:7])[CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:33])[CH2:9][CH2:10]1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@@H](OCCO)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)CC4C[C@@H](OCCOS(C)(=O)=O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
The compound of example 1B (1.0 g, 2.1 mmol) was dissolved in THF (21 mL) and cooled to 0° C. To the cooled solution was added methanesulfonyl chloride (0.25 mL, 3.21 mmol) followed by the dropwise addition of triethylamine (0.45 mL, 3.21 mmol). The reaction solution was warmed to room temperature and allowed to stir overnight. Saturated aqueous NH4Cl was added and the solution was extracted twice with ethyl acetate. The organic phase was washed with brine, dried (MgSO4), concentrated and purified via column chromatography (1:1 hexanes:ethyl acetate). The yield of the product was 429 mg (37%).
Reaction SMILES: C(OC([NH:11][C@H:12]([C:19]([OH:21])=O)[CH2:13][N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1)=O)C1C=CC=CC=1.[NH2:22][C@@H:23]([CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[C@@H:24]([OH:30])[C@H:25]([CH:27]1[CH2:29][CH2:28]1)[OH:26]>>[NH2:11][C@@H:12]([CH2:13][N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1)[C:19]([NH:22][C@@H:23]([CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[C@@H:24]([OH:30])[C@H:25]([CH:27]1[CH2:29][CH2:28]1)[OH:26])=[O:21]
Reactant: O=C(N[C@@H](Cn1ccnc1)C(=O)O)OCc1ccccc1
Reactant: N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1
Product: N[C@@H](Cn1ccnc1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1

Procedure:
In an analogous manner to that described above, by the condensation of N-[(benzyloxy)carbonyl]-3-(imidazol-1-yl)-L-alanine and (1S,2R,3S)-3-amino-4-cyclohexyl-1-cyclopropyl-1,2-butanediol followed by catalytic hydrogenation there was obtained (S)-α-amino-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-3-(imidazol-1-yl)propionamide, MS: 365 (M+H)+, as a colourless foam.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][N:9]=1)[C:5]#[N:6].C1C(=O)N([Br:17])C(=O)C1>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[CH:3]=[C:4]([C:7]([Br:17])=[CH:8][N:9]=1)[C:5]#[N:6]
Reactant: N#Cc1ccnc(N)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1cc(N)ncc1Br
Temperature: -18 °C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
A solution of 2-amino-isonicotinonitrile (10.0 g, 83.9 mmol) in DMF (20 mL) was cooled to −18° C. (ice/MeOH bath), treated with NBS (16.5 g, 92.3 mmol), and stirred at −18° C. for 1 h. The reaction mixture was diluted in AcOEt (500 mL) and washed with water (200 mL). The aqueous phase was separated and extracted with AcOEt (2×500 ml). The combined organic fractions were dried over Na2SO4, filtered and evaporated. The residue was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, [hexane/DCM 1:1]/TBME 98:2→6:4) to yield the title compound (13.0 g, 65.6 mmol, 78%) as a pale yellow solid. MS: 199 [M+1]+; HPLC: AtRet=1.13; TLC: RF 0.39 (hexane/DCM/TBME 1:1:2).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH2:12][NH:13][C:14]([C:16]1[C:21]([NH2:22])=[N:20][C:19]([NH2:23])=[C:18]([Cl:24])[N:17]=1)=[O:15])[CH2:9][CH2:10][CH3:11])(C)(C)C.Cl>O1CCOCC1>[ClH:24].[NH2:7][C@H:8]([CH2:9][CH2:10][CH3:11])[CH2:12][NH:13][C:14]([C:16]1[C:21]([NH2:22])=[N:20][C:19]([NH2:23])=[C:18]([Cl:24])[N:17]=1)=[O:15]
Reactant: CCC[C@H](CNC(=O)c1nc(Cl)c(N)nc1N)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCC[C@@H](N)CNC(=O)c1nc(Cl)c(N)nc1N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of ((R)-1-{[(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-amino]-methyl}-butyl)-carbamic acid tert-butyl ester (0.65 g, 1.74 mmol) in 1,4-dioxane (15 mL) is added HCl (30 mL of a 4 M solution in 1,4-dioxane, 120 mmol) and the reaction mixture is stirred at RT for 16 h. The reaction mixture is concentrated in vacuo and the yellow solid obtained is triturated with diethyl ether; the ether layer is decanted and the product is dissolved in minimal MeOH and is precipitated by the addition of diethyl ether. The solvent is decanted and the resulting solid is dried under vacuum to afford the title compound. [M+H]+ 273.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:21][CH2:20][C:11]3[NH:12][C:13]4[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][C:18]=4[C:10]=3[CH2:9]2)=[CH:4][CH:3]=1.[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]=[CH2:30])=[CH:25][N:24]=1.[OH-].[K+]>CN1C(=O)CCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:21][CH2:20][C:11]3[N:12]([CH2:30][CH2:29][C:26]4[CH:25]=[N:24][C:23]([CH3:22])=[CH:28][CH:27]=4)[C:13]4[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][C:18]=4[C:10]=3[CH2:9]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(c1ccc(Br)cc1)CC3
Reactant: C=Cc1ccc(C)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C)nc2)CCN(c2ccc(Br)cc2)C1

Procedure:
The title compound is prepared from a mixture of 2-(4-bromophenyl)-2,3,4,5-tetrahydro-8-methyl-1H-pyrido[4,3-b]indole, 2-methyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.