Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Br[CH2:3][CH:4](OCC)OCC.[O-]S([O-])(=O)=O.[Na+].[Na+].BrCC=O.[NH2:22][C:23]1[C:28]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:27][CH:26]=[CH:25][N:24]=1.C([O-])(O)=O.[Na+]>>[CH2:30]([O:29][C:28]1[C:23]2[N:24]([CH:3]=[CH:4][N:22]=2)[CH:25]=[CH:26][CH:27]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CCOC(CBr)OCC
Reactant: Nc1ncccc1OCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: O=CCBr
Product: c1ccc(COc2cccn3ccnc23)cc1
Temperature: 55 °C
Reaction time: 1 h

Procedure:
As shown in FIG. 6, concentrated HCl (34 mL, 345 mmol) was added drop-wise to 2-bromo-1,1-diethoxyethane 17 (29.56, 150 mmol) at room temperature in a 250-mL three neck round bottomed flask. The mixture was then heated at 55° C. for 30 minutes. The pale yellow mixture was then cooled to 0° C. and anhydrous Na2SO4 (64 g) added and the reaction stirred for 1.0 hour. The reaction mixture now containing crude bromoacetaldehyde 18 was filtered into a three neck 1000-mL round bottomed flask and the cake washed with ethanol (100 mL). The flask was then cooled to 0° C. and 2- amino-3-benzyloxypyridine 19 (10.0 g, 50 mmol) added portion wise followed by the addition of NaHCO3 (42 g, 500 mmol). There was evolution of gas. After the bubbling had ceased, the mixture was refluxed at 70° C. for 1.0 hour. The reaction mixture was then cooled to room temperature, filtered and concentrated under reduced pressure. CH2Cl2 was added to the residue at 0° C. and 40% NaOH (30 mL) added to pH 10. The mixture was then diluted with water (100 mL) and the organic phase separated, dried (Na2SO4) and concentrated under reduced pressure. Purification on silica gel (CombiFlash, Heptanes/EtOAc elution) afforded 8-benzyloxy-imidazo[1,2-α]pyridine 24 as colorless needles. 7.2 g, 64%, yield.
Reaction SMILES: Cl.Cl.[C:3]1([C@H:9]2[C@@H:14]([NH2:15])[CH2:13][CH2:12][CH2:11][NH:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:16][C:17]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:18]=1[CH:19]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:16][C:17]1[CH:24]=[CH:23][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:21][C:18]=1[CH2:19][NH:15][C@H:14]1[CH2:13][CH2:12][CH2:11][NH:10][C@H:9]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: N[C@H]1CCCN[C@H]1c1ccccc1
Reactant: O=Cc1cc(C(F)(F)F)ccc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Product: Fc1ccc(C(F)(F)F)cc1CN[C@H]1CCCN[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 6.5 h

Procedure:
To a stirred suspension of Compound 1 (150 mg, 0.60 mmol) and 2-fluoro-5-(trifluoromethyl)benzaldehyde (116 mg, 0.60 mmol) in dry CH2Cl2 (6 ml) was added NaBH(OAc)3 (179 mg, 0.84 mmol) portionwise under nitrogen at room temperature. The reaction mixture was stirred at room temperature for 6.5 hr. This was basified with sat. NaHCO3 aq., extracted with CH2Cl2, dried with MgSO4, and concentrated to give crude (2S,3S)-3-(2-fluoro-5-(trifluoromethyl)benzyl)amino-2-phenylpiperidine as a colorless oil. This was purified with chromatography to give pure (2S,3S)-3-(2-fluoro-5-(trifluoromethyl)benzyl)amino-2-phenylpiperidine as a colorless oil (75 mg). This was diluted with ethyl acetate, added HCl-MeOH, and concentrated. The white solid was recrystallized from MeOH-ether to give Compound 2 as a white crystalline (67 mg, 26.3%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]3[C:17]([C:20]([O-:22])=O)=[CH:18][N:19]=[C:13]3[CH:12]=2)[CH2:4][CH2:3]1.[Li+].C(Cl)(=O)C(Cl)=O.[CH2:30]([N:37]1[C:45]2[CH:44]=[CH:43][CH:42]=[C:41]([NH2:46])[C:40]=2[CH:39]=[N:38]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[CH2:30]([N:37]1[C:45]2[C:40](=[C:41]([NH:46][C:20]([C:17]3[N:14]4[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][N:5]5[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]5)=[CH:12][C:13]4=[N:19][CH:18]=3)=[O:22])[CH:42]=[CH:43][CH:44]=2)[CH:39]=[N:38]1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: Nc1cccc2c1cnn2Cc1ccccc1
Reactant: CN1CCN(CCOc2ccn3c(C(=O)[O-])cnc3c2)CC1
Agent: O=C(Cl)C(=O)Cl
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1CCN(CCOc2ccn3c(C(=O)Nc4cccc5c4cnn5Cc4ccccc4)cnc3c2)CC1
Temperature: 25 °C
Yield: 7.3 %

Procedure:
To a solution of lithium 7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate (0.0585 g, 0.189 mmol) in CH2Cl2 was added a drop of DMF. Oxalyl chloride (1.1 equivalents, 2M CH2Cl2) was added and the reaction stirred at ambient temperature until bubbling ceased (about 5 minutes). 1-Benzyl-1H-indazol-4-amine (0.042 g, 0.189 mmol) was added followed by DIEA (1.2 equivalents). The reaction was stirred at ambient temperature for 4 hours. The reaction was concentrated and washed with Et2O, water, and finally with Et2O again. The pale yellow solid was dried, providing 0.027 g of crude product. The crude material was purified using reverse phase chromatography eluting with a gradient of 0 to 90% ACN/water to give 0.007 g (7%) of the desired product. MS (ES+APCI) m/z=510 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.[OH:11][C:12]1[CH:20]=[C:19]2[C:15]([CH2:16][CH2:17][C:18]2=[O:21])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][O:11][C:12]2[CH:20]=[C:19]3[C:15]([CH2:16][CH2:17][C:18]3=[O:21])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1
Reactant: O=C1CCc2ccc(O)cc21
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(COc2ccc3c(c2)C(=O)CC3)cc1
Yield: 99.4 %

Procedure:
4-methoxybenzylchloride (9.19 mL, 67.5 mmol) was added to a mixture of 6-hydroxy-1-indanone (10 g, 67.5 mmol) and potassium carbonate (14 g, 101 mmol) in 15 mL DMF. The mixture was reacted at RT for 14 h. The reaction mixture was diluted with water and extracted with DCM. The organic layer was separated and the solvents were removed by evaporation. The residue was dissolved in DCM and filtered through a plug of activated basic alumina. 6-(4-Methoxy-benzyloxy)-indan-1-one (18 g, 99%) was obtained after evaporation of the filtrate. The material was taken to the next step without further purification.
Reaction SMILES: Cl.[C:2]1(=[O:20])[N:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([NH2:14])=[NH:13])[C:5](=[O:15])[C:4]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:3]12.C(N(CC)CC)C.Cl[C:29](=[CH2:32])[C:30]#[N:31]>CCO>[NH2:31][C:30]1[CH:29]=[CH:32][N:14]=[C:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][N:6]2[C:5](=[O:15])[C:4]3=[CH:16][CH:17]=[CH:18][CH:19]=[C:3]3[C:2]2=[O:20])[N:13]=1
Reactant: C=C(Cl)C#N
Reactant: N=C(N)CCCCCN1C(=O)c2ccccc2C1=O
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Nc1ccnc(CCCCCN2C(=O)c3ccccc3C2=O)n1

Procedure:
A mixture of 6-phthalimidohexanamidine hydrochloride (71.1 g.), triethylamine (170 ml.) and 2-chloroacrylonitrile (57.4 ml.) in EtOH (500 ml.) was heated under reflux for 2 hours. The solvent was evaporated and the residue was partitioned between EtOAc and 2 N aqueous HCl. The aqueous layer was basified with 10 N aqueous NaOH and the product was extracted with EtOAc, dried (MgSO4) and evaporated to dryness. The residual gum was dissolved in EtOAc and treated with excess of a solution of maleic acid in EtOAc. The precipitated solid was dissolved in water, basified with 10 N aqueous sodium hydroxide, extracted with EtOAc, the extract dried (MgSO4) and evaporated. The residual solid was triturated with acetonitrile to give 4-amino-2-(5-phthalimidopentyl)pyrimidine as a brown solid (37.9 g.), m.p. 101°-104°.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[N:6]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:23]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1.[Cl-].[Na+].O>[Cl:23][C:9]1[N:5]([CH2:4][CH2:3][O:2][CH3:1])[N:6]=[CH:7][C:8]=1[N+:10]([O-:12])=[O:11]
Reactant: COCCn1cc([N+](=O)[O-])cn1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COCCn1ncc([N+](=O)[O-])c1Cl
Temperature: -78 °C
Reaction time: 2.5 h
Yield: 83 %

Procedure:
To a solution of 1-(2-methoxyethyl)-4-nitro-1H-pyrazole (1 equiv) in THF (0.5 M) was added dropwise lithium bis(trimethylsilyl)amide (2.7 equiv) in THF (1.0 M) at −78° C. The reaction was stirred at −78° C. for 30 min before the addition of hexachloroethane (1.5 equiv) in THF (1.84 M). The reaction was stirred at −78° C. for 2.5 h before warming to room temperature. The reaction was diluted with brine and extracted with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography (10-20% ethyl acetate in petroleum ether) to afford the desired product as a yellow solid (83% yield). 1H NMR (400 MHz, CHLOROFORM-d1) δ ppm 8.13 (s, 1H), 8.08 (s, 1H), 4.31-4.28 (t, J=4.2 Hz, 2H), 3.74-3.72 (t, J=5.36 Hz, 2H), 3.37 (s, 3H).
Reaction SMILES: [Mg].[CH3:2]I.[CH3:4][C:5]1[CH2:10][CH2:9][C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[CH:6]=1.Cl>CCOCC.[Cu]I>[CH3:11][C:8]1([CH3:12])[CH2:9][CH2:10][C:5]([CH3:2])([CH3:4])[CH2:6][C:7]1=[O:13]
Reactant: CI
Reactant: CC1=CC(=O)C(C)(C)CC1
Agent: [Cu]I
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: CC1(C)CCC(C)(C)C(=O)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 76.2 %

Procedure:
5.3 g of magnesium shavings are covered with 100 ml of ether and 30.8 g of methyl iodide are added dropwise in such a manner that the mixture boils slightly. After the addition of 100 ml of ether, the mixture is held at reflux temperature for a further 3 hours, cooled by means of an ice-bath and treated with 20.7 g of copper (I) iodide. After stirring for 15 minutes at 0° C., a solution of 10 g of 3,6,6-trimethyl-2-cyclohexenone in 40 ml of ether is added and the mixture is stirred at 0° C. for a further 3 hours. The green suspension is subsequently poured on to ice, acidified with 2N hydrochloric acid and extracted with ether. The insoluble constituents of the organic phase are filtered off, the filtrate is washed with dilute sodium thiosulphate solution, dried and evaporated. After distillation of the crude product, there are obtained 8.5 g of 2,2,5,5-tetramethylcyclohexanone as a colourless liquid of boiling point 60°-67° C./13 mm Hg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].C1C=C(Cl)C=C(C(OO)=[O:37])C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([S:22]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:37])[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)cc(SC3CCCCC3)c2C)c(=O)[nH]1
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2cc(Cl)cc(S(=O)C3CCCCC3)c2C)c(=O)[nH]1
Temperature: 0 °C
Reaction time: 2 h
Yield: 81.4 %

Procedure:
To a stirred solution of 5-chloro-3-(cyclohexylthio)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide (0.2 g, 0.48 mmol) in DCM (7 mL) at 0° C., m-CPBA (0.098 g, 0.57 mmol) was added and stirred at 0° C. for 2 h. Reaction was monitored by TLC. After completion, the reaction mixture was diluted with DCM and washed with aqs. NaHCO3. The product was purified by solvent washings to afford the title compound (0.17 g, 82.3%).
Reaction SMILES: [CH3:1][C:2]([OH:8])([CH2:5][CH2:6][CH3:7])[C:3]#[CH:4].Br[C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1/[C:12](=[CH:20]/[C:21]1[NH:22][CH:23]=[CH:24][C:25]=1[O:26][CH3:27])/[C:13](=[O:19])[NH:14]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C.CCN(CC)CC>[OH:8][C:2]([CH3:1])([CH2:5][CH2:6][CH3:7])[C:3]#[C:4][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1/[C:12](=[CH:20]/[C:21]1[NH:22][CH:23]=[CH:24][C:25]=1[O:26][CH3:27])/[C:13](=[O:19])[NH:14]2
Reactant: C#CC(C)(O)CCC
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCC(C)(O)C#Cc1cccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method D above, 3-methyl-1-hexyn-3-ol (98 mg, 0.87 mmol) (Aldrich) was coupled with (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (Starting Material 1 supra) (127 mg, 0.4 mmol) using (Ph3P)2PdCl2 (46 mg) and Cul (22 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 70° C. for 22 h yielding rac-(Z)-1,3-dihydro-4-(3-hydroxy-3-methyl-1-hexynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 92 mg, 66%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=1)=O.[Br:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][CH:29]=O>>[Br:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[CH:29]=[N:1][C:2]2[C:3]([C:12]=1[C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1)=[CH:4][CH:5]=[CH:6][C:7]=2[C:8]([F:11])([F:10])[F:9]
Reactant: Nc1c(C(=O)c2cccc(O)c2)cccc1C(F)(F)F
Reactant: O=CCc1ccccc1Br
Product: Oc1cccc(-c2c(-c3ccccc3Br)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from [2-amino-3-(trifluoromethyl)phenyl]-(3-hydroxy-phenyl)methanone and (2-Bromo-phenyl)-acetaldehyde following the procedure of Example 457: MS (ES) m/z 441.8; HRMS: calcd for C22H13BrF3NO+H+, 444.02053; found (ESI, [M+H]+), 444.0191.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]2=[O:21].[F:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]3=[O:21])=[CH:25][CH:24]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(F)cc3)ccn2c1=O
Temperature: 80 °C
Yield: 82.1 %

Procedure:
A mixture of ethyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (120 mg, 0.400 mmol), 4-fluoro-phenyl boronic acid (67 mg, 0.48 mmol), (Ph3P)2PdCl2 (28 mg, 0.040 mmol), and Na2CO3 (190 mg in 0.8 mL of water, 1.80 mmol) in THF (5 mL) was degassed 3 times under N2 and heated to 80° C. overnight. The reaction mixture was diluted with ethyl acetate (50 mL), and washed with water (2×20 mL). The organic phase was separated, dried, and concentrated. The residue was purified by flash silica column chromatography (hexane:ethyl acetate, 1:2) to afford the title compound as a yellow solid (120 mg, 82%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:10](=[O:17])[C@@H:9]([CH2:18][C:19](O)=[O:20])[O:8][C@H:7]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])[C:6]=2[CH:29]=1.CN1CCOCC1.C(Cl)(=O)OCC.[BH4-].[Na+]>O1CCCC1.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:10](=[O:17])[C@@H:9]([CH2:18][CH2:19][OH:20])[O:8][C@H:7]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])[C:6]=2[CH:29]=1
Reactant: CC(C)(C)CN1C(=O)[C@@H](CC(=O)O)O[C@H](c2ccccc2Cl)c2cc(Cl)ccc21
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: CO
Product: CC(C)(C)CN1C(=O)[C@@H](CCO)O[C@H](c2ccccc2Cl)c2cc(Cl)ccc21
Reaction time: 0.25 h
Yield: 99.8 %

Procedure:
In 200 ml of tetrahydrofuran was dissolved 14.7 g of trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid obtained in Example 2 and 4.51 ml of N-methylmorpholine. To the solution was added 3.92 ml of ethyl chlorocarbonate at -10° C; the mixture was then stirred for 15 minutes. After the addition of 3.86 g of sodium borohydride, 200 ml of methanol was added dropwise to the solution. The mixture was stirred for one hour at room temperature and then concentrated. After the addition of 200 ml of 1N hydrochloric acid, the concentrate was extracted with 200 ml of ethyl acetate. The organic layer was washed with a saturated sodium bicarbonate aqueous solution and dried over anhydrous magnesium sulfate. The solvent was evaporated off under reduced pressure. The residue was purified by silica gel column chromatography (eluent, hexane:ethyl acetate=1:1) to yield 14.2 g of trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-ethanol as colorless crystals, m.p. 157° to 159° C.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][C@@H:27]4[CH2:32][CH2:31][NH:30][CH2:29][C@H:28]4[OH:33])=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1.C([O:37][CH2:38][C:39](Cl)=[O:40])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][C@@H:27]4[CH2:32][CH2:31][N:30]([C:38](=[O:37])[CH2:39][OH:40])[CH2:29][C@H:28]4[OH:33])=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@@H]1CCNC[C@H]1O
Agent: Cl
Product: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@@H]1CCN(C(=O)CO)C[C@H]1O

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-fluorophenyl]-N-[(3R*,4R*)-3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f16) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH2:8][C:9](O)=[O:10])=[C:5]([CH3:7])[N:6]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:1][C:2]1[S:3][C:4]([CH2:8][CH2:9][OH:10])=[C:5]([CH3:7])[N:6]=1
Reactant: Cc1nc(C)c(CC(=O)O)s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc(C)c(CCO)s1
Temperature: 25 °C
Reaction time: 6 h
Yield: 85.3 %

Procedure:
A solution of 2-(2,4-dimethylthiazol-5-yl)acetic acid (230 mg, 1.343 mmol) in dry THF (10 mL) was carefully added over 2 min to solution of 2M LAH (1.343 mL, 2.69 mmol) in dry THF (10 mL) at 0° C. The reaction mixture was allowed to warm to rt and was stirred for 6 h. The reaction was quenched with 0.2 mL of water (stir for 10 min), 0.2 mL of 15% NaOH/water (stir for 10 min), and then 0.4 mL of water. After stirring for 18 h, the mixture was filtered through celite. The filtrate was concentrated in vacuum. The residue was dried under high vacuum for 16 h to afford 2-(2,4-dimethylthiazol-5-yl)ethanol (180 mg, 1.145 mmol, 85% yield) as a clear viscous oil. 1H NMR (500 MHz, CDCl3) δ 3.83 (t, J=6.3 Hz, 2H), 2.97 (t, J=6.3 Hz, 2H), 2.64 (s, 3H), 2.35 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:13][CH:12]([C:14]([O:16]CC)=[O:15])[CH:11]([CH2:19][CH3:20])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:13][CH:12]([C:14]([OH:16])=[O:15])[CH:11]([CH2:19][CH3:20])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C1CC(NC(=O)OC(C)(C)C)CC1CC
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCC1CC(NC(=O)OC(C)(C)C)CC1C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.3 %

Procedure:
A 250 mL round-bottomed flask was charged with ethyl 4-(tert-butoxycarbonylamino)-2-ethylcyclopentanecarboxylate (3.00 g, 10.5 mmol) in THF (96 mL) to give a colorless solution. An aqueous solution of NaOH (1 N, 16.0 mL, 16.0 mmol) was added and the reaction mixture was stirred for about 24 h at ambient temperature. Additional aqueous NaOH (1 N, 5.00 mL, 5.00 mmol) was added and stirring was continued for about 48 h at room temperature. The reaction mixture was heated to about 50° C. for about 24 h. The solvent was removed under reduced pressure. AcOH was added until pH 5 was reached. EtOAc (50 mL) was added and the layers were partitioned. The aqueous layer was further extracted with EtOAc (2×30 mL). The combined organic extracts were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to give a yellow oil. The oil was further dried under high vacuum, resulting in formation of a solid that was dissolved in DCM and concentrated to dryness, re-suspended in DCM and re-concentrated to dryness. The residue was then suspended in Et2O and concentrated to dryness and further dried under vacuum for about 3 h to give 4-(tert-butoxycarbonylamino)-2-ethylcyclopentanecarboxylic acid (2.36 g, 87%): LC/MS (Table 2, Method a) Rt=2.09 min; MS m/z: 256 (M−H)−.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:36])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:33][CH3:34])[CH2:25][NH:26][S:27]([CH:30]([CH3:32])[CH3:31])(=[O:29])=[O:28])[C:5]1=[O:35])[CH:2]=[CH2:3].I[CH2:38][CH3:39]>>[CH2:1]([C@@:4]1([CH3:36])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@@H:24]([CH2:33][CH3:34])[CH2:25][N:26]([CH2:38][CH3:39])[S:27]([CH:30]([CH3:31])[CH3:32])(=[O:28])=[O:29])[C:5]1=[O:35])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CNS(=O)(=O)C(C)C)C1=O
Reactant: CCI
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CN(CC)S(=O)(=O)C(C)C)C1=O

Procedure:
The title compound was prepared from N-((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butyl)propane-2-sulfonamide (Example 183, Step A) by a procedure similar to the one described in Example 182, Step A, replacing iodomethane with iodoethane. MS (ESI) m/z=579 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14](=[O:26])[C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH3:25])[CH2:22][CH2:23][OH:24])=[CH:17][CH:16]=2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)([O-])=O.[O:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[CH:37][C:36]([NH:39][C:40]([C:42]3[CH:49]=[CH:48][C:45]([CH:46]=O)=[CH:44][CH:43]=3)=[O:41])=[CH:35][CH:34]=2)[CH2:29][CH2:28]1>>[OH:24][CH2:23][CH2:22][N:21]([CH3:25])[C:18]1[CH:19]=[CH:20][C:15]([C:14]([NH:13][C:6]2[CH:7]=[CH:8][C:9]3[NH:10][C:46]([C:45]4[CH:48]=[CH:49][C:42]([C:40](=[O:41])[NH:39][C:36]5[CH:37]=[CH:38][C:33]([N:30]6[CH2:29][CH2:28][O:27][CH2:32][CH2:31]6)=[CH:34][CH:35]=5)=[CH:43][CH:44]=4)=[N:1][C:4]=3[CH:5]=2)=[O:26])=[CH:16][CH:17]=1
Reactant: CN(CCO)c1ccc(C(=O)Nc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)cc1
Reactant: O=Cc1ccc(C(=O)Nc2ccc(N3CCOCC3)cc2)cc1
Product: CN(CCO)c1ccc(C(=O)Nc2ccc3[nH]c(-c4ccc(C(=O)Nc5ccc(N6CCOCC6)cc5)cc4)nc3c2)cc1

Procedure:
Compound 252 was prepared according to the procedure similar to that described in Scheme III from N-(3,4-dinitrophenyl)-4-(N-methyl-N-2-hydroxyethylamino)-benzamide and 4-(4-morpholinophenyl)aminocarbonylbenzaldehyde. [M+H]+ calcd for C34H34N6O4: 591.26; found: 591.06.