Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([CH3:14])([CH3:13])[C:8](OCC)=[O:9].[Li+].[BH4-].CO>C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([CH3:14])([CH3:13])[CH2:8][OH:9]
Reactant: CCOC(=O)C(C)(C)CCCCCBr
Agent: [BH4-]
Agent: [Li+]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(CO)CCCCCBr
Yield: 101.4 %

Procedure:
According to the method for the synthesis of 206e, 205g (43.0 g, 0.16 mol) was treated with LiBH4 (5.55 g±0.25 mol) and methanol (7.75 g, 0.24 mol) in CH2Cl2 (200 mL) to give 206g (36.2 g, 98%) as a colorless, viscous oil. 1H NMR (CDCl3): δ 3.41 (t, 2H, J=6.9), 3.30 (br. s, 2H), 1.90-1.84 (m, 3H), 1.42-1.22 (m, 6H), 0.86 (s, 6H). 13C NMR (CDCl3): δ 71.9, 38.6, 35.1, 34.1, 32.9, 29.2, 24.0, 23.2. HRMS (LSIMS, nba): Calcd for C9H28Br (MH+−H2O): 205.0592, found: 205.0563.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H](C(O)=O)CCC)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C@@H:20]([C:24]([OH:26])=O)[CH2:21][CH2:22][CH3:23].CC1(C)[C@@H](O)C(C)(C)[C@@H]1N>>[C:9]([NH:11][C:24](=[O:26])[C@H:20]([CH2:21][CH2:22][CH3:23])[NH2:19])([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: CCC[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCC[C@@H](N)C(=O)O
Agent: CC1(C)[C@H](N)C(C)(C)[C@H]1O
Product: CCC[C@H](N)C(=O)NC(=O)OCc1ccccc1

Procedure:
N-Benzyloxycarbonyl-D-norvaline (0.1 mole), prepared from commercial D-norvaline by the procedure of Example 19, is reacted with cis/trans 2,2,4,4-tetramethyl-3-hydroxycyclobutylamine by the method of Example 20, Part A, to provide the N-Cbz-norvaline amide.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[CH:32]=[CH:31][C:9]3[C:10]4[C:14]([CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)=[CH:13][N:12]([C:18]2[N:19]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])[N:20]=[CH:21][N:22]=2)[N:11]=4)[CH2:3]1.Br[CH2:34][C:35]([NH2:37])=[O:36].CO>C(Cl)Cl>[F:30][C:24]1[CH:25]=[C:26]([F:29])[CH:27]=[CH:28][C:23]=1[N:19]1[C:18]([N:12]2[N:11]=[C:10]3[C:14]([CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([CH:4]5[CH2:3][N:2]([CH2:34][C:35]([NH2:37])=[O:36])[CH2:5]5)[CH:32]=[CH:31][C:9]=43)=[CH:13]2)=[N:22][CH:21]=[N:20]1
Reactant: NC(=O)CBr
Reactant: Fc1ccc(-n2ncnc2-n2cc3c(n2)-c2ccc(C4CNC4)cc2OCC3)c(F)c1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: NC(=O)CN1CC(c2ccc3c(c2)OCCc2cn(-c4ncnn4-c4ccc(F)cc4F)nc2-3)C1

Procedure:
Following the procedure for 143, 8-azetidin-3-yl-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene hydrochloride was reacted with bromo acetamide, the crude product was subjected to flash chromatography (SiO2, gradient 0 to 10% MeOH in DCM) to give 172 as a white solid. 1H NMR (400 MHz, DMSO-d): δ 8.42 (s, 1 H); 8.28 (s, 1 H); 7.81 (td, J=8.75, 5.92 Hz, 1 H); 7.63 (ddd, J=10.33, 9.01, 2.79 Hz, 1 H); 7.39-7.27 (m, 2 H); 7.11 (s, 1 H); 7.03 (s, 1 H); 6.96-6.89 (m, 2 H); 4.23 (t, J=5.01 Hz, 2 H); 3.66 (t, J=7.02 Hz, 2 H); 3.62-3.52 (m, 1 H); 3.16 (t, J=6.65 Hz, 2 H); 3.10-2.98 (m, 4 H). LCMS: RT=7.00 min, M+H+=478
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH2:3][CH:2]1[C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=[O:10].N1C(C)=CC=CC=1C.[H][H]>[Pd].C1COCC1>[O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]1[CH:7]=[C:8]([CH2:9][OH:10])[CH:11]=[CH:12][CH:13]=1
Reactant: O=Cc1cccc(C2CC=CO2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: Cc1cccc(C)n1
Solvent: C1CCOC1
Product: OCc1cccc(C2CCCO2)c1
Yield: 70 %

Procedure:
EX-608C) A THF (15 mL) solution of the aldehyde from EX-608B (0.70 g, 4.0 mmol) and 2,6-lutidine (0.46 mL, 4.0 mmol) was stirred in a hydrogen atmosphere (50 psi) in the presence of 10% Pd/C (0.29 g) for 18 h at room temperature. The slurry was filtered through celite, and the solvent was removed. The residue was taken up in ethyl acetate and washed with 1 N HCl and brine. The organic layer was dried (MgSO4) and evaporated to give 0.50 g (70%) of the desired 3-(tetrahydro-2-furanyl)phenylmethanol product as a yellow oil. The formation of the desired product was monitored by the disappearance of the aldehyde (δ˜10) and olefin peaks in the 1H NMR spectrum.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@H:9]([CH3:26])[CH2:10][O:11][C:12]1[CH:25]=[CH:24][C:15]([CH2:16][CH:17]2[S:21][C:20](=[O:22])[NH:19][C:18]2=[O:23])=[CH:14][CH:13]=1.[Si:27]([O:34][C@H:35]([C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([Cl:44])[CH:39]=1)[CH:36]=O)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].C([BH3-])#N.[Na+]>CO>[Cl:44][C:40]1[CH:39]=[C:38]([C@@H:35]([O:34][Si:27]([C:30]([CH3:31])([CH3:33])[CH3:32])([CH3:29])[CH3:28])[CH2:36][NH:8][C@H:9]([CH3:26])[CH2:10][O:11][C:12]2[CH:25]=[CH:24][C:15]([CH2:16][CH:17]3[S:21][C:20](=[O:22])[NH:19][C:18]3=[O:23])=[CH:14][CH:13]=2)[CH:43]=[CH:42][CH:41]=1
Reactant: C[C@@H](N)COc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](C=O)c1cccc(Cl)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](COc1ccc(CC2SC(=O)NC2=O)cc1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 91.5 %

Procedure:
A mixture of 36.5 g of 5-{4-[2(R)-aminopropoxy]benzyl}thiazolidine-2,4-dione trifluoroacetate [prepared as described in Preparation 2], 98.4 g of (R)-α-(t-butyldimethylsilyloxy)-α-(3-chlorophenyl)acetaldehyde [prepared as described in Preparation 12] and 400 ml of absolute methanol was stirred at room temperature for 2.5 hours, after which the mixture was cooled using a salted ice-bath. 29.0 g of sodium cyanoborohydride were then added to the mixture in small portions, and the mixture was allowed to stand overnight at room temperature. At the end of this time, the methanol was distilled off under reduced pressure, the residue was mixed with water and ethyl acetate, and the ethyl acetate layer was separated from the mixture. The ethyl acetate layer was then washed with a saturated aqueous solution of sodium chloride, after which it was dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. The residue was purified by column chromatography through silica gel, using a 2:1 by volume mixture of ethyl acetate and hexane as the eluent, to give 46.5 g of the title compound.
Reaction SMILES: [Cl-].[CH2:2]([N+:4]1[C:9](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:14][CH:13]=2)=[CH:8][CH:7]=[CH:6][C:5]=1/[CH:23]=[CH:24]/[C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)=[CH:27][CH:26]=1)[CH3:3].[Na].[NH2:37][C:38]1[CH:46]=[CH:45][C:41]([C:42]([OH:44])=[O:43])=[CH:40][CH:39]=1>CO>[NH2:37][C:38]1[CH:46]=[CH:45][C:41]([C:42]([O-:44])=[O:43])=[CH:40][CH:39]=1.[CH2:2]([N+:4]1[C:9](/[CH:10]=[CH:11]/[C:12]2[CH:13]=[CH:14][C:15]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:16][CH:17]=2)=[CH:8][CH:7]=[CH:6][C:5]=1/[CH:23]=[CH:24]/[C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:32][CH2:33][CH2:34][CH2:35]2)=[CH:27][CH:26]=1)[CH3:3]
Reactant: Nc1ccc(C(=O)O)cc1
Agent: CC[n+]1c(/C=C/c2ccc(N3CCCC3)cc2)cccc1/C=C/c1ccc(N2CCCC2)cc1
Agent: [Cl-]
Agent: [Na]
Solvent: CO
Product: Nc1ccc(C(=O)[O-])cc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A total of 52.8 g (0.12 mole) of 1-ethyl-(E,E)-2,6-bis[2-[4-(pyrrolidinyl)phenyl]ethenyl]pyridinium chloride and 18.6 grams (0.12 mole) of the sodium salt of 4-aminobenzoic acid (sodium salt of p-aminobenzoic acid, Na+ PABA−) were dissolved in 1.3 liters of methanol and this mixture was allowed to stir at room temperature for 4 days during which time a precipitate formed. The reaction mixture was then filtered and the solid salt was air dried and vacuum dried to yield a first crop of 28.0 grams of 1-ethyl-(E,E)-2,6-bis[2-[4-(pyrrolidinyl)phenyl]ethenyl]pyridinium 4-aminobenzoate salt (also termed the PABA salt). The filtrate was concentrated under vacuum to produce more precipitate. Isolation of the second crop was effected by filtration followed by air drying and vacuum drying of the solid to afford a second crop of 42.6 grams of 1-ethyl-(E,E)-2,6-bis[2-[4-(pyrrolidinyl)phenyl]ethenyl]pyridinium 4-aminobenzoate salt (also termed the PABA salt)—high performance liquid chromatography area percent (HPLC A %) first crop=99.6% excluding PABA; HPLC A % second crop=99.9% excluding PABA; 1H NMR and Mass Spectral analyses for both crops were consistent with structure of the desired material 1-ethyl-(E,E)-2,6-bis[2-[4-(pyrrolidinyl)phenyl]ethenyl]pyridinium 4-aminobenzoate salt. This product is also named 1-ethyl-(E,E)-2,6-bis[2-[4-(pyrrolidinyl)phenyl]ethenyl]pyridinium p-aminobenzoate salt or 1-ethyl-(E,E)-2,6-bis[2-[4-(pyrrolidinyl)phenyl]ethenyl]pyridinium PABA salt.
Reaction SMILES: COC[O:4][C:5]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:6]=1[CH2:7][OH:8].OS(O)(=O)=O>CO>[OH:8][CH2:7][C:6]1[CH:9]=[C:10]([C:13]([F:15])([F:16])[F:14])[CH:11]=[CH:12][C:5]=1[OH:4]
Reactant: COCOc1ccc(C(F)(F)F)cc1CO
Agent: O=S(=O)(O)O
Solvent: CO
Product: OCc1cc(C(F)(F)F)ccc1O
Yield: 97.6 %

Procedure:
To the solution of 2-methoxymethoxy-5-(trifluoromethyl)benzyl alcohol (3.15 g) from Example 60 in methanol (20 ml) was added 10% H2SO4 (5 ml) for reflux under heating for 1 hour. The solvent was removed under reduced pressure. To the residue was added water, the aqueous layer was extracted with ether. The ether layer was washed with water and saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, to give the title compound (2.5 g; 98%).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:16]3[CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[C:28]([N:20]1[CH2:21][C:16]2[C:15]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)=[N:14][C:13]([C:10]3[CH:11]=[CH:12][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:8][CH:9]=3)=[N:18][C:17]=2[CH2:19]1)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CNC3)cc1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CN(C(=O)c2ccccc2)C3)cc1

Procedure:
Compound ed was prepared according to the procedure described in Example 5 by reacting 1-ethyl-3-(4-(4-morpholino-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea with benzoyl chloride. LC-MS: m/z=+501 (M+H)+.
Reaction SMILES: [NH2:1][C:2](=[O:22])[C@H:3]([NH:11]C(=O)OCC1C=CC=CC=1)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CO.[Pd]>[NH2:11][C@@H:3]([C:2]([NH2:1])=[O:22])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: NC(=O)[C@@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: NC(=O)[C@H](N)Cc1ccccc1
Reaction time: 16 h
Yield: 98.4 %

Procedure:
A mixture of (R)-benzyl 1-amino-1-oxo-3-phenylpropan-2-ylcarbamate (910 mg, 3.05 mmol) and Pd—C (10%, 200 mg) in MeOH (20 mL) was hydrogenated under balloon H2 for 16 h. It was filtered through celite. The filtrate was concentrated in vacuo to give D-phenylalanine amide as a white solid (493 mg).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:5][CH:4]=[C:3]1[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([O:23][CH2:24][C:25]#[N:26])[CH:17]=[CH:16]2.[Cl-].[NH4+].[N-:29]=[N+:30]=[N-:31].[Na+]>CN(C=O)C>[CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[CH:5][CH:4]=[C:3]1[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([O:23][CH2:24][C:25]1[NH:31][N:30]=[N:29][N:26]=1)[CH:17]=[CH:16]2
Reactant: [N-]=[N+]=[N-]
Reactant: Cn1c(-c2ccccc2)ccc1-c1ccc2cc(OCC#N)ccc2c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(-c2ccccc2)ccc1-c1ccc2cc(OCc3nnn[nH]3)ccc2c1

Procedure:
In a similar manner as described in step 2 of Example 3, the title compound was prepared from {[6-(1-methyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}acetonitrile (0.20 g, 0.48 mmol), prepared in the previous step, ammonium chloride (0.077 g, 1.44 mmol) and sodium azide (0.094 g, 1.44 mmol) in DMF (10 mL). The precipitated solids were isolated by vacuum filtration to give 5-({[6-(1-methyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}methyl)-1H-tetraazole. as a white solid (0.228 g, 81%), mp 231–233° C. (dec). Elemental Analysis for C23H19N5O.0.34 H2O.0.07 C3H7NO Calc'd: C, 70.99; H, 5.18; N, 18.08. Found: C, 70.84; H, 5.07; N, 18.18.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6](Br)[N:5]=1)=[N+:2]=[N-:3].N(C1C=CC=C(F)N=1)=[N+]=[N-].N(C1C=CC=C(C(F)(F)F)N=1)=[N+]=[N-].N(C1C=NC=C(C(F)(F)F)C=1)=[N+]=[N-].N(C1C([Cl:56])=C(Cl)N=C(Cl)C=1Cl)=[N+]=[N-]>>[N:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:56])[N:5]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1c(Cl)c(Cl)nc(Cl)c1Cl
Reactant: [N-]=[N+]=Nc1cccc(Br)n1
Agent: [N-]=[N+]=Nc1cccc(C(F)(F)F)n1
Agent: [N-]=[N+]=Nc1cccc(F)n1
Agent: [N-]=[N+]=Nc1cncc(C(F)(F)F)c1
Product: [N-]=[N+]=Nc1cccc(Cl)n1

Procedure:
The following were prepared analogously and analyzed by nmr spectroscopy: 2-azido-6-bromopyridine, m.p. 106°-110° C.; 2-azido-6-fluoropyridine, m.p. 45°-48° C.; 2-azido-6-(trifluoromethyl)pyridine, brown oil; 3-azido-5-(trifluoromethyl)pyridine, dark oil; 4-azido-2,3,5,6-tetrachloropyridine, light brown solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:11]([F:14])([F:13])[F:12])=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1>CO.[Ni]>[Cl:1][C:2]1[C:3]([C:11]([F:12])([F:13])[F:14])=[C:4]([CH2:8][CH2:9][NH2:10])[CH:5]=[CH:6][CH:7]=1
Reactant: N#CCc1cccc(Cl)c1C(F)(F)F
Agent: [Ni]
Solvent: CO
Product: NCCc1cccc(Cl)c1C(F)(F)F
Reaction time: 8 h
Yield: 14.8 %

Procedure:
To a solution of 2-(3-chloro-2-(trifluoromethyl)phenyl)acetonitrile (0.10 g, 3.03 mmol) in MeOH (5 mL) was added Raney-nickel (100 mg). The mixture was degassed under vacuum for 10 min, and then hydrogenated under a fully-inflated balloon at room temperature overnight. The mixture was filtered through a pad of celite and the cake was washed with MeOH (10 mL). The filtrate was concentrated under vacuum to give the crude product (100 mg). MS (ESI) m/z 224.1 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:9][CH2:10][C:11]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])[CH:8]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[N:6][N:7]([CH2:9][CH2:10][C:11]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])[CH:8]=1
Reactant: O=C(CCn1cc([N+](=O)[O-])cn1)N1CCCCC1
Agent: [Pd]
Solvent: CO
Product: Nc1cnn(CCC(=O)N2CCCCC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(4-nitro-1H-pyrazol-1-yl)-1-(piperidin-1-yl)propan-1-one (4.4 mmol) was dissolved in 5 mL methanol and palladium on carbon added under an inert atmosphere. The reaction mixture was stirred overnight at rt under hydrogen atmosphere. The resulting mixture was filtered through Celite and the filtrate concentrated in vacuo to give 3-(4-amino-1H-pyrazol-1-yl)-1-(piperidin-1-yl)propan-1-one in a quantitative yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([CH3:22])[N:13]([CH2:14][C:15]([OH:17])=O)[C:12](=[O:18])[N:11]([CH2:19][CH3:20])[C:10]2=[O:21])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:23][C:24]1[CH:25]=[C:26]2[C:39](=[CH:40][CH:41]=1)[CH2:38][C@:28]1([C:36]3[C:31](=[N:32][CH:33]=[CH:34][CH:35]=3)[NH:30][C:29]1=[O:37])[CH2:27]2.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(N(CC)C(C)C)(C)C>CN(C=O)C>[F:8][C:6]1[CH:5]=[C:4]([C:9]2([CH3:22])[N:13]([CH2:14][C:15]([NH:23][C:24]3[CH:25]=[C:26]4[C:39](=[CH:40][CH:41]=3)[CH2:38][C@:28]3([C:36]5[C:31](=[N:32][CH:33]=[CH:34][CH:35]=5)[NH:30][C:29]3=[O:37])[CH2:27]4)=[O:17])[C:12](=[O:18])[N:11]([CH2:19][CH3:20])[C:10]2=[O:21])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CCN1C(=O)N(CC(=O)O)C(C)(c2cc(F)cc(F)c2)C1=O
Reactant: Nc1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN1C(=O)N(CC(=O)Nc2ccc3c(c2)C[C@@]2(C3)C(=O)Nc3ncccc32)C(C)(c2cc(F)cc(F)c2)C1=O
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A mixture of [5-(3,5-difluorophenyl)-5-methyl-2,4-dioxo-3-ethylimidazolidin-1-yl]acetic acid, isomer A (18 mg, 0.058 mmol, described in Intermediate 17), (R)-5-amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (14 mg, 0.058 mmol, described in Intermediate 3), HOBT (13 mg, 0.086 mmol), EDC (17 mg, 0.086 mmol), and N,N-diisopropylethylamine (0.050 mL, 0.29 mmol) in DMF (0.5 mL) was stirred at 50° C. for 2 h. The reaction mixture was purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. Lyophilization provided the title compound. MS: m/z=546 (M+1). HRMS: m/z=546.1944; calculated m/z=546.1948 for C29H26F2N5O4.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][CH2:10][O:11][C:7]=2[CH:6]=[C:5]([CH:12]=[O:13])[CH:4]=1.[CH3:14][Mg]Cl>C1COCC1>[CH3:1][O:2][C:3]1[C:8]2[O:9][CH2:10][O:11][C:7]=2[CH:6]=[C:5]([CH:12]([OH:13])[CH3:14])[CH:4]=1
Reactant: C[Mg]Cl
Reactant: COc1cc(C=O)cc2c1OCO2
Solvent: C1CCOC1
Product: COc1cc(C(C)O)cc2c1OCO2
Yield: 45 %

Procedure:
A solution of 7-Methoxy-benzo[1,3]dioxole-5-carbaldehyde (I) (1.8 g, 10 mmol) in THF (20 mL) was cooled to −78° C. A solution of methylmagnesium chloride in THF (5.0 mL of 3M, 15 mmol) was added to the solution of i in THF in a dropwise fashion. The reaction was quenched by the addition of HCl (1N, aqueous) and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel; 40%-60% ethyl acetate in hexanes) to afford 2 (0.89 g, 45%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][N:10]2[C:18]3[CH:17]=[CH:16][C:15]([C:19](O)=[O:20])=[CH:14][C:13]=3[C:12]3[CH2:22][N:23]([CH3:26])[CH2:24][CH2:25][C:11]2=3)=[CH:4][CH:3]=1.C[CH2:28][N:29]=C=NCCCN(C)C.Cl.CN.C1COCC1>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][N:10]2[C:18]3[CH:17]=[CH:16][C:15]([C:19]([NH:29][CH3:28])=[O:20])=[CH:14][C:13]=3[C:12]3[CH2:22][N:23]([CH3:26])[CH2:24][CH2:25][C:11]2=3)=[CH:6][CH:7]=1
Reactant: CN1CCc2c(c3cc(C(=O)O)ccc3n2C#Cc2ccc(F)cc2)C1
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc2c(c1)c1c(n2C#Cc2ccc(F)cc2)CCN(C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-(4-Fluoro-phenylethynyl)-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxylic acid (20 mg, 0.0044 mmol) was dissolved in DMF and EDCI.HCl (42.17 mg, 0.22 mmol) was added. Methyl amine (2.0 M) in THF (0.0446 mL, 0.0089 mmol) was added. The reaction mixture was stirred at RT overnight. The progress of reaction was monitored by TLC and LCMS. The DMF was evaporated under vacuum and the product purified by HPLC. 1H NMR (CD3OD, TFA salt) δ (ppm): 8.05 (s, 1H), 7.82 (d, 1H), 7.62 (m, 3H), 7.20 (t, 2H), 4.40 (m, 1H), 3.70 (m, 1H), 3.38 (m, 4H), 3.20 (s, 3H), 2.90 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:23])([CH3:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=[CH:11][C:10]=1[CH2:24][CH2:25][C:26](=[O:28])[CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[BH4-].[Na+].[Cl-].[Na+]>CCOCC>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:22])([CH3:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=[CH:11][C:10]=1[CH2:24][CH2:25][CH:26]([OH:28])[CH3:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCC(C)(C)c1ccc(CCC(C)=O)c(OCc2ccccc2)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: CCCCCCC(C)(C)c1ccc(CCC(C)O)c(OCc2ccccc2)c1
Reaction time: 0.5 h
Yield: 84 %

Procedure:
To a -15° C. solution of 0.5 g. (1.31 mmols.) of 4-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-2-butanone in 5 ml. of methanol was added 50 mg. (1.31 mmols.) of sodium borohydride. The reaction mixture was stirred for 30 minutes and then added to 100 ml. of saturated sodium chloride 150 ml. ether. The ether extract was washed once with 100 ml. of saturated sodium chloride, dried over magnesium sulfate and evaporated in an oil. The oil was purified via column chromatography on 100 g. of silica gel eluted with 1:1 ether:cyclohexane to yield 419 mg. (84%) of the title compound as an oil.
Reaction SMILES: [F:1][C:2]1[C:11]([C:12](=[O:29])[CH2:13][N:14]2[CH2:19][CH2:18][C:17]([OH:28])([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=3)[CH2:16][CH2:15]2)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:30])[NH:7]2.[BH4-].[Na+].O>C(O)C>[F:1][C:2]1[C:11]([CH:12]([OH:29])[CH2:13][N:14]2[CH2:15][CH2:16][C:17]([OH:28])([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=3)[CH2:18][CH2:19]2)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:30])[NH:7]2
Reactant: COc1cccc(C2(O)CCN(CC(=O)c3ccc4c(c3F)CCC(=O)N4)CC2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1cccc(C2(O)CCN(CC(O)c3ccc4c(c3F)CCC(=O)N4)CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.4 %

Procedure:
The mixture of 5-Fluoro-6-[[4-hydroxy-4-(3-methoxyphenyl)-1-piperidinyl]acetyl]-3,4-dihydroquinolin-2(1H)-one (630 mg, 1.5 mmol) and sodium borohydride (57 mg, 1.5 mmol) in ethanol (17 ml) was stirred at room temperature overnight. To the mixture was added water and extracted with dichloromethane. The extract was dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (dichloromethane/methanol=10/1) to afford 5-Fluoro-6-[1-hydroxy-2-[4-hydroxy-4-(3-methoxyphenyl)-1-piperidinyl]ethyl]-3,4-dihydroquinolin-2(1H)-one as a yellow solid (220 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[S:13](=[O:15])(=[O:14])[N:12]([CH2:16][C:17]([OH:19])=O)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH:21]12[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]3)[CH:22]1[NH2:31])[CH2:28]2.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH:21]12[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]3)[CH:22]1[NH:31][C:17](=[O:19])[CH2:16][N:12]1[S:13](=[O:14])(=[O:15])[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9][CH2:10][CH2:11]1)[CH2:28]2
Reactant: CC(C)(C)OC(=O)N1CCCN(CC(=O)O)S1(=O)=O
Reactant: NC1C2CC3CC(C2)CC1C3
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCN(CC(=O)NC2C3CC4CC(C3)CC2C4)S1(=O)=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 6.1 %

Procedure:
To a solution of 2-(6-(tert-butoxycarbonyl)-1,1-dioxido-1,2,6-thiadiazinan-2-yl)acetic acid (60 mg, 0.204 mmol) in CH2Cl2 (5 mL), were added 2-adamantan amine HCl (57.5 mg, 0.306 mmol), TEA (41.3 mg, 0.408 mmol) and EDCI (117.3 mg, 0.612 mmol). The reaction mixture was agitated for 5 hr at room temperature and extracted using CH2Cl2 and brine. The organic layer was dried over MgSO4. The residue was purified by silica gel column chromatography to give tert-butyl 6-(2-(adamantan-2-yl amino)-2-oxoethyl)-1,2,6-thiadiazinan-2-carboxylate 1,1-dioxide (5.30 mg, 35%). 1H NMR (300 MHz, CDCl3): δ 6.90 (brd, 1H), 4.06 (m, 1H), 4.00 (t, J=5.8 Hz, 2H), 3.83 (s, 2H), 3.66 (t, J=5.8 Hz, 2H), 1.92-1.63 (m, 15H), 1.52 (s, 9H).