Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9](B2OC(C)(C)C(C)(C)O2)[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].Br[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][C:26]=1[CH:27]([OH:29])[CH3:28].C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[OH:29][CH:27]([C:26]1[CH:25]=[CH:24][N:23]=[CH:22][C:21]=1[C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[C:3]([O:2][CH3:1])[CH:10]=1)[CH3:28]
Reactant: CC(O)c1ccncc1Br
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1C#N
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(-c2cnccc2C(C)O)ccc1C#N
Temperature: 100 °C
Yield: 66.8 %

Procedure:
To the solution of 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (3.53 g, 13.61 mmol), 1-(3-bromopyridin-4-yl)ethanol (2.50 g, 12.37 mmol) and PdCl2(dppf). CH2Cl2 adduct (505 mg, 0.62 mmol) in DMF (60 mL) was added 2M Na2CO3 solution (12.3 ml, 24.6 mmol) under Nitrogen atmosphere. The mixture was stirred and heated at 100° C. for 4 hrs. After letting cool to room temperature, solvent was removed in vacuo. The resulting residue was dissolved in DCM and saturated NH4Cl solution. After extraction and separation, the extracts were concentrated and purified by ISCO 40 g (10% MeOH/DCM=0-25%) to give 4-(4-(1-hydroxyethyl)pyridin-3-yl)-2-methoxybenzonitrile (2.1 g, 67%) as a white solid; ESI-MS m/z: 255 [M+1]+, Retention time 1.24 min. 1H-NMR (MeOD, 400 MHz) δ 1.36 (d, J=6.4 Hz, 3H), 3.98 (s, 3H), 4.88 (q, J=6.4 Hz, 1H), 7.06 (dd, J=8.0, 1.2 Hz, 1H), 7.18 (s, 1H), 7.71 (d, J=5.2 Hz, 1H), 7.73 (d, J=1.2 Hz, 1H), 8.36 (s, 1H), 8.58 (d, J=5.2 Hz, 1H). The racemate was separated by HPLC (ChiralPak IA-H, 5% MeOH/5% EtOH/Heptane) to give 4-[4-((R)-1-Hydroxy-ethyl)-pyridin-3-yl]-2-methoxy-benzonitrile 14-(enantiomer-1) retention time: 16.18 min) and 4-[4-((S)-1-Hydroxy-ethyl)-pyridin-3-yl]-2-methoxy-benzonitrile 14-(enantiomer-2), retention time: 19.07 min).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[CH2:7][C:8]([OH:10])=O.[CH2:11]([C@@H:18]1[NH:23][CH2:22][CH2:21][N:20]([C:24]2[CH:32]=[C:31]3[C:27]([C:28]([CH2:36][CH3:37])=[N:29][N:30]3[CH:33]([CH3:35])[CH3:34])=[CH:26][CH:25]=2)[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([C@H:18]1[CH2:19][N:20]([C:24]2[CH:32]=[C:31]3[C:27]([C:28]([CH2:36][CH3:37])=[N:29][N:30]3[CH:33]([CH3:34])[CH3:35])=[CH:26][CH:25]=2)[CH2:21][CH2:22][N:23]1[C:8](=[O:10])[CH2:7][C:2]1[N:1]=[CH:6][CH:5]=[CH:4][N:3]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(O)Cc1ncccn1
Reactant: CCc1nn(C(C)C)c2cc(N3CCN[C@@H](Cc4ccccc4)C3)ccc12
Product: CCc1nn(C(C)C)c2cc(N3CCN(C(=O)Cc4ncccn4)[C@@H](Cc4ccccc4)C3)ccc12
Yield: 64 %

Procedure:
Prepared by the method outlined for Example 189 using 2-(pyrimidin-2-yl)acetic acid and 6-((S)-3-benzyl-piperazin-1-yl)-1-isopropyl-3-ethyl-1H-indazole as starting materials. Product was obtained as a colorless solid (64%). LC/MS (Method B) 3.7 min, [M+1]+ 483.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1>>[Cl:11][C:12]1[CH:17]=[C:16]([C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[CH:7][NH:8]3)=[CH:4][CH:3]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: Brc1ccc2cc[nH]c2c1
Product: Clc1cccc(-c2ccc3cc[nH]c3c2)c1

Procedure:
Prepared by Procedure I and Scheme T using 6-bromo-1H-indole and 3-chlorophenylboronic acid: ESMS m/e: 227.9 (M+H)+.
Reaction SMILES: [NH2:1][C:2]([C:9]1([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10]1)=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].C([BH3-])#N.[Na+].C([O-])(=O)C.[NH4+].C(O)(=O)C>C(O)C>[NH2:1][CH:2]([C:9]1([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[CH2:10][CH2:11][CH2:12]1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C=C(N)C1(c2ccc(Cl)cc2)CCC1
Agent: CC(=O)[O-]
Agent: [BH3-]C#N
Agent: [NH4+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)CC(N)C1(c2ccc(Cl)cc2)CCC1
Reaction time: 120 h

Procedure:
A solution of ethyl 3-amino-3-[1-(4-chlorophenyl)cyclobutyl]acrylate (90 g), sodium cyanoborohydride (36 g), ammonium acetate (27 g) and acetic acid (60 ml) in ethanol (1.5 liters) was allowed to stand at room temperature for 5 days and then concentrated to 600 ml and poured into water (2.5 liters). The aqueous solution was basified, extracted with ether and the ether extract back extracted with 2N hydrochloric acid. The acidic aqueous extract was cooled with ice, basified and extracted with ether and the extract dried and evaporated to give ethyl 3-amino-3-[1-(4-chlorophenyl)cyclobutyl]propanoate.
Reaction SMILES: [CH2:1]([CH:3]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:13])[CH3:2].Br[CH2:15][CH2:16][CH2:17][CH2:18][Cl:19]>>[Cl:19][CH2:18][CH2:17][CH2:16][CH2:15][C:3]1([CH2:1][CH3:2])[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:13]
Reactant: ClCCCCBr
Reactant: CCC1C(=O)Nc2cc(F)ccc21
Product: CCC1(CCCCCl)C(=O)Nc2cc(F)ccc21

Procedure:
The title compound is prepared according to process E starting from 3-ethyl-6-fluoro-1,3-dihydro-2H-indol-2-one and 1-bromo-4-chloro-butane.
Reaction SMILES: C(OC(N(C)[C@@H](C)C(N[C@@H](C(C)(C)C)C(N1C[C@@H]([C:21]2[CH:30]=[C:29]3[C:24]([CH2:25][C@@H:26]([C:52](=[O:64])[NH:53][C@H:54]4[C:63]5[C:58](=CC=CC=5)CCC4)[N:27]([C:31](=[O:51])[C@@H](NC(=O)[C@@H](N(C(OC(C)(C)C)=O)C)C)C(C)(C)C)C3)=[CH:23][CH:22]=2)C[C@H]1C(N[C@@H](CC1C=CC=CC=1)C(O)=O)=O)=O)=O)=O)(C)(C)C.[C:85]([O:89]C(N[C@@H](CC1C=CC=CC=1)C(O)=O)=O)([CH3:88])([CH3:87])[CH3:86].C(N)C#C>>[O:64]=[C:52]([NH:53][CH2:54][C:63]#[CH:58])[C@@H:26]([NH:27][C:31](=[O:51])[O:89][C:85]([CH3:88])([CH3:87])[CH3:86])[CH2:25][C:24]1[CH:23]=[CH:22][CH:21]=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: C[C@@H](C(=O)N[C@H](C(=O)N1C[C@@H](c2ccc3c(c2)CN(C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(C)(C)C)[C@H](C(=O)N[C@@H]2CCCc4ccccc42)C3)C[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)O)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Agent: C#CCN
Product: C#CCNC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Yield: 99 %

Procedure:
Following a procedure analogous to that for the synthesis of Compound D of Example 1, (S)-2-((tert-butoxycarbonyl)amino)-3-phenylpropanoic acid (Aldrich, 355 mg, 1.34 mmol) and prop-2-yn-1-amine (Combi-Blocks, 86 μL, 1.34 mmol) were converted to the title compound (401 mg, 99%). 1H NMR (CDCl3) δ 7.39-7.16 (m, 5H), 6.01 (br s, 1H), 4.97 (br s, 1H), 4.33 (d, J=7.0 Hz, 1H), 4.07-3.84 (m, 2H), 3.08 (d, J=6.8 Hz, 2H), 2.20 (t, J=2.5 Hz, 1H), 1.47-1.33 (m, 9H); MS (ESI+) m/z 303.3 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:23].O1CCOCC1>O1CCOCC1>[ClH:23].[ClH:23].[N:11]1([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][N:15]=2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)O)cn2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)c1ccc(N2CCNCC2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-[4-(tert-Butoxycarbonyl)piperazin-1-yl]nicotinic acid (934 mg) was dissolved in dioxane (12 ml), and 4 M hydrogen chloride/dioxane (7 ml) was added thereto, followed by stirring at room temperature overnight. The precipitated solid was collected by filtration to obtain 6-piperazin-1-yl nicotinic acid dihydrochloride (850 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([O:18]CC2C=CC=CC=2)=[CH:14][CH:13]=1>[Pd].C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1
Reactant: COC(=O)c1ccc(-c2ccc(OCc3ccccc3)cc2)c(Cl)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2ccc(O)cc2)c(Cl)c1
Temperature: 20 °C
Reaction time: 24 h
Yield: 99.1 %

Procedure:
The mixture of 286 mg of the product of Stage B, 91 mg of 9.5% palladium on charcoal and 20 ml of ethyl acetate was placed under a hydrogen atmosphere and the mixture was stirred at 20° C. for 24 hours. After filtration and concentration under reduced pressure, 211 mg of the expected product were obtained.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[N:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.F[C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[F:11][C:2]([F:1])([F:10])[C:3]1[N:8]=[CH:7][C:6]([O:9][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=2)=[CH:5][CH:4]=1
Reactant: Oc1ccc(C(F)(F)F)nc1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(Oc2ccc(C(F)(F)F)nc2)cc1
Temperature: 130 °C
Yield: 100 %

Procedure:
To a solution of 6-(trifluoromethyl)-3-pyridinol (2 g, 12.26 mmol) and 4-fluorobenzaldehyde (1.315 ml, 12.26 mmol) in DMF (50 mL), was added K2CO3 (2.54 g, 18.39 mmol). The mixture was heated at 130° C. overnight. After cooling, the reaction mixture was diluted in water, extracted with EA. The organic phase was washed with water and brine, dried over Na2SO4, concentrated to afford the title compound (3.28 g, 12.26 mmol, 100% yield) as a brown oil. LCMS: rt=3.16 min, [M+H+]=268
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24]C)=[O:23])=[CH:17][CH:16]=1.O.[OH-].[Li+].O1CCCC1.Cl>CO.O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][C:22]([OH:24])=[O:23])=[CH:19][CH:20]=1
Reactant: COC(=O)Cc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
A mixture of methyl 4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenylacetate (23.2 g), lithium hydroxide monohydrate (4.33 g), tetrahydrofuran (100 ml), water (60 ml) and methanol (40 ml) was stirred at room temperature for 1 hour. 1N hydrochloric acid (103 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The remaining crystals were recrystallized from acetone to obtain 4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenylacetic acid (21.9 g, yield 98%). m.p. 181-183° C.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]([NH2:10])OCC)C.[Br:12][C:13]1[CH:21]=[CH:20][C:16]([CH2:17][NH:18][NH2:19])=[CH:15][CH:14]=1>>[NH2:10][C:6]1[NH:19][N:18]([CH2:17][C:16]2[CH:20]=[CH:21][C:13]([Br:12])=[CH:14][CH:15]=2)[C:4](=[O:3])[CH:5]=1
Reactant: NNCc1ccc(Br)cc1
Reactant: CCOC(=O)C=C(N)OCC
Product: Nc1cc(=O)n(Cc2ccc(Br)cc2)[nH]1

Procedure:
17.5 g of β-amino-β-ethoxyacrylic acid ethyl ester and 20 g of 4-bromobenzylhydrazine, on stirring for 5 hours in alcohol at 50° and working up as described in Example 1, yield 15.6 g of the compound identified above, corresponding to 58% of theory, as colorless crystals of melting point 139°.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[C:10]([O:11][CH2:12][CH2:13][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH3:15])=[C:9]([O:23][CH3:24])[C:8]([Cl:25])=[C:7]([CH3:26])[C:6]=1[C:27](=[O:29])[CH3:28].Cl.[F:31][C:32]1([F:36])[CH2:35][NH:34][CH2:33]1>>[Cl:25][C:8]1[C:7]([CH3:26])=[C:6]([C:27](=[O:29])[CH3:28])[C:5]([O:4][CH2:3][CH2:2][N:34]2[CH2:35][C:32]([F:36])([F:31])[CH2:33]2)=[C:10]([O:11][CH2:12][CH2:13][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH3:15])[C:9]=1[O:23][CH3:24]
Reactant: FC1(F)CNC1
Reactant: COc1c(Cl)c(C)c(C(C)=O)c(OCCBr)c1OCCC(C)c1ccc(F)cc1
Agent: Cl
Product: COc1c(Cl)c(C)c(C(C)=O)c(OCCN2CC(F)(F)C2)c1OCCC(C)c1ccc(F)cc1
Yield: 37 %

Procedure:
Example 8a (102 mg, 0.21 mmol) was reacted with 3,3-difluoroazetidine hydrochloride (2.6 eq.) as described under General Procedure K and the crude mixture was purified by flash chromatography (silica gel, hexane/Et2O 60:40) to afford the title compound as a pale yellow oil (39 mg, 37%). 1H NMR (300 MHz, CDCl3) δ7.20-7.17 (m, 2H), 7.01-6.95 (m, 2H), 3.98-3.91 (m, 4H), 3.83 (s, 3H), 3.62 (t, J=12.0 Hz, 4H), 2.99 (m, 1H), 2.80 (t, J=5.6 Hz, 2H), 2.50 (s, 3H), 2.18 (s, 3H), 2.07-2.01 (m, 2H), 1.30 (d J=6.9 Hz, 3H). MS (ES+) m/z 500.1 (M+H+).
Reaction SMILES: [O:1]=[S@:2]1[N:6]2[CH2:7][CH2:8][CH2:9][CH:5]2[CH2:4][O:3]1.C(OCC)(=[O:12])C>O>[O:1]=[S:2]1(=[O:12])[N:6]2[CH2:7][CH2:8][CH2:9][C@@H:5]2[CH2:4][O:3]1
Reactant: O=[S@@]1OCC2CCCN21
Reactant: CCOC(C)=O
Solvent: O
Product: O=S1(=O)OC[C@H]2CCCN21
Reaction time: 1 h

Procedure:
The (R)-1-oxo-3a,4,5,6-tetrahydropyrrolo[1,2-c][1,2,3]oxathiazolidine, from the previous step, and 20 mL ethyl acetate were added to a 50 mL round bottom flask equipped with a magnetic stirrer. A catalytic amount of RuCl3.3H2O (a few mg) was added, followed by NaIO4 (3.17 g; 14.82 mmol) in 10 mL water. The mixture was stirred vigorously for one hour. The phases were separated, and the aqueous phase was extracted with three portions (10 mL each) ethyl acetate. The combined organic phases were washed with 10 mL aqueous sodium thiosulfate, 10 mL half-saturated brine, and 10 mL brine, and then dried over MgSO4. The solvent was removed on a rotary evaporator with a 40° C. water bath to yield 0.65 g (3.98 mmol) of (R)-1,1-dioxo-3a,4,5,6-tetrahydropyrrolo[1,2-c][1,2,3]oxathiazolidine as a colorless oil which crystallized spontaneously.
Reaction SMILES: [C:1]([Si:5]([CH3:19])([CH3:18])[O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:17])[CH2:15]Cl)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:20][C:21]1[CH:34]=[CH:33][C:24]([CH2:25][C:26]2([OH:32])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:23][CH:22]=1>>[C:1]([Si:5]([CH3:19])([CH3:18])[O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:17])[CH2:15][N:29]2[CH2:28][CH2:27][C:26]([CH2:25][C:24]3[CH:23]=[CH:22][C:21]([Cl:20])=[CH:34][CH:33]=3)([OH:32])[CH2:31][CH2:30]2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(NC(=O)CCl)cc1
Reactant: OC1(Cc2ccc(Cl)cc2)CCNCC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(NC(=O)CN2CCC(O)(Cc3ccc(Cl)cc3)CC2)cc1

Procedure:
The title compound, m.p. 135°-136° C. and MS: m/e=489.4 (M+), was prepared from N-[4-(tert-Butyl-dimethyl-silanyloxy)-phenyl]-2-chloro-acetamide and 4-(4-Chloro-benzyl)-piperidin-4-ol.
Reaction SMILES: Cl.[CH:2]1([C:8]2[NH:12][C:11](=[O:13])[C:10]3([CH2:18][CH2:17][N:16]([S:19]([CH2:22][CH2:23][CH2:24][C:25]4[CH:26]=[C:27]([NH:31]C(=O)C)[CH:28]=[CH:29][CH:30]=4)(=[O:21])=[O:20])[CH2:15][CH2:14]3)[N:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1>CO>[NH2:31][C:27]1[CH:26]=[C:25]([CH2:24][CH2:23][CH2:22][S:19]([N:16]2[CH2:15][CH2:14][C:10]3([N:9]=[C:8]([CH:2]4[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]4)[NH:12][C:11]3=[O:13])[CH2:18][CH2:17]2)(=[O:21])=[O:20])[CH:30]=[CH:29][CH:28]=1
Reactant: CC(=O)Nc1cccc(CCCS(=O)(=O)N2CCC3(CC2)N=C(C2CCCCC2)NC3=O)c1
Agent: Cl
Solvent: CO
Product: Nc1cccc(CCCS(=O)(=O)N2CCC3(CC2)N=C(C2CCCCC2)NC3=O)c1
Temperature: 35 °C
Reaction time: 4 h
Yield: 55 %

Procedure:
Conc. HCl (0.5 ml) was added to a solution of N-{3-[3-(2-cyclohexyl-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-8-sulfonyl)-propyl]-phenyl}-acetamide (5.0 mg, 0.0105 mmol) in MeOH (1 ml) at room temperature. The mixture was stirred at 30 to 40° C. for four hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was then purified by preparative TLC (CH2Cl2:MeOH=10:1) to give 8-[3-(3-amino-phenyl)-propane-1-sulfonyl]-2-cyclohexyl-1,3,8-triaza-spiro[4.5]dec-1-en-4-one (2.5 mg, yield 55%).
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[C:13]([O:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:28](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C)C=O.ClCCl>[CH3:28][O:20][C:19](=[O:21])[CH2:18][CH2:17][O:16][C:13]1[CH:14]=[CH:15][C:10]2[N:9]=[C:8]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:11]=2[CH:12]=1
Reactant: O=C(O)CCOc1ccc2nc(-c3ccccc3)n(-c3ccccc3)c2c1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CI
Product: COC(=O)CCOc1ccc2nc(-c3ccccc3)n(-c3ccccc3)c2c1
Reaction time: 48 h

Procedure:
45 mg of 3-[(1,2-diphenyl-1H-benzimidazol-6-yl)oxy]propanoic acid was dissolved in 0.5 ml of N,N-dimethylformamide and mixed with 41 mg of cesium carbonate and 10 μl of methyl iodide. It was allowed to stir for 2 days, diluted with dichloromethane, filtered, the filtrate was concentrated by evaporation in a vacuum, and the residue was chromatographed on silica gel.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][O:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][N:10]1[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][C@@H:11]1[CH2:17][OH:18].[H][H]>[Pd].CO>[CH3:1][O:2][C:3](=[O:19])[CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][C@@H:11]1[CH2:17][OH:18]
Reactant: COC(=O)COC/C=C\CN1C(=O)CCC[C@@H]1CO
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)COCCCCN1C(=O)CCC[C@@H]1CO
Reaction time: 2.25 h
Yield: 89.1 %

Procedure:
Palladium on carbon (10 wt. %, 25 mg) was added to a solution of [(Z)-4-((R)-2-hydroxymethyl-6-oxo-piperidin-1-yl)-but-2-enyloxy]-acetic acid methyl ester (318 mg, 1.17 mmol) in MeOH (5.0 mL). A hydrogen atmosphere was established by evacuating and refilling with hydrogen (3×) and the reaction mixture was stirred under a balloon of hydrogen for 2.25 h. The reaction mixture was filtered through celite, washing with MeOH, and the filtrate was concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (30% EtOAc/CH2Cl2→50% EtOAc/CH2Cl2, gradient, then 2% MeOH/CH2Cl2→5% MeOH/CH2Cl2) afforded 285 mg (89%) of [4-((R)-2-hydroxymethyl-6-oxo-piperidin-1-yl)-butoxy]-acetic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8](OC2CCCCO2)[C:9]([C:11]2[O:12][C:13]3[C:19]([NH:20][C:21](=[O:23])[CH3:22])=[CH:18][CH:17]=[CH:16][C:14]=3[CH:15]=2)=[NH:10])[CH:5]=[CH:6][CH:7]=1.C[OH:32]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[O:12][C:13]3[C:19]([NH:20][C:21](=[O:23])[CH3:22])=[CH:18][CH:17]=[CH:16][C:14]=3[CH:15]=2)=[N:10][OH:32])[CH:5]=[CH:6][CH:7]=1
Reactant: CO
Reactant: CC(=O)Nc1cccc2cc(C(=N)N(OC3CCCCO3)c3cccc(Cl)c3)oc12
Product: CC(=O)Nc1cccc2cc(C(=NO)Nc3cccc(Cl)c3)oc12
Yield: 73 %

Procedure:
To a methanol solution of N-{2-[N-(3-chloro-phenyl)-N-(tetrahydro-pyran-2-yloxy)-carbamimidoyl]-benzofuran-7-yl}-acetamide was added 200 mg of acidic Dowex resin. The resulted solution was stirred at reflux temperature for 1 h. The reaction mixture was filtered and concentrated under vacuum. The crude product was purified using a chromatotron and eluting with hexane/ethyl acetate (8:2) to give 25 mg N-{2-[N-(3-chloro-phenyl)-N′-hydroxy-carbamimidoyl]-benzofuran-7-yl}-acetamide in 73% yield.
Reaction SMILES: [CH2:1]([NH2:7])[CH2:2][CH2:3][CH2:4][CH2:5][NH2:6].[C:8]1(=[O:14])[O:13][C:11](=[O:12])[CH2:10][CH2:9]1>CO.C(Cl)Cl>[NH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][NH:7][C:8](=[O:14])[CH2:9][CH2:10][C:11]([OH:13])=[O:12]
Reactant: NCCCCCN
Reactant: O=C1CCC(=O)O1
Solvent: ClCCl
Solvent: CO
Product: NCCCCCNC(=O)CCC(=O)O
Yield: 80 %

Procedure:
To a solution of 1,5-pentanediamine (2.5 g, 24 mmol) in dry methanol (20 mL), a solution of succinic acid anhydride (2 g, 20 mmol) in dry methylene chloride (20 mL) was added dropwise in 2 hrs, the product was precipitated as white solid and collected by filtration. Yield 80 %. 1H NMR (500 MHz, D2O, 25° C.) δ 1.280 (quint., J=7.5, 2H, CH2), 1.449 (quint., J=7.5, 2H, CH2), 1.577 (quint., J=7.5, 2H, CH2), 2.337 (s, 4H, CH2), 2.886 (t, J=7.5, 2H, CH2), 3.072 (t, J=7.5, 2H, CH2). 13C NMR (500 MHz, D2O, 25° C.) δ 22.73, 26.22, 27.66, 32.34, 33.13, 38.76, 39.37, 175.72, 180.90.
Reaction SMILES: O=[C:2]([C:23]#[C:24][CH3:25])[CH2:3][N:4]([S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16])[CH2:5][CH2:6][NH:7]C(=O)OC(C)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:23]([CH:2]1[NH:7][CH2:6][CH2:5][N:4]([S:15]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)(=[O:17])=[O:16])[CH2:3]1)#[C:24][CH3:25]
Reactant: CC#CC(=O)CN(CCNC(=O)OC(C)(C)C)S(=O)(=O)c1cccs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC#CC1CN(S(=O)(=O)c2cccs2)CCN1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl (2-((2-oxo-3-pentyn-1-yl)(2-thiophenylsulfonyl)amino)ethyl)carbamate (330 mg, 0.854 mmol) in CH2Cl2 (10 mL) was added sodium triacetoxyborohydride (1.0 g, 4.72 mmol, Sigma-Aldrich, St. Louis, Mo.) followed by TFA (2.5 mL, 32.4 mmol). The mixture was stirred at room temperature for 1 h and then concentrated to half the original volume. MeOH (5 mL) was added and the solution was concentrated by one-third and then partitioned between NaOH (0.5 N, 20 mL) and CHCl3 (containing 10% i-PrOH) (20 mL). The aqueous layer was extracted twice with CHCl3 (containing 10% i-PrOH) and the combined organic extracts were dried over Na2SO4, filtered, and concentrated to orange oil. The residue was purified by chromatography on silica gel using (1 to 5% MeOH in EtOAc) to give 3-(1-propyn-1-yl)-1-(2-thiophenylsulfonyl)piperazine as a light-yellow film (150 mg).
Reaction SMILES: Cl.[I:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([C@H:13]1[CH2:17][CH2:16][NH:15][CH2:14]1)[CH:8]=[C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:6]2=[O:23].C=O.O.[C:27]([BH3-])#N.[Na+]>CO>[I:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([C@H:13]1[CH2:17][CH2:16][N:15]([CH3:27])[CH2:14]1)[CH:8]=[C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:6]2=[O:23]
Reactant: [BH3-]C#N
Reactant: CCOC(=O)c1cn([C@H]2CCNC2)c2ccc(I)cc2c1=O
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOC(=O)c1cn([C@H]2CCN(C)C2)c2ccc(I)cc2c1=O
Temperature: 23 °C
Reaction time: 16 h
Yield: 82.3 %

Procedure:
(S)-Ethyl 6-iodo-4-oxo-1-(pyrrolidin-3-yl)-1,4-dihydroquinoline-3-carboxylate hydrochloride (Intermediate 136, 484 mg, 1.08 mmol) was suspended in methanol (15 mL) then 37% formaldehyde in water (405 μl, 5.4 mmol) and sodium cyanoborohydride (612 mg, 9 7 mmol) were added. The reaction was stirred at 23° C. for 16 h. The volume of the reaction was reduced by half and water (25 mL) was added. The suspension was extracted with 2:1 ethyl acetate: tetrahydrofuran (3×, 10 mL). The organic phases were combined, dried over sodium sulfate, and the solvent was removed in vacuo. The residue was passed through a plug of silica gel (2 g) eluting with 10% methanol in dichloromethane to remove any remaining borohydride. The solid was then dried in a vacuum oven at 50° C. for 18 h to give 379 mg (82% yield) of (S)-ethyl 6-iodo-1-(1-methylpyrrolidin-3-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate as an off white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]([CH:14]=[CH2:15])=[CH:12][CH:11]=[C:10]([NH:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[C:5]=1[C:6]([O:8][CH3:9])=[O:7])[CH3:2]>CO.[Pd]>[CH2:1]([O:3][C:4]1[C:13]([CH2:14][CH3:15])=[CH:12][CH:11]=[C:10]([NH:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)(=[O:18])=[O:19])[C:5]=1[C:6]([O:8][CH3:9])=[O:7])[CH3:2]
Reactant: C=Cc1ccc(NS(=O)(=O)c2ccc(F)cc2)c(C(=O)OC)c1OCC
Agent: [Pd]
Solvent: CO
Product: CCOc1c(CC)ccc(NS(=O)(=O)c2ccc(F)cc2)c1C(=O)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of Example 388A (66 mg, 0.15 mmol) in methanol was treated with 10% Pd/C (50 mg) and stirred under a hydrogen atmosphere overnight at room temperature. Filtration and evaporation of the solvent gave the desired product.