Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].[CH3:32][C:33]1[NH:34][C:35]([CH2:38][NH2:39])=[N:36][N:37]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:10][CH:11]=1)[C:3]([NH:39][CH2:38][C:35]1[NH:34][C:33]([CH3:32])=[N:37][N:36]=1)=[O:4]
Reactant: Cc1nnc(CN)[nH]1
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1nnc(CNC(=O)C(O)c2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)cc2)[nH]1
Reaction time: 1 h
Yield: 31.4 %

Procedure:
2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-Va, 30 mg, 0.070 mmol), (5-methyl-4H-1,2,4-triazol-3-yl)methanamine (11.70 mg, 0.104 mmol), HATU (34.4 mg, 0.090 mmol), and 4-methylmorpholine (28.1 mg, 0.278 mmol) were added to DMF (1 mL). This was stirred for 1 h before it was purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, 20 mL/min, 220 nM, product retention=11.3 min) to provide 2-hydroxy-N-((5-methyl-4H-1,2,4-triazol-3-yl)methyl)-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (12 mg, 0.022 mmol, 31.7% yield) as a single enantiomer. LCMS=526.4 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.17 (2 H, d, J=8.36 Hz), 7.51-7.76 (7 H, m), 5.21 (1 H, s), 4.46-4.66 (2 H, m), 2.52 (3 H, s); HPLC peak RT=8.4 min (Method A).
Reaction SMILES: [CH3:1]OS(OC)(=O)=O.[C:8]1(=[O:21])[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[NH:13][C:12]=2[CH2:11][CH2:10][NH:9]1.[OH-].[Na+]>CC(C)=O>[CH3:1][N:13]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=2[C:20]2[C:8](=[O:21])[NH:9][CH2:10][CH2:11][C:12]1=2
Reactant: O=C1NCCc2[nH]c3ccccc3c21
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: Cn1c2c(c3ccccc31)C(=O)NCC2

Procedure:
Dimethylsulphate (2.28 ml) was added over 5 min to a stirred mixture of 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one (3 g), acetone (12 ml) and 20% w/v aqueous sodium hydroxide (9 ml) at ca. 50°. The mixture was heated at reflux for 10 min. Further sodium hydroxide (6 ml) was added and the mixture was heated at reflux for 5 min. On cooling a solid crystallised. Water (10 ml) was added and the mixture was filtered. The solid was washed with water (2×20 ml), and dried in vacuo 45° to give the title compound (3.16 g). The t.l.c. data for this material were consistent with those obtained for the product of Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[OH:10].[N+:28]([C:31]1[CH:36]=[CH:35][C:34]([S:37]([N:40]2[CH:44]=[CH:43][CH:42]=[C:41]2[C:45](O)=[O:46])(=[O:39])=[O:38])=[CH:33][CH:32]=1)([O-:30])=[O:29].C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[O:10][C:45]([C:41]1[N:40]([S:37]([C:34]2[CH:35]=[CH:36][C:31]([N+:28]([O-:30])=[O:29])=[CH:32][CH:33]=2)(=[O:38])=[O:39])[CH:44]=[CH:43][CH:42]=1)=[O:46]
Reactant: O=C(O)c1cccn1S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1)c1cccn1S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 27.8 %

Procedure:
A mixture of (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (206 mg, 0.490 mmol), 1-(4-nitrophenylsulfonyl)-1H-pyrrole-2-carboxylic acid (Int. 5) (160 mg, 0.539 mmol), EDC (282 mg, 1.471 mmol) and DMAP (59.9 mg, 0.490 mmol) in DCM (10 ml) was stirred at RT for 24 hours. The reaction was diluted with DCM and washed with 1N HCl, sat. NaHCO3 (40 ml), and finally with brine. The organic phase was dried over sodium sulfate and the solvent was removed under vacuum; the crude was purified by preparative HPLC-Method 1 to yield (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(1-(4-nitrophenylsulfonyl)-1H-pyrrole-2-carbonyloxy)ethyl)pyridine 1-oxide (Int. 6) (95 mg, 0.136 mmol, MS/ESI+698.05 [MH]+, [αD]=−40.97, c=0.6, DCM).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17][CH3:18])=O.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17][CH3:18]
Reactant: CSc1ccccc1C(=O)c1cc(C)ccc1C
Agent: CC[SiH](CC)CC
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CSc1ccccc1Cc1cc(C)ccc1C
Yield: 92.9 %

Procedure:
To a solution of 0.758 g (2,5-dimethylphenyl)(2-(methylthio)phenyl)methanone and 1 ml triethylsilane was added 5 ml TFA. The reaction mixture was stirred at RT for 1 hour before water was added. The reaction mixture was extracted with ethyl acetate (2×70 ml) and the combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. Flash silica chromatography (hexane:ethyl acetate 80:20) yielded 0.666 g product.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[C:9]([C:11]([CH3:13])=[CH2:12])[CH:8]=[C:7]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=1)=[N+]=[N-].[O:22](C(OC(C)(C)C)=O)[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=O>CCOC(C)=O.[Pd]>[CH2:15]([O:14][C:7]1[CH:6]=[C:5]([CH:10]=[C:9]([CH:11]([CH3:13])[CH3:12])[CH:8]=1)[CH2:4][NH:1][C:23](=[O:22])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: C=C(C)c1cc(CN=[N+]=[N-])cc(OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)c1cc(CNC(=O)OC(C)(C)C)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 11.5 h
Yield: 62 %

Procedure:
A mixture of 573 mg (1.97 mmol) of 1-(azidomethyl)-3-(benzyloxy)-5-(prop-1-en-2-yl)benzene, 0.5 mL of BOC2O, and 60.5 mg of 10% Pd/C in 10 mL of EtOAc was stirred at r.t. under H2 balloon for 11.5 h. The mixture was filtered through Celite and concentrated. Purification by flash silica gel chromatography (10% EtOAc/hexanes) provided 336 mg of tert-butyl 3-(benzyloxy)-5-isopropylbenzylcarbamate in 62% yield.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][C:10]1[N:15]=[CH:14][C:13]([NH:16][C:17](=[O:21])[C@@H:18]([CH3:20])[NH2:19])=[CH:12][CH:11]=1.C(N(CC)CC)C.Cl[C:30](Cl)([O:32]C(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+]>ClCCl>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][C:10]1[N:15]=[CH:14][C:13]([N:16]2[C:17](=[O:21])[C@@H:18]([CH3:20])[NH:19][C:30]2=[O:32])=[CH:12][CH:11]=1
Reactant: Cc1cccc(Oc2ccc(NC(=O)[C@@H](C)N)cn2)c1C
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(Oc2ccc(N3C(=O)N[C@H](C)C3=O)cn2)c1C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
N1-{6-[(2,3-dimethylphenyl)oxy]-3-pyridinyl}-D-alaninamide (Intermediate 40, 13 mg) was dissolved in dry dichloromethane (2 mL). The reaction mixture (under argon) was cooled down in an ice bath. Triethylamine (38.1 μl, 0.273 mmol) was added. Then a solution of triphosgene in dry dichloromethane (5.41 mg, 0.018 mmol, 0.40 equiv dissolved in 1 mL of DCM) was added dropwise. The reaction mixture was stirred at 0° C., under argon, during 10 min. A saturated aqueous solution of NaHCO3 was added (3 mL) and the aqueous layer was extracted with dichloromethane 4 times (4×4 mL). After drying over sodium sulphate, the solvents were removed under vacuum. The residue was purified by silica gel chromatography (Companion system, 4 g silica cartridge,) with a gradient cyclohexane/ethylacetate from 100:0 to 55:45 during 10 min and 55:45 during 20 min. This afforded the title compound (9 mg)
Reaction SMILES: C([O:3][C:4](=O)[C@:5]([O:11][CH2:12][C@@:13]([C:28]1[C:33]([F:34])=[CH:32][CH:31]=[C:30]([Br:35])[N:29]=1)([NH:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)(=[O:18])=[O:17])[CH3:14])([CH3:10])[C:6]([F:9])([F:8])[F:7])C.[NH3:37].CO>>[Br:35][C:30]1[N:29]=[C:28]([C@:13]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])([CH3:14])[CH2:12][O:11][C@@:5]([CH3:10])([C:6]([F:9])([F:8])[F:7])[C:4]([NH2:37])=[O:3])[C:33]([F:34])=[CH:32][CH:31]=1
Reactant: N
Reactant: CCOC(=O)[C@@](C)(OC[C@](C)(NS(=O)(=O)c1ccc([N+](=O)[O-])cc1)c1nc(Br)ccc1F)C(F)(F)F
Solvent: CO
Product: C[C@@](CO[C@](C)(C(N)=O)C(F)(F)F)(NS(=O)(=O)c1ccc([N+](=O)[O-])cc1)c1nc(Br)ccc1F

Procedure:
A solution of (R)-2-[(R)-2-(6-bromo-3-fluoro-pyridin-2-yl)-2-(4-nitro-benzenesulfonylamino)-propoxy]-3,3,3-trifluoro-2-methyl-propionic acid ethyl ester (16.93 g, 28.1 mmol) in a NH3/MeOH (7M, 482 ml) was stirred at 50° C. in a sealed vessel for 26 h. The reaction mixture was evaporated and the residue was crystallized from DCM to yield 9.11 g of the title compound as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1.[CH3:9][S:10]SC>>[CH3:9][S:10][C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1
Reactant: O=Cc1cc(Br)cs1
Reactant: CSSC
Product: CSc1csc(C=O)c1

Procedure:
4-bromo-2-thiophenecarboxaldehyde was converted into the 4-lithio derivative (A. L. Johnson, J. Org. Chem. 41, 1976, 1320) of its ethylene acetal and reaction of this organometallic with dimethyl disulphide followed by acid hydrolysis gave 4-methylthio-2-thiophenecarboxaldehyde (R. Noto, L. Lamartina, C. Arnone and D. Spinelli, J. Chem. Soc., Perkin Trans. 2, 1987, 689). Sodium borohydride reduced this aldehyde to the 4-methylthio alcohol (for B.4356), which in turn with one of two equivalents of MCPBA yielded the 4-methylsulphinyl and 4-methylsulphonyl alcohols (for B.4377 and B.4361 respectively). reaction of the above organometallic with naphthalene-2-sulphonyl azide (A. B. Khare and C. E. McKenna, Synthesis, 1991, 405) and sodium pyrophosphate followed by hydrolysis by the method (P. Spagnolo and P. Zamirato, J. Org. Chem., 43, 1978, 3539) for the preparation of other azidothiophene aldehydes gave 4-azido-2-thiophenecarboxaldehyde leading to the alcohol for B.4373.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].N1CCCC1.[CH2:18]([N:20]1[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]1)[CH3:19]>C(O)C>[CH2:18]([N:20]1[CH2:21][CH:22]=[C:23]([C:7]2[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[NH:9][CH:8]=2)[CH2:24][CH2:25]1)[CH3:19]
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Reactant: CCN1CCC(=O)CC1
Solvent: C1CCNC1
Solvent: CCO
Product: CCN1CC=C(c2c[nH]c3ccc([N+](=O)[O-])cc23)CC1
Yield: 41.8 %

Procedure:
A solution of 5-nitroindole (38) (0.5 g, 3.083 mmol) in dry ethanol (15 mL) was treated with pyrrolidine (0.65 mL, 9.250 mmol), N-ethyl-4-piperidone (0.8 mL, 6.167 mmol) at room temperature and the resulting solution was refluxed for 3 days. The reaction was brought to room temperature and solvent was evaporated. The crude was purified by column chromatography (2 M NH3 in methanol: CH2Cl2, 5:95), and washed with ether (3×10 mL) to obtain compound 60 (0.35 g, 42%) as a solid. mp 188-190° C.; 1H NMR (DMSO-d6) δ: 1.07 (t, 3H, J=7.2 Hz), 2.41-2.50 (m, 4H), 2.63 (t, 2H, J=5.1 Hz), 3.10-3.15 (m, 2H), 6.18 (s, 1H), 7.55 (d, 1H, J=9.0 Hz), 7.65 (s, 1H), 8.01 (dd, 1H, J=2.1, 9.0 Hz), 8.69 (d, 1H, J=2.1 Hz), 11.86 (s, 1H); ESI-MS m/z (%): 272 (M+, 100).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[O:8][N:7]=[C:6]([C:9]2[CH:10]=[C:11]([CH:22]=[CH:23][CH:24]=2)[O:12][CH:13]([CH2:19][CH2:20][CH3:21])[C:14]([O:16]CC)=[O:15])[N:5]=1.CO>O>[CH3:3][C:4]1[O:8][N:7]=[C:6]([C:9]2[CH:10]=[C:11]([CH:22]=[CH:23][CH:24]=2)[O:12][CH:13]([CH2:19][CH2:20][CH3:21])[C:14]([OH:16])=[O:15])[N:5]=1
Reactant: CCCC(Oc1cccc(-c2noc(C)n2)c1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCC(Oc1cccc(-c2noc(C)n2)c1)C(=O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2.1 I of 1N sodium hydroxide solution are added to a solution of 347 g (1.14 mol) of ethyl 2-[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]-pentanoate in 1.4 I of methanol, and the mixture is stirred at room temperature for 24 hours. The reaction mixture is diluted with 1 I of water and extracted twice with 1 I of tert-butyl methyl ether each time. The aqueous phase is acidified to a pH of 2 using concentrated hydrochloric acid and extracted twice with 2 I of tert-butyl methyl ether each time. The combined organic phases are evaporated, and the residue is recrystallised from 100 ml of toluene: 2-[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]pentanoic acid is obtained as colourless crystals of m.p. 98-100°.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].C(N(CC)CC)C.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>C1COCC1>[CH3:14][S:15]([O:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])(=[O:17])=[O:16]
Reactant: CN(C)CCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)CCOS(C)(=O)=O

Procedure:
The N,N-dimethylethanolamine (Aldrich, 0.11 g, 1.2 mmol), triethylamine (0.56 mL, 4.1 mmol), and methanesulfonyl chloride (0.15 mL, 1.9 mmol) in 10 mL THF were processed as described in Example 1C to give the title compound that was used directly in the next reaction.
Reaction SMILES: [Br:1]Br.[CH3:3][NH:4][N:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1>C(O)(=O)C.C(#N)C>[CH3:3][NH:4][N:5]=[C:6]([Br:1])[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1
Reactant: BrBr
Reactant: CNN=Cc1ccc(Cl)cc1
Solvent: CC#N
Solvent: CC(=O)O
Product: CNN=C(Br)c1ccc(Cl)cc1
Reaction time: 3 h
Yield: 61 %

Procedure:
9.5 g (0.06 mol) of bromine were added dropwise at (-5) to (-7)° C. to a solution of 10 g (0.06 mol) of 4-chlorobenzaldehyde (N-methyl)hydrazone in 50 ml of acetic acid and 20 ml of acetonitrile. After the mixture had been stirred for 3 hours, the product which had precipitated was separated off and washed with a small amount of pentane. Yield: 61%.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][O:9][C:10]2[CH:11]=[C:12]([O:22][C:23]3[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=3)[CH:13]=[C:14]3[C:18]=2[NH:17][C:16]([C:19](O)=[O:20])=[CH:15]3)[CH:5]=[CH:4][CH:3]=1.Cl.C[N:35](C)CCCN=C=NCC.[NH4+].ON1C2C=CC=CC=2N=N1.CN(C)C=O>O>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][O:9][C:10]2[CH:11]=[C:12]([O:22][C:23]3[CH:24]=[CH:25][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][CH:28]=3)[CH:13]=[C:14]3[C:18]=2[NH:17][C:16]([C:19]([NH2:35])=[O:20])=[CH:15]3)[CH:5]=[CH:4][CH:3]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: CS(=O)(=O)c1ccc(Oc2cc(OCc3cccc(Cl)n3)c3[nH]c(C(=O)O)cc3c2)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)c1ccc(Oc2cc(OCc3cccc(Cl)n3)c3[nH]c(C(N)=O)cc3c2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 87.4 %

Procedure:
A mixture of 7-[(6-chloropyridin-2-yl)methoxy]-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylic acid (780 mg), 1-[3-(dimethylamino)propyl-3-ethylcarbodiimide hydrochloride (632 mg), 1-hydroxybenzotriazole ammonium salt (502 mg) and N,N-dimethylformamide (30 mL) was stirred at room temperature for 15 hr. Water was added to the reaction solution, and the precipitated solid was collected by filtration, and washed successively with water and diethyl ether to give the title compound (680 mg, yield 90%) as a white solid. The obtained crystals were recrystallized from N,N-dimethylformamide-water to give colorless crystals. melting point 259-260° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[C:15](Cl)(=[O:17])[CH3:16].O>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:15](=[O:17])[CH3:16])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CNc1ccc(F)cc1
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CN(C(C)=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-((4-fluorophenyl)amino)acetate (1) (6.68 g, 33.9 mmol) in THF (84 mL) was added acetyl chloride (2.88 mL, 40.6 mmol) and the reaction was stirred overnight at room temperature. Water was added and the reaction was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to yield ethyl 2-(N-(4-fluorophenyl)acetamido)acetate (2) as an orange solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].Cl.Cl[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]Cl>C1(C)C(C)=CC=CC=1.[OH-].[Na+]>[C:5]([C:4]1[CH:3]=[C:2]([N:1]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:9]=[CH:8][CH:7]=1)#[N:6]
Reactant: N#Cc1cccc(N)c1
Reactant: ClCCNCCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Product: N#Cc1cccc(N2CCNCC2)c1
Temperature: 155 °C
Reaction time: 5 h
Yield: 32.7 %

Procedure:
3-Aminobenzonitrile (6.1 g, 52 mmol) and bis(2-chloroethyl)amine hydrochloride (10 g, 57 mmol) were dissolved in xylene (100 ml), and the resulting solution was stirred at 150 to 160° C. for 5 hours. Supernatant fluid of the reaction solution was discarded, the remaining residue was dissolved in sodium hydroxide aqueous solution (1 N) and then the reaction product was extracted therefrom with ethyl acetate. The extract was washed with saturated brine, and then the compound obtained by the evaporation of the solvent under a reduced pressure was separated and purified by a silica gel column chromatography to obtain 3.2 g of the title compound (17 mmol, 34% in yield). A portion of the thus obtained compound was made into hydrochloric acid salt by treating it with hydrochloric acid-saturated methanol.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][NH:7][C:8]2[CH:9]=[CH:10][C:11]([CH:14]=[O:15])=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[OH-:18].[Na+]>O.[N+]([O-])([O-])=O.[Ag+]>[F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]([OH:18])=[O:15])=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(NCc2ccc(F)cc2)cn1
Reactant: [OH-]
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc(NCc2ccc(F)cc2)cn1

Procedure:
4.62 g of 5-(p-fluorobenzylamino)-pyridine-2-carboxaldehyde are added in small portions to the cold stirring mixture consisting of 70.4 g of silver nitrate in 150 ml of water and 33.1 g of sodium hydroxide in 150 ml of water. The mixture is stirred 10 minutes after the last of the aldehyde is added and filtered. The filtrate is cooled, acidified with 12 N hydrochloric acid to a pH=4, filtered and the residue washed with water to yield the 5-(p-fluorobenzylamino)-pyridine-2-carboxylic acid melting at 197°-200°. The starting material is prepared as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([N:23]5[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1.[CH3:36][O:37][CH2:38][CH2:39]Br>>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([N:23]5[CH2:24][CH2:25][N:26]([CH2:39][CH2:38][O:37][CH3:36])[CH2:27][CH2:28]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1
Reactant: COCCBr
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1N1CCNCC1
Product: COCCN1CCN(N2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)CC1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[4-(2-methoxyethyl)piperazin-1-yl]-1,3-thiazolidine-2,4-dione was prepared from ((5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-piperazin-1-yl-1,3-thiazolidine-2,4-dione (Example 351) and 2-bromoethyl methyl ether following General Procedure S.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:9]1.[NH2:22][C:23]1[C:24]([C:30](O)=[O:31])=[N:25][C:26]([Br:29])=[CH:27][CH:28]=1>>[NH2:22][C:23]1[C:24]([C:30]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])[CH2:9]2)=[O:31])=[N:25][C:26]([Br:29])=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccncc2N)C1
Reactant: Nc1ccc(Br)nc1C(=O)O
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccncc2NC(=O)c2nc(Br)ccc2N)C1
Yield: 45 %

Procedure:
Following method 11, (S)-tert-butyl 1-(3-aminopyridin-4-yl)piperidin-3-ylcarbamate was coupled to 3-amino-6-bromopicolinic acid and purified by SiO2 chromatography (EtOAc eluant) yielding (S)-tert-butyl 1-(3-(3-amino-6-bromopicolinamido)pyridin-4-yl)piperidin-3-ylcarbamate (45%). LCMS (m/z): 491.1 (MH+); LC Rt=2.89 min.
Reaction SMILES: [BrH:1].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([C:11]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25]OCCC(C)C)=[CH:21][CH:20]=2)=[CH:12][C@@H:13]2[NH:17][C:16](=[O:18])[CH2:15][CH2:14]2)=[N:7][C:8]=1[O:9]C.C(=O)(O)[O-].[Na+].O>C(#N)C>[Br:1][CH2:25][C:22]1[CH:23]=[CH:24][C:19]([C:11]([C:6]2[NH:7][C:8](=[O:9])[C:3]([Cl:2])=[CH:4][CH:5]=2)=[CH:12][C@H:13]2[CH2:14][CH2:15][C:16](=[O:18])[NH:17]2)=[CH:20][CH:21]=1
Reactant: Br
Reactant: COc1nc(C(=C[C@H]2CCC(=O)N2)c2ccc(COCCC(C)C)cc2)ccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=C1CC[C@H](C=C(c2ccc(CBr)cc2)c2ccc(Cl)c(=O)[nH]2)N1
Temperature: 70 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
48% hydrobromic acid (4 mL) was added to a solution of (5R)-5-[2-(5-chloro-6-methoxypyridin-2-yl)-2-{4-[(3-methylbutoxy)methyl]phenyl}ethenyl]pyrrolidin-2-one (E:Z=1:2 mixture) (396 mg) in acetonitrile (4 mL) at room temperature, and the mixture was stirred at 70° C. for three hours. Saturated aqueous sodium bicarbonate and water were sequentially added to the reaction solution at room temperature, followed by extraction with chloroform. The organic layers were dried over anhydrous sodium sulfate and filtered. The solvent was then evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=50:1→5:1) to give 6-{1-[4-(bromomethyl)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-chloropyridin-2(1H)-one (E:Z=1:2 mixture) (321 mg, 85%).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[CH2:17]([N:24]1[C:32]2[C:27](=[CH:28][C:29]([CH:33]=[C:34]([CH3:38])[C:35](O)=[O:36])=[CH:30][CH:31]=2)[CH:26]=[CH:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([N:24]1[C:32]2[C:27](=[CH:28][C:29]([CH:33]=[C:34]([CH3:38])[C:35]([NH:1][C:2]3[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=3[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:36])=[CH:30][CH:31]=2)[CH:26]=[CH:25]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)CCCOc1ccccc1N
Reactant: CC(=Cc1ccc2c(ccn2Cc2ccccc2)c1)C(=O)O
Product: CC(=Cc1ccc2c(ccn2Cc2ccccc2)c1)C(=O)Nc1ccccc1OCCCC(=O)O

Procedure:
0.67 g of compound 28 was obtained in a similar manner to those described in the Examples 1 and 2 using 1.69 g of ethyl 4-(2-aminophenoxy)butyrate and 1.10 g of 3-(1-benzylindol-5-yl)methacrylic acid obtained according to the procedures described in the Reference Examples 1-4.