Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=[O:12].[CH3:13][Mg]Br.[NH4+].[Cl-]>C1COCC1.C1(C)C=CC=CC=1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([OH:12])[CH3:13]
Reactant: C[Mg]Br
Reactant: O=Cc1ccc2ccccc2n1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(O)c1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cold (0° C.) solution of quinoline-2-carboxaldehyde (7.85 g) in THF (100 mL) was added dropwise 1.4M methyl magnesium bromide in toluene and THF (46 mL). After total addition, the mixture was stirred at room temperature for 30 min. The reaction mixture was poured into aqueous satured NH4Cl (500 mL), extracted with ethyl acetate (2×200 mL), washed with brine (100 mL), and dried (MgSO4). The solution was evaporated to dryness and chromatographed on flash silica gel using ethyl acetate:hexane (3:7) as eluant to yield the title product as a light orange solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:27]3[C:13](=[CH:14][C:15]4[O:16][CH2:17][CH2:18][CH2:19]S[CH2:21][CH2:22][CH2:23][O:24][C:25]=4[CH:26]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.O[O:29][S:30]([O-:32])=O.[K+].O>CO>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:27]3[C:13](=[CH:14][C:15]4[O:16][CH2:17][CH2:18][CH2:19][S:30](=[O:32])(=[O:29])[CH2:21][CH2:22][CH2:23][O:24][C:25]=4[CH:26]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Brc1cccc(Nc2ncnc3cc4c(cc23)OCCCSCCCO4)c1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=S1(=O)CCCOc2cc3ncnc(Nc4cccc(Br)c4)c3cc2OCCC1
Reaction time: 4 h

Procedure:
(3-Bromo-phenyl)-(2,10-dioxa-6-thia-14,16-diaza-tricyclo[9.8.0.013,18]nonadeca-1(11),12,14,16,18-pentaen-17-yl)-amine (21, 17.8 mg, 0.04 mmol) was suspended in MeOH, to which was added a cloudy aqueous solution of oxone (monopersulfate compound) (73 mg, 0.12 mmol) at room temperature. The suspension was stirred and monitored by TLC which indicated that the reaction was completed in 4 h. The reaction mixture was poured into H2O (10 mL), and extracted with EtOAc (3×15 mL). The organic layers were collected, dried and concentrated to give a pale yellow residue which was recrystalized from EtOAc to give the product as an off-white solid: 8 mg (42%). 1H NMR (CD3OD) δ 8.58 (s, 1H), 8.16 (s,1H), 8.11 (s, 1H), 7.81 (d, 1H), 7.72 (d, 1H), 7.48 (d, 1H), 7.35 (s, 1H), 7.30 (s, 1H), 4.35 (t, 4H), 3.70 (t, 2H), 3.40 (t, 2H), 2.40 (m, 2H), 2.15 (m, 2H); ES-MS m/z 478 (MH+).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23]([OH:25])=O)[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:28]=1[C:34](=[N:36]O)[NH2:35]>>[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:28]=1[C:34]1[N:36]=[C:23]([CH:11]2[CH2:10][CH:9]([C:6]3[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=3)[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12]2)[O:25][N:35]=1
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCOCC3)C2)cc1
Reactant: NC(=NO)c1c(F)cccc1F
Product: CCc1ccc(C2CC(c3nc(-c4c(F)cccc4F)no3)CN(C(=O)N3CCOCC3)C2)cc1

Procedure:
69 mg (0.20 mmol) of 5-(4-ethylphenyl)-1-(morpholin-4-ylcarbonyl)piperidine-3-carboxylic acid (Example 38A) and 38 mg (0.22 mmol, 1.1 eq.) of 2,6-difluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 17 mg (18% of theory)
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:15][C:16](=[O:22])[CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH2:9][C:10]([O:12]CC)=[O:11])=[CH:3][CH:2]=1.[OH-].[Na+]>C1COCC1.CO>[C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@@H:8]([NH:15][C:16](=[O:22])[CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:6]=1
Reactant: CCOC(=O)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)CCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCC(=O)N[C@@H](CC(=O)O)Cc1ccc(-c2ccccc2)cc1
Reaction time: 0.75 h
Yield: 96.6 %

Procedure:
To a solution of (R)-4-(1-(biphenyl-4-yl)-4-ethoxy-4-oxobutan-2-ylamino)-4-oxobutanoic acid (61.2 mg, 0.160 mmol) in THF (1.6 mL) and methanol (0.2 mL), aqueous 1M NaOH solution (0.638 mL, 0.638 mmol) is added at room temperature. After stirring for 45 minutes, the reaction is quenched with aqueous 0.1 M HCl and is extracted with ethyl acetate. The organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give (R)-4-(biphenyl-4-yl)-3-(3-carboxypropanamido)butanoic acid (54.9 mg). HPLC retention time=1.33 minutes (condition A); MS (m+1)=356.1; 1H NMR (400 MHz, CD3OD) δ ppm 2.40-2.56 (m, 6H) 2.83-2.94 (m, 2H) 4.43-4.50 (m, 1H) 7.29-7.32 (m, 3H) 7.41 (t, 2H, J=7.7 Hz) 7.53-7.60 (m, 4H).
Reaction SMILES: C[O:2][P:3]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][P:15](=[O:20])([O:18]C)[O:16]C)=[CH:10][CH:9]=1)(=[O:6])[O:4]C>Cl>[C:11]1([CH2:14][P:15](=[O:16])([OH:18])[OH:20])[CH:10]=[CH:9][C:8]([CH2:7][P:3](=[O:2])([OH:4])[OH:6])=[CH:13][CH:12]=1
Reactant: COP(=O)(Cc1ccc(CP(=O)(OC)OC)cc1)OC
Agent: Cl
Product: O=P(O)(O)Cc1ccc(CP(=O)(O)O)cc1
Yield: 0.1 %

Procedure:
A mixture of bisphosphate ester (Example 19, 1.0 g, 3.1 mol) and concentrated HCl (10 ml) is heated to reflux temperature. A clear solution is obtained. The solution is heated at reflux temperature for 3.5 hours during which time a white precipitate formes. The mixture is cooled and then concentrated under reduced pressure to yield a white solid. The solid is recrystallized from water to give 520 mg of a white solid, mp >300° C.
Reaction SMILES: Cl[CH2:2][O:3][C:4](=[O:31])[N:5]([C:28](=[O:30])[CH3:29])[CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][S:22](=[O:26])(=[O:25])[CH2:21][CH2:20]3)=[C:15]([F:27])[CH:14]=2)[CH2:8]1.[C:32]([O-:40])(=[O:39])[C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1.[Cs+].[I-].[Na+].O>C(#N)C>[C:28]([N:5]([CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][S:22](=[O:26])(=[O:25])[CH2:21][CH2:20]3)=[C:15]([F:27])[CH:14]=2)[CH2:8]1)[C:4]([O:3][CH2:2][O:40][C:32](=[O:39])[C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1)=[O:31])(=[O:30])[CH3:29]
Reactant: CC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(=O)OCCl
Reactant: O=C([O-])c1ccncc1
Agent: [Cs+]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(=O)OCOC(=O)c1ccncc1
Temperature: 25 °C
Yield: 80 %

Procedure:
(R)-acetyl-{3-[4-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-3-fluoro-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-carbamic acid chloromethyl ester (10) (0.40 g, 0.84 mmol), cesium isonicotinate (0.33 g, 1.301 mmol) and sodium iodide (0.13 g, 0.86 mmol) in acetonitrile (25 mL) are heated to reflux overnight. After cooling to RT, water is added and the reaction mixture is extracted with EtOAc and then with dichloromethane. The organic phases are washed separately with brine and then the organic layers are combined, dried over MgSO4, filtered, and conc in vacuo. The isolated residue is subjected to silica gel flash chromatography, eluting with MeOH/CH2Cl2 gradient (0-5% MeOH over 1 hour and 20 minutes) to afford the title compound. Isolated yield: 80%. 1H NMR (400 MHz, DMSO-d6): δ 8.78 (d, 2H), 7.82 (d, 2H), 7.36 (d, 1H), 7.30 (t, 1H), 7.18 (d, 1H), 6.02 (dd, 2H), 4.76-4.70 (m, 1H), 4.10-4.05 (m, 2H), 3.89-3.85 (m, 1H), 3.77-3.74 (m, 1H), 3.35-3.26 (m, partially obscured by water, 2H), 3.19-3.11 (m, 1H), 3.07-3.04 (m, 2H), 2.43 (d, partially obscured by DMSO, 3H), 2.11 (q, 2H), 2.01-1.97 (m, 2H); MS-APCI (m/z+): 341, 564.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Br)[C:3]=1[Cl:9].C([Li])CCC.[CH3:15][S:16]SC.O>C(OCC)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:16][CH3:15])[C:3]=1[Cl:9]
Reactant: CSSC
Reactant: Clc1c(Br)cccc1Br
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: CSc1cccc(Br)c1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 41.1 %

Procedure:
To a solution of 1,3-dibromo-2-chlorobenzene (3.4 g, 12.6 mmol) in dry diethyl ether (60 ml), under nitrogen, at −78° C., was added dropwise n-butyllithium (2.5 M in hexane, 5.0 ml, 12.6 mmol). The mixture was stirred for 1 h after which dimethyldisulfide (1.0 ml, 13.9 mmol) was added dropwise. The resulting mixture was stirred at −78° C. for 30 min and then brought to ambient temperature. Water (100 ml) was added and the mixture was extracted with ethylacetate (3×100 ml). The combined organic phases was dried (MgSO4), filtered and evaporated to dryness. The residue was purified by flash column chromatography (isooctane) to give the title compound (1.23 g). MS m/z (rel. intensity, 70 eV) 240 (M+, 28), 238 (M+, bp), 236 (71), 205 (29), 142 (27).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[N:9]2[CH2:14][CH2:13][N:12]([S:15]([C:18]3[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[C:26](O)=[O:27])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[Cl:36]CCl>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[N:9]2[CH2:14][CH2:13][N:12]([S:15]([C:18]3[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[C:26]([Cl:36])=[O:27])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: O=C(O)/C=C/c1ccc(S(=O)(=O)N2CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc1
Reactant: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)/C=C/c1ccc(S(=O)(=O)N2CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.6 %

Procedure:
To a solution of (E)-3-[4-({4-[bis(4-fluorophenyl)methyl]-1-piperazinyl}sulfonyl)phenyl]-2-propenoic acid (b) (0.25 g, 0.5 mmol) in dichloromethane (7 mL) oxalyl chloride (0.15 mL, 1.75 mmol) and a drop of dimethylformamide were added. The reaction mixture was stirred at ambient temperature for 1 hour, then the mixture was evaporated and the residue was dried in vacuum to give (E)-3-[4-({4-[bis(4-fluorophenyl)methyl]-1-piperazinyl}sulfonyl)phenyl]-2-propenoyl chloride (10b) (0.26 g) in a form of a crude product.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=3)[C:20](O)=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[F:34][C:35]1[CH:41]=[C:40]([I:42])[CH:39]=[CH:38][C:36]=1[NH2:37].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CC=CC=1.BrN1C(=O)CCC1=O>ClCCl>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16](=[O:17])[NH:18][C@H:19]([C:20](=[O:21])[NH:37][C:36]3[CH:38]=[CH:39][C:40]([I:42])=[CH:41][C:35]=3[F:34])[CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=3)[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(N[C@@H](Cc1ccc2ccccc2c1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Reactant: Nc1ccc(I)cc1F
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(N[C@@H](Cc1ccc2ccccc2c1)C(=O)Nc1ccc(I)cc1F)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-naphthalen-2-yl-propionic acid (1.0 g, 2.30 mmol) and 2-fluoro-4-iodoaniline (434 mg, 1.84 mmol), triphenylphosphine (0.94 g, 3.45 mmol) and pyridine (0.39 mL, 4.60 mmol) in dichloromethane (10 mL) at 0° C. was added N-bromosuccinimide (0.61 mg, 3.45 mmol) in two portions under an atmosphere of dry nitrogen. The mixture was stirred for 2 hours at 0° C. The reaction mixture was purified by chromatography over silica gel gradient eluted from 100% dichloromethane up to 10% methanol/90% dichloromethane over 30 minutes. Concentration of the product containing fractions gave [(S)-1-(2-fluoro-4-iodo-phenylcarbamoyl)-2-naphthalen-2-yl-ethyl]-carbamic acid 9H-fluoren-9-ylmethyl ester as a yellow solid foam (1.05 g, 70%).
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[CH2:6][NH:7][CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[C:19]1[CH:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[CH:22]=[CH:21][C:20]=1[O:28][CH3:29].[N:39]#[C:40]Br.C(=O)(O)[O-].[Na+]>C(O)C>[F:1][C:2]([F:37])([F:38])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:34])[F:35])[CH:32]=1)[CH2:6][N:7]([CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[C:19]1[CH:24]=[C:23]([CH:25]([CH3:26])[CH3:27])[CH:22]=[CH:21][C:20]=1[O:28][CH3:29])[C:40]#[N:39]
Reactant: N#CBr
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(C#N)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.1 %

Procedure:
(3,5-Bis-trifluoromethyl-benzyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amine (2.0 g) is dissolved in ethanol (20 ml), and thereto are added cyanogen bromide (578 mg) and sodium bicarbonate (928 mg) and the mixture is stirred at room temperature for 2 hours. To reaction mixture is added a saturated aqueous sodium bicarbonate solution and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=10:1→5:1) to give (3,5-bis-trifluoromethyl-benzyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-cyanamide (1.8 g). MS (m/z): 575 [M+H]+
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11](Cl)[CH:10]=[CH:9]2)=[O:5])C.[CH3:17][O:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][NH2:22]>>[CH3:17][O:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][NH:22][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([NH:22][CH2:21][C:20]1[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=1[O:18][CH3:17])[CH:10]=[CH:9]2)=[O:5]
Reactant: COc1ccccc1CN
Reactant: CCOC(=O)c1ccc2nc(Cl)ccc2c1
Product: COc1ccccc1CNC(=O)c1ccc2nc(NCc3ccccc3OC)ccc2c1
Temperature: 120 °C
Yield: 9.4 %

Procedure:
A stirred mixture of 2-chloro-quinoline-6-carboxylic acid ethyl ester [CAS-No. 29969-56-0] (236 mg, 1.0 mmol) and commercially available 2-methoxy-benzylamine (412 mg, 3.0 mmol) was heated in a sealed tube for 16 h at 120° C. Purification by flash chromatography on silica gel (ethyl acetate/heptane) and crystallization of each of the two fractions (dichloromethane/hexane) yielded the title compound as a white solid (40 mg, 9%), MS (ISP) 428.3 [(M+H)+]; m.p. 217° C. as well as 2-(2-methoxy-benzylamino)-quinoline-6-carboxylic acid ethyl ester as a white solid (196 mg, 58%), MS (ISP) 337.3 [(M+H)+]; m.p. 108° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[C:4]2[N:10]([Si](C(C)C)(C(C)C)C(C)C)[CH:11]=[C:12]([CH2:13][CH3:14])[C:3]=12.Cl>O1CCOCC1>[Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[C:4]2[NH:10][CH:11]=[C:12]([CH2:13][CH3:14])[C:3]=12
Reactant: CCc1cn([Si](C(C)C)(C(C)C)C(C)C)c2ncc(C=O)c(Cl)c12
Agent: Cl
Solvent: C1COCCO1
Product: CCc1c[nH]c2ncc(C=O)c(Cl)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.2 %

Procedure:
4-Chloro-3-ethyl-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (1.48 g, 4.05 mmol) in 1,4-dioxane (15 mL) was treated with HCl (4.0 N in 1,4-dioxane, 2.0 mL, 8.1 mmol) then the mixture was stirred for about 16 h at rt. The solvents were evaporated then the material was suspended in Et2O (15 mL) then the solids were collected by filtration and dried under reduced pressure overnight to give 4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (0.762 g, 90%): LC/MS (Table 2, Method a) Rt=2.21 min; MS m/z 209 (M+H)+.
Reaction SMILES: [CH2:1]([CH2:11][C:12](=O)[CH3:13])[C:2]1[CH:10]=[CH:9][C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1.O>C1(C)C=CC=CC=1>[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH:21][CH:12]([CH3:13])[CH2:11][CH2:1][C:2]2[CH:10]=[CH:9][C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=2)=[CH:18][CH:17]=1
Reactant: COc1cc(CCC(C)=O)ccc1O
Reactant: NCc1ccc(Cl)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(CCC(C)NCc2ccc(Cl)cc2)ccc1O
Temperature: 0 °C
Yield: 74.9 %

Procedure:
Vanillylacetone (5.00 g, 25.7 mmol) was dissolved in toluene (250 mL) and 4-chlorobenzylamine (3.82 g, 27.0 mmol) was added. The mixture was maintained under an atmosphere of nitrogen and heated at reflux with removal of water by Dean-Stark distillation for 16 hours. At this time the Dean-Stark trap was removed and the reaction mixture was cooled to 0° C. on an ice bath. A solution of sodium borohydride (5 g) in methanol (100 mL) was added portion-wise over 30 minutes with vigorous stirring. When the addition was complete the mixture was heated at reflux for 16 hours. At this time the reaction mixture was cooled to room temperature and poured into saturated aqueous sodium bicarbonate solution (300 mL). The resulting mixture was concentrated by rotary evaporation and the aqueous residue was partitioned between water and chloroform. The chloroform layer was dried over anhydrous sodium sulfate and then filtered and concentrated. The product was then purified using silica gel column chromatography employing a mobile phase of 5% ammonia-methanol in chloroform. Product-containing fractions were combined and concentrated then dried under high vacuum overnight to provide a light brown oil (6.16 g, 75%). 1H NMR, 13C NMR, and Mass Spectrum of the product were substantially the same as those in Example 1, A (made by the Conditioned Extraction method).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:12]([NH:15][CH2:16][CH2:17][CH2:18][CH3:19])(=[O:14])=[O:13])[CH:5]=[C:6]([CH:10]=[O:11])[C:7]=1[O:8][CH3:9].[C:20]([NH:24][S:25]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=1)(=[O:27])=[O:26])([CH3:23])([CH3:22])[CH3:21]>>[CH2:16]([NH:15][S:12]([C:4]1[CH:3]=[C:2]([C:32]2[CH:31]=[CH:30][CH:29]=[C:28]([S:25]([NH:24][C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:26])=[O:27])[CH:33]=2)[C:7]([O:8][CH3:9])=[C:6]([CH:10]=[O:11])[CH:5]=1)(=[O:14])=[O:13])[CH2:17][CH2:18][CH3:19]
Reactant: CCCCNS(=O)(=O)c1cc(Br)c(OC)c(C=O)c1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B2OC(C)(C)C(C)(C)O2)c1
Product: CCCCNS(=O)(=O)c1cc(C=O)c(OC)c(-c2cccc(S(=O)(=O)NC(C)(C)C)c2)c1
Yield: 89.1 %

Procedure:
Proceeding as in Reference 19, but substituting 3-bromo-N-butyl-5-formyl-4-methoxy-benzenesulfonamide (0.65 g, 1.72 mmol) and N-tert-butyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzenesulfonamide (0.64 g, 1.90 mmol, 1.1 eq.), gave N-butyl-N′-tert-butyl-5-formyl-6-methoxy-biphenyl-3,3′-disulfonamide (0.74 g) as on orange oil.
Reaction SMILES: [Br:1]Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:23][C:24]#[C:25][C:26]1[N:30]=[CH:29][N:28]([C:31]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:27]=1.C(N(CC)CC)C>ClCCl>[Br:1][CH2:23][C:24]#[C:25][C:26]1[N:30]=[CH:29][N:28]([C:31]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:27]=1
Reactant: BrBr
Reactant: OCC#Cc1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: BrCC#Cc1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 0 °C

Procedure:
A solution of bromine (1.72 ml) in dry dichloromethane (10 ml) was added dropwise to a stirred, cooled (-5° C.), solution of triphenylphosphine (8.74 g) in dry dichloromethane (140 ml) whilst maintaining the temperature below 0° C. The solution was stirred for a further ten minutes at 0° C., then treated dropwise over one hour with a solution of the above alcohol (12.17 g) and triethylamine (4.64 ml) in dry dichloromethane (200 ml). After ten minutes, the mixture was evaporated under reduced pressure and the residue chromatographed on silica, using dichloromethane-ether (25:2) as eluant, to give 1-bromo-3(1-trityl-1,2,4-triazol-3-yl)prop-2-yne (8.10 g, m.p. 181-183° C. dec). NMR (CDCl3): δ 4.1(2H,s), 7.05-7.35(15H,m), 7.95(1H,s). M/S: M+ 427,429.
Reaction SMILES: [C:1]1([NH:7][C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16]1([CH2:22][CH:23]=O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:1]1([NH:7][C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:23][CH2:22][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CCc1ccccc1
Reactant: O=C(Nc1ccccc1)N1CCNCC1
Product: O=C(Nc1ccccc1)N1CCN(CCc2ccccc2)CC1

Procedure:
The title compound was prepared from piperazine-1-carboxylic acid phenylamide and phenylacetaldehyde. 1H NMR (400 MHz, CDCl3): 7.37-7.19 (m, 9H), 7.06-7.02 (m, 1H), 6.31 (s, 1H), 3.55-3.53 (m, 4H), 2.85-2.81 (m, 2H), 2.67-2.56 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:11]([O:12][CH3:13])=[C:10]([F:14])[C:5]2[NH:6][C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.[C:15]1([CH3:23])[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]=O)[CH:16]=1.[BH4-].[Na+]>>[F:14][C:10]1[C:5]2[NH:6][C:7](=[O:9])[O:8][C:4]=2[CH:3]=[C:2]([NH:1][CH2:23][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=2)[C:11]=1[O:12][CH3:13]
Reactant: Cc1cccc(C=O)c1
Reactant: COc1c(N)cc2oc(=O)[nH]c2c1F
Agent: [BH4-]
Agent: [Na+]
Product: COc1c(NCc2cccc(C)c2)cc2oc(=O)[nH]c2c1F

Procedure:
Following the procedure of Example 13, 6-amino-4-fluoro-5-methoxy-2-benzoxazolone (Example 11) was reacted with 3-tolualdehyde and the resulting product was reduced with sodium borohydride to give the title compound: m.p. 160°-161° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:25])=[C:6]([CH:24]=1)[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1)=[O:8].[C:26]([O:30][C:31]([NH:33][C@H:34]([C:39]([NH:41][C@H:42]([C:50](O)=[O:51])[CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37])=[O:32])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([O:30][C:31]([NH:33][C@H:34]([C:39]([NH:41][C@H:42]([C:50]([O:25][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:24][C:6]=1[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:21])([F:22])[F:23])[CH:11]=1)=[O:8])=[O:51])[CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37])=[O:32])([CH3:27])([CH3:28])[CH3:29]
Reactant: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(Cl)ccc1O
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1ccccc1)C(=O)Oc1ccc(Cl)cc1C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 38.5 %

Procedure:
Using 5-chloro-2-hydroxy-N-[3,5-bis(trifluoromethyl)phenyl]-benzamide(compound of Example 1(1)) and N-[N-(tert-butoxycarbonyl)-L-leucyl]-L-phenylalanine as the raw materials, the same operation as the Example 24 gave the title compound.
Reaction SMILES: [NH2:1][CH:2]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)[CH3:3].[Br:17][C:18]1[C:19](Cl)=[N:20][C:21]([Cl:24])=[N:22][CH:23]=1.C(N(C(C)C)C(C)C)C>C(O)C>[Br:17][C:18]1[C:19]([NH:1][CH:2]([CH:4]2[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])[CH2:8][CH2:9]2)[CH3:3])=[N:20][C:21]([Cl:24])=[N:22][CH:23]=1
Reactant: CC(N)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(Nc1nc(Cl)ncc1Br)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.1 %

Procedure:
To the solution of tert-butyl 4-(1-aminoethyl)piperidine-1-carboxylate (5 g, 21.9 mmol) in ethanol (50 ml) were added 5-bromo-2,4-dichloropyrimidine (5.97 g, 26.3 mmol), and N-ethyl-N-isopropylpropan-2-amine (8.48 g, 65.7 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuum, and the crude product was added to water (100 ml). The aqueous layer was extracted with ethyl acetate (50 mL×4) and organic layer was dried over sodium sulfate and concentrated to give crude product tert-butyl 4-(1-((5-bromo-2-chloropyrimidin-4-yl)amino)ethyl)piperidine-1-carboxylate (7 g, yield: 97.2%) as a yellow oil. LRMS (M+H+) m/z: calcd 418. found 419.