Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:26])[CH:5]([N:11]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:6]([CH:8]1[CH2:10][CH2:9]1)[OH:7])C.O.[OH-].[Li+]>O1CCCC1.O>[CH:8]1([CH:6]([OH:7])[CH:5]([N:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:4]([OH:26])=[O:3])[CH2:10][CH2:9]1
Reactant: CCOC(=O)C(C(O)C1CC1)N(Cc1ccccc1)Cc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(C(O)C1CC1)N(Cc1ccccc1)Cc1ccccc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To 17.1 g (48.5 mmol) racemic (2R,3S and 2S,3R)-3-cyclopropyl-2-dibenzylamino-3-hydroxy-propionic acid ethyl ester in 446 ml tetrahydrofurane were added 8.22 g (194 mmol) lithium hydroxide monohydrate dissolved in 74 ml water. The mixture was stirred at 60° C. overnight. The organic solvent was removed by distillation. Sodium dihydrogenphosphate was added followed by extraction with ethyl acetate. Chromatography on silicagel with diethylether/heptane (1:1 to 1:0) yielded 9.03 g (57%) racemic (2R,3S and 2S,3R)-3-cyclopropyl-2-dibenzylamino-3-hydroxy-propionic acid, MS m/e (%): 326.1 (M+H+, 100).
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[Br-].[CH2:17]([Zn+])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1COCC1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:11]=1[CH3:12]
Reactant: [Zn+]CCc1ccccc1
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: Cc1c(CCc2ccccc2)nc2cc(F)cc(F)c2c1Cl
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A screw cap vial was charged with 2,4-dichloro-5,7-difluoro-3-methylquinoline (500 mg, 2.016 mmol), tetrakis(triphenylphosphine)palladium(0) (233 mg, 0.202 mmol), and THF (5.04 mL). The mixture was sparged with N2, then phenethyl-zinc(II) bromide (0.5 M in THF, 4.23 mL, 2.116 mmol) was added and the reaction stirred at 60° C. for 2 h. The reaction was then partitioned between EtOAc and water, and the organic layer washed with brine, dried (MgSO4), and concentrated. The crude material was purified by flash chromatography, eluting with a gradient of 0-15% EtOAc in hexane to give 4-chloro-5,7-difluoro-3-methyl-2-phenethylquinoline. Mass Spectrum (ESI) m/e=318.0 (M+1).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[C:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.[H-].[Na+].Br[CH2:20][CH:21]1[CH2:23][CH2:22]1>CN(C=O)C>[CH:21]1([CH2:20][N:1]2[C:9]3[CH:8]=[C:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[N:6]=[CH:5][C:4]=3[CH:3]=[CH:2]2)[CH2:23][CH2:22]1
Reactant: BrCC1CC1
Reactant: CC(C)(C)OC(=O)c1cc2[nH]ccc2cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1cc2c(ccn2CC2CC2)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
To a mixture of tert-butyl 1H-pyrrolo[3,2-c]pyridine-6-carboxylate (1.0 g, 4.6 mmol) in DMF (20 ml) was added sodium hydride (60% in oil) (0.4 g, 10 mmol) and stirred at room temperature for 3 h. To the mixture, (bromomethyl)cyclopropane (1.2 g, 9.2 mmol) was added and stirred at room temperature. for 2 h. The reaction mixture was extracted with EtOAc/H2O. The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The crude mixture was purified by chromatography (SiO2, hexanes:EtOAc=50:50) to give tert-butyl 1-(cyclopropylmethyl)-1H-pyrrolo[3,2-c]pyridine-6-carboxylate (2A, 1.1 g, 4.0 mmol, 88% yield) as a yellow oil. 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.16-0.23 (m, 2 H) 0.44-0.51 (m, 2 H) 0.99-1.11 (m, 1H) 1.48 (s, 9 H) 3.84 (d, J=7.07 Hz, 2 H) 6.45-6.47 (m, 1 H) 7.19 (d, J=3.03 Hz, 1 H) 7.96 (s, 1 H) 8.79 (s, 1 H).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[S:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]([CH2:22][C:23]#[C:24][Si](C)(C)C)[CH2:19][CH2:18][CH2:17]2.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[S:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]([CH2:22][C:23]#[CH:24])[CH2:19][CH2:18][CH2:17]2
Reactant: C[Si](C)(C)C#CCN1CCCc2cccc(CSc3nc4ccccc4[nH]3)c21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#CCN1CCCc2cccc(CSc3nc4ccccc4[nH]3)c21
Yield: 106.4 %

Procedure:
To a solution of 8-(2-benzimidazolyl)thiomethyl-1-(3-trimethylsilyl-2-propinyl)-1,2,3,4-tetrahydroquinoline (400 mg) in tetrahydrofuran (20 ml) was added 1M solution of tetra-n-butylammonium fluoride with stirring under ice-cooling, and the mixture was stirred for 30 minutes at the same temperature. After distilling off the solvent, the resulting residue was extracted with dichloromethane. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography [eluent:n-hexane-ethyl acetate (5.5:1)], and recrystallized from dichloromethane-diethyl ether to give 8-(2-benzimidazolyl)thiomethyl-1-propargyl-1,2,3,4-tetrahydroquinoline (0.35 g).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:11][C:12]1[N:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:13]=1[C:14]([NH2:16])=[O:15].CN(C)[CH:25]=[O:26].Cl>CC1CCCO1>[Cl:11][C:12]1[C:13]2[C:14](=[O:15])[NH:16][CH:25]([OH:26])[C:17]=2[C:18]([F:22])=[C:19]([F:21])[N:20]=1
Reactant: CN(C)C=O
Reactant: NC(=O)c1cc(F)c(F)nc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: CC1CCCO1
Product: O=C1NC(O)c2c(F)c(F)nc(Cl)c21
Temperature: 2.5 °C
Yield: 87.9 %

Procedure:
To an inert 250 mL 3-neck round bottom flask with magnetic stirring was added LiHMDS (1M in THF, 57.3 mL, 57.3 mmol). The solution was cooled in an ice/brine bath to achieve an internal temperature of −4° C. To the cooled LiHMDS solution was added dropwise a solution of 2-chloro-5,6-difluoronicotinamide (4.41 g, 22.9 mmol) dissolved in 2-methyltetrahydrofuran (22 mL) and N,N-dimethylformamide (8.87 mL, 115 mmol) while maintaining the internal temperature between +1° C. to −3° C. The reaction mixture was stirred for 30 minutes at a temperature of about 0° C. The reaction was quenched by adding it dropwise to a cooled (0-5° C.) stirred mixture of 2M aqueous HCl (74.4 mL, 149 mmol) and IPAc (75 mL) while maintaining an internal temperature <10° C. Once the transfer was completed, the biphasic solution was transferred to a separatory funnel and the lower aqueous layer was removed and extracted with IPAc (75 mL). The organic layers were combined, washed with water (25 mL), dried over sodium sulfate, and concentrated on a rotary evaporator. The resulting solid was suspended in heptane (20 mL), and the mixture was stirred for 90 minutes and filtered. The filter cake was washed with heptane (20 mL) and dried to give the title compound as an off-white solid (4.442 g, 88%). 1H NMR (400 MHz, DMSO-d6) δ ppm 6.11-6.14 (m, 1H), 6.98 (d, J=8 Hz, 1H), 9.5 (s br, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.Cl.Cl.[N:20]1([CH2:25][C@H:26]2[CH2:31][CH2:30][C@H:29]([NH2:32])[CH2:28][CH2:27]2)[CH2:24][CH2:23][CH2:22][CH2:21]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:32][C@H:29]1[CH2:28][CH2:27][C@H:26]([CH2:25][N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:31][CH2:30]1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Reactant: N[C@H]1CC[C@H](CN2CCCC2)CC1
Agent: Cl
Product: O=C(c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](CN2CCCC2)CC1)C1CC1

Procedure:
Following general procedure C, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (466 mg, 1.5 mmol) was reacted with trans-4-(pyrrolidin-1-ylmethyl)cyclohexanamine dihydrochloride (847 mg, 3.0 mmol) to afford the desired product (180 mg, 52%) as an off-white solid. ESI MS m/z 456 [C24H30BrN3O+H]+
Reaction SMILES: [N+](C1C=C([N+]([O-])=O)C=CC=1[Cl:13])([O-])=O.[N+:14]([C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:18]=1[OH:26])([O-:16])=[O:15].[N+](COCCOC1C=CC(OC[N+]([O-])=O)=CC=1)([O-])=O.[OH-].[Na+].Cl.[Na].C=O.C1(S(O)(=O)=O)C2C(=CC=CC=2)C=CC=1.I(Cl)(Cl)Cl.ClCl.Cl[O-].[Na+]>[Fe](Cl)(Cl)Cl.O>[Cl:13][C:19]1[C:18]([OH:26])=[C:17]([N+:14]([O-:16])=[O:15])[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=1.[N+:14]([C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:18]=1[OH:26])([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl[Fe](Cl)Cl
Agent: C=O
Agent: Cl
Solvent: O
Product: O=[N+]([O-])c1cc(Cl)c(O)c([N+](=O)[O-])c1

Procedure:
A mixture of 183 parts of 2,4-dinitrochlorobenzene, 16 parts of 2,4-dinitrophenol and 3 parts of 2,4-dinitromethoxyethoxybenzene is saponified to 2,4-dinitrophenol in a mixture of 303 parts of 33% strength sodium hydroxide solution and 3,000 parts of water at 95° C. under an atmosphere of air. The resulting suspension i adjusted to a pH value of 3.5 by adding 185 parts of 31% strength hydrochloric acid. After 10 parts of the sodium salt of a naphthalenesulfonic acid formaldehyde condensation product (dispersing agent), 1 part of iron(III) chloride and 1 part of iodine trichloride have been added, 650 parts of 13 percent strength by weight chlorine bleach liquor (containing 150 g of active chlorine per liter) are added dropwise at 10° C. in the course of 8 hours, the pH increasing meanwhile. In the course of the addition, the pH reaches a value of 4.5. After it has reached this value, the pH is caused to remain, during the chlorination, within the range 4-4.5 by the simultaneous addition of 36 parts of 31% strength hydrochloric acid during the dropwise addition of the remainder of the chlorine bleach liquor. The pH of the suspension is then adjusted to a value of 1.0 by means of 170 parts of 31% strength hydrochloric acid, and small amounts of sodium hypochlorite still present are destroyed by means of 15 parts of 40% strength sodium bisulfite solution. The resulting product is then isolated by being filtered off at about 10° C. 200 parts of pale yellow 6-chloro-2,4-dinitrophenol (melting point: 101°-109° C.), now only containing traces (0.5%) of 2,4-dinitrophenol, are obtained.
Reaction SMILES: [CH3:1]I.C(=O)([O-])[O-].[K+].[K+].O.[C:10]12([N:20](C)[C:21]3[C:22]([NH2:27])=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:19][CH:14]3[CH2:15][CH:16]([CH2:18][CH:12]([CH2:13]3)[CH2:11]1)[CH2:17]2>CN(C=O)C>[C:10]12([NH:20][C:21]3[C:22]([NH:27][CH3:1])=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:17][CH:16]3[CH2:18][CH:12]([CH2:13][CH:14]([CH2:15]3)[CH2:19]1)[CH2:11]2
Reactant: CI
Reactant: CN(c1ccccc1N)C12CC3CC(CC(C3)C1)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CNc1ccccc1NC12CC3CC(CC(C3)C1)C2
Reaction time: 4.5 h

Procedure:
Methyl iodide (0.564 ml) was added to a mixture of intermediate 11 (2 g) and potassium carbonate (1.75 g) in dry DMF (8 ml) at 23° under nitrogen. After 4.5 h, the mixture was poured into water (100 ml) and extracted with EA (2×100 ml). The combined extracts were washed with water and saturated brine then dried and evaporated. The residue was chromatographed with hexane- EA (8:1 to 6:1 to 4:1) as eluent to give a 70:30 mixture of the title compound with N-adamantan-1-yl-N-methylbenzene-1,2-diamine (904 mg) as a yellow solid, m.p. 68°-76° dec.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:7]([I:17])=[C:8]([C:12]([I:16])=[CH:13][C:14]=1[I:15])[C:9]([OH:11])=[O:10])=[O:4].[NH4+:18].[OH-]>>[NH2:18][CH2:2][C:3]([NH:5][C:6]1[C:7]([I:17])=[C:8]([C:12]([I:16])=[CH:13][C:14]=1[I:15])[C:9]([OH:11])=[O:10])=[O:4]
Reactant: [NH4+]
Reactant: O=C(CCl)Nc1c(I)cc(I)c(C(=O)O)c1I
Agent: [OH-]
Product: NCC(=O)Nc1c(I)cc(I)c(C(=O)O)c1I
Reaction time: 35 h
Yield: 98.4 %

Procedure:
6.34 g of 3-[(2-chloroacetyl)amino]-2,4,6-triiodobenzoic acid (prepared as described in Example 3) (10.72 mmol) are dissolved in 250 ml of 25% NH4OH and the solution is kept in autoclave for 35 hours at r.t. The mixture is evaporated to dryness and the residue is then dissolved in H2O, adjusting the pH to 7 and yielding a precipitate, which is filtered. 5.74 g of 3-[(2-aminoacetyl)amino]-2,4,6-triiodobenzoic acid (10.04 mmol) are obtained.
Reaction SMILES: Br[C:2]1[C:3]([CH3:23])=[C:4]([C:7]2[N:11]3[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]3=[N:9][C:8]=2[CH3:22])[S:5][CH:6]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[C:26](B(O)O)[CH:25]=1.C([O-])([O-])=O.[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2].C(O)CC>[CH2:17]([CH:16]([C:15]1[C:10]2[N:11]([C:7]([C:4]3[S:5][CH:6]=[C:2]([C:26]4[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=4)[C:3]=3[CH3:23])=[C:8]([CH3:22])[N:9]=2)[N:12]=[C:13]([CH3:21])[CH:14]=1)[CH2:19][CH3:20])[CH3:18]
Reactant: OB(O)c1cccnc1
Reactant: CCC(CC)c1cc(C)nn2c(-c3scc(Br)c3C)c(C)nc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CCCO
Product: CCC(CC)c1cc(C)nn2c(-c3scc(-c4cccnc4)c3C)c(C)nc12
Temperature: 90 °C
Yield: 20.3 %

Procedure:
A solution of 3-(4-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.25 g, 0.64 mmol), pyridine-3-boronic acid (0.086 g, 0.70 mmol), 2 M Na2CO3 (0.48 mL, 0.96 mmol) and, n-PrOH (3 mL), is degassed with nitrogen for 10 minutes. Pd(OAc)2 (2.7 mg, 0.0013 mmol) and PPh3 (0.010 g, 0.038 mmol) are added and the solution is heated at 90° C. overnight. The solution is diluted with EtOAc (30 mL), washed with 10% Na2CO3 (30 mL), water (30 mL), brine (30 mL), dried over MgSO4, filtered, and concentrated. The residue is purified by ISCO (20-40% EtOAc gradient) furnish the title compound (0.051 g, 0.13 mmol, 20%). 1H NMR (CDCl3) δ 0.88 (t, J=7.5 Hz, 6H), 1.74-1.92 (m, 4H), 2.09 (s, 3H), 2.50 (s, 3H), 2.52 (s, 3H), 3.29-3.40 (m, 1H), 6.69 (s, 1H), 7.33-7.43 (m, 1H), 7.47 (s, 1H), 7.80 (d, J=7.9 Hz, 1H), 8.61 (bs, 1H), 8.78 (bs, 1H). LC/MS (m/z): calcd. for C23H26N4S (M+H)+: 391.2; found: 391.4.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=2)[N:3]=[N:2]1.[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=1)=[O:17]>>[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][N:28]([CH2:10][C:9]3[CH:12]=[CH:13][C:6]([C:4]4[N:3]=[N:2][S:1][CH:5]=4)=[CH:7][CH:8]=3)[CH2:27][CH2:26]2)[CH:20]=1)=[O:17]
Reactant: O=Cc1ccc(-c2csnn2)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc(-c4csnn4)cc3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 4-(1,2,3-thiadiazol-4-yl)benzaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 421.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[C:25]([CH2:27][N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[CH:24]=[CH:23][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH:15]=[C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)=[O:5].[C:35](N1C=CN=C1)(N1C=CN=C1)=[O:36]>O1CCCC1>[CH3:34][N:31]1[CH2:32][CH2:33][N:28]([CH2:27][C:25]2[CH:26]=[C:2]3[C:3]([C:4](=[O:5])[N:6]([CH2:7][CH2:8][CH2:9][CH2:10][N:11]4[CH2:12][CH:13]=[C:14]([C:17]5[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=5)[CH2:15][CH2:16]4)[C:35](=[O:36])[NH:1]3)=[CH:23][CH:24]=2)[CH2:29][CH2:30]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CN1CCN(Cc2ccc(C(=O)NCCCCN3CC=C(c4ccccc4)CC3)c(N)c2)CC1
Solvent: C1CCOC1
Product: CN1CCN(Cc2ccc3c(=O)n(CCCCN4CC=C(c5ccccc5)CC4)c(=O)[nH]c3c2)CC1
Yield: 60.6 %

Procedure:
A mixture of 2-amino-4-(4-methylpiperazin-1-ylmethyl)-N-[4-(4-phenyl-1,2,3,6-tetrahydropyridin 1-yl)butyl]benzamide (0.25 g), carbonyldiimidazole (0.45 g) and dry tetrahydrofuran (10 ml) was stirred under reflux for 14 hours. After evaporation of the solvent, the crude residue was taken up with ethyl acetate, washed with water, dried over magnesium sulfate and evaporated to give crystals. Recrystallization from ethanol afforded 7-(4-methylpiperazin-1-ylmethyl)-3-[4-(4-phenyl-1,2,3,6-tetrahydropyridin 1-yl)butyl]-1,2,3,4-tetrahydroquinazoline-2,4-dione (0.16 g).
Reaction SMILES: C(Cl)(Cl)Cl.[C:5]([O-])([O-])=[O:6].[K+].[K+].[Cl:11][C:12]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][C:13]=1[OH:22].Cl>O>[Cl:11][C:12]1[C:17]([C:18]([F:20])([F:21])[F:19])=[C:16]([CH:15]=[CH:14][C:13]=1[OH:22])[CH:5]=[O:6]
Reactant: O=C([O-])[O-]
Reactant: Oc1cccc(C(F)(F)F)c1Cl
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=Cc1ccc(O)c(Cl)c1C(F)(F)F
Yield: 11.7 %

Procedure:
Chloroform (6.7 g, 2.0 eq.) was added dropwise to a stirred mixture of Ca(OH)2 (8.95 g, 120 mmol.), K2CO3 (13.5 g, 98 mmol.), 2-chloro-3-(trifluoromethyl)phenol (5.0 g, 22 mmol.), and H2O (50 mL) at 60-70° C. over 2 h. The reaction mixture was cooled, and acidified with conc. HCl. The product was extracted into EtOAc and dried over Na2SO4. Solvent was evaporated, the crude product was separated and purified through a silica column, eluting with hexane and EtOAc (3:2) to give 580 mg (10%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:29])=[C:6]([CH:28]=1)[O:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:18]=[C:17]([C:19]3[N:20]=[N:21][N:22]([CH2:24][C:25]([OH:27])=[O:26])[N:23]=3)[O:16][N:15]=2)[CH2:10][CH2:9]1.[F:30][C:31]([F:43])([F:42])[O:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:29][C:5]1[CH:4]=[CH:3][C:2]([C:36]2[CH:35]=[CH:34][C:33]([O:32][C:31]([F:30])([F:42])[F:43])=[CH:38][CH:37]=2)=[CH:28][C:6]=1[O:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:18]=[C:17]([C:19]3[N:20]=[N:21][N:22]([CH2:24][C:25]([OH:27])=[O:26])[N:23]=3)[O:16][N:15]=2)[CH2:10][CH2:9]1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: O=C(O)Cn1nnc(-c2cc(N3CCC(Oc4cc(Br)ccc4Cl)CC3)no2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C(O)Cn1nnc(-c2cc(N3CCC(Oc4cc(-c5ccc(OC(F)(F)F)cc5)ccc4Cl)CC3)no2)n1
Temperature: 80 °C

Procedure:
To a suspension of (5-{3-[4-(5-bromo-2-chlorophenoxy)piperidin-1-yl]isoxazol-5-yl}-2H-tetrazol-2-yl)acetic acid (130 mg, 0.269 mmol), [4-(trifluoromethoxy)phenyl]boronic acid (98 mg, 0.476 mmol) and Pd(Ph3P)4 (25 mg, 0.022 mmol) in toluene (4 mL) was added aqueous 2 M Na2CO3 (1.5 mL, 3.00 mmol). After the resulting heterogeneous mixture was purged with nitrogen, it was gently heated to 80° C. for 6 h with stirring under a nitrogen atmosphere. After cooling to room temperature, the reaction was poured into aqueous 1 N HCl and extracted with EtOAc. The organic layer was washed with brine and dried (Na2SO4). Solvents were removed under reduced pressure and the crude material was purified by column chromatography on silica gel (gradient from 0% to 3% HOAc/EtOAc). After concentration, the white solid was co-evaporated twice and triturated with Et2O/heptane to give the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6): δ13.92 (br s, 1H), 7.88-7.83 (m, 2H), 7.57-7.54 (m, 2H), 7.49 (d, 2H), 7.30 (dd, 1H), 7.27 (s, 1H), 5.83 (s, 2H), 5.00-4.93 (m, 1H), 3.68-3.60 (m, 2H), 3.41-3.35 (m, 2H), 2.12-2.02 (s, 2H), 1.87-1.78 (m, 2H). MS: m/z 565 (MH+).
Reaction SMILES: Br[C:2]1[C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=[C:4]([C:11]2[S:15][C:14]([NH:16][C:17](=[O:26])[C:18]3[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=3[F:25])=[N:13][C:12]=2[CH3:27])[CH:3]=1>CCO.[Pd]>[O:8]1[C:7]2[CH:2]=[CH:3][C:4]([C:11]3[S:15][C:14]([NH:16][C:17](=[O:26])[C:18]4[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=4[F:25])=[N:13][C:12]=3[CH3:27])=[CH:5][C:6]=2[O:10][CH2:9]1
Reactant: Cc1nc(NC(=O)c2c(F)cccc2F)sc1-c1cc(Br)c2c(c1)OCO2
Agent: [Pd]
Solvent: CCO
Product: Cc1nc(NC(=O)c2c(F)cccc2F)sc1-c1ccc2c(c1)OCO2
Reaction time: 8 h
Yield: 89.6 %

Procedure:
A mixture of Compound 56 (50 mg) and 10% Pd/C (10 mg) in EtOH (2.0 mL) was stirred under an atmosphere of hydrogen gas overnight. The mixture was filtered through a short plug of celite. The filtrate was concentrated under reduced pressure to give Compound 57 (37 mg).
Reaction SMILES: [BH4-].[Na+].[NH2:3][CH:4]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:11]=1)[CH2:5][C:6](OC)=[O:7]>CO>[NH2:3][CH:4]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23]2)[CH:11]=1)[CH2:5][CH2:6][OH:7]
Reactant: COC(=O)CC(N)c1ccc(OC)c(OC2CCCC2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(C(N)CCO)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.2 %

Procedure:
To a stirred solid of sodium borohydride (37 grams, 978 mmol) at 0° C., was added methanol (50 mL). To this mixture at 0° C. was added a solution of methyl 3-amino-3-(3'-cyclopentyloxy-4'-methoxyphenyl)propionate (27 grams, 92.2 mmol) in methanol (500 mL) over 1 h. The mixture was stirred in that ice-water bath until the temperature of the reaction mixture stayed at 35° C. or lower for 30 minutes. (Caution: If the ice-water bath was removed too early, a highly exothermic reaction may occur.) The water bath was then removed and the solution was refluxed for 16 h. The solution was allowed to cool to room temperature. To the solution was added water (125 mL), followed by methylene chloride (250 mL) at 0° C. The resulting suspension was filtered. Half of the filtrate was removed in vacuo. The resulting solution was dissolved in methylene chloride (250 mL) and water (200 mL). The organic layer was separated. The aqueous layer was extracted with methylene chloride (3×250 mL). The combined organic layers were washed with brine (100 mL), and dried over magnesium sulfate. Removal of solvent gave an oil. The resulting oil was dried in vacuo to afford 3-amino-3-(3'-cyclopentyloxy-4'-methoxyphenyl)-1-propanol as a white solid (22.3 grams, 91% yield): mp, 216.0°-217.5° C.; 1H NMR (CDCl3)δ1.52-1.68 (m, 2H, CH2), 1.76-1.91 (m, 8H, C5H8), 2.92 (brs, 3H, NH2, OH), 3.76 (t, J=5.5 Hz, 2H, CH2), 3.82 (s, 3H, CH3), 4.06 (t, J=Hz, 1H, OCH), 4.76-4.79 (m, 1H, NCH), 6.82-6.84 (m, 3H, Ar); 13C NMR (CDCl3)δ23.96, 32.75, 39.91, 55.59, 56.10, 61.62, 80.46, 112.11, 112.99, 117.75, 138.65, 147.74, 149.12; Anal Calcd for C15H23NO3 0.05CH2Cl2 : C, 67.05; H, 8.64, N, 5.20. Found: C, 67.02; H, 8.41; N, 5.08.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7](=[O:20])[N:8]([C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=2[Cl:19])[N:9]=1)[CH2:2][CH2:3][CH3:4].[C:21]([NH:25][S:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]1[CH:40]=[CH:39][C:38]([CH2:41]Br)=[CH:37][CH:36]=1)(=[O:28])=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[CH2:1]([C:5]1[N:6]([CH2:41][C:38]2[CH:39]=[CH:40][C:35]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[S:26](=[O:28])(=[O:27])[NH:25][C:21]([CH3:22])([CH3:24])[CH3:23])=[CH:36][CH:37]=2)[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=2[Cl:19])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Cl)c(=O)[nH]1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(CBr)cc1
Product: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1
Yield: 83 %

Procedure:
By the procedure of Example 13, Step A, 5-n-butyl-2-(2-chloro-5-nitrophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (from Step A) was alkylated with [2'-(N-t-butylsulfamoyl)biphenyl-4-yl]methyl bromide (from Example 12, Step D). Flash chromatography of the crude product on silica gel (gradient elution with 0.5-5.0% MeOH in CH2Cl2) gave an 83% yield of the title compound as an orange solid, mp >75° C. (gradual), homogeneous by TLC (98:2 CH2Cl2 --MeOH), mass spectrum (FAB) m/e 598 (M+1)+.