Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=O)=[C:9]([CH3:26])[O:8][N:7]=1)[CH3:5])=[N+]=[N-].CP(C)C>C1(C)C=CC=CC=1>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:17]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[C:10]3=[C:9]([CH3:26])[O:8][N:7]=[C:6]3[CH:4]([CH3:5])[N:1]=2)=[CH:20][CH:21]=1
Reactant: Cc1onc(C(C)N=[N+]=[N-])c1-c1ccccc1C(=O)c1ccc(Cl)cc1
Agent: CP(C)C
Solvent: Cc1ccccc1
Product: Cc1onc2c1-c1ccccc1C(c1ccc(Cl)cc1)=NC2C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a round bottomed flask was added (2-(3-(1-azidoethyl)-5-methylisoxazol-4-yl)phenyl)(4-chlorophenyl)methanone (0.073 g, 0.199 mmol), toluene, and trimethylphosphine (0.239 mL, 1M in toluene, 0.239 mmol). The reaction was stirred at room temperature overnight before concentrating. The crude residue was purified via Biotage (EtOAc/hex) to afford impure 6-(4-chlorophenyl)-1,4-dimethyl-4H-benzo[c]isoxazolo[4,3-e]azepine. This material was purified via preparatory HPLC and the fractions neutralized before being extracted with EtOAc. The organics were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude residue was purified via Biotage (EtOAc/hex) to afford 6-(4-chlorophenyl)-1,4-dimethyl-4H-benzo[c]isoxazolo[4,3-e]azepine (0.0011 g, 0.003 mmol). 1H NMR (400 MHz, Acetone-d6) δ 7.74-7.70 (m, 1H), 7.69-7.63 (m, 1H), 7.49-7.41 (m, 3H), 7.41-7.33 (m, 3H), 4.24-4.16 (m, 1H), 2.66 (s, 3H), 1.86 (d, J=6.35 Hz, 3H); LC/MS m/z 323 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-])=O.Cl[Sn]Cl.C([O-])(O)=O.[Na+]>C(O)C>[F:12][C:11]([F:13])([F:14])[C:9]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([NH2:1])[CH:10]=1
Reactant: Nc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Nc1ccc(C(F)(F)F)cc1N
Temperature: 0 °C
Yield: 96.9 %

Procedure:
A solution of 2-nitro-4-trifluoromethylaniline (5.000 g, 24.26 mmol, Aldrich, used as received) and SnCl2 ·2 H2O (20.00 g, 88.64 mmol, Aldrich, used as received) in absolute ethanol (50 mL) was refluxed for 45 min. It was then poured into ice (85 g) and basified with 10% aq. NaHCO3 (250 mL). The resulting suspension was extracted with ethyl acetate (400 mL). The ethyl acetate extract was dried over Na2SO4 and evaporated to give 4.14 g (87%) of pure 4-trifluoromethyl-1,2-phenylenediamine as a red powder.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:7][NH:8][C:9]([NH2:11])=[S:10])=[N:4][O:5][N:6]=1.[O-]CC.[Na+].[C:16]([CH2:18][C:19](OCC)=[O:20])#[N:17]>>[NH2:17][C:16]1[N:8]([CH2:7][C:3]2[C:2]([CH3:1])=[N:6][O:5][N:4]=2)[C:9](=[S:10])[NH:11][C:19](=[O:20])[CH:18]=1
Reactant: CCOC(=O)CC#N
Reactant: Cc1nonc1CNC(N)=S
Agent: CC[O-]
Agent: [Na+]
Product: Cc1nonc1Cn1c(N)cc(=O)[nH]c1=S
Yield: 57.5 %

Procedure:
The title compound was prepared in accordance with the general method described in Example 12(b) by using 1-[(4-methyl-1,2,5-oxadiazol-3-yl)methyl]thiourea (0.55 g, 3.2 mmol, obtained from Example 16(a)), sodium ethoxide (21% w/v, 3.1 mL, 9.5 mmol) and ethyl cyanoacetate (1.0 mL, 9.5 mmol) which provided the title compound (0.44 g, 58% yield).
Reaction SMILES: BrCCBr.C[Si](Cl)(C)C.I[CH2:11][C@H:12]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13]1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[CH2:40]([O:47][C:48]1[CH:53]=[C:52](I)[CH:51]=[CH:50][C:49]=1[N:55]1[S:59](=[O:61])(=[O:60])[N:58]([CH2:62][CH2:63][Si:64]([CH3:67])([CH3:66])[CH3:65])[C:57](=[O:68])[CH2:56]1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>CN(C=O)C.O.[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:40]([O:47][C:48]1[CH:53]=[C:52]([CH2:11][C@@H:12]2[CH2:13][CH2:14][C:15](=[O:17])[NH:16]2)[CH:51]=[CH:50][C:49]=1[N:55]1[S:59](=[O:60])(=[O:61])[N:58]([CH2:62][CH2:63][Si:64]([CH3:66])([CH3:65])[CH3:67])[C:57](=[O:68])[CH2:56]1)[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(I)cc2OCc2ccccc2)S1(=O)=O
Reactant: O=C1CC[C@@H](CI)N1
Agent: [Pd]
Agent: C[Si](C)(C)Cl
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: BrCCBr
Solvent: O
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(C[C@@H]3CCC(=O)N3)cc2OCc2ccccc2)S1(=O)=O
Temperature: 45 °C

Procedure:
Zinc dust (0.69 g, 10.66 mmol) is placed in a round bottom flask and heated under vacuum to remove traces of water. After cooling, DMF (3 mL) is added, followed by 1,2-dibromoethane (0.061 mL, 0.708 mmol). The solution is heated until effervescence occurs, then cooled under N2. To the solution is added TMSCl (0.135 mL, 1.06 mmol). A solution of (S)-5-iodomethylpyrrolidin-2-one (0.40 g, 1.78 mmol) in DMF (5 mL) is added to the mixture and stirred until TLC indicates the absence of starting material. Pd2(dba)3 (0.043 g, 0.047 mmol) and tri-o-tolylphosphine (0.11 g, 0.365 mmol) are added, followed by the dropwise addition of 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (0.645 g, 1.18 mmol) in DMF (10 mL). The mixture is stirred at RT for 4 h, then heated to 45° C. and stirred for 18 h. The mixture is allowed to cool to RT and diluted with water. A yellow precipitate forms after the addition of water. The precipitate is filtered, washed with water and dried under reduced pressure to afford the title compound: (M+H)+=516.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[CH2:11][NH:12][CH:13]1[C:22]2[N:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:16][CH2:15][CH2:14]1)[C:6]#[N:7].[C:23]([C:27]1[CH:32]=[CH:31][N:30]=[C:29]([CH:33]=O)[CH:28]=1)([CH3:26])([CH3:25])[CH3:24].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:23]([C:27]1[CH:32]=[CH:31][N:30]=[C:29]([CH2:33][N:12]([CH2:11][C:10]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[CH2:2][OH:1])[CH:13]2[C:22]3[N:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:16][CH2:15][CH2:14]2)[CH:28]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)c1ccnc(C=O)c1
Reactant: N#Cc1ccc(CNC2CCCc3cccnc32)c(CO)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)c1ccnc(CN(Cc2ccc(C#N)cc2CO)C2CCCc3cccnc32)c1

Procedure:
Using General Procedure B: Reaction of 3-hydroxymethyl-4-[(5,6,7,8-tetrahydro-quinolin-8-ylamino)-methyl]-benzonitrile in CH2Cl2 with 4-tert-butyl-pyridine-2-carbaldehyde and NaBH(OAc)3 gave 4-{[(4-tert-butyl-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-3-hydroxymethyl-benzonitrile as a pale yellow oil. 1H NMR (CDCl3) δ 1.38 (s, 9H), 1.70 (m, 1H), 1.91-2.04 (m, 2H), 2.21 (m, 1H), 2.71 (m, 1H), 2.81 (m, 1H), 3.52 (d, 1H, J=12.0 Hz), 3.64 (d, 1H, J=12.0 Hz), 3.73 (d, 1H, J=12.0 Hz), 3.80 (m, 1H), 4.07 (m, 1H), 4.13 (d, 1H, J=12.0 Hz), 4.34 (d, 1H, J=12.0 Hz), 7.03 (dd, 1H, J=7.5, 3.0 Hz), 7.19 (dd, 1H, J=4.5, 3.0 Hz), 7.36-7.52 (m, 4H), 7.63 (s, 1H), 7.78 (s, 1H), 8.36 (d, 1H, J=6.0 Hz), 8.51 (d, 1H, J=3.0 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH2:13][CH:12]([CH2:16][N:17]3[CH2:25][C:24]4[C:19](=[CH:20][C:21]([O:28][CH3:29])=[C:22]([O:26][CH3:27])[CH:23]=4)[C:18]3=[O:30])[CH2:11]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:38](Cl)(=[O:40])[CH3:39]>C(Cl)Cl>[NH:1]([C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH2:13][CH:12]([CH2:16][N:17]3[CH2:25][C:24]4[C:19](=[CH:20][C:21]([O:28][CH3:29])=[C:22]([O:26][CH3:27])[CH:23]=4)[C:18]3=[O:30])[CH2:11]2)=[CH:6][CH:7]=1)[C:38]([CH3:39])=[O:40]
Reactant: COc1cc2c(cc1OC)C(=O)N(CC1CCCN(CCc3ccc(N)cc3)C1)C2
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1OC)C(=O)N(CC1CCCN(CCc3ccc(NC(C)=O)cc3)C1)C2
Temperature: 25 °C

Procedure:
819 mg (2 mmol) of 2-[(N-(2-(4-amino-phenyl)-ethyl)-piperidin-3-yl)-methyl]-5,6-dimethoxy-1-oxo-1,3-dihydro-isoindole are mixed with 10 ml of methylene chloride and after the addition of 0.3 ml (2.2 mmol) of triethylamine, 0.16 ml (2.2 mmol) of acetyl chloride are added dropwise. The reaction temperature rises to 30° C. The mixture is stirred for half an hour at ambient temperature, extracted twice with water, the organic phase is dried over magnesium sulphate and evaporated down in vacuo. The residue is crystallised from acetone.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])=[N:7][C:6]=2[CH:5]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[CH:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C(NC(C)C)(C)C.CN(C)C=O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[Na+].[Na+].[Na+].P(C1C=C(S([O-])(=O)=O)C=CC=1)(C1C=C(S([O-])(=O)=O)C=CC=1)C1C=C(S([O-])(=O)=O)C=CC=1.C(OCC)(=O)C.O>[C:11]([C:8]1[O:9][C:10]2[C:2]([C:23]3[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=3)=[CH:3][C:4]([C:15]([O:17][CH3:18])=[O:16])=[CH:5][C:6]=2[N:7]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: OB(O)c1ccc(F)cc1
Reactant: COC(=O)c1cc(Br)c2oc(C(C)(C)C)nc2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=S(=O)([O-])c1cccc(P(c2cccc(S(=O)(=O)[O-])c2)c2cccc(S(=O)(=O)[O-])c2)c1
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1cc(-c2ccc(F)cc2)c2oc(C(C)(C)C)nc2c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 91.5 %

Procedure:
To a mixture of methyl 7-bromo-2-tert-butyl-1,3-benzoxazole-5-carboxylate (218 mg, 0.698 mmol), (4-fluorophenyl)-boronic acid (0.147 g, 1.048 mmol), 3,3′,3″-phosphinidynetris (benzensulfonic acid) trisodium salt (34 mg, 0.052 mmol), palladium(II) acetate (3.92 mg, 0.017 mmol) and diisopropylamine (0.100 mL, 0.698 mmol) were added N,N-dimethylformamide (2.62 mL) and water (0.87 mL). The mixture was heated to 80° C. After 30 min, the mixture was cooled to ambient temperature and ethyl acetate was added. The organic layer was washed with water (3×), brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% hexanes→70% hexanes/ethyl acetate) gave the title compound (0.209 g). LC-MS [M+1]=328.3.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][S:5][CH2:6][CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].[C:16](O)(=[O:24])[C:17]1[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[OH:19].CCN=C=NCCCN(C)C>C(Cl)Cl>[OH:19][C:18]1[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=1[C:16]([NH:1][CH2:2][CH2:3][S:4][S:5][CH2:6][CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:24]
Reactant: CC(C)(C)OC(=O)NCCSSCCN
Reactant: O=C(O)c1ccccc1O
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCSSCCNC(=O)c1ccccc1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.2 %

Procedure:
tert-Butyl 2-(2-(2-aminoethyl)disulfanyl)ethylcarbamate (500 mg, 1.98 mmol) was taken up in CH2Cl2 (20 mL) along with salicylic acid (273 mg, 1.98 mmol) and EDCI (693 mmol, 2.2 mmol). The resulting reaction mixture was stirred at room temperature for 18 h. It was then diluted with CH2Cl2, washed with saturated aqueous NaHCO3, brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by chromatography (40% EtOAc, 60% pentane) afforded tert-butyl 2-(2-(2-(2-hydroxybenzamido)ethyl)disulfanyl)ethylcarbamate (400 mg, 54%). Mass calculated for C16H24N2O4S2: 372.12; found: [M+H]+=373.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([C:9]([F:12])([F:11])[F:10])([OH:8])[CH2:4][CH2:5][CH2:6][OH:7].F[C:16](F)(F)[C:17](C(F)(F)F)(O)CC(O)C.B.CSC.FC(F)(F)C(C(F)(F)F)(O)CC=C.[OH-].[Na+]>O1CCCC1>[F:1][C:2]([F:13])([F:14])[C:3]([C:9]([F:10])([F:11])[F:12])([OH:8])[CH2:4][CH2:5][CH2:6][O:7][CH:16]=[CH2:17]
Reactant: OCCCC(O)(C(F)(F)F)C(F)(F)F
Reactant: CC(O)CC(O)(C(F)(F)F)C(F)(F)F
Agent: B
Agent: C=CCC(O)(C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: CSC
Solvent: C1CCOC1
Product: C=COCCCC(O)(C(F)(F)F)C(F)(F)F

Procedure:
Preparation of 1,1,1-trifluoro-2-trifluoromethyl-2,5-pentanediol and 1,1,1-trifluoro-2 -trifluoromethyl-2,4-pentanediol: To a 3-necked, 3-L round bottomed flask equipped with an overhead stirrer, digital thermometer and a 1-L constant-pressure addition funnel with a nitrogen inlet was added 974 mL (1.95 mol) of borane-dimethylsulfide complex (2.0 M in tetrahydrofuran). The addition funnel was charged with a solution of 353 g (1.7 mol) of 1,1,1-trifluoro-2-trifluoromethyl-4-penten-2-ol in 400 mL of anhydrous tetrahydrofuran. The flask was cooled and the olefin was added slowly with stirring while maintaining a temperature below 15° C. The mixture was stirred at room temperature for two days after which time it was recooled and 750 mL (2.25 mol) of 3M NaOH was added carefully. The reaction mixture was reduced in volume on a rotary evaporator and subsequently co-evaporated with two 500 mL portions of diethyl ether. The resulting heavy oil was taken up in 300 mL of THF and the solution transferred to a 1-L 3-necked round-bottomed flask equipped with a 250-mL addition funnel, a digital thermometer and a magnetic stir bar. The addition funnel was charged with 250 mL of 30% hydrogen peroxide. The flask was cooled and the hydrogen peroxide added slowly with stirring. After stirring overnight at room temperature, the solution was diluted with 1 L of diethyl ether and adjusted to pH 6 (wet litmus) with 5% HCl. The ether layer was separated and the aqueous layer was extracted with 2×500 mL of ether. The combined organic phases were washed with 2×500 mL of saturated ammonium chloride and brine, dried over MgSO4 and evaporated to a crude yield of 379 g of a 45:55 (2°:1°) mixture of the two diols. The diols were separated by distillation through a 12″ Vigreux, bp 47° C. at 1.0 mm Hg (2° alcohol) and bp 55° C. at 1.0 mm Hg (1° alcohol). The 1° alcohol is a viscous oil while the 2° alcohol is a low melting solid.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([CH:19]([OH:21])[CH3:20])[C:5]([O:6][CH2:7][CH2:8][NH:9]C(=O)OC(C)(C)C)=[C:4]([CH:22]=O)[C:3]=1[C:24]#[N:25].Cl>O1CCOCC1>[Cl:1][C:2]1[C:3]([C:24]#[N:25])=[C:4]2[CH:22]=[N:9][CH2:8][CH2:7][O:6][C:5]2=[C:17]([CH:19]([OH:21])[CH3:20])[CH:18]=1
Reactant: CC(O)c1cc(Cl)c(C#N)c(C=O)c1OCCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC(O)c1cc(Cl)c(C#N)c2c1OCCN=C2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The crude tert-butyl {2-[4-chloro-3-cyano-2-formyl-6-(1-hydroxyethyl)phenoxy]ethyl}carbamate was dissolved in 1,4-dioxane (16 mL) and was added to an ice cooled 4.0 M hydrogen chloride in dioxane (40 mL) solution. After stirring for 1 h, the reaction was concentrated in vacuo to give 7-chloro-9-(1-hydroxyethyl)-2,3-dihydro-1,4-benzoxazepine-6-carbonitrile as an oil. LCMS calculated for C12H12ClN2O2(M+H)+: m/z=251.1; found: 251.0. 1H NMR (300 MHz, DMSO-d6) δ 8.55 (t, J=2.0 Hz, 1H), 7.75 (s, 1H), 5.53 (d, J=4.6 Hz, 1H), 5.05-4.82 (m, 1H), 4.53-4.24 (m, 2H), 4.20-4.04 (m, 2H), 1.26 (d, J=6.4 Hz, 3H).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[CH2:13][C:14]([OH:16])=[O:15].[C:17]([OH:26])(=[O:25])[C:18]1[C:19](=[CH:21][CH:22]=[CH:23][CH:24]=1)[SH:20]>>[C:14]([CH2:13][C:3]1[CH:4]=[C:5]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])[CH:6]=[CH:7][C:2]=1[S:20][C:19]1[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=1[C:17]([OH:26])=[O:25])([OH:16])=[O:15]
Reactant: CC(C(=O)O)c1ccc(N)c(CC(=O)O)c1
Reactant: O=C(O)c1ccccc1S
Product: CC(C(=O)O)c1ccc(Sc2ccccc2C(=O)O)c(CC(=O)O)c1

Procedure:
2-(4-Amino-3-carboxymethylphenyl)propionic acid or its salt is diazotized in the same manner as in Preparation-I, and the resulting compound (i.e., diazo compound) is reacted with thiosalicylic acid at 0 to 100° C., preferably under basic conditions, to give the 2-[3-carboxymethyl-4-(2-carboxyphenylthio)phenyl]propionic acid or its salt.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8]2[N:13]=[C:12]([NH2:14])[N:11]=[C:10]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH:9]=2)[CH:7]=1.[C:27]1(=O)[O:32][C:30](=[O:31])[CH2:29][CH2:28]1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8]2[CH:9]=[C:10]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:23])([F:25])[F:24])=[CH:20][CH:21]=3)[N:11]=[C:12]([N:14]3[C:30](=[O:31])[CH2:29][CH2:28][C:27]3=[O:32])[N:13]=2)[CH:7]=1
Reactant: Cc1ccc(Cl)cc1-c1cc(Nc2ccc(C(F)(F)F)cc2)nc(N)n1
Reactant: O=C1CCC(=O)O1
Solvent: Cc1ccccc1
Product: Cc1ccc(Cl)cc1-c1cc(Nc2ccc(C(F)(F)F)cc2)nc(N2C(=O)CCC2=O)n1
Temperature: 25 °C
Yield: 96 %

Procedure:
A mixture of the title compound of Example 29 (0.19 g, 0.50 mmol) and succinic anhydride (0.30 g, 3.0 mmol) in toluene (18 ml) was heated under reflux for 6 hours. After cooled to room temperature, the mixture was filtered. The filtrate was washed with saturated aqueous sodium bicarbonate solution (3×10 ml), dried over magnesium sulfate, and concentrated under reduced pressure to provide 1-[4-(5-chloro-2-methyl-phenyl)-6-(4-trifluoromethyl-phenylamino)-pyrimidin-2-yl]-pyrrolidine-2,5-dione as a white solid (96% yield).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]3[C:12]4[C:13]([C:18](=[O:19])[C:4]2=[CH:3][CH:2]=1)=[N:14][CH:15]=[C:16](Br)[C:11]=4[CH:10]=[CH:9][N:8]=3.[N-:20]=[N+]=[N-].[Na+]>CC(C)=O.O>[CH:1]1[CH:6]=[C:5]2[C:7]3[C:12]4[C:13]([C:18](=[O:19])[C:4]2=[CH:3][CH:2]=1)=[N:14][CH:15]=[C:16]([NH2:20])[C:11]=4[CH:10]=[CH:9][N:8]=3
Reactant: O=C1c2ccccc2-c2nccc3c(Br)cnc1c23
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: Nc1cnc2c3c(nccc13)-c1ccccc1C2=O
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
A mixture of 4-bromosampangine (622 mg, 2.0 mmol) in acetone (40 mL) and sodium azide (1.30 g, 20.0 mmol) in H2O (10 mL) was heated at reflux for 1 h. The acetone was then removed by evaporation, MeOH (40 mL) added, and the mixture transferred to a three necked flask and cooled to 10° C. Piperidine (2 drops) was added and a stream of hydrogen sulfide bubbled through the reaction. After 30 min, the temperature was allowed to rise to 23° C. and the reaction continued for an additional 30 min. The solvent was then removed evaporated and the residue chromatographed as above to give 4-aminosampangine (23) (450 mg, 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[C:5]([Cl:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:12]=1[C:13]#[N:14].[O-]P(OP(OP([O-])([O-])=O)([O-])=O)(=O)[O-].[K+].[K+].[K+].[K+].[K+].C1C=CC(P(C2C(OC3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=CC=3)=CC=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:19][C:17]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([NH:10][C:6]2[C:5]([Cl:9])=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=2)[CH:18]=1
Reactant: N#Cc1ccc(Cl)cc1N
Reactant: Clc1cc(I)c(Cl)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])OP(=O)([O-])OP(=O)([O-])[O-]
Solvent: C1COCCO1
Product: N#Cc1ccc(Cl)cc1Nc1cc(Cl)ncc1Cl
Yield: 57.1 %

Procedure:
To a degassed solution of 2,5-dichloro-4-iodopyridine (4.5 g, 16.43 mmol), 2-amino-4-chlorobenzonitrile (2.507 g, 16.43 mmol) and potassium triphosphate (10.46 g, 49.3 mmol) in 1,4-dioxane (60 ml) stirred under nitrogen at the room temperature was added DPEPhos (0.708 g, 1.314 mmol) and palladium acetate (0.148 g, 0.657 mmol). The reaction mixture was stirred at the reflux for 18 hr. The reaction mixture was filtered. The solution was evaporated. Ether (50 ml) was added and the formed solid was filtered. 4-chloro-2-[(2,5-dichloro-4-pyridinyl)amino]benzonitrile (2.8 g, 9.38 mmol, 57.1% yield) was isolated as an orange solid. 1H NMR (400 MHz, DMSO-d6) ppm 6.70 (s, 1 H) 7.53 (dd, J=8.34, 2.02 Hz, 1 H) 7.65 (d, J=2.02 Hz, 1 H) 7.95 (d, J=8.34 Hz, 1 H) 8.28 (s, 1 H) 9.12 (br. s., 1 H); HPLC Rt=3.50 min, MS (ESI): 298.0, 300.0 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26]([CH:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[O:27])=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:19][C:16]1[CH:17]=[CH:18][C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[C:15]=1[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26]([CH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:27]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CCCCCNC(=O)C3CCCC3)c2CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCCCCCc1c(Cl)ccc2c1CCNCC2)C1CCCC1
Yield: 55.5 %

Procedure:
Dissolve 3-tert-butoxycarbonyl-7-chloro-6-[5-(cyclopentanecarbonyl-amino)-pentyl]-2,3,4,5-tetrahydro-1H-benzo[d]azepine (311 mg, 0.67 mmoles) in dichloromethane (10 mL) and add trifluoroacetic acid (3 mL). Stir the reaction for 1 h. Concentrate in vacuo and purify the residue by preparative HPLC to give 7-chloro-6-[5-(cyclopentanecarbonyl-amino)-pentyl]-2,3,4,5-tetrahydro-1H-benzo[d]azepine (135 mg) as an oil. Dissolve the oil in methanol (5 mL) and add (L)-tartaric acid (56 mg, 0.37 mmoles). Concentrate the mixture in vacuo and then add water (5 mL). The resulting solution is then freeze dried overnight to yield the title compound as a white solid (184 mg, 55%). MS (ES+) m/z=363.2 (M+H)+.
Reaction SMILES: CCN(C(C)C)C(C)C.[Br:10][C:11]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:12]=1[C:13]([OH:15])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[O:43]=[C:44]([N:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1)[CH2:45][NH:46][C:47]([C:49]1[CH:54]=[CH:53][C:52]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)=[CH:51][CH:50]=1)=[O:48]>CN(C=O)C.O>[Br:10][C:11]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:12]=1[C:13]([N:64]1[CH2:63][CH2:62][N:61]([C:44](=[O:43])[CH2:45][NH:46][C:47]([C:49]2[CH:54]=[CH:53][C:52]([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)=[CH:51][CH:50]=2)=[O:48])[CH2:66][CH2:65]1)=[O:15]
Reactant: O=C(O)c1cc(F)ccc1Br
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCN(C(=O)c2cc(F)ccc2Br)CC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
DIPEA (149.8 mg, 1.15 mmol) was added to a stirred solution of 2-bromo-5-fluoro-benzoic acid (56.4 mg, 0.26 mmol) in DMF (3 mL), HOBt (38.2 mg, 0.28 mmol) and EDCI.HCl (123.4 mg, 0.64 mmol) at room temperature. After 2 minutes biphenyl-4-carboxylicacid (2-oxo-2-piperazin-1-yl-ethyl)-amide (100 mg, 0.32 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added, and the resulting precipitate was filtered. The residue was purified by column chromatography (using 60-120 mesh silica gel and 60% EtOAc in hexane as eluent) to afford 60 mg (44.6% yield) of biphenyl-4-carboxylicacid {2-[4-(2-bromo-5-fluoro-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide, LC-MS purity: 98.34%, 1H NMR: (CDCl3) δ 7.96-7.88 (d, 2H), 7.72-7.64 (d, 2H), 7.64-7.54 (m, 3H), 7.52-7.43 (t, 2H), 7.43-7.35 (m, 1H), 7.35-7.28 (m, 1H), 7.08-6.98 (m, 2H), 4.4-4.24 (d, 2H), 4.07-3.85 (m, 2H), 3.8-3.7 (m, 2H), 3.66-3.58 (m, 1H), 3.52-3.42 (m, 1H), 3.42-3.33 (m, 1H), 3.33-3.2 (m, 1H).
Reaction SMILES: C[O-].[Na+].[Cl:4][C:5]1[CH:6]=[N:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([Cl:15])[C:9]=2[CH:16]=O.[CH3:18][C:19]([C:21]1[CH:22]=[CH:23][C:24]([OH:27])=[CH:25][CH:26]=1)=O.[Cl-].C1([PH+](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)(=O)C>CO.C(O)C>[Cl:4][C:5]1[CH:6]=[N:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([Cl:15])[C:9]=2[CH:16]=[CH:18][CH2:19][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1
Reactant: O=Cc1c(Cl)ccc2cc(Cl)cnc12
Reactant: CC(=O)c1ccc(O)cc1
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: CO
Product: Oc1ccc(CC=Cc2c(Cl)ccc3cc(Cl)cnc23)cc1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
36 ml of a 15% strength solution of sodium methylate in methanol were added to 11 g of 3,7-dichloro-8-formylquinoline and 21.6 g of 4-hydroxyacetophenone-triphenylphosphonium chloride in 150 ml of ethanol. The mixture was stirred for 21/2 hours at 20° C., after which 3 ml of glacial acetic acid were added and the precipitate was filtered off under suction, washed with water and dried.