Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[Cl:5][C:6]1[C:12]([NH:13][S:14]([CH2:17][CH3:18])(=[O:16])=[O:15])=[CH:11][C:9]([NH2:10])=[C:8]([F:19])[CH:7]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Cl:5][C:6]1[C:12]([NH:13][S:14]([CH2:17][CH3:18])(=[O:16])=[O:15])=[CH:11][C:9]([N:10]=[C:1]=[S:2])=[C:8]([F:19])[CH:7]=1
Reactant: CCS(=O)(=O)Nc1cc(N)c(F)cc1Cl
Reactant: S=C(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)Nc1cc(N=C=S)c(F)cc1Cl
Yield: 49.3 %

Procedure:
Under a dry nitrogen atmosphere 0.84 ml (0.011 mole) of thiophosgene was added to a stirred solution of 2.8 g (0.011 mole) of 4-chloro-2-fluoro-5-(N-ethylsulfonylamino)aniline in 250 ml of chloroform. To this mixture was added dropwise 1.6 g (0.012 mole) of triethylamine. The resultant mixture was stirred at room temperature for approximately 18 hours. The solvent was removed from the mixture by evaporation under reduced pressure leaving an oily residue. This residue was purified by column chromatography on silica gel, eluting with methylene chloride/hexane (60/40) followed by methylene chloride, to yield 1.6 g of 4-chloro-5-(N-ethylsulfonylamino)-2-fluorophenyl isothiocyanate as a solid, m.p. 104°-105° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:15](Cl)(=[O:17])[CH3:16]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:15](=[O:17])[CH3:16])=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1ccc(F)cc1
Reaction time: 0.25 h
Yield: 91.4 %

Procedure:
To a chilled (ice-bath) solution of 4-fluorophenylamine (2.9 mL, 30 mmol) and anhydrous pyridine (3.7 mL, 45 mmol) in methylene chloride (50 mL) was slowly added a solution of acetyl chloride (2.4 mL, 33 mmol) in methylene chloride (10 mL). After 15 minutes, the mixture was concentrated in vacuo and the residue was diluted with cold water. The resulting precipitate was filtered, washed with water and dried to afford 4.2 g of N-(4-fluorophenyl)acetamide as an off white solid. MS m/z 154 (MH+).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](Cl)(=[O:27])=[O:26]>>[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25]([N:12]1[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]1[CH:2]1[CH:3]2[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]1[CH2:10]3)[CH2:9]2)(=[O:27])=[O:26]
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1S(=O)(=O)c1ccccc1Cl

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 2-chlorobenzene sulfonyl chloride were used for a similar reaction and treatment as Example 169, and the title compound was obtained as a white crystalline powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10](=O)[CH2:11][C:12]#[N:13].O.[NH2:16][NH2:17]>C(O)C>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[NH:17][N:16]=[C:12]([NH2:13])[CH:11]=1
Reactant: NN
Reactant: COc1ccc(C(=O)CC#N)c(F)c1
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2cc(N)n[nH]2)c(F)c1
Yield: 88.6 %

Procedure:
To 3-(2-Fluoro-4-methoxyphenyl)-3-oxopropanenitrile (9.55 g, 49.4 mmol) suspended in ethanol (165 mL) was added hydrazine hydrate (1.743 g, 54.38 mmol). The resulting mixture was heated at reflux overnight. Then, the organic solvent was evaporated in vacuo and the resulting residue was chromatographed (eluting with 9:1 methylene chloride:methanol) to give 9.07 g (88% yield) of the title compound. LCMS (ESI): calc.=207; obs. M+H=208.2.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][CH2:8]1)=[O:5].Cl.[CH:25](OC)(OC)OC>>[CH2:13]([N:10]1[CH2:9][CH2:8][CH:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:1]=[CH:25]2)[CH2:12][CH2:11]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Nc1ccccc1C(=O)NC1CCN(Cc2ccccc2)CC1
Reactant: COC(OC)OC
Agent: Cl
Product: O=c1c2ccccc2ncn1C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of 200 mg 2-amino-N-(1-benzyl-piperidin-4-yl)benzamide (from Step A) in 5 mL of trimethyl orthoformate was added 0.2 mL of concentrated HCl. After stinring at 85° C. for 14 hours, the reaction was cooled to room temperature. The reaction mixture was partitioned betweem EtOAc and aqueous sodium bicarbonate. Aqueous phase was extracted with EtOAc (3×). The combined organic phases were washed with brine and dried over anhydrous MgSO4. Concentration under reduced pressure afforded 120 mg of the title compound as a viscous oil.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([O:9][C@@H:10]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[C:14]([F:19])[C:13]=2[Cl:20])[CH3:11])[C:5]([NH2:8])=[N:6][CH:7]=1.NC1N=CC([C:28]2[CH:29]=[N:30][N:31]([CH:33]3[CH2:38][CH2:37][N:36]([C:39](=O)CO)[CH2:35][CH2:34]3)[CH:32]=2)=CC=1O[C@@H](C1C(Cl)=CC=C(F)C=1Cl)C>>[Cl:20][C:13]1[C:14]([F:19])=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=1[C@H:10]([O:9][C:4]1[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([C:28]2[CH:29]=[N:30][N:31]([CH:33]3[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)[CH:32]=2)[N:3]=1)[CH3:11]
Reactant: C[C@@H](Oc1cc(-c2cnn(C3CCN(C(=O)CO)CC3)c2)cnc1N)c1c(Cl)ccc(F)c1Cl
Reactant: C[C@@H](Oc1nc(Br)cnc1N)c1c(Cl)ccc(F)c1Cl
Product: C[C@@H](Oc1nc(-c2cnn(C3CCN(C)CC3)c2)cnc1N)c1c(Cl)ccc(F)c1Cl

Procedure:
The title compound was prepared according to procedure 62 using 5-bromo-3-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-ylamine and 4-(4-bromo-pyrazol-1-yl)-1-methyl-piperidine (prepared according to general procedure 11). 1H NMR (400 MHz, DMSO-d6) δ 7.88 (s, 1H), 7.76 (s, 1H), 7.64 (s, 1H), 7.49 (m, 1H), 7.36 (t, 1H), 6.46 (q, 1H), 6.15 (s, 2H), 4.02 (m, 1H), 2.84 (m, 2H), 2.19 (s, 3H), 2.00 (m, 4H), 1.85 (m, 3H), 1.75 (d, 3H); LCMS: 465 [M+1]; c-Met Ki: 0.03 μM.
Reaction SMILES: [CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([NH2:24])=[O:23])[C:6]2[C:15]3[N:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3].C1C=C(Cl)C=C(C(OO)=O)C=1.[OH-].[NH4+:37].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>>[NH2:37][C:8]1[C:7]2[N:16]=[C:4]([CH2:1][CH2:2][CH3:3])[N:5]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([NH2:24])=[O:23])[C:6]=2[C:15]2[N:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: [NH4+]
Reactant: CCCc1nc2cnc3cccnc3c2n1CCCCCC(N)=O
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Product: CCCc1nc2c(N)nc3cccnc3c2n1CCCCCC(N)=O
Reaction time: 1 h

Procedure:
A modification of the method described in Part F of Example 53 was used to treat 6-(2-propyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)hexanamide (1.20 g, 3.7 mmol) with mCPBA (2.47 g of 70-77% purity) followed by ammonium hydroxide (4 mL), and p-toluenesulfonyl chloride (0.70 g). After the amination reaction was stirred for one hour, a precipitate was present and was isolated by filtration and washed with chloroform and water. The precipitate was ground up and dried for three days at 70° C. and then overnight at 95° C. to provide 0.46 g of 6-(4-amino-2-propyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)hexanamide as a white solid, mp 216.5-217.5° C.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:8][CH2:7][N:6]1[S:9]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:11])=[O:10])=[O:4].[Li+].[OH-].Cl>CO.O>[C:13]1([CH2:12][S:9]([N:6]2[CH2:7][CH2:8][C@H:5]2[C:3]([OH:4])=[O:2])(=[O:11])=[O:10])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)[C@@H]1CCN1S(=O)(=O)Cc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)[C@@H]1CCN1S(=O)(=O)Cc1ccccc1
Reaction time: 8 h
Yield: 94 %

Procedure:
To a solution of (2S)-Methyl-1-(α-toluenesulfonyl)azetidine-2-carboxylate from Reference Example 7 (378.4 mg; 1.40 mmol) in methanol (7.0 mL) was added 1N LiOH in water (2.6 mL) at about 0° C. The mixture was warmed to about room temperature and stirred under argon overnight. The pH was adjusted to about pH 1 by adding 1N HCl and then the mixture was diluted with water and extracted into ethyl acetate. The organic layer was dried over magnesium sulfate and then concentrated to give 335.7 mg (94% yield) of the product as a white solid. 1H NMR (CDCl3) δ 2.37-2.57 (m, 2H); 3.21-3.31 (m, 1H); 4.01 (q, 1H, J=8.6); 4.33 (d, 1H, J=13.7); 4.44 (d, 1H, J=13.7); 4.98 (dd, 1H, J=9.4, 8.6); 7.34-7.53 (series of m, 5H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1O)=[CH:9][CH:8]=[CH:7][C:6]=2[C:13]([F:16])([F:15])[F:14].FC(F)(F)[C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:28]=1N=CC=C2O.BrBr.[OH-].[Na+]>C(O)(=O)C>[C:5]1([C:2]2[CH:3]=[N:4][C:5]3[C:10]([C:11]=2[C:28]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:9][CH:8]=[CH:7][C:6]=3[C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Oc1ccnc2c(C(F)(F)F)cccc12
Reactant: Oc1c(Br)cnc2c(C(F)(F)F)cccc12
Agent: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: FC(F)(F)c1cccc2c(-c3ccccc3)c(-c3ccccc3)cnc12
Reaction time: 0.5 h
Yield: 83 %

Procedure:
Preparation of 3-Bromo-8-(trifluoromethyl)quinolin-4-ol: 8-Trifluoromethyl-quinolin-4-ol (9.12 g, 42.8 mmol) is dissolved in acetic acid (300 mL). Bromine (2.20 mL 42.8 mmol) is dissolved in acetic acid (30 mL) and then added drop wise to the reaction over 20 min. After 0.5 h, the solution is poured into 500 mL of 2N NaOH and stirred. The white precipitate is filtered and dried in vacuo yielding the title compound as a white solid (10.3 g, 83%). mp 297-299° C.; MS (ESI) m/z 292; MS (ESI) m/z 290; HRMS: calcd for C10H5BrNF3O+H, 291.95848; found (ESI_FT, [M+H]1+), 291.95847.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([F:15])=[CH:9][C:8]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[C:22]([C:26]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[O:27])=[C:23]([CH3:25])[NH:24][C:17]=23)[CH2:4][CH2:3]1.[C:35](Cl)(=[O:38])[CH2:36][CH3:37]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([F:15])=[CH:9][C:8]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[C:22]([C:26]([NH:28][CH:29]4[CH2:30][CH2:31][N:32]([C:35](=[O:38])[CH2:36][CH3:37])[CH2:33][CH2:34]4)=[O:27])=[C:23]([CH3:25])[NH:24][C:17]=23)[CH2:4][CH2:3]1
Reactant: COc1cc(OCC2CC2)c(-c2ccnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)cc1F
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(F)c(OC)cc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-2-methyl-N-piperidin-4-yl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f26) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:18]([N:20]1[CH2:25][CH2:24][C@@:23]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)([OH:26])[C:22]([CH3:35])([CH3:34])[CH2:21]1)=[O:19])[CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH:36]1([C:41](Cl)=[O:42])[CH2:40][CH2:39][CH2:38][CH2:37]1.CCN(C(C)C)C(C)C>ClCCl>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([C@@:23]2([OH:26])[CH2:24][CH2:25][N:20]([C:18](=[O:19])[C@H:3]([NH:2][C:41]([CH:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)=[O:42])[CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:21][C:22]2([CH3:35])[CH3:34])=[CH:32][CH:31]=1
Reactant: CC1(C)CN(C(=O)[C@H](N)CCCNC(=O)OCc2ccccc2)CC[C@]1(O)c1ccc(Cl)cc1
Reactant: O=C(Cl)C1CCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CN(C(=O)[C@@H](CCCNC(=O)OCc2ccccc2)NC(=O)C2CCCC2)CC[C@]1(O)c1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
Benzyl (R)-4-amino-5-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-5-oxopentylcarbamate hydrochloride (50.5 mg, 0.096 mmol) was dissolved in dichloromethane (0.5 mL) and added cyclopentane carbonylchloride (14 μL, 0.12 mmol) followed by DIPEA (42 μL, 0.24 mmol). The solution was stirred for 2 h, concentrated, and partitioned between EtOAc (2 mL) and aq NaHCO3 (0.5 mL). The EtOAc layer was separated, dried over magnesium sulfate, and concentrated to give benzyl (R)-5-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-4-(cyclopentanecarboxamido)-5-oxopentylcarbamate which was used without further purification.
Reaction SMILES: [CH2:1]([NH2:7])[CH2:2][CH2:3][CH2:4][CH2:5][NH2:6].[C:8]1(=[O:14])[O:13][C:11](=[O:12])[CH2:10][CH2:9]1>CO.C(Cl)Cl>[NH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][NH:7][C:8](=[O:14])[CH2:9][CH2:10][C:11]([OH:13])=[O:12]
Reactant: O=C1CCC(=O)O1
Reactant: NCCCCCN
Solvent: CO
Solvent: ClCCl
Product: NCCCCCNC(=O)CCC(=O)O
Yield: 80 %

Procedure:
To a solution of 1,5-pentanediamine (2.5 g, 24 mmol) in dry methanol (20 mL), a solution of succinic acid anhydride (2 g, 20 mmol) in dry methylene chloride (20 mL) was added dropwise in 2 hrs, the product was precipitated as white solid and collected by filtration. Yield 80 %. 1H NMR (500 MHz, D2O, 25° C.) δ 1.280 (quint., J=7.5, 2H, CH2), 1.449 (quint., J=7.5, 2H, CH2), 1.577 (quint., J=7.5, 2H, CH2), 2.337 (s, 4H, CH2), 2.886 (t, J=7.5, 2H, CH2), 3.072 (t, J=7.5, 2H, CH2). 13C NMR (500 MHz, D2O, 25° C.) δ 22.73, 26.22, 27.66, 32.34, 33.13, 38.76, 39.37, 175.72, 180.90.
Reaction SMILES: Cl[C:2]1[C:3]([C:11]#[N:12])=[N:4][C:5]([S:8][CH2:9][CH3:10])=[CH:6][CH:7]=1.[Cl:13][C:14]1[CH:15]=[C:16]([OH:21])[CH:17]=[CH:18][C:19]=1[Cl:20].CC([O-])(C)C.[K+]>C1COCC1.CS(C)=O>[Cl:13][C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][C:19]=1[Cl:20])[O:21][C:2]1[C:3]([C:11]#[N:12])=[N:4][C:5]([S:8][CH2:9][CH3:10])=[CH:6][CH:7]=1
Reactant: CCSc1ccc(Cl)c(C#N)n1
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CCSc1ccc(Oc2ccc(Cl)c(Cl)c2)c(C#N)n1
Yield: 53.5 %

Procedure:
Following a procedure substantially the same as that described in Example 20, 8.0 g of 3-chloro-6-ethylthio-2-pyridinecarbonitrile was reacted with 8.2 g of 3,4-dichlorophenol in the presence of 5.6 g of t-BuOK in 60 ml of THF and 30 ml of DMSO. The reaction was allowed to proceed at boiling temperature for about 40 hours. The product, an oil, was purified by distillation on a Kugelrohr distillation apparatus, separated on a Water's Prep LC 500 instrument, and again distilled on a Kugelrohr apparatus to give about 7 g (54%) of the desired 3-(3,4-dichlorophenoxy)-6-ethylthio-2-pyridinecarbonitrile, having a boiling point (b.p.) of 160° C. at 0.01 mm Hg pressure.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:16](=[O:26])[C:8]4[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.C(=O)([O-])[O-].[K+].[K+].Br[CH2:34]/[CH:35]=[CH:36]/[C:37]([O:39]CC)=[O:38]>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:16](=[O:26])[C:8]4[CH:9]=[C:10]([O:15]/[CH:34]=[CH:35]/[CH2:36][C:37]([OH:39])=[O:38])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: CCOC(=O)/C=C/CBr
Reactant: O=c1c(Cc2cccnc2)cn2c3ccc(Br)cc3c3cc(O)cc1c32
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(O)C/C=C/Oc1cc2c(=O)c(Cc3cccnc3)cn3c4ccc(Br)cc4c(c1)c23
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 10 %

Procedure:
10-bromo-2-hydroxy-5-(3-pyridylmethyl)-4H-pyrido[3,2,1-jk]carbazole-4-one (400 mg) obtained in Example 2 was suspended in dimethyl sulfoxide (30 ml), and to the suspension was added potassium carbonate (0.3 g), and the mixture was stirred at room temperature for 30 minutes. Ethyl 4-bromocrotonate (0.15 ml) was added and the mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into ice water (300 ml), and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent: ethyl acetate). The resulting crude crystals were suspended in ethanol (20 ml), and 1N aqueous solution of sodium hydroxide (5 ml) was added to the suspension followed by stirring at room temperature for 12 hours. The solvent was evaporated under reduced pressure and the residue was extracted with water and ethyl acetate. 1N hydrochloric acid was added to the aqueous layer to a pH of 7, and the precipitated crystals were recovered by filtration to obtain the title compound (50 mg, 10%).
Reaction SMILES: [NH2:1][CH:2]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[NH:34][N:33]=[N:32][N:31]=2)[CH:25]=1)[C:3]1[CH:23]=[CH:22][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[C:11]([OH:18])[C:10]=2[CH2:19][CH2:20][CH3:21])=[CH:5][CH:4]=1.[C:35](Cl)(=[O:37])[CH3:36].N1C=CC=CC=1>ClCCl>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]2[CH:22]=[CH:23][C:3]([CH:2]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]4[NH:34][N:33]=[N:32][N:31]=4)[CH:25]=3)[NH:1][C:35](=[O:37])[CH3:36])=[CH:4][CH:5]=2)=[C:10]([CH2:19][CH2:20][CH3:21])[C:11]=1[OH:18])(=[O:17])[CH3:16]
Reactant: CCCc1c(OCc2ccc(C(N)c3cccc(-c4nnn[nH]4)c3)cc2)ccc(C(C)=O)c1O
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCc1c(OCc2ccc(C(NC(C)=O)c3cccc(-c4nnn[nH]4)c3)cc2)ccc(C(C)=O)c1O
Temperature: 25 °C
Yield: 60.6 %

Procedure:
A mixture of 1-[4-(4-{amino-[3-(1H-tetrazol-5-yl)-phenyl]-methyl}-benzyloxy)-2-hydroxy-3-propyl-phenyl]-ethanone (80 mg, 0.175 mmol), acetyl chloride (15 μL, 0.211 mmol) and dichloromethane (1.5 mL) is stirred at room temperature. Pyridine (50 μL, 0.62 mmol) is added and the mixture is stirred at room temperature 24 hr. An additional portion of acetyl chloride (20 μL, 0.28 mmol) is added and the reaction is stirred an additional 24 hr. The reaction mixture is purified as is via reversed phase C18 preparative chromatography eluting with 4:6 acetonitrile:water (0.1% trifluoroacetic acid) to 8:2 acetonitrile:water (0.1% trifluoroacetic acid) to give the title compound (53 mg, 61%), as a white solid. 1H NMR (DMSO-d6) δ 12.85 (s, 1H), 8.92 (d, 1H), 8.03 (s, 1H), 7.92 (d, 1H), 7.80 (d, 1H), 7.36-7.61 (m, 6H), 6.73 (d, 1H), 6.23 (d, 1H), 5.25 (s, 2H), 2.59-2.62 (m, 5H), 1.97 (s, 3H), 1.46-1.53 (m, 2H), 0.88 (t, 3H). LCMS M−1=498.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[N:22][C:23]([CH2:27][CH2:28][CH3:29])=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:3]=1.[CH:30]([S:33](Cl)(=[O:35])=[O:34])([CH3:32])[CH3:31].C(N(CC)C(C)C)(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][S:33]([CH:30]([CH3:32])[CH3:31])(=[O:35])=[O:34])=[CH:13][CH:14]=2)=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[N:22][C:23]([CH2:27][CH2:28][CH3:29])=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:3]=1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: CCCc1ccc2c(Nc3cc(C)ccc3Sc3ccc(O)cc3)ccnc2n1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1ccc2c(Nc3cc(C)ccc3Sc3ccc(OS(=O)(=O)C(C)C)cc3)ccnc2n1

Procedure:
The product from Example 6 (120 mg, 0.274 mmol) was reacted with isopropyl sulfonyl chloride (43 mg, 0.30 mmol), N,N-diisopropylethylamine (43 mg, 0.33 mmol), and catalytic DMAP in CH2Cl2 for 18 h giving the crude title compound which was purified by HPLC with TFA providing the product as the trifluoroacetic acid (40 mg, 23%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 8.75 (d, J=8.54 Hz, 1H) 8.20 (d, J=6.71 Hz, 1H) 7.58 (d, J=8.54 Hz, 1H) 7.26 (d, J=7.93 Hz, 1H) 7.17-7.21 (m, 2H) 7.08 (d, J=9.16 Hz, 2H) 6.95 (d, J=8.54 Hz, 2H) 6.15 (d, J=6.71 Hz, 1H) 3.43-3.51 (m, J=13.43, 1H) 2.79 (t, J=7.63, 7.63 Hz, 2H) 2.20 (s, 3H) 1.61-1.67 (m, 2H) 1.21 (d, J=6.71 Hz, 6H) 0.78 (t, J=7.32 Hz, 3H); MS (ESI+) m/z 508 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH2:11][CH:10]([CH2:15][NH:16][S:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:9]2)C.[OH-].[Na+]>CO>[C:20]1([S:17]([NH:16][CH2:15][CH:10]2[CH2:9][C:8]3[C:12](=[CH:13][CH:14]=[C:6]([CH2:5][C:4]([OH:26])=[O:3])[CH:7]=3)[CH2:11]2)(=[O:19])=[O:18])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCOC(=O)Cc1ccc2c(c1)CC(CNS(=O)(=O)c1ccccc1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)Cc1ccc2c(c1)CC(CNS(=O)(=O)c1ccccc1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
844 mg (2.26 mmol) of ethyl[2-(phenylsulfonylaminomethyl)-indan-5-yl]acetate was dissolved in 3 ml of methanol, to which was added 5 ml of 1N sodium hydroxide and stirred for 1 hour at room temperature. Methanol was removed and the aqueous phase was washed with chloroform, and added with 1N hydrochloric acid for making the system acidic. The precipitates were extracted with ethyl acetate, dried and condensed. The residue was recrystallized from ethyl acetate to obtain 679 mg crystals. Yield: 87%
Reaction SMILES: CO[C:3]([C:5]1[C:10](=[O:11])[N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[N:8]2[CH:23]=[CH:24][CH:25]=[C:7]2[C:6]=1[OH:26])=[O:4].[CH3:27][CH2:28][C@H:29]([NH2:33])[C:30]([OH:32])=[O:31].C[O-].[Na+]>>[OH:26][C:6]1[C:7]2[N:8]([CH:23]=[CH:24][CH:25]=2)[N:9]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:17][CH:18]=2)[C:10](=[O:11])[C:5]=1[C:3]([NH:33][C@@H:29]([CH2:28][CH3:27])[C:30]([OH:32])=[O:31])=[O:4]
Reactant: COC(=O)c1c(O)c2cccn2n(Cc2ccc(C(F)(F)F)cc2)c1=O
Reactant: CC[C@H](N)C(=O)O
Agent: C[O-]
Agent: [Na+]
Product: CC[C@H](NC(=O)c1c(O)c2cccn2n(Cc2ccc(C(F)(F)F)cc2)c1=O)C(=O)O

Procedure:
Prepared according to the reaction condition used in Example 19 step a) from 4-hydroxy-2-oxo-1-(4-trifluoromethyl-benzyl)-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid methyl ester, L-2-aminobutyric acid and NaOMe. ESI (m/z): 438 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].C(=O)([O-])[O-].[K+].[K+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(#N)C.O>[CH2:14]([O:6][C:5](=[O:7])[C@@H:2]([N:1]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:3][OH:4])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: N[C@@H](CO)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=C(OCc1ccccc1)[C@H](CO)N(Cc1ccccc1)Cc1ccccc1
Temperature: 55 °C
Reaction time: 20 h
Yield: 51.9 %

Procedure:
A solution of L-serine (2.1 g, 20 mmol) in acetonitrile/water (52 mL, 25:1) was added to solid potassium carbonate (13.8 g, 100 mmol) and the mixture was treated with benzyl bromide (8.92 mL, 75 mmol). After stirring for 20 h at 55° C. the mixture was cooled to room temperature, filtered, diluted with ethyl acetate and the organics were washed with water, dried over anhydrous sodium sulfate, filtered and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography eluting with a stepwise gradient of iso-hexanes/ethyl acetate 1:0 to 4:1 to afford the title compound (3.9 g, 52%) as a pale yellow oil. 1H NMR (300 MHz, CDCl3) δ 2.52 (dd, J=7.3, 4.5 Hz, 1H), 3.61 (d, J=7.6 Hz, 1H), 3.67 (d, J=13.6 Hz, 2H), 3.75-3.85 (m, 2H), 3.92 (d, J=13.6 Hz, 2H), 5.23, 5.32 (ABq, JAB=12.0 Hz, 2H), 7.22-7.37 (m, 10H), 7.38-7.48 (m, 5H). LCMS (m/z) 376.2 [M+H], Tr=3.25 min.