Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[OH:2][CH2:3][CH2:4][O:5][NH2:6].[CH:7]([C:9]1[CH:14]=[CH:13][N:12]2[C:15]([C:18]3[CH:19]=[C:20]([C:24]4[CH:28]=[CH:27][S:26][C:25]=4[C:29]#[N:30])[CH:21]=[CH:22][CH:23]=3)=[CH:16][N:17]=[C:11]2[CH:10]=1)=O>>[OH:2][CH2:3][CH2:4][O:5][N:6]=[CH:7][C:9]1[CH:14]=[CH:13][N:12]2[C:15]([C:18]3[CH:19]=[C:20]([C:24]4[CH:28]=[CH:27][S:26][C:25]=4[C:29]#[N:30])[CH:21]=[CH:22][CH:23]=3)=[CH:16][N:17]=[C:11]2[CH:10]=1
Reactant: NOCCO
Reactant: N#Cc1sccc1-c1cccc(-c2cnc3cc(C=O)ccn23)c1
Agent: Cl
Product: N#Cc1sccc1-c1cccc(-c2cnc3cc(C=NOCCO)ccn23)c1

Procedure:
The title compound was prepared in a similar manner to that described in Example 14 using O-(2-hydroxyethyl)hydroxylamine hydrochloride (93 mg, 0.82 mmol) and 3-[3-(7-formylimidazo[1,2-α]pyridin -3-yl)phenyl]thiophene-2-carbonitrile (67 mg, 0.20 mmol) to afford a white crystalline solid (43 mg, 55%), essentially as a single geometric isomer, m.p. 224-225° C. 1H NMR (360 MHz, CDCl3) δH 3.94-3.97 (2H, m), 4.32-4.36 (2H, m), 7.31-7.38 (2H, m), 7.64-7.72 (5H, m), 7.80 (1H, s), 7.88 (1H, s), 8.17 (1H, s), 8.47 (1H, d, J 7); m/z (ES+) 389 (M++H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH:5]([N:14]1[CH:21]=[C:20]([F:22])[C:18](=[O:19])[NH:17][C:15]1=[O:16])[CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>N1C=CC=CC=1>[C:23]([O:1][CH2:2][CH2:3][O:4][CH:5]([N:14]1[CH:21]=[C:20]([F:22])[C:18](=[O:19])[NH:17][C:15]1=[O:16])[CH:6]=[CH:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: O=c1[nH]c(=O)n(C(C=Cc2ccccc2)OCCO)cc1F
Solvent: c1ccncc1
Product: CC(=O)OCCOC(C=Cc1ccccc1)n1cc(F)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the solution of 1-[1-(2-hydroxyethoxy)-3-phenyl-2-propenyl]-5-fluorouracil (3 g) obtained in Example 19 in pyridine (10 ml), acetic anhydride (10 ml) was added followed by stirring at room temperature for 3 hours. The reaction mixture was poured into ice-water and extracted with chloroform. The chloroform layer was washed with water, dried and evaporated to remove chloroform. The residue was treated with a small amount of ethanol to give 2.8 g of crystalline 1-[1-(2-acetoxyethoxy)-3-phenyl-2-propenyl]-5-fluorouracil.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=[CH:13][N+:14]([O-:16])=[O:15])=[C:10]([CH:17]=[S:18](=[O:20])=[O:19])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(Cl)(Cl)Cl.[BH4-].[Na+]>CC(O)C>[Cl:1][C:2]1[C:11]([CH2:12][CH2:13][N+:14]([O-:16])=[O:15])=[C:10]([CH:17]=[S:18](=[O:20])=[O:19])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(C=S(=O)=O)c(C=C[N+](=O)[O-])c1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(C=S(=O)=O)c(CC[N+](=O)[O-])c1Cl

Procedure:
19.4 g (61 mmol) of methyl 2-chloro-3-(2-nitroethenyl)-4-sulfonylmethylbenzoate and 121 g of silica gel 60 are suspended in 180 ml of 2-propanol and 970 ml of chloroform and treated at room temperature with 3.5 g (94 mmol) of sodium borohydride. The reaction mixture is filtered, the filtrate is washed with dichloromethane/methanol 1:1 (v/v) and the organic phase is freed from the solvent under reduced pressure. Yield: 19.5 g; 1H NMR, δ [ppm], CDCl3; 3.2 (s), 3.9 (m), 4.0 (s), 4.7 (m), 7.8 (d), 8.1 (d).
Reaction SMILES: [CH2:1]([Li])CCC.CC1(C)CCCC(C)(C)N1.[Cl:16][C:17]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([OH:21])=[O:20].IC>O1CCCC1>[Cl:16][C:17]1[C:25]([Cl:26])=[C:24]([CH3:1])[CH:23]=[CH:22][C:18]=1[C:19]([OH:21])=[O:20]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: [Li]CCCC
Agent: CC1(C)CCCC(C)(C)N1
Solvent: C1CCOC1
Solvent: CI
Product: Cc1ccc(C(=O)O)c(Cl)c1Cl
Temperature: -20 °C
Reaction time: 0.25 h

Procedure:
n-Butyllithium (23.04 mL, 57.6 mmol) was dissolved in tetrahydrofuran (THF) (100 mL) at −20° C. 2,2,6,6-tetramethylpiperidine (9.72 mL, 57.6 mmol) was added dropwise and stirred for 15 minutes maintaining a temperature of −20° C. The solution was cooled to −78° C. whereupon 2,3-dichlorobenzoic acid (5 g, 26.2 mmol, commercially available from e.g. Sigma-Aldrich, Alfa Aesar or Fluorochem) dissolved in Tetrahydrofuran (THF) (50 mL) was added dropwise. The solution was stirred at −78° C. for 1 hour whereupon iodomethane (6.55 mL, 105 mmol) was added dropwise and the mixture allowed to reach room temperature overnight. Solvents were removed in vacuo and the residue partitioned between ethyl acetate (100 mL) and 5N HCl (50 mL). The aqueous phase was extracted with ethyl acetate (3×50 mL), combined extracts were washed with water (50 mL), brine (50 mL) dried over anhydrous magnesium sulfate and concentrated in vacuo to afford a crude solid in 5.90 g.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[N:10]1)[NH2:5].C(=O)([O-])[O-].[K+].[K+].[CH:26]1[CH:31]=[CH:30][C:29]([CH2:32][O:33][C:34](Cl)=[O:35])=[CH:28][CH:27]=1.O>ClCCl>[CH2:32]([O:33][C:34](=[O:35])[NH:5][C:4]1[CH:6]=[CH:7][C:8]([N:9]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)=[N:10]2)=[C:2]([F:1])[CH:3]=1)[C:29]1[CH:30]=[CH:31][CH:26]=[CH:27][CH:28]=1
Reactant: Nc1ccc(-n2ccc(-c3ccccn3)n2)c(F)c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1ccc(-n2ccc(-c3ccccn3)n2)c(F)c1)OCc1ccccc1
Yield: 81.5 %

Procedure:
The above-described product 19a (1 g, 3.9 mmol) was dissolved in dichloromethane (4 mL), and then anhydrous potassium carbonate (0.6 g) was added thereto. Then, Cbz-Cl (1.863 g, 1.537 mL) was slowly dropped, at a rate of 1-2 drops per second, into the mixture maintained in an ice-salt bath. The resultant mixture was reacted for 4 hours at room temperature. After completion of the reaction, water was added into the reaction mixture, followed by extraction with ethyl acetate. The combined ethyl acetate phase was evaporated in vacuum to get a crude product, which was recrystallized with acetone to afford the product 20a (1.235 g) as a white solid, with a yield of 80.8%.
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(OC=3C3C=CC=CC=3)=C3C(=CC=4)NN=C3)=CC=2)CCC1.C(OC(=O)[NH:38][C:39]1([C:43]2[CH:48]=[CH:47][C:46]([C:49]3[C:50](=[O:68])[C:51]4[C:56]([O:57][C:58]=3[C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)=[C:55]3[NH:65][N:66]=[N:67][C:54]3=[CH:53][CH:52]=4)=[CH:45][CH:44]=2)[CH2:42][CH2:41][CH2:40]1)(C)(C)C>>[NH2:38][C:39]1([C:43]2[CH:44]=[CH:45][C:46]([C:49]3[C:50](=[O:68])[C:51]4[C:56]([O:57][C:58]=3[C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)=[C:55]3[NH:65][N:66]=[N:67][C:54]3=[CH:53][CH:52]=4)=[CH:47][CH:48]=2)[CH2:42][CH2:41][CH2:40]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(ccc5nn[nH]c54)c3=O)cc2)CCC1
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4c(ccc5[nH]ncc54)c3=O)cc2)CCC1
Product: NC1(c2ccc(-c3c(-c4ccccc4)oc4c(ccc5nn[nH]c54)c3=O)cc2)CCC1
Yield: 22 %

Procedure:
Following the procedure used to prepare 3-[4-(1-amino-cyclobutyl)-phenyl]-2-phenyl-7H-pyrano[2,3-e]indazol-4-one, {1-[4-(6-oxo-8-phenyl-1,6-dihydro-9-oxa-1,2,3-triaza-cyclopenta[a]naphthalen-7-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester was reacted to give the title compound as a yellow solid (9 mg, 22%). 1H NMR (400 MHz, DMSO-d6): δ 7.75-7.70 (m, 2H), 7.53-7.49 (m, 2H), 7.47-7.37 (m, 5H), 7.34-7.31 (m, 2H), 2.61-2.54 (m, 2H), 2.49-2.39 (m, 2H), 2.19-2.08 (m, 1H), 1.86-1.75 (m, 1H). LCMS (Method E): RT=2.93 min, [M+H]+=409.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([O:4][C:5]([NH:7][C@H:8]([CH2:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[F:21])[CH2:9][C:10]([OH:12])=O)=[O:6])[CH3:3].CN1CCOCC1.ClC(OCC(C)C)=O.Cl.[Cl:39][C:40]1[C:41]2[CH2:53][CH2:52][NH:51][CH2:50][C:42]=2[N:43]=[C:44]([C:46]([F:49])([F:48])[F:47])[N:45]=1>C1COCC1.CCOCC>[CH3:22][C:2]([CH3:1])([O:4][C:5]([NH:7][C@H:8]([CH2:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[F:21])[CH2:9][C:10]([N:51]1[CH2:52][CH2:53][C:41]2[C:40]([Cl:39])=[N:45][C:44]([C:46]([F:49])([F:48])[F:47])=[N:43][C:42]=2[CH2:50]1)=[O:12])=[O:6])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)ccc1F
Reactant: FC(F)(F)c1nc(Cl)c2c(n1)CNCC2
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCc2c(Cl)nc(C(F)(F)F)nc2C1)Cc1cc(F)ccc1F
Temperature: -15 °C
Reaction time: 0.17 h
Yield: 58 %

Procedure:
A mixture of 60 mg (0.20 mmol) of (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]4-(2,5-difluorophenyl)butanoic acid and 0.033 mL (0.30 mmol) of N-methylmorpholine in 0.6 mL of THF was cooled to −15° C. and 0.031 mL of isobutyl chloroformate was added. After 10 min, 1.0 mL of ether was added. The mixture was transferred to a syringe and filtered through a syringe filter into a mixture of 35 mg (0.20 mmol) of amine hydrochloride from Step A and 0.033 mL (0.30 mmol) of N-methylmorpholine in 0.5 mL of THF at 0° C. The reaction mixture was warmed to ambient temperature. After 30 min, the reaction was judged to be complete by TLC. The mixture was filtered using a syringe filter, washing with ether, and concentrated under nitrogen. The solid was partitioned between ethyl acetate and water. The organics were washed with brine, dried over magnesium sulfate and concentrated to give a yellow oil. Purification by flash chromatography (5 g silica gel cartridge, 10 to 35% ethyl acetate/hexane step gradient) gave 62 mg (58%) of the title compound as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[C:7]([O:10][CH2:11][C:12](=[O:18])[CH2:13][C:14]([O:16][CH3:17])=[O:15])(=[O:9])[CH3:8].Cl[CH2:20][C:21](=[O:23])[CH3:22]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(#N)C>[C:7]([O:10][CH2:11][C:12](=[O:18])[CH:13]([CH2:20][C:21]([CH3:22])=[O:23])[C:14]([O:16][CH3:17])=[O:15])(=[O:9])[CH3:8]
Reactant: COC(=O)CC(=O)COC(C)=O
Reactant: CC(=O)CCl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CC#N
Product: COC(=O)C(CC(C)=O)C(=O)COC(C)=O
Temperature: 0 °C
Yield: 92 %

Procedure:
63.6 g (0.6 mol) of sodium carbonate and 2.3 g (0.01 mol) of benzyltriethylammonium chloride are suspended in 250 ml of acetonitrile. While stirring there are added thereto 87.0 g (0.5 mol) of methyl 4-acetoxyacetoacetate and there are added dropwise thereto within 5 minutes 69.4 g (0.75 mol) of chloroacetone. The mixture is stirred at 20°-25° C. for a further 46 hours. The reaction mixture is poured on to 1 liter of 10% NaH2PO4 solution/ice (pH value=5) and extracted 3 times with 300 ml of ethyl acetate each time. The combined organic phases are dried over magnesium sulphate and concentrated completely on a rotary evaporator to give 105.9 g (92%) of methyl 4-acetoxy-2-acetonylacetoacetate, content 76.9%; b.p. 119°-121° C./0.06 mbar.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([CH3:32])[CH:26]=3)=[C:8]([CH:15]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:16]([O:18][CH3:19])=[O:17])[N:9]([CH3:14])[C:10]2=[O:13])=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.Br[CH2:43][CH2:44][O:45][CH2:46][CH2:47]Br>C1(C)C=CC=CC=1.CCOC(C)=O>[C:21]([O:20][CH:15]([C:8]1[N:9]([CH3:14])[C:10](=[O:13])[C:11]2[C:6]([C:7]=1[C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([CH3:32])[CH:26]=1)=[CH:5][CH:4]=[C:3]([CH2:2][N:1]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1)[CH:12]=2)[C:16]([O:18][CH3:19])=[O:17])([CH3:22])([CH3:23])[CH3:24]
Reactant: BrCCOCCBr
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)c(C)c2)c2ccc(CN)cc2c(=O)n1C
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)c(C)c2)c2ccc(CN3CCOCC3)cc2c(=O)n1C
Temperature: 90 °C
Reaction time: 6 h
Yield: 79.5 %

Procedure:
A solution of methyl 2-(7-(aminomethyl)-4-(3,4-dimethylphenyl)-2-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)-2-(tert-butoxy)acetate (17 mg, 0.039 mmol) in toluene (750 μl) was treated with DIEA (13.60 μl, 0.078 mmol) and 1-bromo-2-(2-bromoethoxy)ethane (5.87 μl, 0.047 mmol). The mixture was stirred at 90° C. for 6 hours. Additional DIEA (13.60 μl, 0.078 mmol) and 1-bromo-2-(2-bromoethoxy)ethane (5.87 μl, 0.047 mmol) were added, the reaction was stirred at 90° C. overnight. The reaction was cooled to rt, diluted with EtOAc, washed with water, brine, dried with Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (0-10% MeOH/DCM) to afford methyl 2-(tert-butoxy)-2-(4-(3,4-dimethylphenyl)-2-methyl-7-(morpholinomethyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)acetate (15.6 mg, 0.031 mmol, 79% yield). The methyl ester was hydrolyzed in a manner similar to that described in Example 165 Step C and purified by reverse phase HPLC to afford 2-(tert-butoxy)-2-(4-(3,4-dimethyl phenyl)-2-methyl-7-(methylsulfonamidomethyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)acetic acid (14 mg, 0.027 mmol, 88% yield) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.42 (s, 1 H), 7.71-7.61 (m, 1 H), 7.24-7.33 (m, 1 H), 7.26-7.17 (m, 2 H), 7.07-6.96 (m, 1 H), 5.35 (s, 1 H), 4.40-4.22 (m, 2 H), 4.03-3.81 (m, 4 H), 3.71 (s, 3 H), 3.59-3.37 (m, 2 H), 2.92 (br. s., 2 H), 2.37 (s, 3 H), 2.32 (s, 1.5 H), 2.29 (s, 1.5 H). 1.06 (s, 4.5 H), 1.05 (s, 4.5 H); LCMS (m/z) ES+=493 (M+1).
Reaction SMILES: CS(O[CH2:6][C@H:7]1[O:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]1)(=O)=O.[CH3:20][C:21]1([CH3:33])[C:25]([CH3:27])([CH3:26])[O:24][B:23]([C:28]2[CH:29]=[N:30][NH:31][CH:32]=2)[O:22]1.C(=O)([O-])[O-].[Ce+3].C(=O)([O-])[O-].C(=O)([O-])[O-].[Ce+3]>C(#N)C>[CH3:20][C:21]1([CH3:33])[C:25]([CH3:26])([CH3:27])[O:24][B:23]([C:28]2[CH:32]=[N:31][N:30]([CH2:6][C@H:7]3[O:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:8]3)[CH:29]=2)[O:22]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](COS(C)(=O)=O)C1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Ce+3]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCO[C@H](Cn2cc(B3OC(C)(C)C(C)(C)O3)cn2)C1
Temperature: 60 °C
Reaction time: 3 h
Yield: 52.2 %

Procedure:
To a mixture of (S)-tert-butyl 2-((methylsulfonyloxy)methyl)morpholine-4-carboxylate (430 mg, 1.46 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (283 mg, 1.46 mmol) in 50 mL of acetonitrile was added cerium carbonate (1.43 g, 4.37 mmol), and the mixture was stirred at 60° C. for 3 h. TLC and LCMS showed the reaction was completed. After the solvents were removed under reduced pressure, the residue was diluted with 50 mL of ethyl acetate, and washed with water (50 mL×3) and brine. The organic layer was separated, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate=5:1) to get the title product (300 mg, 52%) as colorless oil. MS (ES+) C19H32BN3O5 requires: 393. found: 394 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:24]=[CH:23][C:15]([C:16]([O:18]C(C)(C)C)=[O:17])=[CH:14][CH:13]=1)[C:6](=[O:25])[C:5]2([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[Cl:35])[N:26]([CH3:28])[CH3:27].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:24]=[CH:23][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1)[C:6](=[O:25])[C:5]2([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[Cl:35])[N:26]([CH3:28])[CH3:27]
Reactant: CN(C)C1(c2ccccc2Cl)C(=O)N(Cc2ccc(C(=O)OC(C)(C)C)cc2)c2ccc(Cl)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)C1(c2ccccc2Cl)C(=O)N(Cc2ccc(C(=O)O)cc2)c2ccc(Cl)cc21
Reaction time: 0.5 h

Procedure:
A solution of 0.615 g of the compound obtained in EXAMPLE 93 in 2 ml of DCM is cooled to 0° C. and 2 ml of TFA are added. The mixture is stirred for 30 minutes and evaporated under vacuum and the residue is then taken up with DCM and evaporated under vacuum again to give the expected product, which is used as such in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]([C:16]3[CH:24]=[C:23]4[C:19]([C:20]5[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][C:21]=5[N:22]4[CH3:25])=[CH:18][CH:17]=3)[C:12](=[O:37])[CH:11]=2)=[N:6][CH:7]=1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:50].Cl>>[ClH:1].[ClH:50].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]([C:16]3[CH:24]=[C:23]4[C:19]([C:20]5[CH2:29][CH2:28][NH:27][CH2:26][C:21]=5[N:22]4[CH3:25])=[CH:18][CH:17]=3)[C:12](=[O:37])[CH:11]=2)=[N:6][CH:7]=1
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(Cl)cn5)cc4=O)cc31)CCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(Cl)cn5)cc4=O)cc31)CCNC2
Yield: 94 %

Procedure:
tert-Butyl 7-(4-((5-chloropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (145 mg, 0.278 mmol) was deprotected and converted to the dihydrochloride salt according to the procedure of Example 30 (steps e and g) to provide the title compound (114 mg, 94%) as a yellow solid: mp 275-280° C.; 1H NMR (500 MHz, CD3OD) δ 8.61 (s, 1H), 7.77 (dd, J=8.3, 3.8 Hz, 1H), 7.64-7.62 (m, 3H), 7.47 (d, J=1.6 Hz, 1H), 7.03 (dd, J=8.4, 1.8 Hz, 1H), 6.37 (dd, J=7.6, 3.8 Hz, 1H), 6.15 (d, J=2.7 Hz, 1H), 5.28 (s, 2H), 4.54 (s, 2H), 3.71 (s, 3H), 3.60 (t, J=6.1 Hz, 2H), 3.12 (t, J=6.0 Hz, 2H); ESI MS m/z 421 [M+H]+; HPLC (Method B) 98.5% (AUC), tR=12.1 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH3:38][CH:39]1[CH2:44][CH:43]([CH3:45])[CH2:42][NH:41][CH2:40]1>>[CH3:38][CH:39]1[CH2:44][CH:43]([CH3:45])[CH2:42][N:41]([C:21]2[N:20]=[C:19]([O:18][C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:29]=[C:30]([N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)[CH:31]=[C:2]([F:1])[CH:3]=4)=[CH:9][CH:10]=3)[CH:24]=[CH:23][N:22]=2)[CH2:40]1
Reactant: CC1CNCC(C)C1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Product: CC1CC(C)CN(c2nccc(Oc3ccc(NC(=O)c4cc(F)cc(N5CCOCC5)c4)c4ccccc34)n2)C1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and 3,5-dimethylpiperidine according to conditions described in general procedure C. Mp: 102-104° C.; 1H NMR (400 MHz, DMSO-d6) δ 0.76-0.88 (m, 6 H), 1.33-3.22 (m, 8 H), 3.27 (m, 4 H), 3.77 (m, 4H), 6.17 (d, J=5.5 Hz, 1 H), 7.02-7.06 (m, 1H), 7.27 (d, J=8.8 Hz, 1 H), 7.41 (d, J=8.0 Hz, 1 H), 7.25-7.62 (m, 4 H), 7.62-7.83 (m, 1 H), 7.99-8.01 (m, 1 H), 8.24 (d, J=5.5 Hz, 1 H), 10.47 (s, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=2)([CH2:14][CH2:15]OS(C)(=O)=O)[CH2:9]1)=[O:7].[F:36][C:37]1[CH:59]=[CH:58][C:40]([CH2:41][N:42]2[C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=3[N:44]=[C:43]2[NH:51][CH:52]2[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]2)=[CH:39][CH:38]=1.C(N(CC)C(C)C)(C)C.CO.C(OCC)(=O)C>C(#N)C>[CH3:35][O:34][C:30]1[CH:29]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:31]=1[O:32][CH3:33])[C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([CH2:14][CH2:15][N:55]2[CH2:56][CH2:57][CH:52]([NH:51][C:43]3[N:42]([CH2:41][C:40]4[CH:58]=[CH:59][C:37]([F:36])=[CH:38][CH:39]=4)[C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=4[N:44]=3)[CH2:53][CH2:54]2)([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=2)[CH2:9]1)=[O:7]
Reactant: Fc1ccc(Cn2c(NC3CCNCC3)nc3ccccc32)cc1
Reactant: COc1cc(C(=O)N2CCCC(CCOS(C)(=O)=O)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CC#N
Product: COc1cc(C(=O)N2CCCC(CCN3CCC(Nc4nc5ccccc5n4Cc4ccc(F)cc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reaction time: 48 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-methanesulfonyloxyethyl)piperidine (1.14 mmol) and (1-(4-fluorobenzyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine (0.56 g, 1.7 mmol), and N,N-diisopropylethylamine (0.50 g) in acetonitrile (12 mL). Heat to reflux. After 2 days, partition the residue between ethyl acetate and water. Separate the organic layer and extract twice with saturated aqueous sodium bicarbonate solution and brine. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph the residue on silica gel eluting with 30/70/0.33 methanol/ethyl acetate/concentrated aqueous ammonia to give the title compound: Rf=0.50 (silica gel, 30% methanol/ethyl acetate).
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([NH:6][C:7]([NH:9][C:10]2[CH:31]=[CH:30][C:13]([O:14][C:15]3[C:24]4[C:19](=[CH:20][C:21]([O:28][CH3:29])=[C:22]([C:25]([OH:27])=[O:26])[CH:23]=4)[N:18]=[CH:17][CH:16]=3)=[CH:12][CH:11]=2)=[O:8])=[CH:4][CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C.[CH3:53][O:54][CH2:55][CH2:56]O>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:6][C:7]([NH:9][C:10]2[CH:31]=[CH:30][C:13]([O:14][C:15]3[C:24]4[C:19](=[CH:20][C:21]([O:28][CH3:29])=[C:22]([C:25]([O:27][CH2:56][CH2:55][O:54][CH3:53])=[O:26])[CH:23]=4)[N:18]=[CH:17][CH:16]=3)=[CH:12][CH:11]=2)=[O:8])=[CH:32][CH:33]=1
Reactant: COCCO
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(F)cc4)cc3)c2cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COCCOC(=O)c1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4)cc3)ccnc2cc1OC
Yield: 49.6 %

Procedure:
After dissolving 4-(4-(((4-fluoroanilino)carbonyl)amino) phenoxy)-7-methoxy-6-quinolinecarboxylicacid (84 mg, 0.19 mmol) in dimethylformamide (1 ml), there were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (54 mg, 0.28 mmol), 1-hydroxy-1H-benzotriazolemonohydrate (38 mg, 0.28 mmol), triethylamine (0.079 ml, 0.56 mmol) and 2-methoxyethanol (0.15 ml) while stirring on ice, and the mixture was stirred overnight at room temperature. The reaction solution was directly subjected to silica gel column chromatography (eluent—ethyl acetate), the fraction containing the target substance was concentrated, suspended in ethyl acetate and diluted with hexane, and the crystals were filtered out and blow-dried to obtain the title compound (47.1 mg, 0.093 mmol, 49.6%) as white crystals.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[C:11]#[N:12])[C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:4]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[NH:3]1.[NH2:28][OH:29].Cl.C([O-])([O-])=O.[Na+].[Na+]>CO>[OH:29][NH:28][C:11](=[NH:12])[C:10]1[CH:13]=[CH:14][CH:15]=[C:8]([CH:6]2[C:5]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:4]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:3][C:2](=[O:1])[NH:7]2)[CH:9]=1
Reactant: NO
Reactant: N#Cc1cccc(C2NC(=O)NC(c3ccccc3)=C2c2ccccc2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: N=C(NO)c1cccc(C2NC(=O)NC(c3ccccc3)=C2c2ccccc2)c1
Temperature: 25 °C
Yield: 19.5 %

Procedure:
A mixture of 3-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzonitrile (700 mg, 2 mmol, 1 eq), NH2OH—HCl (144 mg, 2.2 mmol, 1.1 eq) and Na2CO3 (414 mg, 4.0 mmol, 2.0 eq) in methanol (5.0 mL) was heated to reflux overnight. The mixture was cooled to room temperature and filtered. The filtered mass was washed with methanol (5.0 mL) and purified by prep-HPLC to afford Compound 99 as a yellow solid (150 mg, 19.5%) and Compound 98 as a white solid (6.7%). Data for Compound 99: 1H NMR (MeOH-d4 500 MHz TMS): δ 7.69-7.72 (m, 2H), 7.58-7.61 (m, 2H), 7.26 (br, 5H), 7.04 (br, 2H), 6.88 (br, 2H), 5.51 (s 1H); MS (ESI): m/z 385.1.1 [M+1]+.