Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[C:9]=2[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.Br[CH2:33][CH2:34][O:35][Si:36]([C:49]([CH3:52])([CH3:51])[CH3:50])([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Si:36]([O:35][CH2:34][CH2:33][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[C:9]=2[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]3[CH2:28][CH2:29][CH2:30][CH2:31]3)=[CH:20][CH:19]=2)=[CH:4][CH:3]=1)([C:49]([CH3:50])([CH3:51])[CH3:52])([C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CC(C)(C)[Si](OCCBr)(c1ccccc1)c1ccccc1
Reactant: Oc1ccc(-c2sc3ccccc3c2Cc2ccc(OCCN3CCCC3)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCCOc1ccc(-c2sc3ccccc3c2Cc2ccc(OCCN3CCCC3)cc2)cc1)(c1ccccc1)c1ccccc1
Temperature: 50 °C
Yield: 126.9 %

Procedure:
A mixture of 2.00 g (4.66 mmol) of 2-(4-hydroxyphenyl)-3-[4-[2-(1-pyrrolidinyl)ethoxy]benzyl]benzo[b]thiophene, 1.86 g (5.12 mmol) of 1-bromo-2-(tert-butyldiphenyl-silyloxy)ethane, and 1.93 g (14.0 mmol) of K2CO3 in 50 mL DMF was heated to 50° C. for 22 h. The reaction was poured into 250 mL of H2O and the mixture extracted with EtOAc (3×100 mL). The combined organic extracts were washed with H2O (2×100 mL), dried over K2CO3, filtered and concentrated in vacuo to give 4.21 g of an oily solid. Purification by flash chromatography (SiO2; 0.1% then 0.2% then 0.5% MeOH in CHCl3 sat'd with NH4OH) afforded 2.76 g (3.88 mmol; 83%) of the title compound as an oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[N:14][O:15][CH3:16])[C:10]([NH:12][CH3:13])=[O:11].[H-].[Na+].[Cl:19][C:20]1[C:21]([C:30]([OH:32])=[O:31])=[N:22][C:23](S(C)(=O)=O)=[CH:24][CH:25]=1.CS(C)=O>C1COCC1.C(OCC)(=O)C.O>[CH3:16][O:15][N:14]=[C:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][O:1][C:23]1[CH:24]=[CH:25][C:20]([Cl:19])=[C:21]([C:30]([O:32][C:3]([CH3:8])([CH3:4])[CH3:2])=[O:31])[N:22]=1)[C:10]([NH:12][CH3:13])=[O:11]
Reactant: CS(=O)(=O)c1ccc(Cl)c(C(=O)O)n1
Reactant: CNC(=O)C(=NOC)c1ccccc1CO
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CNC(=O)C(=NOC)c1ccccc1COc1ccc(Cl)c(C(=O)OC(C)(C)C)n1
Reaction time: 0.33 h

Procedure:
A 50 mL 3-neck round bottom flask equipped with a magnetic stirring bar and N2 inlet was charged with (0.55 g, 0.0024 mol) 2-hydroxymethyl-α-methyoxyimino-N-methyl-benzeneacetamide and 10 mL anhydrous THF. To the reaction was added (0.14 g, 0.003mol) 60% NaH with stirring under nitrogen for 20 minutes. To the reaction was then added 3-chloro-6-methylsulphonylpicolinic acid: t-butyl ester (0.900 g, 0.003 mol) dissolved in 8 mL anhydrous THF, then 2 mL DMSO and stirring for three hours under nitrogen at room temperature. The mixture was then diluted with 20 mL ethyl acetate and 50 mL DI water and extracted four times with 20 mL portions of ethyl acetate. The combined organic extracts were washed three times with 50 mL portions DI water and twice with 25 mL portions brine to give the resulting product, α-(methoxyimino)-N-methyl-2-[[[5-chloro-6-(t-butoxycarbonyl)-2-pyridinyl]oxy]methyl]-benzeneacetamide, as an off-white oily solid after chromatography. M.P. 103-108° C.
Reaction SMILES: OS(C(F)(F)F)(=O)=O.CS[CH:11]([N:13]([CH2:15][CH2:16][O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH3:14])[CH3:12].[NH2:23][C:24]1[CH:32]=[C:31]2[C:27]([CH2:28][C@@H:29]([OH:48])[C@@H:30]2[NH:33][C:34]([C:36]2[CH:41]=[CH:40][C:39](C3C=CC=CC=3)=[CH:38][CH:37]=2)=[O:35])=[CH:26][CH:25]=1>N1C=CC=CC=1>[CH2:18]([O:17][CH2:16][CH2:15][N:13]([CH3:14])[C:11](=[N:23][C:24]1[CH:32]=[C:31]2[C:27]([CH2:28][C@@H:29]([OH:48])[C@@H:30]2[NH:33][C:34]([C:36]2([C:24]3[CH:32]=[CH:31][CH:27]=[CH:26][CH:25]=3)[CH:37]=[CH:38][CH:39]=[CH:40][CH2:41]2)=[O:35])=[CH:26][CH:25]=1)[CH3:12])[CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCOCCN(C)C(C)SC
Reactant: Nc1ccc2c(c1)[C@@H](NC(=O)c1ccc(-c3ccccc3)cc1)[C@H](O)C2
Agent: O=S(=O)(O)C(F)(F)F
Solvent: c1ccncc1
Product: CCCCCOCCN(C)C(C)=Nc1ccc2c(c1)[C@@H](NC(=O)C1(c3ccccc3)C=CC=CC1)[C@H](O)C2
Reaction time: 22 h
Yield: 21.7 %

Procedure:
Dissolve the crude triflic acid salt of (1-methylsulfanylethyl)(2-pentoxyethyl)methylamine (192.1 mg, 0.523 mmol) and biphenyl-4-carboxylic acid (R)-(6-amino-2(R)-hydroxyindan-1-yl)amide (170.8 mg, 0.496 mmol) in 10 mL pyridine and allow it to stir for 22 hours. Remove the solvent in vacuo and partition the residue between methylene chloride and saturated aqueous sodium hydrogen carbonate. Dry the organic layer with magnesium sulfate. Filter and remove the solvent in vacuo to give 112.3 mg of crude product. Purify via Biotage chromatography (10% MeOH/EtOAc 25% MeOH/EtOAc) to afford 27.8 mg of the titled product (11% yield). MS (ES): m/z 514.5 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][C@H:5]([N:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]1=[O:18])[CH3:6].Br[CH2:21][C:22]1[C:26]2[C:27]([CH3:32])=[CH:28][C:29]([CH3:31])=[CH:30][C:25]=2[S:24][N:23]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH3:1][O:2][C:3](=[O:19])[CH2:4][C@H:5]([N:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:21][C:22]2[C:26]3[C:27]([CH3:32])=[CH:28][C:29]([CH3:31])=[CH:30][C:25]=3[S:24][N:23]=2)[C:8]1=[O:18])[CH3:6]
Reactant: COC(=O)C[C@@H](C)n1c(=O)[nH]c2ccccc2c1=O
Reactant: Cc1cc(C)c2c(CBr)nsc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C[C@@H](C)n1c(=O)c2ccccc2n(Cc2nsc3cc(C)cc(C)c23)c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.6 %

Procedure:
(R)-3-(2,4-Dioxo-1,4-dihydro-2H-quinazolin-3-yl)-butyric acid methyl ester (124 mg, 0.5 mmol) (prepared according to example 4, steps 1-2), 3-bromomethyl-4,6-dimethyl-1,2-benzisothiazole (150 mg, 0.59 mmol) (prepared according to example 5, steps 1-6), and potassium carbonate (345.5 mg, 2.5 mmol) are combined in a reaction vial and DMF (1 mL) is added. The reaction mixture is agitated at ambient temperature for 18 hours then diluted with water (15 mL). The product is isolated by filtration and purified by flash chromatography using an ethyl acetate/hexane gradient to provide (R)-3-[1-(4,6-dimethyl-1,2-benzisothiazol-3-ylmethyl)-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]-butyric acid methyl ester (196 mg, 93%).
Reaction SMILES: [OH:1][C:2]([CH2:7][CH3:8])([CH2:5][CH3:6])[C:3]#[CH:4].C([Li])CCC.[Br:14]Br.CCOCC>C1COCC1.O>[Br:14][C:4]#[C:3][C:2]([OH:1])([CH2:7][CH3:8])[CH2:5][CH3:6]
Reactant: BrBr
Reactant: C#CC(O)(CC)CC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CCC(O)(C#CBr)CC
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-hydroxy-3-ethyl-1-pentyne (20 mmol) in dry THF (40 ml) at room temperature was added n-butyl-lithium (42 mmol, 1.6M in hexanes) during 10 minutes. After stirring for 30 minutes, the solution was cooled to −40° C. and a solution of bromine (1.13 ml, 3.52 g, 22 mmol) in dry THF (20 ml), also cooled to −40° C., was added, during 20 minutes, followed by re-heating to 25° C., during about 1 hour. Standard work-up after addition of ether and water (chromatography: 0% to 10% ether in petroleum ether) gave the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[O:14]C=CC=2)=[CH:11][C:10]([C:18]([F:21])([F:20])[F:19])=[N:9]1.Cl[O-].[Na+].[O-:25]Cl=O.[Na+].[OH-].[Na+]>C(#N)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]([OH:14])=[O:25])=[CH:11][C:10]([C:18]([F:21])([F:20])[F:19])=[N:9]1
Reactant: FC(F)(F)c1cc(-c2ccco2)n(-c2ccccc2Cl)n1
Reactant: [O-][Cl+][O-]
Agent: [Na+]
Agent: [O-]Cl
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: O=C(O)c1cc(C(F)(F)F)nn1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A sample of the crude product from Step A (approximately 89%, 56.0 g, 0.18 mole) was dissolved in acetonitrile (400 mL) and a solution of NaH2PO4 (120 g, 0.87 mole) in 520 mL of water was added. Sodium hypochlorite solution (5.25% in water, 128 g, 2.6 mole) was added dropwise over 10-15 minutes. The orange solution was maintained at room temperature for 30 minutes. The reaction mixture was cooled in an ice bath and a solution of NaClO2 in 560 mL of water was added dropwise, keeping the temperature below 11° C. Gas evolution was observed and an aqueous sodium hydroxide scrubber was used to quench evolved chlorine. After the addition was complete, the reaction mixture was kept cold for one hour then allowed to reach room temperature overnight. To the reaction mixture was added 80 mL of concentrated hydrochloric acid dropwise to bring the pH below 3. The reaction mixture was extracted twice with ethyl acetate and the combined organic extracts were added dropwise rapidly with stirring to a cooled (<15° C.) solution of 300 g of NAHSO3 in 1-300 mL of water. The mixture was partitioned and the aqueous phase extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was taken up in chlorobutane and reconcentrated (twice). The resulting brown solid was triturated in 100 mL of ethyl ether in hexane (1%). Small portions of chlorobutane were added to help granulate the solid. The product was collected via filtration, washed with hexanes and dried. The product consisted of 40.8 g of tan solid, which was essentially pure based upon 1H NMR.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([NH2:7])=[N:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=1.[C:18]1([CH:24]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:25][CH2:26][NH:27][CH2:28][CH2:29][CH:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(C(C2C=CC=CC=2)CCN)C=CC=CC=1.BrCCC1CC[O:64][CH2:63]C1>>[Cl:1][C:2]1[S:6][C:5]([NH:7][C:63](=[O:64])[N:27]([CH2:26][CH2:25][CH:24]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:28][CH2:29][CH:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[N:4][C:3]=1[C:8]1[CH:9]=[CH:10][C:11]([S:14]([CH3:17])(=[O:15])=[O:16])=[CH:12][CH:13]=1.[C:18]1([CH:24]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:25][CH2:26][NH:27][CH2:28][CH2:29][CH:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CS(=O)(=O)c1ccc(-c2nc(N)sc2Cl)cc1
Reactant: BrCCC1CCOCC1
Agent: NCCC(c1ccccc1)c1ccccc1
Agent: c1ccc(C(CCNCCC2CCOCC2)c2ccccc2)cc1
Product: CS(=O)(=O)c1ccc(-c2nc(NC(=O)N(CCC3CCOCC3)CCC(c3ccccc3)c3ccccc3)sc2Cl)cc1

Procedure:
Compound 206 was prepared according to Method D using 5-chloro-4-(4-(methylsulfonyl)phenyl)thiazol-2-amine instead of N-(4-(2-amino-5-chlorothiazol-4-yl)phenyl)methanesulfonamide and 3,3-diphenyl-N-(2-(tetrahydro-2H-pyran-4-yl)ethyl)propan-1-amine instead of N-methyl-3,3-diphenylpropan-1-amine. 3,3-diphenyl-N-(2-(tetrahydro-2H-pyran-4-yl)ethyl)propan-1-amine was prepared according to Method C using 3,3-diphenylpropan-1-amine instead of tert-butyl 4-(2-aminoethyl)piperidine-1-carboxylate and 4-(2-bromoethyl)-tetrahydro-2H-pyran instead of 3-bromo-1,1-diphenylpropane.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([CH3:17])[C:9](=[O:18])[C:8]([CH3:20])([CH3:19])[C:7]1=[O:21]>C(OC(=O)C)(=O)C.C(O)(=O)C>[CH3:17][N:10]1[C:11]2[CH:16]=[CH:15][C:14]([N+:1]([O-:4])=[O:2])=[CH:13][C:12]=2[N:6]([CH3:5])[C:7](=[O:21])[C:8]([CH3:19])([CH3:20])[C:9]1=[O:18]
Reactant: O=[N+]([O-])O
Reactant: CN1C(=O)C(C)(C)C(=O)N(C)c2ccccc21
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CN1C(=O)C(C)(C)C(=O)N(C)c2cc([N+](=O)[O-])ccc21
Reaction time: 72 h

Procedure:
1.3 ml of nitric acid (65%) were cautiously added dropwise at 0° C. to 5.1 ml of acetic anhydride. The solution was added to a solution of 3.00 g of 2,3,4,5-tetrahydro-1,3,3,5-tetramethyl-2,4-dioxo-1H-1,5-benzodiazepine in 6.5 ml of acetic anhydride and 2.1 ml of glacial acetic acid. The reaction mixture was left to stand at room temperature for 3 days, filtered, the residue was washed thoroughly with water, dried and recrystallized from ethanol. There were obtained 2.11 g of 2,3,4,5-tetrahydro-1,3,3,5-tetramethyl-7-nitro-2,4-dioxo-1H-1,5-benzodiazepine, m.p. 224°-225° C.
Reaction SMILES: C([N:8]1[C:12]([C:13]2[O:14][C:15]3[CH:21]=[C:20]([O:22][CH2:23][CH:24]4[CH2:26][CH2:25]4)[CH:19]=[CH:18][C:16]=3[N:17]=2)=[CH:11][C:10]([O:27][CH2:28][C@@H:29]([NH:31][C:32](=[O:34])[CH3:33])[CH3:30])=[N:9]1)C1C=CC=CC=1.C(O)C>[OH-].[OH-].[Pd+2].C1COCC1>[CH:24]1([CH2:23][O:22][C:20]2[CH:19]=[CH:18][C:16]3[N:17]=[C:13]([C:12]4[NH:8][N:9]=[C:10]([O:27][CH2:28][C@@H:29]([NH:31][C:32](=[O:34])[CH3:33])[CH3:30])[CH:11]=4)[O:14][C:15]=3[CH:21]=2)[CH2:25][CH2:26]1
Reactant: CC(=O)N[C@@H](C)COc1cc(-c2nc3ccc(OCC4CC4)cc3o2)n(Cc2ccccc2)n1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(=O)N[C@@H](C)COc1cc(-c2nc3ccc(OCC4CC4)cc3o2)[nH]n1
Temperature: 50 °C
Reaction time: 4 h
Yield: 24.2 %

Procedure:
Under a hydrogen atmosphere, a mixture of N-[(1S)-2-({1-benzyl-5-[6-(cyclopropylmethoxy)-1,3-benzoxazol-2-yl]-1H-pyrazol-3-yl}oxy)-1-methylethyl]acetamide (120 mg), 20% palladium hydroxide/carbon (containing water (50%), 60 mg), ethanol (5 mL) and THF (3 mL) was stirred at 50° C. for 4 hr. The catalyst was removed by filtration, and the obtained filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (23.4 mg).
Reaction SMILES: ClC1C=CC(C2SC(C(OCC)=O)=C(C)N=2)=CC=1[N+]([O-])=O.[CH3:22][C:23]1[N:24]=[C:25]([C:33]2[CH:38]=[CH:37][C:36]([N:39]3[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]3)=[C:35]([N+:46]([O-:48])=[O:47])[CH:34]=2)[S:26][C:27]=1[C:28]([O:30]CC)=[O:29]>CN1CCNCC1>[CH3:22][C:23]1[N:24]=[C:25]([C:33]2[CH:38]=[CH:37][C:36]([N:39]3[CH2:40][CH2:41][N:42]([CH3:45])[CH2:43][CH2:44]3)=[C:35]([N+:46]([O-:48])=[O:47])[CH:34]=2)[S:26][C:27]=1[C:28]([OH:30])=[O:29]
Reactant: CCOC(=O)c1sc(-c2ccc(N3CCN(C)CC3)c([N+](=O)[O-])c2)nc1C
Agent: CCOC(=O)c1sc(-c2ccc(Cl)c([N+](=O)[O-])c2)nc1C
Agent: CN1CCNCC1
Product: Cc1nc(-c2ccc(N3CCN(C)CC3)c([N+](=O)[O-])c2)sc1C(=O)O
Yield: 58 %

Procedure:
As described in Example 37, ethyl 2-(4-chloro-3-nitrophenyl)-4-methyl-5-thiazolecarboxylate was reacted in 1-methylpiperazine, and the resulting ethyl 4-methyl-2-(4-(4-methylpiperazinyl)-3-nitrophenyl)-5-thiazolecarboxylate was hydrolyzed by a conventional process to give 4-methyl-2-(4-(4-methylpiperazinyl)-3-nitrophenyl)-5-thiazolecarboxylic acid (yield: 58%).
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([CH:20]4[CH:29]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[C:28](=O)[C:27]5[C:26]([C:37]([O:39]C)=O)=[CH:25][CH:24]=[CH:23][C:22]=5[NH:21]4)=[CH:16][CH:15]=3)=[O:13])[CH2:8][CH2:7]2)=[O:5])[CH2:3][CH2:2]1.O.[NH2:42][NH2:43]>>[CH:1]1([C:4]([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([CH:20]4[NH:21][C:22]5[C:27]6[C:28](=[N:42][NH:43][C:37](=[O:39])[C:26]=6[CH:25]=[CH:24][CH:23]=5)[CH:29]4[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:16][CH:15]=3)=[O:13])[CH2:8][CH2:7]2)=[O:5])[CH2:3][CH2:2]1
Reactant: COC(=O)c1cccc2c1C(=O)C(c1ccccc1)C(c1ccc(C(=O)N3CCN(C(=O)C4CC4)CC3)cc1)N2
Reactant: NN
Solvent: O
Product: O=C(c1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccccc2)cc1)N1CCN(C(=O)C2CC2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 19 %

Procedure:
A mixture of methyl 2-(4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate (300 mg, 0.55 mmol) and hydrazine monohydrate (3 mL) was stirred room temperature for 3 h. The resulting mixture was evaporated under reduced pressure to 10 mL and then filtered; the filtrate was concentrated to give the crude product. The crude product was purified by pre-HPLC to give 8-(4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one as a white solid (4 mg, yield 19%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 0.71-0.74 (m, 4H), 1.97 (t, 1H), 3.46-3.76 (m, 8H), 4.36 (dd, 1H), 4.83 (dd, 1H), 7.13-7.23 (m, 6H), 7.30 (d, 2H), 7.38 (t, 3H), 7.47 (s, 1H), 7.59 (t, 1H), 12.17 (s, 1H); LC-MS (ESI) m/z: 520(M+1)+.
Reaction SMILES: [CH3:1][O:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([CH3:12])[CH:6]=1.C([BH3-])#N.[Na+]>>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][NH:3][O:2][CH3:1])=[CH:6][C:7]=1[CH3:12]
Reactant: CON=Cc1ccc(F)c(C)c1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CONCc1ccc(F)c(C)c1

Procedure:
Reduction of 4-fluoro-3-methyl-benzaldehyde O-methyloxime with sodium cyanoborohydride as described in the preparation of compound 3-B gave the title hydroxylamine as a clear oil after chromatography on silica gel (elution hexane-ethyl acetate 8:2) (94% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 2.27 (3H, broad s, CH3), 3.50 (3H, s, OCH3), 3.97 (2H, broad s, NCH2), 5.67 (1H, broad, NH), 6.95 (1H, m, aromatic), 7.11-7.17 (2H, m, aromatics. The hydrochloride salt was obtained as a white solid: mp 162° C. Anal. calcd for C9H12FNO—HCl: C, 52.56; H, 6.37; N, 6.81. Found: C, 52.80; H, 6.33; N, 6.70.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH2:5][O:6][CH3:7])[CH2:3][OH:4].[CH3:9][Si:10](Cl)([CH3:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH3:1][C:2]([CH3:8])([CH2:3][O:4][Si:10]([CH3:17])([CH3:9])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][O:6][CH3:7]
Reactant: COCC(C)(C)CO
Reactant: C[Si](C)(Cl)c1ccccc1
Product: COCC(C)(C)CO[Si](C)(C)c1ccccc1

Procedure:
According to the procedure as described in Example 1,2,2-dimethyl-1-methoxy-3-[(dimethylphenylsilyl)oxy]propane was prepared from intermediate 2,2-dimethyl-3-methoxy-1-propanol and reagent dimethylphenylsilyl chloride.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:51])[C@@H:5]([NH:21][C:22]([CH:24]1[CH2:33][C:32]2[CH:31]=[C:30]3[O:34][CH2:35][C@H:36]([C:38]4[CH:43]=[CH:42][C:41]([O:44][CH2:45][CH:46]5[CH2:50][CH2:49][CH2:48][CH2:47]5)=[CH:40][CH:39]=4)[O:37][C:29]3=[CH:28][C:27]=2[CH2:26][NH:25]1)=[O:23])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.[C:52]([NH:55][C:56]1[S:57][C:58]([S:62](Cl)(=[O:64])=[O:63])=[C:59]([CH3:61])[N:60]=1)(=[O:54])[CH3:53]>>[CH3:2][O:3][C:4](=[O:51])[C@@H:5]([NH:21][C:22]([CH:24]1[CH2:33][C:32]2[CH:31]=[C:30]3[O:34][CH2:35][C@H:36]([C:38]4[CH:39]=[CH:40][C:41]([O:44][CH2:45][CH:46]5[CH2:47][CH2:48][CH2:49][CH2:50]5)=[CH:42][CH:43]=4)[O:37][C:29]3=[CH:28][C:27]=2[CH2:26][N:25]1[S:62]([C:58]1[S:57][C:56]([NH:55][C:52](=[O:54])[CH3:53])=[N:60][C:59]=1[CH3:61])(=[O:63])=[O:64])=[O:23])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]([C:19]#[N:20])=[CH:17][CH:18]=2)=[CH:9][CH:8]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCC2CCCC2)cc1)CO3
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)Cl)s1
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1S(=O)(=O)c1sc(NC(C)=O)nc1C)O[C@@H](c1ccc(OCC2CCCC2)cc1)CO3
Yield: 75.2 %

Procedure:
(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-(4-cyclopentylmethoxy-phenyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-propionic acid methylester hydrochloride (18 mg) was reacted with 2-acetylamino-4-methyl thiazole-5-sulfonyl chloride (11 mg) according to General Procedure E to give (S)-2-{[(S)-7-(2-acetylamino-4-methyl-thiazole-5-sulfonyl)-3-(4-cyclopentylmethoxy-phenyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester (17 mg). This was hydrolyzed according to General Procedures N and B to give the title compound (4.5 mg). LCMS: (m/z) 835.
Reaction SMILES: [C:1]1([CH3:34])[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][CH2:25][NH:26]C(=O)OC(C)(C)C)[C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:3][CH:2]=1.O1CCOCC1.CCOC(C)=O.C(=O)([O-])[O-].[Na+].[Na+]>Cl>[C:1]1([CH3:34])[CH:2]=[CH:3][C:4]([C:7]2[N:8]=[C:9]3[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][CH2:25][NH2:26])[C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:5][CH:6]=1
Reactant: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)N(CCNC(=O)OC(C)(C)C)CCC3)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)N(CCN)CCC3)cc1

Procedure:
tert-Butyl 2-(2,3-dip-tolyl-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)ethylcarbamate (step 1)(171 mg, 0.373 mmol) was stirred in 4M HCl in Dioxane (1 ml, 4.00 mmol) for 2 h. The suspension was added to EtOAc and saturated sodium carbonate. The organic layer was separated, dried over (MgSO4), filtered and concentrated in vacuo to afford the title compound;
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([N:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]3=[O:17])=[CH:6][N:5]2[C:18]=1[CH3:19].[Cl:20][C:21]1[S:25][C:24]([CH2:26]O)=[CH:23][CH:22]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[Cl:20][C:21]1[S:25][C:24]([CH2:26][O:16][C:13]2[CH:14]=[CH:15][N:10]([C:7]3[CH:8]=[CH:9][C:4]4[N:5]([C:18]([CH3:19])=[C:2]([CH3:1])[N:3]=4)[CH:6]=3)[C:11](=[O:17])[CH:12]=2)=[CH:23][CH:22]=1
Reactant: Cc1nc2ccc(-n3ccc(O)cc3=O)cn2c1C
Reactant: OCc1ccc(Cl)s1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cc1nc2ccc(-n3ccc(OCc4ccc(Cl)s4)cc3=O)cn2c1C
Temperature: 60 °C
Reaction time: 4 h
Yield: 24.7 %

Procedure:
To a solution of 1-(2,3-dimethylimidazo[1,2-a]pyridin-6-yl)-4-hydroxypyridin-2(1H)-one (150 mg), (5-chlorothiophen-2-yl)methanol (174 mg) and tributylphosphine (358 mg) in THF (15 ml) was added 1,1′-(azodicarbonyl)dipiperidine (447 mg), and the mixture was stirred at 60° C. for 4 h. The reaction mixture was then cooled to room temperature, and concentrated in vacuo. The residue was diluted with DCM (100 ml), washed with water and brine successively, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (MeOH/DCM) to afford the title compound (56 mg) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:14]=[C:15]([CH2:19][CH2:20][C:21](O)=[O:22])[CH:16]=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[CH:26]([NH2:29])([CH3:28])[CH3:27]>>[CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:14]=[C:15]([CH2:19][CH2:20][C:21]([NH:29][CH:26]([CH3:28])[CH3:27])=[O:22])[CH:16]=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: CC(C)N
Reactant: COC1=C(OC)C(=O)C(Cc2cccc(CCC(=O)O)c2)=C(C)C1=O
Product: COC1=C(OC)C(=O)C(Cc2cccc(CCC(=O)NC(C)C)c2)=C(C)C1=O
Yield: 16.3 %

Procedure:
3-[3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionic acid (65 mg, 0.19 mmol) obtained in Example 31 and isopropylamine (0.019 ml, 0.21 mmol) were used, and a method similar to that described in Example 24 was employed to obtain the title compound (12 mg, 0.031 mmol, yield 16%).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][C:10]1[N:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[CH2:16]([O:18][C:19](Cl)=[O:20])[CH3:17]>C1(C)C=CC=CC=1>[CH2:16]([O:18][C:19]([NH:8][CH2:9][C:10]1[N:15]=[CH:14][CH:13]=[CH:12][N:11]=1)=[O:20])[CH3:17]
Reactant: NCc1ncccn1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)NCc1ncccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
49.5 g (0.49 mol) of triethylamine are added to 49.5 g (0.45 mol) of 2-aminomethyl-pyrimidine in 450 ml of toluene and then 52 g (0.48 mol) of ethyl chlorocarbonic acid are added dropwise under cooling with ice. The mixture is subsequently stirred at room temperature for 2 hours. Triethylamine hydrochloride is filtered off with suction, the filtrate is washed with brine, dried with MgSO4, concentrated, and distilled.