Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[N+:18]([O-])=O)[C:9]1=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N#N.[H][H]>CCO.[Pd]>[NH2:18][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[CH:16]=[CH:17][N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]2=[O:21]
Reactant: [H][H]
Reactant: O=c1c2cccc([N+](=O)[O-])c2ccn1Cc1ccccc1
Agent: [Pd]
Agent: N#N
Solvent: CCO
Product: Nc1cccc2c(=O)n(Cc3ccccc3)ccc12
Reaction time: 1 h
Yield: 77 %

Procedure:
2-Benzyl-5-nitro-2H-isoquinolin-1-one (1.0 g, 3.57 mmol) from step 3 was dissolved in 10 mL of EtOH, and a catalytic amount (50 mg) of 10% palladium on charcoal was added (under N2 atmosphere). The vessel was then closed and exposed to hydrogen at 1 atmosphere for 2 hours. TLC indicated that reduction of the nitro group was complete after 1 hour, and the mixture was filtered and concentrated in vacuo to give 5-amino-2-benzyl-2H-isoquinolin-1-one (0.687 g, 2.75 mmol) as a pale yellow solid.
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[N:9][N:10]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:11]=2[CH:12]([CH3:14])[CH3:13])[C:3]1=[O:22].[NH:23]1[C:27]2=[N:28][CH:29]=[CH:30][CH:31]=[C:26]2[C:25]([C:32]#[N:33])=[N:24]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:21][C:18]1[CH:19]=[CH:20][C:15]([N:10]2[C:11]([CH:12]([CH3:14])[CH3:13])=[C:7]([N:4]3[CH2:5][CH2:6][CH:2]([N:23]4[C:27]5=[N:28][CH:29]=[CH:30][CH:31]=[C:26]5[C:25]([C:32]#[N:33])=[N:24]4)[C:3]3=[O:22])[CH:8]=[N:9]2)=[CH:16][CH:17]=1
Reactant: N#Cc1n[nH]c2ncccc12
Reactant: CC(C)c1c(N2CCC(Br)C2=O)cnn1-c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)c1c(N2CCC(n3nc(C#N)c4cccnc43)C2=O)cnn1-c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
A mixture of 3-bromo-1-[1-(4-fluorophenyl)-5-isopropylpyrazol-4-yl]pyrrolidin-2-one (0.080 g, 0.22 mmol), 1H-pyrazolo[3,4-b]pyridine-3-carbonitrile (0.045 g, 0.31 mmol) and K2CO3 (0.070 g, 0.50 mmol) in DMF (2.5 mL) was stirred at 60° C. for 1 hr. It was then cooled to room temperature, quenched with water (30 mL) and extracted with EtOAc (100 mL). The organic layer was separated, dried over anhydrous sodium sulfate, concentrated in vacuo and purified by flash chromatography (SiO2, 0˜100% EtOAc/hexanes gradient elution) to give 1-[1-[1-(4-fluorophenyl)-5-isopropyl-pyrazol-4-yl]-2-oxo-pyrrolidin-3-yl]pyrazolo[3,4-b]pyridine-3-carbonitrile (0.085 g, 88%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[CH:10][N:11]=[CH:12][CH:13]=3)[C:8](=[O:15])[N:7]([CH:16]([CH3:18])[CH3:17])[C:6]=2[CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:26]([NH:33][C@H:34]([CH2:39][OH:40])[CH2:35][CH:36]([CH3:38])[CH3:37])([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:16]([N:7]1[C:6]2[CH:19]=[C:2]([O:40][CH2:39][C@@H:34]([NH:33][C:26](=[O:27])[O:28][C:29]([CH3:30])([CH3:32])[CH3:31])[CH2:35][CH:36]([CH3:38])[CH3:37])[CH:3]=[CH:4][C:5]=2[C:14]2[C:9](=[CH:10][N:11]=[CH:12][CH:13]=2)[C:8]1=[O:15])([CH3:18])[CH3:17]
Reactant: CC(C)C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: CC(C)n1c(=O)c2cnccc2c2ccc(Cl)cc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)C[C@@H](COc1ccc2c3ccncc3c(=O)n(C(C)C)c2c1)NC(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 21.6 %

Procedure:
To a solution 8-chloro-6-isopropylbenzo[c][2,7]naphthyridin-5(6H)-one (250 mg, 0.917 mmol) in toluene (2 mL) at room temperature was added cesium carbonate (448 mg, 1.375 mmol) and di-tert-butyl(2′,4′,6′-triisopropyl-[1′,1′-biphenyl]-2-yl)phosphine (234 mg, 0.550 mmol) and the mixture was degassed for 5 min. The mixture was then treated with N-Boc-L-leucinol (591 mg, 2.75 mmol) followed by palladium(II)acetate (61.7 mg, 0.275 mmol) and degassed for another 10 min. The reaction mixture was sealed and heated at 80° C. The reaction mixture was then cooled to room temperature and filtered through diatomaceous earth (Celite®). The bed was washed with ethyl acetate and the combined filtrate was concentrated under reduced pressure to afford crude product which was purified by combi flash (gradient of ethyl acetate and petroleum ether) afford (S)-tert-butyl (1-((6-isopropyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (160 mg, 0.198 mmol, 21% yield) as an off-white solid. LC/MS (ESI) m/e 454.2 [(M+H)+, calcd for C26H36N3O4 454.3]; LC/MS retention time (method C): tR=2.17 min.
Reaction SMILES: Cl.[CH3:2][S:3]([NH:6][CH2:7][C:8]1[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=1)[CH2:11][C:12]1([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)(=[O:5])=[O:4].Cl.C(C1C=CC(CN2C(CCl)=CN=C2)=CC=1)#N.Cl.[C:44]([C:46]1[CH:60]=[CH:59][C:49]([CH2:50][N:51]2[C:55]([CH2:56]Cl)=[CH:54][N:53]=[C:52]2[CH3:58])=[CH:48][CH:47]=1)#[N:45]>>[C:44]([C:46]1[CH:47]=[CH:48][C:49]([CH2:50][N:51]2[C:55]([CH2:56][N:15]3[CH2:16][CH2:17][C:12]([CH2:11][C:10]4[CH:23]=[CH:24][CH:25]=[C:8]([CH2:7][NH:6][S:3]([CH3:2])(=[O:4])=[O:5])[CH:9]=4)([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:13][CH2:14]3)=[CH:54][N:53]=[C:52]2[CH3:58])=[CH:59][CH:60]=1)#[N:45]
Reactant: CCOC(=O)C1(Cc2cccc(CNS(C)(=O)=O)c2)CCNCC1
Reactant: Cc1ncc(CCl)n1Cc1ccc(C#N)cc1
Agent: Cl
Agent: N#Cc1ccc(Cn2cncc2CCl)cc1
Product: CCOC(=O)C1(Cc2cccc(CNS(C)(=O)=O)c2)CCN(Cc2cnc(C)n2Cc2ccc(C#N)cc2)CC1

Procedure:
The title compound was prepared using the protocol described in Example 61, Step C substituting methyl 4-(3-methylbenzyl)piperidine-4-carboxylate hydrochloride salt with ethyl 4-[3-(methanesulfonylamino-methyl)benzyl]piperidine-4-carboxylate hydrochloride salt, and 1-(4-cyanobenzyl)-5-chloromethylimidazole hydrochloride salt with 1-(4-cyanobenzyl)-5-chloromethyl-2-methylimidazole hydrochloride salt (Example 53, Step B). After column chromatography on silica gel, the free base obtained was triturated with anhydrous diethyl ether. The white solid precipitated was filtered, and residual solvent was removed under vacuum overnight to provide the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([CH2:17][NH2:18])=[CH:14][C:13]=2[CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][C:21]1[N:29]=[C:28]([CH2:30][O:31][CH3:32])[CH:27]=[CH:26][C:22]=1[C:23](O)=[O:24].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O.CN(C)C=O>[NH2:20][C:21]1[N:29]=[C:28]([CH2:30][O:31][CH3:32])[CH:27]=[CH:26][C:22]=1[C:23]([NH:18][CH2:17][C:15]1[O:16][C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:19][C:13]=2[CH:14]=1)=[O:24]
Reactant: COCc1ccc(C(=O)O)c(N)n1
Reactant: NCc1cc2cc(OCc3ccccc3)ccc2o1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCc1ccc(C(=O)NCc2cc3cc(OCc4ccccc4)ccc3o2)c(N)n1
Temperature: 25 °C
Reaction time: 27 h
Yield: 74.6 %

Procedure:
To a N,N-dimethylformamide (5 mL) solution of C-(5-benzyloxy-benzofuran-2-yl)-methylamine (135 mg, 533 μmol) described in Production Example 7-1-6 were added 2-amino-6-methoxymethyl-nicotinic acid (107 mg, 586 μmol) described in Production Example 4-1-5, triethylamine (223 μL, 1.60 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (306 mg, 693 μmol) at room temperature, which was stirred at room temperature for 27 hours. Water was added to the reaction solution at room temperature followed by extracting with ethyl acetate. The organic layer was washed with water and sat. NaCl followed by drying over anhydrous magnesium sulfate and filtering. The filtrate was concentrated under a reduced pressure and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=1:5) to obtain the title compound (166 mg, 75%) as a white solid.
Reaction SMILES: C([O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([OH:21])[CH:10]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:11][O:12]2)=[CH:7][CH:6]=1)(=O)C.N1C=CN=C1>C(O)C>[OH:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([OH:21])[CH:10]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:11][O:12]2)=[CH:7][CH:6]=1
Reactant: CC(=O)Oc1ccc2c(c1)OCC(c1ccccc1)C2O
Agent: c1c[nH]cn1
Solvent: CCO
Product: Oc1ccc2c(c1)OCC(c1ccccc1)C2O

Procedure:
7-hydroxyisoflavan-4-ol was prepared from 7-acetoxyisoflavan-4-ol (0.14 g, 0.5 mmol) and Imidazole (0.17 g) in ethanol (3.0 ml) as described for cis- and trans-tetrahydrodaidzein.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11](/[CH:23]=[CH:24]/[CH:25]([CH3:28])[C:26]#[N:27])[CH:12]=[CH:13][C:14]=1[N:15]1[CH2:19][C:18](=[O:20])[NH:17][S:16]1(=[O:22])=[O:21])C1C=CC=CC=1>CCOC(C)=O.CCO.[OH-].[OH-].[Pd+2]>[OH:8][C:9]1[CH:10]=[C:11]([CH2:23][CH2:24][CH:25]([CH3:28])[C:26]#[N:27])[CH:12]=[CH:13][C:14]=1[N:15]1[CH2:19][C:18](=[O:20])[NH:17][S:16]1(=[O:22])=[O:21]
Reactant: CC(C#N)/C=C/c1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C#N)CCc1ccc(N2CC(=O)NS2(=O)=O)c(O)c1
Reaction time: 2 h

Procedure:
A mixture of (E)-4-[3-benzyloxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-2-methyl-but-3-enenitrile (10 mg) and Pd(OH)2 (1 mg) in EtOAc/EtOH (3 mL) is hydrogenated at 1 atm for 2 h. The catalyst is filtered and the filtrate evaporated. The residue is washed with 1N HCl and the residue is purified by preparative HPLC to give the title compound: (M−1)−=308; HPLC retention time=0.78 min (method A).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][CH2:19][C:11]2([C:15](=[O:16])[N:14]([OH:17])[C:13](=[O:18])[CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[CH2:24][C:25]#[N:26].C(OCC)(=O)C>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:20][CH2:19][C:11]2([C:15](=[O:16])[N:14]([O:17][CH2:24][C:25]#[N:26])[C:13](=[O:18])[CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)N(O)C2=O
Reactant: N#CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)N(OCC#N)C2=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 8-tert-butyloxycarbonyl-2-hydroxy-2,8-diazaspiro[4,5]decane-1,3-dione (0.56 g) in dimethylformamide (5 ml) was added 88 mg of sodium hydride (60% in oil), and the mixture was stirred for one hour at room temperature. To the mixture was added chloroacetonitrile (140 μl). The whole mixture was stirred for 2 hours at room temperature, to which was added ethyl acetate (30 ml), followed by washing with a saturated aqueous solution of sodium hydrogencarbonate and then with a 10% aqueous solution of citric acid. The organic layer was dried over anhydrous magnesium sulfate, then the solvent was evaporated off. The residue was recrystallized from ethyl acetate-diethyl ether to obtain 0.53 g of a colorless solid, m.p. 138° to 139° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6](Cl)=[O:7].[N:14]1([CH:20]([CH3:33])[CH2:21][CH2:22][NH:23][C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([N:23]([CH2:22][CH2:21][CH:20]([N:14]1[CH2:15][CH2:16][O:17][CH2:18][CH2:19]1)[CH3:33])[C:24]1[CH:25]=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[CH:28][CH:29]=1)=[O:7]
Reactant: CC(CCNc1ccc([N+](=O)[O-])cc1)N1CCOCC1
Reactant: COc1ccc(C(=O)Cl)cc1OC
Product: COc1ccc(C(=O)N(CCC(C)N2CCOCC2)c2ccc([N+](=O)[O-])cc2)cc1OC

Procedure:
In a manner similar to Preparation 16, react 3,4-dimethoxybenzoyl chloride with N-[3-(morpholin-4-yl)butyl]-4-nitrobenzenamine to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH2:20][NH2:21])=[CH:15][CH:14]=1>>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([C:16]1[CH:15]=[CH:14][C:13]([Cl:12])=[CH:18][CH:17]=1)[CH:22]1[CH2:23][CH2:24][O:25][CH2:26][CH2:27]1)=[O:6]
Reactant: NCC(c1ccc(Cl)cc1)C1CCOCC1
Reactant: O=C(O)c1cccc(F)c1Cl
Product: O=C(NCC(c1ccc(Cl)cc1)C1CCOCC1)c1cccc(F)c1Cl

Procedure:
From 2-chloro-3-fluorobenzoic acid and 2-(4-chlorophenyl)-2-(tetrahydro-2H-pyran-4-yl)ethanamine. LCMS (MH+): m/z=396.1, tR (minutes, Method G)=2.36
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[N:4][C:3]=1[CH3:10].[CH:11](=[O:16])[CH2:12][CH:13]([CH3:15])[CH3:14]>>[OH:16][CH:11]([CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:10][C:3]1[C:2]([CH3:1])=[N:7][C:6]([CH3:8])=[C:5]([CH3:9])[N:4]=1
Reactant: CC(C)CC=O
Reactant: Cc1nc(C)c(C)nc1C
Product: Cc1nc(C)c(CC(O)CC(C)C)nc1C
Yield: 60.7 %

Procedure:
The reaction of 13.6 grams (0.1 mole) of tetramethylpyrazine with 8.6 grams (0.1 mole) isovaleraldehyde was carried out in the manner described in Example II. The crude reaction mixture was washed with 50 milliliters of 6 N HCl, and the aqueous layer was separated and washed with two 50 milliliter portions of methylene chloride. The acidic solution was neutralized with sodium carbonate and the oil that separated was dissolved in methylene chloride. The organic solution was dried over sodium sulfate, and the solvent was evaporated to give 13.5 grams of an oil. Distillation of the oil yielded 7.7 grams (35%) of product, b.p. 98°-100° C./0.05 mm Hg.
Reaction SMILES: [NH2:1][C@H:2]([C:13]1[N:18]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=2)[C:17](=[O:27])[C:16]2=[C:28]([C:31]#[N:32])[CH:29]=[CH:30][N:15]2[N:14]=1)[CH2:3][CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl[C:34]1[N:39]=[CH:38][N:37]=[C:36]([NH2:40])[C:35]=1[I:41].[F-].[Cs+].C(N(CC)C(C)C)(C)C>>[NH2:40][C:36]1[N:37]=[CH:38][N:39]=[C:34]([NH:1][C@H:2]([C:13]2[N:18]([C:19]3[CH:20]=[C:21]([F:26])[CH:22]=[C:23]([F:25])[CH:24]=3)[C:17](=[O:27])[C:16]3=[C:28]([C:31]#[N:32])[CH:29]=[CH:30][N:15]3[N:14]=2)[CH2:3][CH2:4][O:5][CH2:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:35]=1[I:41]
Reactant: Nc1ncnc(Cl)c1I
Reactant: N#Cc1ccn2nc([C@@H](N)CCOCc3ccccc3)n(-c3cc(F)cc(F)c3)c(=O)c12
Agent: [Cs+]
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccn2nc([C@H](CCOCc3ccccc3)Nc3ncnc(N)c3I)n(-c3cc(F)cc(F)c3)c(=O)c12
Yield: 15.3 %

Procedure:
(S)-2-(1-Amino-3-(benzyloxy)propyl)-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-5-carbonitrile (51 mg, 0.12 mmol) was treated with 6-chloro-5-iodopyrimidin-4-amine (50 mg, 0.2 mmol), cesium fluoride (55 mg, 0.36 mmol) and N,N-diisopropylethylamine (170 μl, 0.98 mmol) according to the method of Preparation 13. The residue was purified by reverse phase using SP1® Purification System to give 12 mg (16% yield) of the title compound.
Reaction SMILES: C(OC([N:8]=[C:9]([NH:34]C(OC(C)(C)C)=O)[NH:10][CH2:11][CH2:12][O:13][C:14]1[CH:33]=[CH:32][C:17]([CH2:18]/[C:19](=[C:24](\[CH:29]([CH3:31])[CH3:30])/[C:25]([O:27][CH3:28])=[O:26])/[C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:15]=1)=O)(C)(C)C.[ClH:42]>CO>[ClH:42].[CH3:23][O:22][C:20](=[O:21])/[C:19](/[CH2:18][C:17]1[CH:16]=[CH:15][C:14]([O:13][CH2:12][CH2:11][NH:10][C:9]([NH2:34])=[NH:8])=[CH:33][CH:32]=1)=[C:24](/[CH:29]([CH3:30])[CH3:31])\[C:25]([O:27][CH3:28])=[O:26]
Reactant: COC(=O)/C(Cc1ccc(OCCNC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc1)=C(\C(=O)OC)C(C)C
Agent: Cl
Solvent: CO
Product: COC(=O)/C(Cc1ccc(OCCNC(=N)N)cc1)=C(\C(=O)OC)C(C)C
Reaction time: 4 h

Procedure:
To a solution of dimethyl 2-[4-{2-[2,3-bis(t-butoxycarbonyl)guanidino]ethoxy}benzyl]-3-isopropylmaleate (23.5 mg, 0.0407 mmol) in methanol (470 μL) was added 5 M hydrochloric acid (407 μL) at room temperature, and the mixture was left standing for 4 h. The reaction mixture was concentrated to dryness to give 17.6 mg of the title compound as oil (quantitative).
Reaction SMILES: O[C:2]1([CH2:18][CH2:19][NH:20][C:21](=[O:23])[CH3:22])[C:13]2[C:12]3[O:11][C:10]([CH3:14])=[N:9][C:8]=3[CH:7]=[CH:6][C:5]=2[CH2:4][CH:3]1[CH:15]([CH3:17])[CH3:16].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.S([O-])([O-])(=O)=O.[Mg+2]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH:15]([C:3]1[CH2:4][C:5]2[CH:6]=[CH:7][C:8]3[N:9]=[C:10]([CH3:14])[O:11][C:12]=3[C:13]=2[C:2]=1[CH2:18][CH2:19][NH:20][C:21](=[O:23])[CH3:22])([CH3:17])[CH3:16]
Reactant: CC(=O)NCCC1(O)c2c(ccc3nc(C)oc23)CC1C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(=O)NCCC1=C(C(C)C)Cc2ccc3nc(C)oc3c21
Temperature: 100 °C
Reaction time: 1 h
Yield: 61.2 %

Procedure:
To a solution of N-[2-(8-hydroxy-7-isopropyl-2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]acetamide (132 mg, 0.417 mmol) in toluene (4.2 mL) were added p-toluenesulfonic acid monohydrate (396 mg, 2.08 mmol) and magnesium sulfate (1 g), and the mixture was stirred at 100° C. for 1 hr. The reaction solution was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane=30/70→100/0) to give the title compound (76.1 mg, yield 61%).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[C:9]([CH2:18][C:19]2[C:24]([Cl:25])=[CH:23][N:22]=[CH:21][C:20]=2[Cl:26])=[N:8][N:7]=1.O>CN(C=O)C>[Cl:25][C:24]1[CH:23]=[N:22][CH:21]=[C:20]([Cl:26])[C:19]=1[CH2:18][C:9]1[C:10]2[C:15](=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:6]2=[N:7][N:8]=[N:3][N:2]2[N:1]=1
Reactant: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(Cl)c2c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nn3nnnc3c2c1
Temperature: 80 °C
Reaction time: 7 h
Yield: 78.5 %

Procedure:
NaN3 was added to a solution under N2 of 4-chloro-1-(3,5-dichloro-pyridin4-ylmethyl)-6-methoxy-phthalazine (1 g, 2.82 mmoles), obtained as described in example 13, in anhydrous DMF (20 ml) and the mixture was heated at 80° C. overnight, then at 120° C. for 7 hours, then poured into water (10 volumes) and extracted 3 times with CH2Cl2, dried and concentrated under vacuum to give a solid which was purified by flash chromatography (eluent:60:80 petrolatum/ethyl acetate 6:4). The eluate was crystallised from acetonitrile (75 ml) to give 0.36 g of the title compound (yield: 78.5%). m. p.: 275-276° C.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([C:9]1[O:13][C:12]([CH2:14][CH2:15][C:16](OC)=[O:17])=[CH:11][CH:10]=1)[CH3:8]>C1COCC1>[CH2:7]([C:9]1[O:13][C:12]([CH2:14][CH2:15][CH2:16][OH:17])=[CH:11][CH:10]=1)[CH3:8]
Reactant: CCc1ccc(CCC(=O)OC)o1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1ccc(CCCO)o1
Temperature: 0 °C
Yield: 84.7 %

Procedure:
To a mixture of 3.42 g (90.1 mmol) of LAH in THF under nitrogen and stirring at 0° C., was added dropwise 14.9 g (81.9 mmol) of methyl 3-(5-ethyl-2-furyl)propanoate in THF. The reaction mixture was quenched with 3.4 mL of water, 3.4 mL of sodium hydroxide solution, and 10.2 mL of water. Magnesium sulfate was added to the mixture with stirring, filtered and concentrated in vacuo. The residue was passed through silica gel and eluted with ethyl acetate/hexane (2:8) to yield 10.7 g (85%) of the desired product as a clear colorless oil, used in the next preparation without further purification.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=O)[CH2:9][CH2:8]2.[C:15]([O:18][CH2:19][CH3:20])(=[O:17])[CH3:16]>C1COCC1>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH:10]([CH2:16][C:15]([O:18][CH2:19][CH3:20])=[O:17])[CH2:9][CH2:8]2
Reactant: CCOC(C)=O
Reactant: COc1ccc2c(c1)CCC2=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC1CCc2cc(OC)ccc21
Temperature: 0 °C
Reaction time: 17 h

Procedure:
An oven dried flask was charged with sodium hydride (60 wt %) (173 mg, 4.32 mmol) and THF (15 mL) and cooled to 0° C. Triethyl phosphonoacetate (0.864 mL, 4.32 mmol) was added dropwise and the reaction was then heated to 50° C. for 1 hr. The reaction was then cooled to 0° C., and 5-methoxy-1-indanone (500 mg, 3.08 mmol) was added via cannula in THF (3×5 mL). The reaction was then refluxed for 17 hours. Next, the reaction was cooled to room temperature and diluted with ethyl acetate (50 mL). The organic layer was washed with water (2×50 mL) and brine (50 mL), dried over sodium sulfate, filtered, and concentrated. The residue was dissolved in ethanol (15 mL) and 10% palladium on carbon (150 mg) was added. The reaction was stirred at room temperature under an atmosphere of hydrogen (balloon) for 17 hours. At this point, the catalyst was removed by filtration, and the filtrate was concentrated. Purification of the residue via flash chromatography on silica gel (0 to 40% ethyl acetate/hexanes) afforded ethyl (5-methoxy-2,3-dihydro-1H-inden-1-yl)acetate. 1H NMR (CDCl3, 500 MHz) δ 7.07 (d, J=8.5 Hz, 1H), 6.78 (s, 1H), 6.71 (dd, J=8.2, 2.3 Hz, 1H), 4.18 (m, 2H), 3.78 (s, 3H), 3.53 (m, 1H), 2.95-2.65 (m, 3H), 2.45-2.30 (m, 2H), 1.76 (m, 1H), 1.28 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([OH:22])([C:18]([F:21])([F:20])[F:19])[C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=1[C:23]([O:25]CC)=O)=[O:5])[CH3:2].[OH-].[Na+].Cl>>[CH2:1]([N:3]1[C:23](=[O:25])[C:8]2[C:7](=[CH:12][CH:11]=[C:10]([C:13]([OH:22])([C:18]([F:21])([F:19])[F:20])[C:14]([F:17])([F:16])[F:15])[CH:9]=2)[NH:6][C:4]1=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCn1c(=O)[nH]c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2c1=O
Yield: 98.3 %

Procedure:
Combine 4.02 g (10 mmole) of N-ethyl-N'-[4-(hexafluoro-2-hydroxy-2-propyl)-2-(ethoxycarbonyl)phenyl]urea with 21 ml (20 mmole) 1N NaOH and stir for 1 minute. Acidify the reaction with 1N HCl and extract with 100 ml of Et2O. Dry and concentrate the extract to obtain 3.5 g of white solid. Recrystallize from Et2O-hexane to obtain 2.5 g of white solid 3-ethyl-6-(hexafluoro-2-hydroxy-2-propyl)quinazoline-2,4-dione; m.p. 268°-270° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:9][S:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)(=[O:12])=[O:11])[C:5]([Cl:8])=[N:6][CH:7]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC([O-])(C)C.[Na+].[C:67]1([C:73]([C:75]2[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=2)=[NH:74])[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1>CN(C=O)C.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]>[Cl:8][C:5]1[C:4]([NH:9][S:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:3][C:2]([N:74]=[C:73]([C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)[C:75]2[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=2)=[CH:7][N:6]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: O=S(=O)(Nc1cc(Br)cnc1Cl)N1CCOCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CN(C)C=O
Product: O=S(=O)(Nc1cc(N=C(c2ccccc2)c2ccccc2)cnc1Cl)N1CCOCC1
Temperature: 120 °C
Yield: 72 %

Procedure:
To a 20 mL microwave reaction tube was added N-(5-bromo-2-chloropyridin-3-yl)morpholine-4-sulfonamide (Example 366, Step 3) 0.510 g, 1.43 mmol), xantphos (0.0839 g, 0.145 mmol), Pd2dba3 (0.0646 g, 0.071 mmol), NaOtBu (Aldrich, 0.418 g, 4.35 mmol) and diphenylmethanimine (Aldrich, 0.264 mL, 1.57 mmol) in DMF (6 mL). The mixture was degassed by bubbling argon through for 5 min. The tube was heated in a microwave reactor (Biotage) at 120° C. for 30 min. The reaction mixture was partitioned between saturated aqueous ammonium chloride (40 mL) and EtOAc (40 mL). The aqueous phase was extracted with EtOAc (2×40 mL). The combined organic phases were washed with water (80 mL) and saturated aqueous sodium chloride (80 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (100 g, eluent: EtOAc in hexanes 0% to 70%) to afford N-(2-chloro-5-(diphenylmethyleneamino)pyridin-3-yl)morpholine-4-sulfonamide in 2 fractions (total 0.42 g, 72% yield) as a yellow solid (0.26 g) and a light brown solid (0.21 g). 1H NMR (400 MHz, CDCl3) δ ppm 7.73 (d, J=7.43 Hz, 2H) 7.62 (d, J=2.35 Hz, 1H) 7.49-7.55 (m, 1H) 7.43 (t, J=7.53 Hz, 2H) 7.31-7.37 (m, 4H) 7.11-7.16 (m, 2H) 6.63 (br. s., 1H) 3.60-3.65 (m, 4H) 3.03-3.09 (m, 4H).