Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13]([O:14]C)=[N:12][C:11]2[C:6]1=[N:7][C:8]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])=[N:9][C:10]=2[NH2:16].Cl.N>CO.O1CCOCC1>[NH2:16][C:10]1[N:9]=[C:8]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])[N:7]=[C:6]2[C:11]=1[NH:12][C:13](=[O:14])[N:5]2[CH2:4][CH2:3][CH2:2][Cl:1]
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCl)c2n1
Agent: Cl
Agent: N
Solvent: C1COCCO1
Solvent: CO
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCl)c2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The product of step (vi) (29.8 g) was dissolved in MeOH (60 ml) and treated with 4M hydrogen chloride in dioxane (60 ml). The mixture was stirred at rt for 2 hours, cooled to 0° C. and neutralised with 3.5% aqueous ammonia solution. The solid was filtered off, washed with water then MeOH and dried Yield 27.2 g.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]1[CH2:9][C@H:8]([NH:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][C@H:6]1[C:19]([OH:21])=[O:20])=[O:4].C(N(CC)CC)C.[C:29](OC(=O)C)(=[O:31])[CH3:30]>CC(C)=O>[C:29]([NH:1][CH2:2][C:3]([N:5]1[CH2:9][C@H:8]([NH:10][C:11](=[O:18])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:7][C@H:6]1[C:19]([OH:21])=[O:20])=[O:4])(=[O:31])[CH3:30]
Reactant: CC(=O)OC(C)=O
Reactant: NCC(=O)N1C[C@H](NC(=O)c2ccccc2)C[C@H]1C(=O)O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)NCC(=O)N1C[C@H](NC(=O)c2ccccc2)C[C@H]1C(=O)O
Temperature: 25 °C
Yield: 35.3 %

Procedure:
To a solution of (2S4R)1-(2-Amino-acetyl)-4-benzoylamino-pyrrolidine-2-carboxylic acid (0.05 g, 0.17 mmol) and triethylamine (Aldrich) (0.19 mL, 1.37 mmol, 8 equivalents) in acetone (3 mL) was slowly added acetic anhydride (0.13 mL, 1.37 mmol, 8 equivalents) with stirring at room temperature under nitrogen atmosphere. The mixture was stirred for 3 hours while monitored by LCMS. Upon completion, the volatiles were removed in vacuo and the residue was purified by preparative HPLC (column: Xterra MSC18 50×250 mm, 10 u) using 40/60 to 90/10 methanol/water gradient (0.1% formic acid in methanol and 0.1 formic acid in water) to afford 0.020 g (35% yield) of the desired product as white solid with limited solubility in organic solvents.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[N:10]=[CH:11][N:12]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:38]=[C:24]4[CH:25]([C:31]5[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=5)[CH2:26][C:27](=[CH2:30])[CH2:28][CH2:29][N:23]4[N:22]=3)=[CH:16][C:15]=2[O:39][CH3:40])[CH:13]=1>C(O)C.[Pt]>[Cl:8][C:9]1[N:10]=[CH:11][N:12]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:38]=[C:24]4[CH:25]([C:31]5[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=5)[CH2:26][CH:27]([CH3:30])[CH2:28][CH2:29][N:23]4[N:22]=3)=[CH:16][C:15]=2[O:39][CH3:40])[CH:13]=1
Reactant: C=C1CCn2nc(Nc3ccc(-n4cnc(Cl)c4)c(OC)c3)nc2C(c2ccc(F)cc2)C1
Agent: [Pt]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: COc1cc(Nc2nc3n(n2)CCC(C)CC3c2ccc(F)cc2)ccc1-n1cnc(Cl)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 74 %

Procedure:
N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-9-(4-fluorophenyl)-7-methylene-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine (65 mg, 0.140 mmol, from example 133) was dissolved in ethanol (5 mL), flushed with nitrogen, and chilled to 0° C. Platinum on sulfided carbon (136 mg, 0.140 mmol) was added and the flask was repeated evacuated and flushed with hydrogen gas (balloon). The reaction mixture was stirred under an atmosphere of hydrogen gas at rt for 16 h. The reaction mixture was purged with nitrogen, filtered over celite. The celite was washed with methanol and the combined filtrates were concentrated in vacuo. The crude product was purified using reverse phase preparatory HPLC (AcCN/water/ammonium acetate) to afford the titled compound as a mixture of diasteromers (51.6 mg, 74% yield). LC-MS (M+H)+ 467.2. 1H NMR (500 MHz, CHLOROFORM-d, mixture of diastereomers) δ ppm 7.53 (1 H, dd, J=16.2, 1.5 Hz), 7.41 (1 H, t, J=2.1 Hz), 7.29-7.34 (1 H, m), 6.95-7.16 (5 H, m), 6.71-6.79 (1 H, m), 4.62 (1 H, br. s.), 3.96-4.16 (1 H, m), 3.73-3.88 (3 H, m), 2.00-2.10 (2 H, m), 1.91 (1 H, dd, J=14.2, 6.6 Hz), 1.71-1.85 (1 H, m), 1.50-1.68 (2 H, m), 1.09 (3 H, dd, J=16.9, 6.6 Hz).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]1([CH:19]2[CH2:23][CH2:22][CH2:21][C:20]2=[O:24])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:25](C#N)(=[O:29])[O:26][CH2:27][CH3:28]>C1COCC1>[O:24]=[C:20]1[CH:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:23][CH2:22][CH:21]1[C:25]([O:26][CH2:27][CH3:28])=[O:29]
Reactant: O=C1CCCC1c1ccccc1
Reactant: CCOC(=O)C#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C1CCC(c2ccccc2)C1=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 73.1 %

Procedure:
To a solution of diisopropylamine (6.62 mL, 46.8 mmol) in THF (200 mL) at −78° C. was added a 1.6 M solution of n-butyllithium in hexanes (29.3 mL, 46.8 mmol). The solution was stirred for 30 min at −78° C. and treated with a solution of 2-phenylcyclopentanone (5 g, 31.2 mmol) in 50 mL of dry THF. After stirring for 30 min at −78° C., ethyl carbonocyanidate (3.36 mL, 34.3 mmol) was added to the reaction mixture. The resulting solution was warmed to 25° C. with stirring over 3 h. The reaction mixture was quenched with 10 mL of water, washed with brine, dried over anhydrous sodium sulfate, concentrated in vacuum, and purified by column chromatography on silica gel to afford ethyl 2-oxo-3-phenylcyclopentanecarboxylate (5.3 g, 22.82 mmol, 73% yield) as colorless oil. LC-MS (M+K)+=273.2. 1H NMR (500 MHz, CDCl3) δ ppm 7.32-7.39 (2H, m), 7.25-7.31 (1H, m), 7.19-7.25 (2H, m), 4.18-4.32 (2H, m), 3.29-3.55 (2H, m), 1.87-2.62 (4H, m), 1.28-1.39 (3H, m).
Reaction SMILES: [CH2:1]([N:8]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13](Cl)[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:26][C:27]1[CH:28]=[C:29]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH:30]=[CH:31][CH:32]=1.O>O1CCOCC1>[CH2:1]([N:8]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:9]1[N:10]=[CH:11][N:12]=[C:13]([NH:26][C:27]2[CH:28]=[C:29]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:38])([CH3:37])[CH3:39])[CH:30]=[CH:31][CH:32]=2)[C:14]=1[N+:15]([O-:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1c(Cl)ncnc1N(Cc1ccccc1)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)Nc1cccc(N)c1
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1cccc(Nc2ncnc(N(Cc3ccccc3)Cc3ccccc3)c2[N+](=O)[O-])c1
Temperature: 70 °C
Yield: 88.7 %

Procedure:
To a solution of N,N-dibenzyl-6-chloro-5-nitropyrimidin-4-amine (1) (7.0 g, 19.7 mmol) and TEA (5.5 mL, 40 mmol) in dioxane (100 mL) was added tert-butyl 3-aminophenylcarbamate (4.2 g, 20.0 mmol). The reaction mixture was heated to 70° C. for 6 hrs under N2. After the reaction was cooled down to room temperature, water (150 mL) was introduced. The layers were separated and the aqueous layer was extracted with EtOAc (50 mL×2). The combined organic layer was washed with water (150 mL×2) and brine (100 mL×1), dried over Na2SO4 and concentrated to dryness. tert-Butyl 3-(6-(dibenzylamino)-5-nitropyrimidin-4-ylamino)phenylcarbamate (2) (9.2 g, 88%) was obtained as a brown solid. LC-MS (ESI): m/z (M+1) 527.
Reaction SMILES: C(ON[C:10]([C@H:12]1[C@H:17]2[O:18]C(C)(C)[O:20][C@@H:16]2[C@H:15]([OH:23])[CH2:14][N:13]1[S:24]([C:27]1[CH:32]=[CH:31][C:30]([O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:29][CH:28]=1)(=[O:26])=[O:25])=[O:11])C1C=CC=CC=1.C[OH:41]>>[OH:18][C@H:17]1[C@H:16]([OH:20])[C@H:15]([OH:23])[CH2:14][N:13]([S:24]([C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:29][CH:28]=2)(=[O:25])=[O:26])[C@H:12]1[C:10]([OH:41])=[O:11]
Reactant: CC1(C)O[C@H]2[C@H](O1)[C@H](C(=O)NOCc1ccccc1)N(S(=O)(=O)c1ccc(Oc3ccccc3)cc1)C[C@H]2O
Reactant: CO
Product: O=C(O)[C@H]1[C@@H](O)[C@H](O)[C@H](O)CN1S(=O)(=O)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The above compound (5) (8.68 g) was dissolved in methanol (350 mL) and a cation exchange resin (Muromac, 19.0 g) was added, and then the mixture was stirred overnight at room temperature. The insoluble material was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel medium pressure column chromatography (chloroform:methanol=1:0→30:1→20:1→10:1) to obtain the titled compound (7.35 g) as a colorless powder.
Reaction SMILES: [CH3:1][Mg]Br.[CH3:4][C:5]1([CH3:16])[O:9][C@H:8]2[O:10][C@H:11]([C@H:13]3[CH2:15][O:14]3)[CH2:12][C@H:7]2[O:6]1.[NH4+].[Cl-]>C1COCC1.[Cu]I>[CH3:4][C:5]1([CH3:16])[O:9][C@H:8]2[O:10][C@H:11]([C@H:13]([OH:14])[CH2:15][CH3:1])[CH2:12][C@H:7]2[O:6]1
Reactant: C[Mg]Br
Reactant: CC1(C)O[C@H]2O[C@H]([C@H]3CO3)C[C@H]2O1
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC[C@@H](O)[C@@H]1C[C@H]2OC(C)(C)O[C@H]2O1
Reaction time: 1 h
Yield: 75.5 %

Procedure:
To a suspension of CuI (19.3 g, 107 mmol) in dry THF (2000 mL) under N2 atmosphere was added methyl magnesium bromide (3 M in diethyl ether, 537 mL, 1.61 mol) at −70° C. After being stirred at this temperature for 1 hour, a solution of (3aR,5S,6aR)-2,2-dimethyl-5-[(2R)-oxiran-2-yl]-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxole (compound 6b, 100 g, 537 mmol, dissolved in anhydrous THF 200 mL) was added to reaction mixture dropwise. After being stirred at −70° C. for additional 2 hours, the reaction mixture was poured into saturated NH4Cl solution. The organic layer was separated and the aqueous phase was extracted with EtOAc twice. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 1:3 EtOAc in petroleum ether) to afford 82 g of (1R)-1-[(3aR,5S,6aR)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxol-5-yl]propan-1-ol (compound 6c) as a slight yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C@@H:16]([C:37]([O:39][CH3:40])=[O:38])[NH:17][C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:41]([N:44]=[C:45]=[O:46])[CH2:42][CH3:43].N12CCN(CC1)CC2>C1(C)C=CC=CC=1>[C:25]1([C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[NH:17][C@H:16]([C:37]([O:39][CH3:40])=[O:38])[CH2:15][O:14][C:10]2[CH:9]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:45]([NH:44][CH2:41][CH2:42][CH3:43])=[O:46])[CH:3]=3)[CH:13]=[CH:12][CH:11]=2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CCCN=C=O
Reactant: COC(=O)[C@H](COc1cccc(-c2cccc(N)c2)c1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C1CN2CCN1CC2
Solvent: Cc1ccccc1
Product: CCCNC(=O)Nc1cccc(-c2cccc(OC[C@H](NC(c3ccccc3)(c3ccccc3)c3ccccc3)C(=O)OC)c2)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Methyl O-(3′-amino-1,1′-biphenyl-3-yl)-N-triphenylmethyl-L-serinate (Example 2) (250.0 mg, 0.47 mmol, 1 equiv) was dissolved in toluene (5 mL) and treated at rt with n-propyl isocyanate (402.5 mg, 4.73 mmol, 10 equiv) and DABCO (1,4-diazabicyclo[2,2,2]octane) (5.3 mg, 0.05 mmol, 0.1 equiv). The reaction mixture was stirred at rt for 14 h and then partitioned between toluene and sat. aqueous NH4Cl solution. The organic layer was separated and dried over NaSO4 and the solvents were removed in vacuuo. The crude product was titurated with petroleum ether to give a yellow solid. Yield 210.0 mg, 72.4%. 1H NMR (CDCl3, 200 MHz) δ 7.65-7.50 (m, 9H); 7.40-7.15 (m, 12H); 6.95 (d, 2H); 5.19-4.98 (m, 1H); 4.25 (dd, 1H); 4.03 (dd, 1H); 3.38-3.02 (m, 4H); 2.88 (d, 1H); 1.65-1.45 (m, 2H); 0.90 (t, 3H). MS (EI) 614 (M+H), 243 (CPh3).
Reaction SMILES: [CH3:1][C:2]1([CH2:7][C:8]([OH:10])=O)[O:6][CH2:5][CH2:4][O:3]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:44][C:45]1[CH:46]=[C:47]2[C:51](=[CH:52][CH:53]=1)[N:50]([CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=1[F:61])[C:49]([C:62]([O:64][CH2:65][CH3:66])=[O:63])=[CH:48]2>CN(C=O)C>[F:61][C:56]1[CH:57]=[CH:58][CH:59]=[CH:60][C:55]=1[CH2:54][N:50]1[C:51]2[C:47](=[CH:46][C:45]([NH:44][C:8](=[O:10])[CH2:7][C:2]3([CH3:1])[O:3][CH2:4][CH2:5][O:6]3)=[CH:53][CH:52]=2)[CH:48]=[C:49]1[C:62]([O:64][CH2:65][CH3:66])=[O:63]
Reactant: CCOC(=O)c1cc2cc(N)ccc2n1Cc1ccccc1F
Reactant: CC1(CC(=O)O)OCCO1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(NC(=O)CC3(C)OCCO3)ccc2n1Cc1ccccc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
140 mg (0.96 mmol) of (2-methyl-1,3-dioxolan-2-yl)acetic acid are added to 5 ml of DMF, and 547 mg (1.44 mmol) of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate and 186 mg (0.25 ml, 1.44 mmol) of N,N-diisopropylethylamine are added. 300 mg (0.96 mmol) of ethyl 5-amino-1-(2-fluorobenzyl)-1H-indole-2-carboxylate from Example XXXVI are added. The mixture is stirred at RT for 3 hours. For work-up the DMF is removed using a rotary evaporator. The residue is taken up in dichloromethane and extracted with aqueous hydrochloric acid. The organic phase is dried with sodium sulphate, filtered and dried under reduced pressure.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([NH2:9])=[O:8])=[C:5]([NH2:10])[N:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1.[C:17](OC(=O)C)(=O)[CH3:18].[OH-].[Na+]>C(O)(=O)C>[NH2:10][C:5]1[N:4]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:3]=[C:2]2[C:6]=1[C:7](=[O:8])[NH:9][C:17]([CH3:18])=[N:1]2
Reactant: CC(=O)OC(C)=O
Reactant: NC(=O)c1c(N)nn(-c2ccccc2)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1nc2nn(-c3ccccc3)c(N)c2c(=O)[nH]1

Procedure:
3,5-Diamino-1-phenylpyrazole-4-carboxamide (10.8 g) prepared as in Example 58 was heated with acetic acid (15 ml) and acetic anhydride (5.1 g) for 16 hours. The solution was poured into 2 M sodium hydroxide solution (200 ml) and a trace of solid was filtered off. The filtrate was adjusted to pH=7 with concentrated hydrochloric acid to precipitate 3-amino-2-phenyl-6-methyl-2,5-dihydropyrazolo[3,4-d]pyrimidin-4-one (6.1 g) which was recrystallised from 2-methoxyethanol (3.6 g yield), m.p. 279°-281° C.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15](=[S:17])[NH2:16])[CH2:10][CH2:9]1)=O)(C)(C)C.Br[CH2:19][C:20]([C:22]1[CH:31]=[CH:30][C:29]2[C:28]([CH3:33])([CH3:32])[CH2:27][CH2:26][C:25]([CH3:35])([CH3:34])[C:24]=2[CH:23]=1)=O>>[CH3:32][C:28]1([CH3:33])[CH2:27][CH2:26][C:25]([CH3:34])([CH3:35])[C:24]2[CH:23]=[C:22]([C:20]3[N:16]=[C:15]([N:11]4[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]4)[S:17][CH:19]=3)[CH:31]=[CH:30][C:29]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)CBr)ccc21
Reactant: CC(C)(C)OC(=O)N1CCCN(C(N)=S)CC1
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCCNCC4)n3)ccc21

Procedure:
The preparation is carried out as already described starting from 1.12 g (4.55 mmol) of 4-thiocarbamoyl-1,4-diazepane-1-carboxylic acid tert-butyl ester from step a and 1.93 g (6.25 mmol) of 2-bromo-1-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)ethanone.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:4]=[C:5]3[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[CH:14][C:6]3=[N:7][C:8]=2[N:9]=[CH:10][C:11]=1[C:12]#[N:13].[Cl:22][C:23]1[CH:29]=[C:28]([Cl:30])[C:27]([O:31][CH3:32])=[CH:26][C:24]=1[NH2:25].Cl.N1C=CC=CC=1>C(OCCO)C>[Cl:22][C:23]1[CH:29]=[C:28]([Cl:30])[C:27]([O:31][CH3:32])=[CH:26][C:24]=1[NH:25][C:2]1[C:3]2[CH:4]=[C:5]3[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[CH:14][C:6]3=[N:7][C:8]=2[N:9]=[CH:10][C:11]=1[C:12]#[N:13]
Reactant: COc1cc(N)c(Cl)cc1Cl
Reactant: COc1cc2cc3c(Cl)c(C#N)cnc3nc2cc1OC
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cc(Nc2c(C#N)cnc3nc4cc(OC)c(OC)cc4cc23)c(Cl)cc1Cl
Temperature: 25 °C
Yield: 37.8 %

Procedure:
A mixture of 4-chloro-7.8-dimethoxybenzo[b][1,8]naphthyridine-3-carbonitrile (150 mg, 0.50 mmol), 2,4-dichloro-5-methoxyaniline (160 mg, 0.83 mmol) and pyridine hydrochloride (70 mg, 0.60 mmol) in 15 mL of 2-ethoxyethanol is heated at reflux for 25 minutes then cooled to room temperature. The solution is partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is partitioned between ethyl acetate and an aqueous solution of sodium hydroxide and sodium bicarbonate (pH 14). The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. Diethyl ether is added to the residue and the resultant bright orange solid is collected to provide 86 mg (38%) of 4-(2,4-dichloro-5-methoxyanilino)-7,8-dimethoxybenzo[b][1,8]naphthyridine-3-carbonitrile, mp 297° C. dec.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=1)=[O:7].[CH3:15][CH:16]([CH3:32])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:21]=1)=[O:18]>>[F:14][C:10]1[CH:9]=[C:8]([C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][N:29]2[CH2:30][CH2:31][CH:26]([C:22]3[CH:21]=[C:20]([NH:19][C:17](=[O:18])[CH:16]([CH3:15])[CH3:32])[CH:25]=[CH:24][CH:23]=3)[CH2:27][CH2:28]2)[CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=C(CCCCCl)c1cccc(F)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc(F)c3)CC2)c1

Procedure:
Prepared by Procedure K and Scheme E using 5-chloro-1-(3-fluorophenyl)-1-pentanone and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 425.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10](=[O:25])[NH:11][N:12]=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)[CH:5]=[CH:6][C:7]=1F.[F:26][C:27]1[CH:28]=[C:29](Br)[CH:30]=[CH:31][C:32]=1[F:33].N>>[F:26][C:27]1[CH:28]=[C:29]([N:11]2[C:10](=[O:25])[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[C:14]([C:15]3[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=3)[CH:13]=[N:12]2)[CH:30]=[CH:31][C:32]=1[F:33]
Reactant: CS(=O)(=O)c1ccc(-c2cn[nH]c(=O)c2-c2ccc(F)c(F)c2)cc1
Reactant: Fc1ccc(Br)cc1F
Agent: N
Product: CS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)c(F)c3)c(=O)c2-c2cccc(F)c2)cc1

Procedure:
The title compound was prepared as described in Example 62, starting with 4-(3,4-difluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and substituting 3,4-difluorobromobenzene in place of 1-bromo-4-fluorobenzene (yield: 185 mg, 46.5%). mp 182–185° C. 1H NMR (300 MHz, DMSO-d6) δ 3.23 (s, 3 H), 6.98 (d, J=9 Hz, 1H), 7.18 (m, 2H), 7.32 (m, 1H), 7.52 (d, J=9 Hz, 2 H), 7.6 (m, 2H), 7.85 (m, 1 H), 7.9 (d, J=9 Hz, 2H), 8.3 (s, 1 H). MS (DCI/NH3) m/z 457 (M+H)+, 474 (M+NH4)+.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH:46]=O)[CH:41]=5)[CH:36]=[CH:37][C:38]=4[CH3:39])=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[N:50]1(C(OC(C)(C)C)=O)[CH2:56][CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH2:46][N:50]6[CH2:56][CH2:55][CH2:54][NH:53][CH2:52][CH2:51]6)[CH:41]=5)[CH:36]=[CH:37][C:38]=4[CH3:39])=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(-c3cccc(C=O)c3)ccc2C)c1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(-c3cccc(CN4CCCNCC4)c3)ccc2C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(3′-formyl-4-methyl-3-biphenylyl)methyl]-1,3-benzenedicarboxamide (100 mg, 0.15 mmol) in DCM (2 mL) was added tert-butyl 1-homopiperazine carboxylate (0.04 mL, 0.23 mmol), AcOH (0.01 mL, 0.18 mmol) followed by NaBH(OAc)3 (64.3 mg, 0.30 mmol). The reaction mixture was stirred at RT overnight. The reaction was quenched with saturated NaHCO3 and extracted with DCM twice. The combined organic layers were washed with brine and then concentrated under vacuum to give a crude residue. LC-MS m/z 844 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:18]=[CH:17][C:16]2[S:15][C:14]3[C:9](=[CH:10][C:11]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:12][CH:13]=3)[CH2:8][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[CH2:28]=[O:29].OS(O)(=O)=O>C1COCC1>[C:1]([C:5]1[CH:18]=[CH:17][C:16]2[S:15][C:14]3[C:9](=[CH:10][C:11]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:12][CH:13]=3)[CH:8]([CH2:28][OH:29])[C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=O
Reactant: CC(C)(C)c1ccc2c(c1)Cc1cc(C(C)(C)C)ccc1S2
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc2c(c1)C(CO)c1cc(C(C)(C)C)ccc1S2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 15 g of 2,7-di-t-butylthioxanthene in 150 mL of dry THF cooled to -75°, mL of n-butyl lithium solution (2.45 M) was added dropwise. A deep red color developed. After stirring at -75° for 30 min., 5 g of paraformaldehyde was added slowly. The mixture was then allowed to warm to room temperature and refluxed for 30 min. Completion of the reaction was signaled by discharge of the red color. The mixture, which contained a gray precipitate, was cooled and decomposed with ice and 25% H2SO4. Extraction of the aqueous layer with CH2Cl2, followed by washing of the extracts with H2O and saturated NaCl solution, drying over (MgSO4) and then evaporation gave an oily material which was purified by chromatography on silica gel by elution with hexane-ethyl acetate (95/5). The alcohol was obtained as a white solid, m.p. 158°-159°. Anal. calculated for C22H28OS: C, 77.64; H, 8.13; S, 9.41. Found: C, 77.72; H, 8.52; S, 9.28.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]1([CH3:21])[C@@H:17]2[C@H:13]([CH2:14][O:15][CH2:16]2)[S:12](=[O:19])(=[O:18])[CH2:11][C:10]([NH2:20])=[N:9]1.FC(F)(F)C(O)=O.S(=O)(=O)(O)O.[N+:34]([O-])([OH:36])=[O:35].[OH-].[Na+]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:34]([O-:36])=[O:35])=[CH:4][C:3]=1[C@:8]1([CH3:21])[C@@H:17]2[C@H:13]([CH2:14][O:15][CH2:16]2)[S:12](=[O:18])(=[O:19])[CH2:11][C:10]([NH2:20])=[N:9]1
Reactant: O=[N+]([O-])O
Reactant: C[C@]1(c2ccccc2F)N=C(N)CS(=O)(=O)[C@H]2COC[C@@H]21
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: C[C@]1(c2cc([N+](=O)[O-])ccc2F)N=C(N)CS(=O)(=O)[C@H]2COC[C@@H]21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of (3aR,8S,8aS)-rel-8-(2-fluoro-phenyl)-8-methyl-4,4-dioxo-3,3a,4,5,8,8a-hexahydro-1H-2-oxa-4λ6-thia-7-aza-azulen-6-ylamine (110 mg, 176 μmol) in trifluoroacetic acid (1.33 g, 11.7 mmol) was cooled to 0-5° C. Sulfuric acid (149 mg, 81.2 μl, 1.52 mmol), then nitric acid (12.1 mg, 8.01 μl, 192 μmol) was added slowly. The reaction mixture was stirred at 0° C. for 1 hour. In order to complete the reaction, another equivalent of nitric acid (12.1 mg, 8.01 μl, 192 μmol) was added and stirring continued at 0° C. for 2 hours. For the workup, ice-water was added to the reaction mixture, and the resulting suspension was set to pH ˜12 by addition of a solution of sodium hydroxide (32%). The mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water, dried over sodium sulphate and evaporated. The crude (3aR,8S,8aS)-rel-8-(2-fluoro-5-nitro-phenyl)-8-methyl-4,4-dioxo-3,3a,4,5,8,8a-hexahydro-1H-2-oxa-4λ6-thia-7-aza-azulen-6-ylamine was obtained as a brown solid and was engaged in the next step without purification. MS (ISP): m/z=358.3 [M+H]+.