Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]=1.O1CCOCC1.[Cl:16][C:17]1[C:21]([CH3:22])=[CH:20][S:19][C:18]=1[C:23]1([C:28]([NH:30][NH2:31])=O)[CH2:27][CH2:26][CH2:25][CH2:24]1>C1(C)C=CC=CC=1>[Cl:16][C:17]1[C:21]([CH3:22])=[CH:20][S:19][C:18]=1[C:23]1([C:28]2[N:9]3[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]3=[N:31][N:30]=2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: COC1=NCCCCC1
Reactant: Cc1csc(C2(C(=O)NN)CCCC2)c1Cl
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: Cc1csc(C2(c3nnc4n3CCCCC4)CCCC2)c1Cl
Temperature: 100 °C
Reaction time: 72 h

Procedure:
7-Methoxy-3,4,5,6-tetrahydro-2H-azepine (0.5 ml) was added to a dioxane (20 ml) and toluene (15 ml) solution of 1-(3-chloro-4-methyl-2-thienyl)cyclopentane-carbohydrazide (800 mg), followed by stirring at 100° C. for 3 days. The reaction solution was subjected to evaporation under reduced pressure and the resulting crude product was purified by column chromatography (chloroform:methanol=40:1). The resulting solid was washed with hexane to obtain 770 mg of 3-[1-(3-chloro-4-methyl-2-thienyl)cyclopentyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepine (colorless solid).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8]/[C:9]/2=[CH:12]\[CH2:13][NH2:14])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:24])[CH3:23]>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8]/[C:9]/2=[CH:12]\[CH2:13][NH:14][C:22](=[O:24])[CH3:23])=[CH:5][CH:4]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc2c(c1)/C(=C/CN)CC2
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc2c(c1)/C(=C/CNC(C)=O)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 111.1 %

Procedure:
To a solution of (E)-2-(6-methoxyindan-1-ylidene)-ethylamine (736 mg, 3.89 mmol) and triethylamine (0.59 g, 5.84 mmol) in tetrahydrofuran (20 ml) was added acetyl chloride (0.37 g, 4.70 mmol) gradually dropwise on an ice bath and the mixture was stirred at room temperature for 2 hours. This reaction mixture was poured in water and extracted with ethyl acetate. The extract was washed serially with saturated saline and water and dried over anhydrous magnesium sulfate. Finally the solvent was distilled off under reduced pressure to provide (E)-N-[2-(6-methoxyindan-1-ylidene)ethyl]acetamide (yield 1.0 g, 90%).
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[O:6][C:5]1=[O:13].[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(N(C(C)C)CC)(C)C>C(#N)C>[N:14]1([CH2:2][CH2:3][N:4]2[C:8]3=[N:9][CH:10]=[CH:11][CH:12]=[C:7]3[O:6][C:5]2=[O:13])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: C1CCNCC1
Reactant: O=c1oc2cccnc2n1CCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=c1oc2cccnc2n1CCN1CCCCC1
Reaction time: 12 h

Procedure:
0.01 mol of 3-(2-bromoethyl)-3H-oxazolo[4,5-b]pyridin-2-one, dissolved in acetonitrile, 0.15 mol of piperidine and 0.015 mol of diisopropylethylamine are introduced into a round-bottomed flask placed under argon and surmounted by a condenser. The mixture is brought to 80° C. for 12 hours. It is cooled, the acetonitrile is evaporated off under vacuum and the residue is taken up with water. The alkalinity of the medium is checked and the medium is extracted with dichloromethane. The organic phase is dried over magnesium sulfate and evaporated and the residue is recrystallized.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].Cl.[NH2:23][OH:24].C(O)C>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][C:12](=[N:23][OH:24])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N2CCC(=O)CC2)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COc1ccc(N2CCC(=NO)CC2)cc1

Procedure:
A mixture of 1-(p-methoxyphenyl)-4-piperidinone (prepared following the procedure reported in: Scherer, T. et al., Recl. Trav. Chim. Pays-Bas (1993), 112(10), 535-48.) (5.13 g, 25 mmol), K2CO3 (6.22 g, 45 mmol), hydroxylamine hydrochloride (2.606 g, 37.5 mmol) and ethanol was refluxed for 20 min. After cooling H2O (50 ml) was added and white crystals of 1-(4-methoxy-phenyl)-piperidin-4-one oxime (4.56 g, 83%, Mp. 116-119°, MS: m/e=220 (M+)) was collected.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12]([C:14]3[N:15]=[C:16]([CH3:19])[O:17][CH:18]=3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:21]1[CH2:26][CH2:25][CH2:24][C@@H:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:22]1>CCCCO>[Br:1][C:2]1[C:3]([N:21]2[CH2:26][CH2:25][CH2:24][C@@H:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])[CH2:22]2)=[C:4]2[C:10]([NH:11][C:12]([C:14]3[N:15]=[C:16]([CH3:19])[O:17][CH:18]=3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: Cc1nc(C(=O)Nc2c[nH]c3ncc(Br)c(F)c23)co1
Solvent: CCCCO
Product: Cc1nc(C(=O)Nc2c[nH]c3ncc(Br)c(N4CCC[C@@H](NC(=O)OC(C)(C)C)C4)c23)co1
Temperature: 160 °C

Procedure:
A mixture of N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methyloxazole-4-carboxamide (160 mg, 0.472 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (378 mg, 1.89 mmol) in n-BuOH (3 mL) was stirred at 160° C. in a sealed tube. The mixture was allowed to cool to room temperature and concentrated in vacuo. The residue was dissolved in MeOH (1 mL) and purified by C-18 reverse phase flash chromatography (Biotage Flash 25 M+) on SP4 unit eluting with 10-85% CH3CN/water gradient (25 CV) to provide (R)-tert-butyl 1-(5-bromo-3-(2-methyloxazole-4-carboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate as a solid. This material was treated with neat TFA (3 mL), and after 30 minutes the mixture was concentrated in vacuo. The residue obtained was dissolved in few drops of CH2Cl2 and treated with 2M HCl in ether (3 mL). The solid formed was filtered, washed with additional Et2O and dried under high vacuum to provide (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methyloxazole-4-carboxamide hydrochloride (23 mg, 12% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 11.85 (s, 1H), 10.41 (s, 1H), 8.68 (s, 1H), 8.30 (s, 1H), 8.27 (br s, 3H), 8.02 (s, 1H), 4.01-3.99 (m, 1H), 3.69-3.63 (m, 1H), 3.60-3.52 (m, 1H), 3.36-3.29 (m, 1H), 3.06-2.99 (m, 1H), 2.58 (s, 3H), 2.34-2.25 (m, 2H), 1.89-1.82 (m, 1H), 1.59-1.51 (m, 1H); LCMS (APCI+) m/z 419, 421 (M+H)+, Retention time=2.44 minutes (Method 2).
Reaction SMILES: B(Br)(Br)Br.[Br:5][C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([O:16]C)=[C:11]([F:18])[C:10]=2[CH3:19].CO>C(Cl)Cl>[Br:5][C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([OH:16])=[C:11]([F:18])[C:10]=2[CH3:19]
Reactant: COc1cc2cc(Br)cnc2c(C)c1F
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: Cc1c(F)c(O)cc2cc(Br)cnc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 97.9 %

Procedure:
Boron tribromide (80 ml of a 1M solution in CH2Cl2) was slowly added to a solution of 3-bromo-7-fluoro-6-methoxy-8-methyl-quinoline (5.40 g) in CH2Cl2 (300 ml) at 0° C., under an atmosphere of nitrogen. Upon warming to room temperature, the resulting brown mixture was stirred for 24 hrs and then treated with MeOH (100 ml), stirred for 1 hour and then concentrated under reduced pressure. The crude mixture was dissolved in ethyl acetate and washed with water, brine, dried over sodium sulphate anhydrous, filtered and concentrated under reduced pressure to obtain 3-bromo-7-fluoro-8-methyl-quinolin-6-ol as brown solid (5.01 g) which was used for the next step without any further purification. 1H NMR (DMSO-d6) δ ppm: 10.75 (1H, s); 8.75 (1H, d); 8.52 (1H, d); 7.18 (1H, d); 3.32 (3H, s); 2.56 (3H, d).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](O)=O)[C:7]([CH3:16])=[CH:6]2)#[N:2].[OH:21][NH:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=1)=[NH:24]>>[CH3:16][C:7]1[N:8]([CH2:12][C:13]2[O:21][N:22]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:33])([F:32])[F:34])[CH:26]=3)[N:24]=2)[C:9]2[C:5]([CH:6]=1)=[C:4]([C:17]([F:19])([F:18])[F:20])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=2
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(=O)O
Reactant: N=C(NO)c1cccc(C(F)(F)F)c1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1nc(-c2cccc(C(F)(F)F)c2)no1

Procedure:
Synthesized as described in Example 37 using [5-cyano-2-methyl-4-(trifluoromethyl)-1H-indol-1-yl]acetic acid and N-hydroxy-3-(trifluoromethyl)benzenecarboximidamide: 1H NMR (400 MHz, CDCl3) δ 8.28 (s, 1H), 8.20 (d, J=7.8 Hz, 1H), 7.77 (d, J=7.8 Hz, 1H), 7.60 (m, 3H), 6.69 (s, 1H), 5.60 (s, 2H), 2.65 (s, 3H); MS (ES) m/z 473 (M+Na).
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][CH2:5][CH2:6][N:7]1[CH2:11][CH2:10][CH2:9][C@@H:8]1[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[O:31][CH:30]=[N:29][CH:28]=3)=[CH:23][CH:22]=2)=[CH:16][CH:15]=1.[OH-].[Na+]>CO.O>[O:31]1[C:27]([C:24]2[CH:23]=[CH:22][C:21]([O:20][C:17]3[CH:18]=[CH:19][C:14]([O:13][CH2:12][C@H:8]4[CH2:9][CH2:10][CH2:11][N:7]4[CH2:6][CH2:5][CH2:4][C:3]([OH:32])=[O:2])=[CH:15][CH:16]=3)=[CH:26][CH:25]=2)=[CH:28][N:29]=[CH:30]1
Reactant: COC(=O)CCCN1CCC[C@@H]1COc1ccc(Oc2ccc(-c3cnco3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CCCN1CCC[C@@H]1COc1ccc(Oc2ccc(-c3cnco3)cc2)cc1
Temperature: 50 °C
Yield: 10.7 %

Procedure:
To a solution of the product (90 mg, 0.21 mmol) from step 2 in 4:1 mixture of MeOH/water (2 mL) was added 2M solution of NaOH (124 uL 0.25 mmol). Reaction mixture was heated at 50° C. for 16 h. Solvent was removed in vacuo, residue was dissolved in water and pH was adjusted to 4-5 with 1M HCl solution. Then product was extracted with EtOAc, washed with water, brine, dried over anhydrous MgSO4 and concentrated to give the title compound (9.5 mg, 11%): MS; m/z 423.8 (M+H); 1H NMR (400 MHz, DMSO-d6); δ 1.20-1.30 (m, 2H), 1.82-2.25 (m, 6H), 2.73 (t, 2H, J=7.2 Hz), 3.17 (br, 2H), 3.75 (br, 1H), 4.21-4.27 (m, 2H), 7.01 (dd, 2H, J1=6.8 Hz. J2=2.4 Hz), 7.07-7.08 (m, 4H), 7.59 (s, 1H), 7.71 (dd, 2H, J1=6.8 Hz, J2=2.4 Hz), 8.41 (s, 1H); HPLC (UV); 86%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6](=[O:24])[N:7]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=1)[CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH3:2]>[Pd].C(O)C>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6](=[O:24])[N:7]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1)[CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH3:2]
Reactant: CCOC(=O)CC(=O)N(CCC(=O)OC)Cc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC(=O)N(CCC(=O)OC)Cc1ccc(N)cc1
Yield: 87.7 %

Procedure:
Ethyl[N-(p-nitrobenzyl)-N-(methoxycarbonylethyl)carbamoyl]acetate (1.01 g) obtained in Example 32-(2), ethanol (10 ml) and 10% Pd/C (150 mg) are treated in the same manner as described in Example 33, whereby ethyl[N-(p-aminobenzyl)-N-(methoxycarbonylethyl)carbamoyl]acetate (810 mg, 87.5%) is obtained as pale yellow oil.
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:16](=[O:17])[C:12]3([CH2:15][CH2:14][CH2:13]3)[N:11]([C:18]3[CH:28]=[CH:27][C:21]([C:22]([O:24]CC)=[O:23])=[C:20]([F:29])[CH:19]=3)[C:10]2=[S:30])=[CH:5][C:4]=1[C:31]([F:34])([F:33])[F:32])#[N:2].[OH-].[Na+].Cl>CO>[C:1]([C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:16](=[O:17])[C:12]3([CH2:15][CH2:14][CH2:13]3)[N:11]([C:18]3[CH:28]=[CH:27][C:21]([C:22]([OH:24])=[O:23])=[C:20]([F:29])[CH:19]=3)[C:10]2=[S:30])=[CH:5][C:4]=1[C:31]([F:34])([F:32])[F:33])#[N:2]
Reactant: CCOC(=O)c1ccc(N2C(=S)N(c3cnc(C#N)c(C(F)(F)F)c3)C(=O)C23CCC3)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N#Cc1ncc(N2C(=O)C3(CCC3)N(c3ccc(C(=O)O)c(F)c3)C2=S)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.5 %

Procedure:
A mixture of ethyl 4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluorobenzoate (Compound 3, 1 g, 2.03 mmol) and NaOH (3M, 10 mL) in MeOH (10 mL) was stirred at room temperature for 18 h. Aqueous HCl (2M) was added to the reaction mixture until the pH=2 and the aqueous layer was extracted with DCM (5×), the organics were combined, dried over sodium sulfate, and evaporated to dryness to afford 900 mg of 4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluorobenzoic acid as a light yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 13.58 (s, 1H), 9.22 (s, 1H), 8.75 (s, 1H), 8.13 (t, 1H), 7.51 (dd, 1H), 7.43 (dd, 1H), 2.69-2.49 (m, 4H), 2.03-1.93 (m, 1H), 1.63-1.57 (m, 1H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH2:5]([N:7]([CH2:26][CH3:27])[CH2:8][CH2:9][N:10]1[C:18]2[CH:17]=[CH:16][CH:15]=[C:14]3[S:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:12]([C:13]=23)=[N:11]1)[CH3:6].[CH3:28][O:29]C(Cl)Cl.[OH-].[Na+]>C(Cl)Cl.Cl.C(Cl)(Cl)Cl.O>[CH2:26]([N:7]([CH2:5][CH3:6])[CH2:8][CH2:9][N:10]1[C:18]2[CH:17]=[CH:16][C:15]([CH:28]=[O:29])=[C:14]3[S:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:12]([C:13]=23)=[N:11]1)[CH3:27]
Reactant: COC(Cl)Cl
Reactant: CCN(CC)CCn1nc2c3c(cccc31)Sc1ccccc1-2
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCN(CC)CCn1nc2c3c(c(C=O)ccc31)Sc1ccccc1-2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A suspension of aluminum chloride (1.76 g, 12.8 mmol) in CH2Cl2 (25 mL) is stirred at room temperature for 15 min and the compound of Example 1 (2.07 g, 6.38 mmol) in CH2Cl2 (15 mL) is added at 5° C. and the resulting mixture is stirred 10 min and cooled to 0° C. A solution of dichloromethyl methyl ether (1.52 g, 17.4 mmol) in 10 mL of CH2Cl2 is added dropwise over a period of 15 min. The mixture is allowed to warm to ambient temperature, stirred overnight and then diluted with of 2N HCl (10 mL) and cool water (100 mL). The mixture is poured into CHCl3 (100 mL), basified with 2N NaOH solution to pH 8-9 and the layers are separated. The aqueous layer is extracted with CHCl3 (40 mL). The combined organic layers are washed with water and dried over Na2SO4. Concentration and drying in vacuo gives crude aldehyde (2.16 g, 96%) which can be used without additional purification. The analytical sample is obtained by silica gel chromatography (EtOAc) following by recrystallization from EtOAc/hexane (1:2), mp: 81°-82.5° C. 1H NMR (CDCl3) 0.95 (6H; t), 2.54 (4H; q), 2.95 (2H; t), 4.40 (2H; t), 7.02 (1H; d), 7.23-7.40 (2H; m), 7.51-7.54 (1H; m), 7.64 (1H; d), 8.17-8.20 (1H; m), 10.02 (1H; s)ppm. MS m/z 352 (MH+). Anal. (C20H21N3OS) C, H, N.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.Br[CH2:7][CH2:8][N:9]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]2[C:10]1=[O:19].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[N:1]1([CH2:7][CH2:8][N:9]2[C:10](=[O:19])[C:11]3[C:12](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:14])[CH:5]=[CH:4][N:3]=[N:2]1
Reactant: c1c[nH]nn1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCn1ccnn1
Temperature: 15 °C
Reaction time: 8 h

Procedure:
Add 1H-1,2,3-triazole (250 g, 3.51 mol), N-(2-bromoethyl) phthalimide (942 g, 3.52 mol) and 1500 mL of DMF to a 5-L round bottom flask fitted with a mechanical stirrer, a nitrogen inlet and temperature probe; cool the mixture to 15° C. Stir the mixture until all the solids are nearly dissolved and then cool in an ice-water bath. Add cesium carbonate (1145 g, 3.51 mol) in portions over 10 min. The reaction mixture exotherms to 21° C. Allow the mixture to stir and come to RT overnight. Pour the reaction mixture into a 12-L flask containing 8 L of ice-water. Stir the suspension for 30 min and then filter and rinse the solid with 3 L of water. Air-dry for 2 h. Recrystallize the mixture of regioisomers from 7 L of absolute ethanol. Isolate the solid by filtration and air-dry. Recrystallize again from 16 L of absolute ethanol. Again isolate the solid by filtration and rinse with fresh ethanol (1000 mL). Vacuum-dry the solid at 40° C. to give the title compound as a white solid, 292.7 g (34%). MS (EI) m/z 243 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[C:19]([C:21]([O-:23])=[O:22])[CH:18]=[C:17]2[C:4]=1[C@H:5]1[C@H:14]([CH2:15][S:16]2(=[O:25])=[O:24])[C@:13]2([CH3:26])[C@H:8]([C:9]([CH3:28])([CH3:27])[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1.O[Li].O.[CH2:32]1COCC1>O>[CH3:1][O:2][C:3]1[CH:20]=[C:19]([C:21]([OH:23])=[O:22])[CH:18]=[C:17]2[C:4]=1[C@@:5]1([CH3:32])[C@H:14]([CH2:15][S:16]2(=[O:25])=[O:24])[C@:13]2([CH3:26])[C@H:8]([C:9]([CH3:28])([CH3:27])[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1
Reactant: COc1cc(C(=O)[O-])cc2c1[C@@H]1CC[C@H]3C(C)(C)CCC[C@]3(C)[C@H]1CS2(=O)=O
Reactant: C1CCOC1
Agent: [Li]O
Solvent: O
Product: COc1cc(C(=O)O)cc2c1[C@]1(C)CC[C@H]3C(C)(C)CCC[C@]3(C)[C@H]1CS2(=O)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 98 %

Procedure:
A mixture of (1R,10S,11S,16S)-3-methoxy-11,15,15-trimethyl-8,8-dioxo-8λ6-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene-5-carboxylate (59) (0.29 g, 0.66 mmol) and LiOH.H2O (0.08 g, 3.3 mmol) in THF (15 mL) and water (5.0 mL) was stirred at room temperature for 18 h. The mixture was concentrated under reduced pressure and the residue was acidified with 1 M HCl. The resulting solid was collected by filtration to give (1R,10R,11S,16S)-3-methoxy-1,11,15,15-tetramethyl-8,8-dioxo-8λ6-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene-5-carboxylic acid (80) (0.27 g, 98%) as a white solid. 1H NMR (CD3OD): δ 8.04 (d, 1H), 7.74 (d, 1H), 3.94 (s, 3H), 3.47-3.35 (m, 3H), 2.26 (d, 1H), 1.86-1.16 (m, 11H), 1.10-1.00 (m, 5H), 0.89 (s, 3H), 0.87 (s, 3H). MS m/z 421 (O23H32O5S+H+).
Reaction SMILES: [NH:1]([C:8]1[N:13]=[C:12]2[N:14]([C:26]3[CH:31]=[CH:30][C:29]([CH2:32][N:33]4C(=O)C5=CC=CC=C5C4=O)=[CH:28][CH:27]=3)[C:15](=[O:25])[N:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Br:24])[CH2:17][C:11]2=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>C(O)C>[NH2:33][CH2:32][C:29]1[CH:30]=[CH:31][C:26]([N:14]2[C:12]3=[N:13][C:8]([NH:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[N:9][CH:10]=[C:11]3[CH2:17][N:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Br:24])[C:15]2=[O:25])=[CH:27][CH:28]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc(N2C(=O)N(c3ccccc3Br)Cc3cnc(Nc4ccccc4)nc32)cc1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCc1ccc(N2C(=O)N(c3ccccc3Br)Cc3cnc(Nc4ccccc4)nc32)cc1
Yield: 43.4 %

Procedure:
A solution of 160 mg (0.253 mmol) of 7-anilino-3-(2-bromophenyl)-3,4-dihydro-1-[4-(phthalimidomethyl)phenyl]pyrimido[4,5-d]pyrimidin-2(1H)-one and 0.5 ml of hydrazine hydrate in 5 ml of ethanol was stirred at room temperature under an atmosphere of nitrogen for 4 hours. The reaction mixture was evaporated and the residue purified by flash chromatography on silica gel using dichloromethane/methanol/acetic acid/water (240:24:3:2) as the eluent. Product containing fractions were combined and evaporated and the residue re-evaporated with toluene. The residue was then dissolved in 20 ml of dichloromethane, washed with saturated aqueous sodium bicarbonate (20 ml), dried over magnesium sulfate, filtered and evaporated to give 55 mg (43%) of 1-[4-(aminomethyl)phenyl]-7-anilino-3-(2-bromophenyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid of melting point 133-136° C. [Mass spectrum (ESI) MH+ =501].
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][N:12]([CH3:47])[CH2:13][CH2:14][CH2:15][NH:16][C:17]1[C:29]2[C:28]3[C:23](=[CH:24][C:25]([C:30]([O:32][CH3:33])=[O:31])=[CH:26][CH:27]=3)[NH:22][C:21]=2[N:20]=[C:19]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([C:41](=O)[C:42]([F:45])([F:44])[F:43])[CH:36]=2)[N:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:49][OH:50].N1C=CC=CC=1>CO>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][N:12]([CH3:47])[CH2:13][CH2:14][CH2:15][NH:16][C:17]1[C:29]2[C:28]3[C:23](=[CH:24][C:25]([C:30]([O:32][CH3:33])=[O:31])=[CH:26][CH:27]=3)[NH:22][C:21]=2[N:20]=[C:19]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([C:41](=[N:49][OH:50])[C:42]([F:43])([F:44])[F:45])[CH:36]=2)[N:18]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: COC(=O)c1ccc2c(c1)[nH]c1nc(Cc3cccc(C(=O)C(F)(F)F)c3)nc(NCCCN(C)CCCNC(=O)OC(C)(C)C)c12
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: COC(=O)c1ccc2c(c1)[nH]c1nc(Cc3cccc(C(=NO)C(F)(F)F)c3)nc(NCCCN(C)CCCNC(=O)OC(C)(C)C)c12
Temperature: 65 °C
Yield: 100 %

Procedure:
A mixture of methyl 4-((3-((3-((tert-butoxycarbonyl)amino)propyl)(methyl)amino)propyl)amino)-2-(3-(2,2,2-trifluoroacetyl)benzyl)-9H-pyrimido[4,5-b]indole-7-carboxylate (0.180 g, 0.274 mmol), hydroxylamine hydrochloride (0.023 g, 0.329 mmol) and pyridine (0.355 mL) in MeOH (1.9 mL) was heated in a microwave oven to 65° C. for 48 hours. After concentration of the reaction mixture to dryness, a solution of the residue was washed with sat. NaHCO3 (15 mL), the organic layer was dried over anh. MgSO4, filtered and concentrated to dryness to afford methyl 4-((3-((3-((tert-butoxycarbonyl)amino)propyl)(methyl)amino)propyl)amino)-2-(3-(2,2,2-trifluoro-1-(hydroxyimino)ethyl)benzyl)-9H-pyrimido[4,5-b]indole-7-carboxylate (184 mg, 100% yield) as a light yellow foam: MS m/z 672.3 (M+H)+; HPLC 96.0% @ 220 nm and 91.4% @ 254 nm, RT=2.01 minutes.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O.C(N(CC)CC)C>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH:9][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[F:17])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: OB(O)c1ccccc1F
Reactant: CC(C)(C)OC(=O)N(N)Cc1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N(Cc1ccccc1)Nc1ccccc1F
Temperature: 50 °C
Yield: 38.2 %

Procedure:
A mixture of N-benzyl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 27; 444 mg, 2 mmol), 2-fluorophenylboronic acid (Matrix; 274 mg, 2.01 mmol), copper(II) acetate (363 mg, 2.0 mmol) and triethylamine (280 μL, 2.0 mmol) in 1,2-dichloroethane (3 mL) was heated in an oil bath at 50° C. for 2 h. The mixture was allowed to cool, and it was then adsorbed onto silica gel and purified by chromatography using an ISCO 40 g column, eluting with 20-40% ethyl acetate/hexanes, to give N-benzyl-N′-(2-fluoro-phenyl)-hydrazinecarboxylic acid tert-butyl ester (242 mg, 38%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8]C)[C:5]([F:10])=[CH:4][C:3]=1[C:11]1[C:19]2[C:14](=[N:15][CH:16]=[N:17][C:18]=2[NH2:20])[N:13]([CH:21]([CH3:23])[CH3:22])[N:12]=1.B(Br)(Br)Br>C(Cl)Cl>[NH2:20][C:18]1[N:17]=[CH:16][N:15]=[C:14]2[N:13]([CH:21]([CH3:23])[CH3:22])[N:12]=[C:11]([C:3]3[C:2]([F:1])=[CH:7][C:6]([OH:8])=[C:5]([F:10])[CH:4]=3)[C:19]=12
Reactant: COc1cc(F)c(-c2nn(C(C)C)c3ncnc(N)c23)cc1F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)n1nc(-c2cc(F)c(O)cc2F)c2c(N)ncnc21
Yield: 36.6 %

Procedure:
3-(2,5-difluoro-4-methoxyphenyl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (BA63) (20 mg, 0.06 mmol) was dissolved in CH2Cl2 (2 ml) and BBr3 (0.630 mL, 0.63 mmol) was added slowly with a syringe, while stirring. The reaction was stirred at room temperature for overnight then concentrated in vacuo and purified using by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA93 (6.7 mg, 35% yield). ESI-MS (M+H)+ m/z calcd 306.1, found 306.0.