Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[N:5]=[C:6]([N:11]([CH3:32])[C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:31])[C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=4)[CH:15]=[CH:16][CH:17]=3)[N:7]=[CH:8][C:9]=2[N:10]=1.[C:33](Cl)(=[O:42])[CH:34]=[CH:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[C:29]([C:26]([C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[C:19]([NH:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([N:11]([CH3:32])[C:6]2[N:7]=[CH:8][C:9]3[N:10]=[C:2]([NH:1][C:33](=[O:42])/[CH:34]=[CH:35]/[C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[S:3][C:4]=3[N:5]=2)[CH:13]=1)=[O:31])([CH3:27])[CH3:28])#[N:30]
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: CN(c1cccc(NC(=O)c2cccc(C(C)(C)C#N)c2)c1)c1ncc2nc(N)sc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CN(c1cccc(NC(=O)c2cccc(C(C)(C)C#N)c2)c1)c1ncc2nc(NC(=O)/C=C/c3ccccc3)sc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.4 %

Procedure:
To a solution of N-{3-[(2-amino[1,3]thiazolo[5,4-d]pyrimidin-5-yl)(methyl)amino]phenyl}-3-(1-cyano-1-methylethyl)benzamide (150 mg, 338 μmol) produced in Example D5(i) in pyridine (4 mL) was added cinnamoyl chloride (141 mg, 845 μmol), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (15 mL), and the mixture was extracted with ethyl acetate (20L, 5 mL). The combined organic layer was washed with saturated brine (5 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=30/70→10/90), and the fractions containing the object product were concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate to give the title compound (150 mg, 77%) as yellow crystals.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([OH:36])=[C:17]([CH2:19][N:20]2[N:24]=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)[O:22][C:21]2=[O:35])[CH:18]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:36][C:16]2[CH:15]=[CH:14][C:13]([Cl:12])=[CH:18][C:17]=2[CH2:19][N:20]2[N:24]=[C:23]([C:25]3[CH:26]=[CH:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=3)[O:22][C:21]2=[O:35])=[O:8])=[CH:5][CH:4]=1
Reactant: O=C(Cl)c1ccc(CCl)cc1
Reactant: O=c1oc(-c2ccc(C(F)(F)F)cc2)nn1Cc1cc(Cl)ccc1O
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Oc1ccc(Cl)cc1Cn1nc(-c2ccc(C(F)(F)F)cc2)oc1=O)c1ccc(CCl)cc1
Temperature: 25 °C
Yield: 84.9 %

Procedure:
A solution of 4-(chloromethyl)benzoyl chloride (2.24 g, 11.9 mmol) in methylene chloride (25 mL) was added to a cold (0° C.) stirred suspension of 3-[(5-chloro-2-hydroxyphenyl)methyl]-5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-one (4.0 g, 10.8 mmol) and pyridine (0.96 mL, 11.9 mmol) in methylene chloride (25 mL). The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched with 1 N HCl and extracted with ethyl acetate (100 mL). The organic layer was separated and washed with sat'd NaHCO3, water, brine and then dried (MgSO4). Evaporation of the solvent gave the crude product which was recrystallized from methylene chloride/hexanes to afford the title compound as white crystals (4.8 g, 85%): mp 142-144° C.; MS m/e: 523 (MH+).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH2:12][C:13]1[S:17][C:16]([C:18]([O:20][CH3:21])=[O:19])=[C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:14]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH:12]([C:13]1[S:17][C:16]([C:18]([O:20][CH3:21])=[O:19])=[C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:14]=1)=[O:11]
Reactant: COC(=O)c1sc(CO)cc1-c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: COC(=O)c1sc(C=O)cc1-c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 94.9 %

Procedure:
DMSO (0.643 ml, 9.06 mmol) in 4 mL of DCM at −70° C. was added dropwise to a solution of oxalyl chloride (0.529 ml, 6.04 mmol) in 10 mL of DCM at −78° C. and stirred for 10 min. Then 169 (0.75 g, 3.02 mmol) in 4 mL of DCM and TEA in 4 ml, DCM were added dropwise, stirred for an additional 10 min and warmed up slowly to 0° C. The reaction mixture was poured into an ice-cooled solution of NaHCO3 (ss) and extract the product with DCM, washed with brine, dried over sodium sulfate, filtered, concentrated under vacuum to yield compound 172 (706 mg, 95%) as a beige solid.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>C(OCC)C>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:19]([Cl:18])=[CH:20][CH:21]=2)[NH2:10])=[CH:5][CH:4]=1
Reactant: NNc1ccc(Br)cc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: NN(C(=O)c1ccc(Cl)cc1)c1ccc(Br)cc1
Reaction time: 16 h

Procedure:
A mixture consisting of 44.7 g. (0.20 mole) p-bromophenylhydrazine hydrochloride, 250 ml. diethyl ether, 70 ml. (0.504 mole) triethylamine, and 35.0 g. (0.20 mole) p-chlorobenzoyl chloride in 50 ml. diethyl ether (mixed in that order at -5° to -15°C. during 20 minutes) was stirred continuously for about 16 hrs. at about 25° C. The reaction mixture was filtered, and the solids on the filter were washed with water and then recrystallized from 95% ethanol. There was thus obtained 15.5 g. p-chlorobenzoic acid (p-bromophenyl)hydrazide having a melting point of 185° C. (dec.). An analytical sample melting at 184.5°C. (dec.) was obtained after two recrystallizations from ethyl acetate.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:13]([F:16])([F:15])[F:14])[CH2:11][OH:12])=[CH:6][CH:5]=1.[O:17]([C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[O:17]([C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][O:12][CH2:11][CH:10]([C:7]1[CH:8]=[CH:9][C:4]([Cl:3])=[CH:5][CH:6]=1)[C:13]([F:14])([F:15])[F:16])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: OCC(c1ccc(Cl)cc1)C(F)(F)F
Reactant: BrCc1cccc(Oc2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: FC(F)(F)C(COCc1cccc(Oc2ccccc2)c1)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere, 135 mg of sodium hydride (60% oil dispersion) was added to 20 ml of dry THF. A solution of 0.30 g or 2-(4-chlorophenyl)3,3,3-trifluoropropanol and 0.34 g of 3-phenoxybenzyl bromide in 20 ml of dry THF was then added with ice-cooling, and the reaction solution was stirred with ice-cooling for 1 hour and at room temperature for 12 hours. Thereafter, the reaction mixture was poured into dilute HCl-ice water and extracted twice with diethyl ether. The ether layers were combined, washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed under a reduced pressure, and the residue was subjected to column chromatography on silica gel [eluted with n-hexane/toluene (2:1) mixture] to obtain 250 mg of the desired compound.
Reaction SMILES: [NH2:1]/[C:2](/[CH3:8])=[CH:3]\[C:4]([O:6][CH3:7])=[O:5].[CH3:9][S:10]([OH:13])(=[O:12])=[O:11].[H][H]>CO>[CH3:9][S:10]([OH:13])(=[O:12])=[O:11].[NH2:1][C@H:2]([CH3:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: [H][H]
Reactant: COC(=O)/C=C(/C)N
Agent: CS(=O)(=O)O
Solvent: CO
Product: COC(=O)C[C@@H](C)N
Yield: 61.2 %

Procedure:
Under a nitrogen atmosphere, 78.0 mg (0.0869 mmol) of Ru(OCOCH3)2((R)-tol-binap), 1.00 g (8.69 mmol) of methyl 3-aminocrotonate, 0.83 g (8.69 mmol) of methanesulfonic acid and 5 ml of methanol were placed in a stainless steel autoclave, and the mixture was kept at 50° C. under 3MPa pressure of hydrogen for 15 hours with stirring. After completion of the reaction, the solvent was distilled off, and the residue was recrystallized from methanol/ethyl acetate to give the objective methyl (R)-3-aminobutanoate methanesulfonate (1.135 g, white crystals). The yield was 61.3%.
Reaction SMILES: [H-].[Li+].[CH2:3]([P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])[C:4]([CH3:6])=[O:5].[Cl:15][C:16]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:17]=1[O:18][CH2:19][CH2:20][CH2:21][CH2:22]I>>[C:4]([CH:3]([P:7](=[O:14])([O:8][CH2:9][CH3:10])[O:11][CH2:12][CH3:13])[CH2:22][CH2:21][CH2:20][CH2:19][O:18][C:17]1[CH:24]=[CH:25][C:26]([O:28][CH3:29])=[CH:27][C:16]=1[Cl:15])(=[O:5])[CH3:6]
Reactant: COc1ccc(OCCCCI)c(Cl)c1
Reactant: CCOP(=O)(CC(C)=O)OCC
Agent: [H-]
Agent: [Li+]
Product: CCOP(=O)(OCC)C(CCCCOc1ccc(OC)cc1Cl)C(C)=O
Yield: 15.9 %

Procedure:
[II; Ar is 2-Cl-4-CH3OC6H3, Y is O(CH2)4, R is C2H5, R' is CH3CO] was prepared from 0.79 g of lithium hydride, 19.4 g of diethyl acetonylphosphonate and 34.0 g of 4-(2-chloro-4-methoxyphenoxy)butyl iodide according to the procedure of Example 2(b). The product was chromatographed on Florisil to give 6.45 g of diethyl [1-acetyl-5-(2-chloro-4-methoxyphenoxy)pentyl]phosphonate as a yellow oil; MIC vs. herpes simplex type 2=12 mcg/ml. The NMR spectrum was consistent with the assigned structure.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][C@@H:11]3[CH2:19][N:14]4[CH2:15][CH2:16][NH:17][CH2:18][C@@H:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[F:20][C:21]([F:33])([F:32])[C:22]1[CH:23]=[C:24]([S:28](Cl)(=[O:30])=[O:29])[CH:25]=[CH:26][CH:27]=1.C(N(CC)CC)C>ClCCl>[CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][C@@H:11]3[CH2:19][N:14]4[CH2:15][CH2:16][N:17]([S:28]([C:24]5[CH:25]=[CH:26][CH:27]=[C:22]([C:21]([F:20])([F:32])[F:33])[CH:23]=5)(=[O:30])=[O:29])[CH2:18][C@@H:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: c1nc(C2CC2)cnc1O[C@H]1C[C@H]2CNCCN2C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(c1cccc(C(F)(F)F)c1)N1CCN2C[C@@H](Oc3cnc(C4CC4)cn3)C[C@H]2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 49B (200 mg, 0.674 mmol)) in dichloromethane (3 mL) was added 3-(trifluoromethyl)benzene-1-sulfonyl chloride (198 mg, 0.809 mmol) followed by triethylamine (0.3 mL). The mixture was stirred at room temperature overnight and then concentrated. The residue was purified by flash chromatography (ethyl acetate/hexane=1:1) to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.80 (m, 2H), 0.92 (m, 2H), 1.38 (m, 1H), 2.04-2.20 (m, 4H), 2.42 (m, 3H), 3.00 (m, 2H), 3.66 (m, 1H), 3.82 (m, 1H), 5.20 (m, 1H), 7.92 (m, 1H), 7.98 (m, 1H), 8.03 (m, 1H), 8.11 (m, 3H); MS (ESI) m/z 469 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][CH3:11])[CH2:4][CH2:3]1.[N+:12]([C:15]1[CH:16]=[C:17]2[C:22](=O)[O:21][C:19](=[O:20])[C:18]2=[CH:24][CH:25]=1)([O-:14])=[O:13]>C(Cl)(Cl)Cl>[CH2:8]([N:5]1[CH2:6][CH2:7][CH:2]([N:1]2[C:22](=[O:21])[C:17]3=[CH:16][C:15]([N+:12]([O-:14])=[O:13])=[CH:25][CH:24]=[C:18]3[C:19]2=[O:20])[CH2:3][CH2:4]1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCN1CCC(N)CC1
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Solvent: ClC(Cl)Cl
Product: CCCCN1CCC(N2C(=O)c3ccc([N+](=O)[O-])cc3C2=O)CC1

Procedure:
4.69 Grams of 4-amino-1-n-butylpiperidine in 100 milliliters of chloroform were added to a suspension of 5.79 grams of 4-nitrophthalic anhydride in 75 milliliters of chloroform and the solution was evaporated to dryness. 40 Milliliters of acetic anhydride were added and the mixture was then heated on a steam bath for half an hour. The excess acetic anhydride was evaporated off and the residue dissolved in 40 milliliters of methanol and ethereal hydrogen chloride was added to give a solid which was collected giving 2.50 grams of the title compound as the monohydrochloride.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:17]([CH2:18][C:19]3[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=3[C:21]#[N:22])[C:16](=[O:27])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([F:28])[CH:14]=3)[N:9]=2)[CH2:3]1.[OH-:29].[Na+].OO.Cl>C1COCC1>[NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:17]([CH2:18][C:19]3[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=3[C:21]([NH2:22])=[O:29])[C:16](=[O:27])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([F:28])[CH:14]=3)[N:9]=2)[CH2:3]1
Reactant: [OH-]
Reactant: N#Cc1ccccc1Cn1c(N2CCCC(N)C2)nc2ccc(F)cc2c1=O
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: NC(=O)c1ccccc1Cn1c(N2CCC[C@@H](N)C2)nc2ccc(F)cc2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-[2-(3-amino-piperidin-1-yl)-6-fluoro-4-oxo-4H-quinazolin-3-ylmethyl]-benzonitrile (Example 6,50 mg) in 5 mL of THF was added 2 mL of 1N NaOH, followed by 2 mL H2O2. After stirring at room temperature overnight, the mixture was acidified with concentrated HCl. Removal of the solvent and purification by Preparative LC/MS provided the title compound. 1H NMR (400 MHz, MeOD): δ 7.68-7.74 (m, 1H), 7.59-7.66 (m, 1H), 7.48-7.58 (m, 2H), 7.29-7.40 (m, 2H), 7.02 (d, J=6.57 Hz, 1H), 5.58 (AB q, J=22.74, 15.66 Hz, 2H), 3.49-3.59 (m, 2H), 3.17-3.26 (m, 1H), 3.01-3.10 (m, 2H), 1.64-2.09 (m, 4H). MS: (ES) [m+H] calculated for C21H22FN5O2, 396; found 396.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[C:12](OC(=O)C)(=[O:14])[CH3:13]>O>[C:12]([NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[CH:9][C:3]=1[C:2]([F:10])([F:11])[F:1])(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccccc1C(F)(F)F
Solvent: O
Product: CC(=O)Nc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.1 %

Procedure:
Commercial o-trifluoromethylaniline (13.5 g, 83.9 mmol) was dissolved in acetic anhydride (55 mL, 580.0 mmol) and stirred at room temperature for 1 h. Then the reaction mixture was poured into H2O, the whole was extracted with ethyl acetate (2×300 mL). The combined organic extracts were washed with 5% aqueous NaHCO3, brine, dried (K2CO3), filtered and concentrated to provide the title compound as a white solid (15.7 g, 92%).
Reaction SMILES: [CH2:1]([OH:7])[C@@H:2]1[O:6][CH2:5][CH2:4][CH2:3]1.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1>C(Cl)Cl.N1C=CC=CC=1>[CH3:18][C:8]1[CH:13]=[CH:12][C:11]([S:14]([O:7][CH2:1][C@H:2]2[CH2:3][CH2:4][CH2:5][O:6]2)(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: OC[C@H]1CCCO1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CCCO2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (R)-tetrahydrofurfuryl alcohol (Lancaster, 1.0 g, 9.8 mmol) in 5 mL of CH2Cl2 and 5 mL of pyridine was added p-toluenesulfonyl chloride (2.8 g, 14.7 mmol) in portions over 15 minutes. The mixture was stirred at ambient temperature for 3 hours and was quenched with 5 mL of saturated, aqueous NaHCO3. The layers were separated and the aqueous layer was extracted with three 5 mL of portions of CH2Cl2. The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the title compound. MS (DCI/NH3) m/z 257 (M+H)+, 274 (M+NH4)+.
Reaction SMILES: [F:1][C:2]([C:12]1[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=1)([CH3:11])[CH2:3][NH:4][S:5]([CH:8]([CH3:10])[CH3:9])(=[O:7])=[O:6].[S:19]1[CH:23]=[CH:22][CH:21]=[CH:20]1.C1C=CC=C(B(O)O)C=1.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.O>[F:1][C:2]([C:12]1[CH:17]=[CH:16][C:15]([C:21]2[CH:22]=[CH:23][S:19][CH:20]=2)=[CH:14][CH:13]=1)([CH3:11])[CH2:3][NH:4][S:5]([CH:8]([CH3:10])[CH3:9])(=[O:7])=[O:6]
Reactant: c1ccsc1
Reactant: CC(C)S(=O)(=O)NCC(C)(F)c1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: OB(O)c1ccccc1
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)S(=O)(=O)NCC(C)(F)c1ccc(-c2ccsc2)cc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 80.3 %

Procedure:
Scheme VI, Step A′: Into a 50 mL single neck [2-fluoro-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine (150 mg, 0.39 mmol, prepared in example 1), thiophene-3-benzene boronic acid (74 mg, 0.56 mmol), potassium carbonate (80 mg, 0.56 mmol) and tetrakis(triphenyl phosphine)palladium(0) (31 mg, 0.027 mmol) were combined in dioxane/water (15 mL, 3:1). The mixture was heated at 100° C. under stirring for 18 hours. The reaction was cooled to room temperature and poured into H2O. The desired product was extracted with ethyl acetate and the organic layer was separated and washed twice with H2O, dried over K2CO3, and concentrated under reduced vacuum to yield the crude material (236 mg) as a dark oil. The resulting oil was purified via silica gel chromatography employing the Chromatotron using a 4000 micron rotor and eluting with a solvent of hexane/ethyl acetate 7:3 to yield the title compound (107 mg, 81%) as a white solid. Ion spray M.S. 340.0 (M*−1).
Reaction SMILES: [NH2:1][C:2]1[C:6]([CH3:7])=[CH:5][S:4][C:3]=1[C:8]([O:10]C)=O.O.[NH2:13][NH2:14]>C(O)CCC>[NH2:1][C:2]1[C:6]([CH3:7])=[CH:5][S:4][C:3]=1[C:8]([NH:13][NH2:14])=[O:10]
Reactant: COC(=O)c1scc(C)c1N
Reactant: NN
Solvent: O
Solvent: CCCCO
Product: Cc1csc(C(=O)NN)c1N

Procedure:
A solution of methyl 3-amino-4-methyl-2-thenoate (25 g) and hydrazine hydrate (20 ml) in butanol (150 ml) was heated under reflux for 18 hours. On cooling the solvent was removed and teh residue was recrystallised from toluene to give the title product, m.p. 141-143° C.
Reaction SMILES: [F:1][CH:2]1[CH:7]([N:8]2[CH2:14][CH2:13][C:12]3[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:11]=3[NH:10][C:9]2=[O:21])[CH2:6][CH2:5][NH:4][CH2:3]1.Cl[C:23]1[N:28]=[CH:27][N:26]=[C:25]([C:29]([C:31]2[CH:41]=[C:40]([CH3:42])[C:34]3[N:35]([CH3:39])[C:36](=[O:38])[O:37][C:33]=3[CH:32]=2)=[O:30])[CH:24]=1.CO>CN(C=O)C>[CH3:39][N:35]1[C:34]2[C:40]([CH3:42])=[CH:41][C:31]([C:29]([C:25]3[N:26]=[CH:27][N:28]=[C:23]([N:4]4[CH2:5][CH2:6][CH:7]([N:8]5[CH2:14][CH2:13][C:12]6[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:11]=6[NH:10][C:9]5=[O:21])[CH:2]([F:1])[CH2:3]4)[CH:24]=3)=[O:30])=[CH:32][C:33]=2[O:37][C:36]1=[O:38]
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1F)C(=O)N2
Reactant: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2oc(=O)n(C)c12
Solvent: CN(C)C=O
Solvent: CO
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c5c(c4)oc(=O)n5C)ncn3)CC1F)C(=O)N2

Procedure:
60 mg (0.21 mmol) 3-(3-fluoro-piperidin-4-yl)-7-methoxy-1,3,4,5-tetrahydro-benzo[d]-[1,3]diazepin-2-one, 60 mg (0.20 mmol) 6-(6-chloro-pyrimidine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one and 0.040 mL (0.30 mmol) TEA were stirred overnight in 1 mL DMF at RT. The reaction mixture was combined with 2 mL MeOH and the precipitate formed was suction filtered, washed with MeOH and diethyl ether and dried.
Reaction SMILES: C[O:2][C:3](=[O:32])[C@@H:4]([NH:15][S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([N:25]2[CH2:29][CH2:28][CH2:27][C:26]2=[O:30])[C:20]=1[CH3:31])(=[O:18])=[O:17])[CH2:5][NH:6][C:7]([C:9]1[S:10][C:11]([Cl:14])=[CH:12][CH:13]=1)=[O:8].[OH-].[Na+].Cl>C1COCC1.C(OCC)C>[Cl:14][C:11]1[S:10][C:9]([C:7]([NH:6][CH2:5][C@H:4]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N:25]3[CH2:29][CH2:28][CH2:27][C:26]3=[O:30])[C:20]=2[CH3:31])(=[O:18])=[O:17])[C:3]([OH:32])=[O:2])=[O:8])=[CH:13][CH:12]=1
Reactant: COC(=O)[C@H](CNC(=O)c1ccc(Cl)s1)NS(=O)(=O)c1cccc(N2CCCC2=O)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1c(N2CCCC2=O)cccc1S(=O)(=O)N[C@@H](CNC(=O)c1ccc(Cl)s1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Intermediate 86 was dissolved in 20 ml THF and sodium hydroxide (1N water solution) (38.16 ml, 38.16 mmol) was added. After 2 h stirring at RT the reaction mixture was extracted with diethyl ether and 1 N HCl (38.16 ml, 38.16 mmol) was added to the aqueous layer. The aqueous layer was extracted with n-butanol. The organic layer was dried with Na2SO4, filtered and evaporated to dryness. 8.28 g of crude product were obtained and used without further purification in step 24.6.
Reaction SMILES: [CH3:1][NH2:2].[F:3][C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[C:17]([C:18]([O:20]CC)=O)=[N:16][N:15]([C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)[C:14](=[O:29])[C:9]=3[N:10]([CH3:13])[C:11]=2[CH:12]=1>ClCCl.CO>[F:3][C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[C:17]([C:18]([NH:2][CH3:1])=[O:20])=[N:16][N:15]([C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)[C:14](=[O:29])[C:9]=3[N:10]([CH3:13])[C:11]=2[CH:12]=1
Reactant: CN
Reactant: CCOC(=O)c1nn(-c2cccnc2)c(=O)c2c1c1ccc(F)cc1n2C
Solvent: CO
Solvent: ClCCl
Product: CNC(=O)c1nn(-c2cccnc2)c(=O)c2c1c1ccc(F)cc1n2C

Procedure:
A stream of gaseous methylamine is introduced into a solution of 0.28 g (0.76 mmol) of ethyl 7-fluoro-5-methyl-4-oxo-3-(pyridin-3-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-carboxylate (obtained in stage 4.1.) in 30 ml of dichloromethane and 70 ml of methanol. Stirring is maintained for 4 h. The reaction medium is concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: dichloromethane/methanol: 100/0 to 90/10). The solid obtained is recrystallized from a mixture of dichloromethane and ethyl acetate.
Reaction SMILES: [CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([C:26]([NH:28][CH2:29][C@H:30]([OH:45])[CH2:31][N:32]5[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]5)=[O:27])=[C:21]5[C:25]=4[O:24][CH2:23][CH2:22]5)[N:12]=[CH:11][C:10]=3[N:9]([CH3:46])[C:8](=[O:47])[C@H:7]2[CH2:48][CH3:49])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.C(=O)(O)[O-].[Na+].Br[C:57]1([CH3:60])[CH2:59][CH2:58]1>ClCCl.C(N(CC)CC)C>[CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([C:26]([NH:28][CH2:29][C@H:30]([OH:45])[CH2:31][N:32]5[CH2:37][CH2:36][N:35]([CH2:60][CH:57]6[CH2:59][CH2:58]6)[CH2:34][CH2:33]5)=[O:27])=[C:21]5[C:25]=4[O:24][CH2:23][CH2:22]5)[N:12]=[CH:11][C:10]=3[N:9]([CH3:46])[C:8](=[O:47])[C@H:7]2[CH2:48][CH3:49])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)NC[C@H](O)CN4CCN(C(=O)OC(C)(C)C)CC4)c4c3OCC4)nc2N1C1CCCC1
Reactant: CC1(Br)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)NC[C@H](O)CN4CCN(CC5CC5)CC4)c4c3OCC4)nc2N1C1CCCC1
Reaction time: 0.5 h

Procedure:
Tert-butyl 4-[(2S)-3-[[7-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,3-dihydrobenzofuran-4-carbonyl]amino]-2-hydroxy-propyl]piperazine-1-carboxylate 7d (300 mg, 0.44 mmol) was dissolved in 40 mL of dichloromethane. The reaction solution was filled with gas of hydrogen chloride and stirred for 0.5 hours. The reaction solution was concentrated under reduced pressure. The resulting residue was dissolved in 41 mL of acetonitrile followed by the addition of 183 mL of triethylamine, sodium bicarbonate (148 mg, 1.76 mmol) and bromo-methyl-cyclopropane (130 mg, 0.97 mmol). The resulting solution was stirred for 12 hours and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 7-[[(7R)-8-cyclopentyl-7-ethyl-1-methyl-6-oxo-7H-pteridin-2-yl]amino]-N-[(2S)-3-[4-(cyclopropylmethyl)piperazin-1-yl]-2-hydroxy-propyl]-2,3-dihydrobenzofuran-4-carboxamide 7 (200 mg, yield: 72.0%) as a white solid.
Reaction SMILES: Cl[C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=1>>[C:5]([C:4]1[C:3]([N+:10]([O-:12])=[O:11])=[C:2]([CH:9]=[CH:8][CH:7]=1)[NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=1)#[N:6]
Reactant: Nc1ccc(CCO)cc1
Reactant: N#Cc1cccc(Cl)c1[N+](=O)[O-]
Product: N#Cc1cccc(Nc2ccc(CCO)cc2)c1[N+](=O)[O-]

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 3-chloro-2-nitrobenzonitrile (step 2) and 4-aminophenylethyl alcohol.