Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([CH2:10][CH:11]=[CH:12][CH3:13])[CH2:7][N:6]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:4].[O:21]=O>CN(C=O)C.O.[Pd](Cl)Cl.[Cu]Cl>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([CH2:10][CH2:11][C:12](=[O:21])[CH3:13])[CH2:7][N:6]1[C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])=[O:4]
Reactant: CC=CCC1CC(C(=O)OC)N(C(=O)OC(C)(C)C)C1
Reactant: O=O
Agent: Cl[Cu]
Agent: Cl[Pd]Cl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1CC(CCC(C)=O)CN1C(=O)OC(C)(C)C
Yield: 71 %

Procedure:
To a solution of 4-but-2-enyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (149 mg, 0.42 mmol, 1 equiv) in DMF (1.4 mL) and water (0.2 mL) were added palladium(II)chloride (7.4 mg, 0.042 mmol, 0.1 equiv) and copper(I) chloride (41.1 mg, 0.42 mmol, 1 equiv). The mixture was stirred at 50° C. overnight with oxygen bubbling into the mixture. The mixture was filtered and the filtrate was concentrated under high vacuum. The residue was diluted with ethyl acetate, washed with water (1×), brine (1×), dried and concentrated. The residue was purified by preparative TLC to give 4-(3-oxo-butyl)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (110 mg, 71%).
Reaction SMILES: [CH2:1]([SH:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N1C(=O)C2=CC=CC=[C:14]2[C:13]1=[S:22])C.C1(=O)NC(=O)C2=CC=CC=C12>C1C=CC=CC=1>[C:3]1([CH2:2][CH2:1][S:9][S:22][CH2:13][CH3:14])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCN1C(=O)c2ccccc2C1=S
Reactant: SCCc1ccccc1
Agent: O=C1NC(=O)c2ccccc21
Solvent: c1ccccc1
Product: CCSSCCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 111.3 %

Procedure:
8 g (0.058 mol) of phenethylmercaptan are added with intensive stirring to a suspension of 12 g (0.058 mol) of N-ethylthiophthalimide in 70 ml of benzene. After a few minutes, a homogeneous solution forms and the phthalimide slowly begins to precipitate out therefrom. After stirring for 48 hours at room temperature, the mixture is filtered through a paper filter, the filtrate is concentrated in a vacuum and the crude 2-phenylethyl-ethyl-disulphide (12.8 g) obtained is distilled through a Vigreux column. There are thus obtained 10.5 g of pure product (91% of theory) which has a purity of 99% (gas-chromatographic estimation). Boiling point 87-88 mm Hg/0.04 mm Hg; nD20 = 1.5742. IR (liquid): bands inter alia at 3020, 1610, 1505, 1460, 1260, 710 cm-1.
Reaction SMILES: [C:1]([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([F:18])[CH:16]=2)[C:11]([CH:19]2[CH2:24][CH2:23][N:22](C)[CH2:21][CH2:20]2)=[N:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:27]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:28]>ClCCl>[C:1]([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([F:18])[CH:16]=2)[C:11]([CH:19]2[CH2:24][CH2:23][N:22]([C:27]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:28])[CH2:21][CH2:20]2)=[N:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CN1CCC(c2nn(C(=O)c3ccccc3)c3cc(F)ccc23)CC1
Solvent: ClCCl
Product: O=C(Oc1ccccc1)N1CCC(c2nn(C(=O)c3ccccc3)c3cc(F)ccc23)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 17.9 %

Procedure:
To a solution of 1-benzoyl-6-fluoro-3-(1-methyl-4-piperidinyl)-1H-indazole (2.0 g, 5.93 mmol) in dichloromethane (100 ml) was added phenyl chloroformate (3.9 ml, 29.65 mmol) at room temperature. The reaction mixture was stirred at room temperature for 24 hours, refluxed for an additional 0.5 hours and subsequently concentrated. The remaining residue was dissolved into dichloromethane and washed with 10% HCl (aq.). The organic phase was dried (MgSO4), filtered, and concentrated to give an oil which was purified via flash column chromatography (silica gel, 20% DCM/EtOAc). Concentration of the product-containing fractions gave an oil which solidified on standing. The white solid was washed with EtOAc, leaving 0.47 g of the desired product, m.p. 137°-139° C. ANALYSIS: Calculated for C26H22FN3O3 : 70.42%C 5.00%H 9.48%N Found: 70.38%C 4.81%H 9.42%N
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[O:11])=[C:4]([C:18]([F:21])([F:20])[F:19])[CH:3]=1.Cl[C:23]1[N:28]=[C:27]([NH:29][CH3:30])[C:26]([C:31]([F:34])([F:33])[F:32])=[CH:25][N:24]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>O1CCOCC1.C(Cl)Cl>[CH3:9][O:8][C:7]1[C:2]([NH:1][C:23]2[N:28]=[C:27]([NH:29][CH3:30])[C:26]([C:31]([F:34])([F:32])[F:33])=[CH:25][N:24]=2)=[CH:3][C:4]([C:18]([F:21])([F:20])[F:19])=[C:5]([C:10]([N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)=[O:11])[CH:6]=1
Reactant: CNc1nc(Cl)ncc1C(F)(F)F
Reactant: COc1cc(C(=O)N2CCOCC2)c(C(F)(F)F)cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CNc1nc(Nc2cc(C(F)(F)F)c(C(=O)N3CCOCC3)cc2OC)ncc1C(F)(F)F
Temperature: 100 °C
Yield: 74.7 %

Procedure:
A mixture of (4-amino-5-methoxy-2-(trifluoromethyl)phenyl)(morpholino)methanone (94 mg, 0.31 mmol), 2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (66 mg, 0.31 mmol) and para-toluene sulfonic acid (59 mg, 0.31 mmol) in dioxane (4 mL) was heated to 100° C. for 2 h. Saturated aqueous sodium bicarbonate solution (10 mL) and DCM (10 mL) were added and the organic phase was passed through a hydrophobic frit. The solvent was removed in vacuo and the residue was purified by reversed phase HPLC to give (5-methoxy-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-2-(trifluoromethyl)phenyl)(morpholino)methanone (111 mg, 75%) as an off-white solid. LCMS (10 cm_ESCI_Bicarb_MeCN): [M+H]+=480 at 3.32 min. 1H NMR (400 MHz, CDCl3): δ 9.13 (s, 1H), 8.19 (s, 1H), 7.82 (s, 1H), 6.77 (s, 1H), 5.34 (q, J=4.7 Hz, 1H), 3.97 (s, 3H), 3.95-3.88 (m, 1H), 3.83-3.68 (m, 3H), 3.65-3.55 (m, 2H), 3.27-3.21 (m, 2H), 3.13 (d, J=4.7 Hz, 3H).
Reaction SMILES: [C:1]1([CH2:7][C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16]N(C)C=O.[K].IC>O.CC(O)(C)C>[C:1]1([CH:7]([CH3:16])[C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cc1ccccc1)c1cccnc1
Reactant: CN(C)C=O
Agent: [K]
Solvent: CI
Solvent: O
Solvent: CC(C)(C)O
Product: CC(C(=O)c1cccnc1)c1ccccc1
Reaction time: 0.5 h
Yield: 40 %

Procedure:
To a stirred and cooled (0° C.) solution of 70 parts of 2-phenyl-1-(3-pyridinyl)ethanone in 225 parts of N,N-dimethylformamide were added dropwise 46.9 parts of 2-methyl-2-propanol, potassium salt under nitrogen atmosphere. Upon complete addition, stirring was continued for 30 minutes at 0° C. The reaction mixture was allowed to reach room temperature and 70 parts of iodomethane were added. The reaction mixture was allowed to stand at room temperature for 8 hours. The mixture was poured into water and the product was extracted with 1,1'-oxybisethane. The extract was washed with water, dried, filtered and evaporated to dry, yielding 30 parts (40%) of 2-phenyl-1-(3-pyridinyl)-1-propanone as a residue (intermediate 8).
Reaction SMILES: [CH2:1]([NH:8][C:9]([N:11]1[C@H:16]2[CH2:17][N:18]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34](F)[N:33]=3)[C:19](=[O:30])[C@H:20]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][C:23]=3[F:29])[N:15]2[C:14](=[O:39])[CH2:13][N:12]1[CH2:40][CH:41]=[CH2:42])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1C(=O)CCC1.[NH:50]1[CH2:53][CH:52]([N:54]2[CH2:59][CH2:58][N:57]([CH2:60][CH3:61])[CH2:56][CH2:55]2)[CH2:51]1.C(C1C=CC=CC=1)C1C=CC=CC=1>O>[CH2:1]([NH:8][C:9]([N:11]1[C@H:16]2[CH2:17][N:18]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([N:50]4[CH2:53][CH:52]([N:54]5[CH2:59][CH2:58][N:57]([CH2:60][CH3:61])[CH2:56][CH2:55]5)[CH2:51]4)[N:33]=3)[C:19](=[O:30])[C@H:20]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][C:23]=3[F:29])[N:15]2[C:14](=[O:39])[CH2:13][N:12]1[CH2:40][CH:41]=[CH2:42])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN1CCN(C2CNC2)CC1
Reactant: C=CCN1CC(=O)N2[C@@H](Cc3ccc(O)cc3F)C(=O)N(Cc3cccc(F)n3)C[C@@H]2N1C(=O)NCc1ccccc1
Solvent: c1ccc(Cc2ccccc2)cc1
Solvent: CN1CCCC1=O
Solvent: O
Product: C=CCN1CC(=O)N2[C@@H](Cc3ccc(O)cc3F)C(=O)N(Cc3cccc(N4CC(N5CCN(CC)CC5)C4)n3)C[C@@H]2N1C(=O)NCc1ccccc1
Temperature: 25 °C
Yield: 80.4 %

Procedure:
To a mixed solution of (6S,9aS)-N-benzyl-6-((2-fluoro-4-hydroxyphenyl)methyl)-8-((6-fluoropyridin-2-yl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide (397 mg, 0.689 mmol) described in Production Example 1-1-6 and NMP (10 mL) was added a mixture (1.16 g) of 1-(azetidin-3-yl)-4-ethylpiperazine and benzylbenzene described in Production Example 1-3-2 at room temperature. The resultant mixture was irradiated with a microwave at 140° C. for 12 hours. The reaction mixture was cooled to room temperature, water was then added thereto, then the resultant solution was extracted with ethyl acetate, and an organic layer was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and then filtrated. The solvent was evaporated under a reduced pressure, and the resultant residue was purified by silica gel column chromatography (methanol) and then further purified by NH silica gel column chromatography (ethyl acetate:methanol=20:1) to give the title compound (402 mg, yield: 80%).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][CH2:5][C:6]1[NH:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=1.[H-].[Na+].[CH2:18]([O:20][CH2:21][CH2:22]Cl)[CH3:19].O>CN(C)C=O>[CH2:18]([O:20][CH2:21][CH2:22][N:10]1[C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]=[C:6]1[CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:15])[CH3:19]
Reactant: CCOCCCl
Reactant: CN(C)CCCc1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOCCn1c(CCCN(C)C)nc2ccccc21
Temperature: 60 °C

Procedure:
Grams 6 2-(3-dimethylaminopropyl)benzimidazole in 100 ml N,N-dimethylformamide are treated with 1.8 g 60% sodium hydride, the mixture is warmed up to 60° C. and 4 g 2-ethoxyethyl chloride are added thereto. It is maintained at 60° C. for 5 hours, then it is poured into water, extracted with diethyl ether and the extracts washed thoroughly with water, filtered on charcoal, made anhydrous on sodium sulphate and evaporated to dryness. The residue is chromatographied on silica gel column eluting with chloroform:methyl alcohol (9:1) and it gives 1-(2-ethoxyethyl)-2-(3-dimethylaminopropyl)benzimidazole.
Reaction SMILES: [C:1]([C:5]1N=C(SCC2OCCO2)[NH:7][N:6]=1)(C)(C)C.[CH3:17][N:18]([CH3:22])[C:19](Cl)=[O:20].C([N:25](CC)CC)C>CN(C)C1C=CN=CC=1.O1CCCC1>[CH3:17][N:18]([CH3:22])[C:19]([N:25]1[CH:1]=[CH:5][N:6]=[N:7]1)=[O:20]
Reactant: CN(C)C(=O)Cl
Reactant: CC(C)(C)c1n[nH]c(SCC2OCCO2)n1
Reactant: CCN(CC)CC
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CN(C)C(=O)n1ccnn1

Procedure:
3-t-Butyl-5-(1,3-dioxolan-2-yl-methylthio)-1H-1,2,4-triazole (7 g, 28.8 mmole), 2.8 ml (30.5 mmole) of dimethylcarbamoyl chloride, 8 ml (57 mmole) of triethylamine and 0.5 g (4.1 mmole) of 4-dimethylaminopyridine were dissolved in 50 ml of tetrahydrofuran (THF). The mixture was refluxed for four hours, concentrated in vacuo and partitioned between methylene chloride and dilute hydrochloric acid. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated. Chromatography on silica gel using ethyl ether/hexane gave 1-dimethylcarbamoyltriazole, an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][CH:27]=2)[O:24][CH2:23][C:22]2[N:17]3[CH:18]([CH3:29])[C:19](=[O:28])[NH:20][N:21]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br-:30].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl.CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][C:27]=2[Br:30])[O:24][CH2:23][C:22]2[N:17]3[CH:18]([CH3:29])[C:19](=[O:28])[NH:20][N:21]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [Br-]
Reactant: CC1C(=O)NN=C2COc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3N21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CO
Solvent: ClCCl
Product: CC1C(=O)NN=C2COc3cc(Br)c(C4CCN(C(=O)OC(C)(C)C)CC4)cc3N21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.8 %

Procedure:
To a solution of 4-(4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-piperidine-1-carboxylic acid tert-butyl ester (Example #71, Step B, 0.50 g, 1.249 mmol) in DCM (5 mL) and MeOH (5 mL) was added tetrabutylammonium tribromide (0.662 g, 1.373 mmol) in portions and the mixture was stirred for 30 min at ambient temperature. The reaction was quenched by addition of saturated aqueous Na2S2O3 solution (5 mL) and the pH was adjusted to 7 with saturated aqueous NaHCO3 solution. The mixture was extracted with DCM (3×20 mL). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 20% EtOAc in petroleum ether) to give 4-(7-bromo-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.34 g, 57%). LC/MS (Table 1, Method 2) Rt=1.289 min.; MS m/z: 479/481 [M+H]+.
Reaction SMILES: O/[CH:2]=[C:3]1\[C:4](=[O:13])[NH:5][C:6]2[C:11]\1=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=2.O/C=C1\C(=O)NC2C\1=CC=CC=2.[CH3:26][C:27]1[NH:31][N:30]=[C:29]([NH2:32])[CH:28]=1.NC1C=CNN=1>O1CCCC1>[F:12][C:8]1[CH:7]=[C:6]2[C:11]([C:3](=[CH:2][NH:32][C:29]3[CH:28]=[C:27]([CH3:26])[NH:31][N:30]=3)[C:4](=[O:13])[NH:5]2)=[CH:10][CH:9]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: O=C1Nc2cc(F)ccc2/C1=C/O
Agent: Nc1cc[nH]n1
Agent: O=C1Nc2ccccc2/C1=C/O
Solvent: C1CCOC1
Product: Cc1cc(NC=C2C(=O)Nc3cc(F)ccc32)n[nH]1

Procedure:
The named compound is prepared by substituting E & Z-3-[(hydroxy)-methylene]-6-fluoro-1,3-dihydro-indol-2-one for E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one and 5-methyl-1H-pyrazol-3-ylamine for 3-aminopyrazole in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-6-fluoro-1,3-dihydro-indol-2-one (0.033 gms.) is reacted with 0.040 gms. 5-methyl-1H-pyrazol-3-ylamine by refluxing in tetrahydrofuran (0.88 mL) to afford the named compound in the amount of 0.0163 gms.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26]C(=O)OC(Cl)(Cl)Cl)Cl.[NH2:35][C:36]1[CH:37]=[C:38]([CH:44]=[CH:45][CH:46]=1)[C:39]([O:41][CH2:42][CH3:43])=[O:40].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C(N(CC)CC)C>[CH2:42]([O:41][C:39]([C:38]1[CH:37]=[C:36]([NH:35][C:24]([NH:22][C:19]2[CH:18]=[CH:17][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:21][CH:20]=2)=[O:26])[CH:46]=[CH:45][CH:44]=1)=[O:40])[CH3:43]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cccc(N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cccc(NC(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2)c1
Yield: 100 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (131 mg) was dissolved in toluene (10 ml) with heat, after the addition of triethylamine (2 ml), triphosgene (213 mg) was added, and the admixture was refluxed with heat for 2 minutes. Ethyl 3-aminobenzoate (0.1 ml) was added to the reaction mixture, and the admixture was refluxed with heat for 7 minutes. After the addition of aqueous sodium hydrogen carbonate, the reaction mixture was extracted 2 times with ethyl acetate, and the organic layer was then washed with brine and dried with anhydrous sodium sulfate. The solvent was removed by reduced-pressure distillation, and the resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 214 mg of the title compound (yield: 100%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[O:24])[C:5]1=[O:35].C(N(C(C)C)CC)(C)C.Cl[C:46]([O:48][CH3:49])=O.[CH3:50][N:51]([CH:53]=[O:54])[CH3:52]>>[F:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][C:11]2[CH:12]=[C:13]3[C:8]([C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH2:27][CH2:28][N:29]4[CH2:30][CH2:31][O:32][CH2:33][CH2:34]4)=[O:24])[C:5](=[O:35])[N:4]3[CH2:3][CH2:2][NH:1][C:53]([N:51]3[CH2:52][CH2:49][O:48][CH2:46][CH2:50]3)=[O:54])=[N:9][CH:10]=2)=[CH:20][CH:19]=1
Reactant: NCCn1c(=O)c(C(=O)NCCCN2CCOCC2)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Reactant: CN(C)C=O
Reactant: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCCN1CCOCC1)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCNC(=O)N2CCOCC2)c1=O

Procedure:
A solution of 1-(2-aminoethyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-N-[3-(4-morpholinyl)propyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (0.025 g, 0.052 mmol) and diisopropyl ethylamine (0.05 mL, 0.29 mmol) in DMF (5 mL) under nitrogen was treated with methyl chloroformate (0.008 mL, 0.07 mmol) at 40° C. for 1 h then 3½ h at ambient temperature. The reaction was concentrated in vacuo and the resulting residue was triturated with Et2O:MeOH, and concentrated again in vacuo, before triturating again with EtOAc. Filtered the resulting suspension and dried in vacuo to provide the title compound as an orange solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.23-1.29 (m, 2 H), 1.99-2.05 (m, 1 H), 3.04-3.08 (m, 2 H), 3.10-3.19 (m, 7 H), 3.42 (s, 2 H), 3.44-3.49 (m, 6 H), 3.70 (t, J=11.81 Hz, 2 H), 3.96 (d, J=13.19 Hz, 2 H), 4.14 (s, 2 H), 4.29 (t, J=6.59 Hz, 2 H), 6.81 (t, J=4.67 Hz, 1 H), 7.14 (t, J=8.79 Hz, 2 H), 7.42 (dd, J=8.70, 5.59 Hz, 2 H), 8.32 (s, 1 H), 8.55 (d, J=1.28 Hz, 1 H), 10.15 (s, 1 H), 10.37 (t, J=6.50 Hz, 1 H); ES+ MS: 597 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:16][N:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl>[C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][CH:20]2[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]2)[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cccc(N)c1
Reactant: CN1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN1CCC(Nc2cccc(NC(=O)OC(C)(C)C)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Combine (3-aminophenyl)carbamic acid tert-butyl ester (0.156 g, 0.756 mmol), 1-methylpiperidin-4-one (0.093 mL, 0.756 mmol), sodium triacetoxyborohydride (208 mg, 0.982 mmol), acetic acid (0.043 mL, 0.756 mmol) and dichloromethane (8 mL). Stir at room temperature overnight. Dilute with dichloromethane (5 mL) and wash twice with sodium hydroxide (10 mL 1N aq.). Combine the organic layers and wash with saturated aqueous NaCl (10 mL). Dry over magnesium sulfate, filter under reduced pressure and concentrate to dryness. Purify by flash chromatography on a Biotage® silica cartridge eluting with a 20/1 mixture of dichloromethane and 2N ammonia in methanol to give the free base of the title compound. Dissolve the residue in diethyl ether and treat with ethereal hydrogen chloride. Triturate the resulting gum with ether to give the title compound as a white solid: mp 124–5° C.; mass spectrum (ion spray): m/z =306.2 (M+1), 1H NMR (CDCl3): 7.06 (t, J=8.0 Hz, 1H), 6.86 (bs, 1H), 6.51–6.48 (m, 1H), 6.42 (bs, 1H), 6.30–6.27 (m, 1H), 3.60 (bs, 1H), 3.30 (bs, 1H), 2.80 (bd, J=11.8 Hz, 2H), 2.31 (s, 3H), 2.19–2.02 (m, 4H), 1.89 (bs, 2H), 1.52 (s, 9H).
Reaction SMILES: Cl.[C:2]([N:5]1[C@@H:11]([CH3:12])[C@H:10]([NH2:13])[C:9](=[O:14])[N:8]([CH2:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][C:17]=2[CH3:26])[C:7]2[CH:27]=[CH:28][C:29]([C:31]#[N:32])=[CH:30][C:6]1=2)(=[O:4])[CH3:3].[C:33]([N:40]([CH3:46])[C@H:41]([C:43](O)=[O:44])[CH3:42])([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[C:2]([N:5]1[C@@H:11]([CH3:12])[C@H:10]([NH:13][C:43](=[O:44])[C@@H:41]([N:40]([CH3:46])[C:33](=[O:34])[O:35][C:36]([CH3:37])([CH3:39])[CH3:38])[CH3:42])[C:9](=[O:14])[N:8]([CH2:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][C:17]=2[CH3:26])[C:7]2[CH:27]=[CH:28][C:29]([C:31]#[N:32])=[CH:30][C:6]1=2)(=[O:4])[CH3:3]
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: CC(=O)N1c2cc(C#N)ccc2N(Cc2c(C)ccc3ccccc23)C(=O)[C@@H](N)[C@@H]1C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)N1c2cc(C#N)ccc2N(Cc2c(C)ccc3ccccc23)C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@@H]1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.6 %

Procedure:
To a 0° C. solution of (3S,4S)-5-acetyl-3-amino-4-methyl-1-((2-methylnaphthalen-1-yl)methyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile hydrochloride (162 mg, 361 μmol) in DMF (1.2 ml) was added Boc-N-methyl-L-alanine (80.7 mg, 397 μmol), N,N-diisopropylethylamine (250 μl, 1.44 mmol), and HBTU (151 mg, 397 μmol). The reaction was stirred at rt for 30 min, then diluted with H2O and the solids were collected by vacuum filtration, taken up in EtOAc, washed with H2O, sat. aq. NaHCO3, and sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash chromatography to provide tert-butyl(S)-1-((3S,4S)-5-acetyl-7-cyano-4-methyl-1-((2-methylnaphthalen-1-yl)methyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (189 mg, 88%) as a white solid. MS m/z 620 (MNa)+.
Reaction SMILES: NC1C2C(=CC=C3OC[O:12]C3=2)N=C([Cl:15])N=1.[NH2:16][C:17]1[C:26]2[C:21](=[C:22]([Cl:31])[CH:23]=[C:24]([O:29][CH3:30])[C:25]=2[O:27][CH3:28])[N:20]=[C:19](Cl)[N:18]=1.NC1C2C(=CC=C3OCOC3=2)N=C(O)N=1>>[ClH:15].[NH2:16][C:17]1[C:26]2[C:21](=[C:22]([Cl:31])[CH:23]=[C:24]([O:29][CH3:30])[C:25]=2[O:27][CH3:28])[N:20]=[C:19]([OH:12])[N:18]=1
Reactant: Nc1nc(Cl)nc2ccc3c(c12)OCO3
Reactant: COc1cc(Cl)c2nc(Cl)nc(N)c2c1OC
Agent: Nc1nc(O)nc2ccc3c(c12)OCO3
Product: COc1cc(Cl)c2nc(O)nc(N)c2c1OC
Product: Cl

Procedure:
When in the above procedure 4-amino-2-chloro-5,6-methylenedioxyquinazoline is substituted for 4-amino-2,8-dichloro-5,6-dimethoxyquinazoline the corresponding 4-amino-5,6-methylenedioxy-2-hydroxyquinazoline is obtained.