Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl.Cl[C:6]([N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13])=[O:7].[Cl-].[Na+]>O1CCCC1>[CH3:1][N:2]([CH3:3])[C:6]([N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13])=[O:7]
Reactant: CNC
Reactant: O=C(Cl)N1CCNC1=O
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)C(=O)N1CCNC1=O

Procedure:
A mixture of 50 parts by volume of a 50% strength aqueous dimethylamine solution and 70 parts by volume of tetrahydrofurane was adjusted to pH = 8 with 5 N hydrochloric acid. 14.9 parts by weight of N-chlorocarbonyl-imidazolid-2-one were added gradually thereto while stirring and cooling with ice and the pH value was maintained by simultaneous addition of further dimethylamine solution. The mixture was further stirred until the pH was constant, the tetrahydrofurane was then stripped off and the residue was saturated with sodium chloride and repeatedly extracted with ethyl acetate. The organic solution was washed and saturated sodium chloride solution, dried over MgSO4 and filtered, and the solvent was evaporated off. The residue was recrystallized from acetone and dried in a vacuum desiccator over P2O5.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C@H:18]2[O:22][N:21]=[C:20]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[CH2:19]2)=[O:17])=[CH:11][CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC1C=CC(C2C=CC=CC=2C[C:43]([O:45][CH3:46])=[O:44])=CC=1.CC(N(C(C)C)CC)C.O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[N:25]1[CH:26]=[CH:27][CH:28]=[C:23]([C:20]2[CH2:19][CH:18]([C:16]([NH:15][C:12]3[CH:13]=[CH:14][C:9]([CH:1]([C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:43]([O:45][CH3:46])=[O:44])=[CH:10][CH:11]=3)=[O:17])[O:22][N:21]=2)[CH:24]=1
Reactant: COC(=O)Cc1ccccc1-c1ccc(N)cc1
Reactant: O=C(c1ccccc1)c1ccc(NC(=O)[C@@H]2CC(c3cccnc3)=NO2)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: COC(=O)C(c1ccccc1)c1ccc(NC(=O)C2CC(c3cccnc3)=NO2)cc1
Temperature: 0 °C
Yield: 34.4 %

Procedure:
) Intermediate (3) (0.007 mol) was added to a solution of methyl [(4-aminophenyl) phenyl]acetate (0.007 mol), N,N-bis(1-methylethyl)ethanamine (0.014 mol) and N,N-dimethyl-4-pyridinamine (catalytic quantity) in CH2Cl2 (100 ml), stirred at 0° C. The reaction mixture was stirred overnight at RT. Water was added. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography over silica gel (eluent: CH2Cl2/CH3OH 98/2). The pure fractions were collected and the solvent was evaporated under reduced pressure. The residue was crystallized from EtOAc. The precipitate was filtered off, washed with EtOAc, and dried, yielding 1.0 g (35%) of (±)-methyl 4-[[[4,5-dihydro-3-(3-pyridinyl)-5-isoxazolyl]carbonyl]amino]-α-phenylbenzeneacetate (compound 56).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12]([C:14]3[C:15]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=4)=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:13])[CH:9]=2)[N:4]([CH3:30])[C:3]=1[C:31](O)=[O:32].Cl.[CH:35]([NH:38][C:39](=[O:48])[C@H:40]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[NH2:41])([CH3:37])[CH3:36].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:35]([NH:38][C:39](=[O:48])[CH:40]([NH:41][C:31]([C:3]1[N:4]([CH3:30])[C:5]2[C:10]([C:2]=1[Cl:1])=[CH:9][C:8]([NH:11][C:12]([C:14]1[C:15]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:22][CH:21]=3)=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:13])=[CH:7][CH:6]=2)=[O:32])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([CH3:37])[CH3:36]
Reactant: CC(C)NC(=O)[C@@H](N)c1ccccc1
Reactant: Cn1c(C(=O)O)c(Cl)c2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc21
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)NC(=O)C(NC(=O)c1c(Cl)c2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2n1C)c1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 86.3 %

Procedure:
The product from step (e) (292.5 mg, 0.619 mmol), (S)-N-isopropyl-2-phenylglycinamide hydrochloride salt (182.1 mg, 0.797 mmol), PyBroP (415.8 mg, 0.865 mmol) were suspended in anhydrous CH2Cl2 (6 ml), followed by the addition of DIEA (0.36 ml, 2.07 mmol). The reaction mixture was stirred at room temperature for 3.5 h. The product was purified by flash chromatography using 30:70 of hexane:EtOAc to afford 345.5 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([SH:10])=[N:7][C:6]=2[CH:11]=1.Br[CH:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:14]([OH:16])=[O:15].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10][CH:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:14]([OH:16])=[O:15])=[N:7][C:6]=2[CH:11]=1
Reactant: Sc1nc2cc(Cl)ccc2s1
Reactant: O=C(O)C(Br)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)C(Sc1nc2cc(Cl)ccc2s1)c1ccccc1
Yield: 69.1 %

Procedure:
To a solution of 5-chloro-2-mercaptobenzothiazole (38 g, 0.188 mol) in methylene chloride (750 mL) was added α-bromophenylacetic acid (38 g, 0.177 L mol) and triethylamine (38.5 g, 53 mL, 0.38 mol). The mixture was heated to reflux overnight. The clear solution was evaporated in vacuo and the residue was taken up in ethyl acetate, washed with dilute hydrochloric acid solution, then with water and finally dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to a small volume and treated with n-hexane whereby the product crystallized out. Filtration yielded the product as a beige crystalline compound (41 g, 70%), m.p. 184°-185° C.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([CH3:13])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[C-:14]#[N:15].[Na+]>O>[CH3:13][C:12]1[C:3]([CH2:2][C:14]#[N:15])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: Cc1cc2ccccc2cc1CBr
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Product: Cc1cc2ccccc2cc1CC#N
Temperature: 25 °C
Yield: 98.6 %

Procedure:
A suspension of 2-bromomethyl3-methylnaphthalene (2.87 g, 12.2 mmol) and NaCN (652 mg, 13.3 mmol) in CH3CH/H2O (9:1, 125 mL) was heated to reflux for 1 hour. Upon warming, the suspension became homogeneous. After cooling to room temperature, the volatiles were removed from the reaction mixture in vacuo and the residue was partitioned between 2O (150 mL) and CH2Cl2 (150 mL). The aqueous phase was extracted with CH2Cl2 (1×150 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo to give the title compound as a white solid (2.18 g, 99%). This material was of sufficient purity to be used as such in the next step.
Reaction SMILES: [CH3:1][C:2]([CH3:33])([CH3:32])/[CH:3]=[CH:4]/[C@H:5]1[O:10]C(C)(C)[O:8][C@@H:7]([C@@H:13]([O:29][CH3:30])[C:14]([NH:16][CH:17]2[C:23](=[O:24])[NH:22][C:21]3[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=3[S:19][CH2:18]2)=[O:15])[C@H:6]1[OH:31].Cl.[OH-].[Na+]>C1COCC1>[O:24]=[C:23]1[NH:22][C:21]2[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=2[S:19][CH2:18][CH:17]1[NH:16][C:14](=[O:15])[C@H:13]([O:29][CH3:30])[C@H:7]([OH:8])[C@@H:6]([OH:31])[C@H:5]([OH:10])/[CH:4]=[CH:3]/[C:2]([CH3:33])([CH3:1])[CH3:32]
Reactant: CO[C@@H](C(=O)NC1CSc2ccccc2NC1=O)[C@@H]1OC(C)(C)O[C@H](/C=C/C(C)(C)C)[C@@H]1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CO[C@@H](C(=O)NC1CSc2ccccc2NC1=O)[C@H](O)[C@@H](O)[C@H](O)/C=C/C(C)(C)C
Reaction time: 5 h
Yield: 27.3 %

Procedure:
78 mg of 51 (163 μmol) are mixed with 0.8 ml of THF and 1.6 ml of 1N hydrochloric acid (1.6 mmol), with stirring and under argon. Stirring is continued for 5 hours at room temperature. The solution is then cooled to 0° C. and neutralized to pH 7.0 with 1N sodium hydroxide. The mixture is extracted twice with 5 ml of EtOAc. The organic phases are combined, dried over magnesium sulfate and filtered, and then evaporated to dryness. 19.5 mg of expected product Example 19 are obtained (yield=27%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:18])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)=[CH:4][CH:3]=1.Cl.Cl[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH3:17][O:16][C:12]1[CH:11]=[C:10]([CH2:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:7][CH:6]=2)=[O:18])[CH:15]=[CH:14][CH:13]=1
Reactant: ClCCN1CCCCC1
Reactant: COc1cccc(CC(=O)c2ccc(O)cc2)c1
Agent: Cl
Product: COc1cccc(CC(=O)c2ccc(OCCN3CCCCC3)cc2)c1

Procedure:
1-(4-hydroxyphenyl)-2-(3-methoxyphenyl)ethanone and 1-(2-chloroethyl)piperidine hydrochloride are used as starting materials.
Reaction SMILES: [N:1]1([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:23][CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([OH:24])[CH:20]=4)[C:15]3=[O:25])=[CH:10][C:9]=2[O:26][CH3:27])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:28][O:29][CH2:30][C:31](=O)[CH3:32]>>[OH:24][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:25])[N:14]([C:11]1[CH:12]=[CH:13][C:8]([N:1]3[CH2:7][CH2:6][CH2:5][N:4]([CH:31]([CH3:32])[CH2:30][O:29][CH3:28])[CH2:3][CH2:2]3)=[C:9]([O:26][CH3:27])[CH:10]=1)[CH2:23][CH2:22]2
Reactant: COCC(C)=O
Reactant: COc1cc(N2CCc3cc(O)ccc3C2=O)ccc1N1CCCNCC1
Product: COCC(C)N1CCCN(c2ccc(N3CCc4cc(O)ccc4C3=O)cc2OC)CC1

Procedure:
2-(4-[1,4]Diazepan-1-yl-3-methoxy-phenyl)-6-hydroxy-3,4-dihydro-2H-isoquinolin-1-one and 1-methoxy-propan-2-one were reacted according to Method J1. In this way the product was obtained with molecular weight 439.56 (C25H33N3O4); MS (ESI): 440 (M+H+).
Reaction SMILES: [CH3:1][CH:2]([S:4](Cl)(=[O:6])=[O:5])[CH3:3].C(N(CC)CC)C.Cl.[C@@H:16]12[CH2:23][NH:22][CH2:21][C@@H:20]1[CH2:19][N:18]([C:24]1[NH:25][C:26]3[CH:32]=[C:31]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH:30]=[CH:29][C:27]=3[N:28]=1)[CH2:17]2>C1COCC1>[CH:2]([S:4]([N:22]1[CH2:21][C@@H:20]2[C@@H:16]([CH2:17][N:18]([C:24]3[NH:25][C:26]4[CH:32]=[C:31]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[CH:30]=[CH:29][C:27]=4[N:28]=3)[CH2:19]2)[CH2:23]1)(=[O:6])=[O:5])([CH3:3])[CH3:1]
Reactant: c1ccc(-c2ccc3nc(N4C[C@H]5CNC[C@H]5C4)[nH]c3c2)cc1
Reactant: CC(C)S(=O)(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)S(=O)(=O)N1C[C@H]2CN(c3nc4ccc(-c5ccccc5)cc4[nH]3)C[C@H]2C1
Reaction time: 0.25 h

Procedure:
2-Propanesulfonyl chloride and triethylamine were added to the THF suspension (5 mL) containing 2-(cis-3,7-diazabicyclo[3.3.0]oct-3-yl)-5-phenylbenzimidazole hydrochloride (26 mg) at room temperature, followed by stirring for 15 min. The reaction mixture was concentrated under reduced pressure, and the residue was separated and purified on a collective thin-layer chromatograph (chloroform:methanol=10:1) to give the title compound (12 mg).
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[CH3:23][N:24]1[C:28](=O)[CH2:27][CH2:26][C@@H:25]1[CH2:30][C:31]#[N:32]>C1C=CC=CC=1>[CH3:23][N:24]1[C:28](=[S:10])[CH2:27][CH2:26][C@@H:25]1[CH2:30][C:31]#[N:32]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CN1C(=O)CC[C@@H]1CC#N
Solvent: c1ccccc1
Product: CN1C(=S)CC[C@@H]1CC#N
Yield: 157.5 %

Procedure:
Lawesson's reagent (Tokyo Kasei Kogyo) (2.26 g, 5.6 mmols) was added to a benzene (40 ml) solution of the 2-((2R)-1-methyl-5-oxopyrrolidin-2-yl)ethanenitrile (1.48 g, 10.7 mmols), and the mixture was heated for 2 hours under reflux. The solvent was distilled off under reduced pressure, and then the residue was subjected to silica gel column chromatography (SiO2 80 g, MeOH—CHCl3 5:95 v/v) to obtain 2-((2R)-1-methyl-5-thioxopyrrolidin-2-yl)ethanenitrile (1.36 g, 82.8%).
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].C(OC(N(C)[C@@H](C)C(N[C@H]1C2(CCOCC2)OC2C=CC=CC=2N(C[C:35]2[C:44]([O:45][CH3:46])=[CH:43][CH:42]=[C:41]3[C:36]=2[CH:37]=[CH:38][C:39]([C:47](O)=[O:48])=[CH:40]3)C1=O)=O)=O)(C)(C)C.CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:46][O:45][C:44]1[CH:35]=[C:36]2[C:41](=[CH:42][CH:43]=1)[CH:40]=[C:39]([C:47]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[O:48])[CH:38]=[CH:37]2
Reactant: CS(N)(=O)=O
Reactant: COc1ccc2cc(C(=O)O)ccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C2(CCOCC2)Oc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc2cc(C(=O)NS(C)(=O)=O)ccc2c1
Reaction time: 2 h
Yield: 255.3 %

Procedure:
Methanesulfonamide (10.9 mg, 115 μmol, Eq: 1.25) was added to a mixture of 5-(((S)-3-((S)-2-(tert-butoxycarbonyl(methyl)amino)propanamido)-4-oxo-2′,3′,5′,6′-tetrahydro-3H-spiro[benzo[b][1,4]oxazepine-2,4′-pyran]-5 (4H)-yl)methyl)-6-methoxy-2-nap hthoic acid (59.4 mg, 91.7 μmol, Eq: 1.00), EDCI (22.0 mg, 115 μmol, Eq: 1.25) and DMAP (14.0 mg, 115 μmol, Eq: 1.25) in DCM (5 mL). After 2 h, the mixture was diluted with DCM, washed with 1 M HCl, brine, dried over Na2SO4 and concentrated to afford 5-((S)-3-((S)-2-(tert-butoxycarbonyl(methyl)amino)propanamido)-4-oxo-2′,3′,5′,6′-tetrahydro-3H-spiro[benzo[b][1,4]oxazepine-2,4′-pyran]-5 (4H)-yl)methyl)-6-methoxy-N-(methylsulfonyl)-2-naphthamide (65.4 mg) as a white foam which was used without purification.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].C([Li])CCC.Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([N:18]([CH2:20][CH2:21][CH2:22][CH3:23])[CH3:19])=[O:17].[Cl-].[NH4+]>CCCCCC.O1CCCC1>[CH2:20]([N:18]([CH3:19])[C:16](=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:3]#[C:2][CH2:1][OH:4])[CH2:21][CH2:22][CH3:23]
Reactant: CCCCN(C)C(=O)CCCCCBr
Reactant: C#CCO
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCN(C)C(=O)CCCCCC#CCO
Temperature: -30 °C
Reaction time: 0.75 h

Procedure:
A solution of 1.77 ml of propargyl alcohol, 30 ml of tetrahydrofuran and 7.5 ml of hexamethyl phosphotriamide cooled to -60° C. was admixed with 37.5 ml of a 1.6M solution of butyllithium in hexane and after stirring for 45 minutes at -30° C., 7 g of the product of Step A in solution in 7 ml of tetrahydrofuran were added. The mixture was stirred for 16 hours at ambient temperature and then poured into a saturated solution of ammonium chloride and extracted with ethyl acetate. The organic phase was washed with 2N hydrochloric acid and with a saturated solution of sodium bicarbonate, dried and evaporated to dryness. The 5.78 g of residue were chromatographed on silica (eluant: methylene chloride-ethyl acetate 70-30, then methylene chloride-isopropanol 95-5) to obtain 1.65 g of the desired product.
Reaction SMILES: [S:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].O=[CH:9][C:10]1[CH:18]=[CH:17][C:15]([OH:16])=[C:12]([O:13][CH3:14])[CH:11]=1.CC([O-])=O.[Na+].C(O)(=O)C>O>[OH:16][C:15]1[CH:17]=[CH:18][C:10]([CH:9]=[C:7]2[S:1][C:2](=[S:3])[NH:4][C:5]2=[O:6])=[CH:11][C:12]=1[O:13][CH3:14]
Reactant: O=C1CSC(=S)N1
Reactant: COc1cc(C=O)ccc1O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(C=C2SC(=S)NC2=O)ccc1O
Temperature: 90 °C
Yield: 66.8 %

Procedure:
To a N2-purged flask was added rhodanine (574 mg, 4.31 mmol), vanillin (656 mg, 1 equiv), NaOAc (354 mg, 3.5 equiv) and acetic acid (8.5 mL). The mixture was heated at 90° C. under N2 for 20 h to yield a yellow precipitate. The reaction solution was diluted with water (150 mL) and the solid precipitate was filtered through a Buchner funnel. The solid product was washed with water, and then with hexane, then dried under high vacuum to yield the intermediate compound (770 mg, 67% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH2:13][CH2:14][CH3:15])[N:6]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[N:33]([C:34]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[N:32]=[N:31][N:30]=3)=[CH:19][CH:18]=1)[C:5]2=[O:53].C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[C:70](Cl)(=[O:72])[CH3:71]>C(Cl)Cl>[C:70]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH2:13][CH2:14][CH3:15])[N:6]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[N:33]([C:34]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)([C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)[C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[N:32]=[N:31][N:30]=3)=[CH:21][CH:22]=1)[C:5]2=[O:53])(=[O:72])[CH3:71]
Reactant: CCCCc1nc2ccc(N)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCc1nc2ccc(NC(C)=O)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 58.4 %

Procedure:
To a solution of 0.12 g (0.17 mmol) of the aminoquinazolinone from Example 40 in 2 mL of CH2Cl2 was added 33 mg (0.32 mmol) of triethylamine followed by 10 mg of dimethylaminopyridine. The reaction mixture was cooled to 0° C. and treated with 14 mg (0.19 mmol) of acetyl chloride. The solution was allowed to warm to room temperature at which time a further 0.3 equivalents of acetyl chloride was added and the mixture was stirred overnight. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography over silica gel eluting with 50% EtOAc/hexanes containing a gradually increasing concentration of CH2Cl2 to 10% to give 0.073 g of the title compound, 57% yield. 1H-NMR (CDCl3 250 MHz): 0.88 (t, 3H, J=7.08 Hz), 1.32 (m, 2H), 1.70 (m, 2H), 2.19 (s, 3H), 2.64 (3 line m, 2H, J=7.2 Hz), 5.30 (bs, 2H), 6.89-6.98 (m, 8H), 7.09 (d, 2H, J=8.1 Hz), 7.20-7.35 (m, 10H), 7.46 (m, 2H), 7.66 (d, 1H, J=8.8 Hz), 7.73 (bs, 1H), 7.92 (m, 1H), 8.14 (d, 1H), 8.26 (dd, 1H, J=8.8, 2.3 Hz).
Reaction SMILES: C(O)(=O)C.[CH3:5][O:6][P:7]([CH2:27][NH2:28])([CH2:9][CH:10]([C:15](=[O:26])[NH:16][C@H:17]([C:22](=[O:25])[NH:23][CH3:24])[CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8].[CH3:29][O:30][C:31]1[CH:32]=[C:33]2[C:38](=O)[O:37][C:35](=[O:36])[C:34]2=[CH:40][CH:41]=1>>[CH3:5][O:6][P:7]([CH2:27][N:28]1[C:38](=[O:37])[C:33]2=[CH:32][C:31]([O:30][CH3:29])=[CH:41][CH:40]=[C:34]2[C:35]1=[O:36])([CH2:9][CH:10]([C:15](=[O:26])[NH:16][C@H:17]([C:22](=[O:25])[NH:23][CH3:24])[CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8]
Reactant: COc1ccc2c(c1)C(=O)OC2=O
Reactant: CNC(=O)[C@H](CC(C)C)NC(=O)C(CC(C)C)CP(=O)(CN)OC
Solvent: CC(=O)O
Product: CNC(=O)[C@H](CC(C)C)NC(=O)C(CC(C)C)CP(=O)(CN1C(=O)c2ccc(OC)cc2C1=O)OC
Yield: 50.4 %

Procedure:
In a manner analogous to that described in Example 3(A), from 0.45 g of (aminomethyl)[(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl]phosphinic acid methyl ester acetate and 0.185 g of 4-methoxyphthalic anhydride, there was obtained 0.274 g of [(4-methoxyphthalimido)methyl][(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl]phosphinic acid methyl ester in the form of colorless foam.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8]O.P(Br)(Br)[Br:11].C(=O)(O)[O-]>C(OCC)C>[Br:11][CH2:8][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: BrP(Br)Br
Reactant: OCCc1ccccn1
Agent: O=C([O-])O
Solvent: CCOCC
Product: BrCCc1ccccn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 173.2 %

Procedure:
To an ice-cold solution of 2-pyridin-2-yl-ethanol (1 g, 8.1 mmol) in diethyl ether (20 mL) was added freshly distilled phosphorous tribromide (0.75 g, 2.7 mmol) over 15 min. The reaction mixture was warmed to r.t. and stirred for a further 5 hours. The reaction mixture was poured into an excess of cooled bicarbonate solution and extracted with dichloromethane (×2). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to afford 2-(2-bromo-ethyl)-pyridine (0.87 g, 58%) as a liquid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]1.[Cl:24][C:25]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[C:27]([Cl:40])[C:26]=1[OH:41].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[ClH:1].[ClH:24].[Cl:24][C:25]1[CH:30]=[C:29]([C:2]2[N:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)[CH:28]=[C:27]([Cl:40])[C:26]=1[OH:41]
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1NCC1CCN(C)CC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)nc2c1NCC1CCN(C)CC1
Yield: 10.2 %

Procedure:
Following general procedure II, 1-{6-chloro-4-[(1-methylpiperidin-4-yl)methylamino]-1,5-naphthyridin-3-yl}ethanone (60 mg, 0.18 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (78 mg, 0.27 mmol) followed by formation of the dihydrochloride salt to afford the desired product (7.3 mg, 7.6%) as an off-white solid: 1H NMR (500 MHz, CD3OD) δ 9.18 (s, 1H), 8.48 (d, J=9.0 Hz, 1H), 8.35 (d, J=8.9 Hz, 1H), 8.11 (s, 2H), 4.60 (d, J=7.1 Hz, 2H), 3.65-3.59 (m, 2H), 3.09 (td, J=13.0, 2.8 Hz, 2H), 2.88 (s, 3H), 2.77 (s, 3H), 2.34 (br s, 1H), 2.27 (d, J=14.7 Hz, 2H), 1.80-1.67 (m, 2H); ESI MS m/z 459 [M+H]+; HPLC>99% (AUC), tR=9.39 min.
Reaction SMILES: [CH3:1][O:2][C@H:3]([CH2:6][S:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH3:15])[CH2:4][OH:5].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])O.[Na+]>ClCCl>[CH3:1][O:2][C@H:3]([CH2:6][S:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH3:15])[CH:4]=[O:5]
Reactant: COc1ccccc1SC[C@H](CO)OC
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: COc1ccccc1SC[C@H](C=O)OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 29.4 %

Procedure:
4 g (0.017 mol) of 2-(S)-methoxy-3-(2-methoxyphenylthio)propan-1-ol (XIV-1), 100 ml of dichloromethane and 11.13 g (0.026 mol) of Dess-Martin reagent are introduced into a round-bottomed flask kept under an inert atmosphere. The mixture is stirred at ambient temperature for 3 hours. 190 ml of a saturated aqueous sodium thiosulfate solution are subsequently added, followed by 190 ml of a saturated aqueous sodium hydrogencarbonate solution, and the mixture is extracted with dichloromethane. The combined organic phases are washed with water and with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by flash chromatography on silica gel (eluent: dichloromethane/ethyl acetate=95:5). 1.2 g (0.005 mol) of the title compound (IIa-1) are recovered in the form of a yellow oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[C:9]([NH:15][CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:16]1([N:15]2[C:9]3[N:10]=[C:11]([NH2:14])[N:12]=[CH:13][C:8]=3[C:7]3[CH:6]=[CH:5][N:4]=[CH:3][C:2]2=3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Nc1ncc(-c2ccncc2Cl)c(NC2CCCC2)n1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: Nc1ncc2c3ccncc3n(C3CCCC3)c2n1
Temperature: 150 °C
Yield: 85.5 %

Procedure:
To a solution of 3 (2.3 g, 7.9 mmol) in dioxane (60 mL) were added tris(dibenzylideneacetone)dipalladium(0) (368 mg, 0.4 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (696 mg, 1.2 mmol), and sodium t-butoxide (1.15 g, 12 mmol). The mixture thus obtained was heated at 150° C. under microwave irradiation for 3 h. The reaction mixture was passed through a short pack silica gel column and concentrated. The residue was purified by flash chromatography on silica gel eluting with 2% methanol in dichloromethane to give the title compound (4) as a white solid (1.71 g, 85%). 1H NMR (500 MHz, DMSO-d6) δ 9.05 (1H, s), 8.87 (1H, br. s), 8.37 (1H, d, J=4.9 Hz), 7.93 (1H, d, J=5.1 Hz), 6.97 (2H, br. s), 5.33 (1H, p, J=8.6 Hz), 2.27 (2H, m), 2.04 (4H, m), 1.76 (2H, m) ppm; LCMS-ESI (POS), M/Z, M+1: Found 254.1, Calculated 254.1.