Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC[O-].[Na+].Cl.[C:6]([NH2:9])(=[NH:8])[CH3:7].[C:10]([CH:13]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:14](OCC)=[O:15])(=O)[CH3:11]>CCO>[CH3:7][C:6]1[NH:9][C:14](=[O:15])[C:13]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:10]([CH3:11])[N:8]=1
Reactant: CC(=N)N
Reactant: CCOC(=O)CCC(C(C)=O)C(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CCc1c(C)nc(C)[nH]c1=O
Yield: 51 %

Procedure:
A mixture of NaOEt (0.069 mol) in EtOH (prepared from 1.6 g of Na and 35 mL of EtOH), acetamidine hydrochloride (3.3 g, 0.035 mol), and diethyl acetylglutarate (8.0 g, 0.035 mol) was heated under reflux for 22 h. The mixture was concentrated, taken up in water, acidified to pH 4 with conc. HCl, and extracted with EtOAc. The extracts were washed with brine, dried (MgSO4), and concentrated. Trituration with hexane gave 4.0 g (51%) of product as a white solid. An analytical sample was crystallized from ether/hexane, mp 114°-116° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[C:26]1([S:36](Cl)(=[O:38])=[O:37])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([S:36]([C:26]4[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[CH:29]=[CH:28][CH:27]=4)(=[O:38])=[O:37])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(S(=O)(=O)c4cccc5ccccc45)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) and naphthalene-1-sulfonyl chloride as starting compounds. The crude product is purified by crystallization from methanol to yield the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([C:18](=[O:26])[C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=4)[CH:16]=3)[N:11]([CH3:27])[C:10](=[O:28])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[Si:29]([C:33]#[CH:34])([CH3:32])([CH3:31])[CH3:30]>C1COCC1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]([C:15]2[CH:16]=[C:17]3[C:12](=[N:13][CH:14]=2)[N:11]([CH3:27])[C:10](=[O:28])[CH:9]=[C:8]3[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:34]#[C:33][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:3]=2)=[O:26])=[CH:20][CH:21]=1
Reactant: C#C[Si](C)(C)C
Reactant: Cn1c(=O)cc(-c2cccc(Br)c2)c2cc(C(=O)c3ccc(Cl)cc3)cnc21
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1c(=O)cc(-c2cccc(C#C[Si](C)(C)C)c2)c2cc(C(=O)c3ccc(Cl)cc3)cnc21
Temperature: 60 °C
Yield: 79.3 %

Procedure:
To a solution of compound I (1 g, 2.21 mmol) in THF (10.0 mL), TEA (4 mL) was added followed by (PPh3)4Pd (0.25 g, 0.22 mmol) and CuI (42 mg, 0.22 mmol). The mixture was degassed using N2 for 30 min and TMS-acetylene (0.92 g, 6.64 mmol) was added. The mixture was heated in a microwave oven at 60° C. for 30 min. The reaction mixture was diluted with EtOAc (25 mL) and passed through a pad of celite. The filtrate was concentrated. Purification of the crude product provided 825 mg (80%) of compound J.
Reaction SMILES: [C:1]([N:8](C)[C@H:9](C(O)=O)C)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]>CN(C)C=O>[C:4]([O:3][C:1](=[O:2])[NH:8][CH3:9])([CH3:7])([CH3:6])[CH3:5]
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Solvent: CN(C)C=O
Product: CNC(=O)OC(C)(C)C

Procedure:
The product from Step 1 was coupled with Boc-N-methyl-L-alanine according to General procedure 4 (but using dimethyl formamide instead of dichloromethane) to afford (S)-1-(6-cyano-5-nitro-pyridin-2-ylcarbamoyl)-ethyl]-methyl-carbamic acid tert-butyl ester. MS: [M−H]−=348.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]([O:12][CH2:13][CH3:14])(=[O:11])[CH:9]=[CH2:10].[Sn](Cl)(Cl)(Cl)Cl>C1C=CC=CC=1>[C:2]1([NH:1][CH2:10][CH2:9][C:8]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC(=O)OCC
Reactant: Nc1ccccc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CCOC(=O)CCNc1ccccc1
Temperature: 25 °C
Yield: 60.2 %

Procedure:
According to the procedure of P. L. Southwick, J. Am. Chem. Soc. 75 3413 (1953), to a solution of aniline (31.86 g, 0.35 mol) and ethyl acrylate (35.0 g, 0.35 mol) in 200 ml of dry benzene (freshly distilled from CaH2) was added 0.5 ml of tin tetrachloride and the resulting solution was heated under reflux for 24 h. After cooling to room temperature the suspension was filtered to remove the inorganic solids and then concentrated in vacuo to give a dark green oil which was chromatographed on silica gel eluting with ethyl acetate/toluene (30/70) to give the title compound (40.7 g, 60%) as a light yellow oil. B.p. 95°-98° C. at 0.1 mm Hg.
Reaction SMILES: [CH2:1]([C:4]1([CH3:40])[S:9](=[O:11])(=[O:10])[C:8]([CH3:13])([CH3:12])[C:7]([N:14]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[N:6][C@@:5]1([C:30]1[CH:35]=[C:34]([N+:36]([O-:38])=[O:37])[CH:33]=[CH:32][C:31]=1[F:39])[CH3:29])[CH:2]=C.C(=O)(O)[O-:42].[Na+].O=[O+][O-].[BH4-].[Na+]>C(Cl)Cl.CO.C(=O)=O.CC(C)=O.O=O>[C:17]([O:16][C:15]([N:14]([C:7]1[C:8]([CH3:13])([CH3:12])[S:9](=[O:11])(=[O:10])[C:4]([CH2:1][CH2:2][OH:42])([CH3:40])[C@:5]([C:30]2[CH:35]=[C:34]([N+:36]([O-:38])=[O:37])[CH:33]=[CH:32][C:31]=2[F:39])([CH3:29])[N:6]=1)[C:22](=[O:23])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:21])([CH3:19])([CH3:18])[CH3:20]
Reactant: O=C([O-])O
Reactant: C=CCC1(C)[C@@](C)(c2cc([N+](=O)[O-])ccc2F)N=C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(C)(C)S1(=O)=O
Agent: O=C=O
Agent: O=O
Agent: O=[O+][O-]
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@](C)(c2cc([N+](=O)[O-])ccc2F)C(C)(CCO)S(=O)(=O)C1(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl N-[(5R)-6-allyl-5-(2-fluoro-5-nitro-phenyl)-2,2,5,6-tetramethyl-1,1-dioxo-1,4-thiazin-3-yl]-N-tert-butoxycarbonyl-carbamate (0.18 g, 0.31 mmol) in DCM (2.4 ml) and MeOH (0.8 ml) was added sodium bicarbonate (0.053 g, 0.63 mmol) and then cooled in dry ice-acetone bath. A mixture of O3 in oxygen gas was bubbled through the solution until the blue color persisted. The excess ozone was removed by bubbling through oxygen gas for 5 minutes. Sodium borohydride (0.018 g, 0.47 mmol) was added and the mixture was stirred and allowed to warm to 0° C. After 30 minutes, the reaction was quenched by sat.NH4Cl and extracted with DCM. The combined extracts were washed with brine, dried and concentrated to give crude tert-butyl N-tert-butoxycarbonyl-N-[(5R)-5-(2-fluoro-5-nitro-phenyl)-6-(2-hydroxyethyl)-2,2,5,6-tetramethyl-1,1-dioxo-1,4-thiazin-3-yl]carbamate as a white solid. m/z (ESI) 611.0 (M+Na)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH2:23][C:22](=[O:24])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[C:25]([F:28])([F:27])[F:26])[N:15]=2)=[CH:10][CH:9]=1.Cl[CH2:30][C:31]([N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)=[O:32]>CC(=O)CC>[CH3:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:23]=[C:22]([O:24][CH2:30][C:31]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[O:32])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[C:25]([F:28])([F:26])[F:27])[N:15]=2)=[CH:12][CH:13]=1
Reactant: Cc1ccc(C2=Nc3cccc(C(F)(F)F)c3C(=O)C2)cc1
Reactant: O=C(CCl)N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Cc1ccc(-c2cc(OCC(=O)N3CCOCC3)c3c(C(F)(F)F)cccc3n2)cc1
Temperature: 20 °C
Yield: 76.3 %

Procedure:
Anhydrous potassium carbonate (2.2 g) is added to a stirred suspension of 2-(4-methylphenyl)-5-trifluoromethyl-4-quinolone (2.4 g) and 4-(2-chloroacetyl)morpholine (1.3 g) in 2-butanone (50 cc). The mixture is heated to reflux for 3 hours and cooled to room temperature (approximately 20° C.). The insoluble matter is removed by filtration and rinsed with 2-butanone. The organic phases are combined and the solvent is removed under reduced pressure. After recrystallation of the residue from acetonitrile, 4-{[2(4-methylphenyl)-5-trifluoromethyl-4-quinolyl]oxyacetyl}morpholine (2.6 g), m.p. 172° C. is isolated.
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][C:4]([CH:7]([N:13]2[C:17]3[CH:18]=[CH:19][C:20]([N+:22]([O-])=O)=[CH:21][C:16]=3[N:15]=[CH:14]2)[CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:3][CH:2]=1.C([O-])=O.[NH4+].O>C(O)C.[Pd]>[NH2:22][C:20]1[CH:19]=[CH:18][C:17]2[N:13]([CH:7]([C:4]3[CH:5]=[CH:6][C:1]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:2][CH:3]=3)[CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:14]=[N:15][C:16]=2[CH:21]=1
Reactant: COC(=O)CC(c1ccc(-c2ccccc2)cc1)n1cnc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COC(=O)CC(c1ccc(-c2ccccc2)cc1)n1cnc2cc(N)ccc21
Temperature: 25 °C

Procedure:
To a solution of methyl 3-(1,1′-biphenyl)-4-yl-3-(5-nitro-1H-benzimidazol-1-yl)propanoate (47 mg, 117 μmol) in ethanol (2 mL) was added palladium on carbon (9.0 mg, 10% active Pd), ammonium formate (37 mg, 587 μmol) and water (0.5 mL). The solution was heated at reflux for 4 hours, the cooled to room temperature, and filtered through Celite®. The filtrate was evaporated in vacuo, and the residue was purified by flash column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (97:3) to afford the title compound, [LCMS (Method B, Mobile Phase I) RT=2.26 min, MH+ 372].
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]([OH:11])=O)[CH3:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:45]1[C:53]2[C:48](=[C:49]([C:54]3[CH:55]=[C:56]([NH2:63])[C:57]4[CH:58]=[N:59][NH:60][C:61]=4[CH:62]=3)[CH:50]=[CH:51][CH:52]=2)[CH:47]=[CH:46]1>CN(C=O)C.C(Cl)Cl.O>[NH:45]1[C:53]2[C:48](=[C:49]([C:54]3[CH:62]=[C:61]4[C:57]([CH:58]=[N:59][NH:60]4)=[C:56]([NH:63][C:9]([C:5]4[N:4]([CH:2]([CH3:1])[CH3:3])[CH:8]=[CH:7][N:6]=4)=[O:11])[CH:55]=3)[CH:50]=[CH:51][CH:52]=2)[CH:47]=[CH:46]1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Reactant: CC(C)n1ccnc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CC(C)n1ccnc1C(=O)Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 18.2 %

Procedure:
A mixture of 1-(1-methylethyl)-1H-imidazole-2-carboxylic acid (467 mg, contained 50% ethyl 1H-imidazole-2-carboxylate plus inorganic impurities) (now available pure from AKos), HATU (576 mg), and DIPEA (0.793 ml) in DMF (2 ml) was stirred at RT for 10 min. 6-(1H-Indol-4-yl)-1H-indazol-4-amine (188 mg) in DMF (3 ml) was then added and the mixture was stirred at RT. After 3 h at RT, a further quantity of premixed [1-(1-methylethyl)-1H-imidazole-2-carboxylic acid (467 mg), HATU (576 mg), and DIPEA (0.793 ml) in DMF (2 ml)] was added to the reaction mixture and stirring was continued for 2 h at RT. Water (0.5 ml) was added to the reaction mixture, and it was then evaporated to dryness. The residue was partitioned between ethyl acetate (25 ml) and water (10 ml). The phases were separated and the aqueous phase was extracted with further ethyl acetate (2×25 ml). The combined organic extracts were dried over anhydrous sodium sulphate and evaporated to give a brown oily residue which was dissolved in DCM (15 ml) and applied to a 100 g silica SPE cartridge. The cartridge was eluted on a Flashmaster (II) using a gradient of 0-100% ethyl acetate in cyclohexane over 60 min to give a pale brown oil which was dissolved in DCM (5 ml) and applied to a 20 g silica SPE cartridge. The cartridge was eluted with a gradient of 0-100% ethyl acetate in cyclohexane over 40 min followed by 0-20% methanol in ethyl acetate over 15 min to give the title compound (53 mg) as a buff-coloured solid.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:9]([CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[C:8]2[C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.C(=O)([O-])O.[Na+].[C-:52]#[N:53].[K+]>O1CCCC1.C(OCC)(=O)C>[C:52]([CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:9]([CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[C:8]2[C:28]1[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=1)#[N:53]
Reactant: [C-]#N
Reactant: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(CCCO)cc23)cc1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(CCCC#N)cc23)cc1
Reaction time: 0.5 h
Yield: 89.3 %

Procedure:
To a solution of tert-butyl {[6-(3-hydroxypropyl)-2-isobutyl-4-(4-methylphenyl)quinolin-3-yl]methyl}carbamate (3.00 g, 6.48 mmol) and triethylamine (1.8 ml, 12.9 mmol) in tetrahydrofuran (50 ml) was added dropwise methanesulfonyl chloride (1.12 g, 9.73 mmol) at 0° C., and the mixture was stirred at the same temperature for 30 min. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was dissolved in dimethyl sulfoxide (40 ml). Potassium cyanide (2.1 g, 32.4 mmol) was added and the mixture was stirred at 60° C. for 2.5 hrs. The reaction mixture was diluted with ethyl acetate, washed twice with saturated aqueous sodium hydrogen carbonate, water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give tert-butyl {[6-(3-cyanopropyl)-2-isobutyl-4-(4-methylphenyl)quinolin-3-yl]methyl}carbamate (2.73 g, yield 89%) as yellow crystals.
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:19]([CH:20]4[CH2:22][CH2:21]4)=[N:18][NH:17][C:16](=O)[CH:15]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:16]1[N:17]=[N:18][C:19]([CH:20]2[CH2:22][CH2:21]2)=[C:14]([C:11]2[CH:12]=[CH:13][C:8]([O:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:9][CH:10]=2)[CH:15]=1
Reactant: O=c1cc(-c2ccc(OC3CCCCC3)cc2)c(C2CC2)n[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1cc(-c2ccc(OC3CCCCC3)cc2)c(C2CC2)nn1
Temperature: 90 °C
Yield: 29 %

Procedure:
A suspension of 5-(4-cyclohexyloxy-phenyl)-6-cyclopropyl-2H-pyridazin-3-one (0.86 mmol, 0.29 g) in phosphorous oxychloride (4.30 mmol, 0.40 mL) was heated at 90° C. for 20 min with stirring during which period the starting material was fully consumed as judged by TLC. The reaction mixture was cooled to room temperature and the volatiles were removed in vacuo. The residue was dissolved in ethyl acetate (5 mL), washed with water (2 mL), saturated NaHCO3 (2×2 mL) and dried (Na2SO4). The residue was purified on a 12 g SiO2 cartridge eluting with an ethyl acetate/hexanes gradient to afford 6-chloro-4-(4-cyclohexyloxy-phenyl)-3-cyclopropyl-pyridazine (0.082 g).
Reaction SMILES: [P:1]([CH2:5][NH:6][CH2:7][C:8]([OH:10])=[O:9])([OH:4])([OH:3])=[O:2].[OH-].[Na+].[CH2:13]1O[CH:14]1[CH2:15][CH3:16]>O>[CH2:14]([CH:15]1[CH2:16][N:6]([CH2:5][P:1]([OH:4])([OH:3])=[O:2])[CH2:7][C:8](=[O:10])[O:9]1)[CH3:13]
Reactant: CCC1CO1
Reactant: O=C(O)CNCP(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCC1CN(CP(=O)(O)O)CC(=O)O1
Reaction time: 8 h

Procedure:
To a solution of N-phosphonomethylglycine (8.5 grams, 0.05 mole) in 30 ml. of water is added 50% aqueous sodium hydroxide (8.0 grams). The solution is cooled, and 1,2-butylene oxide (3.6 grams, 0.05 mole) is added, after which the solution is rotated overnight on a polymer wheel. Additional amounts of 1,2-butylene oxide are added to complete the reaction, and any unreacted butylene oxide is then extracted with ethyl ether and benzene. A portion of the reaction product is diluted with water and passed through a column of ion exchange resin in the acid form. Cuts 3 through 20 are collected, combined and evaporated to dryness to give 6-ethyl-4-phosphonomethyl-2-morpholinone as a friable glassy solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:9](=[O:10])[CH2:8][O:7][C:6]2[N:11]=[C:12]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4([NH:31]C(=O)OC(C)(C)C)[CH2:30][CH2:29][CH2:28]4)=[CH:23][CH:22]=3)[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:14][C:5]1=2.Cl>ClCCl>[NH2:31][C:27]1([C:24]2[CH:25]=[CH:26][C:21]([C:12]3[C:13]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)=[CH:14][C:5]4[N:4]([CH2:3][CH2:2][OH:1])[C:9](=[O:10])[CH2:8][O:7][C:6]=4[N:11]=3)=[CH:22][CH:23]=2)[CH2:28][CH2:29][CH2:30]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(CCO)C(=O)CO4)cc2)CCC1
Agent: Cl
Solvent: ClCCl
Product: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(CCO)C(=O)CO4)cc2)CCC1
Reaction time: 16 h
Yield: 77.7 %

Procedure:
to a round bottomed flask containing tert-butyl 1-(4-(1-(2-hydroxyethyl)-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutylcarbamate (25 mg, 0.048 mmol) was added dichloromethane (2.5 ml) followed with hydrochloric acid (2.5 ml, 2M in diethyl ether). The resulting solution was stirred for 16 h. The precipitate was filtered and washed with ether (2×10 ml) and dried to afford the product (15.5 mg). 1H NMR (500 MHz, CH3OD) 7.78 (s, 1H), 7.42 (d, 2H), 7.38 (d, 2H), 7.30 (m, 3H), 7.22 (m, 2H), 4.96 (s, 2H), 4.16 (t, 2H), 3.86 (t, 2H), 2.73-2.79 (m, 2H), 2.54-2.60 (m, 2H), 2.21-2.26 (m, 1H), 1.94-1.99 (m, 1H). LCMS (Method D): RT=1.99 min, M+H+=416.2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:17]=2Cl)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:32][C:33]1[CH:34]=[CH:35][C:36]([CH3:41])=[C:37]([CH:40]=1)[CH2:38]Br>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:17]=2[CH2:38][C:37]2[CH:40]=[C:33]([F:32])[CH:34]=[CH:35][C:36]=2[CH3:41])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(F)cc1CBr
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2c(Cl)n(-c3ccccc3)c3ccccc23)CC1
Product: Cc1ccc(F)cc1Cc1c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c2ccccc2n1-c1ccccc1

Procedure:
From the compound of example 16, step 1, (150 mg, 341 μmol) the title compound was prepared analogously as described in example 17, step 1, using 5-fluoro-2-methylbenzyl bromide. Yield: 9 mg.
Reaction SMILES: [NH2:1][C:2]1[C:18]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=[CH:15][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)=[O:5].[C:27](=S)=[S:28].C1CCN2C(=NCCC2)CC1.CN(C=O)C>O.C(OCC)(=O)C>[CH3:26][O:25][C:17]1[C:18]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:2]2[C:3]([C:4](=[O:5])[N:6]([CH2:7][CH2:8][C:9]3[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=3)[C:27](=[S:28])[NH:1]2)=[CH:15][CH:16]=1
Reactant: S=C=S
Reactant: CCCCCOc1c(OC)ccc(C(=O)NCCc2ccncc2)c1N
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: CCCCCOc1c(OC)ccc2c(=O)n(CCc3ccncc3)c(=S)[nH]c12
Yield: 11 %

Procedure:
2-Amino-4-methoxy-3-pentyloxy-N-(2-pyridin-4-ylethyl)benzamide (200 mg, 0.560 mmol) obtained in Example 2-61, carbon disulfide (0.6 ml), 1,8-diazabicyclo [5.4.0]-7-undecene (0.0837 ml, 0.56 mmol) and DMF (1.0 ml) were mixed, and this mixture was refluxed under heating for 4 hours. Ethyl acetate (4 ml) and water were added to this reaction mixture. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution (5 ml) and saturated brine (5 ml), and dried over anhydrous magnesium sulfate. The drying agent was filtered off and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to column chromatography on silica gel (chloroform/methanol=10/1) and recryst alli ztion from ethyl acetate to give 7-methoxy-8-pentyloxy-3-(2-pyridin-4-ylethyl)-2-thioxo-2,3-dihydro-1H-quinazolin-4-one (24 mg, 11%) as colorless crystals.
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][C:4]([CH2:7][CH:8]([NH:17]C(OC(C)(C)C)=O)[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:3][CH:2]=1.Cl.O1CCOCC1.[CH2:38]([O:45][C:46](=[O:56])[CH2:47][C:48]1([C:53](O)=[O:54])[CH2:52][CH2:51][CH2:50][CH2:49]1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.CCN=C=NCCCN(C)C.Cl.ON1C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH2:38]([O:45][C:46](=[O:56])[CH2:47][C:48]1([C:53]([NH:17][CH:8]([CH2:7][C:4]2[CH:5]=[CH:6][C:1]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:2][CH:3]=2)[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:14])[CH3:15])=[O:11])=[O:54])[CH2:49][CH2:50][CH2:51][CH2:52]1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CC(C)(C)OC(=O)CC(Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C
Reactant: O=C(CC1(C(=O)O)CCCC1)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)CC(Cc1ccc(-c2ccccc2)cc1)NC(=O)C1(CC(=O)OCc2ccccc2)CCCC1
Reaction time: 2 h
Yield: 32 %

Procedure:
A mixture of tert-butyl 4-(biphenyl-4-yl)-3-(tert-butoxycarbonylamino)butanoate (110 mg, 0.267 mmol) and HCl in 1,4-dioxane (0.668 ml, 2.67 mmol) was stirred for 2 hours, and the reaction mixture was concentrated under reduced pressure. To a solution of 1-(2-(benzyloxy)-2-oxoethyl)cyclopentanecarboxylic acid (65.6 mg, 0.214 mmol, 86% purity), EDC.HCl (51.2 mg, 0.267 mmol) and 1-hydroxy-7-azabenzotriazole (36.4 mg, 0.267 mmol) in DMF (1 ml) stirred for 1.5 hour, the obtained residue and DIPEA (0.093 ml, 0.535 mmol) were added. After stirred for 2.5 hours, the reaction was diluted with water. The products were extracted with EtOAc, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by flash column chromatography on silica gel (eluent: heptane/EtOAc=100:0 to 0:100) to give tert-butyl 3-(1-(2-(benzyloxy)-2-oxoethyl)cyclopentanecarboxamido)-4-(biphenyl-4-yl)butanoate (38 mg); Retention time=1.89 minutes (condition B); MS (m+1)=556.3.
Reaction SMILES: [C:1](Cl)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:4]1([CH:3]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:1](=[O:10])[CH2:2]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Nc1ccccc1
Reactant: O=C(Cl)C=Cc1ccccc1
Product: O=C1CC(c2ccccc2)c2ccccc2N1

Procedure:
4-Phenyl-3,4-dihydrocarbostyril (CAS#4888-33-9) was prepared in two steps using the procedure described by Conley, R. T.; Knopka, W. N. J. Org. Chem. 1964, 29, 496-497. The starting materials for this preparation were cinnamoyl chloride (Aldrich) and aniline (Aldrich). The title compound was purified by flash chromatography eluting with CH2Cl2/EtOAc (4:1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]#[C:6][C:7]([O:9][CH3:10])=[O:8])=[O:4].[C:11]([O:15][C:16]([N:18]1[CH:22]=[CH:21][CH:20]=[CH:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>>[CH3:14][C:11]([O:15][C:16]([N:18]1[CH:19]2[CH:20]=[CH:21][CH:22]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]2[C:3]([O:2][CH3:1])=[O:4])=[O:17])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)n1cccc1
Reactant: COC(=O)C#CC(=O)OC
Product: COC(=O)C1=C(C(=O)OC)C2C=CC1N2C(=O)OC(C)(C)C
Temperature: 120 °C
Yield: 50 %

Procedure:
Freshly distilled acetylenedicarboxylic acid dimethyl ester (6.7 mL, 54 mmol) and N-(tert-butyloxycarbonyl)-1H-pyrrole (9.0 mL, 54 mmol) were combined and heated at 120° C. for 3 h. Purification by flash chromatography on SiO2 eluting with EtOAc/CH2Cl2 gave 8.3 g (27 mmol, 50%) of compound 31A as a yellow solid.