Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH:9]2[C:13](=[O:14])[CH:12]([CH2:15][CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH2:11][C:10]2=[O:22])=[C:4]([CH3:23])[CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH:32]1(B(O)O)[CH2:34][CH2:33]1.C1(C)C=CC=CC=1>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.O.C(COC)OC>[CH:32]1([C:2]2[CH:7]=[C:6]([CH3:8])[C:5]([CH:9]3[C:13](=[O:14])[CH:12]([CH2:15][CH:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[CH2:11][C:10]3=[O:22])=[C:4]([CH3:23])[CH:3]=2)[CH2:34][CH2:33]1
Reactant: OB(O)C1CC1
Reactant: Cc1cc(Br)cc(C)c1C1C(=O)CC(CC2CCOCC2)C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: COCCOC
Product: Cc1cc(C2CC2)cc(C)c1C1C(=O)CC(CC2CCOCC2)C1=O
Temperature: 130 °C
Yield: 13.6 %

Procedure:
A mixture of 2-(4-bromo-2,6-dimethylphenyl)-4-(tetrahydropyran-4-ylmethyl)cyclopentane-1,3-dione (0.1 g, 0.26 mmol), potassium phosphate (0.11 g, 0.53 mmol), cyclopropyl boronic acid (0.09 g, 1.05 mmol) and tetrakis(triphenylphosphine)palladium (0) (0.06 g, 0.053 mmol), toluene (2 ml), dimethoxyethane (0.5 ml) and water (0.5 ml) is heated under microwave conditions at 130° C. for 22 minutes. The organic solvent is evaporated under vacuo, diluted with water and extracted with ethylacetate (3×25 ml). The combined organic extracts are combined, washed with water and brine, dried over anhydrous sodium sulphate, filtered and the filtrate is concentrated in vacuo. The residue is purified by column chromatography on silica gel followed by preparative HPLC to give 2-(4-cyclopropyl-2,6-dimethyl-phenyl)-4-(tetrahydropyran-4-ylmethyl)-cyclopentane-1,3-dione (0.012 g).
Reaction SMILES: [CH2:1]([C:4]1([C:13]([C:16]([OH:18])=O)([CH3:15])[CH3:14])[C:9](=[O:10])[NH:8][C:7](=[O:11])[NH:6][C:5]1=[O:12])[CH:2]=[CH2:3].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:31][CH2:32][CH2:33][CH2:34][NH2:35]>O1CCCC1>[CH2:1]([C:4]1([C:13]([C:16](=[O:18])[NH:31][CH2:32][CH2:33][CH2:34][NH2:35])([CH3:14])[CH3:15])[C:5](=[O:12])[NH:6][C:7](=[O:11])[NH:8][C:9]1=[O:10])[CH:2]=[CH2:3]
Reactant: C=CCC1(C(C)(C)C(=O)O)C(=O)NC(=O)NC1=O
Reactant: NCCCN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: C=CCC1(C(C)(C)C(=O)NCCCN)C(=O)NC(=O)NC1=O

Procedure:
5-Allyl-5-[1-(3-aminopropylcarbamoyl)-isopropyl]barbituric acid was prepared from 2.5 g. of 5-allyl-5-(1-carboxy-isopropyl)barbituric acid, 2 g. of 1,1'-carbonyldiimidazole, 100 ml. of tetrahydrofuran and 4 g. of 1,3-diaminopropane by the above procedure. The product melted at 202°-203°.
Reaction SMILES: C([O:4][CH2:5][C@@H:6]1[C@@H:13]2[C@@H:9]([O:10][C:11]([CH3:15])([CH3:14])[O:12]2)[C@H:8]([N:16]2[CH:24]=[N:23][C:22]3[C:17]2=[N:18][CH:19]=[N:20][C:21]=3I)[CH2:7]1)(=O)C.CCN(C(C)C)C(C)C.[C:35]1([C:41]#[CH:42])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.N>CN(C=O)C.C(Cl)Cl.CO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:14][C:11]1([CH3:15])[O:10][C@H:9]2[C@H:8]([N:16]3[CH:24]=[N:23][C:22]4[C:17]3=[N:18][CH:19]=[N:20][C:21]=4[C:42]#[C:41][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:7][C@H:6]([CH2:5][OH:4])[C@H:13]2[O:12]1
Reactant: C#Cc1ccccc1
Reactant: CC(=O)OC[C@H]1C[C@@H](n2cnc3c(I)ncnc32)[C@@H]2OC(C)(C)O[C@H]12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1(C)O[C@@H]2[C@@H](CO)C[C@@H](n3cnc4c(C#Cc5ccccc5)ncnc43)[C@@H]2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
A solution of [(3aR,4R,6R,6aS)-6-(6-iodo-9H-purin-9-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]methyl acetate (140.0 mg, 0.31 mmol), Pd(PPh3)2Cl2 (25 mg, 0.036 mmol), DIPEA (140 μL, 0.80 mmol), CuI (20 mg, 0.1 mmol) and phenylacetylene (170 μL, 1.5 mmol) in DMF (5.0 mL) under an atmosphere of nitrogen was stirred at room temperature for 20 minutes. The reaction was concentrated and the residue taken up in DCM (50 mL). This was washed with saturated aq EDTA.Na2 (2×10 mL) then water (10 mL). The organics were concentrated to provide a black gum. This crude product was dissolved in DCM (5 mL) and 7.0 M of ammonia in methanol (5.0 mL) was added. This was stirred at room temperature for 2 hours. The reaction was concentrated and the residue was purified by flash chromatography (0 to 100% EtOAc/DCM) to provide the title compound (75 mg, 63%).
Reaction SMILES: C([O:5][C:6](=[O:35])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH:14]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:27][CH:26]=2)[C:15](=[O:24])[NH:16][C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][CH:18]=2)=[CH:9][CH:8]=1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[C:31]([C:28]1[CH:27]=[CH:26][C:25]([CH:14]([NH:13][C:10]2[CH:9]=[CH:8][C:7]([C:6]([OH:35])=[O:5])=[CH:12][CH:11]=2)[C:15](=[O:24])[NH:16][C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][CH:18]=2)=[CH:30][CH:29]=1)([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)c1ccc(NC(C(=O)Nc2ccc(I)cc2)c2ccc(C(C)(C)C)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)c1ccc(C(Nc2ccc(C(=O)O)cc2)C(=O)Nc2ccc(I)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87 %

Procedure:
4-{[(4-tert-Butyl-phenyl)-(4-iodo-phenylcarbamoyl)-methyl]-amino}-benzoic acid tert-butyl ester (430 mg, 0.74 mmol) was taken up in 10 mL of dichloromethane followed by addition of 1 mL of TFA and stirred for 16 h at RT. Removal of the organic layer under reduced pressure followed by addition of water to the precipitate. The solids were filtered to give 340 mg (87%) of white solids. 1H NMR showed the compound to be very clean and sufficient for the following step. LCMS (M+1=529.6).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7](OC)=[O:8])=[CH:5][C:4]=1[F:13])#[N:2].[Cl-].[Cl-].[Ca+2].[BH4-].[Na+]>C1COCC1.C(O)C>[F:13][C:4]1[CH:5]=[C:6]([CH2:7][OH:8])[CH:11]=[CH:12][C:3]=1[C:1]#[N:2]
Reactant: COC(=O)c1ccc(C#N)c(F)c1
Agent: [BH4-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCO
Product: N#Cc1ccc(CO)cc1F
Reaction time: 1.25 h

Procedure:
A solution of Example 52A (1.0 g, 5.58 mmol) in THF (20 mL) at room temperature was treated with a solution of CaCl2 (1.24 g, 11.16 mmol) in ethanol (20 mL). The resulting solution was treated with NaBH4 (845 mg, 22.33 mmol) over 20 minutes, stirred for 1.25 hours, then slowly quenched with saturated ammonium chloride (100 mL), and concentrated. The remaining aqueous portion was extracted with ethyl acetate (3×100 mL) and the combined extracts were dried (MgSO4), filtered, and concentrated to provide the desired product. MS (APCI) m/z 169 (M+NH4)+; 1H NMR (300 MHz, CDCl3) δ 7.60 (t, 1H), 7.29-7.23 (m, 2H), 4.80 (s, 2H).
Reaction SMILES: [C:1]1([CH3:20])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([OH:19])=O)=[CH:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl.[C:29]([NH:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[NH2:43])([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>C(Cl)CCl.CN(C=O)C>[C:32]([O:31][C:29](=[O:30])[NH:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[NH:43][C:17](=[O:19])/[CH:16]=[CH:15]/[C:12]1[CH:13]=[CH:14][N:10]([S:7]([C:4]2[CH:3]=[CH:2][C:1]([CH3:20])=[CH:6][CH:5]=2)(=[O:8])=[O:9])[CH:11]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1N
Reactant: Cc1ccc(S(=O)(=O)n2ccc(/C=C/C(=O)O)c2)cc1
Agent: Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)n2ccc(/C=C/C(=O)Nc3ccccc3NC(=O)OC(C)(C)C)c2)cc1

Procedure:
Starting materials: (E)-3-[1-(toluene-4-sulfonyl)-1H-pyrrol-3yl]-acrylic acid (compound A1) (0.400 g), HOBtH2O (0.285 g), triethylamine (652 μl), DMF (25 ml), EDC?HCl (0.698 g), N—BOC-1,2-phenylenediamine (0.286 g). Reaction conditions: room temperature, 1 hour; room temperature, 2 hours.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:29])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7](/[CH:11]=[C:12]2/[CH2:13][C@@H:14]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=3)[C@@H:15]([CH2:18][N:19]([CH3:21])[CH3:20])[CH2:16][CH2:17]/2)[CH:6]=1>>[CH3:2][O:3][C:4](=[O:29])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7](/[CH:11]=[C:12]2\[CH2:13][C@@H:14]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=3)[C@@H:15]([CH2:18][N:19]([CH3:21])[CH3:20])[CH2:16][CH2:17]\2)[CH:6]=1
Reactant: COC(=O)c1cccc(/C=C2\CC[C@H](CN(C)C)[C@H](c3cccc(O)c3)C2)c1
Agent: Cl
Product: COC(=O)c1cccc(/C=C2/CC[C@H](CN(C)C)[C@H](c3cccc(O)c3)C2)c1

Procedure:
hydrochloride (51) and rac-cis-E-3-[4-dimethylaminomethyl-3-(3-hydroxy-phenyl)-cyclohexylidenmethyl]-benzoic acid methyl ester; hydrochloride (50)
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([NH2:35])=[N:23][C:24]([C:26]2[C:31]([NH2:32])=[N:30][C:29]([NH2:33])=[C:28]([Cl:34])[N:27]=2)=[O:25])=[CH:13][CH:12]=1)(C)(C)C.Cl.C(Cl)Cl.CO>CO>[NH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([NH:23][C:24]([C:26]2[C:31]([NH2:32])=[N:30][C:29]([NH2:33])=[C:28]([Cl:34])[N:27]=2)=[O:25])=[NH:35])=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)NCCOc1ccc(CCCCNC(N)=NC(=O)c2nc(Cl)c(N)nc2N)cc1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: N=C(NCCCCc1ccc(OCCN)cc1)NC(=O)c1nc(Cl)c(N)nc1N
Reaction time: 1 h
Yield: 125.9 %

Procedure:
[2-(4-{4-[N-(3,5-Diamino-6-chloropyrazine-2-carbonyl)guanidino]butyl}phenoxy)ethyl]-carbamic acid tert-butyl ester 3 (2.63 g, 5.0 mmol) was dissolved in methanol (25 mL). 12N HCl (30 mL) was added in 10 ml portions. After stirring for 1 h, the reaction was complete by TLC (silica gel, methylene chloride/methanol/concentrated ammonium hydroxide, 100:10:1). The solvent was evaporated and methanol (300 mL) was added and, this process was repeated. The residue was placed under high vacuum overnight to afford the product (2.65 g, 99%) as a yellow solid, which was used without further manipulation. 1H NMR (300 MHz, DMSO-d6) δ 1.58 (m, 4H), 2.57 (m, 2H), 3.16 (m, 2H), 3.37 (m, 2H), 4.18 (t, 2H), 6.91 (d, 2H), 7.15 (d, 2H), 7.45 (m, 4H), 8.45 (br s, 3H), 9.03 (br s, 2H), 9.46 (t, 1H), 10.63 (s, 1H).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:26]=[C:25]([O:27][CH2:28][C@H:29]([OH:34])[C@@H:30]([OH:33])[CH2:31][OH:32])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>CO.[Pd]>[OH:34][C@H:29]([C@@H:30]([OH:33])[CH2:31][OH:32])[CH2:28][O:27][C:25]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[C:17]([N:14]2[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]2)[N:26]=1
Reactant: O=C(OCc1ccccc1)N1CCN(c2nc(OC[C@H](O)[C@@H](O)CO)c3ccccc3n2)CC1
Agent: [Pd]
Solvent: CO
Product: OC[C@H](O)[C@@H](O)COc1nc(N2CCNCC2)nc2ccccc12
Temperature: 25 °C
Reaction time: 17 h
Yield: 74.7 %

Procedure:
2-[4-(Benzyloxycarbonyl)piperazin-1-yl]-4-[(2S,3S)-(2,3,4-trihydroxybutan-1-yl)oxy]quinazoline (1.5 g) is dissolved in methanol (30 ml), and thereto is added 10% palladium/carbon (0.15 g), and the mixture is stirred under hydrogen atmosphere and under atmospheric pressure at room temperature for 17 hours. The reaction mixture is filtered, and the filtrate is evaporated to dryness under reduced pressure to give 4-[(2S,3S)-(2,3,4-trihydroxybutan-1-yl)oxy]-2-(1-piperazinyl)quinazoline (0.8 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:33])=[C:14]([C:28]([O:30]CC)=O)[C:15](=[O:27])[N:16]3[CH2:19][C:20](=[O:26])[N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:34][NH2:35]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:33])=[C:14]([C:28]([NH:35][CH3:34])=[O:30])[C:15](=[O:27])[N:16]3[CH2:19][C:20](=[O:26])[N:21]3[CH2:22][CH2:23][CH2:24][CH2:25]3)=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N2CCCC2)c1=O
Reactant: CN
Product: CNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N2CCCC2)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[2-oxo-2-(1-pyrrolidinyl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and methylamine employing methods similar to those those described in Example 9 and was purified by reverse phase preparative HPLC (C-18 stationary phase;10-100% CH3CN/water/0.1% formic acid mobile phase). The product was obtained as a white solid: 1H NMR (CDCl3) δ 14.3 (1H, br), 9.94 (1H, m), 8.54 (1H, s), 7.14 (3H, m), 7.02 (2H, t, J=8.6 Hz), 4.86 (2H, s), 4.11 (2H, s), 3.51 (2H, t, J=7 Hz), 3.46 (2H, t, J=7 Hz), 2.99 (3H, d, J=5 Hz), 2.05 (2H, m, J=7 Hz), 1.89 (2H, m, J=7 Hz); HRMS calcd for C23H23FN4O4+H+: 439.1782. Found: 439.1794.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.C1C=CC2N(O)N=NC=2C=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH2:28][C:29](O)=[O:30])[CH:25]=[CH:26][CH:27]=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[Cl:21][C:22]1[CH:23]=[C:24]([CH2:28][C:29]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][N:6]=[CH:5]3)=[O:30])[CH:25]=[CH:26][CH:27]=1
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: O=C(O)Cc1cccc(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(Cc1cccc(Cl)c1)Nc1ccc2[nH]ncc2c1
Reaction time: 0.17 h

Procedure:
To a solution of 5-aminoindazole (1 mmol), HOBt (1 mmol) and 3-chlorophenylacetic acid (1.1 mmol) in DMF (4 mL) was added N-methylmorpholine (1.1 mmol). After stirring for 10 minutes, EDC-HCl (1.1 mmol) was added and the reaction mixture stirred overnight at ambient temperature. The reaction mixture was concentrated and the residue purified by reverse phase preparative HPLC [Waters Delta-Pak C18, 15 uM, 100A column, gradient 10%–100% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 10 minutes at 25 mL/min] to afford compound I-6 (79 mg, 42%). 1H NMR (400 MHz, DMSO-d6) δ 3.68 (2H, s), 7.12–7.73 (6H, m), 8.00 (1H, s), 8.11 (1H, s), 10.10 (1H, s), 12.97 (1H, bs); MS (ES+): m/e=(M+H) 286.
Reaction SMILES: [C:1]([OH:7])(=O)[CH2:2][CH2:3][CH2:4][CH3:5].C(Cl)(=O)C(Cl)=O.[CH:14]([C@H:17]1[CH2:21][O:20][C:19](=[O:22])[NH:18]1)([CH3:16])[CH3:15].[Li]CCCC>C(Cl)Cl.CN(C=O)C.C1COCC1>[CH:14]([C@H:17]1[CH2:21][O:20][C:19](=[O:22])[N:18]1[C:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH3:5])([CH3:16])[CH3:15]
Reactant: CC(C)[C@H]1COC(=O)N1
Reactant: CCCCC(=O)O
Agent: O=C(Cl)C(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCC(=O)N1C(=O)OC[C@@H]1C(C)C
Temperature: 25 °C
Reaction time: 2.75 h

Procedure:
To a stirred solution of pentanoic acid (5.98 g, 58.6 mmol) in CH2Cl2 (100 mL) and 10 drops DMF was added oxalyl chloride (5.64 mL, 64.4 mmol) dropwise over 5 min and the solution stirred for 2.75 h, at which time all bubbling subsided. The solution was concentrated in vacuo. In a separate flask, to a cold (−78° C.), stirred solution of (S)-4-isopropyloxazolidin-2-one (7.56 g, 58.6 mmol) in THF (280 mL) was added n-BuLi (2.5M in hexane, 23.42 mL, 58.6 mmol) dropwise via addition funnel over 20 min (temperature never exceeded −68° C.). After stirring 10 min, the above acid chloride dissolved in THF (50 mL) was added via addition funnel over 25 min. After the addition was complete, the reaction mixture was allowed to warm to room temperature as bath warmed and stirred overnight. The reaction was quenched with water and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated to an amber oil. The residue was purified by flash chromatography (Teledyne ISCO CombiFlash Rf, 0% to 60% solvent A/B=hex/EtOAc, REDISEP® SiO2 120 g, applied as a DCM solution) to give Preparation 4A (6.51 g, 52%) as a colorless oil: 1H NMR (400 MHz, chloroform-d) δ ppm 4.44 (1H, ddd, J=8.16, 3.51, 3.39 Hz), 4.27 (1H, t, J=9.00 Hz), 4.21 (1H, dd, J=9.00, 3.01 Hz), 2.99 (1H, ddd, J=16.60, 8.50, 6.50 Hz), 2.86 (1H, ddd, J=16.60, 8.50, 6.78 Hz), 2.31-2.44 (1H, m), 1.56-1.72 (2H, m), 1.39 (2H, sxt, J=7.43 Hz), 0.94 (3H, t, J=7.28 Hz), 0.92 (3H, d, J=7.03 Hz), 0.88 (3H, d, J=6.78 Hz); HPLC: RT=2.497 min (CHROMOLITH® SpeedROD 4.6×50 mm (4 min grad) eluting with MeOH/H2O/0.1% TFA, 4 mL/min, monitoring at 220 nm).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH2:16])[CH3:15])[N:5]=[C:4]([CH3:17])[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[OH:23][CH2:24][CH2:25][O:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[C:30](O)=[O:31]>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH:16][C:30](=[O:31])[C:29]2[CH:33]=[CH:34][C:35]([O:36][CH3:37])=[C:27]([O:26][CH2:25][CH2:24][OH:23])[CH:28]=2)[CH3:15])[N:5]=[C:4]([CH3:17])[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)c1c(C)nc2cccc(OC[C@H](C)N)c2c1N
Reactant: COc1ccc(C(=O)O)cc1OCCO
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@H](C)NC(=O)c3ccc(OC)c(OCCO)c3)c2c1N

Procedure:
Prepared as in Example 24a from (S)-ethyl 4-amino-5-(2-aminopropoxy)-2-methylquinoline-3-carboxylate (Example 26b) and 3-(2-hydroxyethoxy)-4-methoxybenzoic acid as a brown solid. MS 498 (MH+).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.[N+]([O-])(O)=O.[O:13]([CH2:17][CH2:18][NH2:19])[N+:14]([O-:16])=[O:15].C(OC(C)C)(C)C>>[O:13]([CH2:17][CH2:18][NH:19][C:6]([C:3]1[CH:4]=[CH:5][O:1][CH:2]=1)=[O:8])[N+:14]([O-:16])=[O:15]
Reactant: NCCO[N+](=O)[O-]
Reactant: O=C(O)c1ccoc1
Solvent: CC(C)OC(C)C
Solvent: O=[N+]([O-])O
Product: O=C(NCCO[N+](=O)[O-])c1ccoc1
Yield: 42.2 %

Procedure:
Following a similar treatment to that in Example 2 and using 0.48 g of 3-furancarboxylic acid and 0.60 g of nitroxyethylamine nitrate, 0.30 g of the title compound was obtained as colorless plates (solvent for recrystallization; diisopropyl ether).
Reaction SMILES: C([N:20]1[CH2:25][CH2:24][CH:23]2[S:26][C:27](=[O:29])[CH:28]=[C:22]2[CH2:21]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1>[S:26]1[CH:23]2[C:22]([CH2:21][NH:20][CH2:25][CH2:24]2)=[CH:28][C:27]1=[O:29]
Reactant: O=C1C=C2CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CCC2S1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Product: O=C1C=C2CNCCC2S1
Temperature: 50 °C
Reaction time: 2 h
Yield: 204.9 %

Procedure:
A mixture of 2.85 g of 5-trityl-5,6,7,7a-tetrahydro-4H-thieno [3,2-c]pyridin-2-one (see Japanese Provisional Patent Publication No. 246148/1986), 1.36 g of p-toluenesulfonic acid monohydrate and 50 ml of tetrahydrofuran was stirred at 50° C. for 2 hours. The precipitated solid was filtered, washed with 10 ml of tetrahydrofuran and then dried to obtain 2.28 g of 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]-pyridin-2one.p-toluenesulfonate (yield based on 5-trityl-5,6,7,7a-tetrahydro-4H-thieno[3,2-c]pyridin-2-one: 93%).
Reaction SMILES: [C:1]1([CH3:38])[CH:6]=[CH:5][C:4]([S:7]([NH:10][C:11](=[O:37])[CH:12]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][N:25]3[C:29]([CH:30]=[O:31])=[C:28]([Cl:32])[N:27]=[C:26]3[CH2:33][CH2:34][CH2:35][CH3:36])=[CH:20][CH:19]=2)[CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[Mn]([O-])(=O)(=O)=[O:40].C([N+](CCCC)(CCCC)CCCC)CCC>N1C=CC=CC=1>[C:1]1([CH3:38])[CH:2]=[CH:3][C:4]([S:7]([NH:10][C:11](=[O:37])[CH:12]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][N:25]3[C:29]([C:30]([OH:40])=[O:31])=[C:28]([Cl:32])[N:27]=[C:26]3[CH2:33][CH2:34][CH2:35][CH3:36])=[CH:20][CH:19]=2)[CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)(=[O:9])=[O:8])=[CH:5][CH:6]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(C(C(=O)NS(=O)(=O)c2ccc(C)cc2)C2CCCC2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: c1ccncc1
Product: CCCCc1nc(Cl)c(C(=O)O)n1Cc1ccc(C(C(=O)NS(=O)(=O)c2ccc(C)cc2)C2CCCC2)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
250 mg (0.45 mmol) of the compound from Example III are dissolved in 2.5 ml (0.45 mmol) of pyridine and 162 mg of tetrabutylammonium permanganate, dissolved in 1.5 ml of pyridine, are added at 60° C., and the mixture is stirred at 60° C. for 2 h. The pyridine is evaporated, and the residue is taken up in water, acidified with dilute HCl and extracted with ethyl acetate. The organic phase is concentrated and the residue is chromatographed on silica gel 60 using CH2Cl2 /MeOH (10:1).
Reaction SMILES: Br[C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[CH3:7].C([Li])CCC.[B:14](OC(C)C)([O:19]C(C)C)[O:15]C(C)C>C1COCC1>[CH3:8][C:3]1[C:2]([B:14]([OH:19])[OH:15])=[C:6]([CH3:7])[O:5][N:4]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cc1noc(C)c1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1noc(C)c1B(O)O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 12.5 %

Procedure:
To a 500 mL three RB flask fitted with magnetic stirrer was charged 4-bromo-3,5-dimethyl-1,2-oxazole (4.0 g, 22.7 mmol) in THF (40 mL), cooled −78° C. To the stirred solvent was added n-butyl lithium (28.4 mL, 1.6M solution, 45.0 mmol) drop wise and stirred at −65° C. about 30 minutes. The RM was brought to −78° C., was added tri-isopropyl borate (12.81 g, 68.0 mmol), once the temperature to reached room temperature and stirred about 16 h. Then removed the solvent under reduced pressure and quenched with saturated NH4Cl solution and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous Na2SO4 and removed the solvent under reduced pressure. The obtained crude material was purified by silica gel column chromatography to obtain white solid. (0.4 g, yield: 12.5%).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[N:14]=[CH:13][C:12]([N+:18]([O-])=O)=[CH:11][C:10]=2[CH2:9]1)=O)(C)(C)C>CCO.[Pd]>[N:14]1[C:15]2[C:10](=[CH:9][N:8]=[CH:17][CH:16]=2)[CH:11]=[C:12]([NH2:18])[CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ncc([N+](=O)[O-])cc2C1
Agent: [Pd]
Solvent: CCO
Product: Nc1cnc2ccncc2c1
Temperature: 170 °C

Procedure:
3-Nitro-7,8-dihydro-5H-[1,6]naphthyridine-6-carboxylic acid tert-butyl ester (1.0 g, 3.6 mmol), was added to EtOH (10 mL) in a sealed tube. 10% Pd/C (500 mg) was added and the mixture was heated to 170° C. for 16 h. The reaction mixture was cooled to RT, diluted with EtOH (10 mL), and filtered through Celite®. The solvent was removed under reduced pressure affording [1,6]naphthyridin-3-ylamine as yellow solid.
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])=[O:11])=[CH:6][CH:5]=1.[P:20]([O:27]CC)([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23]>>[CH2:22]([O:21][PH:20](=[O:27])[O:24][CH2:25][CH3:26])[CH3:23].[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])=[O:11])=[CH:8][CH:9]=1
Reactant: CCOP(OCC)OCC
Agent: COc1ccc(C(=O)C(=O)c2ccccc2)cc1
Agent: [Cl-]
Product: CCO[PH](=O)OCC

Procedure:
156.6 parts of 4-methoxy benzil chloride and 332.0 parts of triethyl phosphite are reacted at 150° C. for 5 hours.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[Cl:9][C:10]1[N:19]=[CH:18][C:17]2[C:12](=[C:13]([OH:20])[CH:14]=[CH:15][CH:16]=2)[N:11]=1>CN1C(=O)CCC1.C(OCC)(=O)C>[Br:8][C:16]1[CH:15]=[CH:14][C:13]([OH:20])=[C:12]2[C:17]=1[CH:18]=[N:19][C:10]([Cl:9])=[N:11]2
Reactant: O=C1CCC(=O)N1Br
Reactant: Oc1cccc2cnc(Cl)nc12
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Oc1ccc(Br)c2cnc(Cl)nc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
Solid NBS (1 eq) was added to a stirred solution of 2-chloroquinazolin-8-ol (1 eq) (See example 1 for synthesis) in NMP at 0° C. under argon. After stirring at 0° C. for 30 min, LCMS showed that the reaction was complete. The formation of both 5-bromo (Major) and 7-bromo (Minor) isomers along with 5,7 dibromo product was observed. The reaction mixture was diluted with ethyl acetate and washed with satd. sodium bicarbonate, water and brine. Dried, filtered and concentrated. The crude was purified by flash chromatography (3-5% EtOAc/Hexane) to provide 5-bromo-2-chloroquinazolin-8-ol as a white solid in 60% yield. ES/MS m/z 259.2 (MH+).