Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[N:15]2[C:16](=[O:22])[NH:17][C:18]3=[CH:19][CH:20]=[CH:21][C:13](=[C:14]23)[O:12][CH2:11]1.C(O)(=O)C.C(#N)C>C(OCC)(=O)C>[Br:1][C:21]1[C:13]2[O:12][CH2:11][C:10]([CH3:9])([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[N:15]3[C:16](=[O:22])[NH:17][C:18]([C:14]=23)=[CH:19][CH:20]=1
Reactant: CC1(c2ccccn2)COc2cccc3[nH]c(=O)n1c23
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CC#N
Product: CC1(c2ccccn2)COc2c(Br)ccc3[nH]c(=O)n1c23
Temperature: 0 °C
Reaction time: 1 h

Procedure:
N-Bromosuccinimide (60 mg, 0.3 mmol) was added to a solution of 4-methyl-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one (90 mg, 0.3 mmol), acetic acid (6 mL) and acetonitrile (6 mL) at 0° C. The reaction mixture was stirred for 1 h at 0° C., quenched with water, and was concentrated to give the crude product. The crude product was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate. The combined organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated to give a dark oil. The product was purified by FCC on silica gel eluting a hexane:ethyl acetate gradient containing 20% ethanol to give 7-bromo-4-methyl-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one as an off white solid (0.090 g. 80%). LCMS calculated for C15H13BrN3O2 (M+H)+: m/z=346.1, 348.1. found: 345.9, 347.9.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[O:5][C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]([NH2:13])[C:7]=1[NH2:14].[N:19]([O-])=O.[Na+]>C(O)(=O)C.O.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[O:5][C:6]1[C:7]2[N:14]=[N:19][NH:13][C:8]=2[CH:9]=[CH:10][C:11]=1[Cl:12]
Reactant: O=N[O-]
Reactant: Nc1ccc(Cl)c(Oc2cc(Cl)cc(Br)c2)c1N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: Clc1cc(Br)cc(Oc2c(Cl)ccc3[nH]nnc23)c1
Reaction time: 1.5 h

Procedure:
3-(3-bromo-5-chlorophenoxy)-4-chlorobenzene-1,2-diamine (4.97 g, 14.3 mmol) in acetic acid (25 mL) was cooled to 15° C. under N2 and sodium nitrite (1.08 g, 15.7 mmol) in water (39.3 mL) was added dropwise. After 1.5 hours, the reaction was diluted with EtOAc (300 mL), and the organic phase was separated and washed with water (3×100 mL). The organic phase was then dried (MgSO4), filtered, concentrated to afford the title product. LRMS (M+1) 359.7.
Reaction SMILES: CN(C)C=O.CS([O:10][CH2:11][CH2:12][C:13]([CH3:17])=[C:14]([F:16])[F:15])(=O)=O.[S:18]1[C:22]([C:23](O)=[O:24])=[CH:21][C:20]2[CH:26]=[CH:27][CH:28]=[CH:29][C:19]1=2.C(=O)([O-])O.[Na+]>O>[S:18]1[C:22]([C:23]([O:10][CH2:11][CH2:12][C:13]([CH3:17])=[C:14]([F:15])[F:16])=[O:24])=[CH:21][C:20]2[CH:26]=[CH:27][CH:28]=[CH:29][C:19]1=2
Reactant: CC(CCOS(C)(=O)=O)=C(F)F
Reactant: O=C(O)c1cc2ccccc2s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(CCOC(=O)c1cc2ccccc2s1)=C(F)F
Temperature: 100 °C
Reaction time: 2 h
Yield: 94.5 %

Procedure:
To 5 ml of N,N-dimethylformamide were dissolved 0.40 g (1.8 mmol) of 4,4-difluoro-3-methyl-3-butenyl methanesulfonate and 0.33 g (1.9 mmol) of benzo[b]thiophene-2-carboxylicacid, followed by the addition of 0.46 g (5.5 mmol) of sodium hydrogencarbonate and stirring at 100° C. for 2 hours. The reaction liquid was then poured in water and extracted with diethyl ether. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentrating under reduced pressure. The residue was purified with silica gel column chromatography (diisopropyl ether:hexane=1:7) to obtain 0.48 g (yield: 93%) of 4,4-difluoro-3-methyl-3-butenyl benzo[b]thiophene-2-carboxylate.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([F:24])=[C:7]([N:9]([CH2:18][C:19]2[CH:23]=[CH:22][NH:21][N:20]=2)[C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[CH:8]=1)[CH3:2].N1C=CC=CC=1.[C:31]1(B(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([F:24])=[C:7]([N:9]([CH2:18][C:19]2[CH:23]=[CH:22][N:21]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:20]=2)[C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[CH:8]=1)[CH3:2]
Reactant: CCc1ccc(F)c(N(Cc2cc[nH]n2)c2ccc(C#N)cc2)c1
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCc1ccc(F)c(N(Cc2ccn(-c3ccccc3)n2)c2ccc(C#N)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.4 %

Procedure:
To a mixture of Intermediate 264.1 (40 mg, 0.125 mmol), 4 A molecular sieves, TEA (70 uL, 0.25 mmol), pyridine (20 mg, 0.25 mmol), phenyl boronic acid (31 mg, 0.25 mmol) in CH2Cl2 was added Cu(OAc)2 (34 mg, 0.19 mmol). The reaction mixture was stirred at rt for 2 h, which was then diluted with EtOAc and washed with 0.5 N HCl, H2O, sat NaHCO3 and brine, dried over (Na2SO4), filtered and concentrated. The crude product was purified by flash chromatography (0 to 50% EtOAc/hexanes, gradient) to afford 20 mg (45%) of Intermediate 264.2.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=O.[CH2:9]([NH2:12])[CH2:10][CH3:11].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C.ClCCCl>[CH2:9]([NH:12][CH:2]([CH2:3][CH3:5])[C:1]([O:7][CH3:8])=[O:6])[CH2:10][CH3:11]
Reactant: COC(=O)CC(C)=O
Reactant: CCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Product: CCCNC(CC)C(=O)OC
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of 6 g of methyl acetoacetate, 5 mL of 1-propylamine, 40 mL of 1,2-dichloroethane, 3 mL of glacial acetic acid and 16 g of sodium triacetoxyborohydride was stirred at room temperature for 4 days. The reaction mixture was poured into 200 mL chloroform and 50 mL saturated aqueous Na2CO3 and the layers separated. The aqueous layer was extracted with 200 mL of chloroform and the combined organic layers dried over MgSO4 and concentrated under reduced pressure. After drying under vacuum, 9 g of (±)-methyl 2-(1-propylamino)butyrate was obtained as an oil: TLC (EtOAc); 1H NMR (400 MHz, CDCl3) 6.2 (br s, 1H), 3.65 (s, 3H), 3.2 (complex m, 2H), 2.65 (complex m, 2H), 2.45 (dd, 1H), 1.55 (m, 2H), 1.4 (d, 3H), 0.95 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:18][CH2:19][CH3:20]>CN(C)C=O.O>[Cl:1][C:2]1[C:3]2[N:10]([CH2:18][CH2:19][CH3:20])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CCCBr
Reactant: Clc1ncnc2cc[nH]c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCn1ccc2ncnc(Cl)c21
Temperature: 25 °C
Yield: 84.2 %

Procedure:
To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (150 mg) in N,N-dimethylformamide (1.6 mL) was added cesium carbonate (798 mg) under ice-cooling, and the mixture was stirred while warming to room temperature for 15 min. To the reaction mixture was added 1-bromopropane (301 mg), and the mixture was stirred at room temperature for 15 hrs. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL×3). The organic layer was washed with saturated brine (30 mL×3) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (silica gel, eluent:hexane/ethyl acetate=90/10→20/80). The object fraction was concentrated under reduced pressure and dried to give the title compound (161 mg) as a white solid.
Reaction SMILES: [Na].[CH:2]([C:5]1[CH:6]=[N:7][NH:8][C:9]=1[NH2:10])([CH3:4])[CH3:3].[C:11](OCC)(=[O:18])[CH2:12][C:13](OCC)=[O:14]>CCO>[CH:2]([C:5]1[CH:6]=[N:7][N:8]2[C:13]([OH:14])=[CH:12][C:11]([OH:18])=[N:10][C:9]=12)([CH3:4])[CH3:3]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(C)c1cn[nH]c1N
Agent: [Na]
Solvent: CCO
Product: CC(C)c1cnn2c(O)cc(O)nc12
Temperature: 25 °C

Procedure:
Sodium (1.58 g, 68.7 mmol) was dissolved in EtOH (250 mL) and to this solution was added 4-isopropyl-1H-pyrazol-5-amine (7.17 g, 57 mmol) and diethyl malonate (10.2 mL, 63 mmol). The solution was heated under reflux for 16 h, cooled to rt and concentrated in vacuo. The residue was dissolved in water (60 mL) and acidified to pH=3 with 2 M HCl and the formed precipitate collected by filtration. 3-Isopropyl-5,7-dihydroxypyrazolo[1,5-α]pyrimidine was obtained as an off-white solid (8.10 g, 35% over three steps). M.p. 242-243° C. (ethanol).
Reaction SMILES: I[C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7]([O:19][CH:20]([C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)[C:21]([F:24])([F:23])[F:22])[C:8]([NH:12][S:13]([CH2:16][CH2:17][CH3:18])(=[O:15])=[O:14])=[N:9]2)=[CH:4][CH:3]=1.C[Si]([C:35]#[CH:36])(C)C.C(N(CC)CC)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CN(C=O)C.[Cu](I)I.O>[C:35]([C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7]([O:19][CH:20]([C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)[C:21]([F:24])([F:22])[F:23])[C:8]([NH:12][S:13]([CH2:16][CH2:17][CH3:18])(=[O:14])=[O:15])=[N:9]2)=[CH:4][CH:3]=1)#[CH:36]
Reactant: C#C[Si](C)(C)C
Reactant: CCCS(=O)(=O)Nc1nc2cc(I)ccc2nc1OC(c1cccnc1)C(F)(F)F
Agent: I[Cu]I
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: C#Cc1ccc2nc(OC(c3cccnc3)C(F)(F)F)c(NS(=O)(=O)CCC)nc2c1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 44.9 %

Procedure:
Compound 77 (70.0 mg, 0.127 mmol) obtained in Example 74 was dissolved in DMF (2.00 mL). To the solution were added trimethylsilylacetylene (0.089 mL, 0.634 mmol), triethylamine (0.088 mL, 0.634 mmol), copper iodide (I) (9.66 mg, 0.051 mmol), and tetrakis (triphenylphosphine)palladium (29.3 mg, 0.025 mmol), and the mixture was stirred at 120° C. for 30 minutes. Water was added to the reaction mixture and the mixture was filtered through Celite. The filtrate was extracted with ethyl acetate. Washing with saturated brine and drying over anhydrous magnesium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/0 to 2/3). The obtained purified product was dissolved in THF (1.80 mL). Tetrabutylammonium fluoride (1.0 mol/L solution in THF, 0.107 mL, 0.107 mmol) was added and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture. Extraction with ethyl acetate, washing with saturated brine and drying over anhydrous magnesium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/0 to 1/1) to give Compound 79 (25.7 mg, 46% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](O)=[O:8].C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.Cl.[CH3:25][NH:26][O:27][CH3:28]>C1COCC1.O>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([N:26]([O:27][CH3:28])[CH3:25])=[O:8]
Reactant: O=C(O)c1cncc(Br)c1
Reactant: CNOC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CON(C)C(=O)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
40 g (198 mmol) of 5-bromonicotinic acid are dissolved in 300 mL of THF and treated with 19 mL of oxalyl chloride at 0° C. 66 mL (475 mmol) of triethylamine are then added, followed by 23.2 g (237 mmol) of N,O-dimethylhydroxylamine hydrochloride. After stirring at room temperature for 4 hours, the reaction medium is poured into water and extracted with ethyl acetate. The organic phase is separated out after settling, dried over magnesium sulphate and evaporated. 45.1 g (93%) of the expected product are collected in the form of a light brown oil.
Reaction SMILES: C([O:3][C:4](=[O:23])[CH:5]([C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][C:12]=1[N+:20]([O-:22])=[O:21])C(OCC)=O)C.C(OCC)(=O)CC(OCC)=O>Cl.O1CCOCC1>[C:17]([C:14]1[CH:15]=[CH:16][C:11]([CH2:5][C:4]([OH:23])=[O:3])=[C:12]([N+:20]([O-:22])=[O:21])[CH:13]=1)(=[O:19])[CH3:18]
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(C(C)=O)cc1[N+](=O)[O-]
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(=O)CC(=O)OCC
Product: CC(=O)c1ccc(CC(=O)O)c([N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of diethyl(4-acetyl-2-nitrophenyl)malonate and diethyl malonate (54.1 g) prepared by step a) was dissolved in 4M HCl (800 mL)/dioxane (800 mL), and the solution was stirred at 100° C. for 8 hours. After cooling, dioxane was removed in vacuo, and the aqueous layer was extracted with chloroform (200 mL×1, 100 mL×2). The organic layers were combined, dried over magnesium sulfate, filtered, and the solvent was removed in vacuo to give the object compound (23.1 g, quantitatively) as a brown solid.
Reaction SMILES: Cl[C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[CH3:19][C:20]1[CH:33]=[CH:32][C:23]([C:24]([NH:26][N:27]2[NH:31][CH:30]=[CH:29][S:28]2)=[O:25])=[CH:22][C:21]=1B1OC(C)(C)C(C)(C)O1>>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:17]=[CH:18][C:2]([C:21]3[CH:22]=[C:23]([C:24](=[O:25])[NH:26][N:27]4[NH:31][CH:30]=[CH:29][S:28]4)[CH:32]=[CH:33][C:20]=3[CH3:19])=[N:3][CH:4]=2)=[CH:10][CH:11]=1
Reactant: COc1ccc(NC(=O)c2ccc(Cl)nc2)cc1
Reactant: Cc1ccc(C(=O)NN2NC=CS2)cc1B1OC(C)(C)C(C)(C)O1
Product: COc1ccc(NC(=O)c2ccc(-c3cc(C(=O)NN4NC=CS4)ccc3C)nc2)cc1

Procedure:
N-(4-Methoxyphenyl)-6-[2-methyl-5-(thiadiazol-2-ylcarbamoyl)-phenyl]-nicotinamide was prepared from 6-chloro-N-(4-methoxyphenyl)nicotinamide (Intermediate 2) and 4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-N-(thiadiazol-2-yl)-benzamide (Intermediate 12) using General Method B. LCMS: retention time 3.05 min, MH+446. NMR: δH [2H6]-DMSO 13.15, (1H, b), 10.41, (1H, s), 9.24, (2H, m), 8.45, (1H, dd), 8.28, (1H, s), 8.11, (1H, d), 7.88, (1H, d), 7.71, (2H, d), 7.56, (1H, d), 6.97, (2H, d), 3.76, (3H, s), 2.48, (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:5][CH:4]=1.Cl[CH2:24][C:25]1[CH:30]=[CH:29][N:28]=[C:27]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=2)[CH:26]=1>>[C:19]([O:18][C:16]([N:13]1[CH2:14][CH2:15][CH:10]([N:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:24][C:25]2[CH:30]=[CH:29][N:28]=[C:27]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=3)[CH:26]=2)[CH2:11][CH2:12]1)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: COc1cccc(-c2cc(CCl)ccn2)c1
Reactant: COc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Product: COc1ccc(N(Cc2ccnc(-c3cccc(OC)c3)c2)C2CCN(C(=O)OC(C)(C)C)CC2)cc1

Procedure:
4-(p-Anisidino)-1-(tert-butoxycarbonyl)piperidine (306 mg) and 4-chloromethyl-2-(3-methoxyphenyl)pyridine (234 mg) were condensed in the same manner as described in Example 9 to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[O:11][CH:12]=[C:13]([CH2:15]Cl)[N:14]=2)=[C:4]([F:17])[CH:3]=1.[CH3:18][S:19]([CH2:22][C:23]1[N:24]([CH2:28][CH2:29][CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=2)[CH:25]=[CH:26][N:27]=1)(=[O:21])=[O:20].[H-].[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[O:11][CH:12]=[C:13]([CH2:15][O:38][C:35]3[CH:34]=[CH:33][C:32]([CH2:31][CH2:30][CH2:29][CH2:28][N:24]4[CH:25]=[CH:26][N:27]=[C:23]4[CH2:22][S:19]([CH3:18])(=[O:21])=[O:20])=[CH:37][CH:36]=3)[N:14]=2)=[C:4]([F:17])[CH:3]=1
Reactant: Fc1cc(Br)ccc1/C=C/c1nc(CCl)co1
Reactant: CS(=O)(=O)Cc1nccn1CCCCc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Product: CS(=O)(=O)Cc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(Br)cc3F)n2)cc1
Yield: 65.6 %

Procedure:
Using 2-[(E)-2-(4-bromo-2-fluorophenyl)ethenyl]-4-(chloromethyl)-1,3-oxazole (282 mg), 4-[4-[2-[(methylsulfonyl)methyl]-1H-imidazol-1-yl]butyl]phenol (250 mg) and 65% sodium hydride (32.9 mg), the same reaction as Example 11-(i) was carried out to yield the titled compound (313 mg) as a colorless crystal powder.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)[CH3:2].[C:13](Cl)(=[O:23])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].CCN(CC)CC>C(Cl)Cl.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:13](=[O:23])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CCCCCCCCCC(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCC(=O)Nc1ccc(C(=O)OCC)cc1

Procedure:
(Scheme 3, Compound H) To a solution of 4-amino-benzoic acid ethyl ester (2.0 g, 12.1 mmol) and decanoyl chloride (2.35 g, 13.3 mmol) in methylene chloride (20 mL) was added Et3N (1.34 g, 13.3 mmol). The resultant mixture was stirred at room temperature for one hour and then was diluted with EtOAc, washed by H2O, dried over MgSO4. After filtration and concentration in vacuo, the product was directly used in the next step.
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([C:12]([OH:14])=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][O:16][C:17](=[O:28])[CH:18]=[CH:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[C:22]([NH2:27])[CH:21]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH3:15][O:16][C:17](=[O:28])[CH:18]=[CH:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[C:22]([NH:27][C:12]([C:10]2[O:11][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][CH:9]=2)=[O:14])[CH:21]=1
Reactant: COC(=O)C=Cc1ccc(F)c(N)c1
Reactant: O=C(O)c1ccc(-c2ccccc2)o1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C=Cc1ccc(F)c(NC(=O)c2ccc(-c3ccccc3)o2)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
5-phenyl-2-furoic acid (36) (18 mg, 0.15 mmol) was coupled to aniline (43) (30 mg, 0.15 mmol) using Method B, except that DIPEA (40 mg, 0.31 mmol) and DMF (2 mL) were used and the reaction was stirred at ambient temperature for 2.5 hours, then at 40° C. for 24 hours. Further TBTU (1 eq) and acid (1 eq) were added and the reaction heated at 60° C. for a further 6 hours to give the crude title compound after work-up. The residue was purified using column chromatography eluting with 20% EtOAc in heptane to give the title compound. Yield: 18 mg, 32%; LC-MS tr 1.55 min; HPLC Purity: 83%; MS (ES+) m/z 366 (M+H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([C:14]([OH:16])=O)[NH:12][C:11](=[O:17])[C:10]3[S:18][C:19]([C:21]4[CH:26]=[CH:25][N:24]=[C:23]([CH3:27])[CH:22]=4)=[CH:20][C:9]2=3)=[CH:4][CH:3]=1.[CH3:28][N:29](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C)C=O.CN.O1CCCC1.C(N(CC)C(C)C)(C)C>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@H:13]([C:14]([NH:29][CH3:28])=[O:16])[NH:12][C:11](=[O:17])[C:10]3[S:18][C:19]([C:21]4[CH:26]=[CH:25][N:24]=[C:23]([CH3:27])[CH:22]=4)=[CH:20][C:9]2=3)=[CH:6][CH:7]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1cc(-c2cc3c(s2)C(=O)N[C@@H](C(=O)O)[C@@H]3c2ccc(Cl)cc2)ccn1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)[C@@H]1NC(=O)c2sc(-c3ccnc(C)c3)cc2[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.6 %

Procedure:
To a mixture of rel-(4R,5R)-4-(4-chlorophenyl)-2-(2-methylpyridin-4-yl)-7-oxo-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-5-carboxylic acid (326.0 mg, 0.817 mmol) and HATU (435.1 mg, 1.144 mmol) in N,N-dimethylformamide (4.28 mL, 55.3 mmol) were added methylamine as a 2M solution in tetrahydrofuran (1.64 mL, 3.27 mmol) followed by N,N-diisopropylethylamine (0.427 mL, 2.45 mmol). The mixture was stirred at rt for 16 hr. The mixture was diluted with water (4 mL) and the precipitate was filtered. The aqueous solution was extracted with DCM (3×6 mL). The solid cake and DCM layers were combined and washed with water (3 mL) and brine (3 mL), dried over sodium sulfate, and evaporated. The obtained residue purified by preparative HPLC to give the title compound as a white solid (140 mg) then the racemic mixture was separated by chiral preparative HPLC to give 30.6 mg (9.0% yield) as a white solid for peak 1. LCMS: (FA) ES+ , 412/414. 1H NMR (400 MHz, DMSO) δ 8.46 (d, J=5.3 Hz, 1H), 8.16 (d, J=4.4 Hz, 1H), 7.94 (d, J=4.2 Hz, 1H), 7.62 (s, 1H), 7.55 (s, 1H), 7.49-7.37 (m, 3H), 7.25 (d, J=8.5 Hz, 2H), 4.66 (d, J=1.6 Hz, 1H), 4.14 (dd, J=4.2, 2.3 Hz, 1H), 2.59 (d, J=4.5 Hz, 3H). 37.0 mg (11% yield) as a white solid for peak 2. LCMS: (FA) ES+ , 412. 1H NMR (400 MHz, DMSO) δ 8.46 (d, J=5.2 Hz, 1H), 8.16 (d, J=4.4 Hz, 1H), 7.95 (d, J=4.3 Hz, 1H), 7.62 (s, 1H), 7.55 (s, 1H), 7.50-7.35 (m, 3H), 7.25 (d, J=8.5 Hz, 2H), 4.66 (d, J=1.8 Hz, 1H), 4.14 (dd, J=4.3, 2.3 Hz, 1H), 2.59 (d, J=4.5 Hz, 3H).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([CH:12]([C:18](OCC)=[O:19])[C:13](OCC)=[O:14])[CH2:8][CH2:9][CH2:10][CH3:11].Cl>C1COCC1>[CH2:7]([CH:12]([CH2:18][OH:19])[CH2:13][OH:14])[CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCC(C(=O)OCC)C(=O)OCC
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CCCCCC(CO)CO
Temperature: 25 °C
Yield: 75.4 %

Procedure:
34 g (0.9 mol) of LiAlH4 was dispersed in 690 cm3 of anhydrous THF, and 159 g (0.69 mol) of diethyl pentylmalonate was added dropwise under stirring. After the dropping was completed, it was refluxed for 2 hours in a hot water bath, and after cooling to room temperature, the excess LiAlH4 was decomposed by dropwise addition of THF including 10% water. 500 cm3 of concentrated hydrochloric acid was added, it was extracted with chloroform and washed in 10% HC1 and water. The chloroform was removed, and the remaining oily substance was distilled under reduced pressure (b. p. 110° C./4 mmHg) to obtain 76 g (0.52 mol) of 2-pentylpropane-1,3diol).
Reaction SMILES: C([Li])CCC.[CH3:6][CH:7]1[S:12][CH2:11][CH2:10][CH2:9][S:8]1.[CH:13](=[O:17])[CH2:14][CH2:15][CH3:16].O>CCCCCC.O1CCCC1>[OH:17][CH:13]([C:7]1([CH3:6])[S:12][CH2:11][CH2:10][CH2:9][S:8]1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCC=O
Reactant: CC1SCCCS1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC(O)C1(C)SCCCS1
Temperature: -30 °C
Reaction time: 2 h

Procedure:
56 mmol of n-butyllithium (35 ml of a 1.6 M solution in hexane) were added with stirring to a solution of 2-methyl-1,3-dithian (7 g, 52.1 mmol) in 100 ml of dry tetrahydrofuran at −30° C. under argon. After stirring at −30° C. for 2 hours, the mixture was cooled to −78° C. 4.2 g (58.3 mmol) of freshly distilled n-butyraldehyde were added dropwise in the course of 15 minutes and the mixture was stirred for a further 30 minutes. After warming to 20° C., it was poured into a beaker containing 300 ml of water and 100 ml of n-hexane. The organic phase was separated off and the aqueous phase was extracted three times with 50 ml of dichloromethane in each case. The combined organic phases were washed with 10% strength by weight potassium hydroxide solution, water and concentrated sodium chloride solution, dried over anhydrous sodium sulfate and then distilled. 8.82 g of 2-(1-hydroxybutyl)-2-methyl-1,3-dithian were isolated as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[CH3:10].Cl.[NH2:12][OH:13].C([O-])(=O)C.[Na+].O>C(O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:12][OH:13])=[CH:4][C:3]=1[CH3:10]
Reactant: NO
Reactant: Cc1cc(C=O)ccc1Br
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cc(C=NO)ccc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.9 %

Procedure:
To a solution of 4-bromo-3-methyl-benzaldehyde (4.3 g) (Example 1.1) in ethanol (50 ml), were added at ambient temperature hydroxylamine hydrochloride (1.75 g), sodium acetate (2.07 g) and water (15 ml). The reaction mixture was stirred at ambient temperature for 3 hours. The reaction mixture was concentrated and the residue was partitioned between ethyl acetate and aqueous sodium hydroxide (2M). The phases were separated and the organic phase was washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 4:1) to give 4-bromo-3-methyl-benzaldehyde oxime (3.65 g) as a white solid. 1H-NMR (400 MHz, CDCl3): 8.05 (s, 1H), 7.50 (m, 2H), 7.25 (d, 1H), 2.40 (s, 3H) ppm.