Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:11](OC)(=[O:19])[C:12]1[C:13](=[CH:15][CH:16]=[CH:17][CH:18]=1)[NH2:14].C[O-].[Na+].C(O)=O>C1(C)C(C)=CC=CC=1.CO>[CH2:1]([N:8]1[C:11](=[O:19])[C:12]2[C:13](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:14][C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccccc1N
Reactant: O=C=NCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: CO
Solvent: O=CO
Product: O=c1[nH]c2ccccc2c(=O)n1Cc1ccccc1
Temperature: 110 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
A solution of benzyl isocyanate (13.3 g, 0.10 mol) in xylene (40 ml) is metered, at room temperature, into a solution of methyl anthranilate (15.1 g, 0.10 mol) in xylene (80 ml). After the addition has ended, the batch is stirred at 110° C. for 2 hours. 1.80 ml of a 30% solution of methanolic sodium methylate (0.010 ml) are metered in, and the mixture is stirred at 90° C. for a further 2 hours, during which process methanol is distilled off. 0.9 ml of 85% formic acid (0.020 mol) is subsequently added and the mixture is stirred at 90° C. for a further hour. After cooling, the product is filtered off with suction, washed with 3×25 ml of xylene, 3×25 ml of ethanol and 3×25 ml of water, and dried. 22.2 g of 3-(benzyl)-2,4(1H,3H)-quinazolinedione (yield: 88.0% of theory) of melting point 231° to 232° C. (lit. 227° to 228° C.) are obtained.
Reaction SMILES: C([NH:4][C@:5]1([C:22](NC(C)(C)C)=[O:23])[C@@H:9]([CH2:10][CH2:11][CH2:12][B:13]2[O:17]C(C)(C)C(C)(C)[O:14]2)[CH2:8][NH:7][CH2:6]1)(=O)C.Cl.C(O)(=[O:32])C>O>[NH2:4][C@:5]1([C:22]([OH:23])=[O:32])[C@@H:9]([CH2:10][CH2:11][CH2:12][B:13]([OH:14])[OH:17])[CH2:8][NH:7][CH2:6]1
Reactant: CC(=O)N[C@@]1(C(=O)NC(C)(C)C)CNC[C@@H]1CCCB1OC(C)(C)C(C)(C)O1
Reactant: CC(=O)O
Agent: Cl
Solvent: O
Product: N[C@@]1(C(=O)O)CNC[C@@H]1CCCB(O)O
Temperature: 130 °C
Reaction time: 18 h
Yield: 79 %

Procedure:
A solution of (3R,4S)-3-acetamido-N-tert-butyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl)pyrrolidine-3-carboxamide (198 mg, 0.5 mmol) in 2:1:1 concentrated HCl:glacial acetic acid:water (8 mL) in a pressure bottle was stirred for 2 h at 60° C., then capped and stirred for 18 h at 130° C., cooled to room temperature, and uncapped. The solution was diluted with water (20 mL), then extracted with methylene chloride (20 mL) and concentrated. The residue was treated with water (20 mL) and concentrated three times to remove excess HCl, then dissolved in water (40 mL) and treated with DOWEX® 550A-OH resin (3 g) which had been rinsed with methanol. The mixture was stirred for 40 min, then filtered and the resin washed successively with water, methanol, methylene chloride, water, methanol, and methylene chloride. The resin was then stirred four times with 1N HCl (15 mL) and filtered, and the combined filtrates were concentrated. The residue was treated with water (20 mL) and concentrated three times to remove excess HCl, then dissolved in 1.5-2.0 mL water and subjected to HPLC gradient purification as follows: 0-25% B with A=0.1% trifluoroacetic acid/water and B=0.1% trifluoroacetic acid/acetonitrile. The appropriate fractions were concentrated, treated three times with 1 N HCl (10 mL) and concentrated, treated three times with water (10 mL) and concentrated, then dissolved in water (10 mL), frozen, and lyophilized overnight to afford (3R,4S)-3-amino-4-(3-boronopropyl)pyrrolidine-3-carboxylic acid (114 mg, 79%) as a pale amber glass. NMR (D2O) δ 3.90 (d, J=13 Hz, 1 H), 3.71 (dd, J111.5 Hz, J2=8.5 Hz, 1 H), 3.46 (d, J=13 Hz, 1 H), 3.21 (t, J=12 Hz, 1 H), 2.50-2.65 (m, 1 H), 1.5-1.65 (m, 1 H), 1.10-1.40 (m, 3 H), 0.60-0.75 (m, 2 H). MS (m+1): 217.3; MS (m−H2O+1): 199.1.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][N:4]([C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1.CCN(C(C)C)C(C)C.[C:25]12([CH2:35][NH2:36])[CH2:34][CH:29]3[CH2:30][CH:31]([CH2:33][CH:27]([CH2:28]3)[CH2:26]1)[CH2:32]2.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.O>[C:25]12([CH2:35][NH:36][C:7]([C:6]3[C:2]([NH2:1])=[N:3][N:4]([C:10]4[N:15]=[CH:14][CH:13]=[CH:12][N:11]=4)[CH:5]=3)=[O:9])[CH2:32][CH:31]3[CH2:30][CH:29]([CH2:28][CH:27]([CH2:33]3)[CH2:26]1)[CH2:34]2
Reactant: NCC12CC3CC(CC(C3)C1)C2
Reactant: Nc1nn(-c2ncccn2)cc1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nn(-c2ncccn2)cc1C(=O)NCC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 3-amino-1-pyrimidin-2-yl-1H-pyrazole-4-carboxylic acid (50 mg, 0.24 mmol) in 1.0 mL of DMF is added sequentially DIEA (0.08 mL, 0.48 mmol), 1-adamantan-1-ylmethan-amine (40 mg, 0.24 mmol), and BOP (128 mg, 0.29 mmol). The resulting mixture is stirred at RT for 18 h. Water (3 mL) is added, and the mixture is filtered. The solid is washed well with water and dried in vacuo to give the title compound as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ9.22 (1H, s), 8.75 (2H, s), 8.07 (1H, s), 7.33 (1H, s), 5.85 (2H, s), 2.90 (2H, d, J 5.2), 1.91 (3H, s), 1.61 (6H, m), 1.46 (6H, s). MS (M+1)=353.23; RT=1.31 min *IC50.
Reaction SMILES: [CH3:1][CH:2]([CH2:41][CH3:42])[C:3]([O:5][CH:6]1[CH:15]2[CH:10]([CH2:11][CH2:12][CH:13]([CH3:35])[CH:14]2[CH2:16][CH2:17][CH:18]2[CH2:23][CH:22]([O:24][CH2:25][O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:21][C:20](=[O:34])[O:19]2)[CH2:9][CH:8]([O:36]C(C)(C)C)[CH2:7]1)=[O:4].C1C=CN=CC=1.F>C(#N)C.C(OCC)(=O)C>[CH3:1][CH:2]([CH2:41][CH3:42])[C:3]([O:5][CH:6]1[CH:15]2[CH:10]([CH2:11][CH2:12][CH:13]([CH3:35])[CH:14]2[CH2:16][CH2:17][CH:18]2[CH2:23][CH:22]([O:24][CH2:25][O:26][CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:21][C:20](=[O:34])[O:19]2)[CH2:9][CH:8]([OH:36])[CH2:7]1)=[O:4]
Reactant: CCC(C)C(=O)OC1CC(OC(C)(C)C)CC2CCC(C)C(CCC3CC(OCOCc4ccccc4)CC(=O)O3)C21
Agent: F
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCC(C)C(=O)OC1CC(O)CC2CCC(C)C(CCC3CC(OCOCc4ccccc4)CC(=O)O3)C21
Temperature: 0 °C
Yield: 9.3 %

Procedure:
A solution of 28.8 g (44.7 mmol) of intermediate 3B in 400 ml of acetonitrile was cooled at -20° C. under argon and treated with three 10 ml portions of HF-pyridine over 2 hours, with warming to 0° C. after 1.5 hours. The reaction mixture was diluted with 500 ml of ethyl acetate and washed sequentially with saturated copper sulfate (aqueous 2×150 ml), brine (1×250, 200 and 150 ml) and saturated sodium bicarbonate (aqueous, 2×250 ml, 1×200 ml). After drying the ethyl acetate solution with sodium sulfate and concentrating, the crude product was purified by silica gel chromatography, eluting with 40% hexanes in ethyl acetate to yield 2.2 g (93.7%) of intermediate 3C as a clear, colorless oil.
Reaction SMILES: Br[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:3].[Li]C(C)(C)C.[B:15](OC(C)C)([O:20]C(C)C)[O:16]C(C)C.Cl>C(OCC)C>[CH2:3]=[C:2]([B:15]([OH:20])[OH:16])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: C=C(Br)c1ccccc1
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: C=C(B(O)O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of α-bromo styrene (5.5 g, 30 mmol) in diethyl ether (30 mL) at −78° C. was treated with a solution of tert-BuLi (1.7 M solution, 21.2 mL, 36 mmol), stirred at −78° C. for 0.5 hours, treated with triisopropyl borate (8.31 mL, 36 mmol) over 48 minutes, stirred for 1 hour, warmed to room temperature over 18 hours, diluted with diethyl ether (100 mL), treated with 1M HCl (100 mL), stirred at room temperature for 5 hours, concentrated to remove the THF, adjusted pH 14 with IN NaOH, washed with hexane, adjusted to pH 1 with 1M HCl, and extracted with ethyl acetate. The extract was dried (Na2SO4), filtered and concentrated to provide the title compound.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3](B(O)O)[CH:2]=1.Cl[C:15]1[N:20]=[C:19]([C:21]2[NH:29][C:28]3[C:27]4([CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30]4)[CH2:26][NH:25][C:24](=[O:41])[C:23]=3[CH:22]=2)[CH:18]=[CH:17][N:16]=1.C([O-])([O-])=O.[K+].[K+].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.CCO>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:15]2[N:20]=[C:19]([C:21]3[NH:29][C:28]4[C:27]5([CH2:33][CH2:32][NH:31][CH2:30]5)[CH2:26][NH:25][C:24](=[O:41])[C:23]=4[CH:22]=3)[CH:18]=[CH:17][N:16]=2)[CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CNC(=O)c3cc(-c4ccnc(Cl)n4)[nH]c32)C1
Reactant: OB(O)c1cnc2ccccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C1NCC2(CCNC2)c2[nH]c(-c3ccnc(-c4cnc5ccccc5c4)n3)cc21
Temperature: 140 °C
Reaction time: 0.25 h
Yield: 47.9 %

Procedure:
A mixture of quinolin-3-ylboronic acid (53.2 μmol, 9.2 mg), D7 (53.2 μmol, 21.5 mg), 2 N aqueous K2CO3 (106 μL), toluene (837 μL) and EtOH (209 μL) was purged with nitrogen. Then tetrakis(triphenylphosphine)palladium(0) (2.7 μmol; 3.1 mg) was added. The reaction mixture was stirred for 15 minutes at 140° C. in the microwave. The mixture was washed with water (1 mL). Brine (1 mL) was added to the aqueous phase, followed by an extraction with EtOAc (2×2 mL). The combined organic phase was concentrated. The residue was treated with 4N HCl in dioxane (2 mL) at room temperature for 30 minutes. The mixture was centrifuged and decanted. Subsequently, the residue was suspended in diethyl ether, centrifuged and decanted for another 2 times. The residue was dried in vacuo and purified by semi-preparative HPLC (method A), which obtained 10.1 mg of the desired product as a TFA salt (37%). 1H NMR (400 MHz, DMSO-D6, 300K): δ=2.21 (1H, m), 2.55 (1H, m), 3.50 (6H, m), 7.50 (1H, d, J=2.2 Hz), 7.56 (1H, br s), 7.73 (1H, m), 7.90 (1H, m), 7.91 (1H, d, J=5.4 Hz); 8.14 (1H, br d, J=8.6 Hz), 8.23 (1H, br d, J=8.2 Hz), 8.90 (1H, d, J=5.4 Hz), 9.10 (1H, br s), 9.25 (1H, br s), 9.49 (1H, d, J=2.1 Hz), 10.08 (1H, d, 2.1 Hz), 12.02 (1H, br s); MS (ES) C23H20N6O requires: 396. found: 397.3 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[CH:16]=[C:15]([N:17]([S:19]([CH3:22])(=[O:21])=[O:20])[CH3:18])[CH:14]=[C:6]([C:7]([N:9]([CH3:13])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1.[OH-].[Na+].Cl>C1COCC1.C(OCC)(=O)C>[CH3:22][S:19]([N:17]([CH3:18])[C:15]1[CH:14]=[C:6]([C:7]([N:9]([CH3:13])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=[C:4]([CH:16]=1)[C:3]([OH:23])=[O:2])(=[O:21])=[O:20]
Reactant: CCCN(C)C(=O)c1cc(C(=O)OC)cc(N(C)S(C)(=O)=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCN(C)C(=O)c1cc(C(=O)O)cc(N(C)S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Dissolve 5-(methanesulfonyl-methylamino)-N-methyl-N-propyl-isophthalamic acid methyl ester (1.09 g, 3.18 mmol) in THF (80 mL) and add 1 N NaOH (16 mL, 16 mmol). Stir at room temperature for 16 h and add 5 N HCl (5 mL). Dilute with ethyl acetate, wash with saturated aqueous sodium chloride, dry (magnesium sulfate) and concentrate to give the title compound.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[CH2:7]([N:9]1[C:15]2[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:14]=2[O:13][CH2:12][C:11](CO)([OH:23])[CH2:10]1)[CH3:8]>CC(C)=O.O.O1CCCC1>[CH2:7]([N:9]1[C:15]2[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:14]=2[O:13][CH2:12][C:11](=[O:23])[CH2:10]1)[CH3:8]
Reactant: CCN1CC(O)(CO)COc2ccc([N+](=O)[O-])cc21
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CCN1CC(=O)COc2ccc([N+](=O)[O-])cc21
Reaction time: 1 h
Yield: 73.7 %

Procedure:
Sodium periodate (0.454 g, 2.12 mmol) was added to 9-Ethyl-7-hydroxymethyl-2-nitro-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-ol (0.114 g, 0.425 mmol) in Acetone (15 mL) and Water (5 mL). After 1 h, the heterogenous mixture was further diluted with Water (10 mL) and Tetrahydrofuran (10 mL), which did not create a homogenous mixture. The mixture was stirred overnight, then was partitioned between water and DCM. Extraction with DCM and washing with brine, followed by drying gave 9-Ethyl-2-nitro-8,9-dihydro-5-oxa-9-aza-benzocyclohepten-7-one (74 mg, 74%). 1H-NMR (CDCl3): 7.69 (s, 1H), 7.62 (d, 1H, J=8.8 Hz), 7.02 (d, 1H, J=8.8 Hz), 4.61 (s, 2H), 4.10 (s, 2H), 3.42 (q, 2H, J=7.2 Hz), 1.26 (t, 3H, J=7.2 Hz).
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]2[NH:19][CH:20]=[C:21]([C:23]#[N:24])[N:22]=2)=[O:17])=[C:11]([C:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]=2)[CH:10]=1)[C:5](OC)=[O:6].[BH4-].[Na+].CO.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)(C)(C)C.CCOC(C)=O>[C:25]1([C:11]2[CH:10]=[C:9]([CH:4]([CH2:3][OH:2])[CH2:5][OH:6])[CH:14]=[CH:13][C:12]=2[NH:15][C:16]([C:18]2[NH:19][CH:20]=[C:21]([C:23]#[N:24])[N:22]=2)=[O:17])[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]=1
Reactant: COC(=O)C(C(=O)OC)c1ccc(NC(=O)c2nc(C#N)c[nH]2)c(C2=CCCCC2)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CC(C)(C)O
Product: N#Cc1c[nH]c(C(=O)Nc2ccc(C(CO)CO)cc2C2=CCCCC2)n1
Temperature: 80 °C
Reaction time: 16 h
Yield: 61 %

Procedure:
To a mixture of 2-{4-[(4-cyano-1H-imidazole-2-carbonyl)-amino]-3-cyclohex-1-enyl-phenyl}-malonic acid dimethyl ester (as prepared in the previous step, 30.0 mg, 0.0710 mmol) and NaBH4 (13.4 mg, 0.355 mmol) in 1 mL of tert-butyl alcohol (t-BuOH) at 80° C. was added MeOH (50 μL) over 5 min. The resulting mixture was stirred at 80° C. for 16 h under Ar. After cooling to RT, the mixture was treated with 10% aq citric acid to a pH of 7. The mixture was then treated with 30 mL of EtOAc, washed with H2O (5 mL) and brine (10 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel with 1-5% MeOH-DCM to afford 14.1 mg (61%) of the title compound as a white solid: 1H-NMR (CD3OD; 400 MHz): δ 8.00 (s, 1H), 7.54 (dd, 1H, J=8.2, 2.3 Hz), 7.46 (d, 1H, J=2.3 Hz), 7.27 (d, 1H, J=8.2 Hz), 5.59 (m, 1H), 3.71-3.84 (m, 4H), 3.29 (m, 1H), 2.15-2.29 (m, 4H), 1.67-1.84 (m, 4H). Mass spectrum (ESI, m/z): Calcd. for C20H22N4O3, 367.2 (M+H). found 366.8.
Reaction SMILES: C([Si]([O:8][CH2:9][CH2:10][CH:11]([S:21]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)(=[O:23])=[O:22])[C:12]1[C:17]([F:18])=[CH:16][CH:15]=[C:14]([F:19])[C:13]=1[F:20])(C)C)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.O>C1COCC1>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([S:21]([CH:11]([C:12]2[C:17]([F:18])=[CH:16][CH:15]=[C:14]([F:19])[C:13]=2[F:20])[CH2:10][CH2:9][OH:8])(=[O:22])=[O:23])=[CH:25][CH:26]=1
Reactant: CC(C)(C)[Si](C)(C)OCCC(c1c(F)ccc(F)c1F)S(=O)(=O)c1ccc(Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: O=S(=O)(c1ccc(Cl)cc1)C(CCO)c1c(F)ccc(F)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Tert-butyl-[3-(4-chloro-benzenesulfonyl)-3-(2,3,6-trifluoro-phenyl)-propoxy]-dimethyl-silane (2.62 g, 5.47 mmol) was dissolved in 80 mL of THF and tetrabutylammonium fluoride (1.96 g, 7.51 mmol) was added at room temperature. The solution was stirred at room temperature overnight. 200 mL of EtOAc and 200 mL of water were added and the organic layer was separated. The organic layer was dried over Na2SO4 and concentrated. The product was purified by column chromatography using hex./EtOAc as the eluent (gradient from 0/100 to 75/25 in 45 min, 1.38 g, 69%). 1H NMR (CDCl3 400 MHz) δ 7.63 (d, J=8.8 Hz, 2H), 7.45 (d, J=8.8 Hz, 2H), 7.12 (m, 1H), 6.82 (m, 0.5H), 6.71 (m, 0.5H), 4.91 (m, 1H), 3.89 (m, 1H), 4.44 (m, 1H), 2.60 (m, 2H).
Reaction SMILES: [C:1]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][CH:11]=[CH:10][CH:9]=2)([O:3][CH2:4][CH3:5])=[O:2].[C:21](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>C(#N)C>[C:1]([C:6]1[N:7]([CH3:21])[C:8]2[C:13]([C:14]=1[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][CH:11]=[CH:10][CH:9]=2)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)[nH]c2ccccc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: COS(=O)(=O)OC
Product: CCOC(=O)Cc1c(C(=O)OCC)n(C)c2ccccc12

Procedure:
Ethyl 2-Carboethoxy-3-indoleacetate (1 gm) in acetonitrile (50 ml) was combined with potassium carbonate (2 gm) and dimethyl sulfate (0.38 ml). The mixture was heated to reflux for 20 hours, filtered warm, and the solvent removed on the rotary evaporator. The residue was suspended in ether (150 ml) and the mixture washed with 5% hydrochloric acid (3×50 ml), 5% sodium bicarbonate (3×50 ml) and water (3×50 ml). The ether solution was dried over magnesium sulfate and the solvent removed on a rotary evaporator to provide the product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:12][C:9]3([CH2:11][CH2:10]3)[CH2:8][NH:7][C:6]=2[CH:13]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C>[CH2:20]([N:7]1[C:6]2[CH:13]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[O:12][C:9]2([CH2:10][CH2:11]2)[CH2:8]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: Brc1ccc2c(c1)NCC1(CC1)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1ccc2c(c1)N(Cc1ccccc1)CC1(CC1)O2
Temperature: 60 °C
Yield: 26.5 %

Procedure:
To a stirred solution of 6-bromospiro[3,4-dihydro-1,4-benzoxazine-2,1′-cyclopropane] (3.11 g, 12.9 mmol) in DMF (20 mL) was added potassium carbonate (3.6 g, 26.0 mmol) and benzyl bromide (1.61 mL, 13.6 mmol). The reaction mixture was heated at 60° C. for 6 h then cooled to room temperature and quenched by the addition of water. The reaction mixture was extracted with ethylacetate (2×50 mL) and the combined organic layers were washed with water (20 mL) and brine (20 mL), then dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography to furnish 4-benzyl-6-bromo-spiro[3H-1,4-benzoxazine-2,1′-cyclopropane] (1.13 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1F)[OH:5].[CH3:13][OH:14]>>[NH2:1][CH2:2][CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:14][CH3:13])[OH:5]
Reactant: CO
Reactant: NCCC(O)c1ccccc1F
Product: COc1ccccc1C(O)CCN

Procedure:
3-Amino-1-(2-methoxy-phenyl)-propan-1-ol was prepared by the same procedure as 3-amino-1-(2-fluoro-phenyl)-propan-1-ol without adding methanol in the acidification step in example 6. 1H NMR (DMSO-d6) δ 7.45-7.19 (m, 1H), 7.11-7.08 (m, 3H), 6.48 (s, 2H), 6.40 (t, J=7.1 Hz, 1H), 5.10 (d, J=4.7 Hz, 1H), 4.83-4.75 (m, 1H), 3.05-2.95 (m, 2H), 2.25 (s, 3H), 1.81-1.62 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:13](=[O:22])[C:14]3[CH:19]=[CH:18][C:17]([CH2:20][NH2:21])=[CH:16][CH:15]=3)[S:11][C:7]=2[C:6]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:5][CH:4]=1.N1C=CC=CC=1.[CH3:35][O:36][CH2:37][C:38](Cl)=[O:39].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH3:35][O:36][CH2:37][C:38]([NH:21][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]([NH:12][C:10]2[S:11][C:7]3[C:6]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=3[N:9]=2)=[O:22])=[CH:15][CH:16]=1)=[O:39]
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(CN)cc3)nc12
Reactant: COCC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COCC(=O)NCc1ccc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 71 %

Procedure:
N-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4-aminometyl-benzamide (100 mg, 0.24 mmol), dissolved in dichloromethane (5 ml) is treated with pyridine (29 μl, 0.36 mmol) and methoxy-acetyl chloride (24 μl, 0.32 mmol) and stirred at ambient temperature for 15 h. Saturated aqueous sodium carbonate (6 ml) is added, the phases are separated and the aqueous solution extracted twice with each 5 ml dichloromethane. The combined organic phases are dryed over sodium sulphate, filtered and evaporated to dryness. Flash chromatography (silica, eluent: dichloromethane containing 3% methanol) afforded the title compound as white crystals (71% yield). MS: m/e=471(M+H+).
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:15]([OH:17])[CH3:16]>>[CH2:7]([O:17][C:15]1[CH:7]=[C:8]([CH:9]=[CH:10][CH:16]=1)[CH:1]=[O:4])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C([O-])[O-]
Reactant: BrCc1ccccc1
Reactant: CCO
Agent: [K+]
Product: O=Cc1cccc(OCc2ccccc2)c1
Yield: 81.1 %

Procedure:
15.0 g of m-hydroxybenzaldehyde was dissolved in 200 ml of ethanol, and 25.0 g of potassium carbonate and 32 g of benzyl bromide were added. With stirring, the mixture was heated under reflux for 6 hours. After the reaction, the insoluble inorganic salts were removed by filtration. The filtrate was evaporated under reduced pressure, and purified by silica gel column chromatography [Wakogel C-200, 150 g; hexane/chloroform=1/1] and then recrystallized from hexane to give 21.1 g (yield 81.1%) of 3-benzyloxybenzaldehyde having a melting point of 56° to 57° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:11]=[C:10]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[N:13]=2)[O:9][N:8]=1.[Br:24]N1C(=O)CCC1=O>C(#N)C>[Br:24][C:11]1[C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[N:8][O:9][C:10]=1[C:12]1[O:16][N:15]=[C:14]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:13]=1
Reactant: Cc1ccc(-c2noc(-c3cc(-c4ccccn4)no3)n2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: Cc1ccc(-c2noc(-c3onc(-c4ccccn4)c3Br)n2)cc1
Yield: 393.3 %

Procedure:
A solution of 5-(3-(pyridin-2-yl)isoxazol-5-yl)-3-p-tolyl-1,2,4-oxadiazole (655 mg, 2.15 mmol), N-bromosuccinimide (536 mg, 3.01 mmol), and PdOAc2 (97 mg, 0.430 mmol) in acetonitrile (12 mL) was heated to 120° C. via microwave for 30 minutes. The reaction was repeated three additional times on a similar scale, and the contents of each reaction tube were combined and filtered. The solid was collected, triturated with methanol (10 mL), and collected by vacuum filtration to give 5-(4-bromo-3-(pyridin-2-yl)isoxazol-5-yl)-3-p-tolyl-1,2,4-oxadiazole (3.24 g, 87% yield). The compound had an HPLC retention time=3.96 minutes (YMC-Combi 4.6×50 mm S-5 ODS column) eluting with 10-90% aqueous methanol+0.2% phosphoric acid over a 4 minute gradient. MS: (M+H)=385+. 1H NMR (400 MHz, CDCl3) δ ppm 2.46 (s, 3H), 7.35 (d, J=8.03 Hz, 2H), 7.49 (ddd, J=7.65, 4.89, 1.00 Hz, 1H), 7.91 (td, J=7.78, 1.76 Hz, 1H), 8.03 (d, J=7.78 Hz, 1H), 8.12 (d, J=8.28 Hz, 2H), and 8.86 (d, J=4.77 Hz, 1H).
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[Cl:17].[SH2:19].[Na]>C(O)C>[CH3:7][N:6]1[C:2]([SH:19])=[C:3]([C:9](=[O:18])[C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])[C:4]([CH3:8])=[N:5]1
Reactant: Cc1nn(C)c(Cl)c1C(=O)c1ccc(Cl)cc1Cl
Reactant: S
Agent: [Na]
Solvent: CCO
Product: Cc1nn(C)c(S)c1C(=O)c1ccc(Cl)cc1Cl
Yield: 33.3 %

Procedure:
A mixture of 0.3 g. of 5-chloro-4-(2,4-dichlorobenzoyl)-1,3-dimethylpyrazole, 2.1 g. of sodium hydrogen sulfide 2 hydrate and 6 ml. of ethanol is heated under reflux on a water bath for 3 hours. After completion of the reaction, the ethanol is distilled off under reduced pressure from the reaction mixture and 15 ml. of water is added followed by extraction with benzene. To an aqueous layer is added conc. hydrochloric acid to adjust the pH to 1 and the mixture is extracted with chloroform. The extract is washed with water and then dried over anhydrous sodium sulfate. The solvent is distilled off from the extract to give the crude crystalline substance, which is then recrystallized from n-hexane to give 0.10 g. of the desired product as yellow powders having a melting point of 85°-86° C. Yield 33.3%.