Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@:9]([CH3:31])([C:27]([O:29][CH3:30])=[O:28])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19](=O)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.[CH2:36]([NH2:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH2:36]([NH:43][CH:19]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:18][O:17][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[CH2:10][C@@:9]([CH3:31])([C:27]([O:29][CH3:30])=[O:28])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: COC(=O)[C@](C)(Cc1cccc(OCC(=O)c2ccccc2)c1)NC(=O)OC(C)(C)C
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: COC(=O)[C@](C)(Cc1cccc(OCC(NCc2ccccc2)c2ccccc2)c1)NC(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To a solution of methyl N-(tert-butoxycarbonyl)-alpha-methyl-3-(2-oxo-2-phenylethoxy)phenylalaninate (0.600 g, 1.40 mmol), 4 A sieves (spatula tip), acetic acid (0.089 mL, 1.54 mmol), and benzylamine (0.184 mL, 1.68 mmol) in 10.0 mL dichloroethane was added sodium triacetoxyborohydride (0.357 g, 1.68 mmol). After 16 hr, additional benzylamine (0.092 mL, 0.840 mmol), sodium triacetoxyborohydride (0.178 g, 0.840 mmol), and acetic acid (0.045 mL, 0.770 mmol) were added. After an additional 16 hr, the temperature was raised to 50° C. for 30 hr., and additional amounts of 4 A sieves, acetic acid, benzylamine, and sodium triacetoxyborohydride were added over 72 hr to achieve full conversion. The reaction was quenched with bicarb. and filtered, washing with water and EtOAc. The layers of the filtrate were separated, and the aqueous layer was back extracted with EtOAc. The organic layers were combined, washed with bicarb. and brine (×2), dried over sodium sulfate, and concentrated in vacuo. Purification by flash chromatography (90 g silica, 0-30% EtOAc in hexanes) gave methyl 3-[2-(benzylamino)-2-phenylethoxy]-N-(tert-butoxycarbonyl)-alpha-methylphenylalaninate as a yellow foam.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:14]=[CH:15][CH:16]=1)[CH2:8][C@@H:9]([C:11]([OH:13])=[O:12])[NH2:10])([CH3:4])([CH3:3])[CH3:2].[ClH:17].[CH3:18][C:19](=[CH2:21])[CH3:20].OS(O)(=O)=O.Cl>O1CCOCC1>[C:1]([C:5]1[CH:6]=[C:7]([CH:14]=[CH:15][CH:16]=1)[CH2:8][C@@H:9]([C:11]([O:13][C:19]([CH3:21])([CH3:20])[CH3:18])=[O:12])[NH2:10])([CH3:4])([CH3:2])[CH3:3].[ClH:17]
Reactant: CC(C)(C)c1cccc(C[C@H](N)C(=O)O)c1
Reactant: C=C(C)C
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)[C@@H](N)Cc1cccc(C(C)(C)C)c1
Yield: 87 %

Procedure:
According to example 54, 0.50 g of 3-tert-butyl-L-phenylalanine·HCl was treated with 30 mL of isobutylene in 25 mL of 1,4-dioxane in the presence of 0.4 mL of conc. H2SO4. Work-up in the usual manner followed by acidification of the free amine with ethereal HCl afforded 0.53 g (87%) of tert-butyl 3-tert-butyl-L-phenylalaninate·HCl as a light yellow foam.
Reaction SMILES: [F:1][C:2]1([F:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[C:3]1([CH3:13])[CH3:12].[BH4-].[Na+]>C(O)C>[F:1][C:2]1([F:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([OH:11])[C:3]1([CH3:12])[CH3:13]
Reactant: CC1(C)C(=O)c2ccccc2C1(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC1(C)C(O)c2ccccc2C1(F)F

Procedure:
To a solution of 3,3-difluoro-2,2-dimethyl-indan-1-one (520 mg, 2.65 mmol) in ethanol (15 mL) is added NaBH4 (100 mg, 2.65 mmol). After 15 minutes the reaction is quenched with saturated aqueous NH4Cl and concentrated to near dryness. The resulting residue is diluted with ethyl acetate and washed with brine, dried with Na2SO4, filtered, and concentrated. The resulting residue is purified by silica gel flash chromatography (ethyl acetate-heptane, 0:1 to 1:6) to provide 3,3-difluoro-2,2-dimethyl-indan-1-ol; 1H NMR (400 MHz, CDCl3) δ ppm 1.07 (d, J=2.3 Hz, 2 H), 1.27 (d, J=2.3 Hz, 2 H), 4.79-4.83 (m, 1 H), 7.41-7.46 (m, 1 H), 7.48-7.60 (m, 3 H).
Reaction SMILES: C[Si](C)(C)CCOC[N:7]1[CH:11]=[C:10]([C:12]2([NH2:15])[CH2:14][CH2:13]2)[N:9]=[CH:8]1>CCO.Cl>[NH:7]1[CH:11]=[C:10]([C:12]2([NH2:15])[CH2:14][CH2:13]2)[N:9]=[CH:8]1
Reactant: C[Si](C)(C)CCOCn1cnc(C2(N)CC2)c1
Agent: Cl
Solvent: CCO
Product: NC1(c2c[nH]cn2)CC1
Temperature: 90 °C
Reaction time: 4 h
Yield: 137.2 %

Procedure:
To a round bottom flask was added 1-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl]-cyclopropylamine (400 mg, 1.58 mmol) in EtOH (20 ml) and 3N HCl (15 ml). The reaction mixture was stirred at 90° C. for 4 h. The reaction mixture was concentrated in vacuo. The residue was purified by prepHPLC by eluting with 0.5% acetonitrile/water to afford 267 mg of 1-(1H-imidazol-4-yl)-cyclopropylamine as a formic acid salt, m/z 124 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[N:8][NH:7][C:6]=2[CH:10]=1.[CH3:11]I>>[CH3:11][N:7]1[C:6]2[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[N:9]=[N:8]1
Reactant: Cc1ccc2nn[nH]c2c1
Reactant: CI
Product: Cc1ccc2nnn(C)c2c1

Procedure:
6-Methylbenzotriazole is reacted with methyl iodide, yielding the title compound (in addition to the isomeric 2-methyl-2H and 3-methyl-3H compounds). The title compound is obtained in pure form by chromatography.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[N:22])[N:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:24][OH:25].C(=O)([O-])[O-].[Na+].[Na+]>CCO.O>[C:1]([NH:5][S:6]([C:9]1[CH:10]=[C:11]([C:15]2[N:16]=[C:17]([C:21]([NH:24][OH:25])=[NH:22])[CH:18]=[CH:19][CH:20]=2)[CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: NO
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2cccc(C#N)n2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2cccc(C(=N)NO)n2)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 74.6 %

Procedure:
A mixture of N-tert-butyl-3-(6-cyano-pyridin-2-yl)-benzenesulfonamide (example B.13) (1.03 g, 3.27 mmol), hydroxylamine hydrochloride (794 mg, 11.4 mmol) and sodium carbonate (692 mg, 6.53 mmol) in EtOH (20 ml) and water (20 ml) was stirred under argon atmosphere at 100° C. for 2 h. The EtOH was evaporated, the mixture was diluted with water and stirred for 1 h at 0° C. The crude product was filtered and dried in HV to give the pure title compound as a white solid (850 mg, 75%). MS (ISP) 349.3 [(M+H)+].
Reaction SMILES: [CH2:1]([C:5]1[CH:22]=[CH:21][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br)=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3].C(=O)([O-])[O-].[K+].[K+].Cl.[NH:30]1[CH2:34][CH2:33][C:32](=[O:35])[NH:31]1.[I-].[K+]>C(#N)C.O>[CH2:1]([C:5]1[CH:22]=[CH:21][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:30]2[CH2:34][CH2:33][C:32](=[O:35])[NH:31]2)=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3]
Reactant: O=C1CCNN1
Reactant: CC(=O)Cc1ccc(OCCCCCCCCCCBr)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CC#N
Product: CC(=O)Cc1ccc(OCCCCCCCCCCN2CCC(=O)N2)cc1
Reaction time: 3 h

Procedure:
A mixture of 10-(4-acetonylphenoxy)decylbromide, ethylene ketal (3.0 g), potassium carbonate (3.8 g), pyrazolidin-3-one hydrochloride (1.47 g) and potassium iodide (0.5 g) in acetonitrile:water (95:5), was heated under reflux for 3 hr. The reaction mixture was allowed to cool, filtered and the solvent evaporated in vacuo. The residue was dissolved in chloroform, washed with water (2×50 ml), dried (magnesium sulphate), fitered and the solvent removed in vacuo. The residue was dissolved in acetone (50 ml) and treated with 2M hydrochloric acid solution (3 ml) and allowed to stand at room temperature for 3 hr. The solvent was removed in vacuo and the residue was dissolved in chloroform and washed with 1.2M sodium bicarbonate solution (1×50 ml), water (2×50 ml), dried (magnesium sulphate), filtered and the solvent removed in vacuo to give 1-[10-(4-acetonylphenoxy)decyl]pyrazolidin-3-one (0.66 g).
Reaction SMILES: Br[CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[C@H:18]([NH:19][C:20](=[O:29])[CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17](=[O:30])[N:7]2[C:8]=1[C:9]([O:11][CH2:12][C:13]([Cl:16])([Cl:15])[Cl:14])=[O:10].[CH3:31][SH:32]>CN(C)C=O>[CH3:31][S:32][CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[C@H:18]([NH:19][C:20](=[O:29])[CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17](=[O:30])[N:7]2[C:8]=1[C:9]([O:11][CH2:12][C:13]([Cl:16])([Cl:15])[Cl:14])=[O:10]
Reactant: CS
Reactant: O=C(COc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)=C(CBr)CS[C@H]12
Solvent: CN(C)C=O
Product: CSCC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)[C@@H](NC(=O)COc3ccccc3)[C@H]2SC1

Procedure:
2,2,2-Trichloroethyl 3-bromomethyl-7β-phenoxyacetamidoceph-3-em-4-carboxylate, 1β-oxide (11.48g, 20 mmole) was reacted with methanethiol as in Example D18(i) and the resulting solution in N,N-dimethylformamide used directly in a reduction step as described in Example D18(ii) to provide the solvated title compound as a pale-yellow foam (10.90 g,), [α]D + 37.5° (c, 1.25) λmax. 269 nm (E1cm1% 165) and 276 nm. (E1cm1% 160) inflexion at 263 nm (E1cm1% 151). The P.M.R. spectrum of this product closely resembled that of the product from Example D18(ii)
Reaction SMILES: CC(C)([O-])C.[K+].[CH:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:15][O:16][C:17](=[O:24])[CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21]>C(O)(C)(C)C>[CH3:15][O:16][C:17](=[O:24])[CH2:18]/[C:19](/[C:20]([O:22][CH3:23])=[O:21])=[CH:7]\[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=Cc1ccccc1
Reactant: COC(=O)CCC(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: COC(=O)C/C(=C\c1ccccc1)C(=O)OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66.1 %

Procedure:
To a solution of potassium t-butoxide (16.8 g) in t-butyl alcohol (150 ml) is added dropwise with stirring a solution of benzaldehyde (15.9 g) and succinic acid dimethyl ester (26.3 g) in t-butyl alcohol (20 ml) at room temperature, and the mixture is stirred for 30 minutes. The reaction mixture is poured into ice-water (200 ml), and the mixture is extracted with isopropyl ether. The pH value of the aqueous layer is adjusted to pH 2-3, and the mixture is extracted with ethyl acetate. The ethyl acetate layer is washed, dried, and evaporated to remove the solvent. The residue is dissolved in methanol (75 ml), and thereto is added dropwise thionyl chloride (10.9 ml) under ice-cooling. The mixture is allowed to stand at room temperature overnight, and then evaporated to remove the solvent. To the residue is added isopropyl ether, and the mixture is washed, dried, and evaporated to remove the solvent. The resulting residue is distilled under reduced pressure to give (E)-3-methoxycarbonyl-4-phenyl-3-butenoic acid methyl ester (23.2 g) as colorless oil.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:28])[CH2:21][CH2:22][CH2:23][S:24][CH2:25][CH2:26][OH:27])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:28])[CH2:21][CH2:22][CH2:23][S:24][CH2:25][CH2:26][O:27][C:29](=[O:31])[CH3:30])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(CCCSCCO)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OCCSCCCC(=O)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Yield: 80 %

Procedure:
Following a procedure similar to that described in Example 2, but using N-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]-4-(2-hydroxyethylthio)butyramide (prepared as described in Example 3) and acetic anhydride as starting materials, in relative proportions similar to those used in that Example, the title compound, melting at 36°-40° C., was obtained in an 80% yield.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1.Cl.[NH2:15][CH2:16][CH2:17][SH:18]>CCO.O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:13]=[CH:12][C:9]([CH:10]2[NH:15][CH2:16][CH2:17][S:18]2)=[CH:8][CH:7]=1
Reactant: NCCS
Reactant: O=Cc1ccc(-c2cccs2)cc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: c1csc(-c2ccc(C3NCCS3)cc2)c1
Yield: 13.6 %

Procedure:
To a solution of 4-(2-thienyl)benzaldehyde (500.0 mg, 2.66 mmol) in EtOH (5.0 mL) was added a solution of cysteamine HCl (101.0 mg, 0.89 mmol) in water (2.0 mL) dropwise with stirring. The solution was then stirred at room temperature for 18 hours before the bulk of the EtOH was removed by rotary evaporator. The resulting residue was diluted with water (15.0 mL) and extracted with ether (3×30.0 mL) to remove excess aldehyde. The acidic aqueous layer was then basified with the slow addition of solid sodium carbonate (300.0 mg) to afford a white precipitate, which was filtered and washed carefully with water (3×20.0 mL). The solid was dried under reduced pressure to afford 2-[4-(2-thienyl)phenyl]-1,3-thiazolane (15) as a yellow powder (30 mg, 4.6%). 1H nmr (CDCl3, 300 MHz) 3.14, m, H4,4,5; 3.64, m, H5; 5.95, s, H2; 7.08, m, thienyl-H; 7.31, m, 2×thienyl-H; 7.50, d (8.1 Hz), 2×phenyl-H; 7.59, d (8.4 Hz), 2×phenyl-H. ESI (+ve) MS m/z 248 (M+H, 100%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:11][CH3:12])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.[H-].[Na+].C([Li])(C)(C)C.CN(C)[CH:22]=[O:23]>O1CCCC1>[CH3:12][O:11][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([CH:22]=[O:23])[CH:3]=1)[NH:9][N:8]=[CH:7]2
Reactant: CN(C)C=O
Reactant: COc1cc(Br)c2[nH]ncc2c1
Agent: [H-]
Agent: [Li]C(C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(C=O)c2[nH]ncc2c1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 107.5 %

Procedure:
To a solution of 7-bromo-5-methoxy-1H-indazole (1.32 g, 5.81 mmol) in tetrahydrofuran (27 mL) at 0° C. was added sodium hydride (0.465 g, 11.62 mmol). The ice bath was removed and stirring continued for 20 min. The solution was cooled to −78° C. and treated with tert-butyllithium (1.7 M in pentane, 6.84 mL, 11.63 mmol) dropwise. The reaction was stirred at −78° C. for 10 min, allowed to warm gradually in the dewar to −50° C., recooled to −78° C., and then treated with dimethylformamide (1.8 mL, 23.25 mmol). After 15 min, the ice bath was removed and stirring continued for 1 h. The reaction was poured onto ice/1 M hydrochloric acid (20 mL). The mixture was extracted with ethyl acetate (2×). The organics were washed with water, then brine, dried over magnesium sulfate, and concentrated to give 1.1 g of 5-methoxy-1H-indazole-7-carbaldehyde (100%) as a tan solid. 1H-NMR (CDCl3, 300 MHz) δ 10.08 (s, 1H), 8.04 (s, 1H), 7.52 (s, 1H), 7.44 (m, 1H), 3.90 (s, 3H); Mass spec.: 177.09 (MH)+.
Reaction SMILES: [BH4-].[Li+].C(C1C=CC=CC=1O[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[C:24]([CH2:25][CH2:26][CH3:27])=[C:23]2[C:18]([C:19](=O)[CH2:20][CH:21]([C:28]([OH:30])=O)[O:22]2)=[CH:17][CH:16]=1)CC.[BH4-].Cl.[CH3:38][CH2:39]OCC>O>[OH:30][CH2:28][CH:21]1[CH2:20][CH2:19][C:18]2[C:23](=[C:24]([CH2:25][CH2:26][CH3:27])[C:15]([O:14][CH2:13][C:12]3[CH:11]=[CH:10][CH:9]=[CH:39][CH:38]=3)=[CH:16][CH:17]=2)[O:22]1
Reactant: CCOCC
Reactant: CCCc1ccccc1OCCCCCOc1ccc2c(c1CCC)OC(C(=O)O)CC2=O
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Product: CCCc1c(OCc2ccccc2)ccc2c1OC(CO)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
A 3 neck 250 ml round bottom flask fitted with a magnetic stirring bar, a dropping funnel, a gas inlet tube, and a glass stopper was flame dried and flushed with argon. 100 ml of dry ether was introduced and 331 mg (15.2 mmole) of lithium borohydride was added to the ether. A solution of 5.17 g (15.2 mmole) of the compound of Example 32 in 50 ml of ether was added dropwise to the stirred slurry of borohydride. After the addition was completed, the solution was stirred for 2 hours additional at room temperature. The flask was cooled in an ice bath and 20 ml of water added dropwise followed by the careful dropwise addition of dilute hydrochloric acid until the solution cleared. The aqueous layer was drained off in a separatory funnel and the ether washed once with saturated sodium bicarbonate solution and then with brine. Drying the ether with anhydrous magnesium sulfate, filtration to separate the drying agent and ether removal by rotary evaporation gave 4.34 g (91%) of the title compound as an oil. Calc: C, 76.89; H, 7.74; Found: C, 76.75; H, 7.66.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[CH:5]2.Cl[CH2:19][CH2:20][N:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[C:29]3[CH:30]=[CH:31][CH:32]=[C:23]([C:24]=23)[S:22]1(=[O:34])=[O:33].C(=O)([O-])O.[Na+]>O1CCCC1.CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][CH:12]1[CH2:13][CH2:14][N:15]([CH2:19][CH2:20][N:21]3[C:25]4[CH:26]=[CH:27][CH:28]=[C:29]5[CH:30]=[CH:31][CH:32]=[C:23]([C:24]=45)[S:22]3(=[O:34])=[O:33])[CH2:16][CH2:17]1)=[CH:5]2
Reactant: Fc1ccc2[nH]c(CC3CCNCC3)cc2c1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=S1(=O)c2cccc3cccc(c23)N1CCN1CCC(Cc2cc3cc(F)ccc3[nH]2)CC1
Yield: 39.7 %

Procedure:
A mixture of 4-[(5-fluoro-2-indolyl)methyl]piperidine (2.9 g), 2-(2-chloroethyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (3.5 g) and sodium hydrogen carbonate (1.1 g) in tetrahydrofuran (30 cc) and dimethylformamide (30 cc) is brought to reflux for 12 hours. After evaporation to dryness at 80° C. under reduced pressure (20 mm Hg; 2.7 kPa), the residue is taken up with water (150 cc) and extracted with ethyl acetate (2×75 cc). The combined organic phases are dried over magnesium sulphate and taken to dryness at 80° C. under reduced pressure (20 mm Hg; 2.7 kPa). The residue is purified by flash chromatography on a silica column under a stream of nitrogen at moderate pressure (0.5-1.5 bar) with a cyclohexane/ethyl acetate mixture (50:50 by volume) as eluent. 2-{2-[4-((5-Fluoro-2-indolyl)methyl)piperidino]ethyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (2.3 g), m.p. 154° C., is obtained.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1.Cl.[N+:14]([C:17]1[CH:18]=[C:19]([NH2:26])[C:20](=[CH:24][CH:25]=1)[C:21](Cl)=[O:22])([O-:16])=[O:15]>>[N+:14]([C:17]1[CH:18]=[C:19]2[C:20]([C:21](=[O:22])[N:6]3[C:5]4[CH:7]=[C:8]([Cl:12])[C:9]([Cl:11])=[CH:10][C:4]=4[NH:3][C:2]3=[N:26]2)=[CH:24][CH:25]=1)([O-:16])=[O:15]
Reactant: Clc1nc2cc(Cl)c(Cl)cc2[nH]1
Reactant: Nc1cc([N+](=O)[O-])ccc1C(=O)Cl
Agent: Cl
Product: O=c1c2ccc([N+](=O)[O-])cc2nc2[nH]c3cc(Cl)c(Cl)cc3n12

Procedure:
3-Nitro-8,9-dichlorobenzimidazo[2,1-b]quinazolin-12(6H)-one is prepared with 2,5,6-trichlorobenzimidazole and 4-nitroanthraniloyl chloride hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([OH:19])=[O:18])(=[O:12])=[O:11])=[C:7]([CH3:23])[C:6]=2[CH:24]=1.[CH2:25](O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([O:19][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:18])(=[O:12])=[O:11])=[C:7]([CH3:23])[C:6]=2[CH:24]=1
Reactant: Cc1c(S(=O)(=O)Nc2cccc(C(=O)O)c2)sc2ccc(Cl)cc12
Reactant: OCc1ccccc1
Product: Cc1c(S(=O)(=O)Nc2cccc(C(=O)OCc3ccccc3)c2)sc2ccc(Cl)cc12
Yield: 68 %

Procedure:
The product was prepared from 3-{[(5-chloro-3-methyl-1-benzothien-2-yl)sulfonyl]amino}benzoic acid (21 mg, 0.055 mmol) (Intermediate 19) and benzyl alcohol (10.8 mg, 0.100 mmol) according to the General Procedure 7, described in Example 107, using a slightly modified reaction time (2 days). The title compound was obtained in 68% yield (17.6 mg). 1H NMR (500 MHz, CDCl3) δ ppm 2.44 (s, 3 H) 5.31 (s, 2 H) 6.96 (s, 1 H) 7.33-7.40 (m, 5 H) 7.36 (dd, J=8.05, 7.70 Hz, 1 H) 7.43 (ddd, J=8.05, 2.36, 1.20 Hz, 1 H) 7.43 (dd, J=8.63, 2.06 Hz, 1 H) 7.68 (dd, J=8.63, 0.58 Hz, 1 H) 7.69 (dd, J=2.06, 0.58 Hz, 1 H) 7.74 (dd, J=2.36, 1.58 Hz, 1 H) 7.86 (ddd, J=7.70, 1.58, 1.20 Hz, 1 H). MS (ESI+) m/z 472 [M+H]+.
Reaction SMILES: [N:1]12[CH2:10][CH2:9][CH:8]1[CH2:7][CH:6]1[CH:2]2[CH2:3][N:4](C(OCC)=O)[CH2:5]1.C(=O)([O-])[O-].[K+].[K+]>O>[N:1]12[CH2:10][CH2:9][CH:8]1[CH2:7][CH:6]1[CH:2]2[CH2:3][NH:4][CH2:5]1
Reactant: CCOC(=O)N1CC2CC3CCN3C2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: C1NCC2C1CC1CCN12

Procedure:
13.7 g (65.1 mmol) of ethyl 1,4-diazatricyclo[6.2.0.02,6 ]decane-4-carboxylate are heated under reflux overnight with 42 g of Ba(OH)2.8H2O in 150 ml of water. Potassium carbonate is added, barium carbonate is filtered off with suction and the filtrate is extracted ten times using 100 ml of chloroform each time. The extracts are dried over potassium carbonate and concentrated, and the residue is distilled.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([NH:24][C:25](=[O:27])[CH3:26])[S:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1>CO.C(Cl)(Cl)Cl.[O-2].[Mn+4].[O-2]>[CH:2]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([NH:24][C:25](=[O:27])[CH3:26])[S:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1)=[O:1]
Reactant: CC(=O)Nc1nc(-c2ccc(CO)cc2)c(-c2ccc(S(C)(=O)=O)cc2)s1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(=O)Nc1nc(-c2ccc(C=O)cc2)c(-c2ccc(S(C)(=O)=O)cc2)s1
Reaction time: 19 h

Procedure:
To a solution of N-{4-[4-(hydroxymethyl)phenyl]-5-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}acetamide (867.4 mg) in methanol (0.6 ml) and chloroform (10 ml) was added manganese(IV) oxide (6.65 g) at 20° C. under N2 atmosphere, and the mixture was stirred for 19 hrs. The reaction mixture was filtered through a celite pad. The filtrate was evaporeted to give N-{4-(4-formylphenyl)-5-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}acetamide as a yellow solid, that was used as crude in the next reaction.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[N:12]=[C:13]([C@@H:17]([NH:25][C:26](=[O:32])OC(C)(C)C)[CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[NH:14][C:15]=3[Cl:16])=[CH:8][CH:9]=2)[NH:4][N:3]=1.[C:33]([C:35]1[CH:43]=[CH:42][C:38](C(O)=O)=[CH:37][C:36]=1[F:44])#[N:34]>>[NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[N:12]=[C:13]([C@@H:17]([NH:25][C:26](=[O:32])[C:38]4[CH:42]=[CH:43][C:35]([C:33]#[N:34])=[C:36]([F:44])[CH:37]=4)[CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[NH:14][C:15]=3[Cl:16])=[CH:8][CH:9]=2)[NH:4][N:3]=1
Reactant: N#Cc1ccc(C(=O)O)cc1F
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)c1nc(-c2ccc3c(N)n[nH]c3c2)c(Cl)[nH]1
Product: N#Cc1ccc(C(=O)N[C@@H](Cc2ccccc2)c2nc(-c3ccc4c(N)n[nH]c4c3)c(Cl)[nH]2)cc1F

Procedure:
The product from Example 122 Part B was coupled with 4-cyano-3-fluorobenzoic acid using the methods described in Part F of Example 120. MS: 500.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12]CC1C=CC(OC)=CC=1OC)[C:6]([O:24][CH3:25])=[N:5]2.FC(F)(F)C(O)=O>ClCCl>[NH2:12][C:7]1[C:6]([O:24][CH3:25])=[N:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=2)[N:8]=1
Reactant: COc1ccc(CNc2nc3ccc(Cl)cc3nc2OC)c(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1nc2cc(Cl)ccc2nc1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.9 %

Procedure:
To 6-chloro-2-(2,4-dimethoxybenzylamino)-3-methoxyquinoxaline (4.42 g, 12.3 mmol), 50 ml of 50% trifluoroacetic acid in dichloromethane was added at room temperature. The resulting mixture was stirred at room temperature for 18 hours and concentrated under the reduced pressure to remove the solvent. The residue was neutralized with saturated sodium bicarbonate solution and then NaCl solution was added thereto. The product was extracted with dichloromethane and the organic layer was dried over MgSO4. After concentration under the reduced pressure, the crude product was purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (4:1) mixture and concentration gave 1.52 g of the titled compound (yield, 59%).