Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([NH:18][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)c1cccnc1Cl
Product: O=C(O)c1cccnc1NCc1ccccc1
Temperature: 130 °C

Procedure:
A mixture of 2-chloronicotinic acid (10.0 g) and benzylamine (13.34 ml) was heated at 130° C. for 2 hours. The mixture was cooled and the resulting solid was broken up, triturated with water, acidified to pH 6 and filtered. The solid obtained was boiled up in IMS (200 ml), cooled and filtered to give 2-benzylaminonicotinic acid, m.p. 223°-225° C.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[O:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]=1[CH2:15][OH:16].[CH2:17]([O:19][C:20]([C:22]1[S:26][C:25](Cl)=[N:24][CH:23]=1)=[O:21])[CH3:18].O>O1CCCC1>[CH2:17]([O:19][C:20]([C:22]1[S:26][C:25]([O:16][CH2:15][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH3:3])=[N:24][CH:23]=1)=[O:21])[CH3:18]
Reactant: Cc1onc(-c2ccccc2)c1CO
Reactant: CCOC(=O)c1cnc(Cl)s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cnc(OCc2c(-c3ccccc3)noc2C)s1
Temperature: 25 °C
Yield: 51.7 %

Procedure:
To a stirred suspension of sodium hydride (304 mg, 6.98 mmol, 60% dispersion in mineral oil) in tetrahydrofuran (30 mL) at 0° C. under argon was added (5-methyl-3-phenyl-isoxazol-4-yl)-methanol (1.0 g, 5.28 mmol) The mixture was warmed to room temperature and after 1 h the reaction mixture was cooled to 0° C. then a solution of 2-chloro-thiazole-5-carboxylic acid ethyl ester (1.01 g, 5.28 mmol) in THF (15 mL) added. The reaction mixture was warmed to room temperature and after 15 h, water (20 mL) was added and the resulting mixture extracted with ethyl acetate. The combined organic extracts were dried, filtered and concentrated. Purification by chromatography (silica, 20% ethyl acetate in heptane) gave the title compound (940 mg, 52% yield) as an off-white solid. MS: m/e=345.0 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[CH:4][C:3]=1[C:7](Cl)=[O:8].[OH:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>>[OH:10][CH:11]1[CH2:16][CH2:15][N:14]([C:7]([C:3]2[CH:4]=[N:5][O:6][C:2]=2[CH3:1])=[O:8])[CH2:13][CH2:12]1
Reactant: Cc1oncc1C(=O)Cl
Reactant: OC1CCNCC1
Product: Cc1oncc1C(=O)N1CCC(O)CC1

Procedure:
of melting point 70.5° to 72.5° C., prepared from 5-methyl-4-isoxazolecarboxylic acid chloride and 4-hydroxypiperidine.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:22])=[CH:8][C:9]=2[NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)(=[O:14])=[O:13])[S:4][C:3]=1[CH3:23].[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(Cl)Cl.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.C1(C)C=CC=CC=1>[Cl:21][C:17]1[CH:16]=[C:15]([S:12]([NH:11][C:9]2[CH:8]=[C:7]([CH3:22])[N:6]=[C:5]3[S:4][C:3]([CH3:23])=[C:2]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:10]=23)(=[O:14])=[O:13])[CH:20]=[CH:19][CH:18]=1
Reactant: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(Br)c(C)sc2n1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(-c3ccccc3)c(C)sc2n1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 16.1 %

Procedure:
Under nitrogen, N-(3-bromo-2,6-dimethylthieno[2,3-b]pyridin-4-yl)-3-chlorobenzenesulfonamide (90 mg, 0.208 mmol) (Example 61) was dissolved in 1,4-dioxane (3 mL). Phenylboronic acid (38.1 mg, 0.313 mmol), PdCl2(dppf).DCM (17.02 mg, 0.021 mmol) and Cs2CO3 (204 mg, 0.625 mmol) were added and the mixture heated in a microwave at 120° C. for 30 min. Toluene (3 mL) was added and the mixture heated in a microwave as follows: 130° C. for 30 min, 150° C. for 30 min (×2) and finally 180° C. for 15 min (×2). Water (10 mL) was then added and the mixture extracted with ethyl acetate (3×10 mL). The organic layer was dried over MgSO4, filtered and the solvent removed in vacuo. Purification by chromatography on silica gel, eluting with a gradient of 0-30% ethyl acetate in cyclohexane was followed by further purification by MDAP (basic conditions), to afford the title compound (14.4 mg). LCMS (A) m/z: 429 [M+1]+, Rt 1.10 min (basic), Rt 1.47 min (acidic).
Reaction SMILES: N1C=CC=CC=1.[ClH:7].[C:8]([NH:11][CH2:12][CH2:13][NH:14][N:15]=[CH:16][NH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1)(=[O:10])[CH3:9].Cl.[C:28]([C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[C:37]([CH2:41][C:42](=[O:44])[NH2:43])=[C:36](O)[CH:35]=[CH:34]2)(=[NH:30])[NH2:29].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(C(C)=O)C.O.C(O)(=O)C>[ClH:7].[ClH:7].[C:8]([NH:11][CH2:12][CH2:13][NH:14][N:15]=[CH:16][NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][C:36]2[CH:35]=[CH:34][C:33]3[C:38](=[CH:39][CH:40]=[C:31]([C:28](=[NH:29])[NH2:30])[CH:32]=3)[C:37]=2[CH2:41][C:42](=[O:44])[NH2:43])=[O:23])=[CH:25][CH:26]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)NCCNN=CNc1ccc(C(=O)O)cc1
Reactant: N=C(N)c1ccc2c(CC(N)=O)c(O)ccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)NCCNN=CNc1ccc(C(=O)Oc2ccc3cc(C(=N)N)ccc3c2CC(N)=O)cc1
Reaction time: 2 h
Yield: 88.4 %

Procedure:
40 Milliliters of 10% hydrous pyridine was added to 1.5 g of 4-[(2-acetylaminoethyl)aminoiminomethylamino]benzoic acid.hydrochloride, 1.12 g of 6-amidino-1-carbamoylmethyl-2-naphthol.hydrochloride, 1.55 g of DCC and 61 mg of DMAP, followed by stirring for 2 hours under cooling with ice and then 48 hours at room temperature. The precipitate was filtered and the filtrate was concentrated under reduced pressure. To the residue was added 15 ml of methanol, and this solution was added dropwise to 400 ml of acetone, followed by stirring for 24 hour under cooling with ice. The precipitate was collected by filtration to obtain a crude product. Then, the product was subjected to silica gel column chromatography using methyl ethyl ketone-water-acetic acid (80:15:5) as an eluent, and the desired fractions were collected and the solvent was distilled off under reduced pressure. To the residue were added 15 ml of methanol and 0.96 ml of concentrated hydrochloric acid, and the solution was added dropwise to 400 ml of acetone, followed by stirring for 24 hours under cooling with ice. Then, the precipitate was collected by filtration to obtain 1.24 g of the desired product.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[CH2:14][CH2:13][CH2:12][CH:11]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:10][C:9]=2[CH:23]=1)=O.C[O-].[Na+].O.C([NH2:30])=O>>[CH2:16]([NH:15][CH:11]1[CH2:10][C:9]2[CH:23]=[C:5]([C:3]([NH2:30])=[O:2])[CH:6]=[CH:7][C:8]=2[CH2:14][CH2:13][CH2:12]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NC=O
Reactant: COC(=O)c1ccc2c(c1)CC(NCc1ccccc1)CCC2
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: NC(=O)c1ccc2c(c1)CC(NCc1ccccc1)CCC2
Temperature: 110 °C

Procedure:
A mixture of 8-benzylamino-6,7,8,9-tetrahydro-5H-benzocycloheptene-2-carboxylic acid methyl ester (4.21 g) and sodium methoxide (2.21 g) in formamide (42 ml) was heated at 110° C. for 2 hours. After cooling, the reaction mixture was poured into water, and the product was extracted with ethyl acetate. The organic layer was washed with water (twice) and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with a mixture of chloroform and methanol (30:1 to 10:1) to afford 8-benzylamino-6,7,8,9-tetrahydro-5H-benzocycloheptene-2-carboxamide (2.71 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH3:14])[CH3:13])(=[O:10])=[O:9])=[C:4]([O:15][C:16]([F:19])([F:18])[F:17])[CH:3]=1.[C:20]([C:22]1[N:26]([CH3:27])[C:25](B(O)O)=[CH:24][CH:23]=1)#[N:21].[F-].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[C:20]([C:22]1[N:26]([CH3:27])[C:25]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH3:14])[CH3:13])(=[O:10])=[O:9])=[C:4]([O:15][C:16]([F:19])([F:18])[F:17])[CH:3]=2)=[CH:24][CH:23]=1)#[N:21]
Reactant: Cn1c(C#N)ccc1B(O)O
Reactant: CC(C)NS(=O)(=O)c1ccc(Br)cc1OC(F)(F)F
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC(C)NS(=O)(=O)c1ccc(-c2ccc(C#N)n2C)cc1OC(F)(F)F
Reaction time: 16 h
Yield: 34.6 %

Procedure:
According to general procedure B, 4-bromo-N-isopropyl-2-(trifluoromethoxy)benzenesulfonamide (217 mg, 0.59 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (107 mg, 0.71 mmol), potassium fluoride (113 mg, 1.95 mmol), and tris(dibenzylideneacetone)dipalladium (0) (15 mg, 0.01 mmol) were placed in an oven dried flask under nitrogen and dry THF (1.4 mL) was added. Tri-t-butylphosphine (89 μL, 0.02 mmol, 10 wt % in hexane) was added and the reaction was stirred for 16 hours. 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-isopropyl-2-(trifluoromethoxy)benzenesulfonamide (79 mg, 35%) was provided after purification. MS (ESI) m/z 387. HPLC purity 100.0% at 210-370 nm, 9.8 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=[CH2:12]>>[C:8]([C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH2:12][CH2:11][C:10]([O:14][CH2:15][CH3:16])=[O:13])[CH2:12][CH2:11][C:10]([O:14][CH2:15][CH3:16])=[O:13])#[N:9]
Reactant: N#CCc1ccccc1
Reactant: C=CC(=O)OCC
Product: CCOC(=O)CCC(C#N)(CCC(=O)OCC)c1ccccc1

Procedure:
The required diethyl γ-cyano-γ-phenylpimelate was prepared by reacting phenylacetonitrile with ethyl acrylate according to the general method of Koelsch, J. Am. Chem. Soc., 65, 437 (1943). This product, boiling point 148°-151° C. at 0.04 mm [Branchini et al., Ann. Chim. (Rome) 51, 1382 (1961) report 170°-172° C. at 0.2 mm] was obtained in addition to the mono-Michael addition product reported by Koelsch.
Reaction SMILES: Br[CH:2]([CH3:12])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:4].[N:13]1(C(OCC)=O)[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(N(CC)CC)C.[OH-].[Na+]>C(OCC)C.C(OCC)(=O)C>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH:2]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH3:12])=[CH:6][CH:7]=1
Reactant: CCOC(=O)N1CCNCC1
Reactant: CC(Br)C(=O)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(C(=O)c1ccc(Cl)cc1)N1CCNCC1

Procedure:
A solution of 2-bromo-4′-chloropropiophenone, (741 mg, 3 mmol); ethyl 1-piperazinecarboxylate (474 mg, 3 mmol); triethylamine (0.42 mL, 3 mmol) in diethyl ether (10 mL) was heated at reflux for 3 hours (reaction was monitored by Thin Layer Chromatography (TLC)). The reaction mixture was cooled and further diluted with ethyl acetate and washed with water, brine and dried over Na2SO4. After evaporation of the solvent in vacuo, the crude viscous liquid was treated with conc. HCl (15 mL) at refluxing temperature for 48 hrs. The cooled reaction mixture was made alkaline by addition of 50% NaOH and extracted with ethyl acetate. The combined extracts were washed with water, brine and dried over Na2SO4. After evaporation of the solvent 4′chloro-2-(piperazin-1-yl)propiophenone was obtained as a semisolid which was reacted without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([Cl:12])[N:6]=[CH:5]2.[CH3:13][O:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[C:19]([O:21][CH3:22])[CH:20]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.O1CCOCC1.O.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>[Cl:12][C:7]1[N:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:17]3[CH:16]=[C:15]([O:14][CH3:13])[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=3)[CH:3]=2)[N:8]=1
Reactant: Clc1ncc2cc(Br)ccc2n1
Reactant: COc1cc(OC)cc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(OC)cc(-c2ccc3nc(Cl)ncc3c2)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 38.9 %

Procedure:
A mixture of 6-bromo-2-chloroquinazoline (32) (5.0 g, 20.5 mmol), 3,5-dimethoxyphenylboronic acid (33) (3.7 g, 20.5 mmol), Cs2CO3 (20.0 g, 61.5 mmol) and Pd(PPh3)2Cl2 (1.4 g, 2.1 mmol) in THF (50 mL), dioxane (50 mL) and water (10 mL) was degassed with N2 three times, and stirred at 80° C. for 3 hours. An aliquot of the reaction mixture was analyzed by both TLC and LCMS, which indicated that the reaction had proceeded to completion. The mixture was cooled to room temperature, and extracted with EtOAc (3×200 mL). The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether/EtOAc=8:1) to obtain 2-chloro-6-(3,5-dimethoxyphenyl)quinazoline (34) as a light yellow solid (2.4 g, 38%). MS (ES+) C16H13ClN2O2 requires: 300. found: 301, 303 [M+H]+.
Reaction SMILES: [CH2:1]1[O:11][C:10]2[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][C:3]=2[O:2]1.[CH3:12][O:13][C:14](=[O:35])[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:22]=[C:23](Cl)[C:24]3[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[S:27][C:25]=3[N:26]=2)=[CH:17][CH:16]=1>>[CH3:12][O:13][C:14](=[O:35])[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:22]=[C:23]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:10]4[O:11][CH2:1][O:2][C:3]=4[CH:4]=3)[C:24]3[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[S:27][C:25]=3[N:26]=2)=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3cc(C(F)(F)F)sc3n2)cc1
Reactant: NCc1ccc2c(c1)OCO2
Product: COC(=O)c1ccc(-c2nc(NCc3ccc4c(c3)OCO4)c3cc(C(F)(F)F)sc3n2)cc1

Procedure:
The reaction procedure as above wherein 3,4-methylenedioxy-benzylamine is reacted with 4-(4-chloro-6-trifluoromethyl-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(3,4-methylenedioxybenzylamino)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([S:16][CH2:17][CH2:18][NH:19]C(OC(C)(C)C)=O)[N:13]=[C:12]([NH2:27])[N:11]=2)[C:7]([CH3:28])=[CH:6][C:5]=1[CH3:29].FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([S:16][CH2:17][CH2:18][NH2:19])[N:13]=[C:12]([NH2:27])[N:11]=2)[C:7]([CH3:28])=[CH:6][C:5]=1[CH3:29]
Reactant: COC(=O)c1cc(-c2cc(SCCNC(=O)OC(C)(C)C)nc(N)n2)c(C)cc1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(-c2cc(SCCN)nc(N)n2)c(C)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 108.3 %

Procedure:
5-[2-Amino-6-(2-tert-butoxycarbonylaminoethylsulfanyl)pyrimidin-4-yl]-2,4-dimethylbenzoic acid methyl ester (531 mg, 1.23 mmol) obtained in Step 1 above was dissolved in dichloromethane (3.0 ml). Trifluoroacetic acid (1.5 ml) was added to the solution, and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure. The resulting residue was diluted with ethyl acetate, and then a saturated aqueous sodium bicarbonate solution was added thereto. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined together, and sequentially washed with water and a saturated aqueous sodium chloride solution. The ethyl acetate solution was dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to yield the crude product of 5-[2-amino-6-(2-aminoethylsulfanyl)pyrimidin-4-yl]-2,4-dimethylbenzoic acid methyl ester (443 mg) as a white solid material.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8](=[O:14])[CH:7]=[CH:6]2.[C:15]([S:19][C:20]1([C:26]2[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([OH:33])[CH:27]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)([CH3:18])([CH3:17])[CH3:16]>>[C:15]([S:19][C:20]1([C:26]2[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([O:33][CH2:2][C:3]3[CH:4]=[C:5]4[C:10](=[CH:11][CH:12]=3)[N:9]([CH3:13])[C:8](=[O:14])[CH:7]=[CH:6]4)[CH:27]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)([CH3:18])([CH3:16])[CH3:17]
Reactant: Cn1c(=O)ccc2cc(CBr)ccc21
Reactant: CC(C)(C)SC1(c2cc(O)cc(F)c2)CCOCC1
Product: Cn1c(=O)ccc2cc(COc3cc(F)cc(C4(SC(C)(C)C)CCOCC4)c3)ccc21
Yield: 30 %

Procedure:
Using a similar procedure to that described in Example 11, 6-bromomethyl-1-methyl-1,2-dihydroquinolin-2-one was reacted with 4-tert-butylthio-4-(5-fluoro-3-hydroxyphenyl)tetrahydropyran to give 4-tert-butylthio-4-[5-fluoro-3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-ylmethoxy)phenyl]tetrahydropyran in 30% yield, m.p. 54°-56° C.
Reaction SMILES: [O-]CC.[Na+].Cl.[C:6]([NH2:14])(=[NH:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([O:17][C:18](=O)[CH:19]([CH3:25])[C:20](OCC)=[O:21])C.Cl>C(O)C>[CH3:25][C:19]1[C:20]([OH:21])=[N:13][C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:14][C:18]=1[OH:17]
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: N=C(N)c1ccccc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1c(O)nc(-c2ccccc2)nc1O
Temperature: 40 °C
Reaction time: 22 h

Procedure:
To ethanol (180 ml) was added sodium ethoxide solution (38 ml of a 21% wt solution in ethanol), benzamidine hydrochloride (5.0 g) and diethylmethylmalonate (4.91 ml). The suspension was stirred at 40° C. in an inert atmosphere for 22 hrs after which time it was cooled to 5° C. (ice bath) and treated dropwise with concentrated hydrochloric acid to a pH of 2.5. The resulting pink suspension was filtered and washed with excess water. Purification by recrystallisation from boiling acetic acid (300 ml) afforded the title compound (4.22 g) after filtration and washing with ethanol (20 ml) and diethyl ether (20 ml).
Reaction SMILES: [CH:1]1([CH2:4][C@H:5]([NH:23]C(=O)OC(C)(C)C)[C:6]([NH:8][C@@H:9]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]([C@@:12]2([CH3:15])[CH2:14][O:13]2)=[O:11])=[O:7])[CH2:3][CH2:2]1.[C:31]([OH:37])([C:33]([F:36])([F:35])[F:34])=[O:32]>C(Cl)Cl>[OH:37][C:31]([C:33]([F:36])([F:35])[F:34])=[O:32].[NH2:23][C@@H:5]([CH2:4][CH:1]1[CH2:3][CH2:2]1)[C:6]([NH:8][C@@H:9]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10]([C@@:12]1([CH3:15])[CH2:14][O:13]1)=[O:11])=[O:7]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CC1)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@@]1(C)CO1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@]1(C(=O)[C@H](Cc2ccccc2)NC(=O)[C@@H](N)CC2CC2)CO1
Reaction time: 0.5 h

Procedure:
To tert-butyl ((S)-3-cyclopropyl-1-(((S)-1-((R)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)amino)-1-oxopropan-2-yl)carbamate (663 mg, 1.59 mmol) was added DCM (2.5 mL) and TFA (2.5 mL). The mixture was allowed to stand at ambient temperature for 30 min before it was concentrated to provide (S)-2-amino-3-cyclopropyl-N-((S)-1-((R)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)propanamide TFA salt (657 mg, quant.) as a yellow oil that was carried forward without further purification. MS (EI) for C20H24F3N2O4, found 317.2 [M-TFA]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:10]2=[CH:11][C:12]3[NH:13][C:14]4[C:19]([C:20]=3[CH:21]=[C:9]2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4.[H-].[Na+].[C:25]([C:29]1[CH:34]=[CH:33][C:32]([C:35]2[N:40]=[C:39]([C:41]3[CH:46]=[CH:45][C:44]([C:47]([CH3:50])([CH3:49])[CH3:48])=[CH:43][CH:42]=3)[N:38]=[C:37](Cl)[N:36]=2)=[CH:31][CH:30]=1)([CH3:28])([CH3:27])[CH3:26]>CN(C)C=O.C1COCC1>[C:25]([C:29]1[CH:30]=[CH:31][C:32]([C:35]2[N:40]=[C:39]([C:41]3[CH:42]=[CH:43][C:44]([C:47]([CH3:50])([CH3:49])[CH3:48])=[CH:45][CH:46]=3)[N:38]=[C:37]([N:13]3[C:12]4[CH:11]=[C:10]5[C:2]([CH3:22])([CH3:1])[C:3]6[C:8]([C:9]5=[CH:21][C:20]=4[C:19]4[C:14]3=[CH:15][CH:16]=[CH:17][CH:18]=4)=[CH:7][CH:6]=[CH:5][CH:4]=6)[N:36]=2)=[CH:33][CH:34]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CC1(C)c2ccccc2-c2cc3c(cc21)[nH]c1ccccc13
Reactant: CC(C)(C)c1ccc(-c2nc(Cl)nc(-c3ccc(C(C)(C)C)cc3)n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(-c2nc(-c3ccc(C(C)(C)C)cc3)nc(-n3c4ccccc4c4cc5c(cc43)C(C)(C)c3ccccc3-5)n2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
12.5 g (44 mmol) of 12,12-dimethyl-10,12-dihydro-10-azaindeno[2,1-b]-fluorene are dissolved in 200 ml of dimethylformamide under a protective-gas atmosphere, and 2.1 g of 60% NaH in mineral oil (52.7 mmol) are added. After 1 h at room temperature, a solution of 2,4-bis(4-tert-butylphenyl)-6-chloro-1,3,5-triazine (20 g, 52.7 mmol) in 100 ml of THF is added dropwise. The reaction mixture is stirred at room temperature for 12 h. After this time, the reaction mixture is poured onto ice and extracted three times with dichloromethane. The combined organic phases are dried over Na2SO4 and evaporated. The residue is extracted with hot toluene, recrystallised from toluene and finally sublimed in a high vacuum. Yield: 17 g, 60%. The purity is 99.9%.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[CH2:19][CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1C(=O)N(C)CCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:42][O:43][C:44]1[CH:51]=[CH:50][CH:49]=[CH:48][C:45]=1[CH2:46]I.C(O)(=O)CC.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.C(OCC)(=O)C.O>[C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH2:46][C:45]2[CH:48]=[CH:49][CH:50]=[CH:51][C:44]=2[O:43][CH3:42])[CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: COc1ccccc1CI
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1CCC(=O)O1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCC(=O)O
Product: COc1ccccc1C[C@@H]1C[C@@H]([C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)OC1=O
Reaction time: 0.25 h

Procedure:
A solution of 1 g (3.275 mmol) of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]dihydrofuran-2-(3H)-one [Example 2b)] in 4 ml of abs. THF and 0.66 ml of DMPU (1.67 equivalents) is cooled down to -75° C., under argon, and treated dropwise, at an internal temperature of below -70° C. and over the space of 30 min, with 6.42 ml (1.96 equivalents) of a 1M solution of lithium bis(trimethylsilyl)amide in THF (Aldrich, Steinheim, FRG). After a further 15 min, 812 mg (3.275 mmol) of 2-methoxybenzyl iodide, dissolved in 2 ml of THF, are added dropwise to this mixture within the space of 10 min, and the whole is allowed to react at -70° C. for 2 h. 1.22 ml of propionic acid and 1.22 ml of water are subsequently added to this solution, and the temperature is allowed to rise to 0° C. The reaction mixture is diluted with 50 ml of (cold) ethyl acetate and stirred, for 5 min, with 20 ml of (cold) 10% citric acid, and, after that, the phases are separated. The organic phase is washed, in succession, with saline, sat. sodium bicarbonate solution and once again with saline, dried over Na2SO4 and concentrate. The title compound is isolated by means of flash chromatography on silica gel (hexane:ethyl acetate=3:1). TLC Rf (hexane:ethyl acetate=3:1)=0.54. MS M+ =455. HPLC tRet =17.09 min (gradient II). IR(CH2Cl2)=inter alia 3429, 1769, 1712, and 1495 cm-1. 1H-NMR(CDCl3)=inter alia 7.38-7.13/m (5H); 7.20/d (1H); 7.08/d (1H); 6.87/t (1H); 6.81/d (1H); 3.74/s (3H); 1.34/s (9H).
Reaction SMILES: C1(C#CC2CC3(CCNCC3)ON=2)C=CC=CC=1.[Cl:19][C:20]1[CH:21]=[C:22]([C:26]#[C:27][C:28]2[CH2:32][C:31]3(CC[N:34]([C:37](OC(C)(C)C)=O)[CH2:33]3)[O:30][N:29]=2)[CH:23]=[CH:24][CH:25]=1>>[Cl:19][C:20]1[CH:21]=[C:22]([C:26]#[C:27][C:28]2[CH2:32][C:31]3([CH2:33][NH:34][CH2:37]3)[O:30][N:29]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC(C#Cc3cccc(Cl)c3)=NO2)C1
Agent: C(#Cc1ccccc1)C1=NOC2(CCNCC2)C1
Product: Clc1cccc(C#CC2=NOC3(CNC3)C2)c1

Procedure:
The title compound was synthesized following the method reported for the Compound 1c, substituting Compound 1b with Compound 27c. The crude residue was used without further purification in the next reaction step.