Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2](=[N:13][OH:14])[C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)#[CH:16].C(N(CC)CC)C.O>O1CCCC1>[C:17]1([C:15]2[O:14][N:13]=[C:2]([C:3]3[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=3)[C:6]([O:8][CH3:9])=[O:7])[CH:16]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C#Cc1ccccc1
Reactant: COC(=O)c1cccc(C(Cl)=NO)c1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(-c2cc(-c3ccccc3)on2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To a solution (40 ml) of methyl 3-[chloro(hydroxyimino)methyl]benzoate (1.42 g) and ethynylbenzene (1.0 ml) in tetrahydrofuran was added dropwise a solution (10 ml) of triethylamine (2.5 ml) in tetrahydrofuran under an argon atmosphere at 0° C. This mixture was stirred overnight at room temperature and poured into water. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized from hexane-ethyl acetate to give methyl 3-(5-phenyl-3-isoxazolyl)benzoate. (2.43 g, yield 96%) as colorless crystals. melting point: 99–100° C.
Reaction SMILES: [CH:1]1([C:4]2[N:5]([CH2:10][C:11]([O-:13])=[O:12])[C:6]([CH3:9])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH2:14]([SiH](CC)CC)[CH3:15].FC(F)(F)S(O[Si](C)(C)C)(=O)=O.[N:33]1([S:38]([C:41]2[CH:48]=[CH:47][CH:46]=[CH:45][C:42]=2[CH:43]=O)(=[O:40])=[O:39])[CH2:37][CH2:36][CH2:35][CH2:34]1>>[CH:1]1([C:4]2[N:5]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([CH3:9])=[C:7]([CH2:43][C:42]3[CH:45]=[CH:46][CH:47]=[CH:48][C:41]=3[S:38]([N:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)(=[O:40])=[O:39])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: CC[SiH](CC)CC
Reactant: O=Cc1ccccc1S(=O)(=O)N1CCCC1
Reactant: Cc1ccc(C2CC2)n1CC(=O)[O-]
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Product: CCOC(=O)Cn1c(C2CC2)cc(Cc2ccccc2S(=O)(=O)N2CCCC2)c1C
Yield: 24.7 %

Procedure:
was followed using 2-(2-cyclopropyl-5-methyl-1H-pyrrol-1-yl)acetate (1.25 g, 6.03 mmol), triethylsilane (2.89 mL, 18.1 mmol), trimethylsilyl trifluoromethanesulfonate (2.18 mL, 12.1 mmol) and 2-(pyrrolidin-1-ylsulfonyl)benzaldehyde (1.44 g, 6.03 mmol) to afford ethyl 2-(5-cyclopropyl-2-methyl-3-(2-(pyrrolidin-1-ylsulfonyl)benzyl)-1H-pyrrol-1-yl)acetate (642 mg, 1.49 mmol, 25% yield) as an oil.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]1[S:12][N:11]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:9]=1.[O:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[C:21]([N:28](C(OCC(Cl)(Cl)Cl)=O)[C:29](OCC(Cl)(Cl)Cl)=[O:30])=[N:20]1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[O:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[C:21]([NH:28][C:29]([N:6]2[CH2:5][CH2:4][N:3]([C:8]3[S:12][N:11]=[C:10]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:9]=3)[CH:2]([CH3:1])[CH2:7]2)=[O:30])=[N:20]1
Reactant: CC1CNCCN1c1nc(-c2ccccc2)ns1
Reactant: O=C(OCC(Cl)(Cl)Cl)N(C(=O)OCC(Cl)(Cl)Cl)c1noc2ccccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: CC1CN(C(=O)Nc2noc3ccccc23)CCN1c1nc(-c2ccccc2)ns1

Procedure:
A solution of 2-methyl-1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (390 mg, 1.50 mmol), bis(2,2,2-trichloroethyl) 1,2-benzisoxazol-3-ylimidodicarbonate (363 mg, 0.750 mmol), diisopropylethylamine (0.131 ml, 0.750 mmol) and dimethylsulfoxide (10 ml) was stirred at 70° C. for 2 hours, the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain the desired product as a solid. This was recrystallized from a mixed solvent of ethyl acetate and hexane to obtain the desired product (220 mg, 69.8%) as a solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([C:13]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:14])[CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[Br:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Br:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[CH:12]=[C:11]([C:13]([N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)=[O:14])[CH:10]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:3]=2)=[CH:23][CH:22]=1
Reactant: OB(O)c1ccc(Br)cc1
Reactant: CCOC(=O)c1cc(Br)cc(C(=O)N2CCCC2)c1
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: [Cs+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1cc(C(=O)N2CCCC2)cc(-c2ccc(Br)cc2)c1

Procedure:
To a mixture of ethyl 3-bromo-5-(pyrrolidine-1-carbonyl)benzoate (3.20 g, 9.81 mmol), 4-bromophenylboronic acid (2.17 g, 10.8 mmol), toluene (40 mL), cesium carbonate (3.52 g, 10.8 mmol), and water (5 mL) under argon was added tetrakis(triphenylphosphine)palladium(0) (567 mg, 0.49 mmol). The mixture was heated under reflux for 15 h. After cooling, the mixture was filtered through Celite and the filter cake was washed with EtOAc. The filtrate was washed with brine, dried (Na2SO4), and concentrated. The residue was purified by silica gel column (0-80% EtOAc/hexane) to afford a syrup. LC-MS: 404.0 [M+1]+.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[CH:9][N:10]([CH3:11])[C:6]=2[C:5]([C:12]([O:14]C)=[O:13])=[CH:4][N:3]=1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20].[OH-].[Na+].C(OCC)C>O1CCOCC1.CO>[Cl:16][C:17]1[CH:18]=[C:19]([NH:20][C:2]2[C:7]3[CH:8]=[CH:9][N:10]([CH3:11])[C:6]=3[C:5]([C:12]([OH:14])=[O:13])=[CH:4][N:3]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: Nc1cccc(Cl)c1
Reactant: COC(=O)c1cnc(Cl)c2ccn(C)c12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: CO
Product: Cn1ccc2c(Nc3cccc(Cl)c3)ncc(C(=O)O)c21
Temperature: 110 °C

Procedure:
To a suspension of methyl 4-chloro-1-methyl-1H-pyrrolo[3,2-c]pyridine-7-carboxylate (23.1 g) in 1,4-dioxane (300 ml) was added 3-chloroaniline (27 ml). The reaction was heated at 110° C. for 17 hours during which time a solution was rapidly formed upon heating followed by the precipitation of a solid. The reaction was allowed to cool and then partitioned between dichloromethane (700 ml) and saturated sodium carbonate (500 ml). The aqueous layer was separated and further extracted with dichloromethane (300 ml). The organic extracts were combined and dried (MgSO4). This was then combined with another dichloromethane extract of a reaction conducted as above (weight of methyl 4-chloro-1-methyl-1H-pyrrolo[3,2-c]pyridine-7-carboxylate is 22.9 g). The solvent was removed to yield an orange/brown solid. This was heated in methanol (650 ml) and 2N sodium hydroxide (350 ml) to 80° C. and stirred for 3 hours. The reaction was cooled and then reduced in vacuo. The residue was stirred with diethyl ether (400 ml) for 15 minutes. The orange liquid was decanted and the solid residue triturated with diethyl ether (400 ml). The solid was filtered then added to water (400 ml). The solution was altered in pH to around 7 with 5N hydrochloric acid. The precipitate was filtered, however was in the form of a sticky gum. All material was transferred into a flask with methanol (>1 L in total). The solution was reduced in vacuo. A precipitate formed after the majority of the methanol had been removed. This was filtered and dried in vacuo to yield the title compound (60.23 g).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C@@H:18]3[CH2:22][CH2:21][CH2:20][C@H:19]3[CH2:23][C:24]3[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=3)[C:27](O)=[O:28])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:33]1[CH:38]=[CH:37][C:36]([O:39][C:40]2[C:45]([NH2:46])=[CH:44][CH:43]=[CH:42][CH:41]=2)=[CH:35][CH:34]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.CN(C)C1C=CN=CC=1.CCOC(C)=O>[O:39]([C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][C:45]=1[NH:46][C:27](=[O:28])[C:26]1[CH:30]=[CH:31][CH:32]=[C:24]([CH2:23][C@@H:19]2[CH2:20][CH2:21][CH2:22][C@H:18]2[C:9]2[O:10][C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)[CH:25]=1)[C:36]1[CH:35]=[CH:34][CH:33]=[CH:38][CH:37]=1
Reactant: O=C(O)c1cccc(C[C@@H]2CCC[C@H]2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reactant: Nc1ccccc1Oc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Nc1ccccc1Oc1ccccc1)c1cccc(C[C@@H]2CCC[C@H]2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.5 %

Procedure:
To a mixture of 3-{[(1S,2R)-2-(4,5-diphenyloxazol-2-yl)-1-cyclopentyl)methyl}benzoic acid (120 mg, 0.284 mmol) and 2-aminodiphenyl ether (68 ml, 0.369 mmol) in DMF (5 ml) was added 1-hydroxybenzotrioxazole (58 mg, 0.426 mmol), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (109 mg, 0.568 mmol), and 4-dimethylaminopyridine (27 mg, 0.284 mmol). After stirring the mixture at room temperature for 2 hours, the reaction mixture was heated at 80° C. for 3 hours. Then, the resultant mixture was diluted with EtOAc (30 ml), washed with 1N hydrochloric acid, water, saturated sodium hydrogencarbonate solution, water, and brine. The resultant mixture was dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane:EtOAc, 4:1 elution) to give N-(2-phenoxyphenyl)-3-{[(1S,2R)-2-(4,5-diphenyloxazol-2-yl)-1-cyclopentyl]methyl}benzamide (84.7 mg, 51%).
Reaction SMILES: [N:1]([C@H:4]1[CH2:28][CH2:27][C@@:26]2([CH3:29])[C:6](=[CH:7][CH2:8][C@@H:9]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:30])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C@H:14]([CH3:21])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:5]1)=[N+]=[N-].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C(OCC)C>[NH2:1][C@H:4]1[CH2:28][CH2:27][C@@:26]2([CH3:29])[C:6](=[CH:7][CH2:8][C@@H:9]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:30])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C@H:14]([CH3:21])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:5]1
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](N=[N+]=[N-])CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](N)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 4 °C
Reaction time: 2 h
Yield: 96.3 %

Procedure:
A solution of 3β-azido-5-cholestene (6.18 g, 15.0 mmol) in anhydrous diethyl ether (100 mL) was cooled to 4° C. by ice-water bath. To this solution, LiAlH4 (855 mg, 22.5 mmol) was added in four equal portions. The reaction was maintained at 4° C. for 30 min, warmed to 22° C. and stirred for 2 h. When the starting material disappeared by TLC analysis (hexanes), the reaction was cooled to 4° C. and carefully quenched by slow dropwise addition of cold deionized water (10 mL). The resulting solution was poured into ice water (90 mL), the organic layer was separated, and the aqueous layer was extracted with ethyl acetate (50 mL×2). The organic layers was combined, washed with saturated aqueous sodium chloride (100 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The resulting residue was redissolved in CHCl3 (30 mL) and insoluble salts were removed by filtration. Concentration of the filtrate afforded the product (5.57 g, 96.3%) as white solid, mp 92-94° C.; 1H NMR (300 MHz, CDCl3) δ 5.27 (s, 1H), 2.60-2.52 (m, 1H), 2.10-0.81 (m, 40H), 0.64 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 141.7, 120.5, 56.7, 56.1, 51.9, 50.2, 43.3, 42.2, 39.7, 39.4, 38.1, 36.5, 36.1, 35.7, 32.6, 31.8 (×2), 28.2, 27.9, 24.2, 23.8, 22.7, 22.5, 20.9, 19.4, 18.6, 11.8; IR (film) ν 3354, 3260, 3154, 2936, 2896, 2849, 1464, 1437, 1381 cm−1;
Reaction SMILES: CS[C:3]1[N:4]=[C:5]([CH2:12][C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[NH:6][C:7](=[O:11])[C:8]=1[C:9]#[N:10].[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([NH:25][C:3]1[N:4]=[C:5]([CH2:12][C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[NH:6][C:7](=[O:11])[C:8]=1[C:9]#[N:10])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCc1ccccc1
Reactant: CSc1nc(Cc2ccsc2)[nH]c(=O)c1C#N
Product: N#Cc1c(NCc2ccccc2)nc(Cc2ccsc2)[nH]c1=O

Procedure:
In analogy to the preparation of Example 1, 100 mg (0.38 mmol) of 4-(methylsulphanyl)-6-oxo-2-(3-thienylmethyl)-1,6-dihydropyrimidine-5-carbonitrile are reacted with 407 mg (3.80 mmol) of benzylamine to give 43 mg (35% of theory) of the title compound.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([CH2:20][C:21](=[O:27])[N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[N:16]=2)[CH2:11][C:12](O)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:41][OH:42]>O1CCCC1>[NH3:16].[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([CH2:20][C:21](=[O:27])[N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[N:16]=2)[CH2:11][C:12]([NH:41][OH:42])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NO
Reactant: O=C(O)C[C@@H](CCCC1CCCCC1)c1nc(CC(=O)N2CCCC2)no1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: N
Product: O=C(C[C@@H](CCCC1CCCCC1)c1nc(CC(=O)N2CCCC2)no1)NO
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.1 %

Procedure:
A solution of (3R)-6-cyclohexyl-3-{3-[2-oxo-2-(1-pyrrolidinyl)ethyl]-1,2,4-oxadiazol-5yl}hexanoic acid (Preparation 53) (200 mg, 0.53 mmol) in anhydrous tetrahydrofuran (10 ml) was treated with 1,1′-carbonyldiimidazole (86 mg, 0.53 mmol) and the mixture stirred at room temperature under a nitrogen atmosphere for 2 hours. Hydroxylamine hydrochloride (37 mg, 0.53 mmol) was then added and the mixture stirred for 18 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol:0.88 ammonia (90:10:1) to afford the title compound as a colourless oil (50 mg).
Reaction SMILES: [O:1]1[C@@H:5]2[CH2:6][O:7][CH2:8][C@@H:4]2[C:3]([CH2:9]O)=[N:2]1.C(N(S(F)(F)[F:17])CC)C>ClCCl>[F:17][CH2:9][C:3]1[C@H:4]2[CH2:8][O:7][CH2:6][C@H:5]2[O:1][N:2]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: OCC1=NO[C@@H]2COC[C@H]12
Solvent: ClCCl
Product: FCC1=NO[C@@H]2COC[C@H]12
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 40.1 %

Procedure:
Intermediate IV-2: A solution of (3aS,6aS)-rel-1-(3a,4,6,6a-tetrahydro-furo[3,4-d]isoxazol-3-yl)-methanol (14.0 mmol) in dichloromethane (40 ml) was treated dropwise with a solution of (diethylamino)sulfur trifluoride (15.4 mmol) in dichloromethane (5 ml) at −70° C. The colorless turbid solution was stirred at −70° C. for 30 minutes and then allowed to warm to room temperature while its color turned to brown. After stirring for one hour the dark brown solution was cooled in an ice-bath and quenched with a saturated solution of sodium hydrogencarbonate (50 ml). The aqueous layer was separated and extracted twice with dichloromethane. The combined organic layers were dried over sodium sulphate, then evaporated. The crude product was purified by chromatography on silica gel using a gradient of heptane and ethyl acetate=100:0 to 80:20 as the eluent. The (3aS,6aS)-rel-3-fluoromethyl-3a,4,6,6a-tetrahydro-furo[3,4-d]isoxazole (814 mg, 40% yield) was obtained as a light yellow solid. MS: m/z=146.2 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3]([NH:5][C:6]1[S:7][C:8](=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[C:9](=[O:11])[N:10]=1)=[NH:4].[NH2:27][CH2:28][C@H:29]([OH:39])[CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1>>[OH:39][C@H:29]([CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)[CH2:28][NH:27][CH:22]1[CH2:23][CH2:24][N:19]([C:16]2[CH:17]=[CH:18][C:13]([CH:12]=[C:8]3[S:7][C:6]([NH:5][C:3](=[NH:4])[N:2]([CH3:1])[CH3:26])=[N:10][C:9]3=[O:11])=[CH:14][CH:15]=2)[CH2:20][CH2:21]1
Reactant: CN(C)C(=N)NC1=NC(=O)C(=Cc2ccc(N3CCC(=O)CC3)cc2)S1
Reactant: NC[C@H](O)COc1ccc(O)cc1
Product: CN(C)C(=N)NC1=NC(=O)C(=Cc2ccc(N3CCC(NC[C@H](O)COc4ccc(O)cc4)CC3)cc2)S1

Procedure:
The title compound was prepared from N,N-dimethyl-N′-{4-oxo-5-[4-(4-oxo-piperidin-1-yl)-benzylidene]-4,5-dihydro-thiazol-2-yl}-guanidine(which was obtained in Intermediate 23) and 4-((2S)-3-amino-2-hydroxy-propoxy)-phenol (which was obtained in Intermediate 5) according to the procedure of Example 1 as a yellowish solid; 1H NMR (300 MHz, DMSO-d6) δ 1.20-1.40 (m, 2 H), 1.75-1.95 (m, 2 H), 2.50-3.30 (m, 9H), 3.70-3.90 (m, 7H), 4.90 (brs, 1 H), 6.66 (d, J=6.8 Hz, 1 H), 6.74 (d, J=6.8 Hz, 1 H), 7.01 (d, J=8.8 Hz, 2 H), 7.41 (d, J=8.8 Hz, 2 H), 7.47 (s, 1 H); MS (ES) m/z: 270.0 ((M+2 H)2+, 100%); 539.1 (MH+, 10%); HRMS Calcd. for C27H35N6O4S (MH+): 539.2441. Found: 539.2422.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([C:26]([OH:28])=O)([CH3:25])[CH3:24])[CH:17]=1)[C:10]([CH3:30])([CH3:29])[CH2:9]2)=[O:5])[CH3:2].Cl.[CH3:32][NH:33][CH3:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([C:26](=[O:28])[N:33]([CH3:34])[CH3:32])([CH3:24])[CH3:25])[CH:17]=1)[C:10]([CH3:30])([CH3:29])[CH2:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC(C)(C)C(=O)O)c1)N2
Reactant: CNC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC(C)(C)C(=O)N(C)C)c1)N2
Yield: 91.4 %

Procedure:
2-[3-(1-carboxy-1-methyl-ethylamino)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (820 mg, 2 mmol), dimethylamine hydrochloride (490 mg, 6 mmol) and o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1140 mg, 3 mmol) in dichloromethane (5 mL) and triethyl-amine (1.7 mL, 12 mmol) was stirred at 25° C. for 12 h. Then the reaction mixture was extracted with dichloromethane (2×100 mL), washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-[3-(1-dimethylcarbamoyl-1-methyl-ethylamino)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.8 g, 91%) as a brown oil which was used for next step without further purification: LC/MS m/e calcd for C26H35N3O3 (M+H)+: 438.59, observed: 438.2.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].CC(C)([O-])C.[Na+].Br[C:14]1[CH:15]=[CH:16][C:17]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])=[C:18]([CH:22]=1)[C:19]([OH:21])=[O:20].Cl>O.CN(C=O)C>[F:26][C:25]([F:28])([F:27])[CH2:24][O:23][C:17]1[CH:16]=[CH:15][C:14]([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])=[CH:22][C:18]=1[C:19]([OH:21])=[O:20]
Reactant: O=C(O)c1cc(Br)ccc1OCC(F)(F)F
Reactant: OCC(F)(F)F
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Temperature: 100 °C
Reaction time: 10 h
Yield: 75.3 %

Procedure:
To a solution of 2,2,2-trifluoroethanol (14.7 g) and DMF (125 ml) was added sodium tert-butoxide (12.8 g) at 0° C. The solution was stirred at 20 to 25° C. for 1 hour at which point 5-bromo-2-(2,2,2-trifluoroethoxy)benzoic acid (20 g) was added followed by cupric bromide (2.0 g). The mixture was stirred at 100° C. for 10 hours, cooled to 10° C., and water (30 ml) was added followed by 20% HCl solution (90 ml). The solution was extracted with dichloromethane (3×80 ml), and the combined organic layers were washed with water (3×60 ml). The solution was concentrated to one-third of the original volume and hexane (200 ml) was added. The resulting suspension was stirred at room temperature for 2 hours, filtered and the damp cake was rinsed with hexane (2×40 ml). The damp cake was dried in vacuo at 40° C. for 5 hours to give the product as a white solid (16.02 g, yield 75.3%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:36][C:37]1[C:69]([C:70]([F:73])([F:72])[F:71])=[CH:68][CH:67]=[CH:66][C:38]=1[CH2:39][N:40]([CH2:52][CH:53]([C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[CH2:41][CH2:42][CH2:43]OC1C=C(N)C=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:43][CH2:42][CH2:41][N:40]([CH2:39][C:38]2[CH:66]=[CH:67][CH:68]=[C:69]([C:70]([F:71])([F:72])[F:73])[C:37]=2[Cl:36])[CH2:52][CH:53]([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Nc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Reactant: CC(C)(C)OC(=O)NCc1cccc(O)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
(3-Hydroxy-benzyl)-carbamic acid tert butyl ester was dissolved in THF, triphenylphosphine (0.44 g, 2.2 mmole), 3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethylamino]-propoxy}-phenylamine (1.0 g, 2.3 mmole) and DIAD (0.43 ml, 2.2 mmole) were added subsequently. The mixture was stirred overnight at room temperature. The reaction was concentrated, chromatographed on silica gel (0 to 15% EtOAc/hexanes) to give the titled compound (0.51 g, 48%). MH+652.0
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH2:5].C(=O)(O)[O-].[K+].[I:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1>CC(C)=O>[CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH:5][C:18](=[O:19])[C:17]1[CH:21]=[CH:22][C:14]([I:13])=[CH:15][CH:16]=1
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: COC(CN)OC
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC(C)=O
Product: COC(CNC(=O)c1ccc(I)cc1)OC
Yield: 96.8 %

Procedure:
A solution of 2-aminoacetaldehyde dimethylacetal (12.3 mL, 112 mmol) in a mixture of acetone (50 mL) and aqueous potassium bicarbonate (12 g, 122 mmol in 110 mL of water) was stirred and cooled to −5° C., as a solution of 4-iodobenzoyl chloride (25 g, 94 mmol) was added dropwise. The cooling bath was removed and the reaction stirred for 3 hours. The reaction was concentrated and diluted with water. The resulting solid was isolated by filtration and dried to give 30.5 g of N-(2,2-dimethoxyethyl)-4-iodobenzamide, 1H NMR (400 MHz, CDCl3) δ 7.78 (d, 2H), 7.46 (d, 2H), 6.34 (s, 1H), 4.44 (t, 1H), 3.58 (t, 2H), 3.42 (s, 6H) ppm.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=[O:19])[NH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1C=CC=CC=1.C(OC(=O)C)(=[O:24])C.C([O-])(=O)C.[Na+]>[Pd].C1(C)C=CC=CC=1>[C:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=[O:19])[NH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])(=[O:24])[CH3:2]
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCc1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cc2c(=O)[nH]cnc2cc1OC(C)=O
Reaction time: 3 h
Yield: 27 %

Procedure:
A mixture of 7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one (5.0 g, mmol), (prepared as described for the starting material in Example 4), acetic anhydride (200 ml), sodium acetate (12 g), 10% palladium-on-charcoal catalyst (1.5 g) in toluene (100 ml) was stirred under an atmosphere of hydrogen for 3 hours. The mixture was filtered and the filtrate was evaporated. The residue was partitioned between a mixture of ethyl acetate (500 ml), methanol (20 ml) and water (300 ml). The organic phase was separated, dried (MgSO4) and the solvent removed by evaporation. The residue was triturated with hexane to give 7-acetoxy-6-methoxy-3,4-dihydroquinazolin-4-one (1.1 g, 27%).