Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N-]CC)C.[Li+].[O:7]=[C:8]1[CH2:13][CH2:12][CH2:11][CH2:10][N:9]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[OH:20].IC.O>C1COCC1>[CH3:1][CH:13]1[CH2:12][CH2:11][CH2:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[OH:20])[C:8]1=[O:7]
Reactant: CC[N-]CC
Reactant: O=C1CCCCN1c1ccccc1O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Solvent: O
Product: CC1CCCN(c2ccccc2O)C1=O
Reaction time: 0.5 h

Procedure:
Lithium diethylamide (2M solution in THF) (3.92 mL, 7.84 mmol) was added to a solution of 2-(2-oxo-piperidin-1-yl)-phenol (as described in Example 1, Step F) (0.50 g, 2.61 mmol) in THF (5 mL) at −78° C. with stirring under Ar. After 30 min, iodomethane (0.488 mL, 7.84 mmol) was added and the reaction left to come to room temperature overnight. The reaction was treated with H2O, concentrated to remove the THF, then partitioned between diethyl ether and H2O. The organic layer was separated, washed with brine, dried (Na2SO4), filtered, and concentrated to dryness to give the title compound after chromatography (silica gel, 1% CH3OH, 29% EtOAc, 70% hexane).
Reaction SMILES: [F:1][CH:2]([F:20])[C:3]1[CH:10]=[C:9]([O:11][CH2:12][C@H:13]2[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[O:14]2)[CH:8]=[CH:7][C:4]=1[CH:5]=O.[NH2:21][C:22]1[C:30]([NH2:31])=[CH:29][CH:28]=[CH:27][C:23]=1[C:24]([OH:26])=[O:25].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>CN(C=O)C.O>[F:1][CH:2]([F:20])[C:3]1[CH:10]=[C:9]([O:11][CH2:12][C@H:13]2[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[O:14]2)[CH:8]=[CH:7][C:4]=1[C:5]1[NH:31][C:30]2[CH:29]=[CH:28][CH:27]=[C:23]([C:24]([OH:26])=[O:25])[C:22]=2[N:21]=1
Reactant: Nc1cccc(C(=O)O)c1N
Reactant: CC1(C)OC[C@H](COc2ccc(C=O)c(C(F)F)c2)O1
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OC[C@H](COc2ccc(-c3nc4c(C(=O)O)cccc4[nH]3)c(C(F)F)c2)O1
Temperature: 110 °C
Reaction time: 18 h
Yield: 31.4 %

Procedure:
To a solution of (S)-2-(difluoromethyl)-4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)benzaldehyde (66; 1.83 g, 6.40 mmol) in DMF (150 ml) was added 2,3-diaminobenzoic acid (1; 0.97 g, 6.40 mmol), and Na2S2O5 (1.82 g, 9.60 mmol). The reaction mixture was stirred at 110° C. for 18 h. It was then cooled to room temperature and diluted with water. The resulting solids were collected by filtration and dried to afford (S)-2-(2-(difluoromethyl)-4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)phenyl)-1H-benzo[d]imidazole-4-carboxylic acid 67 as dark yellow solid (0.84 g, 51%). MS (ESI) calcd for C21H20F2N5O5: 418.13; found: 419 [M+H].
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[CH:15]2[CH2:19][CH2:18][O:17][CH2:16]2)[CH2:3][CH2:2]1.C1(COC2N=C(C(O)=O)C=CC=2C2CCCO2)CC1.[NH2:39][C@@H:40]([CH2:44][CH:45]1[CH2:47][CH2:46]1)[C:41]([NH2:43])=[O:42]>>[C:41]([C@@H:40]([NH:39][C:12]([C:10]1[CH:9]=[CH:8][C:7]([CH:15]2[CH2:19][CH2:18][O:17][CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])[CH2:44][CH:45]1[CH2:47][CH2:46]1)(=[O:42])[NH2:43]
Reactant: O=C(O)c1ccc(C2CCOC2)c(OCC2CC2)n1
Reactant: NC(=O)[C@@H](N)CC1CC1
Agent: O=C(O)c1ccc(C2CCCO2)c(OCC2CC2)n1
Product: NC(=O)[C@H](CC1CC1)NC(=O)c1ccc(C2CCOC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using the mixture of 6-(cyclopropylmethoxy)-5-(tetrahydrofuran-3-yl)-pyridine-2-carboxylic acid and 6-(cyclopropylmethoxy)-5-(tetrahydrofuran-2-yl)-pyridine-2-carboxylic acid (mixture from Example 114 d), and (S)-2-amino-3-cyclopropyl-propionamide (CAN 156077-93-9) as starting materials, MS (EI): m/e=374.2 [M+H]+.
Reaction SMILES: [ClH:1].[C:2]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]([N:18]3[CH2:23][C@H:22]([CH3:24])[NH:21][C@H:20]([CH3:25])[CH2:19]3)=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)#[N:3].[C:26]1(=O)[CH2:29][CH2:28][CH2:27]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>C(Cl)Cl>[ClH:1].[CH:26]1([N:21]2[C@@H:20]([CH3:25])[CH2:19][N:18]([C:16]([CH:13]3[CH2:14][CH2:15][N:10]([C:7]4[CH:6]=[CH:5][C:4]([C:2]#[N:3])=[CH:9][CH:8]=4)[CH2:11][CH2:12]3)=[O:17])[CH2:23][C@H:22]2[CH3:24])[CH2:29][CH2:28][CH2:27]1
Reactant: C[C@@H]1CN(C(=O)C2CCN(c3ccc(C#N)cc3)CC2)C[C@H](C)N1
Reactant: O=C1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H]1CN(C(=O)C2CCN(c3ccc(C#N)cc3)CC2)C[C@H](C)N1C1CCC1
Yield: 15.4 %

Procedure:
(2R,6S)-4-[1-(4-Cyanophenyl)-piperidine-4-carbonyl]-2,6-dimethylpiperazine hydrochloride (D13)(0.30 g), TEA (0.4 ml), cyclobutanone (0.13 g) and sodium triacetoxyborohydride (0.40 g) in DCM (5 ml) were heated to 100° C. in a microwave reactor for 5 min. The reaction mixture was then washed with saturated potassium carbonate solution (2×30 ml), and brine (30 ml). The organic layer was then dried (MgSO4) and evaporated give the crude product which was purified by column chromatography [silica gel, step gradient 0-10% MeOH (containing 10% 0.880 ammonia solution) in DCM]. Fractions containing the required product were evaporated to give the free base compound which was converted to the HCl salt by redissolving in DCM and then treating with excess hydrogen chloride (1 M solution in diethyl ether), evaporating and then crystallising from acetone to give the title compound (E33) as a pale grey solid (0.053 g). MS electrospray (+ve) 381 (MH+). 1H NMR δ [DMSO-d6]: 11.28 plus 10.10 (1H, m, rotomers), 7.59 (2H, d, J=8.4 Hz), 7.00 (2H, d, J=8.OHz), 4.31-3.73 (6H, m), 3.60-3.22 (3H, m), 2.97 (3H, m), 2.50-2.08 (4H, m), 1.78-1.61 (6H, m), 1.50-1.10 (6H, m).
Reaction SMILES: [CH3:1][S:2][C:3]1[S:7][C:6]2[C:8]([CH2:12][NH:13][CH3:14])=[CH:9][CH:10]=[CH:11][C:5]=2[C:4]=1Br.CCOCC.C([Li])CCC.Cl>CCCCCC>[CH3:1][S:2][C:3]1[S:7][C:6]2[C:8]([CH2:12][NH:13][CH3:14])=[CH:9][CH:10]=[CH:11][C:5]=2[CH:4]=1
Reactant: CNCc1cccc2c(Br)c(SC)sc12
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CNCc1cccc2cc(SC)sc12

Procedure:
To a solution of 0.3 g of N-(2-methylthio-3-bromo-7-benzo[b]thienylmethyl)methylamine in abs. ether are added dropwise under inert gas at -70°, 1.4 ml of a 15% solution of n-butyllithium in n-hexane and stirring continued at -70° for half an hour. The mixture is then poured into ice-cooled 2N HCl, shaken and the acidic phase separated, made alkaline with NaOH and extracted with ether. The ether phase is dried, concentrated in vacuum and the resulting oil directly further reacted.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]([CH2:24][C:23]2[CH:26]=[CH:27][C:20]([Cl:19])=[CH:21][CH:22]=2)[CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=Cc1ccc(Cl)cc1
Reactant: COC(=O)CNC1CCN(C(=O)OC(C)(C)C)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)CN(Cc1ccc(Cl)cc1)C1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(methoxycarbonylmethyl-amino)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.5 g, 2.03 mmol) in dichloroethane (5.0 mL) was added 4-chlorobenzaldehyde (0.34 g, 2.44 mmol), sodium triacetoxy borohydride (0.86 g, 4.06 mmol) and catalytic acetic acid and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated, dissolved in dichloromethane and washed with 10% aqueous sodium bicarbonate. The combined organics were washed with brine and dried over sodium sulfate. The crude product was purified on silica using ethyl acetate. 1H-NMR (CDCl3) δ: 1.40 (9H, s), 1.80 (1H, m), 2.10 (1H, m), 3.00-3.80 (7H, m), 4.70 (1H, br, s), 7.20 (4H, m). ESI-MS m/z: 383 (M+1), UV retention time: 2.91 min.
Reaction SMILES: C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[F:14][C:15]1[CH:16]=[C:17]([CH:29]=[CH:30][CH:31]=1)[CH2:18][C:19]1[S:23][C:22]([CH:24]2OCC[O:25]2)=[CH:21][CH:20]=1.O.C(OCC)(=O)C>CO>[F:14][C:15]1[CH:16]=[C:17]([CH:29]=[CH:30][CH:31]=1)[CH2:18][C:19]1[S:23][C:22]([CH:24]=[O:25])=[CH:21][CH:20]=1
Reactant: Fc1cccc(Cc2ccc(C3OCCO3)s2)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: O=Cc1ccc(Cc2cccc(F)c2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
An aqueous solution of saturated citric acid (20 mL) was added to a solution of 2-(5-(3-fluoro-benzyl)thiophen-2-yl)-[1,3]dioxolane described in Preparation Example 52 (670 mg, 2.53 mmol) in methanol (20 mL), and the solution was stirred at room temperature for 30 minutes. Water and ethyl acetate were added to the reaction solution, which was then partitioned, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, and the title compound (485 mg, 2.2 mmol, 87.0%) was obtained as a brown oil.
Reaction SMILES: [CH3:1][N:2]([S:24]([C:27]1[S:28][CH:29]=[CH:30][CH:31]=1)(=[O:26])=[O:25])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([NH:14][NH:15][C:16](=O)[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=O)=[CH:8]2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:41])=CC=1>O1CCCC1>[CH3:1][N:2]([S:24]([C:27]1[S:28][CH:29]=[CH:30][CH:31]=1)(=[O:26])=[O:25])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:41][C:16]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:15][N:14]=1)=[CH:8]2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)CC(=O)NNC(=O)c1cc2cccc(N(C)S(=O)(=O)c3cccs3)c2[nH]1
Solvent: C1CCOC1
Product: CCOC(=O)Cc1nnc(-c2cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)s1
Temperature: 50 °C
Reaction time: 2 h
Yield: 73.2 %

Procedure:
A mixture of ethyl 3-[2-({7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}carbonyl)hydrazino]-3-oxopropanoate (0.96 g), Lawesson's reagent (0.97 g) and tetrahydrofuran (20 mL) was stirred at 50° C. for 2 hr. The reaction mixture was concentrated, and the residue was subjected to silica gel column chromatography, and the title compound (0.70 g, yield 71%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point 201-202° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([C:21]#[C:22][CH2:23][CH2:24][CH2:25][OH:26])=[C:17]([F:20])[CH:18]=3)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.C(N(C(C)C)C(C)C)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38].CCOCC>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([C:21]#[C:22][CH2:23][CH2:24][CH2:25][O:26][S:37]([CH3:36])(=[O:39])=[O:38])=[C:17]([F:20])[CH:18]=3)[CH2:13][CH2:12]2)=[O:10])=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(Oc1ccc(Cl)cc1)N1CCc2cc(C#CCCCO)c(F)cc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: CS(=O)(=O)OCCCC#Cc1cc2c(cc1F)N(C(=O)Oc1ccc(Cl)cc1)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.7 %

Procedure:
A solution of 120 mg (0.321 mmol) 6-Fluoro-5-(5-hydroxy-pent-1-ynyl)-2,3-dihydro-indole-1-carboxylic acid 4-chloro-phenyl ester and 0.164 ml (0.96 mmol) N-ethyldiisopropylamine in 2 ml CH2Cl2 was treated with 0.03 ml (0.385 mmol) of methanesulfonyl chloride and stirred at room temperature for 1 hour. The mixture was poured into Et2O and washed with 0.5 M HCl. Drying of the organic layer with MgSO4, evaporation of the solvent, and chromatography on silica gel with CH2Cl2 gave 91 mg (61%) of 6-Fluoro-5-(5-methanesulfonyloxy-pent-1-ynyl)-2,3-dihydro-indole-1-carboxylic acid 4-chloro-phenyl ester as a colorless oil, MS: 452 (MH+, 1Cl).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([OH:19])=O)[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:21]([O:25][C:26](=[O:33])[C@H:27]([CH2:29][CH:30]([CH3:32])[CH3:31])[NH2:28])([CH3:24])([CH3:23])[CH3:22].ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.CN1CCOCC1>C(Cl)Cl>[C:21]([O:25][C:26](=[O:33])[C@H:27]([CH2:29][CH:30]([CH3:31])[CH3:32])[NH:28][C:17](=[O:19])[C@H:12]([CH2:13][CH:14]([CH3:15])[CH3:16])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)C[C@H](N)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CC(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 99.5 %

Procedure:
Under atmosphere of argon, to a solution of N-benzyloxycarbonylleucine (26.5 g) and leucine t-butyl ester hydrochloride (22.4 g) in methylene chloride (20.0 ml.) were added 1-hydroxybenzotriazole (HOBt) (14.2 g) and 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDC) hydrochloride (20.1 g) at 0° C. Thereto was added N-methylmorpholine (11.5 ml) over a period of 5 minutes and the mixture was stirred for 20 hours at room temperature. The reaction solution was concentrated and to the residue were added ice-water and ethyl acetate. In order to dissolve HOBt that appeared, was added sodium bicarbonate. The aqueous layer was extracted with ethyl acetate and combined organic layer was washed with 10% aqueous solution of citric acid, a saturated aqueous solution of sodium bicarbonate and saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and was concentrated to give the title compound (43.2 g) having the following physical data.
Reaction SMILES: CS(C)=O.[Br:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[OH:14])[CH:9]=O.[NH2:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[SH:23].C(OCC)(=O)C>O>[Br:5][C:6]1[CH:7]=[C:8]([C:9]2[S:23][C:17]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:16]=3[N:15]=2)[CH:11]=[CH:12][C:13]=1[OH:14]
Reactant: Nc1cc(Cl)ccc1S
Reactant: O=Cc1ccc(O)c(Br)c1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Oc1ccc(-c2nc3cc(Cl)ccc3s2)cc1Br
Yield: 30.3 %

Procedure:
In a dimethyl sulfoxide (DMSO) (2 mL) solvent, a solution including 3-bromo-4-hydroxybenzaldehyde (163.7 mg, 0.81 mmol) and 2-amino-4-chlorobenzenethiol (100 mg, 0.45 mmol) was refluxed for 1 hour. After cooling, the residual was distributed between ethyl acetate and water, and an organic layer was dried by using MgSO4, filtered, and evaporated under reduced pressure. The resultant residual was added to water, and then, the precipitate was filtered and the filtered product was washed with water and methylene chloride to obtain a solid Compound 95 (46.4 mg, 17.6%).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:34](=[O:35])[N:6]2[C:7]([C:28]([O:30][CH2:31][CH:32]=[CH2:33])=[O:29])=[C:8](OP(OC3C=CC=CC=3)(OC3C=CC=CC=3)=O)[C@H:9]([CH3:10])[C@@H:5]12)[CH3:3].[CH2:36]([O:39][C:40]([N:42]1[CH2:46][C@@H:45]([SH:47])[CH2:44][C@H:43]1[CH2:48][CH:49]1[CH2:53][N:52]([C:54]([O:56][CH2:57][CH:58]=[CH2:59])=[O:55])[C@H:51]([C:60](=[O:62])[NH2:61])[CH2:50]1)=[O:41])[CH:37]=[CH2:38].C(N(CC)C(C)C)(C)C>>[CH2:36]([O:39][C:40]([N:42]1[CH2:46][C@@H:45]([S:47][C:8]2[C@H:9]([CH3:10])[C@@H:5]3[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:34](=[O:35])[N:6]3[C:7]=2[C:28]([O:30][CH2:31][CH:32]=[CH2:33])=[O:29])[CH2:44][C@H:43]1[CH2:48][CH:49]1[CH2:53][N:52]([C:54]([O:56][CH2:57][CH:58]=[CH2:59])=[O:55])[C@H:51]([C:60](=[O:62])[NH2:61])[CH2:50]1)=[O:41])[CH:37]=[CH2:38]
Reactant: C=CCOC(=O)N1C[C@@H](S)C[C@H]1CC1C[C@@H](C(N)=O)N(C(=O)OCC=C)C1
Reactant: C=CCOC(=O)C1=C(OP(=O)(Oc2ccccc2)Oc2ccccc2)[C@H](C)[C@H]2[C@@H]([C@@H](C)O)C(=O)N12
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](CC3C[C@@H](C(N)=O)N(C(=O)OCC=C)C3)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 78.9 %

Procedure:
The same procedure as in Example 8-1 was carried out by using allyl (1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-diphenoxyphosphoryloxy-1-carbapen-2-em-3-carboxylate (264 mg, 0.49 mmol), (2R,4S)-N-allyloxycarbonyl-2-[(2S)-N-allyloxycarbonyl-2-carbamoylpyrrolidin-4-ylmethyl]-4-mercaptopyrrolidine (210 mg, 0.49 mmol) and N,N-diisopropylethylamine (92 μl, 0.49 mmol) to obtain allyl (1R,5S,6S)-2-[(2R,4S)-N-allyloxycarbonyl-2-[(2S)-N-allyloxycarbonyl-2-carbamoylpyrrolidin-4-ylmethyl]pyrrolidin-4-ylthio]-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (250 mg, yield: 73%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[CH:6]=[CH:7][CH:8]=1.[CH3:20][C:21](C)([O-:23])[CH3:22].[K+].C(C1OC1)Br>CC(N(C)C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH2:20][CH:21]2[CH2:22][O:23]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(CCCCc2ccccc2O)c1
Reactant: CC(C)(C)[O-]
Agent: BrCC1CO1
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cccc(CCCCc2ccccc2OCC2CO2)c1
Yield: 90 %

Procedure:
Following a procedure similar to that described in Example 1(a), 3.40 g of 2-[4-(3-methoxyphenyl)butyl]phenol (prepared as described in Preparation 7), 1.5 g of potassium t-butoxide and 3.63 9 of epibromohydrin were reacted in 70 ml of dimethylacetamide. The crude product, extracted as described in Example 1(a), was purified as described in Example 1(a), to give 3.73 g (yield 90%) of the title compound as a colorless oil.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=O)=[CH:16][CH:15]=[CH:14][C:13]=2[C:27]([F:30])([F:29])[F:28])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:33][C:34](=[O:43])[C:35]1[CH:40]=[CH:39][C:38]([CH2:41][NH2:42])=[CH:37][CH:36]=1)C>>[C:1]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][NH:42][CH2:41][C:38]1[CH:37]=[CH:36][C:35]([C:34]([OH:33])=[O:43])=[CH:40][CH:39]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:27]([F:30])([F:29])[F:28])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(CN)cc1
Reactant: O=Cc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: O=C(O)c1ccc(CNCc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1

Procedure:
The title compound was prepared from 3-[3-benzoyl-8-(trifluoromethyl)quinolin-4-yl]benzaldehyde and 4-aminomethyl-benzoic acid ethyl ester according to the procedure of Example 66. MS m/z 541; MS m/z 539.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.CO.[OH2:13].Cl.O[NH2:16].C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH2:16])=[N:10][OH:13])=[CH:4][CH:3]=1
Reactant: O
Reactant: N#CCc1ccc(Br)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: NC(Cc1ccc(Br)cc1)=NO
Temperature: 60 °C
Reaction time: 5 h

Procedure:
To a stirring solution of 2-(4-bromophenyl) ethanenitrile in methanol/water (1 eq/1 eq, 0.1 M) was added hydroxyamine hydrochloride (2.1 eq) and sodium carbonate (2.0 eq). The reaction was stirred at 60° C. for 5 hrs. The reaction was diluted with ethyl acetate and separated. The organic layer was washed with 10% hydochloric acid and separated. The aqueous layer was neutrized with 10% sodium carbonate and extracted with ethyl acetate. The organic layer was dried with magnesium sulfate, filtered and concentrated in vacuo to afford the product. EI-MS m/z 229, 231(M+H)+
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:24][C:25]1[C:33]([OH:34])=[CH:32][CH:31]=[C:30]2[C:26]=1[CH:27]=[CH:28][NH:29]2.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:24][C:25]1[C:33]([O:34][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:32][CH:31]=[C:30]2[C:26]=1[CH:27]=[CH:28][NH:29]2
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCCC1
Reactant: Oc1ccc2[nH]ccc2c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]ccc4c3F)ncnc2cc1OCCCN1CCCCC1
Temperature: 95 °C
Yield: 67.3 %

Procedure:
Using an analogous procedure to that described in Example 244, 4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (407 mg, 1.21 mmol), (prepared as described for the starting material in Example 67), 4-fluoro-5-hydroxyindole (220 mg, 1.45 mmol) (prepared as described for the starting material in Example 242), and potassium carbonate (251 mg, 1.82 mmol) in DMF (6 ml) were heated at 95° C. for 90 minutes and purified to give 4-(4-fluoroindol-5-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline (367 mg, 67%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([Cl:12])[C:6]=2[C:13](Cl)=[O:14].C([N:18](CC)CC)C.[CH2:23]([CH2:26]OC)[O:24]C>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([Cl:12])[C:6]=2[C:13]([NH:18][O:24][CH2:23][CH3:26])=[O:14]
Reactant: COCCOC
Reactant: O=C(Cl)c1c(Cl)ccc2cc(Cl)cnc12
Reactant: CCN(CC)CC
Product: CCONC(=O)c1c(Cl)ccc2cc(Cl)cnc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 77 %

Procedure:
13.0 g (50 millimoles) of 3,7-dichloroquinoline-8-carbonyl chloride were suspended in 50 ml of dimethoxyethane, and 5.8 g (60 millimoles ) of 0-ethylhydroxyamine hydrochloride and 15 g (150 millimoles) of triethylamine were added. The mixture was stirred for 5 hours at room temperature, after which the solvent was removed in a rotary evaporator, the residue was triturated with water and the mixture was filtered under suction. 11.0 g (77%) of a product of melting point 140° C. were obtained (compound No. 21).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]4[O:22][CH2:23][CH2:24][O:25][C:18]=4[CH:17]=3)[C:12]([F:26])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.Br[CH2:28][CH2:29][OH:30]>>[CH2:24]1[CH2:23][O:22][C:19]2[CH:20]=[CH:21][C:16]([NH:15][C:13]3[C:12]([F:26])=[CH:11][N:10]=[C:9]([NH:8][C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][CH2:28][CH2:29][OH:30])[CH:3]=4)[N:14]=3)=[CH:17][C:18]=2[O:25]1
Reactant: OCCBr
Reactant: Nc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Product: OCCNc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1

Procedure:
N2-(3-Aminophenyl)-N4-(3,4-Ethylenedioxyphenyl)-5-Fluoro-2,4-pyrimidinediamine and 2-bromoethanol were reacted together to give N4-(3,4-ethylenedioxyphenyl)-N2-[3-(hydroxyethylamino)phenyl]-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time: 15.44 min.; purity: 98.6%; MS (m/e): 398.05 (MH+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:12][CH:13]([O:19][CH:20]([CH3:22])[CH3:21])[C:14]([O:16]CC)=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]=[C:31]=[O:32]>>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30][C:31]([O:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:12][CH:13]([O:19][CH:20]([CH3:21])[CH3:22])[C:14]([OH:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])=[O:32]
Reactant: CCOC(=O)C(Cc1ccc(OC)c(CCO)c1)OC(C)C
Reactant: O=C=Nc1ccccc1Cl
Product: COc1ccc(CC(OC(C)C)C(=O)O)cc1CCOC(=O)Nc1ccccc1Cl

Procedure:
Using ethyl 3-[3-(2-hydroxyethyl)-4-methoxyphenyl]-2-isopropoxypropanoate and 2-chlorophenylisocyanate, the title compound was obtained in the same manner as described in Example 148.