Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([N:5]([CH2:9][CH3:10])[CH2:6][CH2:7][OH:8])[CH3:4].F[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1>O1CCCC1>[CH2:3]([N:5]([CH2:9][CH3:10])[CH2:6][CH2:7][O:8][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)[CH3:4]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CCN(CC)CCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(CC)CCOc1ccc([N+](=O)[O-])cc1
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 54 %

Procedure:
Sodium hydride (4.8 g, 50% in oil, 100 mmol) was added to a solution of 2-diethylamino-ethanol (11.7 g, 100 mmol) (Aldrich) in tetrahydrofuran (500 mL) and stirred for 15 minutes and then heated to 40° C. for an additional 15 minutes. The mixture was cooled to −10° C. and a solution of 1-fluoro-4-nitrobenzene (10 g, 70 mmol) in tetrahydrofuran (50 mL) was added dropwise and stirred at room temperature for 2 hours. The solvent was evaporated and the residue was dissolved in dichloromethane and washed twice with a 4:1 water/brine mixture. The dichloromethane was evaporated under vacuo and the residue chromatographed on silica gel using 1:1 hexane/ethyl acetate, ethyl acetate, then 20% methanol in dichloromethane. The product fractions were concentrated in vacuo, dissolved in ether, treated with activated charcoal, filtered through Celite™ and concentrated to give 9 g, (54%) of diethyl-[2-(4-nitro-phenoxy)-ethyl]-amine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]#[C:13]O)=[CH:7][CH:6]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:36]>O1CCCC1>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]#[C:13][Cl:36])=[CH:7][CH:6]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: COC(=O)Cc1ccc(CC#CO)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(CC#CCl)cc1
Temperature: 60 °C

Procedure:
To a solution of 4-(3-Hydroxyprop-2-ynyl)phenylacetic acid methyl ester (5.5 g, 0.027M) in tetrahydrofuran (110 ml) and carbon tetrachloride (110 ml) was added triphenylphosphine (7.81 g, 1.1 molar equivalents). The reaction mixture was heated at 60° C. for 3 h. After cooling, the solid obtained was removed by filtration and the mother liquors were concentrated under vacuum. The residue was purified by chromatography on silica gel using 50% diethyl ether in hexane as eluent to give the required product (5.35 g) as a colourless oil. δ (360 MHz, CDCl3) 3.62 (2H, s, CH2CO2CH3), 3.69 (3H, s, CH2CO2CH3), 4.36 (2H, s, CH2Cl), 7.23 (2H, d, J=8.2 Hz, ArH), 7.40 (2H, d, J=8.2 Hz, ArH).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[N:9][NH:8][C:5]2=[CH:6][N:7]=1.C([O-])([O-])=O.[Na+].[Na+].CC1(C)C(C)(C)OB([C:25]2[NH:29][N:28]=[CH:27][CH:26]=2)O1>COCCOC.CCO.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]>[NH:28]1[CH:27]=[C:26]([C:2]2[CH:3]=[C:4]3[CH:10]=[N:9][NH:8][C:5]3=[CH:6][N:7]=2)[CH:25]=[N:29]1
Reactant: Brc1cc2cn[nH]c2cn1
Reactant: CC1(C)OB(c2ccn[nH]2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: COCCOC
Product: c1n[nH]cc1-c1cc2cn[nH]c2cn1
Temperature: 150 °C
Reaction time: 1 h
Yield: 21.6 %

Procedure:
To a solution of 5-bromo-1H-pyrazolo[3,4-c]pyridine (100 mg, 0.5 mmol) in DME:EtOH (5:1, 5 mL) was added Pd(dppf)Cl2 (20 mg), saturated solution of Na2CO3 (1 mL) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (116 mg, 0.6 mmol). Under argon the mixture was stirred under microwave irradiation at 150° C. for 60 min. After cooling down, the solvent was removed under reduced pressure and the residue was purified by silica-gel column chromatography (mobile phase: EA:PE=1:1) to afford 5-(1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine (20 mg, 22%). 1H NMR (500 MHz, MeOD) δ 9.05 (s, 1H), 8.24 (m, 2H), 7.75 (s, 1H), 6.89 (s, 1H). ESI MS m/z=186.1 (M+1)
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[CH:14]=[C:13]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:12]=2)=[CH:7][CH:6]=1)(=O)C>N1C=CC=CC=1>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[CH:14]=[C:13]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:12]=2)=[CH:7][CH:6]=1
Reactant: CC(=O)Nc1ccc(-c2cc(-c3ccc(C)cc3)cc(-c3ccccc3)n2)cc1
Solvent: c1ccncc1
Product: Cc1ccc(-c2cc(-c3ccccc3)nc(-c3ccc(N)cc3)c2)cc1

Procedure:
The following compound was obtained substantially in the same manner as above, using a corresponding pyridine derivative having an acetamide group in place of 2-(4-acetamidophenyl)-4-(4-methylphenyl)-6-phenylpyridine.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:10][CH3:11])[C:5]([NH2:9])=[N:6][C:7]=1[Cl:8].[Cl:12][C:13]1[CH:14]=[C:15]([S:19](Cl)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1>>[Cl:12][C:13]1[CH:14]=[C:15]([S:19]([NH:9][C:5]2[C:4]([O:10][CH3:11])=[N:3][C:2]([Cl:1])=[C:7]([Cl:8])[N:6]=2)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Reactant: COc1nc(Cl)c(Cl)nc1N
Product: COc1nc(Cl)c(Cl)nc1NS(=O)(=O)c1cccc(Cl)c1

Procedure:
Prepared by the method of Example 1 (reaction performed at room temperature) using 5,6-dichloro-3-methoxy-2-pyrazinamine (0.1 g) and 3-chlorobenzenesulphonyl chloride (0.13 g). Yield 0.047 g.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[CH3:5][O:6][C:7]1[CH:28]=[CH:27][C:10]([C:11](Cl)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:9][CH:8]=1.C(N(CC)CC)C.O>C(Cl)Cl>[CH3:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([C:11]([C:10]2[CH:9]=[CH:8][C:7]([O:6][CH3:5])=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:3][CH2:2][CH2:1][OH:4])=[CH:17][CH:16]=1
Reactant: OCCO
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C(OCCO)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.4 %

Procedure:
Ethylene glycol (0.92 g, 14.8 mmol) (Wako Pure Chemical Industries, Ltd.), 4,4′-dimethoxytrityl chloride (1.00 g, 2.95 mmol) (Wako Pure Chemical Industries, Ltd.), and triethylamine (0.89 g, 8.81 mmol) (Wako Pure Chemical Industries, Ltd.) were dissolved in methylene chloride (25 mL) (Wako Pure Chemical Industries, Ltd.), and the mixture was stirred at room temperature overnight. Water (50 mL) was added to reaction solution, and mixture was extracted with methylene chloride (Wako Pure Chemical Industries, Ltd.). The organic layer was dried with anhydrous sodium sulfate (Wako Pure Chemical Industries, Ltd.), and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform (Wako Pure Chemical Industries, Ltd.) as an eluent), to thereby obtain the title compound (0.51 g, 47% yield).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7]CC)=[O:6].[CH3:13][C:14]([CH3:18])=[CH:15][CH2:16]Br.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH3:13][C:14]([CH3:18])=[CH:15][CH2:16][O:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([OH:7])=[O:6]
Reactant: CC(C)=CCBr
Reactant: CCOC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)=CCOc1cccc(C(=O)O)c1

Procedure:
The reaction of ethyl 3-hydroxybenzoate and 3,3-dimethylallyl bromide in 2-butanone in the presence of potassium carbonate was performed as described in Example 2 to give 3-(3-Methyl-but-2-enyloxy)-benzoic acid as white powder. 1H-NMR (400 MHz, d6-DMSO): 12.97 (br, —CO2H); 7.48 (m, 1 arom.H); 7.42 (m, 1 arom.H); 7.41 (m, 1 arom.H); 7.15 (m, 1 arom.H); 5.40 (m, CH═C(CH3)2); 4.54 (d-like, CH2CH═C(CH3)2); 1.69, 1.63 (2s, CH═C(CH3)2). 13C-NMR (100 MHz, d6-DMSO): 167.16 (C═O); 158.38; 137.32; 132.24; 129.59; 121.43; 119.68; 119.48; 114.67; 64.46; 25.40; 18.00.
Reaction SMILES: [NH2:1][C:2]1[CH2:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]2[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:4]=2[N:3]=1.CO.O.[NH2:24]N>C(O)(=O)C>[NH:1]([C:2]1[CH2:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]2[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:4]=2[N:3]=1)[NH2:24]
Reactant: NN
Reactant: COc1ccc2c(c1)C(c1ccccc1)=NCC(N)=N2
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc2c(c1)C(c1ccccc1)=NCC(NN)=N2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 26.5 parts of 2-amino-7-methoxy-5-phenyl-3H-1,4-benzodiazepine, 500 parts by volume of methanol and 1.2 parts of glacial acetic acid is added 25 parts of 100% hydrazine hydrate. The mixture is stirred for 1 hour at room temperature and treated in a similar manner to Example 1, whereby 2-hydrazino-7-methoxy-5-phenyl-3H-1,4-benzodiazepine is yielded as crystals melting at 110° C to 120° C.
Reaction SMILES: [NH:1]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:2]([C:6]([N:8]1[CH2:20][CH2:19][CH2:18][C@H:9]1[C:10]([NH:12][CH2:13][C:14]([O:16]C)=O)=[O:11])=[O:7])[CH:3]([CH3:5])[CH3:4].[NH2:28][NH2:29]>CO>[NH:1]([C:21]([O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22])[C@H:2]([C:6]([N:8]1[CH2:20][CH2:19][CH2:18][C@H:9]1[C:10]([NH:12][CH2:13][C:14]([NH:28][NH2:29])=[O:16])=[O:11])=[O:7])[CH:3]([CH3:5])[CH3:4]
Reactant: NN
Reactant: COC(=O)CNC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Solvent: CO
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)NCC(=O)NN
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of III (64.0 g, 166 mmol) in methanol (50 ml) was added 95% hydrazine (120 ml, 2.49 mol) and the mixture was stirred for 1 day at room temperature. The reaction mixture was evaporated and the residue, dissolved in chloroform, was washed with water and dried over sodium sulfate. The solution was evaporated and the residue was triturated with petroleum ether. A non-crystalline product obtained gave a single spot on TLC; yield 45.8 g (72%), Rf1 0.69.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:22])[CH2:10][CH2:11][C:12]([N:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16]([OH:18])=O)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:23]1[CH2:29][CH2:28][CH2:27][C@H:24]1[CH2:25][OH:26].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:22])[CH2:10][CH2:11][C:12]([N:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16]([N:23]1[CH2:29][CH2:28][CH2:27][C@H:24]1[CH2:25][OH:26])=[O:18])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC[C@@H]1CCCN1
Reactant: O=C(CCC(=O)N1CCC[C@H]1C(=O)O)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCC(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1CO)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.3 %

Procedure:
N-(benzyloxysuccinyl)-L-proline (152.5 g, 0.5 mol), L-prolinol (50.5 g, 0.5 mol) and triethylamine (200 ml) are dissolved in methylene chloride (2 l), and a solution of DMC (127 g, 0.75 mol) in methylene chloride (500 ml) is added dropwise thereto over a period of 40 minutes under water-cooling. The mixture is stirred for a further three hours at room temperature. The reaction liquid is washed successively with water (1 l), a saturated aqueous solution of sodium hydrogen carbonate (1 l), 1N hydrochloric acid (1 l) and water (1 l), and the organic layer is dried over anhydrous magnesium sulfate and filtered. The filtrate is concentrated to dryness under reduced pressure and the residue is purified by column chromatography on silica gel (chloroform:methanol) to give N-(benzyloxysuccinyl)-L-prolyl-prolinol (90 g, 46.4%).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:24][CH2:25][CH2:26][NH:27][C:28]1[C:38]2[CH2:37][CH2:36][N:35]([C:39](=[O:44])[C:40]([F:43])([F:42])[F:41])[CH2:34][CH2:33][C:32]=2[CH:31]=[CH:30][C:29]=1[Cl:45]>C(Cl)Cl.O>[Cl:45][C:29]1[CH:30]=[CH:31][C:32]2[CH2:33][CH2:34][N:35]([C:39](=[O:44])[C:40]([F:42])([F:41])[F:43])[CH2:36][CH2:37][C:38]=2[C:28]=1[NH:27][CH2:26][CH2:25][NH:24][C:1]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)=[O:9]
Reactant: O=C(O)c1cccnc1
Reactant: NCCNc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: O
Product: O=C(NCCNc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2)c1cccnc1

Procedure:
Dissolve nicotinic acid (28.2 mg, 0.23 mmol) in DCM (3 mL). Add EDC (40 mg, 0.208 mmol), HOBT (28.1 mg, 0.2081 mmol) and stir at ambient temperature for 10 min. Add 6-(2-amino-ethylamino)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (70 mg, 0.208 mmol) and stir at ambient temperature for 10 hr. Dilute with DCM, add water and extract the aqueous layer three times with DCM. Wash combined organic extracts with 1N aqueous NaOH, and brine. Dry the organic layer over MgSO4, concentrate in vacuo and purify by chromatography on silica gel eluting with hexane/EtOAc (1:0, 1:1, 3:7 and 1:9) to obtain 7-chloro-6-{2-[(pyridine-3-carbonyl)-amino]-ethylamino}-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:41])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:28](=[O:32])[N:29]([CH3:31])[CH3:30])[CH:25]=[C:24](Br)[CH:23]=2)[C:10]=1[CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH3:2].[F:42][C:43]1[CH:44]=[C:45](B(O)O)[CH:46]=[CH:47][C:48]=1[F:49].C(=O)([O-])[O-].[Cs+].[Cs+].C(COC)OC>O.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]>[CH2:1]([O:3][C:4](=[O:41])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:46]3[CH:45]=[CH:44][C:43]([F:42])=[C:48]([F:49])[CH:47]=3)[CH:25]=[C:26]([C:28](=[O:32])[N:29]([CH3:31])[CH3:30])[CH:27]=2)[C:10]=1[CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH3:2]
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(C(=O)N(C)C)c2)c1CCC(=O)OCC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)N(C)C)cc(-c3ccc(F)c(F)c3)c2)c1CCC(=O)OCC
Temperature: 97 °C
Reaction time: 15 h
Yield: 96.4 %

Procedure:
To a mixture of 4-{3-[6-(3-bromo-5-dimethylcarbamoyl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy}-butyric acid ethyl ester (150 mg, 0.236 mmol), 3,4-difluorophenylboronic acid (75 mg, 0.472 mmol), PdCl2(dppf) (29 mg, 0.04 mmol) and cesium carbonate (153 mg, 0.472 mmol) was added dimethoxyethane (5 mL) at room temperature under nitrogen atmosphere. The resulting light brown suspension was heated to 97° C. and stirred for 15 h. Then, the reaction mixture was cooled to room temperature and diluted with water (50 mL). The organic compound was extracted into ethyl acetate (2×50 mL) and the combined organic extracts were washed with brine solution (50 mL). The organic layer was dried over anhydrous magnesium sulfate, filtration of the drying agent and removal of the solvent under vacuum gave the crude dark brown residue which was purified by using an ISCO™ (40 g) column chromatography eluting with 30-60% ethyl acetate in hexanes to afford 4-{3-[6-(5-dimethylcarbamoyl-3′,4′-difluoro-biphenyl-3-yloxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy}-butyric acid ethyl ester (152 mg, 97%) as a colorless oil
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][OH:10])=[C:6]([CH3:11])[N:5]=[C:4]([SH:12])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C.Br[CH2:26][CH2:27][CH2:28]Br>O>[OH:10][CH2:9][CH2:8][C:7]1[C:2](=[O:1])[N:3]2[C:4]([S:12][CH2:26][CH2:27][CH2:28]2)=[N:5][C:6]=1[CH3:11]
Reactant: Cc1nc(S)nc(O)c1CCO
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1nc2n(c(=O)c1CCO)CCCS2
Temperature: 25 °C
Yield: 58 %

Procedure:
A mixture of 30 parts of 4-hydroxy-2-mercapto-6-methyl-5-pyrimidineethanol, 25 parts of potassium carbonate, 270 parts of N,N-dimethylacetamide and 75 parts of water was stirred at room temperature and 36 parts of 1,3-dibromopropane were added at once: temperature rises to 50° C. The whole was stirred overnight at room temperature. The reaction mixture was evaporated and water was added to the residue. The solid product was washed with water and dried in vacuo at 100° C., yielding 21 parts (58%) of 3,4-dihydro-7-(2-hydroxyethyl)-8-methyl-2H,6H-pyrimido[2,1-b][1,3]thiazin-6-one; mp. 155° C. (intermediate 166).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][S:8][CH2:9][CH2:10][C:11]([O:13]C)=[O:12].CCCC[N+](CCCC)(CCCC)CCCC.[F-].[F:33]CCCCCCCCCCCCSCCC(O)=O>[OH-].[K+].C(O)C>[F:33][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][S:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12]
Reactant: COC(=O)CCSCCCCCCBr
Reactant: O=C(O)CCSCCCCCCCCCCCCF
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [K+]
Solvent: CCO
Product: O=C(O)CCSCCCCCCF
Yield: 37 %

Procedure:
Compound 5 (0.5 g, 1,8 mmol) was caused to react with TBAF (3 mmol) according to the procedure for compound 2. The resultant fluoroester was hydrolyzed in KOH/ethanol as previously described, and isolated as an oil by HPLC (Table 1) to yield 0.14 g (37% yield) product 6. 1H-NMR δ1.3 (m, 8H, CH2), 2.55 (t, 2H, C(2)H2), 2,65 (t,2H, C(5)H2), 2.80 (t, 2H, C(3)H2), 4.44 (dt, 2H, C(16)H2JHF=47.5 Hz, JHH=6.2 Hz).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:9][C:8]([C:19]([O:21][CH3:22])=[O:20])=[CH:7][C:6]=2[CH:23]=1.B([O-])([O-])O[C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>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.C1(C)C=CC=CC=1>[C:15]([O:14][C:12]([N:11]1[C:5]2[CH:4]=[CH:3][C:2]([C:26]3[CH:27]=[CH:28][C:29]([N:32]4[CH2:33][CH2:34][O:35][CH2:36][CH2:37]4)=[CH:30][CH:31]=3)=[CH:23][C:6]=2[CH:7]=[C:8]([C:19]([O:21][CH3:22])=[O:20])[CH2:9][CH2:10]1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: [O-]B([O-])Oc1ccc(N2CCOCC2)cc1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2N(C(=O)OC(C)(C)C)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)C1=Cc2cc(-c3ccc(N4CCOCC4)cc3)ccc2N(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 149.8 %

Procedure:
A mixture of methyl 7-bromo-1-(t-butoxycarbonyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (2.0 g), 4-morpholinophenyl borate (1.2 g), and 1M potassium carbonate solution (15 ml), ethanol (15 ml) and toluene (100 ml) was stirred under argon atmosphere at room temperature for 20 minutes. To the mixture was added tetrakis(triphenylphosphine)palladium (0.24 g), and the mixture was refluxed under argon atmosphere for 12 hours and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give methyl 1-(t-butoxycarbonyl)-7-(4-morpholinophenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (3.64 g) as pale yellow crystals.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][CH3:20])[CH:13]=3)=[CH:10][C:9]([NH2:21])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:22]=[C:23]1[O:27][CH2:26][CH:25]([C:28](O)=[O:29])[CH2:24]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(=O)([O-])O.[Na+]>CN(C)C=O.O1CCCC1.O>[C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][CH3:20])[CH:13]=3)=[CH:10][C:9]([NH:21][C:28]([CH:25]3[CH2:24][C:23](=[O:22])[O:27][CH2:26]3)=[O:29])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCc1cccc(-c2cc(N)nn2-c2ccccc2)c1
Reactant: O=C1CC(C(=O)O)CO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1cccc(-c2cc(NC(=O)C3COC(=O)C3)nn2-c2ccccc2)c1
Yield: 62.7 %

Procedure:
To a solution of 1-phenyl-5-(3-propylphenyl)-1H-pyrazol-3-ylamine (109 mg) prepared according to the same procedures as Preparation 8 in N,N-dimethylformamide/tetrahydrofuran (1/1, 2 ml) were sequentially added 5-oxotetrahydrofuran-3-carboxylic acid (82 mg) prepared in Preparation 9, HOBt.H2O (96 mg) and WSC.HCl (121 mg), and the mixture was stirred at room temperature overnight. To this reaction solution was added a saturated aqueous solution of sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The separated organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel thin-layer chromatography (eluent: chloroform/methanol=10/1) to give the titled compound (96 mg).
Reaction SMILES: BrBr.[OH:3]CCC1CC2C(C)=C(OCC3C=CC=CC=3)C(C)=C(C)C=2O1.[C:26]1([P:32]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.N1C=CN=C1>C1(C)C=CC=CC=1>[C:39]1([P:32](=[O:3])([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CC(CCO)O2
Agent: BrBr
Agent: c1c[nH]cn1
Solvent: Cc1ccccc1
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 0.8 ml of bromine in 15 ml of toluene is added, dropwise, to a solution of 4.0 gr. of 2-(RS)-(2-hydroxyethyl)-2,3-dihydro-5-benzyloxy-4,6,7-trimethylbenzofurane, 5.1 g of triphenylphosphine and 1.3 gr of imidazol in 70 ml of toluene. The mixture is stirred at room temperature for 15 minutes, after which the imidazol*HBr is filtered out and the filtrate is evaporated. The residue is treated with ethylic ether to obtain a precipitate of triphenylphosphine oxide, which is filtered out. After the residue has been evaporated, the obtained 7.7 g of raw material is purified by means of the column chromatography (SiO2), which produces 4.0 g of a yellow solid. m.p. 66°-68° C.; IR(KBr): 1549 (νC--C), 1075 cm-1 (νC--O--C); 1H-NMR (CDCl3): δ7.4-7.1 (5H,m), 5.0-4.5 (1H,m), 4.6 (2H,s), 3.5 (2H,t), 3.3-2.6 (2H,m), 2.3-2.1 (2H,m), 2.05 (9H,s).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][N:5]=1.BrCC1CCCCO1.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C@@:21]2([C:39]3[C:30](=[CH:31][C:32]4[O:37][CH2:36][CH2:35][O:34][C:33]=4[CH:38]=3)[O:29][CH2:28]2)[C:20]1=[O:40]>>[F:10][C:9]1[C:4]([CH2:3][N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C@@:21]3([C:39]4[C:30](=[CH:31][C:32]5[O:37][CH2:36][CH2:35][O:34][C:33]=5[CH:38]=4)[O:29][CH2:28]3)[C:20]2=[O:40])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C1Nc2ccccc2[C@]12COc1cc3c(cc12)OCCO3
Reactant: Fc1cccnc1CCl
Agent: BrCC1CCCCO1
Agent: Cl
Product: O=C1N(Cc2ncccc2F)c2ccccc2[C@]12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2-(chloromethyl)-3-fluoropyridine hydrochloride to replace 2-(bromomethyl)tetrahydro-2H-pyran, and (8S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, (8S)-1′-[(3-fluoropyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (33%) as a colorless solid: mp 125-126° C. (diethyl ether); 1H NMR (300 MHz, CDCl3) δ 8.38-8.32 (m, 1H), 7.43-7.34 (m, 1H), 7.28-7.11 (m, 3H), 7.02-6.95 (m, 1H), 6.78 (d, J=7.6 Hz, 1H), 6.48 (s, 1H), 6.44 (s, 1H), 5.31 (d, J=16.2 Hz, 1H), 5.04 (d, J=16.2 Hz, 1H), 4.95 (d, J=8.9 Hz, 1H), 4.67 (d, J=8.9 Hz, 1H), 4.21-4.07 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 177.5, 159.6, 156.2, 155.2, 145.4, 144.5, 142.9, 142.8, 142.2, 138.3, 132.6, 128.6, 124.3, 123.8, 123.3, 123.1, 121.3, 112.2, 109.0, 99.2, 80.2, 64.5, 63.9, 58.1, 40.7; MS (ES+) m/z 404.9 (M+1). Anal. Calcd. for C23H17FN2O4: C, 68.31; H, 4.24; N, 6.93. Found: C, 67.27; H, 4.24; N, 6.93.