Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([C@@H:11]([O:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[N:21]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[N:20]=[CH:19]4)[C@@H:12]([NH2:14])[CH3:13])[CH:9]=[CH:10][C:2]1=2.CCN(C(C)C)C(C)C.[CH:41]1([S:44](Cl)(=[O:46])=[O:45])[CH2:43][CH2:42]1>CN1C(=O)CCC1.O>[O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([C@@H:11]([O:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[N:21]([C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[N:20]=[CH:19]4)[C@@H:12]([NH:14][S:44]([CH:41]3[CH2:43][CH2:42]3)(=[O:46])=[O:45])[CH3:13])[CH:9]=[CH:10][C:2]1=2
Reactant: O=S(=O)(Cl)C1CC1
Reactant: C[C@H](N)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccc2c(c1)OCCO2
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: O
Product: C[C@H](NS(=O)(=O)C1CC1)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccc2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(1R,2S)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)propan-2-amine (43a, 102 mg, 0.24 mmol) and DIPEA (170 μL, 0.97 mmol) was dissolved in NMP (2 mL). cyclopropanesulfonyl chloride (40 μL, 0.39 mmol) was added and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2×10 mL), the organic phase was washed with brine, dried (Na2SO4), filtered and evaporated to give an oily residue (NMP residues). The crude material was further purified by HPLC. Yield 80 mg (62%)
Reaction SMILES: [CH2:1]([CH:8]([C:14](OCC)=O)[C:9]([O:11]CC)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].BrC[C:23](OCC)=[O:24].[OH-].[Na+]>C(O)C.O>[O:24]=[C:23]1[C:3]2[C:2](=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:1][CH:8]([C:9]([OH:11])=[O:10])[CH2:14]1
Reactant: CCOC(=O)CBr
Reactant: CCOC(=O)C(Cc1ccccc1)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C1CC(C(=O)O)Cc2ccccc21
Temperature: 50 °C
Reaction time: 2 h
Yield: 18.6 %

Procedure:
100 mL (0.425 mol) of diethyl benzylmalonate were added dropwise to a stirred suspension of 28 g (0.7 mol) of NaH (60% dispersion in mineral oil) in 550 mL of absolute ethanol at room temperature. The reaction mixture was refluxed 2 h, then cooled to 50° C. and 47.1 mL (0.425 mol) of ethyl bromoacetate were added dropwise. The reaction mixture was refluxed 2 h, then quenched with 150 mL of water; a solution of 140 g (3.5 mol) of NaOH in 400 mL of water was added and the mixture was heated to reflux for 1 h. EtOH was removed in vacuo, the aqueous solution was washed with Et2O and then carefully brought to acidic pH with 350 mL of 37% HCl and extracted with AcOEt. The solvent was removed in vacuo and the resulting residue was heated to 180° C. for 30 min. After cooling to room temperature, 100 mL of 95% H2SO4 were added and the reaction mixture stirred for 2 h, then it was poured onto 500 g of crushed ice and extracted with Et2O. The organic phase was dried and the solvent removed in vacuo. The resulting residue was taken up in Et2O, washed with 40% NaOH solution then brought to acidic pH with 37% HCl and extracted with Et2O. The organic phase was dried and the solvent removed in vacuo. The resulting solid residue was triturated with Et2O, filtered and dried yielding 15 g of the title compound, used without further purification. m.p.=146-147° C. IR (cm−1): 2924, 1692, 1600; NMR (300 MHz, DMSO, δ ppm): 12.6-12.5 (bs, 1H); 7.9 (d, 1H); 7.6-7.5 (m, 1H); 7.4-7.3 (m, 2H); 3.3-3.1 (m, 3H); 2.7 (m, 2H). MS (m/z): 191.1 (MH+).
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([N:10]=[C:11]=[O:12])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:13][NH:14][CH2:15][CH:16]=[O:17]>C1C=CC=CC=1>[CH3:13][N:14]([CH2:15][CH:16]=[O:17])[C:11]([NH:10][C:8]1[S:9][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[N:6][N:7]=1)=[O:12]
Reactant: CNCC=O
Reactant: CC(C)(C)c1nnc(N=C=O)s1
Solvent: c1ccccc1
Product: CN(CC=O)C(=O)Nc1nnc(C(C)(C)C)s1
Reaction time: 0.08 h

Procedure:
A mixture of 5-t-butyl-1,3,4-thiadiazol-2-yl isocyanate dimer (6 grams), the dimethyl acetal of 2-methylaminoacetaldehyde (3.9 grams) and benzene (50 ml) was charged into a glass reaction flask equipped with a mechanical stirrer and reflux condenser. The reaction mixture was heated at reflux, with stirring for a period of about 5 minutes. After this time the reaction mixture was stripped of benzene to yield an oil which solidified upon standing. The resulting solid was then recrystallized from pentane to yield the desired product the dimethyl acetal of 2-[1-methyl-3-(5-t-butyl-1,3,4-thiadiazol-2-yl)ureido]acetaldehyde having a melting point of 80° to 82° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[NH:8]1[CH2:11][CH:10]([C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)=[O:13])[CH2:9]1.[NH:34]1CC(C(NC2C=CC(OC3CCN(C(OC(C)(C)C)=O)CC3)=CC=2)=O)C1>>[CH3:3][C:2]1[N:34]=[N:4][C:5]([N:8]2[CH2:11][CH:10]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH:21]4[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:25][CH2:26]4)=[CH:17][CH:16]=3)=[O:13])[CH2:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NC(=O)C3CNC3)cc2)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(NC(=O)C3CNC3)cc2)CC1
Reactant: Brc1cccnc1
Product: Cc1ccc(N2CC(C(=O)Nc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3)C2)nn1

Procedure:
The title compound was prepared as described in Example 1C, substituting 3-bromo-6-methylpyridazine for 3-bromopyridine and tert-butyl 4-(4-(azetidine-3-carboxamido)phenyl)piperidine-1-carboxylate for tert-butyl 4-(4-(azetidine-3-carboxamido)phenoxy)piperidine-1-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:14]2[C:13](=[O:15])[O:12][CH2:11][C:10]3[CH:16]=[C:17]([CH3:22])[CH:18]=[C:19]([O:20][CH3:21])[C:9]=3[O:8][C:7]=2[CH:6]=[CH:5][C:4]=1[C:23](=[O:28])[CH2:24][CH:25]([CH3:27])[CH3:26].[CH3:29][Mg]Br.[Cl-].[NH4+]>O1CCCC1.C(OCC)C>[OH:28][C:23]([C:4]1[CH:5]=[CH:6][C:7]2[O:8][C:9]3[C:19]([O:20][CH3:21])=[CH:18][C:17]([CH3:22])=[CH:16][C:10]=3[CH2:11][O:12][C:13](=[O:15])[C:14]=2[C:3]=1[O:2][CH3:1])([CH3:29])[CH2:24][CH:25]([CH3:26])[CH3:27]
Reactant: C[Mg]Br
Reactant: COc1cc(C)cc2c1Oc1ccc(C(=O)CC(C)C)c(OC)c1C(=O)OC2
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cc(C)cc2c1Oc1ccc(C(C)(O)CC(C)C)c(OC)c1C(=O)OC2
Reaction time: 4 h

Procedure:
100 mg (0.26 mmol) of 4,11-dimethoxy-9-methyl-3-(3-methylbutan-1-onyl)-7H-dibenzo[b,g][1,5]dioxocin-5-one are dissolved in 5 ml of absolute tetrahydrofuran under argon and 0.2 ml (0.6 mmol) of a 3M methylmagnesium bromide solution in diethyl ether are added at room temperature. After 4 h, the reaction is discontinued by addition of 0.2 ml of ammonium chloride solution. The mixture is concentrated in vacuo, the residue is taken up in dichloromethane and the solution is washed with water. After drying the organic phase over magnesium sulphate, it is concentrated and the residue is purified by column chromatography on silica gel using petroleum ether/ethyl acetate 10:1.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][CH:15]=[CH:16][C:9]=23)[C:5]([C:17]2[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=2)=[N:4]1)[CH3:2].N1C=CC=CC=1.[CH:30]([N:33]=[C:34]=[O:35])([CH3:32])[CH3:31].O>ClCCl>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][CH:15]=[CH:16][C:9]=23)[C:5]([C:17]2[CH:23]=[CH:22][C:20]([NH:21][C:34]([NH:33][CH:30]([CH3:32])[CH3:31])=[O:35])=[CH:19][CH:18]=2)=[N:4]1)[CH3:2]
Reactant: CC(C)N=C=O
Reactant: CCn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc(N)cc2)n1
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CCn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc(NC(=O)NC(C)C)cc2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 45 %

Procedure:
A solution of 4-[1-ethyl-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl]aniline (0.19 mmol) in dichloromethane (1 mL) was treated with pyridine (0.39 mmol) and isopropyl isocyanate (0.39 mmol). The reaction mixture was stirred for 18 h at room temperature and poured into water (1 mL), followed by extraction with (3×3 mL) ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. Purification of the residue by Gilson reverse phase HPLC provided the title product as a white powder (45%). ESMS [M+H]+: 389.2
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[NH:9][CH:8]=[CH:7]2.[CH3:15]I.O>CN(C=O)C.C(OCC)(=O)C>[F:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[N:9]([CH3:15])[CH:8]=[CH:7]2
Reactant: O=c1[nH]ccc2cc(F)ccc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ccc2cc(F)ccc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 107.5 %

Procedure:
Sodium hydride (60% in mineral oil) (211 mg, 5.27 mmol) was added to 6-fluoro-1,2-dihydroisoquinolin-1-one (716 mg, 4.39 mmol) in anhydrous DMF (6 mL) cooled in an ice bath. The mixture was stirred for about 30 min at room temperature and methyl iodide (0.328 mL, 5.27 mmol) was added dropwise. After 1 h, the reaction was judged to be about 60% complete and additional methyl iodide (0.2 mL, 3.2 mmol) was added. After about 1 h, ice and water and ethyl acetate were added to the mixture. After extractive work up with ethyl acetate, the title compound (836 mg) was obtained as a cream solid and carried on without purification.
Reaction SMILES: COC1C=CC(C([NH:24][C:25]2[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:34])([CH3:33])[C@:27]([C:36]3[CH:41]=[C:40](Br)[CH:39]=[CH:38][C:37]=3[F:43])([CH3:35])[N:26]=2)(C2C=CC(OC)=CC=2)C2C=CC=CC=2)=CC=1.[NH2:44][C:45]1[CH:46]=[CH:47][C:48]([CH3:53])=[C:49]([CH:52]=1)[C:50]#[N:51]>>[NH2:24][C:25]1[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:33])([CH3:34])[C@:27]([C:36]2[CH:41]=[C:40]([NH:44][C:45]3[CH:46]=[CH:47][C:48]([CH3:53])=[C:49]([CH:52]=3)[C:50]#[N:51])[CH:39]=[CH:38][C:37]=2[F:43])([CH3:35])[N:26]=1
Reactant: Cc1ccc(N)cc1C#N
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)C(C)(C)C(=O)N2C)(c2ccccc2)c2ccc(OC)cc2)cc1
Product: Cc1ccc(Nc2ccc(F)c([C@@]3(C)N=C(N)N(C)C(=O)C3(C)C)c2)cc1C#N

Procedure:
The coupling of (S)-2-{[bis-(4-methoxy-phenyl)-phenyl-methyl]-amino}-6-(5-bromo-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate K) and 5-amino-2-methyl-benzonitrile according to procedure B followed by deprotection yielded the title compound as an off-white solid. MS (ESI): m/z=394.1 [M+H]+.
Reaction SMILES: [NH:1]1[C:10](=[O:11])[C:9]2[NH:8][CH:7]=[N:6][C:5]=2[N:4]=[C:2]1[NH2:3].[C:12](OC(=O)C)(=[O:14])[CH3:13].P(=O)(O)(O)O.[C:24](O)(=[O:26])[CH3:25]>>[C:12]([N:3]([C:24](=[O:26])[CH3:25])[C:2]1[NH:1][C:10](=[O:11])[C:9]2[NH:8][CH:7]=[N:6][C:5]=2[N:4]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)O
Reactant: Nc1nc2nc[nH]c2c(=O)[nH]1
Agent: O=P(O)(O)O
Product: CC(=O)N(C(C)=O)c1nc2nc[nH]c2c(=O)[nH]1
Yield: 91 %

Procedure:
A mixture of guanine 3 (30 g, 0.199 mol), acetic anhydride (450 ml), and acetic acid (300 ml) was heated to reflux. Phosphoric acid (85.5%, 1.5 ml) was added to the mixture and the mixture then refluxed for 15 hours. Some product precipitated on the side of flask. Solvents were removed under reduced pressure (water aspirator) to dryness. After cooling, the resulting solid was collected, and then washed twice with water (30 ml) and methanol (20 ml) to give diacetylguanine (42.5 g, 91%). The filtrate (water and methanol) obtained above was concentrated to near dryness to give additional 4 (1.7 g, 3.6%). The total yield of 4 was 44.26 g (94.6%).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)=[CH:10][C:11](=[O:15])[O:12]2)=[CH:7][CH:6]=1)=[N+:2]=[N-:3].[N+:23]([C:26]1[CH:43]=[CH:42][C:29]([C:30]([O:32][C:33]([CH2:40][CH3:41])([C:36]([F:39])([F:38])[F:37])[C:34]#[CH:35])=[O:31])=[CH:28][CH:27]=1)([O-:25])=[O:24].C1COCC1>C(OCC)(=O)C.[Cu](I)I>[N+:23]([C:26]1[CH:27]=[CH:28][C:29]([C:30]([O:32][C@@:33]([C:34]2[N:3]=[N:2][N:1]([CH2:4][C:5]3[CH:14]=[C:13]4[C:8]([C:9]([C:16]5[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=5)=[CH:10][C:11](=[O:15])[O:12]4)=[CH:7][CH:6]=3)[CH:35]=2)([C:36]([F:37])([F:38])[F:39])[CH2:40][CH3:41])=[O:31])=[CH:42][CH:43]=1)([O-:25])=[O:24]
Reactant: [N-]=[N+]=NCc1ccc2c(-c3cccc(F)c3)cc(=O)oc2c1
Reactant: C#CC(CC)(OC(=O)c1ccc([N+](=O)[O-])cc1)C(F)(F)F
Agent: I[Cu]I
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC[C@](OC(=O)c1ccc([N+](=O)[O-])cc1)(c1cn(Cc2ccc3c(-c4cccc(F)c4)cc(=O)oc3c2)nn1)C(F)(F)F
Reaction time: 8 h

Procedure:
To a solution of 7-(azidomethyl)-4-(3-fluorophenyl)-2H-chromen-2-one (30 mg, 0.1 mmol) and 1-ethyl-1-(trifluoromethyl)prop-2-yn-1-yl 4-nitrobenzoate (S-isomer, the second, slower eluting enantiomer from step 2) (27 mg, 0.1 mmol) in THF (5 mL) N,N-diisopropylethylamine (79 uL, 0.45 mmol) and copper iodide (26 mg, 0.14 mmol) were added. After overnight stirring, the reaction was diluted with ethyl acetate, filtered and washed with water and brine. The organic layer was then dried over MgSO4, filtered and concentrated. The crude residue obtained was purified by column chromatography (acetone/CH2Cl2 5:95) to afford the title compound. 1H NMR (400 MHz, acetone-d6): 8.5 (s, 1H), 8.42 (d, 2H), 8.31 (d, 2H), 7.7-7.6 (m, 1H), 7.51 (d, 1H), 7.4-7.25 (m, 5H), 6.42 (s, 1H), 5.89 (s, 2H), 3.1-2.98 (m, 1H), 2.91-2.8 (m, 1H), 1.14 (t, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([CH3:10])[N:3]=1.[F:11][C:12]1[N:17]=[CH:16][C:15]([CH:18]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH3:19])=[CH:14][C:13]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[F:11][C:12]1[N:17]=[CH:16][C:15]([CH:18]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH3:19])=[CH:14][C:13]=1[C:2]1[CH:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([CH3:10])[N:3]=1
Reactant: CC(c1cnc(F)c(B2OC(C)(C)C(C)(C)O2)c1)N1CCOCC1
Reactant: CSc1cc(Cl)nc(C)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CSc1cc(-c2cc(C(C)N3CCOCC3)cnc2F)nc(C)n1
Temperature: 90 °C
Yield: 78.8 %

Procedure:
To a 20 mL microwave vials was added 4-chloro-2-methyl-6-(methylthio)pyrimidine (0.175 g, 1.002 mmol), 2-fluoro-5-(1-morpholinoethyl)pyridin-3-ylboronic acid (Example 339 Step 3) (0.305 g, 1.202 mmol), trans-dichlorobis(triphenyl-phosphine)palladium (II) (Strem) (0.056 g, 0.080 mmol), sodium carbonate (JT Baker) (0.531 mg, 5.01 mmol), DME (10 mL), and water (2.5 mL). The vial was degassed by bubbling N2 for 5 min then sealed off and microwave heated at 90° C. for 20 min. The reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (2×10 mL). The combined organic layers were dried over MgSO4 and concentrated. The crude product was purified by column chromatography (40 g, 10% to 20% acetone in hexanes) to afford the product as white solid (275 mg). MS (ESI pos. ion) m/z: 349.1. 1H NMR (300 MHz, CDCl3) δ ppm 1.43 (d, J=6.72 Hz, 3H) 2.33-2.46 (m, 2H) 2.48-2.58 (m, 2H) 2.61 (s, 3H) 2.74 (s, 3H) 3.52 (q, J=6.58 Hz, 1H) 3.71 (t, J=4.46 Hz, 4H) 7.55 (s, 1H) 8.25 (s, 1H) 8.56 (dd, J=9.43, 2.27 Hz, 1H).
Reaction SMILES: F[B-](F)(F)F.[O:6]=[N+:7]=[O:8].N1C(C)=CC(C)=CC=1C.[OH:18][CH2:19][CH2:20][NH:21][C:22]([C@@H:24]1[CH2:28][S:27][C:26](=[O:29])[NH:25]1)=[O:23]>C(#N)C>[N+:7]([O:18][CH2:19][CH2:20][NH:21][C:22]([C@@H:24]1[CH2:28][S:27][C:26](=[O:29])[NH:25]1)=[O:23])([O-:8])=[O:6]
Reactant: O=[N+]=O
Reactant: O=C1N[C@H](C(=O)NCCO)CS1
Agent: F[B-](F)(F)F
Solvent: Cc1cc(C)nc(C)c1
Solvent: CC#N
Product: O=C1N[C@H](C(=O)NCCO[N+](=O)[O-])CS1
Reaction time: 0.5 h
Yield: 13.9 %

Procedure:
0.44 g of nitronium tetrafluoroborate and a solution of 0.41 g of 2,4,6-collidine in 20 ml of acetonitrile were added at a temperature of from -10° C. to 0° C. to 30 ml of acetonitrile, and the resulting mixture was stirred at the same temperature for 30 minutes. At the end of this time, 0.50 g of (4R)-N-(2-hydroxyethyl)-2-oxothiazolidine-4-carboxamide was added to the mixture, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was then freed from the solvent by distillation under reduced pressure. The residue was mixed with ethyl acetate and insoluble materials were filtered off. The filtrate was concentrated by evaporation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using ethyl acetate as the eluent. The pale yellow crystals thus obtained were recrystallized from ethyl acetate, to give 86 mg of the title compound as colorless crystals. The melting point and nuclear magnetic resonance spectrum of the product were identical with those of the compound produced as described in Example 1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:14]1[O:15][CH:16]=[CH:17][CH:18]=1)CCC>O>[O:15]1[CH:16]=[CH:17][CH:18]=[C:14]1[C:2]1[CH:7]=[CH:6][C:5]([C:16]2[O:15][CH:14]=[CH:18][CH:17]=2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(Br)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Solvent: O
Product: c1coc(-c2ccc(-c3ccco3)cc2)c1
Temperature: 100 °C
Yield: 91 %

Procedure:
To a stirred solution of 1,4-dibromobenzene (5 mmol) was added palladium tetrakis-triphenylphosphine (400 mg). The reaction mixture was kept stirring for 15 min after which 2-tributylstannylfuran (10 mmol) was added and the reaction mixture was refluxed at 100° C. for 24 h. The solvent was then evaporated to dryness to give a dark brown residue that was suspended in water and extracted with CH2Cl2. The organic layer was passed over hyflo, dried (Na2SO4) and evaporated to dryness under reduced pressure to give 15 in 91% yield; mp 149-150° C. 1H NMR (DMSO-d6); δ 6.62 (d, 2H), 7.01 (d, 2H), 7.76-7.79 (m, 6H). MS (ESI) m/e (rel. int.): 210 (M+, 100), 181 (40), 153 (30). Anal. Calc. for C14H10O2: C %, 79.98; H %, 4.79. Found C %, 80.12; H %, 4.59.
Reaction SMILES: [C:1]1(=[O:19])[N:5]([CH2:6][CH2:7][CH2:8][C:9]2[N:10]=[CH:11][NH:12][CH:13]=2)[C:4](=[O:14])[C:3]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:2]12.F[C:21]1[CH:33]=[CH:32][C:24]([C:25]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:26])=[CH:23][CH:22]=1.[H-].[Na+].O>CS(C)=O>[C:4]1(=[O:14])[N:5]([CH2:6][CH2:7][CH2:8][C:9]2[N:10]=[CH:11][N:12]([C:21]3[CH:33]=[CH:32][C:24]([C:25]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:26])=[CH:23][CH:22]=3)[CH:13]=2)[C:1](=[O:19])[C:2]2=[CH:18][CH:17]=[CH:16][CH:15]=[C:3]12
Reactant: O=C(O)CCC(=O)c1ccc(F)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCCc1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)CCC(=O)c1ccc(-n2cnc(CCCN3C(=O)c4ccccc4C3=O)c2)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
5.10 g (20 mmol) of 4-(3-phthalimidopropyl)-imidazole followed by 3.92 g (20 mmol) of 3-(4-fluorobenzoyl)-propionic acid are added portionwise to a suspension of 1.20 g (40 mmol) of sodium hydride (80% on paraffin oil) in 50 ml of dimethyl sulphoxide. The reaction mixture is initially stirred at room temperature until gas evolution ceases and then at 100° C. for 17 hours. After cooling, the mixture is poured out on 50 ml of water and extracted with 3×50 ml dichloromethane. The aqueous phase is then adjusted to pH 5 with 2N hydrochloric acid and the precipitated solid is suction filtered and recrystallized from methanol.
Reaction SMILES: Cl.[N:2]1([C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[S:12][C:11]3[CH:19]=[CH:20][CH:21]=[CH:22][C:10]=3[N:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:23](=[O:26])([O-:25])[O-:24].[Na+].[Na+].Cl[CH2:30][CH2:31][O:32][CH:33]([OH:35])[CH3:34].C(O)CC>[I-].[Na+].C(OCC)(=O)C.CN1CCCC1=O>[C:33]([OH:35])(=[O:32])/[CH:34]=[CH:3]/[C:23]([OH:25])=[O:26].[OH:24][CH2:30][CH2:31][O:32][CH2:33][CH2:34][N:5]1[CH2:4][CH2:3][N:2]([C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[S:12][C:11]3[CH:19]=[CH:20][CH:21]=[CH:22][C:10]=3[N:9]=2)[CH2:7][CH2:6]1
Reactant: O=C([O-])[O-]
Reactant: CC(O)OCCCl
Reactant: c1ccc2c(c1)N=C(N1CCNCC1)c1ccccc1S2
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCCO
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: O=C(O)/C=C/C(=O)O
Product: OCCOCCN1CCN(C2=Nc3ccccc3Sc3ccccc32)CC1
Reaction time: 24 h
Yield: 115.3 %

Procedure:
11-piperazinyl-dibenzo[b,f][1,4]thiazepine hydrochloride (40 g) obtained in step c), sodium carbonate (69.3 g), sodium iodide (0.65 g), and 2-chloroethoxyethanol (14.7 g) were added to a solution of n-propyl alcohol (260 ml) and N-methylpyrrolidone (65 ml), and reflux was conducted for 24 hours. Ethyl acetate (327 ml) was added thereto, washing was conducted using water (2×1000 ml), an organic layer was separated to be dried with magnesium sulfate, and a solvent was removed at reduced pressure, thereby oil was created. The resulting oil was completely dissolved in ethanol, and fumaric acid (7.1 g) was added thereto, to produce 11-[4-[2-(hydroxyethoxy)ethyl]-1-piperazinyl]-dibenzo[b,f][1,4]thiazepine fumarate (34 g).
Reaction SMILES: C([O:5][C:6](=[O:31])[CH2:7][CH:8]([N:15]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:17])[CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:24]([N:15]([CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:17])[CH:8]([CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[CH2:7][C:6]([OH:31])=[O:5])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(c1ccccc1)N(Cc1ccccc1)C(CC(=O)OC(C)(C)C)C1CCCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(c1ccccc1)N(Cc1ccccc1)C(CC(=O)O)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-[benzyl-(1-phenyl-ethyl)-amino]-3-cyclohexyl-propionic acid tert-butyl ester (13.7 g, 32.5 mmol) in dichloromethane (65 mL) at 0° C., trifluoroacetic acid (65 mL) was slowly added (over 30 min). The reaction mixture was then stirred for 2 hours at room temperature. The solvent was evaporated and the residue azeotroped (3×50 ml, toluene) to yield a residue.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.C([Li])CCC.CN(C)[CH:16]=[O:17].[BH4-].[Na+]>C1(C)C=CC=CC=1.O1CCCC1.O>[F:8][C:5]1[CH:6]=[CH:7][C:2]([CH2:16][OH:17])=[N:3][CH:4]=1
Reactant: Fc1ccc(Br)nc1
Reactant: CN(C)C=O
Agent: [BH4-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: OCc1ccc(F)cn1
Reaction time: 0.5 h
Yield: 35.7 %

Procedure:
To a solution of 2-bromo-5-fluoropyridine (3.67 g, 20.8 mmol) in toluene (100 mL) was added dropwise n-butyl lithium (15.6 mL, 1.6 M hexane solution, 25.0 mmol) under nitrogen atmosphere at −78° C., which was stirred for 30 minutes. N,N-Dimethylformamide (8.05 mL, 104.0 mmol) was added dropwise to this solution at −78° C., and stirred for 20 minutes at 0° C. This reaction solution was vigorously stirred after addition of water and tetrahydrofuran. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and filtered. Sodium borohydride (1.58 g, 41.8 mmol) was added to the filtrate at 0° C., and stirred for 1 hour at room temperature. This reaction solution was partitioned by addition of water and tetrahydrofuran. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under a reduced pressure. The resulting residue was purified by NH silica gel column chromatography (hexane: diethyl ether=1:2) to obtain the title compound (945 mg, 36%).