Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH2:20][CH2:21][O:22][CH3:23])[N:15]=[CH:14][C:13]([C:24]#[N:25])=[C:12]2O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:29])=O>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH2:20][CH2:21][O:22][CH3:23])[N:15]=[CH:14][C:13]([C:24]#[N:25])=[C:12]2[Cl:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COCCOc1cc2ncc(C#N)c(O)c2cc1OCc1ccccc1
Product: COCCOc1cc2ncc(C#N)c(Cl)c2cc1OCc1ccccc1
Yield: 67 %

Procedure:
Following the procedure used to prepare Reference Example 12, reaction of 6-benzyloxy-4-hydroxy-7-(2-methoxyethoxy)-3-quinolinecarbonitrile with phosphorous oxychloride provides 6-benzyloxy-4-chloro-7-(2-methoxyethoxy)-3-quinolinecarbonitrile in 67% yield, mp 142-145° C.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][S:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH2:3][CH2:2]1.O[CH2:19][CH2:20][NH:21]C(=O)OC(C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.Cl.C(OCC)(=O)C>C1(C)C=CC=CC=1.O>[NH2:21][CH2:20][CH2:19][N:5]([CH2:4][CH:1]1[CH2:2][CH2:3]1)[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)NCC1CC1
Reactant: CC(C)(C)OC(=O)NCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: NCCN(CC1CC1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.6 %

Procedure:
To a solution of N-(cyclopropylmethyl)-2-nitrobenzenesulfonamide (1.7 g, 6.4 mmol), t-butyl N-(2-hydroxyethyl)carbamate (1.3 g, 8.3 mmol) and triphenylphosphine (2.2 g, 8.3 mmol) in toluene (20 mL) was added a 40% solution of diethyl azodicarboxylate in toluene (3.6 g, 8.3 mmol) with ice cooling, and the mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure to a half its original volume, and diethyl ether (30 mL) was added thereto. The precipitates were filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane:ethyl acetate=49:1 to hexane:ethyl acetate=1:1) to obtain a condensed compound as an oily matter. A 4 M hydrogen chloride/ethyl acetate solution (20 mL) was added thereto, and the mixture was stirred at room temperature for 30 minutes. To the reaction solution was added water (70 mL) and extracted. The aqueous layer was collected by separation and washed with ethyl acetate. The aqueous layer was basified with a 4 N aqueous sodium hydroxide solution (pH=12), and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified with amino silica gel column chromatography (hexane:ethyl acetate=19:1 to ethyl acetate) to obtain the title compound (1.2 g, yield 62%).
Reaction SMILES: [CH3:1][N:2]([CH3:34])[CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14](=[O:33])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[C:17]([O:31]C)[CH:16]=2)[CH2:6][CH2:5][CH2:4]1.B(Br)(Br)Br.O.C(=O)([O-])O.[Na+]>ClCCl>[CH3:34][N:2]([CH3:1])[CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14](=[O:33])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[C:17]([OH:31])[CH:16]=2)[CH2:6][CH2:5][CH2:4]1
Reactant: COc1cc(C(=O)N2CCCC(N(C)C)c3ccccc32)ccc1NC(=O)c1ccccc1C
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(N(C)C)c3ccccc32)cc1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 68.1 %

Procedure:
A solution of 5-dimethylamino-1-[3-methoxy-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.50 g) in dichloromethane (30 ml) is added dropwise to a solution of 1M boron tribromide in dichloromethane (5.46 ml) at -45° C. After completion of the dropping, the mixture is stirred for 1 day while the temperature of the reaction mixture is gradually raised to room temperature. To the reaction solution is added water and the mixture is neutralized with sodium hydrogen carbonate, and extracted with dichloromethane. The extract is washed with saturated saline solution and dried over magnesium sulfate. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (eluent; chloroform:methanol=500:1), and recrystallized from methanol/diethyl ether to give 5-dimethylamino-1-[3-hydroxy-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.33 g) as white powder, m.p. 201.5°-202.5° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:17])[C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1.[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(#N)C>[Cl:17][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1
Reactant: OB(O)c1ccccc1
Reactant: NC(=O)C1CCN(c2c(Cl)cncc2Cl)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: [Na+]
Solvent: CC#N
Product: NC(=O)C1CCN(c2c(Cl)cncc2-c2ccccc2)CC1
Yield: 21.6 %

Procedure:
General procedure D (See Example 4) was followed using 1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide 23 (24 mg, 0.088 mmol), benzene boronic acid (13 mg, 0.11 mmol), tetrakis(triphenylphosphine)palladium(0) (5 mg, 5 mol %), acetonitrile (1 mL) and 0.5 M sodium carbonate (0.25 mL, 0.12 mmol) for 30 min. The crude product was purified by preparative hplc (H2O, MeCN, gradient 90:10 to 10:90 over 30 min) to furnish the title compound as a white solid (6 mg, 22%), LC-MS (ESI) Rt 1.63 min, m/z 316 (100%, [M+H]+); m/z (ESI) C17H18ClN3NaO requires 338.1031 found [M+Na]+ 338.1030.
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[SH:19][C:20]1[S:21][C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[N:24]=1.C(=O)(O)[O-].[Na+].Cl>O.CC(C)=O>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][S:19][C:20]3[S:21][C:22]4[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=4[N:24]=3)[CH2:15][S:14][C@H:9]12
Reactant: Sc1nc2ccccc2s1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: NC1C(=O)N2C(C(=O)O)=C(CSc3nc4ccccc4s3)CS[C@H]12
Yield: 58.1 %

Procedure:
To a mixture of 7-aminocephalosporanic acid (23.1 g., purity 86.4%) and 2-mercaptobenzothiazole (14.7 g.) in water (800 ml.), sodium bicarbonate (13.5 g.) was added portionwise with stirring, and acetone (250 ml.) was added thereto. The mixture was stirred at 73° C. for 4.5 hours, cooled below 20° C. and adjusted to pH 3.4 with 6 N hydrochloric acid. The precipitating crystals were collected by filtration, washed with water and acetone in turn and dried under reduced pressure to give 7-amino-3-(benzothiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (18.7 g.).
Reaction SMILES: [NH2:1][C:2]1[N:6](/[CH:7]=[CH:8]/OCC)[N:5]=[CH:4][C:3]=1[CH3:12].Cl.C(OCC)(=O)C>O1CCCC1>[CH3:12][C:3]1[CH:4]=[N:5][N:6]2[CH:7]=[CH:8][NH:1][C:2]=12
Reactant: CCO/C=C/n1ncc(C)c1N
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cnn2cc[nH]c12
Yield: 90.1 %

Procedure:
To a solution of 5-amino-4-methyl-1-[(E)-2-ethoxyvinyl]pyrazole (10.6 g) in tetrahydrofuran (212 ml) was added 4N hydrochloric acid, and the mixture was refluxed for 3 hours. The reaction mixture was adjusted to pH 8 under ice-cooling, thereto was added ethyl acetate (100 ml). The separated organic layer was dried over magnesium sulfate and evaporated in vacuo to give 7-methyl-1H-imidazo[1,2-b]pyrazole (6.92 g) as crystals. IR (Nujol) : 3100, 1620, 1500 cm-1
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:23])[C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:12][CH:11]=2)=[CH:4][C:3]=1[NH:24][C:25]1[N:30]=[C:29]([C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)[CH:28]=[CH:27][N:26]=1.Br[CH2:38][CH2:39][P:40](=[O:47])([O:44][CH2:45][CH3:46])[O:41][CH2:42][CH3:43].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:42]([O:41][P:40]([CH2:39][CH2:38][N:20]1[CH2:19][CH2:18][N:17]([CH2:16][C:13]2[CH:12]=[CH:11][C:10]([C:9](=[O:23])[NH:8][C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([NH:24][C:25]4[N:30]=[C:29]([C:31]5[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=5)[CH:28]=[CH:27][N:26]=4)[CH:4]=3)=[CH:15][CH:14]=2)[CH2:22][CH2:21]1)(=[O:47])[O:44][CH2:45][CH3:46])[CH3:43]
Reactant: Cc1ccc(NC(=O)c2ccc(CN3CCNCC3)cc2)cc1Nc1nccc(-c2cccnc2)n1
Reactant: CCOP(=O)(CCBr)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOP(=O)(CCN1CCN(Cc2ccc(C(=O)Nc3ccc(C)c(Nc4nccc(-c5cccnc5)n4)c3)cc2)CC1)OCC
Temperature: 110 °C
Yield: 72.5 %

Procedure:
A mixture of N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-4-piperazin-1-ylmethyl-benzamide (30 mg, 0.06 mmol, Zimmermann et al., Bioorg. Med. Chem. Lett. 1996, 6, 1221), diethyl 2-bromoethylphosphonate (30 μL, 0.12 mmol) and K2CO3 (20 mg, 0.16 mmol) in 2.5 mL of DMF was heated at 110° C. for 8 hours when most of the starting materials were consumed as judged by LCMS analysis. The solid material was filtered off. The filtrate was diluted with water and then extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated to dryness. The crude material was purified by silica gel chromatography using 10% MeOH/CH2Cl2 to provide 28 mg (55%) of the desired product. 1H NMR (300 MHz, CDCl3) δ 1.32 (t, 6H), 1.92-20.3 (m, 4H), 2.35 (s, 3H), 2.5 (bs, 6H), 2.64 (m, 2H), 3.56 (s, 2H), 4.05-4.14 (m, 4H), 7.07(s, 1H), 7.18 (d, 2H, J=5 Hz), 7.30 (dd, 1H, J=6, 8 Hz), 7.33-7.45 (m, 3H), 7.84 (d, 2H, J=8 Hz), 8.01 (s, 1H), 8.51 (dd, 2H, J=4, 9 Hz), 8.58 (d, 1H, J=2 Hz), 8.70 (dd, 1H, J=2, 5 Hz), 9.25 (s, 1H); 31P (121.4 MHz, CDCl3) δ 30.5; MS (m/z) 644 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[O:10].[C:18]([N:20]=[C:21](SC)[S:22][CH3:23])#[N:19]>ClC(Cl)C>[C:18]([N:20]=[C:21]([N:15]1[CH2:16][CH2:17][CH:12]([NH:11][C:9]([C:3]2[NH:4][C:5]([CH3:8])=[C:6]([Cl:7])[C:2]=2[Cl:1])=[O:10])[CH2:13][CH2:14]1)[S:22][CH3:23])#[N:19]
Reactant: CSC(=NC#N)SC
Reactant: Cc1[nH]c(C(=O)NC2CCNCC2)c(Cl)c1Cl
Solvent: CC(Cl)Cl
Product: CSC(=NC#N)N1CCC(NC(=O)c2[nH]c(C)c(Cl)c2Cl)CC1

Procedure:
A solution of 3,4-dichloro-5-methyl-N-piperidin-4-yl-1H-pyrrole-2-carboxamide (Intermediate 90, 2.73 g, 10 mmol) and dimethyl cyanodithioimidocarbonate (1.61 g, 10 mmol) in dichloroethane was heated to reflux for 5 hours. The reaction mixture was concentrated to an orange oil which was purified by flash chromatography on silica gel (gradient elution from 100% DCM to 5% MeOH in DCM). Pure fractions were combined to yield the title compound in 2.25 g (61%).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[F:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28]([OH:30])=O.CCN(C(C)C)C(C)C.[O:44]([CH2:51][C:52]1[CH:60]=[C:55]2[CH2:56][NH:57][CH2:58][CH2:59][N:54]2[N:53]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>CN(C=O)C.[NH4+].[Cl-]>[F:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28]([N:57]1[CH2:58][CH2:59][N:54]2[N:53]=[C:52]([CH2:51][O:44][C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[CH:60]=[C:55]2[CH2:56]1)=[O:30]
Reactant: O=C(O)c1ccccc1F
Reactant: c1ccc(OCc2cc3n(n2)CCNC3)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccccc1F)N1CCn2nc(COc3ccccc3)cc2C1
Reaction time: 0.08 h
Yield: 40.7 %

Procedure:
2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.146 g, 0.38 mmol) was added portionwise to a stirred solution of 2-fluorobenzoic acid (0.063 g, 0.45 mmol) in DMF (2.0 mL) at 0° C. The reaction mixture was stirred for 5 minutes and then DIPEA (0.09 mL, 0.52 mmol) and 4,5,6,7-tetrahydro-2-(phenoxymethyl)-pyrazolo[1,5-a]pyrazine (0.08 g, 0.35 mmol) were added. The reaction mixture was stirred at room temperature for 15 hours, diluted with a saturated solution of NH4Cl and extracted with DCM. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 30/70). The desired fractions were collected, the solvents evaporated in vacuo and the product repurified by flash column chromatography (silica; AcOEt in DCM 0/100 to 70/30). The desired fractions were collected and the solvents evaporated in vacuo. The residue was suspended in a saturated solution of NH4Cl, stirred for 1 hour and extracted with DCM. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The product was repurified by reverse phase HPLC (gradient from 80% of 0.1% solution of ammonium formate/ammonium hydroxide buffer pH 9 solution in water and 20% CH3CN to 0% of 0.1% solution of ammonium formate/ammonium hydroxide buffer pH 9 solution in water and 100% CH3CN) to yield 5-(2-fluorobenzoyl)-4,5,6,7-tetrahydro-2-(phenoxymethyl)-pyrazolo[1,5-a]pyrazine (0.050 g, 41% yield) as a clear oil. C20H18FN3O2 1H NMR (400 MHz, CDCl3) δ ppm 3.80 (br. s., 1.1; H), 4.22 (br. s., 1.5; H), 4.31 (br. s., 1.4; H), 4.61 (s, 0.9; H), 4.99 (s, 1.1; H), 5.03 (s, 0.9; H), 5.07 (s, 1.1; H), 6.07 (s, 0.45; H), 6.27 (s, 0.55H), 6.90-7.09 (m, 3H), 7.15 (td, J=8.8, 3.6 Hz, 1H), 7.21-7.35 (m, 3H), 7.38-7.53 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[N:6]=[C:5]2[N:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1.[Br:19]C1C=C2C(C(N)=NN2C)=CC=1>>[Br:19][C:10]1[CH:9]=[C:8]2[C:4]([C:5]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)=[N:6][N:7]2[CH3:11])=[CH:3][CH:2]=1
Reactant: CN1CCN(c2nn(C)c3ccc(Br)cc23)CC1
Reactant: Cn1nc(N)c2ccc(Br)cc21
Product: CN1CCN(c2nn(C)c3cc(Br)ccc23)CC1

Procedure:
Prepared in a manner similar to 5-bromo-1-methyl-3-(4-methylpiperazin-1-yl)-1H-indazole but using 6-bromo-1-methyl-1H-indazol-3-amine instead of 5-bromo-1-methyl-1H-indazol-3-amine. LCMS-ESI+: calc'd for C13H17BrN4: 309.1, 311.1 (M+H+); Found: 309.2, 311.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([SH:12])[N:11]=[C:4]2[N:3]=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=1[Cl:24])[O:17][CH2:18][CH2:19][Br:20].ClC1C=CC(OCCBr)=CC=1F.ClC1C=C(O)C=CC=1Cl.BrCCBr>>[Cl:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=1[Cl:24])[O:17][CH2:18][CH2:19][S:12][C:10]1[N:11]=[C:4]2[N:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=1[Cl:24])[O:17][CH2:18][CH2:19][Br:20]
Reactant: Cc1cc(C)n2nc(S)nc2n1
Agent: Clc1ccc(OCCBr)cc1Cl
Agent: Fc1cc(OCCBr)ccc1Cl
Agent: Oc1ccc(Cl)c(Cl)c1
Solvent: BrCCBr
Product: Cc1cc(C)n2nc(SCCOc3ccc(Cl)c(Cl)c3)nc2n1
Yield: 85 %

Procedure:
The title compound was prepared according to the experimentals described for Example 1 above from 5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-thiol and 3,4-dichlorophenoxy-ethylbromide in 85% yield. The reagent 3,4-dichlorophenoxy-ethylbromide was prepared by a similar procedure for the synthesis of 4-chloro-3-fluorophenoxy-ethylbromide in Example 4 above from 3,4-dichlorophenol and 1,2-dibromoethane. EM (calc.): 368.0; MS (ESI) m/e: 369.0 (M+H)+.
Reaction SMILES: [CH2:1]([NH2:6])[CH2:2][CH:3]([CH3:5])[CH3:4].[C:7]([NH:14][C@H:15]([C:23]([OH:25])=O)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>ClCCl>[C:7]([NH:14][C@H:15]([C:23]([NH:6][CH2:1][CH2:2][CH:3]([CH3:5])[CH3:4])=[O:25])[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8]
Reactant: CC(C)CCN
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)CCNC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 90 %

Procedure:
Isopentylamine (3.00 ml, manufactured by Wako Pure Chemical Industries, Ltd.) and Boc-L-phenylalanine (7.52 g, manufactured by Peptide Institute, Inc.) were dissolved in dichloromethane (50 ml). To the solution were added, under ice-cooling, HOBT (3.84 g) and WSC (5.44 g). The mixture was stirred for 18 hours at room temperature. The reaction mixture was concentrated, to which was added ethyl acetate (300 ml). The mixture was washed with a 10% aqueous solution of citric acid, a 3% aqueous solution of sodium hydrogen carbonate and a saturated aqueous saline solution. The organic layer was dried over anhydrous sodium sulfate, which was then concentrated to dryness. The concentrate was treated with ether to give N-(Boc-L-phenylalanyl)isopentylamine (7.77 g) (yield 90%). The compound thus obtained (1.00 g) was dissolved in dichloromethane (5 ml), to which was added trifluoroacetic acid (TFA, 5 ml), and the mixture was left standing for one hour at room temperature. The reaction mixture was concentrated, to which was added chloroform, followed by washing with a saturated aqueous solution of sodium hydrogen carbonate, water and a saturated aqueous saline solution, successively. The organic layer was dried over anhydrous sodium sulfate, which was then concentrated to dryness. The residue was dissolved in dichloromethane (26 ml). To the solution were added, under ice-cooling, (2S,3S)-ethyl hydrogen N-Z-aziridine-2,3-dicarboxylate (Compound 1, 965 mg) obtained in Working Example 1, HOBT (445 mg) and WSC (631 mg). The mixture was stirred for 18 hours at room temperature. The reaction mixture was concentrated, to which was added ethyl acetate. The mixture was washed with a 10% aqueous solution of citric acid, water, a saturated aqueous solution of sodium hydrogen carbonate, a 2% aqueous solution of sodium hydrogen carbonate, water and a saturated aqueous saline solution, successively. The organic layer was dried over anhydrous sodium sulfate, which was subjected to a silica gel column chromatography (Kieselgel 60 (Merck A.G.), 200 ml). The column was subjected to elution with eluents prepared by adding methanol to chloroform in sequence. From the fraction of chloroform containing 1% (V/V) methanol, the above-titled compound (Compound 2; 1.15 g) was obtained as a white powdery product (yield 76%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[CH3:25])=[CH:9]\[N:10]2[C:18]3[CH:17]=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=3[C:12]3[CH2:20][N:21]([CH3:24])[CH2:22][CH2:23][C:11]2=3)=[CH:4][CH:3]=1.FC1C=CC(C(=C)CN2C3C=CC(C)=CC=3C3CN(C)CCC2=3)=CC=1>CO.C(O)(=O)C.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:25])[CH2:9][N:10]2[C:18]3[CH:17]=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=3[C:12]3[CH2:20][N:21]([CH3:24])[CH2:22][CH2:23][C:11]2=3)=[CH:6][CH:7]=1
Reactant: C/C(=C/n1c2c(c3cc(C)ccc31)CN(C)CC2)c1ccc(F)cc1
Agent: [Pd]
Agent: C=C(Cn1c2c(c3cc(C)ccc31)CN(C)CC2)c1ccc(F)cc1
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ccc2c(c1)c1c(n2CC(C)c2ccc(F)cc2)CCN(C)C1

Procedure:
A mixture of compound 5-((Z)-2-(4-fluorophenyl)prop-1-enyl)-2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole and 5-(2-(4-fluorophenyl)allyl)-2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (of ratio 1:3, 1.8 g, 5.38 mmol, 1 equiv) were shaken in a 250 ml Parr Shaker vessel with 180 mg of Pd/C in 50 ml of Methanol/acetic acid (10:1) mixture for 18 hours under 60 psi H2. It was filtered over a celite bed with methanol and evaporated under vacuum. The residue was diluted with ethyl acetate (500 ml) and washed with 50 ml of satd. sodium bicarbonate solution and then brine. The organic part was concentrated under reduced pressure and column purified over 100-200 silica gel using 0 to 50% ethyl acetate in hexanes as eluant, at an interval of 5%, Yield: 685 mg (38%).
Reaction SMILES: C[S-:2].[Na+].Cl[C:5]1[CH:10]=[CH:9][C:8]([S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1.Cl>CN(C)P(N(C)C)(N(C)C)=O>[C:14]1([S:11]([C:8]2[CH:7]=[CH:6][C:5]([SH:2])=[CH:10][CH:9]=2)(=[O:13])=[O:12])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: C[S-]
Reactant: O=S(=O)(c1ccccc1)c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=S(=O)(c1ccccc1)c1ccc(S)cc1
Temperature: 100 °C
Yield: 301 %

Procedure:
1.25 g of sodium thiomethylate are added under a nitrogen atmosphere to a solution of 15 g (0.0593 mol) of 1-chloro-4-(phenylsulfonyl)benzene in 150 ml of hexamethylphosphoramide. The mixture obtained is heated for 4 hours at 100° C. and then cooled and hydrolyzed in an ice/water mixture. The reaction medium obtained is extracted with ethyl acetate and the aqueous phase obtained is then poured into a 4 N solution of hydrochloric acid at 0° C. The product formed precipitates. After filtration, washing with water until the pH of the washings is neutral, and drying, 13.44 g (yield: 90.5%) of the expected product are obtained. M.p.=117° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([I:11])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17](Cl)=[O:18].Cl>N1C=CC=CC=1>[I:11][C:4]1[S:3][C:2]([NH:1][C:17]([C:13]2[S:12][CH:16]=[CH:15][CH:14]=2)=[O:18])=[N:6][C:5]=1[C:7]([F:10])([F:8])[F:9]
Reactant: O=C(Cl)c1cccs1
Reactant: Nc1nc(C(F)(F)F)c(I)s1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(Nc1nc(C(F)(F)F)c(I)s1)c1cccs1
Temperature: 0 °C
Yield: 72.8 %

Procedure:
2-Amino-5-iodo-4-trifluoromethylthiazole (1.2 g) was dissolved in pyridine (2 ml) and thiophene-2-carbonyl chloride (0.80 g) was added at room temperature with stirring. The mixture was stirred for 6 hr at room temperature. The mixture was poured into ice water and acidified with aqueous hydrochloric acid then extracted with chloroform The chloroform layer was dried over magnesium sulfate and the solvent was removed under reduced pressure. The solid thus obtained was recrystallized from methanol to give N-(5-iodo-4-trifluoromethylthiazol-2-yl)thiophene-2-carboxamide (1.2 g), m. p. 184-185° C.
Reaction SMILES: [CH2:1]([C:5](=[C:11]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)C(OCC)=O)[C:6](OCC)=O)[CH2:2][CH2:3][CH3:4]>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH2:6]([C:5]1[CH:11]=[N:17][C:18]2[C:19]([C:1]=1[CH2:2][C:3]1[CH:4]=[CH:6][C:5]([C:11]#[N:17])=[CH:1][CH:2]=1)=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:19][CH2:18][CH3:23]
Reactant: CCCCC(C(=O)OCC)=C(Nc1ccccc1)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCCCc1cnc2ccccc2c1Cc1ccc(C#N)cc1
Temperature: 250 °C
Yield: 154.8 %

Procedure:
A mixture of 2.5 g of the product of Step B and 30 ml of diphenylether was heated for 30 minutes in a bath at 250° C. The mixture was allowed to return to ambient temperature, separated and washed with pentane to obtain 1.82 g of the desired product.