Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:6][N:7]=1.[CH3:17][I:18]>C(O)C>[I-:18].[CH3:1][C:2]1[C:3]2[N:4]([C:8]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:6][N+:7]=1[CH3:17]
Reactant: CC1=NCCn2c1ccc2-c1ccccc1
Reactant: CI
Solvent: CCO
Product: CC1=[N+](C)CCn2c1ccc2-c1ccccc1
Product: [I-]
Reaction time: 8 h
Yield: 78 %

Procedure:
3,4-Dihydro-1-methyl-6-phenylpyrrolo[1,2-a]pyrazine (0.6 g) was dissolved in 10 ml of ethanol and treated with 0.9 ml of methyl iodide under argon. The solution was boiled overnight, cooled and the separated crystals were filtered off. There was obtained 0.8 g (78%) of 3,4-dihydro-1,2-dimethyl-6-phenylpyrrolo[1,2-a]pyrazinium iodide; m.pt.: 213°-216° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].[C:10](Cl)(=[O:12])[CH3:11].[Cl-].[Cl-].[Cl-].[Al+3]>>[Cl:1][C:2]1[C:3]([F:9])=[CH:4][C:5]([OH:8])=[C:6]([C:10](=[O:12])[CH3:11])[CH:7]=1
Reactant: Oc1ccc(Cl)c(F)c1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)c1cc(Cl)c(F)cc1O
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To 4-chloro-3-fluorophenol (Oakwood #004459, 5.1 g, 35 mmol) was added acetyl chloride (3.6 mL, 51 mmol) and the resulting mixture was heated at 60° C. for 2 hours. Aluminum trichloride (7.0 g, 52 mmol) was added and the mixture was heated at 180° C. for 30 minutes. The reaction mixture was then cooled to room temperature and slowly quenched with 1M HCl while cooling in an ice-bath and stirred for 30 minutes. The precipitate was washed well with water and dried under vacuum to give the desired product (quantitative). This material was used without further purification. 1H NMR (300 MHz, CDCl3): δ 12.41 (s, 1H), 7.80 (m, 1H), 6.79 (m, 1H), 2.60 (s, 3H).
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:13]1[NH:14][C:15]([CH2:22][CH2:23][C:24](O)=O)=[C:16]2[C:21]=1[CH2:20][CH2:19][CH2:18][CH2:17]2.Cl[C:28]1C=CC(C2CCNCC2)=CC=1>>[C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:24][CH2:23][CH2:22][C:15]3[NH:14][N:13]=[C:21]4[CH2:20][CH2:19][CH2:18][CH2:17][CH2:28][C:16]=34)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: Clc1ccc(C2CCNCC2)cc1
Reactant: O=C(O)CCc1[nH]nc2c1CCCC2
Product: c1ccc(N2CCN(CCCc3[nH]nc4c3CCCCC4)CC2)cc1

Procedure:
In the same manner as in Example 102 except that 3-(2,4,5,6,7,8-hexahydrocycloheptapyrazol-3-yl)propionic acid obtained in Starting Material Synthesis Example 5 and 1-phenylpiperazine are used instead of 3-(4,5,6,7-tetrahydro-2H-indazol-3-yl)propionic acid obtained in Starting Material Synthesis Example 1 and 4-(4-chlorophenyl)piperidine, 2,4,5,6,7,8-hexahydro-3-(3-(4-phenylpiperazin-1-yl)propyl)cycloheptapyrazole is obtained.
Reaction SMILES: [C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]2[NH:12][C:11](=[O:13])[C@:10]([CH3:17])([C:14](O)=[O:15])[CH2:9]2)=[CH:3][CH:2]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[BH4-].[Na+]>O.C1COCC1>[C:1]1([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@H:8]2[NH:12][C:11](=[O:13])[C@@:10]([CH2:14][OH:15])([CH3:17])[CH2:9]2)=[CH:5][CH:6]=1
Reactant: C[C@@]1(C(=O)O)C[C@@H](Cc2ccc(-c3ccccc3)cc2)NC1=O
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: O
Solvent: C1CCOC1
Product: C[C@@]1(CO)C[C@@H](Cc2ccc(-c3ccccc3)cc2)NC1=O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 96.4 %

Procedure:
(3R,5R)-5-Biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-3-carboxylic acid (25.0 g, 80.8 mmol) was combined with THF (500 mL) and NMM (25 mL, 230 mmol). The resulting mixture was cooled at 0° C. (jacket temp set at −5° C.) and isobutyl chloroformate (21.0 mL, 162 mmol) was added dropwise via addition funnel, while maintaining the internal temperature below 5° C.). The mixture was stirred at 0° C. for 20 minutes. Sodium borohydride (12.2 g, 323 mmol) dissolved in water (40 mL) was added dropwise and the mixture was stirred at 0° C. for 20 minutes (>98% conversion). The reaction was quenched with 1M aqueous HCl (300 mL) and the mixture was stirred at room temperature for 1 hour. Most of solvent was distilled off, leaving a white slurry. The slurry was stirred for 60 minutes and then filtered (small particles, slow filtration) to yield the title compound as a white solid (23 g; >98% purity).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:6][CH2:7][C:8]1[N:9]=[C:10]([C:13]2[CH:28]=[CH:27][C:16]([CH2:17][N:18]3[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[N:20]=[CH:19]3)=[CH:15][CH:14]=2)[S:11][CH:12]=1>>[ClH:6].[N:1]1([CH2:7][C:8]2[N:9]=[C:10]([C:13]3[CH:28]=[CH:27][C:16]([CH2:17][N:18]4[C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[N:20]=[CH:19]4)=[CH:15][CH:14]=3)[S:11][CH:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: ClCc1csc(-c2ccc(Cn3cnc4ccccc43)cc2)n1
Product: Cl
Product: c1ccc2c(c1)ncn2Cc1ccc(-c2nc(CN3CCCC3)cs2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Pyrrolidine (0.260 g, 3.66 mmol) was added to 1-{4-[4-(chloromethyl)-1,3-thiazol-2-yl]benzyl}-1H-benzimidazole (0.250 g, 0.737 mmol) at 5° C. and the mixture was allowed to stir for 1 h, allowed to warm to room temperature and evaporated to dryness in vacuo. The resultant residue was purified by flash chromatography (silica, CHCl3:MeOH 98:2) to afford the free amine of the title product. The purified material was stirred under HCl/ether and concentrated in vacuo to provide the title product, identified by NMR and mass spectral analyses. 1H NMR (300 MHz, DMSO-d6): 0.99 (br s, 1H), 9.61 (br s, 1H), 7.99 (s, 1H), 7.99 (d, 2H), 7.76-7.93 (m, 2H), 7.59 (d, 2H), 7.46-7.56 (m, 2H), 5.80 (s, 2H), 4.51 (d, 2H), 3.42-3.54 (m, 2H), 3.17 (s, 2H), 1.81-2.05 (m, 4H). LCMS (ESI+) 375.14 (MH+).
Reaction SMILES: [N:1]([C@@H:4]([C@@H:40]([C:47]1[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[C:49]([Cl:55])[CH:48]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:5]([NH:7][C:8]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:9]=1[CH2:10][CH2:11][C@H:12]1[O:17][CH2:16][C@@H:15]([CH2:18][O:19][C:20](=[O:27])[NH:21][CH2:22][C:23]([F:26])([F:25])[F:24])[N:14]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:13]1)=[O:6])=[N+]=[N-].CP(C)C>CCOC(C)=O.O>[NH2:1][C@@H:4]([C@@H:40]([C:47]1[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[C:49]([Cl:55])[CH:48]=1)[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[C:5]([NH:7][C:8]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:9]=1[CH2:10][CH2:11][C@H:12]1[O:17][CH2:16][C@@H:15]([CH2:18][O:19][C:20](=[O:27])[NH:21][CH2:22][C:23]([F:26])([F:25])[F:24])[N:14]([C:28]([O:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:29])[CH2:13]1)=[O:6]
Reactant: COc1ccc([C@@H](c2ccccc2)[C@H](N=[N+]=[N-])C(=O)Nc2cccc(F)c2CC[C@@H]2CN(C(=O)OC(C)(C)C)[C@H](COC(=O)NCC(F)(F)F)CO2)cc1Cl
Agent: CP(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc([C@@H](c2ccccc2)[C@H](N)C(=O)Nc2cccc(F)c2CC[C@@H]2CN(C(=O)OC(C)(C)C)[C@H](COC(=O)NCC(F)(F)F)CO2)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the product from step 2 (160 mg, 0.20 mmol) in EtOAc (8 mL) and water (2 mL), was added trimethylphosphine (1.0 mL, 1M solution in THF, 1.0 mmol). The reaction mixture was stirred at ambient temperature for 2 h, then diluted with water (20 mL) and extracted with EtOAc (25 mL×3). The combined organic extracts were washed with brine (25 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide the title compound as colorless oil. (M+H)+=767.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC(=O)[NH:14][CH2:15][CH:16]([CH2:27][O:28][C:29]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:17][CH2:18][N:19]1[CH:24]=[CH:23][C:22](=[O:25])[NH:21][C:20]1=[O:26])(C)(C)C>ClCCl>[NH2:14][CH2:15][CH:16]([CH2:27][O:28][C:29]([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH2:17][CH2:18][N:19]1[CH:24]=[CH:23][C:22](=[O:25])[NH:21][C:20]1=[O:26]
Reactant: CC(C)(C)OC(=O)NCC(CCn1ccc(=O)[nH]c1=O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCC(CCn1ccc(=O)[nH]c1=O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 63.4 %

Procedure:
TFA (2 ml) was added to a solution of compound 42 (100 mg, 0.18 mmol) in dichloromethane (4 ml) and the solution was stirred at room temperature. After 30 min the solvents were evaporated in vacuo and the afforded residue was purified by column chromatography on silica gel which gave the title compound (52 mg, 65%).
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[S:7][CH:8]=1)([OH:3])=O.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CC1C=CC(C)=CC=1CC(N1CCC(C2SC=C([C:75]([N:77](C)[C@@H:78]([C:81]3[CH:86]=[CH:85][CH:84]=[CH:83][CH:82]=3)[CH2:79][CH3:80])=O)N=2)CC1)=O>C(#N)C>[CH3:75][N:77]([C@@H:78]([C:81]1[CH:86]=[CH:85][CH:84]=[CH:83][CH:82]=1)[CH2:79][CH3:80])[C:1]([C:4]1[N:5]=[C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[S:7][CH:8]=1)=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C(=O)O)cs2)CC1
Reactant: CC[C@H](c1ccccc1)N(C)C(=O)c1csc(C2CCN(C(=O)Cc3cc(C)ccc3C)CC2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC[C@H](c1ccccc1)N(C)C(=O)c1csc(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
1-(1,1-Dimethylethyl) 4-(4-carboxy-2-thiazolyl)-1-piperidinecarboxylate (i.e. the product of Example 1, Step B) (3.1 g, 9.9 mmol) was suspended in 10 mL of dry acetonitrile and treated with triethylamine (3.0 mL, 21 mmol) to give a homogeneous solution. To this was added O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (3.98 g, 10.5 mmol) followed by (α,R)-α-ethyl-N-methylbenzenemethanamine (i.e. the product of Example 1, Step C) (10 mmol, 1.50 g). The mixture was stirred at ambient temperature for 4 days, concentrated under reduced pressure, diluted with ethyl acetate, washed with 1 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate solution and brine, dried over MgSO4 and concentrated under reduced pressure to give 5.1 g of a dark oil. Purification by silica gel chromatography using 25% ethyl acetate in hexanes gave 3.6 g of the title compound as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].F[C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[F:8])[O:9][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1
Reactant: Oc1ccc(F)c(F)c1
Reactant: O=Cc1ccc(F)cc1
Product: O=Cc1ccc(Oc2ccc(F)c(F)c2)cc1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 3,4-difluorophenol and 4-fluorobenzaldehyde.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[CH:9][C:10]2[O:14][C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[C:12]([C:22](=[O:25])[NH:23][CH3:24])[C:11]=2[CH:26]=1)(=O)=O.B([C:32]1[CH:33]=[CH:34][C:35]([O:41][CH3:42])=[C:36]([CH:40]=1)[C:37]([OH:39])=[O:38])(O)O.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>O>[F:21][C:18]1[CH:17]=[CH:16][C:15]([C:13]2[O:14][C:10]3[CH:9]=[CH:8][C:7]([C:32]4[CH:33]=[CH:34][C:35]([O:41][CH3:42])=[C:36]([CH:40]=4)[C:37]([OH:39])=[O:38])=[CH:26][C:11]=3[C:12]=2[C:22](=[O:25])[NH:23][CH3:24])=[CH:20][CH:19]=1
Reactant: COc1ccc(B(O)O)cc1C(=O)O
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(OS(=O)(=O)C(F)(F)F)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3ccc(OC)c(C(=O)O)c3)cc12
Temperature: 85 °C
Reaction time: 0.5 h

Procedure:
To a 150 mL sealed tube was added 2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl trifluoromethanesulfonate (1.252 g, 3 mmol), 5-borono-2-methoxybenzoic acid (0.882 g, 4.50 mmol), cesium carbonate (1.466 g, 4.50 mmol), tetrakis(triphenyl phosphine)palladium(0) (0.069 g, 0.060 mmol), dioxane (18 mL) and water (3.60 mL). The vial was sealed and heated in an oil bath over night at 85° C. The reaction mixture was then filtered through CELITE® and concentrated in vacuo. Cold 0.5N HCl was then added and the heterogeneous mixture was stirred for 30 minutes. The resulting product, a white solid was filtered, washed with water and dried overnight to give a quantitative yield of 5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy benzoic acid which was carried on without further purification. LCMS m/z 420.92 (M+H), Rt 2.003 min., 87% purity.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:26])/[CH:11]=[CH:12]\[CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)([O-])=O.[H][H]>C(OCC)(=O)C.[Pt](=O)=O>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:26])[CH2:11][CH2:12][CH:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH2:17][CH2:18]1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCC(/C=C\C(=O)c2ccccc2[N+](=O)[O-])CC1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CCC(=O)c2ccccc2N)CC1
Yield: 83.4 %

Procedure:
The compound prepared in Example 301 (1.30 g) was suspended in ethyl acetate (4.0 mL) and platinum (IV) oxide (81.9 mg, 0.361 mmol) added. The reaction mixture was stirred at room temperature under a balloon of hydrogen for 18 hours and then concentrated under reduced pressure to afford the crude material, which was purified by flash column chromatography (eluant: 10% ethyl acetate/hexane) to furnish the title compound (1.00 g) with the following physical properties.
Reaction SMILES: ClC1C=CC=CC=1.CO[CH:10](OC)[CH2:11][S:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19].[CH3:22][O:23]C(Cl)Cl.C([O-])(O)=O.[Na+]>O.C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[F:19][C:14]1[C:13]2[S:12][CH:11]=[C:10]([CH:22]=[O:23])[C:18]=2[CH:17]=[CH:16][CH:15]=1
Reactant: COC(Cl)Cl
Reactant: COC(CSc1ccccc1F)OC
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Clc1ccccc1
Solvent: ClCCl
Solvent: O
Product: O=Cc1csc2c(F)cccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Fluorothiophenol (4.14 g, 32.6 mmol) was dissolved in anhydrous THF (100 mL). Potassium tert-butoxide (1.0 M in THF, 35.8 mL) was added and the suspension was stirred at room temperature for 15 minutes. 2-Chloroacetaldehyde dimethyl acetal was added and the mixture was stirred for 3 days. Water (100 mL) was added and the solution was extracted with diethyl ether (3×100 mL). The extracts were concentrated to a yellow oil and chromatographed (5 to 20% ethyl acetate in hexane) to yield 1-(2,2-dimethoxy-ethylsulfanyl)-2-fluoro-benzene (6.42 g) as a colorless oil. Chlorobenzene (25 mL) was heated to reflux and polyphosphoric acid (1 mL) was added. The 1-(2,2-dimethoxy-ethylsulfanyl)-2-fluoro-benzene was then added slowly turning the solution dark. After 3 hours of heating, the reaction was cooled to room temperature and diluted with water (50 mL). The solution was extracted with benzene (2×50 mL). The extracts were concentrated and chromatographed (0 to 15% ethyl acetate in hexane) to yield 7-fluorobenzothiophenyl (0.77 g). The 7-fluorobenzothiophenyl (0.77 g, 5.1 mmol) and dichloromethyl methyl ether (0.872 g, 7.6 mmol) were dissolved in anhydrous DCM (25 mL). Titanium tetrachloride (1.0 M in DCM, 7.6 mL, 7.6 mmol) was added, turning the solution dark. After 30 minutes at room temperature, the reaction was poured into a mixture of saturated aqueous NaHCO3 and ice. The mixture was stirred for about 30 minutes and then was extracted with DCM (2×50 mL). The extracts were concentrated and chromatographed (0 to 15% ethyl acetate in hexane) to yield 7-fluorobenzothiophene-3-carboxaldehyde (0.642 g). The 7-fluorobenzothiophene-3-carboxaldehyde (0.642 g, 3.77 mmol) and sulfamide (1.7 g, 18 mmol) were combined in anhydrous ethanol (20 mL) and heated to reflux for three days. The reaction was cooled to room temperature and sodium borohydride (0.148 g, 3.92 mmol) was added. After two hours, water (25 ml) was added and the solution was extracted with chloroform (3×25 mL). The extracts were concentrated, suspended in a minimal amount of DCM, and filtered to yield the title compound as a yellow solid.
Reaction SMILES: Cl[C:2]([S:4]Cl)=[O:3].[CH3:6][O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][CH:9]=1.Cl>>[CH3:6][O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]2[O:13][C:2](=[O:3])[S:4][N:14]=2)=[CH:10][CH:9]=1
Reactant: O=C(Cl)SCl
Reactant: COc1ccc(C(N)=O)cc1
Agent: Cl
Product: COc1ccc(-c2nsc(=O)o2)cc1
Temperature: 25 °C
Yield: 64.1 %

Procedure:
Chlorocarbonyl sulphenyl chloride (13.2 g, 0.10 mol) is added dropwise to a stirred solution of 4-methoxybenzamide (13.8 g, 0.091 mol) under dry nitrogen at room temperature. When the addition is complete, the mixture is refluxed for 8 hours, during which time hydrogen chloride gas is evolved. The solution is allowed to cool to room temperature and the solvent is removed in vacuo. The residue is triturated with methyl tert.-butyl ether and the crystalline solid is filtered off and dried, to give 5-(4-methoxyphenyl)-[1,3,4]oxathiazolin-2-one (12.2 g, 64%) as colourless crystals, m.p. 117°-118° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][CH2:5][C:6](Cl)=[O:7].Cl.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:13][CH:12]=1>C1(C)C=CC=CC=1>[Cl:1][CH2:2][CH2:3][O:4][CH2:5][C:6]([NH:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:15][CH:16]=1)=[O:7]
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: O=C(Cl)COCCCl
Agent: Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)Cc1ccc(NC(=O)COCCCl)cc1

Procedure:
14.6 g (92.7 mmol) of (2-chloroethoxy)acetyl chloride are added to a suspension of 20.0 g (92.7 mmol) of ethyl 4-aminophenylacetate hydrochloride in 25 ml of toluene, and the mixture is heated at the boil for 24 hours. The reaction mixture is evaporated and dried, giving ethyl {4-[2-(2-chloroethoxy)acetylamino]phenyl}acetate as a yellowish solid; ESI 300.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N:12]2[CH2:17][CH2:16][NH:15][C:14]([CH3:19])([CH3:18])[CH2:13]2)=[N:4][N:3]=1.C(N(CC)CC)C.C(Cl)(=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>ClCCl.C(OCC)(=O)C>[CH3:18][C:14]1([CH3:19])[NH:15][CH2:16][CH2:17][N:12]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:3][N:4]=2)[CH2:13]1
Reactant: CC1(C)CN(c2nnc(Cl)c3ccccc23)CCN1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC1(C)CN(c2nnc(-c3ccccc3)c3ccccc23)CCN1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-chloro-4-(3,3-dimethylpiperazin-1-yl)phthalazine (540 mg, 2 mmol) in 10 mL of dichloromethane was added triethylamine (0.56 mL, 4 mmol, 2 eq), followed by benzoyl chloride (0.26 mL, 2.2 mmol, 1.1 eq). The reaction was stirred at rt for 30 min and diluted with 100 mL of ethyl acetate. The organic layer was washed with 1×10 mL of sat. NaHCO3 solution and 1×10 mL of sat. NaCl solution. Purification by column chromatography (100:2 dichloromethane:methanol) afforded 1-(3,3-dimethylpiperazin-1-yl)-4-phenylphthalazine (BSL-7). 1H-NMR (400 Mhz) δ 1.65 (s, 6H), 3.46 (s, 2H), 3.63 (m, 4H), 7.34 (m, 3H), 7.42 (m, 3H), 7.42 (m, 3H), 7.83 (m, 2H), 8.03 (m, 1H), 8.17 (m, 1H).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]1[C:27]2[C:22](=[CH:23][C:24]([O:28][CH3:29])=[CH:25][CH:26]=2)[S:21][CH2:20][C:19]1([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1)[CH3:30])(C(C)(C)C)(C)C.Cl.O>O1CCCC1>[OH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]1[C:27]2[C:22](=[CH:23][C:24]([O:28][CH3:29])=[CH:25][CH:26]=2)[S:21][CH2:20][C:19]1([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1)[CH3:30]
Reactant: COc1ccc(C2(C)CSc3cc(OC)ccc3C2CCCCCCCCCO[Si](C)(C)C(C)(C)C)cc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C2(C)CSc3cc(OC)ccc3C2CCCCCCCCCO)cc1
Temperature: 25 °C
Reaction time: 2.33 h
Yield: 92.1 %

Procedure:
4-[9-(t-Butyldimethylsilyloxy)nonyl]-7-methoxy-3-(4-methoxyphenyl)-3-methylthiochroman (2.2 g, 3.95 mmol) was dissolved in tetrahydrofuran (150 ml), and 3N-HCl (11 ml) was added thereto. The reaction mixture was stirred at room temperature for 140 minutes. After the reaction was completed, water was added to the reaction solution, and the resulting mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to flash chromatography on silica gel (n-hexane:ethyl acetate=8:2 and 1:1) to give the title compound (1.61 g, yield 92%) as a white solid.
Reaction SMILES: I.[F:2][C:3]1[CH:4]=[C:5]([NH:15][C:16](SC)=[NH:17])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[N:12][C:11]([CH3:14])=[N:10]1.[Cl:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]([F:40])([F:39])[F:38])=[CH:31][CH:30]=1)[C:26](O)=O.CN1CCOCC1.C(N(CC)C(C)C)(C)C.[NH2:57][NH2:58]>>[Cl:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]([C:26]1[NH:58][N:57]=[C:16]([NH:15][C:5]2[CH:4]=[C:3]([F:2])[C:8]([N:9]3[CH:13]=[N:12][C:11]([CH3:14])=[N:10]3)=[CH:7][CH:6]=2)[N:17]=1)[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]([F:38])([F:39])[F:40])=[CH:31][CH:30]=1
Reactant: O=C(O)C(CCCCCl)c1ccc(OCC(F)(F)F)cc1
Reactant: CSC(=N)Nc1ccc(-n2cnc(C)n2)c(F)c1
Reactant: NN
Agent: I
Solvent: CN1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ncn(-c2ccc(Nc3n[nH]c(C(CCCCCl)c4ccc(OCC(F)(F)F)cc4)n3)cc2F)n1

Procedure:
Methyl 3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenylcarbamimidothioate, hydroiodide (0.750 g, 1.91 mmol, from preparation Q) and 6-chloro-2-(4-(2,2,2-trifluoroethoxy)phenyl)hexanoic acid (0.650 g, 2.00 mmol, from preparation AW) were coupled [N-methylmorpholine (1.05 mL, 9.54 mmol) was substituted for N,N-diisopropylethylamine] and then reacted with hydrazine (0.300 mL, 9.54 mmol) using a procedure analogous to Step A of Example 13. After an aqueous workup, 5-(5-chloro-1-(4-(2,2,2-trifluoroethoxy)phenyl)pentyl)-N-(5-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-1H-1,2,4-triazol-3-amine was obtained as a brown solid. The crude product was used in the next step without purification. LC-MS (M+H)+ 538.5.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][O:6][CH2:7][CH:8]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[CH:15]([O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21]1)[CH2:14][CH2:13]2)[OH:9])[CH3:3].[C:26](OC(=O)C)(=[O:28])[CH3:27].N1C=CC=CC=1>C(OCC)C>[C:26]([O:9][CH:8]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[CH:15]([O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21]1)[CH2:14][CH2:13]2)[CH2:7][O:6][CH2:5][CH2:4][N:2]([CH3:1])[CH3:3])(=[O:28])[CH3:27]
Reactant: CN(C)CCOCC(O)c1ccc2c(c1)CCC2OC1CCCCO1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(=O)OC(COCCN(C)C)c1ccc2c(c1)CCC2OC1CCCCO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2.5 g of 2-[2-(N,N-dimethylamino)ethoxy]-1-[1-(tetrahydropyran-2-yloxy)indan-5-yl]ethanol, 8 ml of acetic anhydride and 0.64 ml of pyridine was stirred at room temperature for 1 hour. The reaction mixture was added to a mixture of 50 ml of ice water and 50 ml of diethyl ether. The organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (eluant: chloroform/methanol=10/1) to obtain 1.9 g of oily 1-acetoxy-2-[2-(N,N-dimethylamino)ethoxy]-1-[1-(tetrahydropyran-2-yloxy) indan-5-yl]ethane (compound No. 295).