Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([OH:11])[C@@H:8]([OH:10])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:18](Cl)([CH3:21])(=[O:20])=[O:19]>>[CH3:21][S:18]([O:10][C@@H:8]([CH3:9])[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[OH:11])(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H](O)C(O)(c1ccccc1)c1ccccc1
Product: C[C@H](OS(C)(=O)=O)C(O)(c1ccccc1)c1ccccc1

Procedure:
By treating (S)-1,1-diphenyl-1,2-propanediol with mesyl chloride, (S)-2-methanesulfonyloxy-1,1-diphenyl-1-propanol was obtained. Namely, as a result of the treatment of (S)-1,1-diphenyl-1,2-propanediol with CH3SO2Cl (1.2 equivalent)-(C2H5)3 -N(1.5 equivalent) at 0° C. in CH2Cl2, (S)-2-methanesulfonyloxy-1,1-diphenyl-1-propanol was obtained in a yield of 87% (the position selectivity of this sulfonylation reaction was more than 95% from the measurement with 1H NMR).
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[N:19]=CC(C4CCNCC4)=[CH:16][CH:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[BH-](O[C:43]([CH3:45])=O)(OC(C)=O)OC(C)=O.[Na+].ClCCl.[CH3:50][C:51]([CH3:53])=O>C(O)(=O)C>[CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[N:19]=[N:9][C:8]([N:26]4[CH2:45][CH2:43][N:2]([CH:51]([CH3:53])[CH3:50])[CH2:3][CH2:5]4)=[CH:16][CH:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CC(C)=O
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C4CCNCC4)cn3)nc2n1C1CCCC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)N1CCN(c2ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCC5)c4n3)nn2)CC1
Yield: 70 %

Procedure:
To a suspension of 7-cyclopentyl-2-(1′,2′,3′,4′,5′,6′-hexahydro-[3,4′]bipyridinyl-6-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (100 mg, 0.23 mmol) in dichloromethane/acetone is added NaBH(OAc)3 (488 mg, 2.3 mmol) followed by 3 drops of glacial acetic acid. After reaction is completed and concentrated. Diluted with 100 mL of H2O and basified to pH12 with 50% NaOH solution dropwise (2 mL). Extracted with dichloromethane (3×100 mL), and concentrated to give 7-cyclopentyl-2-[6-(4-isopropyl-piperazin-1-yl)-pyridazin-3-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (77 mg, 70%). MS (ESI) m/z 478.3 (M+H)+
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:12][C:13]([C:15]2[CH:16]=[N:17][N:18]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:19]=2)=O)[CH:8]=[C:9]([CH3:11])[CH:10]=1)=O)C.C([O-])(=O)C.[NH4+:28].O>C(O)(=O)C>[C:20]([N:18]1[CH:19]=[C:15]([C:13]2[NH:28][C:4](=[O:3])[C:6]3[N:7]([CH:8]=[C:9]([CH3:11])[CH:10]=3)[CH:12]=2)[CH:16]=[N:17]1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CCOC(=O)c1cc(C)cn1CC(=O)c1cnn(C(C)(C)C)c1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc2c(=O)[nH]c(-c3cnn(C(C)(C)C)c3)cn2c1
Temperature: 25 °C

Procedure:
A solution of 375 mg (1.18 mmol) 1-[2-(1-tert-butyl-1H-pyrazol-4-yl)-2-oxo-ethyl]-4-methyl-1H-pyrrole-2-carboxylic acid ethyl ester and 4.89 g (63.5 mmol) ammonium acetate in 4.15 ml acetic acid is stirred for 28 hours at 110° C. The reaction mixture is allowed to cool to room temperature and excess water is added. The resulting precipitate is filtered off, washed with water and dried. It is chromatographed on a silica gel column with cyclohexane/ethyl acetate as eluent to give 3-(1-tert-butyl-1H-pyrazol-4-yl)-7-methyl-2H-pyrrolo[1,2-a]pyrazin-1-one as light yellow solid; HPLC/MS 2.27 min (B), [M+H] 271;
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:20])[NH:5][C:6](=[O:19])[NH:7][C:8]=1[C:9](=[O:18])[C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[F:21][C:22]([F:33])([F:32])[O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>>[F:21][C:22]([F:32])([F:33])[O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][N:7]2[C:8]([C:9](=[O:18])[C:10]3[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=3)=[C:3]([CH2:1][CH3:2])[C:4](=[O:20])[NH:5][C:6]2=[O:19])=[CH:26][CH:25]=1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Reactant: CCc1c(C(=O)c2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Product: CCc1c(C(=O)c2cc(C)cc(C)c2)n(Cc2ccc(OC(F)(F)F)cc2)c(=O)[nH]c1=O
Yield: 63.8 %

Procedure:
5-Ethyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and 4-trifluoromethoxybenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (285 mg, yield: 63.8%).
Reaction SMILES: Cl.[C:2](=N)([O:4]C)C.[CH2:7]([C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:20])[CH2:18][CH3:19])=[CH:13][CH:12]=1)[CH:8]([CH3:10])[CH3:9].[CH3:21]O>>[CH3:21][O:20][C:17]([O:4][CH3:2])([C:14]1[CH:13]=[CH:12][C:11]([CH2:7][CH:8]([CH3:10])[CH3:9])=[CH:16][CH:15]=1)[CH2:18][CH3:19]
Reactant: CCC(=O)c1ccc(CC(C)C)cc1
Reactant: CO
Reactant: COC(C)=N
Agent: Cl
Product: CCC(OC)(OC)c1ccc(CC(C)C)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To 11.33 g. (0.10 mole) of methyl acetimidate hydrochloride, prepared by known methods, in a 100 ml. 3-necked, round bottom flask there was added a solution of 9.71 g. (actual 9.42 g.; 49.6 mmole) of crude p-isobutylpropiophenone, prepared as described in part A above, in 23 ml. of absolute methanol. The resulting solution was stirred for 12 hours at room temperature to insure complete reaction. Gas liquid chromatographic analysis (GLC analysis) of an aliquot of the reaction mixture indicated greater than 99% ketal formation. The resulting mixture was filtered to remove the precipitated ammonium chloride and concentrated under vacuum. Hexane (50 ml.) was added to the residue and the resulting solution was again filtered to remove any acetamide which might be present. Removal of the hexane solvent under vacuum gave p-isobutylpropiophenone dimethyl ketal as a pale yellow oil which was used without further purification. The NMR was in accord.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:11]=[C:10]([O:12][CH:13]([F:15])[F:14])[N:9]([CH3:16])[N:8]=2)[N:5]=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C.[N+:24]([O-])([OH:26])=[O:25]>C(O)(=O)C>[NH2:1][C:2]1[N:6]([C:7]2[CH:11]=[C:10]([O:12][CH:13]([F:14])[F:15])[N:9]([CH3:16])[N:8]=2)[N:5]=[CH:4][C:3]=1[N+:24]([O-:26])=[O:25]
Reactant: Cn1nc(-n2nccc2N)cc1OC(F)F
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: Cn1nc(-n2ncc([N+](=O)[O-])c2N)cc1OC(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
15 g (0.065 mol) 5-Amino-1-(5-difluoromethoxy-1-methyl-3-pyrazolyl)pyrazole was dissolved in 60 ml acetic acid and treated with 7.35 g (0.072 mol) acetic anhydride. After stirring at room temperature for 3 hours, the reaction mixture was cooled to 10° C. 4.95 g (0.078 mol) Fuming nitric acid was added dropwise and the mixture treated with 8.0 g (0.078 mol) acetic anhydride. After stirring for 18 hours at room temperature, the reaction mixture was added to 500 ml ice-water. It was extracted three times with ethyl acetate, the organic phases were washed with water and concentrated. The residue was treated with 80 ml ethanol and 40 ml concentrated hydrochloric acid. After heating for 8 hours under reflux, the ethanol was removed and the residue extracted with ethyl acetate. The concentrated ethyl acetate phases were washed with saturated aqueous sodium hydrogen carbonate, dried over magnesium sulfate and concentrated. The residue was recrystallised from diisopropyl ether and ethyl acetate.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C@@H:4]([NH:11][C@H](C2C=CC=CC=2)CO)[CH2:3]1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].Cl>CO>[CH3:1][C:2]1([CH3:21])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C@@H:4]([NH2:11])[CH2:3]1
Reactant: CC1(C)C[C@H](N[C@@H](CO)c2ccccc2)c2ccccc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Pb+4]
Solvent: CO
Product: CC1(C)C[C@H](N)c2ccccc21
Reaction time: 0.75 h
Yield: 51 %

Procedure:
A solution of (2R)-2-{[(1S)-3,3-dimethyl-2,3-dihydro-1H-inden-1-yl]amino}-2-phenylethanol (1.44 g, 5.13 mmol) in MeOH (40.0 mL) was added to a stirred solution of lead tetraacetate (3.75 g, 8.03 mmol) in MeOH (60.0 mL) at 0° C. dropwise over 20 min. After stirring for 45 min, the reaction was quenched via addition of a 10% solution of Na2CO3 in H2O (76.0 mL) and the mixture was stirred for 10 min. DCM (200 mL) was then added and the layers were separated. The aqueous layer was extracted with DOA (50.0 mL). The combined organic layers were concentrated in vacuo and the residue was dissolved in EtOH (190. mL) and treated with a 10.4 M aqueous solution of HCl (5.70 mL, 59.3 mmol). The resulting mixture was then heated to reflux for 16 h. The cooled reaction was concentrated in vacuo and partitioned between H2O (150. mL) and Et2O (50.0 mL). The aqueous layer was adjusted to pH 10 via addition of Na2CO3 and extracted with Et2O (3×50.0 mL). The combined organic layers were concentrated in vacuo and silica gel chromatography eluting with a gradient of 0 to 10% MeOH in DCM to afford the title compound as a pale yellow oil (420. mg, 51%). 1H NMR (CD3OD, 300 MHz) δ: 7.34-7.14 (m, 4H), 4.45-4.37 (m, 1H), 2.38 (dd, J=7.1, 12.4 Hz, 1H), 1.73 (bs, 2H), 1.60 (dd, J=8.7, 12.4 Hz, 1H), 1.39 (s, 3H), 1.19 (s, 3H) ppm.
Reaction SMILES: CN([P+](O[N:12]1N=[N:19][C:14]2C=CC=C[C:13]1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.[C:28]([C:31]1[CH:36]=[N:35][N:34]2[CH:37]=[C:38]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH:39]=[C:33]2[C:32]=1[NH:46][C@@H:47]([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:48](O)=[O:49])(=[O:30])[NH2:29].NCC#N.C(N(CC)CC)C>CN(C=O)C>[C:13]([CH2:14][NH:19][C:48](=[O:49])[C@@H:47]([NH:46][C:32]1[C:33]2[N:34]([CH:37]=[C:38]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH:39]=2)[N:35]=[CH:36][C:31]=1[C:28]([NH2:29])=[O:30])[C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)#[N:12]
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: NC(=O)c1cnn2cc(-c3ccccc3)cc2c1N[C@H](C(=O)O)c1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Agent: N#CCN
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#CCNC(=O)[C@@H](Nc1c(C(N)=O)cnn2cc(-c3ccccc3)cc12)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.4 %

Procedure:
BOP reagent (17.2 mg, 0.039 mmol) was added in one portion to a solution of (S)-2-(3-carbamoyl-6-phenylpyrrolo[1,2-b]pyridazin-4-ylamino)-2-phenylacetic acid (Example 122, 10 mg, 0.026 mmol), 2-aminoacetonitrile (1.82 mg, 0.032 mmol) and triethylamine (0.011 ml, 0.078 mmol) in DMF (0.01 ml). The reaction was allowed to stir at rt for 1 hour before being purified by reverse-phase Prep HPLC (condition A). The fraction containing the major product was concentrated on the rotovap to remove the MeOH and the aqueous slurry of the product was neutralized by addition of ˜1 mL of saturated aq sodium bicarbonate. Sonication of the slurry followed by vacuum filtration and air drying in the funnel afforded the title compound (7 mg, 60% yield). HPLC (condition B): retention time=1.57 min. LCMS (condition B): MH+ m/z 425.2. 1H NMR (500 MHz, MeOD) δ ppm 8.33 (1H, s), 8.07 (1 H, d, J=1.66 Hz), 7.86 (1 H, s), 7.75 (4 H, dd, J=7.63, 2.08 Hz), 7.60 (2H, t, J=7.49 Hz), 7.49-7.57 (3 H, m), 7.41 (1 H, t, J=7.35 Hz), 7.31 (1 H, d, J=1.66 Hz), 6.11 (1 H, s), 4.22-4.44 (1 H, m), 3.17 (2 H, s).
Reaction SMILES: [C:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:27][O:28][C:29]1[C:30](=[O:57])[C:31]([CH3:56])=[C:32]([CH2:38][C:39]2[CH:40]=[CH:41][C:42]([O:48][CH2:49][C:50]3[CH:51]=[N:52][CH:53]=[CH:54][CH:55]=3)=[C:43]([CH:47]=2)[C:44](O)=[O:45])[C:33](=[O:37])[C:34]=1[O:35][CH3:36]>C(Cl)Cl>[CH3:27][O:28][C:29]1[C:30](=[O:57])[C:31]([CH3:56])=[C:32]([CH2:38][C:39]2[CH:40]=[CH:41][C:42]([O:48][CH2:49][C:50]3[CH:51]=[N:52][CH:53]=[CH:54][CH:55]=3)=[C:43]([CH:47]=2)[C:44]([NH:8][C:7]2[CH:9]=[CH:10][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][CH:6]=2)=[O:45])[C:33](=[O:37])[C:34]=1[O:35][CH3:36]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OCc3cccnc3)c(C(=O)O)c2)=C(C)C1=O
Reactant: CC(=O)c1ccc(N)cc1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(OCc3cccnc3)c(C(=O)Nc3ccc(C(C)=O)cc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 31.3 %

Procedure:
4-Acetylaniline (0.128 g, 0.946 mmol), triethylamine (0.096 g, 0.946 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.160 g, 0.946 mmol) were added to a methylene chloride solution (20 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-(3-pyridylmethyloxy)benzoic acid (0.200 g, 0.473 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) and then recrystallized from ether to obtain the titled compound (0.080 g, 0.148 mmol, 31%).
Reaction SMILES: [CH2:1]([Mg]Br)[CH:2]=[CH2:3].[CH3:6][C:7]1([CH3:14])[O:11][C@@H:10]([CH:12]=[O:13])[CH2:9][O:8]1>O1CCCC1>[CH3:6][C:7]1([CH3:14])[O:11][CH:10]([CH:12]([CH2:3][CH:2]=[CH2:1])[OH:13])[CH2:9][O:8]1
Reactant: C=CC[Mg]Br
Reactant: CC1(C)OC[C@H](C=O)O1
Solvent: C1CCOC1
Product: C=CCC(O)C1COC(C)(C)O1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a stirring -78° C. solution, under argon, of 556 ml of 1M allylmagnesium bromide is added, dropwise over 20 minutes, a solution of 36.4 g of product from Example 330 in 17 ml of tetrahydrofuran. The reaction mixture is stirred at -78° C. for 2 hours. Thin layer chromatography indicates the presence of starting material. An additional 280 ml of 1M allylmagnesium bromide is added and the reaction is stirred overnight at -78° C. The reaction is quenched with dropwise addition of saturated ammonium chloride, filtered through diatomaceous earth and washed with diethyl ether, ethyl acetate and 20% isopropyl alcohol/chloroform. The combined extracts are washed with saturated sodiumchloride, dried and concentrated in vacuo to give, after Kugelrohr distillation at 85° C., 38.25 g of the desired product.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:10][C@@H:11]1[O:15]C(C)(C)[N:13]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[C@H:12]1[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[C:39]([CH3:41])[CH:38]=[CH:37][N:36]=2)=[CH:31][CH:30]=1)=O)(C)(C)C.CO.Cl>C1COCC1>[NH2:8][C@@H:9]([CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)[CH2:10][C@H:11]([OH:15])[C@@H:12]([NH:13][C:18](=[O:19])[O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:28][C:29]1[CH:30]=[CH:31][C:32]([C:35]2[CH:40]=[C:39]([CH3:41])[CH:38]=[CH:37][N:36]=2)=[CH:33][CH:34]=1
Reactant: Cc1ccnc(-c2ccc(C[C@H]3[C@H](C[C@H](Cc4ccccc4)NC(=O)OC(C)(C)C)OC(C)(C)N3C(=O)OCc3ccccc3)cc2)c1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccnc(-c2ccc(C[C@H](NC(=O)OCc3ccccc3)[C@@H](O)C[C@@H](N)Cc3ccccc3)cc2)c1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
A solution containing the product from Example 80B (0.065 g, 0.100 mmol) in a mixture of THF (0.3 mL), methanol (0.3 mL), and aqueous HCl (0.5 mL, 1 N) was stirred at 50° C. for 16 hours. The solvent was removed under reduced pressure to give the title compound as the hydrochloride salt, which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][C:11](=[O:13])[CH2:10][C@H:9]2[C:14]([OH:16])=O)=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.O[N:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2N=N1.CN1CCOCC1.[Cl-].[CH:47]1([C:53]2([CH2:59][N:60]3[C:64]([CH3:66])([CH3:65])[CH2:63][O:62][C:61]3=[O:67])CC[NH2+][CH2:55][CH2:54]2)CCCC[CH2:48]1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[CH2:12][C:11](=[O:13])[CH2:10][C@H:9]2[C:14]([C:34]2([N:30]3[CH2:55][CH2:54][CH:53]([CH2:59][N:60]4[C:64]([CH3:65])([CH3:66])[CH2:63][O:62][C:61]4=[O:67])[CH2:47][CH2:48]3)[CH2:33][CH2:38][CH2:37][CH2:36][CH2:35]2)=[O:16])=[CH:6][CH:7]=1
Reactant: O=C1C[C@@H](C(=O)O)[C@H](c2ccc(Cl)cc2)C1
Reactant: CC1(C)COC(=O)N1CC1(C2CCCCC2)CC[NH2+]CC1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Cl-]
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC1(C)COC(=O)N1CC1CCN(C2(C(=O)[C@@H]3CC(=O)C[C@H]3c3ccc(Cl)cc3)CCCCC2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A 25 mL round bottom flask equipped with a magnetic stir bar was charged with 0.412 g (1.73 mmol) of the product of Step D dissolved in 6 mL of methylene chloride. To the reaction mixture was added 0.451 g (2.35 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 0.318 g (2.35 mmol) of 1-hydroxybenzotriazole, 0.518 μL (4.71 mmol) of N-methylmorpholine, followed by 0.520 g (1.57 mmol) of 4-cyclohexyl-4-[(4,4-dimethyl-2-oxo -1,3-oxazolidin-3-yl)methyl]piperidinium chloride. The resulting clear yellow solution was stirred at room temperature for 48 h, then was partitioned between methylene chloride and saturated aqueous sodium bicarbonate. The organic layer was separated, washed with 1 N hydrochloric acid, saturated aqueous sodium bicarbonate, brine, then dried (Na2SO4), filtered and evaporated in vacuo. The residual oil was purified on a Biotage Flash 40i chromatography apparatus (40 g Flash 40S silica gel cartridge) eluted sequentially with hexane for 2 min, 30% ethyl acetate-hexanes for 2 min and finally 75% ethyl acetate-hexanes for 20 min. Evaporation of the purified fractions and drying in vacuo afforded the title compound.
Reaction SMILES: [CH2:1]([N:8]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:9]1[CH2:15][CH2:14][CH2:13][C:12]2[CH:16]=[CH:17][C:18]([OH:20])=[CH:19][C:11]=2[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:28]NC(=O)CCC(N)=O.C(=O)([O-])O.[Na+]>O1CCOCC1>[CH2:1]([N:8]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:9]1[CH2:15][CH2:14][CH2:13][C:12]2[CH:16]=[C:17]([Cl:28])[C:18]([OH:20])=[CH:19][C:11]=2[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)CCC(=O)NCl
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)C1CCCc2ccc(O)cc2C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N(Cc1ccccc1)C1CCCc2cc(Cl)c(O)cc2C1
Temperature: 100 °C
Reaction time: 9 h
Yield: 51.8 %

Procedure:
Under nitrogen, a suspension of N-benzyl-N-(3-hydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-tert-butoxycarbonylamine (300 mg) and N-chlorosuccinamide (110 mg) in 1,4-dioxane (5 ml) was stirred at 100° C. for 9 hours. The resulting mixture was poured into saturated aqueous sodium hydrogencarbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (toluene:ethyl acetate=50:1 to 10:1) to give N-benzyl-N-(2-chloro-3-hydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-tert-butoxycarbonylamine (152 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].FC1C=CC(C)=CC=1N.[OH-:22].[Na+].[Mn]([O-])(=O)(=O)=[O:25].[K+]>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:25])=[O:22])=[CH:4][C:3]=1[S:9](=[O:11])(=[O:10])[NH2:12]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: [OH-]
Reactant: Cc1ccc(F)c(S(N)(=O)=O)c1
Agent: Cc1ccc(F)c(N)c1
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: NS(=O)(=O)c1cc(C(=O)O)ccc1F
Temperature: 70 °C
Reaction time: 4 h

Procedure:
A suspension of 2-fluoro-5-methylbenzenesulphonamide (5.3 mmol), obtained according to the process described in Step A of Example 1 starting from 2-fluoro-5-methylaniline, in water (50 mL) is heated at 70° C. and then NaOH 10% w/v is added dropwise until the compound has completely dissolved. Potassium permanganate (3 g) is added in small portions. After stirring for 4 hours, the suspension is discharged by filtration in the hot state and the filtrate is brought to pH 1 by adding 12N HCl. The precipitate obtained is collected by filtration, washed with water and dried to yield the title product in the form of a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:14])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:7]=1.[B:15]1(B2OCC(C)(C)CO2)[O:20]CC(C)(C)C[O:16]1.C([O-])(=O)C.[K+].O1CCOCC1>CS(C)=O>[F:14][C:5]1[CH:4]=[CH:3][C:2]([B:15]([OH:20])[OH:16])=[CH:7][C:6]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: Fc1ccc(Br)cc1-c1ccccn1
Reactant: CC1(C)COB(B2OCC(C)(C)CO2)OC1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1COCCO1
Product: OB(O)c1ccc(F)c(-c2ccccn2)c1
Temperature: 85 °C
Reaction time: 15 h

Procedure:
To 2-(5-bromo-2-fluorophenyl)pyridine (544 mg, 2.16 mmol) and bis(neopentyl glycolato)diboron (585 mg, 2.60 mmol) under nitrogen was added dry potassium acetate (450 mg, 4.58 mmol), anhydrous dioxane (8 mL) and DMSO (1 mL). The mixture was degassed with nitrogen, and [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) complex with dichloromethane (50 mg, 3 mol %) was added. After stirring at 85° C. under nitrogen for 15 h, the mixture was cooled to room temperature, and sodium hydroxide solution (20 mL of a 1 M solution) was added. The mixture was stirred for 10 min, and was then extracted twice with diethyl ether. The combined ether extractions were washed with water, then the combined aqueous layers were filtered through a glass fibre filter paper. The pH of the filtrate was adjusted to 6 by the addition of 2 N hydrochloric acid-precipitating a white solid. This was collected by filtration, washed with water and dried in vacuo at 60° C., and was found to be 4-fluoro-3-(pyridin-2-yl)phenylboronic acid (455 mg, 97%). δH (400 MHz, DMSO) 7.30 (1H, dd, J 8.2, 11.7), 7.41 (1H, m), 7.77 (1H, m), 7.90 (2H, m), 8.16 (2H, s), 8.36 (1H, dd, J 1.6, 8.6), 8.72 (1H, m); MS (ES+) 218.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].C(=O)([O-])[O-].[K+].[K+].[Cl:16][CH2:17][CH2:18][CH2:19][CH2:20]Cl>>[Cl:16][CH2:17][CH2:18][CH2:19][CH2:20][N:4]1[C:3](=[O:8])[C:2]([CH3:9])([CH3:1])[NH:6][C:5]1=[O:7]
Reactant: CC1(C)NC(=O)NC1=O
Reactant: ClCCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC1(C)NC(=O)N(CCCCCl)C1=O

Procedure:
A mixture of 538 g of 5,5-dimethyl-hydantoin (4,2 mols), 290 g of anhydrous potassium carbonate (2.1 mols) and 2,130 g of 1,4-dichlorobutane (16.77 mols) is reacted analogously to A for 8 hours at 138° to 141°C internal temperature (external temperature 200°C). Working up takes place analogously to A and 830.9 g of a brown viscous crude product (90.5% of theory) are obtained, and are purified by vacuum distillation (boiling point0.2 : 151°-153°C) and subsequent recrystallisation from diethyl ether. The pure product melts at 54.4° to 56.3°C.
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]([C:7](Cl)=[O:8])=[CH:3][CH:2]=1.[CH:16]1[C:26]2[CH2:25][NH:24][C:23]3[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=3[NH:21][C:20]=2[CH:19]=[CH:18][CH:17]=1.O.ClCCl>CN(C)C=O>[C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]([C:7]([N:24]2[CH2:25][C:26]3[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=3[NH:21][C:22]3[CH:30]=[CH:29][CH:28]=[CH:27][C:23]2=3)=[O:8])=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: c1ccc2c(c1)CNc1ccccc1N2
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(c1ccc(-c2ccccc2)cc1)N1Cc2ccccc2Nc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.3 %

Procedure:
4-Biphenyl-carbonyl chloride (1.19 g) dissolved in N,N-dimethylformamide (10 mL) was added dropwise to an ice cooled solution of 5,11-dihydro-10H-dibenzo[b,e][1,4]diazepine (0.98 g) in N,N-dimethylformamide (10 mL). After stirring at room temperature overnight, the reaction mixture was poured into water and dichloromethane. The organic layer was sequentially washed with water and saturated sodium bicarbonate, and dried over anhydrous sodium sulfate. The solution was filtered through a short column of Magnesol® and eluted with additional dichloromethane. The combined eluate was refluxed with gradual addition of hexane until incipient crystallization occurred. Cooling and filtration provided the title compound (0.72 g), m.p. 180–182° C.