Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N:14]3[C:18](=[O:19])[C:17]([CH3:21])([CH3:20])[N:16]([CH2:22][C:23]4[CH:28]=[CH:27][N:26]=[C:25]([Cl:29])[CH:24]=4)[C:15]3=[O:30])[CH:12]=2)[C:7]([CH3:32])([CH3:31])[CH2:6]1)=[O:4].[CH:33]1([NH2:38])[CH2:37][CH2:36][CH2:35][CH2:34]1>>[Cl:29][C:25]1[CH:24]=[C:23]([CH2:22][N:16]2[C:17]([CH3:20])([CH3:21])[C:18](=[O:19])[N:14]([C:11]3[CH:12]=[C:13]4[C:8]([C:7]([CH3:32])([CH3:31])[CH2:6][N:5]4[C:3](=[O:4])[CH2:2][NH:38][CH:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)=[CH:9][CH:10]=3)[C:15]2=[O:30])[CH:28]=[CH:27][N:26]=1
Reactant: NC1CCCC1
Reactant: CC1(C)CN(C(=O)CCl)c2cc(N3C(=O)N(Cc4ccnc(Cl)c4)C(C)(C)C3=O)ccc21
Product: CC1(C)CN(C(=O)CNC2CCCC2)c2cc(N3C(=O)N(Cc4ccnc(Cl)c4)C(C)(C)C3=O)ccc21

Procedure:
A solution of 3.423 g of 3-[1-(chloroacetyl)-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl]-1-[(2-chloropyridin-4-yl)methyl]-5,5-dimethylimidazolidine-2,4-dione obtained in stage j) below in 42 mL of cyclopentylamine is heated at 70° C. for 4 hours. The reaction mixture is then concentrated under reduced pressure and the residue is taken up in 100 mL of water and extracted with three times 60 mL of ethyl acetate. The combined organic phases are then washed with water, dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica, eluting with a mixture of dichloromethane and methanol (95/5 by volume) to give 3.5 g of 1-[(2-chloropyridin-4-yl)methyl]-3-[1-(N-cyclopentylglycyl)-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl]-5,5-dimethylimidazolidine-2,4-dione, the characteristics of which are as follows:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8]O)=[N:4][CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.CS(Cl)(=O)=O.C(OC(=O)[NH:28][CH2:29][CH2:30][CH2:31][CH2:32][NH:33][CH2:34][C:35]1[C:40]([Cl:41])=[CH:39][CH:38]=[CH:37][N:36]=1)(C)(C)C>C(Cl)Cl.CC#N>[Cl:1][C:2]1[C:3]([CH2:8][N:33]([CH2:34][C:35]2[C:40]([Cl:41])=[CH:39][CH:38]=[CH:37][N:36]=2)[CH2:32][CH2:31][CH2:30][CH2:29][NH2:28])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCCCNCc1ncccc1Cl
Reactant: OCc1ncccc1Cl
Agent: CS(=O)(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NCCCCN(Cc1ncccc1Cl)Cc1ncccc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 68.7 %

Procedure:
Using General Procedure C: (3-Chloro-pyridin-2-yl)-methanol (167 mg, 1.17 mmol) (Iqbal, N. et al. J. Med. Chem. 1998, 41, 1827-1837) was dissolved in CH2Cl2 (10 mL) at 0° C. Et3N (212 μL, 1.52 mmol) was added to the colorless solution followed by subsequent addition of MsCl (90 μL, 1.17 mmol). The reaction mixture was stirred at 0° C. for one hour and then the solvent was removed under reduced pressure. The resulting crude mesylate mixture was dissolved in CH3CN (5 mL) and added to a mixture of {4-[(3-chloro-pyridin-2-ylmethyl)-amino]-butyl}-carbamic acid tert-butyl ester (265 mg, 0.88 mmol) and Et3N (169 μL, 1.21 mmol) in CH3CN (10 mL). The reaction mixture was stirred at 50° C. for 16 hours. The solvent was removed under reduced pressure and the brown oil was purified via column chromatography on silica gel (CH2Cl2:MeOH, 95:5, v/v) to give the product as a pale yellow oil (205 mg, 52%). 1H NMR (CDCl3) δ 1.35 (m, 2H), 1.43 (s, 9H), 1.55 (m, 2H), 2.67 (t, 2H, J=7.5 Hz), 2.98 (m, 2H), 3.98 (s, 4H), 4.86 (s, 1H), 7.11 (dd, 2H, J=9.0, 6.0 Hz), 7.61 (d, 2H, J=9.0 Hz), 8.45 (m, 2H). Conversion to the HBr salt using General Procedure D gave COMPOUND 235 as a white solid. 1H NMR (D2O) δ 1.75 (m, 2H), 1.97 (m, 2H), 3.02 (t, 2H, J=7.5 Hz), 3.52 (t, 2H, J=8.1 Hz), 4.80 (s, 2H), 4.82 (s, 2H), 7.42 (dd, 2H, J=8.4, 4.8 Hz), 7.92 (d, 2H, J=8.1 Hz), 8.45 (m, 2H). 13C NMR (D2O) δ 21.51, 24.37, 39.25, 48.71, 55.98, 126.19, 131.75, 139.55, 147.09, 147.26. ES-MS m/z 339 [M+H]+. Anal. Calcd. for C16H20N4Cl2−.3.5HBr.0.8H2O: C, 30.18, H, 3.97; N, 8.80; Cl, 11.13; Br, 43.91. Found: C, 30.18; H, 4.04; N, 8.72; Cl, 10.77; Br, 44.05.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[C:4]([C:13]2[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:15][CH:14]=2)=[N:3]1.N([CH2:33][C@H:34]([OH:36])C)N>>[N:10]1[CH:9]=[CH:8][C:7]([C:5]2[C:4]([C:13]3[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]4[CH:28]=[CH:27][C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[N:20]=4)=[CH:15][CH:14]=3)=[N:3][N:2]([CH2:1][C@H:34]([OH:36])[CH3:33])[CH:6]=2)=[CH:12][CH:11]=1
Reactant: C[C@@H](O)CNN
Reactant: Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1
Product: C[C@@H](O)Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1

Procedure:
Following the procedure for the preparation of 2-[4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline but substituting (R)-1-Hydrazino-propan-2-ol provided the title compound. 1H NMR (400 MHz, CDCl3) δ 8.42 (m, 2 H), 8.18 (d, J=8.3 Hz, 1 H), 8.06 (d, J=8.4 Hz, 1 H), 7.81 (d, J=8.3 Hz, 1H), 7.73 (m, 1H), 7.66 (d, J=8.7 Hz, 1H), 7.61 (s, 1 H), 7.54 (m, 1H), 7.36 (d, J=9.1 Hz, 2 H), 7.12 (m, 2H), 6.99 (d, J=8.7 Hz, 2H) 5.37 (s, 2H), 4.30 (m, 1H), 4.21 (dd, J=13.6, 2.5 Hz, 1H), 4.03 (dd, J=13.6, 7.9 Hz, 1H), 1.26 (d, J=6.2 Hz, 3H); MS: (M+H m/z=437.2).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[CH3:19])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:20].[O:21]1[C:25]2[CH:26]=[CH:27][C:28]([C:30](O)=[O:31])=[CH:29][C:24]=2[O:23][CH2:22]1>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[CH3:19])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:20][C:30]([C:28]1[CH:27]=[CH:26][C:25]2[O:21][CH2:22][O:23][C:24]=2[CH:29]=1)=[O:31]
Reactant: O=C(O)c1ccc2c(c1)OCO2
Reactant: Cc1cc(N2CCC(CN3CCCC3C)C2)ccc1N
Product: Cc1cc(N2CCC(CN3CCCC3C)C2)ccc1NC(=O)c1ccc2c(c1)OCO2

Procedure:
The title compound was prepared in a manner substantially the same as Example 1 by coupling 2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenylamine with benzo[1,3]dioxole-5-carboxylic acid. MS: 422.5 (M+H).
Reaction SMILES: C(OO)(=[O:3])C.[Cl:6][C:7]1[C:16]2[C:11](=[CH:12][N:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][N:8]=1.S(OS([O-])=O)([O-])=O.[Na+].[Na+].[OH-].[Na+]>C(OCC)(=O)C.O.C(O)(=O)C>[Cl:6][C:7]1[C:16]2[C:11](=[CH:12][N+:13]([O-:3])=[CH:14][CH:15]=2)[CH:10]=[CH:9][N:8]=1
Reactant: Clc1nccc2cnccc12
Reactant: CC(=O)OO
Agent: O=S([O-])OS(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: [O-][n+]1ccc2c(Cl)nccc2c1

Procedure:
Under stirring, 205 ml (1.2 mol) peracetic acid (39% solution in acetic acid) was added to a solution of 98.8 g (0.60 mol) 1-chloro-[2,6]naphthyridine in 500 ml ethyl acetate and the mixture was stirred 18 hours at room temperature. The reaction mixture was diluted with water and acetic acid, treated with portions of sodium disulfite under stirring until a peroxide test was negative. Then the mixture was adjusted to pH value of 8 with aqueous NaOH. The solids were filtered off, washed with water and dried yielding 1-chloro-[2,6]-naphthyridine 6-oxide as slightly yellow crystals. The organic phase of the filtrate was separated, dried over sodium sulfate and evaporated. The residue was crystallized from tert-butyl-methyl-ether yielding another crop of product. HPLC/MS (A): 1.16 min, [M+H] 181.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:21])=[C:4]([C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([Br:20])[CH:18]=3)[NH:13][CH:12]=2)=[O:10])[C:5]([F:8])=[CH:6][CH:7]=1.ClCCl.N1C=CC=CC=1.[CH2:31]([S:34](Cl)(=[O:36])=[O:35])[CH2:32][CH3:33]>O>[Br:20][C:17]1[CH:18]=[C:19]2[C:11]([C:9]([C:4]3[C:3]([F:21])=[C:2]([NH:1][S:34]([CH2:31][CH2:32][CH3:33])(=[O:36])=[O:35])[CH:7]=[CH:6][C:5]=3[F:8])=[O:10])=[CH:12][NH:13][C:14]2=[N:15][CH:16]=1
Reactant: CCCS(=O)(=O)Cl
Reactant: Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(Br)cc23)c1F
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(Br)cc23)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.7 %

Procedure:
Into a reaction flask under nitrogen, (3-amino-2,6-difluoro-phenyl)-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone (7, 13.00 g, 36.9 mmol) is combined with 150 mL of dichloromethane and anhydrous pyridine (5.84 g, 73.8 mmol), and propane-1-sulfonyl chloride (8, 6.05 g, 42.5 mmol) is added. The reaction is stirred at room temperature overnight, and additional pyridine (1.46 g, 18.5 mmol) and propane-1-sulfonyl chloride (1.51 g, 10.6 mmol) are added. The reaction is stirred at room temperature another 3 hours, then diluted with 500 mL of water and extracted 3×250 mL with dichloromethane. The organic layers are combined and washed with 250 mL of brine, dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with a gradient of ethyl acetate:hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (9, 8.41 g, 50%).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:24]#[N:25])[C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].[NH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32].C[O-].[Na+]>CCOC(C)=O>[CH2:16]([N:10]1[C:9](=[O:23])[C:8]2[C:7]([C:24]#[N:25])=[N:6][C:5]([C:3]([NH:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:4])=[C:14]([OH:15])[C:13]=2[CH:12]=[CH:11]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)c1nc(C#N)c2c(=O)n(Cc3ccccc3)ccc2c1O
Reactant: NCCCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: N#Cc1nc(C(=O)NCCCCC(=O)O)c(O)c2ccn(Cc3ccccc3)c(=O)c12
Temperature: 25 °C
Yield: 47.6 %

Procedure:
A mixture of 7-benzyl-1-cyano-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (30 mg, 0.090 mmol), 5-aminovaleric acid (525 mg, 4.5 mmol) and NaOMe solution (6.7 mL, 3.36 mmol, 0.5 M in MeOH) was refluxed for 48 h. After the mixture was cooled to r.t., solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stilling until pH was about 2. The organic layer was dried over MgSO4 and concentrated. The residue was chromatographed (20-100% EtOAc/hexanes+2% AcOH) to give a crude solid. The solid was dissolved in EtOAc and washed several times with 1 M HCl. The organic layer was dried over MgSO4 and concentrated. The residue was taken up in saturated NaHCO3 and washed with ether. The aqueous layer was acidified to pH 1 with 4 M HCl, and the resulting precipitate was isolated by filtration to give 18 mg of the title compound as an off-white solid. MS: (−) m/z 418.94 (M−1).
Reaction SMILES: C1(C(Cl)=O)CC1.[Br:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([C:14]([C:17]([NH:19][NH2:20])=O)=[CH:15][N:16]=2)[CH:13]=1.C(=O)(O)[O-].[Na+].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1.[C:48]1([CH3:54])[CH:53]=[CH:52]C=CC=1>O.O1CCCC1>[Br:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([C:14]([C:17]3[S:35][C:54]([CH:48]4[CH2:53][CH2:52]4)=[N:20][N:19]=3)=[CH:15][N:16]=2)[CH:13]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1ccccc1
Reactant: NNC(=O)c1cnc2ccc(Br)cn12
Agent: O=C(Cl)C1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Brc1ccc2ncc(-c3nnc(C4CC4)s3)n2c1
Reaction time: 8 h

Procedure:
0.22 mL cyclopropane carbonyl chloride was added at room temperature to a mixture of 510 mg 6-bromoimidazo[1,2-a]pyridine-3-carboxylic acid hydrazide (compound in Production Example 276), 202 mg sodium bicarbonate, 15 mL tetrahydrofuran and 15 mL water, and the mixture was stirred overnight. The organic layer was separated by adding saturated sodium bicarbonate, common salt and tetrahydrofuran to the reaction solution. The aqueous layer was further extracted with tetrahydrofuran, and the combined organic layer was washed with brine and then dried over anhydrous sodium sulfate. The drying agent was filtered off, and the filtrate was evaporated. Diisopropyl ether was added to the resulting residues, and the formed crystals were collected by filtration and dried under reduced pressure by a vacuum pump. 606 mg crude product of cyclopropane carboxylic acid N′-(6-bromoimidazo[1,2-a]-pyridine-3-carbonyl)hydrazide was obtained as pale brown crystals. A mixture of 200 mg of this carboxylic acid hydrazide derivative, 250 mg Lawesson's reagent and 20 mL anhydrous toluene was heated for 1 hour under reflux. The reaction solution was evaporated, and the resulting residue was purified by NH silica gel column chromatography (ethyl acetate/hexane) to give 48 mg of the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13](S(C)(=O)=O)=[N:14][CH:15]=2)[N:10]([CH3:22])[C:9]1=[O:23].[OH:24][CH2:25][CH:26]1[O:31][C:30]2[CH:32]=[CH:33][C:34]([NH2:36])=[CH:35][C:29]=2[O:28][CH2:27]1.C(O)(C(F)(F)F)=O.Cl>CN1C(=O)CCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13]([NH:36][C:34]3[CH:33]=[CH:32][C:30]4[O:31][CH:26]([CH2:25][OH:24])[CH2:27][O:28][C:29]=4[CH:35]=3)=[N:14][CH:15]=2)[N:10]([CH3:22])[C:9]1=[O:23]
Reactant: Nc1ccc2c(c1)OCC(CO)O2
Reactant: CN1C(=O)N(c2ccccc2Br)Cc2cnc(S(C)(=O)=O)nc21
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)N(c2ccccc2Br)Cc2cnc(Nc3ccc4c(c3)OCC(CO)O4)nc21
Temperature: 140 °C

Procedure:
1.2 g 3-(2-bromo-phenyl)-3,4-dihydro-7-methanesulphonyl-1-methyl-pyrimido[4,5-d]pyrimidin-2(1H)-one and 1.54 g 2 hydroxymethyl-6-amino-1,4-benzodioxane (starting material b)) were mixed in 20 ml NMP. 0.348 g TFA were added and the mixture was heated to 140° C. for 7 hrs. The mixture was poured into 10% aqueous HCl and extracted with ethyl acetate. The aqueous phase was adjusted to pH>9 and extracted with CH2Cl2. The organic phases were combined and evaporated. The residue was suspended in CH2Cl2 at room temperature and solid impurities were filtered off. The filtrate was washed again with water to remove remainders of NMP, then evaporated. The residue was triturated with water, filtered and dried to give 0.6 g of the title product (mp: 156–158° C.). NMR (CDCl3, δ in ppm): 2.03 (broad s, 1 H); 3.48 (s, 3H); 3.89 (dd, 1H); 3.95 (dd, 1H); 4.15 (dd, 1H); 4.28 (m, 1H); 4.33 (dd, 1H); 4.55 (d, 1H); 4.71 (d, 1H); 6.89 (m, 1H); 6.98 (m, 2H); 7.25 (m, 1H); 7.40 (m, 3H); 7.71 (d, 1H); 7.98 (s, 1H). MS (APCI+): 498 (M+1), 420 (M-Br)
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:11][C@H:10]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=O)(C)(C)C.O.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26]([OH:29])(=[O:28])=[O:27])=[CH:22][CH:21]=1>C(OCC)C>[C:20]1([CH3:30])[CH:21]=[CH:22][C:23]([S:26]([OH:29])(=[O:27])=[O:28])=[CH:24][CH:25]=1.[NH2:8][C@H:9]1[CH2:11][CH2:21][CH2:20][C@H:10]1[C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H]1C(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)[C@@H]1CCC[C@@H]1N
Temperature: 25 °C
Reaction time: 5 h
Yield: 180.9 %

Procedure:
To a mixture of tert-butyl rel-(1R,2S)-2-[(tert-butoxycarbonyl)amino]cyclopropanecarboxylate (0.54 g) and diethyl ether (4.0 ml) was added a solution of p-toluene sulfonic acid monohydrate (0.40 g) in diethyl ether (16 ml) at room temperature, followed by stirring at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure to obtain tert-butyl rel-(1R,2S)-2-aminocyclopentanecarboxylate p-toluene sulfonate (0.68 g). Tert-butyl rel-(1R,2S)-2-({N5-[(benzyloxy)carbonyl]-N2-[(1-methyl-1H-indol-2-yl)carbonyl]-L-ornithyl}amino)cyclopropanecarboxylate (0.20 g) was obtained by using tert-butyl rel-(1R,2S)-2-aminocyclopropanecarboxylate p-toluene sulfonate (0.64 g) in the same method as for Production Process A1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[NH:16][CH2:15][CH2:14][NH:13][C:12]2=[O:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:18](OC(=O)C)(=[O:20])[CH3:19]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[N:16]([C:18](=[O:20])[CH3:19])[CH2:15][CH2:14][NH:13][C:12]2=[O:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(C2NCCNC2=O)cc1OC
Product: COc1ccc(C2C(=O)NCCN2C(C)=O)cc1OC

Procedure:
23.6 l g (0.1 mol) of the 3-(3,4-dimethoxyphenyl)-piperazin-2-one prepared in accordance with Example 1 are introduced into 100 ml of acetic anhydride.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([CH3:20])[CH:14]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[NH2:8].[Cl:21][C:22]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:23]=1[CH:24]=O.CO>CS(C)=O>[CH3:20][C:15]1[CH:14]=[C:13]([NH:12][S:9]([C:4]2[CH:5]=[CH:6][C:7]3[N:8]=[C:24]([C:23]4[C:22]([Cl:21])=[CH:29][CH:28]=[CH:27][C:26]=4[Cl:30])[NH:1][C:2]=3[CH:3]=2)(=[O:11])=[O:10])[CH:18]=[CH:17][C:16]=1[CH3:19]
Reactant: O=Cc1c(Cl)cccc1Cl
Reactant: Cc1ccc(NS(=O)(=O)c2ccc(N)c(N)c2)cc1C
Solvent: CS(C)=O
Solvent: CO
Product: Cc1ccc(NS(=O)(=O)c2ccc3nc(-c4c(Cl)cccc4Cl)[nH]c3c2)cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A freshly prepared solution of 3,4-diamino-N-(3,4-dimethyl-phenyl)-benzenesulfonamide in DMSO (0.2 M, 0.40 mL) was placed in a vial. To it was added 2,6-dichloro-benzaldehyde (0.2 M in toluene, 0.48 mL), followed by FeCl3 (0.02 M in THF, 0.2 mL). The mixture was stirred in open air at ambient temperature overnight. The mixture was then diluted by MeOH and the whole was loaded onto a solid phase extraction (SPE) cartridge that contained strong cation exchange (SCX) (1 g media in 6 mL cartridge, United Chemical Technology). Wash-to-waste (5 mL MeOH) was followed by elute-to-collect (5 mL 20:2:1 ethyl acetate-MeOH-Et3N) and, after evaporation of volatiles, the crude was further purified by silica gel column chromatography to give 2-(2,6-dichloro-phenyl)-3H-benzoimidazole-5-sulfonic acid (3,4-dimethyl-phenyl)-amide: MS (m/z) 446 (M+1).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#[N:9].Br[CH2:14][CH2:15][O:16][CH3:17]>O1CCCC1>[CH3:17][O:16][CH2:15][CH2:14][O:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#[N:9]
Reactant: N#Cc1cccc(CO)c1
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOCc1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (55% in mineral oil, 1.76 g, 40.5 mmol) was suspended in 100 mL tetrahydrofurane. 3-(Hydroxymethyl)benzonitrile (5.0 g, 36.5 mmol), dissolved in 200 mL tetrahydrofuran was added drop wise. The reaction mixture was stirred at room temperature for 1 h. 2-Bromoethylmethylether (7.0 mL, 76 mmol) was added and the reaction mixture was refluxed overnight. The reaction mixture was quenched with 3 mL 2N sodium carbonate solution and the solvent was evaporated. The residue was taken up in 100 mL water and extracted three times with ethyl acetate (100 mL each). The organic phases ware pooled, dried with sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 100:0->50:50 gradient). 3-(2-Methoxy-ethoxymethyl)-benzonitrile was obtained as a yellow liquid (2.63 g, 38%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11](=[O:20])[C:12]1[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.C([Li])CCC.C1C[O:29][CH2:28][CH2:27]1>CCCCCC>[CH2:11]1[O:20][CH2:12]1.[CH3:1][C:2]1[N:3]([CH2:27][CH2:28][OH:29])[C:4]2[C:9]([C:10]=1[C:11](=[O:20])[C:12]1[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Cc1[nH]c2ccccc2c1C(=O)c1ccc(C#N)cc1
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: CCCCCC
Product: C1CO1
Product: Cc1c(C(=O)c2ccc(C#N)cc2)c2ccccc2n1CCO

Procedure:
Following a procedure similar to that described in Preparation 7A above, 9.75 g. (0.0375 mole) of 2-methyl-3-(4-cyanobenzoyl)indole (Preparation 1T) in 125 ml. of THF was treated with 16.65 ml. (0.04 mole) of a 2.4M solution of n-butyl lithium in hexane followed by 11.4 ml. of a 3.5M solution of ethylene oxide in THF to give 2-methyl-3-(4-cyanobenzoyl)-1-(2-hydroxyethyl)-1H-indole. Reaction of 30.4 g. (0.1 mole) of the latter with 21.0 g. (0.11 mole) of p-toluenesulfonyl chloride in 50 ml. of methylene dichloride in the presence of 50 ml. of 35% sodium hydroxide and 0.91 g. (0.004 mole) of benzyl trimethylammonium chloride afforded 38.3 g. (84%) of 2-methyl-3-(4-cyanobenzoyl)-1-(2-p-toluenesulfonyloxyethyl)-1H-indole, m.p. 165°-167° C.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[C:6]([O:9][CH3:10])=[CH:5][N:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:3]=1>[Pd].C1COCC1>[CH3:10][O:9][C:6]1[C:7](=[O:8])[CH:2]=[N:3][N:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:18])[F:19])[CH:12]=2)[CH:5]=1
Reactant: COc1cn(-c2cccc(C(F)(F)F)c2)nc(Br)c1=O
Agent: [Pd]
Solvent: C1CCOC1
Product: COc1cn(-c2cccc(C(F)(F)F)c2)ncc1=O
Temperature: 25 °C
Reaction time: 60 h
Yield: 29.9 %

Procedure:
3-Bromo-5-methoxy-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (0.800 g) and palladium on carbon (0.24 g, palladium 10%, 50% water moistened product) were suspended in THF (14 mL), and the suspension was stirred at room temperature for 2.5 days under a hydrogen atmosphere. The reaction mixture was filtered through celite, and the filtrate was concentrated and purified by silica gel column chromatography (ethyl acetate/hexane→methanol/ethyl acetate) to give the title compound (0.185 g).
Reaction SMILES: [NH:1]1[C:10]2=[CH:11][CH:12]=[CH:13][C:8]3=[C:9]2[N:3]([CH2:4][CH2:5][C:6](=[N:15]O)[C:7]3=[O:14])[C:2]1=[O:17].[H][H].[BH4-].[Na+]>[Pd]>[NH2:15][C@H:6]1[C@H:7]([OH:14])[C:8]2[CH:13]=[CH:12][CH:11]=[C:10]3[NH:1][C:2](=[O:17])[N:3]([C:9]=23)[CH2:4][CH2:5]1
Reactant: O=C1C(=NO)CCn2c(=O)[nH]c3cccc1c32
Reactant: [H][H]
Agent: [Pd]
Agent: [BH4-]
Agent: [Na+]
Product: N[C@@H]1CCn2c(=O)[nH]c3cccc(c32)[C@H]1O

Procedure:
Using the methods reported in U.S. Pat. No. 4,585,770, 5,6-dihydro-imidazo[4,5,1-jk][1]benzazepin-2,7-[1H,4H]-dione may be reacted with an alkyl nitrite (e.g., tert-butyl nitrite or isoamyl nitrite), in the presence of a base or acid (e.g., HCl), to form 4,5-dihydro-imidazo[4,5,1-jk][1]benzazepin-2,6,7[1H]-trione-6-oxime. The 4,5-dihydro-imidazo[4,5,1-jk][1]benzazepin-2,6,7[1H]-trione-6-oxime, in turn, is reduced via catalytic hydrogenation (with, for example, hydrogen in the presence of palladium on carbon) or sodium borohydride to form racemic trans 6-amino-7-hydroxy-4,5,6,7-tetrahydro-imidazo[4,5,1-jk][1]-benzazepin-2[1H]-one:
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[N+:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](Cl)(=[O:27])=[O:26])([O-:18])=[O:17].[OH:29][CH2:30][C:31](=[O:34])[CH:32]=[CH2:33]>C(Cl)Cl.CCCCCCC.CC(C)([O-])C.[K+]>[CH2:1]([N:8]([CH2:33][CH2:32][C:31](=[O:34])[CH2:30][OH:29])[S:25]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[N+:16]([O-:18])=[O:17])(=[O:27])=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: C=CC(=O)CO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCCCCCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CO)CCN(Cc1ccccc1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 77 %

Procedure:
To a solution of benzylamine (10.92 ml, 100 mmol) in DCM (150 ml) was added triethylamine (13.67 ml, 100 mmol) followed by a solution of 2-nitrobenzene-1-sulfonyl chloride (22.16 g, 100 mmol) in DCM (70 ml) at 5-10° C. with stirring. The mixture was stirred for 1 hour, stirring continued for 1 hour, washed with water, brine, most of DCM removed under reduced pressure. Ethyl acetate (150 ml) was added, another 25-30 ml distilled off under reduced pressure. To the resulting solution potassium tert-butoxide (0.561 g, 5.00 mmol) was added followed by 1-hydroxybut-3-en-2-one (9.47 g, 110 mmol) with stirring in one portion at 20-25° C. The mixture was stirred for 1 hour at 20-25° C., diluted with heptane (70 ml), washed with brine and 1N HCl (5 ml), organic phase was dried (MgSO4), evaporated to dryness under reduced pressure. The resulting oil was purified on a column with ethyl acetate-petroleum ether mixture as eluent. Fractions containing the wanted product were collected and evaporated to dryness under reduced pressure to give N-benzyl-2-nitro-N-(4-hydroxy-3-oxobutyl)benzenesulfonamide (29.1 g, 77 mmol, 77% yield).