Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[C:5](N)=[C:6]([Br:13])[C:7]2[S:11][CH:10]=[N:9][C:8]=2[CH:12]=1)([O-:3])=[O:2].N(OS(=O)(=O)O)=O.O[PH2]=O.CCOC(C)=O>S(=O)(=O)(O)O>[N+:1]([C:4]1[CH:5]=[C:6]([Br:13])[C:7]2[S:11][CH:10]=[N:9][C:8]=2[CH:12]=1)([O-:3])=[O:2]
Reactant: Nc1c([N+](=O)[O-])cc2ncsc2c1Br
Agent: O=NOS(=O)(=O)O
Agent: O=S(=O)(O)O
Agent: O=[PH2]O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc(Br)c2scnc2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 86.5 %

Procedure:
To a solution of 5 -nitro-6-amino-7-bromobenzothiazole (1.0 g, 3.7 mmol) in 4 mL of sulfuric acid was added nitrososulfuric acid (1.2 g, 9.5 mmol) in a portion. The resulting reaction mixture was stirred for 12 h at 25° C. The reaction mixture was then cooled to 0° C. and 1 mL of H3PO2 was added into the solution. It was stirred for 12 h at another 25° C. and for 2 h at 50° C. The reaction mixture was then poured into EtOAc and washed with aq. NaHCO3. Organic layer was dried over Na2SO4 and concentrated in vacuo to provide an oil (0.85 g, 3.2 mmol, 89%), whicn was characterized as the desired product(>95% pure) and subjected to a following reaction without further purification.
Reaction SMILES: Cl[CH2:2][C:3]([O:5][C@H:6]1[CH2:25][C@@:24]2([CH3:26])[C@@H:17]([CH2:18][CH2:19][C@@H:20]2[C:21](=[O:23])[CH3:22])[C@H:16]2[C@H:7]1[C@:8]1([CH3:31])[C@@H:13]([CH2:14][CH2:15]2)[CH2:12][C@H:11]([OH:27])[C@@H:10]([O:28][CH2:29][CH3:30])[CH2:9]1)=[O:4].[I-:32].[Na+]>CC(C)=O>[CH2:29]([O:28][C@H:10]1[CH2:9][C@@:8]2([CH3:31])[C@@H:13]([CH2:14][CH2:15][C@@H:16]3[C@@H:7]2[C@@H:6]([O:5][C:3](=[O:4])[CH2:2][I:32])[CH2:25][C@@:24]2([CH3:26])[C@H:17]3[CH2:18][CH2:19][C@@H:20]2[C:21](=[O:23])[CH3:22])[CH2:12][C@@H:11]1[OH:27])[CH3:30]
Reactant: CCO[C@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2[C@@H](OC(=O)CCl)C[C@]2(C)[C@@H](C(C)=O)CC[C@@H]32)C[C@@H]1O
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCO[C@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2[C@@H](OC(=O)CI)C[C@]2(C)[C@@H](C(C)=O)CC[C@@H]32)C[C@@H]1O
Yield: 101.1 %

Procedure:
11β-Chloroacetoxy-2β-ethoxy-3α-hydroxy-5α-pregnan-20-one (420 mg) in acetone (42 ml) was treated with sodium iodide (550 mg) and the solution was refluxed for one hour, during which time a fine white precipitate formed. The filtered solution was evaporated to an oily solid which was partitioned between ether/ethyl acetate and water. The organic layer was washed with water, dried over sodium sulphate and evaporated to give title compound (510 mg) as a white form, [α]D +80° (c 0.32%).
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.Cl.[C:12]1([C:18]2[C:19]([N:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)=[C:20]3[C:26]([O:27][CH2:28][C@@H:29]([OH:32])[CH2:30][OH:31])=[N:25][NH:24][C:21]3=[N:22][CH:23]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:39]([O:43][C:44]([NH:46][C@H:47]([CH2:51][C:52]1[CH:57]=[CH:56][C:55]([Cl:58])=[CH:54][CH:53]=1)[C:48](O)=[O:49])=[O:45])([CH3:42])([CH3:41])[CH3:40].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[Cl:58][C:55]1[CH:56]=[CH:57][C:52]([CH2:51][C@@H:47]([NH:46][C:44](=[O:45])[O:43][C:39]([CH3:41])([CH3:40])[CH3:42])[C:48]([N:36]2[CH2:35][CH2:34][N:33]([C:19]3[C:18]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[CH:23][N:22]=[C:21]4[NH:24][N:25]=[C:26]([O:27][CH2:28][C@@H:29]([OH:32])[CH2:30][OH:31])[C:20]=34)[CH2:38][CH2:37]2)=[O:49])=[CH:53][CH:54]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)O
Reactant: OC[C@H](O)COc1n[nH]c2ncc(-c3ccccc3)c(N3CCNCC3)c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2c(-c3ccccc3)cnc3[nH]nc(OC[C@@H](O)CO)c23)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
DIEA (0.055 mL, 0.32 mmol) was added to a solution of (S)-3-(5-phenyl-4-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridin-3-yloxy)propane-1,2-diol dihydrochloride (0.050 g, 0.079 mmol), (R)-2-(tert-butoxycarbonylamino)-3-(4-chlorophenyl)propanoic acid (0.024 g, 0.079 mmol) and TBTU (0.031 g, 0.095 mmol) in DCM (1 mL) and stirred at room temperature for 1 hour. The reaction was then concentrated to dryness, and the residue was dissolved in THF/MeOH (2 mL, 1:1), and an aqueous LiOH solution (1 mL, 2 M) was added. The reaction was then stirred for an additional 10 minutes. Ethyl acetate (20 mL) was added, and the organic layer was separated, washed with brine (10 mL), and dried over sodium sulfate. After removal of the solvent, the resulting residue was purified by column chromatography (ethyl acetate:MeOH, 20:1) to give tert-butyl(R)-3-(4-chlorophenyl)-1-(4-(3-((S)-2,3-dihydroxypropoxy)-5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)-1-oxopropan-2-ylcarbamate as a solid. The solid was then dissolved in DCM (1 mL), and TFA (0.4 mL) was added. The mixture was stirred at room temperature for 1 hour and concentrated to dryness. The resulting residue was dissolved in DCM (0.5 mL), and HCl in ether (1 mL, 2 N) was added. The resulting solid was collected by filtration to give (R)-2-amino-3-(4-chlorophenyl)-1-(4-(3-((S)-2,3-dihydroxypropoxy)-5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)propan-1-one dihydrochloride (0.018 g, 36%). MS APCI (+) m/z 551.2 detected.
Reaction SMILES: [Cl:1][C:2]1[N:12]2[C:13]3[C:8]([CH2:9][CH2:10][CH2:11]2)=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=1>N1CCCCC1>[ClH:1].[N:12]1([C:2]2[N:12]3[C:13]4[C:8]([CH2:9][CH2:10][CH2:11]3)=[CH:7][CH:6]=[CH:5][C:4]=4[N:3]=2)[CH2:13][CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: Clc1nc2cccc3c2n1CCC3
Solvent: C1CCNCC1
Product: Cl
Product: c1cc2c3c(c1)nc(N1CCCCC1)n3CCC2
Yield: 170.4 %

Procedure:
A solution of 2-chloro-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline (3.5 g) in piperidine (20 ml) was stirred under reflux, under nitrogen, for four hrs. The reaction mixture was quenched with dilute sodium bicarbonate solution (200 ml) and the aqueous suspension was extracted with chloroform. The combined organic extracts were dried over anhydrous magnesium sulfate and concentrated. The residue was purified by high performance liquid chromatography (silica gel; 3:1 dichloromethane-ethyl acetate). The appropriate fractions were collected and concentrated. This residue was dissolved in ether and treated dropwise with a solution of hydrogen chloride/ether. The precipitate was collected and washed with ether to give 4.3 g (85%) of product, mp 260° C.
Reaction SMILES: ClC1C=C(NC2N=C(N[C@@H]3C[C@H]4N(CCC4)C(C)(C)C3)C(F)=CN=2)C=CC=1OCCO.F[C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][C:34]=1[CH3:42].CC(C)([O-])C.[K+].[Si:49]([O:56][CH2:57][CH2:58][OH:59])([C:52]([CH3:55])([CH3:54])[CH3:53])([CH3:51])[CH3:50]>C1COCC1>[C:52]([Si:49]([CH3:51])([CH3:50])[O:56][CH2:57][CH2:58][O:59][C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][C:34]=1[CH3:42])([CH3:55])([CH3:54])[CH3:53]
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Reactant: CC(C)(C)[Si](C)(C)OCCO
Agent: CC(C)(C)[O-]
Agent: CC1(C)C[C@H](Nc2nc(Nc3ccc(OCCO)c(Cl)c3)ncc2F)C[C@@H]2CCCN21
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cc([N+](=O)[O-])ccc1OCCO[Si](C)(C)C(C)(C)C

Procedure:
A similar procedure as detailed above for Compound 133 was used. 2-fluoro-5-nitrotoluene (310 mg, 2.0 mmol), potassium tert-butoxide (494 mg, 4.4 mmol) and 2-((tert-butyldimethylsilyl)oxy)ethan-1-ol (705 mg, 4.0 mmol) in THF (6 mL) was stirred for 3 hr at room temperature to give the product after workup (yield assumed quantitative=623 mg). The product was used in the next step without further purification.
Reaction SMILES: COC1C=CC(N=[N:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[C:13]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:12]=2[OH:40])=CC=1.C(O)C.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[NH2:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:12]=1[OH:40]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc2ccccc2c(N=Nc2ccc(OC)cc2)c1O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCCCCCCCOc1cc2ccccc2c(N)c1O

Procedure:
To a mixture of 17 g (0.031 mole) 1-(p-methoxyphenylazo)-3-octadecyloxy-2-naphthol and 700 ml ethanol was added a solution 13.5 g (0.070 mole) sodium dithionite in 80 ml water. The mixture was refluxed for 2.5 hours, cooled, and filtered. The while solid, 11 g, was recrystallized from a mixture of hexane and ethyl acetate to give an off-white solid, m.p. 97°-99° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:65][C:66]1[CH:72]=[CH:71][C:69]([NH2:70])=[CH:68][CH:67]=1>C(Cl)Cl>[NH2:65][C:66]1[CH:72]=[CH:71][C:69]([NH:70][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:25])([CH3:26])[CH3:27])[NH:10]2)=[O:29])=[CH:68][CH:67]=1
Reactant: Nc1ccc(N)cc1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(N)cc2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (300 mg, 0.66 mmol) in methylene chloride (10 mL), HATU (Aldrich, 266 mg, 0.66 mmol) was added followed by the addition of DIPEA (0.30 mL) and 4-amino-aniline (Aldrich, 143 mg, 1.32 mmol). The mixture was stirred at rt for overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (24 g column, eluent, 40-85% EtOAc/hexanes) to give an off-white solid. 298 mg.
Reaction SMILES: [CH3:1][N:2]([CH3:50])[C:3](=[O:49])[CH2:4][C@@H:5]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH:24][C:25]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][C:41](O)=[O:42])=[CH:35][C:34]=3[O:44][CH3:45])=[CH:29][CH:28]=2)=[O:26])(=[O:23])=[O:22])=[CH:17][C:16]=1[N+:46]([O-:48])=[O:47])[CH2:6][S:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:51]([NH2:56])[C:52]([CH3:55])([CH3:54])[CH3:53].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C)C(=O)C.ClC(Cl)C>[CH3:45][O:44][C:34]1[CH:35]=[C:36]([CH2:39][CH2:40][C:41]([NH:56][CH2:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:42])[CH:37]=[CH:38][C:33]=1[C:30]1[CH:29]=[CH:28][C:27]([C:25]([NH:24][S:21]([C:18]2[CH:19]=[CH:20][C:15]([NH:14][C@@H:5]([CH2:6][S:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:4][C:3]([N:2]([CH3:50])[CH3:1])=[O:49])=[C:16]([N+:46]([O-:48])=[O:47])[CH:17]=2)(=[O:23])=[O:22])=[O:26])=[CH:32][CH:31]=1
Reactant: CC(C)(C)CN
Reactant: COc1cc(CCC(=O)O)ccc1-c1ccc(C(=O)NS(=O)(=O)c2ccc(N[C@@H](CSc3ccccc3)CC(=O)N(C)C)c([N+](=O)[O-])c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: CC(Cl)Cl
Product: COc1cc(CCC(=O)NCC(C)(C)C)ccc1-c1ccc(C(=O)NS(=O)(=O)c2ccc(N[C@@H](CSc3ccccc3)CC(=O)N(C)C)c([N+](=O)[O-])c2)cc1

Procedure:
A solution of Example 126C (50 mg, 0.069 mmol), neopentylamine (21 mg, 0.20 mmol), EDCI (20 mg, 0.104 mmol), and HOBT (15 mg, 0.104 mmol) in N,N-dimethylacetamide (1 mL) and dichloroethane (0.5 mL) at room temperature was stirred for 16 hours. The mixture was concentrated, dissolved in 1:1 DMSO/methanol (1.0 mL) and purified by reverse phase preparative HPLC (using a C-18 column and a solvent system increasing in gradient from 20 to 95% acetonitrile/water containing 0.1% TFA) to provide the desired product. MS (ESI(−)) m/e 788 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ8.89 (br d, 1H), 8.57 (d, 1H), 7.90 (d, 2H), 7.85 (dd, 1H), 7.70(br t, 1H), 7.58 (d, 2H), 7.30-7.12 (m, 7H), 7.00 (d, 1H), 6.90 (dd, 1H), 4.45 (m, 1H), 3.75 (s, 3H), 3.42 (t, 2H), 2.90 (s, 3H), 2.79 (s, 3H), 3.00-2.70 (m, 8H), 0.80 (s, 9H).
Reaction SMILES: [CH3:1][C:2]([C:4]([CH3:6])=[CH2:5])=[CH2:3].[C:7]1([OH:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.P(=O)(O)(O)O.O>C1(C)C(C)=CC=CC=1.C1C2NC3C(=CC=CC=3)SC=2C=CC=1>[CH3:1][CH:2]1[C:4]([CH3:6])([CH3:5])[C:11]2[C:10](=[CH:9][CH:8]=[C:7]([OH:13])[CH:12]=2)[CH2:3]1
Reactant: Oc1ccccc1
Reactant: C=C(C)C(=C)C
Agent: O=P(O)(O)O
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: Cc1ccccc1C
Solvent: O
Product: CC1Cc2ccc(O)cc2C1(C)C
Reaction time: 8 h
Yield: 40.9 %

Procedure:
90 g of 2,3-dimethyl-1,3-butadiene, stabilized with 0.2 g of phenothiazine, were added dropwise over the course of 7 hours to a solution of 94 g of phenol, 13 g of 85% strength phosphoric acid and 1 ml of water in 240 ml of xylene at 110° C. To complete the reaction, stirring was continued overnight at 110° C. The acid phase was separated off and extracted by shaking with toluene. The combined organic phases were washed until neutral. Fractional distillation gave 72 g of 2,3,3-trimethyl-5-hydroxy-indane; boiling point: 148° C/12 mm Hg; melting point 66° - 67° C. ##STR36##
Reaction SMILES: [Cl-].[C:2]1([PH+](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C[C:22]([O-:25])(C)C.[K+].[Br:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[C:30]([F:36])[CH:29]=1>O1CCCC1>[CH3:2][O:25][CH:22]=[CH:32][C:31]1[CH:34]=[CH:35][C:28]([Br:27])=[CH:29][C:30]=1[F:36]
Reactant: CC(C)(C)[O-]
Reactant: O=Cc1ccc(Br)cc1F
Reactant: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC=Cc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methoxymethyl)triphenylphosphonium chloride (147 g, 0.48 mol) was suspended in tetrahydrofuran (1.5 L) under argon atmosphere, stirred with ice-water cooling. t-BuOK (51.6 g, 0.46 mol) was added in portions. A solution of 4-bromo-2-fluorobenzaldehyde (40.6 g, 0.2 mol) in tetrahydrofuran (500 mL) was then added to the reaction mixture. The solution was stirred at room temperature for 1 hour. The solution was poured into ice-water and extracted with ethyl acetate (2×). The combined organic phases were dried and concentrated in vacuo. Purification via flash chromatography afforded the title compound.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[CH2:22]([O:21][C:19]([CH2:18][N:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[Cl:1])=[O:20])[CH3:23]
Reactant: CCOC(=O)CCl
Reactant: Clc1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)Cn1c(Cl)nc2ccccc21

Procedure:
2-Chlorobenzimidazole was treated with potassium carbonate and ethyl chloroacetate to yield 1-(ethoxycarbonylmethyl)-2-chlorobenzimidazole. This compound (1 eq.) was combined with L-4-(N,N-dimethylcarbamyloxy)phenylalanine ter-butyl ester (1.1 eq., prepared as described in Method L) and 2 drops of acetonitrile in a sealed tube and the reaction was heated for two days at 120° C. and the resultant mixture purified by column chromatography (1:3 ethyl acetate/hexanes) to yield the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9].Cl.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18]N)=[CH:14][CH:13]=1.[CH3:20][N:21]1[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1>C(N(CC)CC)C>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]2[N:18]([CH2:2][CH2:3][N:4]3[CH2:8][CH2:7][CH2:6][C:5]3=[O:9])[C:24]3[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][C:23]=3[C:14]=2[CH:13]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: CN1CCC(=O)CC1
Reactant: O=C1CCCN1CCBr
Agent: Cl
Solvent: CCN(CC)CC
Product: CN1CCc2c(c3cc(Cl)ccc3n2CCN2CCCC2=O)C1

Procedure:
The title compound is prepared by following Method 8 by using 1-(2-bromoethyl)pyrrolidin-2-one, 4-chlorophenylhydrazine hydrochloride, triethylamine and N-methyl-4-piperidone
Reaction SMILES: N[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:45]=[CH:44][CH:43]=[CH:42][C:7]=1[C:8]([NH:10][C:11]1[CH:41]=[CH:40][C:14]([C:15]([N:17]([CH3:39])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([N:32]2[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]2)=[O:31])=[O:16])=[CH:13][CH:12]=1)=[O:9].[CH2:46]=O.[C:48]([BH3-])#[N:49].[Na+]>CO.C(O)(=O)C.C(Cl)(Cl)Cl>[CH3:46][N:49]([CH3:48])[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:45]=[CH:44][CH:43]=[CH:42][C:7]=1[C:8]([NH:10][C:11]1[CH:41]=[CH:40][C:14]([C:15]([N:17]([CH3:39])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([N:32]2[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]2)=[O:31])=[O:16])=[CH:13][CH:12]=1)=[O:9]
Reactant: C=O
Reactant: [BH3-]C#N
Reactant: CN1CCN(C(=O)CCCCCOc2ccccc2N(C)C(=O)c2ccc(NC(=O)c3ccccc3OCCCN)cc2)CC1
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CN(C)CCCOc1ccccc1C(=O)Nc1ccc(C(=O)N(C)c2ccccc2OCCCCCC(=O)N2CCN(C)CC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.5 %

Procedure:
To a mixture of 4-[2-[(3-aminoprop-1-yl)oxy]benzoyl]amino-N-methyl-N-[2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (220 mg) and 37% aqueous formaldehyde (290 mg) in a mixture of methanol (10 ml) and acetic acid (0.2 ml) was added sodium cyanoborohydride (44.8 mg) and the mixture was stirred at ambient temperature for 4 hours. The reaction mixture was diluted with chloroform (20 ml) and the solution was washed successively with saturated aqueous sodium hydrogen carbonate solution (20 ml), water (10 ml) and brine (10 ml). The organic phase was dried over magnesium sulfate and the solvent was evaporated to give 4-[2-[(3-dimethylaminoprop-1-yl)oxy]benzoyl]amino-N-methyl-N-[2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (215 mg) as a colorless amorphous.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]3[O:10][CH2:11][O:12][C:8]=3[C:7]=2[C:15]2[C:16]3[NH:23][CH:22]=[C:21]([C:24](O)=[O:25])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.[C:56]([O:60][C:61]([N:63]1[CH2:68][CH2:67][CH:66]([NH2:69])[CH2:65][CH2:64]1)=[O:62])([CH3:59])([CH3:58])[CH3:57]>ClCCl>[C:56]([O:60][C:61]([N:63]1[CH2:68][CH2:67][CH:66]([NH:69][C:24]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:7]4[C:8]5[O:12][CH2:11][O:10][C:9]=5[CH:13]=[CH:14][C:6]=4[O:5][CH2:4][CH:1]4[CH2:3][CH2:2]4)[C:16]=3[NH:23][CH:22]=2)=[O:25])[CH2:65][CH2:64]1)=[O:62])([CH3:59])([CH3:57])[CH3:58]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=C(O)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.9 %

Procedure:
To a suspension of 4-(5-cyclopropylmethoxy-1,3-benzodioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (3.53 g; 10.0 mmol) from example A67 in dry dichloromethane (50 mL) is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (12.0 mmol), triethylamine (15.0 mmol) and 1-hydroxybenzotriazole (10.0 mmol). The suspension is stirred at ambient temperature for one hour. To the resulting solution, 4-amino-piperidine-1-carboxylic acid tert-butyl ester (12.0 mmol) is added and stirring is continued overnight at ambient temperature. The reaction mixture is loaded onto a silica gel column and purified by flash chromatography using acetic acid ethyl ester/2-propanol (98:2 v/v). The eluate containing the product fraction is collected and evaporated. The product is triturated with n-hexane and dried in high vacuo at 50° C. to yield 3.85 g of the title compound as white solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][N:5]([C:7](=[O:17])[C:8]2[CH:13]=[CH:12][C:11]3[O:14][CH2:15]O[C:10]=3[CH:9]=2)[CH:4]([C:18]([OH:20])=[O:19])[CH2:3]1.O[CH:22]1CN(C(=O)C2C=CC(OC)=CC=2)C(C(O)=O)C1>>[OH:1][CH:2]1[CH2:6][N:5]([C:7](=[O:17])[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[CH:4]([C:18]([O:20][CH3:22])=[O:19])[CH2:3]1
Reactant: O=C(O)C1CC(O)CN1C(=O)c1ccc2c(c1)OCO2
Reactant: COc1ccc(C(=O)N2CC(O)CC2C(=O)O)cc1
Product: COC(=O)C1CC(O)CN1C(=O)c1ccc(OC)cc1
Yield: 40 %

Procedure:
By carrying out the procedure as in Example 11, but replacing 4-hydroxy-1-(3,4-methylenedioxybenzoyl)pyrrolidine-2-carboxylic acid by the 4-hydroxy-1-(4-methoxy-benzoyl)pyrrolidine-2-carboxylic acid obtained in Example 57, the title product is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14](=[O:18])[CH:15]=[N+]=[N-])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BrH:19]>C(OCC)(=O)C.C(O)(=O)C.COC(C)(C)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14](=[O:18])[CH2:15][Br:19])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCCC1C(=O)C=[N+]=[N-]
Reactant: Br
Solvent: COC(C)(C)C
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCCCC1C(=O)CBr
Temperature: 25 °C
Yield: 45 %

Procedure:
A solution of 2-(2-diazo-acetyl)-piperidine-1-carboxylic acid tert-butyl ester (0.51 g, 2.0 mmol) in dry ethyl acetate (11 mL) was cooled to −45° C. and treated with a 33% solution of hydrobromic acid in acetic acid (0.24 mL), which was added dropwise over 45 min. The cold reaction mixture was diluted with tert-butyl methyl ether (34 mL) and left to warm to room temperature. The mixture was washed twice with saturated sodium hydrogenocarbonate (2*11 mL) and with saturated sodium chloride. The organic phase was dried over sodium sulphate and evaporated. The residue was purified by flash chromatography (heptane/ethyl acetate gradient) to yield 2-(2-bromo-acetyl)-piperidine-1-carboxylic acid tert-butyl ester (0.28 g, 45%) as a light yellow oil, MS (ISP): 306.1, 308.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].[CH3:10][C:11](=O)[C:12](=O)[CH3:13]>C(O)C>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[N:4]=[C:11]([C:12](=[N:4][C:3]1[C:5]([CH3:9])=[CH:6][CH:7]=[CH:8][C:2]=1[CH3:1])[CH3:13])[CH3:10]
Reactant: Cc1cccc(C)c1N
Reactant: CC(=O)C(C)=O
Solvent: CCO
Product: CC(=Nc1c(C)cccc1C)C(C)=Nc1c(C)cccc1C
Reaction time: 12 h
Yield: 77.5 %

Procedure:
A mixture of 37.2 ml (36.3 g, 0.3 moles) of 2,6-dimethylaniline, 13.1 ml (12.9 g, 0.15 moles) of 2,3-butanedione and 100 ml of ethanol is boiled for 12 hours. The solvent is evaporated under reduced pressure, 80 ml of water and 20 ml of acetic acid are added to the residue, and the resulting mixture is stirred for 6 hours at 0° to ±5° C. The mixture is allowed to stand overnight, thereafter the separated precipitate is filtered off, washed with water and dried. 34.0 g (77.5%) of crude 2,3-bis(2',6'-dimethylphenyl-imino)-butane are obtained; m.p.: 78°-86° C. After recrystallization from ethanol 25.1 g (57.2%) of the pure substance, melting at 88°-90° C., are obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10](=[O:12])[NH:9][C:8]=2[CH:13]=1)([O-:3])=[O:2].[H-].[Na+].[CH3:16]I>CN(C=O)C>[CH3:16][N:9]1[C:8]2[CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=2[O:11][C:10]1=[O:12]
Reactant: CI
Reactant: O=c1[nH]c2cc([N+](=O)[O-])ccc2o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)oc2ccc([N+](=O)[O-])cc21
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A solution of 5-nitro-3H-benzooxazol-2-one (26 g) in DMF (100 mL) was added to a suspension of NaH (60% in mineral oil, 10.71 g) in DMF (100 mL) over a period of 1 hour. Stirring was continued for 45 minutes at r.t. The mixture was cooled to 0° C. and methyl iodide dissolved in DMF (20 mL) was added dropwise over a period of 30 minutes. The mixture was stirred over night at r.t. The reaction mixture was poured into ice/water and extracted two times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. CH2Cl2:methanol=4:1 (150 mL) was added to the resulting precipitate and the suspension was stirred for 1 hour at r.t. The solid was filtered off and dried in vacuo. The title compound was obtained as a orange solid (18.33 g, 62%). MS (EI)=194.0 [M+].