Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C@H:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]([OH:13])[O:5]1)([CH3:3])[CH3:2].[CH2:14]([Mg]Cl)[CH:15]([CH3:17])[CH3:16].C(Cl)C(C)C.[Mg]>C1COCC1>[OH:5][C@H:4]([C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C@@H:6]([OH:13])[CH2:14][CH:15]([CH3:17])[CH3:16])[CH:1]([CH3:3])[CH3:2]
Reactant: CC(C)C[Mg]Cl
Reactant: CC(C)[C@@H]1OC(O)c2ccccc21
Agent: [Mg]
Solvent: CC(C)CCl
Solvent: C1CCOC1
Product: CC(C)C[C@H](O)c1ccccc1[C@@H](O)C(C)C

Procedure:
To a solution of (3S)-3-isopropyl-1,3-dihydro-isobenzofuran-1-ol (14.11 g, 0.129 mol) in THF (250 ml) was added at reflux temperature through a Teflon tube, which ended under the surface in the reaction mixture, a solution of isobutyl magnesium chloride (freshly prepared from 0.387 mol isobutyl chloride and 0.58 mol magnesium in 250 ml of THF) slowly within 20 minutes under efficient stirring. The mixture was then quenched with a solution of ammonium chloride (10%). The organic layer was separated, and the solvent was removed on the rotavapor. The residue was re-dissolved in ethyl acetate (200 ml), and this solution was washed with water (150 ml) and brine (150 ml). After drying and removal of the solvent the product was obtained as a yellow oil (31.5 g). 1H/13C-NMR (300 MHz, CDCl3, HSQC/HMBC) δ/δ 0.78 (d, J=6.9 Hz)/19.00, 1.04 (d, J=6.5 Hz)/20.22 (2 i-Pr CH3); 0.95 (d, J=6.5 Hz)/23.87, 0.96 (d, J=6.5 Hz)/22.32 (2 i-Bu CH3); 1.80 (m)/25.33 (i-Bu CHMe2); 2.02 (m)/35.13 ((i-Pr CHMe2); 1.47/1.72 (m)/48.03 (CH2); 3.09 (br s, 2 OH); 4.53 (d, J=8.1 Hz)/77.55 (CH(OH)i-Pr); 5.08 (dd, J=4.7 Hz, J=9.5 Hz)/68.87 (CH(OH)i-Bu); 7.40 (m)/126.44 (Ar i-Bu ortho-CH); 7.21 (m)/127.37 (Ar meta-CH); 7.28 (m)/127.55 (Ar i-Pr ortho-CH); 7.23 (m)/127.71 (Ar meta-CH); 140.56 (Ar i-Pr ipso-C); 142.66 (Ar i-Bu ipso-CH).
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6]([Br:8])[CH:7]=1.[NH2:11][C:12]1[N:17]=[CH:16][C:15]([N:18]2[CH2:22][CH:21]3[CH2:23][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][CH:20]3[CH2:19]2)=[CH:14][CH:13]=1>>[Br:8][C:6]1[CH:7]=[C:2]([NH:11][C:12]2[N:17]=[CH:16][C:15]([N:18]3[CH2:19][CH:20]4[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23][CH:21]4[CH2:22]3)=[CH:14][CH:13]=2)[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=1
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: CC(C)(C)OC(=O)N1CC2CN(c3ccc(N)nc3)CC2C1
Product: Cn1cc(Br)cc(Nc2ccc(N3CC4CN(C(=O)OC(C)(C)C)CC4C3)cn2)c1=O
Yield: 59.9 %

Procedure:
Following Example 188c, 3,5-dibromo-1-methylpyridin-2(1H)-one (212 mg, 0.79 mmol) and 335b (200 mg, 0.66 mmol) were reacted to give 335c as a yellow solid (194 mg, 60%). MS: [M+H]+ 492
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.Br[CH:26]([CH3:33])[CH2:27][CH2:28][CH2:29][C:30](Cl)=[O:31]>C1COCC1>[O:31]=[C:30]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:33][N:1]1[CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:6][CH2:7]1
Reactant: CC(Br)CCCC(=O)Cl
Reactant: NC1CCN(C(=O)OCc2ccccc2)CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCC(N2CCCCCC2=O)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 10 %

Procedure:
To a solution of benzyl 4-aminopiperidin-1-carboxylate (1.7 g) and triethylamine (1.1 mL) in THF (40 mL) was added dropwise 5-bromohexanoyl chloride (1.1 mL), and the mixture was stirred at 0° C. for 2 hours. The solvent was distilled off under reduced pressure and the residue was diluted with water, and extracted with ethyl acetate. The extract was washed with an aqueous 5% citric acid solution and a saturated saline solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in DMF (40 mL), and cooled at 0° C., sodium hydride (60% in oil; 0.60 g) was added thereto, and the mixture was stirred at 0° C. for one hour, at room temperature for one hour and at 80° C. for 15hours. The solvent was distilled-off under reduced pressure, the residue was diluted with water, and the solution was acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water and saturated saline solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=2/1 to 5/1) to obtain the title compound (0.25 g, 10%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[NH:8][C:5]2=[N:6][CH:7]=1.Cl.[NH2:15][CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18].C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-].CN1CCOCC1>C1COCC1>[O:18]=[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:16][NH:15][C:11]([C:9]1[NH:8][C:5]2=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=[C:4]2[CH:10]=1)=[O:13]
Reactant: O=C(O)c1cc2cc(Cl)cnc2[nH]1
Reactant: NCC(=O)c1ccccc1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: O=C(CNC(=O)c1cc2cc(Cl)cnc2[nH]1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5-Chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (Preparation 57, 50 mg, 0.25 mmol), 2-aminoacetophenone hydrochloride (48 mg, 0.28 mmol) and DMTMM (85 mg, 0.31 mmol) were dissolved in THF (5 mL) and 4-methylmorpholine (31 μL, 0.28 mmol). The reaction mixture was stirred at rt for 16 h. The solvent was removed in vacuo and the residue partitioned between water (20 mL) and EtOAc (3×20 mL). The combined organics were dried (MgSO4), concentrated in vacuo and purified by chromatography on silica gel eluting with methanol:dichloromethane (1:19) to give the title compound. m/z (ES+)=314 [M+H]+; RT=3.47 min.
Reaction SMILES: Cl.[CH2:2]([NH:4][C:5]([N:7]1[N:11]=[CH:10][C:9]2([CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:8]1)=[NH:6])[CH3:3].[C:16]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1)(=[O:18])[CH3:17].C(N(CC)CC)C>ClCCl>[CH2:8]1[C:9]2([CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:10]=[N:11][N:7]1[C:5](=[N:6][S:26]([C:23]1[CH:22]=[CH:21][C:20]([NH:19][C:16](=[O:18])[CH3:17])=[CH:25][CH:24]=1)(=[O:28])=[O:27])[NH:4][CH2:2][CH3:3]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCNC(=N)N1CC2(C=N1)CCCC2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCNC(=NS(=O)(=O)c1ccc(NC(C)=O)cc1)N1CC2(C=N1)CCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.6 %

Procedure:
N-Ethyl-2,3-diaza-spiro[4.4]non-3-ene-2-carboxamidine hydrochloride (60 g, 260.08 mmol; isolated from reaction of N-ethyl-2,3-diaza-spiro[4.4]non-3-ene-2-carboxamidine, synthesized as described in WO 2009/115515, with HCl in isopropanol) was dissolved in 1000 mL dichloromethane, and 4-acetylamino-benzenesulfonyl chloride (60.7 g, 260.08 mmol) was added. Under mechanical stirring, triethylamine (131.6 g, 1300.4 mmol) was added over a period of 20 minutes, and the mixture was stirred overnight at room temperature. The reaction mixture was extracted with water (250 mL) and the organic phase was concentrated under reduced pressure (40° C., 600 mbar). The oily residue was coevaporated twice with 96% ethanol (250 mL) and taken up in 500 mL dichloromethane. The organic phase was extracted with 1N aqueous HCl (75 mL) and subsequently twice with water (200 mL) and evaporated to dryness under reduced pressure to yield 78 g (199.2 mmol, 77%) of N-(4-{[(2,3-diaza-spiro[4.4]non-3-en-2-yl)-ethylamino-methylene]sulfamoyl}-phenyl)-acetamide. 1H NMR identical to spectrum obtained from material prepared via novel route (vide supra).
Reaction SMILES: [CH2:1]([CH:8]([C:25]([O-:27])=[O:26])[CH2:9][C:10](=O)[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:28]CCCl>>[CH2:1]([CH:8]1[C:25](=[O:26])[O:27][C:10]([Cl:28])([C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=2)=[O:12])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCCCl
Reactant: O=C(CC(Cc1ccccc1)C(=O)[O-])C(=O)OCc1ccc([N+](=O)[O-])cc1
Product: O=C1OC(Cl)(C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1Cc1ccccc1

Procedure:
In 18 ml of 1,2-dichloroethane was dissolved 475 mg of the Compound (73) obtained in Example 73. The solution was heated for 5 hours under reflux. The solvent was evaporated off, and the residue was subjected to a column chromatography using Florisil, followed by elution with hexaneethyl acetate (5:1) to give 370 mg of the subject Compound (74) as a pale yellow oily product.
Reaction SMILES: [F:1][C:2]1([F:35])[CH2:7][N:6](C(OCC2C=CC=CC=2)=O)[C@H:5]([C:18]([O:20]CC2C=CC=CC=2)=[O:19])[C@@H:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.[H][H]>CCO.[Pd]>[C:31]([O:30][C:28]([C@H:4]1[CH2:3][C:2]([F:1])([F:35])[CH2:7][NH:6][C@@H:5]1[C:18]([OH:20])=[O:19])=[O:29])([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)[C@H]1CC(F)(F)CN(C(=O)OCc2ccccc2)[C@@H]1C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)[C@H]1CC(F)(F)CN[C@@H]1C(=O)O

Procedure:
A solution of 1,2-dibenzyl 3-tert-butyl(2S,3S)-5,5-difluoropiperidine-1,2,3-tricarboxylate (0.370 g, 0.000756 mol) in EtOH (7.0 mL) was hydrogenated in the presence of 10% Pd/C, under a ballon pressure of hydrogen, for 2 h. After filtered off the catalyst, the filtration was evaporated to dry. The residue was used directly in next step (190 mg, 94.77%). LC MS (M-Bu+1) 210.0.
Reaction SMILES: [CH3:1]/[C:2](/[O:8][Si:9]([CH3:12])([CH3:11])[CH3:10])=[N:3]\[Si](C)(C)C.O[C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][C:22]=1O)NC=C2>ClCCl>[CH3:10][Si:9]([CH3:12])([CH3:11])[O:8][C:1]1[C:21]2[C:22](=[CH:14][CH:15]=[CH:16][CH:20]=2)[NH:3][C:2]=1[O:8][Si:9]([CH3:10])([CH3:11])[CH3:12]
Reactant: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Reactant: Oc1cc2cc[nH]c2cc1O
Solvent: ClCCl
Product: C[Si](C)(C)Oc1[nH]c2ccccc2c1O[Si](C)(C)C
Temperature: 25 °C
Yield: 71 %

Procedure:
To 0.81 g (0.004 mole) of N,O-bis(trimethylsilyl) acetamide is added, stirring at room temperature, 0.3 g (0.002 mole) of 5,6-dihydroxy indole. When dissolution is completed, 2 ml dichloromethane are added and the solution is passed through a column of silica 60, eluating with dichloromethane. The first fraction obtained is concentrated in a rotavapor, then vacuum-dried. Thus are obtained 0.42 g (yield: 71%) of white crytal of 5,6[di(trimethylsilyloxy]indole.
Reaction SMILES: [ClH:1].[NH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1.[N+:12]([O-])([O-:14])=[O:13].[K+]>S(=O)(=O)(O)O>[ClH:1].[N+:12]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[CH2:11][CH:3]([NH2:2])[CH2:4]2)([O-:14])=[O:13]
Reactant: O=[N+]([O-])[O-]
Reactant: NC1Cc2ccccc2C1
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [K+]
Product: NC1Cc2ccc([N+](=O)[O-])cc2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 2-aminoindane hydrochloride (19.11 g, 0.112 mol) at 0° C. was added sulfuric acid (60 ml) followed by potassium nitrate (11.84 g, 0.117 mol). The mixture was allowed to warm to room temperature, stirred for an additional 2 hr, then dumped onto ice/50% NaOH (500 ml total). The mixture was extracted with ether (3×20 ml) and the combined extracts were washed with water, dried over magnesium sulfate, filtered, and concentrated to an oil which was converted to the hydrochloride salt. Recrystallization from isopropanol/methanol afforded 5-nitro-2-aminoindane hydrochloride: (14.58 g, 60%); m.p. >300° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:4]=1[C:5](Cl)=[O:6].[NH2:14][C:15]1[N:19]=[CH:18][NH:17][N:16]=1>>[NH:17]1[CH:18]=[N:19][C:15]([NH:14][C:5](=[O:6])[C:4]2[C:3]([O:2][CH3:1])=[CH:11][CH:10]=[CH:9][C:8]=2[O:12][CH3:13])=[N:16]1
Reactant: COc1cccc(OC)c1C(=O)Cl
Reactant: Nc1nc[nH]n1
Product: COc1cccc(OC)c1C(=O)Nc1nc[nH]n1

Procedure:
2,6-Dimethoxybenzoyl chloride was reacted with 3-amino-1H-1,2,4-triazole according to the procedure of Example 118 to provide N-(1H-1,2,4-triazol-3-yl)-2,6-dimethoxybenzamide.
Reaction SMILES: [N:1]1([CH:6]([C:9]2[CH:10]=[C:11]([NH2:16])[C:12]([NH2:15])=[CH:13][CH:14]=2)[CH2:7][CH3:8])[CH:5]=[CH:4][N:3]=[CH:2]1.[F:17][C:18]([F:23])([F:22])[C:19](O)=O.[OH-].[NH4+]>>[N:1]1([CH:6]([C:9]2[CH:14]=[CH:13][C:12]3[NH:15][C:19]([C:18]([F:23])([F:22])[F:17])=[N:16][C:11]=3[CH:10]=2)[CH2:7][CH3:8])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCC(c1ccc(N)c(N)c1)n1ccnc1
Reactant: O=C(O)C(F)(F)F
Agent: [NH4+]
Agent: [OH-]
Product: CCC(c1ccc2[nH]c(C(F)(F)F)nc2c1)n1ccnc1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 22 %

Procedure:
A mixture of 6.1 parts of 4-[1-(1H-imidazol-1-yl)propyl]-1,2-benzenediamine and 90 parts of trifluoroacetic acid was stirred for 15 minutes at 80° C. The reaction mixture was poured into crushed ice and treated with ammonium hydroxide. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane, methanol and ammonium hydroxide (90:10:1 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 2-propanone and 2,2'-oxybispropane (4 parts-17.5 parts). The product was filtered off and dried, yielding 1.8 parts (22%) of 5-[1-(1H-imidazol-1-yl)propyl]-2-(trifluoromethyl)-1H-benzimidazole; mp. 173.2° C. (compound 83).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][C:16]=2[F:22])[C:10](=[O:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24]([Si:28]([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)Cl)([CH3:27])([CH3:26])[CH3:25].N1C=CN=C1.CCOC(C)=O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[C:19]([O:21][Si:28]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:18]=[CH:17][C:16]=2[F:22])[C:10](=[O:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cc(O)ccc2F)C(=O)C1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2cc(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc2F)C(=O)C1

Procedure:
A solution of product from Step D (2.75 g, 8.48 mmol), tert-butyldiphenylchlorosilane (2.2 mL, 8.48 mmol), and imidazole (860 mg, 12.7 mmol) in DMF (50 mL) was stirred at 60° C. for 15 hours. The reaction was poured into EtOAc (200 mL), and washed with H2O (300×100 mL). The organic layer was dried with magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by column chromatography (25-30% ethyl acetate/hexane) to provide the title compound.
Reaction SMILES: [NH2-].[Na+].[C:3](#[N:5])[CH3:4].C[O:7][C:8]([CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=O.Cl>O1CCCC1>[CH:10]1([C:8](=[O:7])[CH2:4][C:3]#[N:5])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: COC(=O)C1CCCCC1
Reactant: CC#N
Agent: Cl
Agent: [NH2-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CCC(=O)C1CCCCC1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
To a solution of sodium amide (1.87 g) in tetrahydrofuran (1.87 g) was added acetonitrile (2.72 ml) at −50˜−40° C. dropwise and then was added cyclohexanecarboxylic acid methyl ester (2.86 ml) and the mixture was stirred for 1 hour at −20° C. The reaction mixture was poured into cool hydrochloric acid and was extracted with ethyl acetate. The extract was washed with water and a saturated aqueous solution of sodium chloride successively, and was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=4:1) to give the title compound (0.91 g) having the following physical data.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][CH2:8][N:9]([CH3:11])[CH3:10])=[C:4]([N+:14]([O-])=O)[CH:3]=1.[Cl-].[NH4+]>[Zn].C1COCC1.O>[Br:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][CH2:8][N:9]([CH3:11])[CH3:10])=[C:4]([CH:3]=1)[NH2:14]
Reactant: CN(C)CCOc1ccc(Br)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)CCOc1ccc(Br)cc1N
Reaction time: 4 h
Yield: 51.7 %

Procedure:
Zinc dust (4.52 g, 69.2 mmol) was added to a stirred solution of 2-(4-bromo-2-nitrophenoxy)-N,N-dimethylethanamine (4 g, 13.8 mmol), ammonium chloride (3.7 g, 69.2 mmol), THF/Water (40/40 mL) at RT. Reaction completed in 4 hours. The RM was filtered and the filtrate was concentrated. The residue was dissolved in ethyl acetate and washed with water, dried over sodium sulfate, concentrated to get the crude mass which was washed with hexanes to afford titled compound 1.85 g (51.67% yield) as solid. 1H NMR (DMSO-d6, 300 MHz): δ 6.74-6.70 (m, 2H), 6.59-6.56 (m, 1H), 4.99 (s, 2H), 3.97-3.93 (t, 2H), 2.59-2.56 (t, 2H), 2.18 (s, 6H). LCMS: m/z=260.8 (M+2).
Reaction SMILES: Br[C:2]1[C:10]([CH:11]([CH3:13])[CH3:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[Li]C(C)(C)C.[B:19](OCCCC)([O:25]CCCC)[O:20]CCCC>CCOCC>[CH:11]([C:10]1[CH:9]=[CH:8][C:7]2[NH:6][N:5]=[CH:4][C:3]=2[C:2]=1[B:19]([OH:25])[OH:20])([CH3:13])[CH3:12]
Reactant: CCCCOB(OCCCC)OCCCC
Reactant: CC(C)c1ccc2[nH]ncc2c1Br
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: CC(C)c1ccc2[nH]ncc2c1B(O)O
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
A solution of 4-bromo-5-isopropyl-1H-indazole (1.6 g, 6.9 mmol) in Et2O (4 mL) is added slowly to a suspension of KH (1.0 g of 30% dispersion in mineral oil, 7.7 mmol) in Et2O (20 mL) at 0° C. and the mixture is stirred for 20 minutes. After cooling to −78° C., t-BuLi (8.9 mL of 1.7 M in Hex, 15 mmol) is added and the resulting mixture is stirred for 40 minutes at −78° C. To this is added B(On-Bu)3 (5.6 mL, 21 mmol) and the mixture is stirred for 24 hours at room temperature. The reaction mixture is quenched with 1N H3PO4 and extracted with Et2O. The combined Et2O layers are back-extracted with 1N NaOH (3×10 mL). The combined NaOH extracts are acidified with 1N H3PO4 and extracted with EtOAc. The EtOAc extracts are washed with saturated brine, dried (MgSO4), and concentrated to yield 5-isopropyl-1H-indazole-4-boronic acid. 1H NMR (CDCl3) 7.85 (s, 1H), 7.42 (d, 1H), 7.37 (d, 1H), 3.6 (br s, 2H), 2.88 (m, 1H), 1.32 (d, 6H).
Reaction SMILES: CO[CH:3](OC)[C:4](=[N:7][OH:8])[C:5]#[N:6].[OH:11][CH2:12][CH2:13][NH:14][NH2:15].O.[S:17](=[O:21])(=[O:20])([OH:19])[OH:18]>CO>[S:17]([OH:21])([OH:20])(=[O:19])=[O:18].[NH2:6][C:5]1[N:14]([CH2:13][CH2:12][OH:11])[N:15]=[CH:3][C:4]=1[N:7]=[O:8]
Reactant: COC(OC)C(C#N)=NO
Reactant: NNCCO
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CO
Product: Nc1c(N=O)cnn1CCO
Temperature: 66.5 °C
Yield: 88.1 %

Procedure:
To a flask having an inner volume of 25 ml and equipped with a stirring device, a thermometer and a reflux condenser were charged 1.47 g (10.0 mmol) of 3,3-dimethoxy-2-hydroxyiminopropionitrile with a purity of 98.1% by weight synthesized in the same manner as in Example 1, 0.84 g (10.5 mmol) of 2-hydroxyethylhydrazine with a purity of 95% by weight, 0.54 ml of water, 10 ml of methanol and 1.18 g (12.0 mmol) of conc. sulfuric acid, and the mixture was reacted under reflux (66 to 67° C.) for 3 hours. After completion of the reaction, when the reaction mixture was analyzed by high performance liquid chromatography (absolute calibration curve method), it was found that 2.24 g of 5-amino-1-(2-hydroxyethyl)-4-nitrosopyrazole hydrogen sulfate (Reaction yield: 88.2%) had been formed.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:20]4=[N:21][S:22](=[O:26])(=[O:25])[CH2:23][CH2:24][N:19]4[CH:18]=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1>C1COCC1.CO.[Pt](=O)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]([CH:15]3[C:20]4=[N:21][S:22](=[O:26])(=[O:25])[CH2:23][CH2:24][N:19]4[CH2:18][CH2:17][CH2:16]3)=[CH:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2ccc(C3=CC=CN4CCS(=O)(=O)N=C34)cc2)c1
Agent: O=[Pt]=O
Solvent: C1CCOC1
Solvent: CO
Product: COc1cccc(-c2ccc(C3CCCN4CCS(=O)(=O)N=C34)cc2)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 36.9 %

Procedure:
Platinum(IV) oxide (9.7 mg) was added to a solution of 9-(3′-methoxybiphenyl-4-yl)-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (17.4 mg) in THF (dry) (15 mL) and MeOH (15 mL) and the mixture was stirred at 50° C. under hydrogen overnight. Activated carbon was added and the insoluble solid was removed by filtration through NH-silica gel/Celite pad (eluted with EtOAc). Silica-gel was added to the filtrate and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) to give the title compound (6.5 mg) as colorless gum.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][CH2:13][CH:14]2[CH2:16][CH2:15]2)=[N:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[NH2:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]1[OH:24]>>[Br:1][C:2]1[C:3]([O:12][CH2:13][CH:14]2[CH2:16][CH2:15]2)=[N:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([NH:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]1[OH:24])=[O:9]
Reactant: Cc1nc(OCC2CC2)c(Br)cc1C(=O)O
Reactant: N[C@@H]1CCCC[C@H]1O
Product: Cc1nc(OCC2CC2)c(Br)cc1C(=O)N[C@@H]1CCCC[C@H]1O

Procedure:
The title compound was synthesized in analogy to the procedure described for the preparation of Example 31b, using 5-bromo-6-cyclopropylmethoxy-2-methyl-nicotinic acid and (1R,2R)-2-amino-1-cyclohexanol as starting materials, MS (ISP): 383.1, 385.1 (M+H)+.
Reaction SMILES: Br[C:2]1([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:7](=[O:8])[NH:6][C:5](=[O:9])[NH:4][C:3]1=[O:10].[OH:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.O>CS(C)=O>[CH2:11]([C:2]1([CH:25]2[CH2:26][NH:27][CH2:28][CH2:29][N:24]2[CH2:23][CH2:22][OH:21])[C:7](=[O:8])[NH:6][C:5](=[O:9])[NH:4][C:3]1=[O:10])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: OCCN1CCNCC1
Reactant: CCCCCCCCCCC1(Br)C(=O)NC(=O)NC1=O
Solvent: O
Solvent: CS(C)=O
Product: CCCCCCCCCCC1(C2CNCCN2CCO)C(=O)NC(=O)NC1=O
Temperature: 0 °C
Yield: 43.7 %

Procedure:
To a solution of 5-bromo-5-decylbarbituric acid (0.619 g) in 1.3 ml of dimethylsulfoxide, kept under stirring at 0° C., a solution of 0.93 g of N-(2-hydroxyethyl)piperazine in 0.7 ml of dimethylsulfoxide is added dropwise, then the reaction mixture is stirred at room temperature for 1 hour. The mixture is then cooled to 0° C. and added with 30 ml of water. A white solid separates, which is kept under stirring for 1 hour, then is filtered and dried under vacuum at 50° C. 0.309 g of the product are obtained, m.p. 181-182° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](Cl)=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.[NH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:24][CH2:23][CH2:22][C:21]1=[O:25]>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][C:21]3=[O:25])=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: NCCCN1CCCC1=O
Reactant: O=[N+]([O-])c1cnc2cc(Br)ccc2c1Cl
Product: O=C1CCCN1CCCNc1c([N+](=O)[O-])cnc2cc(Br)ccc12
Yield: 84 %

Procedure:
7-Bromo-4-chloro-3-nitroquinoline (35.26 g, 123.8 mmol) was treated with 1-(3-aminopropyl)pyrrolidin-2-one (19.1 mL, 136.2 mmol) according to the method described in Part E of Example 1 to provide 40.87 g of 1-[3-(7-bromo-3-nitroquinolin-4-ylamino)propyl]pyrrolidin-2-one as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH2:9][NH:8][CH2:7][CH2:6]2.C1C2C(=CC=CC=2)CCN1[C:25]([Cl:27])=[O:26]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH2:9][N:8]([C:25]([Cl:27])=[O:26])[CH2:7][CH2:6]2
Reactant: O=C(Cl)N1CCc2ccccc2C1
Reactant: COc1cc2c(cc1OC)CNCC2
Product: COc1cc2c(cc1OC)CN(C(=O)Cl)CC2
Yield: 94 %

Procedure:
6,7-Dimethoxy-3,4-dihydro-1H-isoquinoline-2-carbonyl chloride (25A) is prepared from 6,7-Dimethoxy-1,2,3,4-tetrahydro-isoquinoline as described for 24A.