Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([Cl:11])[N:5]=[C:4]([Cl:12])[N:3]=1.[H][H].O>CO.[Ni]>[NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([Cl:11])[N:5]=[C:4]([Cl:12])[N:3]=1
Reactant: Nc1nc(Cl)nc(Cl)c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: O
Solvent: CO
Product: Nc1nc(Cl)nc(Cl)c1N

Procedure:
To a solution of 4-amino-2,6-dichloro-5-nitropyrimidine, prepared as described in a), in methanol (30 ml), was added Raney nickel freshly prepared from 500 mg of alloy. The reaction mixture was stirred 20 hours in the hydrogen atmosphere. Then a new catalyst, prepared from 500 mg of alloy, was added and the reaction mixture was stirred next 24 hours in the hydrogen atmosphere. The catalyst was removed, the reaction mixture was concentrated in vacuo and the residue was extracted with hot water. Product, which was obtained after cooling of the water solution, was purified by chromatography (SiO2, VI—1:1)
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:5]=[CH:6][O:7][CH:8]=1.[CH2:9]([O:11][C:12](=[O:33])[N:13]([C:22]1[CH:27]=[C:26](Br)[N:25]=[C:24]([NH2:29])[C:23]=1[N+:30]([O-:32])=[O:31])[CH2:14][C:15]1[CH:16]=[N:17][C:18]([CH3:21])=[CH:19][CH:20]=1)[CH3:10]>[Cl-].[Cl-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd+2]>[CH2:9]([O:11][C:12](=[O:33])[N:13]([C:22]1[CH:27]=[C:26]([C:6]2[O:7][CH:8]=[C:4]([CH2:3][O:2][CH3:1])[N:5]=2)[N:25]=[C:24]([NH2:29])[C:23]=1[N+:30]([O-:32])=[O:31])[CH2:14][C:15]1[CH:16]=[N:17][C:18]([CH3:21])=[CH:19][CH:20]=1)[CH3:10]
Reactant: CCOC(=O)N(Cc1ccc(C)nc1)c1cc(Br)nc(N)c1[N+](=O)[O-]
Reactant: COCc1cocn1
Agent: [Pd+2]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)N(Cc1ccc(C)nc1)c1cc(-c2nc(COC)co2)nc(N)c1[N+](=O)[O-]

Procedure:
The title compound was prepared following the example in preparation 70, using 4-methoxymethyl-oxazole (110 mg), (2-amino-6-bromo-3-nitro-pyridin-4-yl)-(6-methyl-pyridin-3-ylmethyl)-carbamic acid ethyl ester (200 mg) and palladium bis(triphenylphosphine)dichloride (68 mg), giving the product (107 mg) as a yellow gum.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[ClH:10].[CH2:11]([OH:13])[CH3:12]>>[ClH:10].[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6](=[NH:7])[O:13][CH2:11][CH3:12])=[CH:4][CH:3]=1
Reactant: CCO
Reactant: N#Cc1ccc(Br)cc1
Agent: Cl
Product: CCOC(=N)c1ccc(Br)cc1
Reaction time: 16 h
Yield: 99 %

Procedure:
A solution of 4-bromobenzonitrile (17.65 g, 97 mmol) in ethanol (500 mL) was acidified with hydrogen chloride gas at 0° C. for fifteen minutes. The solution was allowed to stir for 16 h. The solution was condensed under reduced pressure to afford the title compound (25.35 g, 99%). MS (ESI) m/z 228.1 [M]+, 230.4 [M+2]+.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([CH3:16])[CH3:15])[CH2:10][C@H:9]1[CH3:17])(OC(C)(C)C)=O.Cl>O1CCOCC1>[CH:14]([N:11]1[CH2:12][CH2:13][NH:8][C@H:9]([CH3:17])[CH2:10]1)([CH3:16])[CH3:15]
Reactant: CC(C)N1CCN(C(=O)OC(C)(C)C)[C@H](C)C1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)N1CCN[C@H](C)C1
Temperature: 25 °C
Reaction time: 28 h

Procedure:
To crude (R)-1-Boc-2-methyl-4-isopropylpiperazine in 1,4-dioxane (10 mL) was added HCl (5 mL of a 4M solution in 1,4-dioxane). The reaction mixture was stirred at room temperature for 28 h then concentrated. The resulting solid was suspended in diethyl ether, concentrated and dried on high vacuum for 1 d. The resulting solid was taken up in aq. 2N NaOH and the solution extracted three times with DCM. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to provide the free base of the product which was used without further purification. LCMS-ESI+: calc'd for C8H18N2 (M+H+): 143.1; Found: 143.7 (M+H+).
Reaction SMILES: [BH4-].[Na+].O.C(=O)(O)[O-].[Na+].[F:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[C:16]([C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=1)=[N:15][CH2:14][CH2:13]2>C(OCC)(=O)C>[F:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]([C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:28])([F:27])[F:29])=[CH:22][CH:21]=1)[NH:15][CH2:14][CH2:13]2
Reactant: Fc1ccc2c(c1)CCN=C2c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: Fc1ccc2c(c1)CCNC2c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 6-fluoro-1-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline (2.6 g, 8.9 mmol) in methanol (50 mL) from step 2 was cooled to 0° C. and sodium borohydride (1.0 g, 2.7 mmol) was added in small portions over 5 min and the reaction mixture was stirred at RT for 16 h. The reaction was quenched with ethyl acetate (20 mL) and concentrated to yield a reddish-yellow residue which was taken up in ethyl acetate (100 mL), water (30 mL), and saturated sodium bicarbonate (30 mL). After stirring for 15 min, it was transferred to a separatory funnel, the organic layer was separated, dried over anhydrous sodium sulfate, and concentrated to yield the crude product. The crude product was purified by silica gel chromatography (20-30% EtOAc in hexanes) to give 6-fluoro-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline as a pale-yellow solid. MS (ESI pos. ion) m/z: 296 (M+H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C1CC=CC=1.[CH2:11]1[CH:15]2C3C=C[CH:18]([CH:14]2[CH:13]=[CH:12]1)[CH2:17]3.O=C(C)CCCC#N.[Cl-].[Na+]>CO>[C:14]1(=[C:18]([CH3:17])[CH2:5][CH2:4][CH2:3][C:2]#[N:1])[CH:15]=[CH:11][CH:12]=[CH:13]1
Reactant: C1CCNC1
Reactant: C1=CC2C3C=CC(C3)C2C1
Agent: C1=CCC=C1
Agent: CC(=O)CCCC#N
Agent: [Cl-]
Solvent: CO
Product: CC(CCCC#N)=C1C=CC=C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Pyrrolidine (18.5 g; 0.26 mol) was added to a solution of cyclopentadiene (10.8 g; 0.16 mol; freshly prepared by cracking of dicyclopentadiene) and 5-oxohexanenitrile (15.4 g; 0.13 mol) in methanol (175 ml) at 0° C. After 1 hour stirring at this temperature, the reaction mixture was poured into ice-cold 2 N HCl (500 ml), saturated with sodium chloride, and extracted with MTBE (400 ml). The organic phase was washed with brine (3×300 ml), dried (MgSO4), concentrated in vacuo, and used in the next step without further purification.
Reaction SMILES: C[O-].[Na+].[O:4]1[CH:8]=[CH:7][C:6]([CH:9]=O)=[CH:5]1.[N+:11]([CH3:14])([O-:13])=[O:12].CCOCC>CO>[N+:11]([CH:14]=[CH:9][C:6]1[CH:7]=[CH:8][O:4][CH:5]=1)([O-:13])=[O:12]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccoc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: O=[N+]([O-])C=Cc1ccoc1
Temperature: 0 °C
Yield: 69 %

Procedure:
A freshly prepared solution of sodium methoxide (prepared by dissolving sodium (0.46 g, 20 mmol) in MeOH (5 mL)) was added very slowly via a double ended needle to a solution of 3-furaldehyde (1.73 mL, 20 mM) and nitromethane (1.08 mL, 20 mmol) in MeOH (4 mL) cooled to 0° C. The mixture was stirred at 0° C. an addition 5 min, then Et2O (10 mL) was added. The resultant salt was collected via filtration, thoroughly washed with Et2O, taken up in a minimum amount of water then the solution was added to an ice cold solution of 25% HCl (80 mL). The solid that formed was collected by filtration and washed with water, then the moist product was taken up in CHCl3/MeOH and solvents removed to give 3-(2-nitrovinyl) furan (69%) as a pale yellow solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Br[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:38][CH2:39][O:40][CH3:41])=[C:14]([CH:37]=1)[C:15]([NH:17][C:18]1[CH:30]=[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:28]=[CH:27][C:19]=1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:16]>CC(C)=O>[CH3:41][O:40][CH2:39][O:38][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[CH:37][C:14]=1[C:15]([NH:17][C:18]1[CH:30]=[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:28]=[CH:27][C:19]=1[C:20]([O:22][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:21])=[O:16]
Reactant: COCOc1ccc(CBr)cc1C(=O)Nc1cc(-c2ccccc2)ccc1C(=O)OC(C)(C)C
Reactant: CN1CCNCC1
Solvent: CC(C)=O
Product: COCOc1ccc(CN2CCN(C)CC2)cc1C(=O)Nc1cc(-c2ccccc2)ccc1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under ice-cooling, 1-methylpiperazine (0.16 mL) was added to an acetone (2.3 mL) suspension of tert-butyl 2-(5-(bromomethyl)-2-(methoxymethoxy)benzamido)-4-phenylbenzoate (0.15 g), followed by stirring at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and a 1.0 mol/L aqueous solution of sodium hydroxide and chloroform were added to the residue. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 100-95% chloroform/methanol] to obtain 0.14 g of tert-butyl 2-(2-(methoxymethoxy)-5-((4-methylpiperazin-1-yl)methyl)benzamido)-4-phenylbenzoate as a yellow oil substance.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:6][C:7](=[O:24])[NH:8][C:9]3[CH:16]=[C:15]([Cl:17])[C:14]([C:18]#[C:19][CH2:20][N:21]([CH3:23])[CH3:22])=[CH:13][C:10]=3[C:11]=2[N:12]=1>O.C1COCC1.[Ni]>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:6][C:7](=[O:24])[NH:8][C:9]3[CH:16]=[C:15]([Cl:17])[C:14]([CH2:18][CH2:19][CH2:20][N:21]([CH3:22])[CH3:23])=[CH:13][C:10]=3[C:11]=2[N:12]=1
Reactant: CN(C)CC#Cc1cc2c(cc1Cl)NC(=O)Cc1cnc(N)nc1-2
Agent: [Ni]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)CCCc1cc2c(cc1Cl)NC(=O)Cc1cnc(N)nc1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.9 %

Procedure:
A slurry of Raney Ni (3.0 mL) in water was added to 2-amino-9-chloro-10-[3-(dimethylamino)prop-1-yn-1-yl]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one (0.30 g, 0.88 mmol) in THF (6 mL). The reaction mixture was allowed to stir under an atmosphere of H2 at rt overnight. The reaction mixture was filtered over Celite and the filter cake was washed with THF. The filtrate was concentrated and the resulting solid was triturated with MeOH, diethyl ether, and hexanes. The solid was collected via suction filtration to give 2-amino-9-chloro-10-[3-(dimethylamino)propyl]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one (0.158 g, 52%) as a light yellow solid. LCMS (FA): m/z=346 (M+H).
Reaction SMILES: [CH2:1]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[C:19](OC(=O)C)(=[O:21])[CH3:20]>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([NH:9][C:19](=[O:21])[CH3:20])=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(N)cc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCc1ccc(NC(C)=O)cc1
Yield: 58.5 %

Procedure:
To 4-butyl aniline (20 g; 134 mmol) dissolved in toluene (160 mL) with stirring was added 4-dimethylaminopyridine (0.82 g; 6.70 mmol) and triethylamine (26.0 mL; 188 mmol). The mixture was then treated with acetic anhydride (15.2 mL; 161 mmol) dropwise via an addition funnel over 30 minutes. After addition, the ice bath was removed and the reaction mixture was stirred for 12 hours at room temperature. The mixture was poured into aqueous hydrochloric acid (240 mL; 2M) and stirred 20 minutes. The layers were separated and the organic layer was washed with water. The organic layer was separated and crystals formed while standing. The resulting precipitate was isolated by filtration and dried under vacuum to give the title product as white crystals (15.0 g).
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](Cl)=[O:4].[CH3:8][C:9]1([CH3:27])[O:14][C:13]2[CH:15]=[CH:16][C:17]([C:19]#[N:20])=[CH:18][C:12]=2[C@@H:11]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[C@@H:10]1[OH:26]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:8][C:9]1([CH3:27])[O:14][C:13]2[CH:15]=[CH:16][C:17]([C:19]#[N:20])=[CH:18][C:12]=2[C@@H:11]([N:21]2[CH2:22][CH2:23][CH2:24][CH2:25]2)[C@@H:10]1[O:26][C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N2CCCC2)[C@@H]1O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)C(=O)O[C@H]1[C@H](N2CCCC2)c2cc(C#N)ccc2OC1(C)C

Procedure:
To a solution of 4-dimethylaminopyridine (0.98 g) in dichloromethane (50 ml) was added 2,2-dimethylpropanoyl chloride (0.69 ml) dropwise and with gentle stirring, followed by crude trans-2,2-dimethyl-4-pyrrolidino-6-cyano-3,4-dihydro-2H-benzo[b]-pyran-3-ol (2.50 g) in dichloromethane (50 ml) during 4 minutes. The resulting red solution was heated under reflux for 40 hours before cooling and evaporation of solvent. The orange residue was taken up in ethyl acetate and washed with water, dried and evaporated leaving a mustard coloured solid (2.97 g) which was separated by chromatography on silica gel (110 g) with mixtures of ethyl acetate and 60°-80° petroleum ether using a gradient elution technique, into crude ester (1.12 g) and starting material (1.13 g). Recrystallization of the crude material from 60°-80° petroleum ether gave trans-2,2-dimethyl-3-(2,2-dimethylpropanoyloxy)-4 pyrrolidino-6-cyano-3,4-dihydro-2H-benzo[b]pyran (0.73 g) as white crystals of m.p. 109°-110° C.; IR absorptions at 1730, 2220 cm-1 ; nmr (CDCl3) δ 1.24 (9H), 1.29 (3H), 1.41 (3H), 1.75 (4H, broad m), 2.73 (4H, broad m), 4.09 (1H, d, J=9), 5.33 (1H, d, J=9), 6.86 (1H, d, J=8), 7.43 (1H, q, J=8, 2), 7.74 (1H, d, J=2). Anal. Calcd. for C21H28N2O3 : C, 70.76; H, 7.92; N,7.86. Found: C, 70.74; H, 8.03, N, 7.76%.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]([CH2:18][CH:19]([CH3:21])[CH3:20])[S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])(=[O:10])=[O:9])=[C:4]([F:24])[CH:3]=1.[CH3:25][S:26]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)(=[O:28])=[O:27].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[Cl:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[S:8]([N:7]([CH2:6][C:5]1[CH:22]=[CH:23][C:2]([C:33]2[CH:32]=[CH:31][CH:30]=[C:29]([S:26]([CH3:25])(=[O:28])=[O:27])[CH:34]=2)=[CH:3][C:4]=1[F:24])[CH2:18][CH:19]([CH3:21])[CH3:20])(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: CC(C)CN(Cc1ccc(Br)cc1F)S(=O)(=O)c1ccccc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)CN(Cc1ccc(-c2cccc(S(C)(=O)=O)c2)cc1F)S(=O)(=O)c1ccccc1Cl

Procedure:
In analogy to example 1, step 3, N-(4-bromo-2-fluoro-benzyl)-2-chloro-N-isobutyl-benzenesulfonamide was reacted with (3-methylsulfonylphenyl)-boronic acid, Na2CO3 and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium dichloromethane adduct in dioxane/water to give 2-chloro-N-(3-fluoro-3′-methanesulfonyl-biphenyl-4-ylmethyl)-N-isobutyl-benzenesulfonamide as a colorless solid. MS: 568.2 ([M+OAc]−)
Reaction SMILES: [C:1]([C:6]1([C:9]([OH:11])=O)[CH2:8][CH2:7]1)([O:3][CH2:4][CH3:5])=[O:2].ClC(OCC)=O.[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([NH:23][CH3:24])=[CH:21][CH:20]=1.C(N(CC)CC)C>>[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([N:23]([CH3:24])[C:9]([C:6]2([C:1]([O:3][CH2:4][CH3:5])=[O:2])[CH2:7][CH2:8]2)=[O:11])=[CH:21][CH:20]=1
Reactant: CCOC(=O)C1(C(=O)O)CC1
Reactant: CNc1ccc(Cl)cc1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(C(=O)N(C)c2ccc(Cl)cc2)CC1
Yield: 22.9 %

Procedure:
1-Carboethoxycyclopropanecarboxylic acid (5.54 grams, 0.035 mole), ethyl chloroformate (3.80 grams, 0.035 mole) and 4-chloro-N-methylaniline (4.96 grams, 0.035 mole) were reacted sequentially in the presence of triethylamine (3.54 grams, 0.035 mole) in a manner similar to that described in Example XXXIII to give 2.26 grams (0.008 mole) of ethyl 1-[N-(4-chlorophenyl)-N-methylaminocarbonyl]cyclopropanecarboxylate having a melting point of 53° C.-56.5° C. NMR analysis of the product indicated the following:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.[C:27]([O:31][C:32](=[O:42])[CH2:33][O:34][CH:35]1[CH2:40][CH2:39][CH:38](O)[CH2:37][CH2:36]1)([CH3:30])([CH3:29])[CH3:28]>C(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[C:27]([O:31][C:32](=[O:42])[CH2:33][O:34][CH:35]1[CH2:40][CH2:39][CH:38]([I:25])[CH2:37][CH2:36]1)([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)COC1CCC(O)CC1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)COC1CCC(I)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Triphenylphosphine (1.18 g, 4.49 mmol), imidazole (0.31 g, 4.49 mmol) and iodine (1.14 g, 4.49 mmol) are added to a solution of (4-hydroxy-cyclohexyloxy)-acetic acid tert-butyl ester (cis:trans=ca. 1:1) (0.86 g, 3.74 mmol) in a mixture of CH2Cl2 (10 ml)/CCl4 (20 ml) at 0° C. The cooling bath is removed and the reaction mixture is stirred at room temperature for 18 hours. Saturated aq. Na2S2O3 (10 ml) is added and the mixture is stirred for 15 minutes. The layers are separated and the aqueous layer is re-extracted with CH2Cl2 (×3). The combined organic extracts are washed with brine (×1), dried (Na2SO4), filtered and concentrated. Purification by chromatography on silica gel, eluting with 5% ethyl acetate in isohexane, gives the product.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:8]([CH2:9][CH3:10])=[N:7][C:6]2[N:11]([CH2:14][CH3:15])[N:12]=[CH:13][C:5]=2[C:4]=1[NH:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.[Cl:23][CH2:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](O)=[O:29].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>C(Cl)Cl>[Cl:23][CH2:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28]([NH:1][CH2:2][C:3]1[C:4]([NH:16][CH:17]2[CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)=[C:5]2[CH:13]=[N:12][N:11]([CH2:14][CH3:15])[C:6]2=[N:7][C:8]=1[CH2:9][CH3:10])=[O:29]
Reactant: O=C(O)c1cccc(CCl)c1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(CCl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.5 %

Procedure:
To a solution of 5-(aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine-4-amine (0.303 g, 1.0 mmol) in CH2Cl2 (10 mL) was added 3-(chloromethyl)benzoic acid (0.188 g, 1.1 mmol), EDC (0.288 g, 1.5 mmol), HOBt (0.0135 g, 0.1 mmol), and Et3N (0.141 mL, 1.0 mmol). This mixture was stirred at room temperature for 1 h, then washed with H2O (1 mL) and purified by CombiFlash chromatograph to afford the title compound 0.285 g (63%). LC-MS m/z 456 (M+H)+.
Reaction SMILES: Cl.[F:2][C:3]([F:14])([F:13])[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([NH2:12])[CH2:8][CH2:7]1)=[O:5].[O:15]1[C:20]2[CH:21]=[CH:22][C:23]([CH:25]=O)=[CH:24][C:19]=2[O:18][CH2:17][CH2:16]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[O:15]1[C:20]2[CH:21]=[CH:22][C:23]([CH2:25][NH:12][CH:9]3[CH2:10][CH2:11][N:6]([C:4](=[O:5])[C:3]([F:2])([F:13])[F:14])[CH2:7][CH2:8]3)=[CH:24][C:19]=2[O:18][CH2:17][CH2:16]1
Reactant: NC1CCN(C(=O)C(F)(F)F)CC1
Reactant: O=Cc1ccc2c(c1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(N1CCC(NCc2ccc3c(c2)OCCO3)CC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.6 %

Procedure:
To a suspension of 1.0 g of 1-(trifluoroacetyl)piperidin-4-amine hydrochloride in 20 mL of dichloromethane, 0.71 g of 2,3-dihydro-1,4-benzodioxine-6-carbaldehyde and 0.25 mL of acetic acid were added, and the mixture was stirred at room temperature for 2 hours. To the reaction mixture, 1.37 g of sodium triacetoxyborohydride was added, and the mixture was stirred at the same temperature for 30 minutes. The solvent was distilled off under reduced pressure, water and ethyl acetate were then added thereto, and the mixture was adjusted to pH 1.5 with 1 mol/L hydrochloric acid. The aqueous layer was separated and washed with ethyl acetate, thereto was added ethyl acetate, and the aqueous layer was adjusted to pH 7.8 with a saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, the resultant solution was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 1.4 g of N-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-1-(trifluoroacetyl)piperidin-4-amine as a colorless oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([CH2:20][O:21][CH3:22])=[N:7][N:8]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15](Br)[CH:14]=2)[C:9]=1[CH2:10][O:11][CH3:12])=[O:4].[Cl:23][C:24]1[CH:29]=[CH:28][C:27](/[CH:30]=[CH:31]/B(O)O)=[CH:26][CH:25]=1>>[CH3:1][O:2][C:3]([C:5]1[C:6]([CH2:20][O:21][CH3:22])=[N:7][N:8]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15](/[CH:31]=[CH:30]/[C:27]3[CH:28]=[CH:29][C:24]([Cl:23])=[CH:25][CH:26]=3)[CH:14]=2)[C:9]=1[CH2:10][O:11][CH3:12])=[O:4]
Reactant: OB(O)/C=C/c1ccc(Cl)cc1
Reactant: COCc1nn(-c2cccc(Br)c2)c(COC)c1C(=O)OC
Product: COCc1nn(-c2cccc(/C=C/c3ccc(Cl)cc3)c2)c(COC)c1C(=O)OC

Procedure:
In analogy to the procedures described for intermediates 1A-E, the title compound has been obtained by i) condensation of methyl 4-methoxyacetoacetate with methoxyacetyl chloride to give 4-methoxy-2-(2-methoxy-acetyl)-3-oxo-butyric acid methyl ester; ii) methylation of 4-methoxy-2-(2-methoxy-acetyl)-3-oxo-butyric acid methyl ester with methyl trifluoromethanesulfonate to give (E and/or Z)-3,4-dimethoxy-2-(2-methoxy-acetyl)-but-2-enoic acid methyl ester; iii) condensation of (E and/or Z)-3,4-dimethoxy-2-(2-methoxy-acetyl)-but-2-enoic acid methyl ester with (3-bromo-phenyl)-hydrazine to give 1-(3-bromo-phenyl)-3,5-bis-methoxymethyl-1H-pyrazole-4-carboxylic acid methyl ester; iv) reaction of 1-(3-bromo-phenyl)-3,5-bis-methoxymethyl-1H-pyrazole-4-carboxylic acid methyl ester with (E)-2-(4-chlorophenyl)vinyl boronic acid to give 1-{3-[(E)-2-(4-chloro-phenyl)-vinyl]-phenyl}-3,5-bis-methoxymethyl-1H-pyrazole-4-carboxylic acid methyl ester; v) saponification of 1-{3-[(E)-2-(4-chloro-phenyl)-vinyl]-phenyl}-3,5-bis-methoxymethyl-1H-pyrazole-4-carboxylic acid methyl ester to give the title compound as light brown solid. MS: 411.2 ([M−H]−, 1 Cl).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14]O)=[CH:10][CH:9]=1)=[O:7].S(Cl)([Cl:18])=O>C1C=CC=CC=1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][Cl:18])=[CH:10][CH:9]=1)=[O:7]
Reactant: O=C(c1ccc(CO)cc1)c1cccs1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=C(c1ccc(CCl)cc1)c1cccs1
Reaction time: 8 h

Procedure:
To a stirred and cooled suspension of 31 parts of α-hydroxy-p-tolyl 2-thienyl ketone in 160 parts of dry benzene are added dropwise 24 parts of thionyl chloride at 10° C. Upon completion, stirring is continued overnight at room temperature. The reaction mixture is evaporated and the residue is evaporated twice more from toluene. The latter residue is triturated in petroleumether. The product is filtered off and dissolved in 320 parts of ether. This solution is stirred with charcoal, filtered and the filtrate is evaporated. The residue is crystallized from ethanol at -20° C, yielding α-chloro-p-tolyl 2-thienyl ketone.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([Cl:19])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])CCC.[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23][NH2:24]>C(O)C>[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23][NH:24][C:6]([C:8]1[N:9]=[C:10]([Cl:19])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7]
Reactant: CN(C)CCN
Reactant: CCCCOC(=O)c1nc(Cl)c2ccccc2c1O
Solvent: CCO
Product: CN(C)CCNC(=O)c1nc(Cl)c2ccccc2c1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.7 %

Procedure:
A mixture of 28 mg (0.1 mmol) of 1-chloro-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester from example A-1 c), 116 μl (1 mmol) of N,N-dimethyl-ethane-1,2-diamine and 0.5 ml of absolute ethanol was stirred at ambient temperature for 18 h. Then the solvent was evaporated in vacuo, the residue suspended in 5 ml of water, and mixture was extracted with 2×35 ml of ethyl acetate. The combined organic phases were dried over sodium sulfate and evaporated in vacuo to give a yellowish solid. 29 mg of the title compound were obtained; MS-(+)-ion: M+1=294.1.