Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]1[C:15]2[C:10](=[C:11]([OH:16])[CH:12]=[CH:13][CH:14]=2)[C:9](=[O:17])[C:8]2[C:7]([OH:18])=[CH:6][CH:5]=[CH:4][C:3]1=2.[CH2:19]([SH:21])[CH3:20]>ClCCl>[OH:18][C:7]1[C:8]2[C:9](=[O:17])[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][C:11]=3[OH:16])[CH:2]([S:21][CH2:19][CH3:20])[C:3]=2[CH:4]=[CH:5][CH:6]=1
Reactant: CCS
Reactant: O=C1c2c(O)cccc2C(Br)c2cccc(O)c21
Solvent: ClCCl
Product: CCSC1c2cccc(O)c2C(=O)c2c(O)cccc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 91 %

Procedure:
10-Bromo-1,8-dihydroxy-9-anthrone (3.05 g) was dissolved in dichloromethane (100 ml) and ethanethiol (1 ml) was added. The solution was left stirring at room temperature for 6 hours, during which time the red-brown solution became yellow-green. Removal of the solvent gave a yellow solid which, recrystallised from hexane, gave 1,8-dihydroxy-10-ethylthio-9-anthrone (2.63 g, 91%) as bright yellow needles, melting point 117°-118° C. (Found: C 67.3, H 5.1, S 11.1; C16H14O3S requires C 67.1, H 4.93, S 11.2%.)
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[NH:17][C:18](=[O:21])[O:19][CH3:20])=O)(C)(C)C.C(OCC)(=O)C.Cl>C(O)C>[ClH:16].[NH2:8][CH2:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[NH:17][C:18](=[O:21])[O:19][CH3:20]
Reactant: COC(=O)Nc1ccc(Cl)cc1CNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)Nc1ccc(Cl)cc1CN
Reaction time: 8 h
Yield: 170.5 %

Procedure:
(Step 3) To a solution (2 ml) of methyl (2-{[(t-butoxycarbonyl)amino]methyl}-4-chlorophenyl)carbamate obtained in Step 2 (1.25 g) in ethanol was added 4N hydrogen chloride-ethyl acetate solution (2 ml) at room temperature, and the mixture was stirred overnight. The resulting crystals were collected by filtration, and recrystallized from ethanol and ethyl acetate to give methyl [2-(aminomethyl)-4-chlorophenyl]carbamate hydrochloride (0.85 g) as a white solid.
Reaction SMILES: [Si:1](Cl)([C:4](C)(C)C)([CH3:3])[CH3:2].[NH2:9][C:10]1[CH:27]=[CH:26][C:13]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH2:22][CH2:23][CH2:24][OH:25])[N:16]=2)=[CH:12][CH:11]=1.C(N(CC)CC)C>ClCCl>[NH2:9][C:10]1[CH:27]=[CH:26][C:13]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH2:22][CH2:23][CH2:24][O:25][Si:1]([CH3:2])([CH3:3])[CH3:4])[N:16]=2)=[CH:12][CH:11]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Nc1ccc(Oc2ccnc(NCCCO)n2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[Si](C)(C)OCCCNc1nccc(Oc2ccc(N)cc2)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 86.4 %

Procedure:
1.99 ml (1.99 mmol) of 1M t-butyl-dimethylsilyl chloride in dichloromethane were added at 0° C. to a solution of 470 mg (1.81 mmol) 3-[4-(4-Amino-phenoxy)-pyrimidin-2-ylamino]-propan-1-ol and 256 mg (2.53 mmol) triethylamine in 5 ml dichloromethane. The reaction mixture was stirred for 12 h at r.t. and extracted with water. The organic phase was dried (sodium sulphate) and evaporated. The obtained material was purified by chromatography on silica (ethyl acetate/n-heptane 1:1) to give 520 mg (77%) oily [4-(4-Amino-phenoxy)-pyrimidin-2-yl]-(3-trimethylsilanyloxy-propyl)-amine.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([NH:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([NH:21][CH:22]3[CH2:27][CH2:26][N:25]([S:30]([CH3:29])(=[O:32])=[O:31])[CH2:24][CH2:23]3)[C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[CH3:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc2c(cc(NC3CCNCC3)c3nnc(C)n32)n1Cc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc2c(cc(NC3CCN(S(C)(=O)=O)CC3)c3nnc(C)n32)n1Cc1ccccc1
Reaction time: 0.42 h

Procedure:
To 6-benzyl-1,7-dimethyl-N-piperidin-4-yl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridin-4-amine (7.0 mg, 0.019 mmol, from Example 206) in DCM (2.4 mL) was added methanesulfonyl chloride (1.6 μL, 0.020 mmol, Aldrich) and triethylamine (5.2 μL, 0.037 mmol). After 25 minutes, the solvent was removed in vacuo, and the product was purified via preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH). Yield: (4.2 mg, 50%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.N1C=CN=C1.[C:16]([Si:20](Cl)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH3:19])([CH3:18])[CH3:17]>CN(C)C=O>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][Si:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:16]([CH3:19])([CH3:17])[CH3:18])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OC(=O)c1ccc(O)cc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
To a solution of 20 g of 4-hydroxybenzoic acid and 10 g of imidazole in 100 ml of dry dimethylformamide at 0° C. was added 40 g of t-butylchlorodiphenylsilane. The mixture was stirred at 0° C. for 30 minutes, then at 20° C. for 18 hours, and then partitioned between diethyl ether and water. The organic layer was washed with water, with 10% aqueous potassium hydrogen carbonate, with water and with brine, and then dried over magnesium sulphate. Evaporation in vacuo of the solvent afforded 47.5 g of the title compound as a crystalline white powder.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH2:8][N:9]([CH3:23])[CH2:10][C:11]3[N:12]([C:13](=O)[NH:14][C:15]=3[C:16]#[C:17][Si](C)(C)C)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH-:24].[K+]>CO>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]#[CH:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN1Cc2c(Cl)cccc2-n2c(c(C#C[Si](C)(C)C)[nH]c2=O)C1
Reactant: [OH-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ncn2c1CN(C)C(=O)c1c(Cl)cccc1-2

Procedure:
12.7 g (37 mmol) of 7-chloro-4,5-dihydro-5-methyl-3-[(trimethylsilyl)ethynyl]-6H-imidazo[1,5-a][1,4]benzodiazepine--one was dissolved in 40 ml of methanol and treated with 40 ml of 1N potassium hydroxide solution. After stirring for 1 hour the methanol was distilled off and the aqueous suspension was cooled and suction filtered. After drying there was obtained 7-chloro-3-ethynyl-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 194°-195°.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.Cl.[CH3:12][NH:13][O:14][CH3:15].C(N(CC)CC)C>ClCCl>[CH3:15][O:14][N:13]([CH3:12])[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[N:3][CH:4]=1
Reactant: CNOC
Reactant: O=C(Cl)c1ccc(Cl)nc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.9 %

Procedure:
To a solution of 6-chloronicotinoyl chloride (10.0 g) and N,O-dimethylhydroxyamine hydrochloride (6.65 g) in dichloromethane (200 ml) was added dropwise triethylamine (17.2 g) at 0° C. Subsequently the mixture was stirred at room temperature overnight. The mixture was washed successively with water, 5% aqueous citric acid solution, water and brine, and then, dried over sodium sulfate. The solvent was evaporated under reduced pressure to give N-methoxy-N-methyl-6-chloronicotinamide (11.73 g) as pale yellow oil. APCI-Mass m/Z 201/203 (M+H).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]([OH:24])[N:8]([C:15]([CH3:23])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16])[C:9]2=[O:14].CN(CCN(C)C)C.C([Li])(CC)C.CCCCCC.[I:44]I>C1COCC1>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:11]([I:44])=[C:10]2[C:6]=1[CH:7]([OH:24])[N:8]([C:15]([CH3:16])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:23])[C:9]2=[O:14]
Reactant: COCOc1cccc2c1C(O)N(C(C)(C)c1ccccc1)C2=O
Reactant: II
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COCOc1ccc(I)c2c1C(O)N(C(C)(C)c1ccccc1)C2=O
Yield: 64.9 %

Procedure:
In a similar manner to Step 3 of Example 16, 4-methoxymethoxy-3-hydroxy-2-(1-methyl-1-phenylethyl)isoindolinone (8.50 mg, 26.0 mmol) was dissolved in THF (340 mL), and the solution was treated with TMEDA (12.5 mL, 83.1 mmol), sec-butyllithium-hexane solution (0.99 mol/L, 8.4.0 mL, 83.1 mmol) and iodine (7.91 g, 31.2 mmol), followed by purification by flash column chromatography (hexane/ethyl acetate=90/10, 70/30) to obtain 4-methoxymethoxy-3-hydroxy-7-iodo-2-(1-methyl-1-phenylethyl)isoindolinone (7.65 g, yield 65%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[O:9])=[CH:6][N:5]=[C:4](S(CC)=O)[N:3]=1.FC(F)(F)C(O)=O.[CH3:29][S:30]([N:33]1[CH2:38][CH2:37][CH:36]([NH2:39])[CH2:35][CH2:34]1)(=[O:32])=[O:31]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)=[O:9])=[CH:6][N:5]=[C:4]([NH:39][CH:36]2[CH2:37][CH2:38][N:33]([S:30]([CH3:29])(=[O:32])=[O:31])[CH2:34][CH2:35]2)[N:3]=1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Reactant: CCS(=O)c1ncc(C(=O)c2ccc(OC)cc2)c(N)n1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C(=O)c2cnc(NC3CCN(S(C)(=O)=O)CC3)nc2N)cc1

Procedure:
The same procedure as described in Example 326 was used, starting with (4-amino-2-ethanesulfinyl-pyrimidin-5-yl)-(4-methoxy-phenyl)-methanone (Example 358) and 1-methanesulfonyl-piperidin-4-ylamine; compound with trifluoroacetic acid (Example 162) to give [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(4-methoxy-phenyl)-methanone. MS (M+H)+, 406
Reaction SMILES: [CH3:1][O:2][P:3]([CH2:7][P:8]([O:12][CH3:13])([O:10][CH3:11])=[O:9])([O:5][CH3:6])=[O:4].Br[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].CC(C)([O-])C.[K+]>C1COCC1>[C:19]([O:18][C:16](=[O:17])[CH2:15][CH:7]([P:3]([O:5][CH3:6])([O:2][CH3:1])=[O:4])[P:8]([O:10][CH3:11])([O:12][CH3:13])=[O:9])([CH3:22])([CH3:21])[CH3:20]
Reactant: COP(=O)(CP(=O)(OC)OC)OC
Reactant: CC(C)(C)OC(=O)CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COP(=O)(OC)C(CC(=O)OC(C)(C)C)P(=O)(OC)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ice cooled solution of bis(dimethoxyphosphoryl)methane (4.64 g, 20 mmol) and tert-butyl bromoacetate (7.35 ml, 50 mmol) in dry THF (40 ml) under nitrogen was added potassium tert-butoxide (5.8 g, 43 mmol). The reaction mixture was stirred at room temperature overnight and then quenched with 4 ml of saturated ammonium chloride. The volatiles were removed in vacuum and by two cycles of toluene addition and evaporation. Flash chromatography in dichloromethane:methanol, 95:5 on gave the product as an oil. Yield 4.0 g.
Reaction SMILES: [CH2:1]([N:3]1[C:8](=[O:9])[C:7]([Br:10])=[C:6](Br)[CH:5]=[N:4]1)[CH3:2].[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH2:17][NH2:18].C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1>[CH2:1]([N:3]1[C:8](=[O:9])[C:7]([Br:10])=[C:6]([NH:18][CH2:17][C:13]2[O:12][CH:16]=[CH:15][CH:14]=2)[CH:5]=[N:4]1)[CH3:2]
Reactant: NCc1ccco1
Reactant: CCn1ncc(Br)c(Br)c1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCn1ncc(NCc2ccco2)c(Br)c1=O
Reaction time: 5 h

Procedure:
A mixture comprising 564 mg of 2-ethyl-4,5-dibromo-3(2H)pyridazinone, 291 mg of 2-furanylmethylamine, 530 mg of sodium carbonate, 15 ml of water and 15 ml of 1,4-dioxane, was refluxed under stirring for 5 hours. The solvent was distilled off under reduced pressure, and water was poured to the residue thus obtained. The mixture was extracted with ethyl acetate. The extract was washed with water and dried over sodium sulfate. Then, the solvent was distilled off. The residue oily substance thus obtained was purified by silica gel column chromatography by using a mixture of benzene/ethyl acetate (volume ratio of 2/1) as developer to obtain 294 mg of the above identified compound as colorless crystals having a melting point of from 120° to 123° C. (as recrystallized from a mixture of ethyl acetate/ethyl ether/n-hexane).
Reaction SMILES: [C:1]1([CH3:29])[C:2]([NH:7][C:8]2[C:9]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([O:20]C)=[O:19])=[CH:13][CH:12]=3)=[CH:3][CH:4]=[CH:5][CH:6]=1.[H-].[Na+].[CH3:32]I>O1CCCC1>[F:28][C:25]1[CH:24]=[CH:23][C:22]([C:9]2[C:8]([N:7]([CH3:32])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[CH3:29])=[N:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:18]([OH:20])=[O:19])[CH:15]=3)[N:10]=2)=[CH:27][CH:26]=1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(Nc3ccccc3C)nc2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccccc1N(C)c1nc2cc(C(=O)O)ccc2nc1-c1ccc(F)cc1
Reaction time: 0.5 h
Yield: 30 %

Procedure:
To a solution of methyl 3-(o-toluidino)-2-(4-fluorophenyl)quinoxaline-6-carboxylate (145 mg, 0.37 mmol) in tetrahydrofuran (30 mL) was added sodium hydride (74.9 mg, 3.12 mmol) at 0° C. with stirring for 30 min, followed by the addition of CH3I (1.5 mL) dropwise. The reaction mixture was stirred overnight at room temperature. The reaction was then quenched with water (50 mL), adjusted to pH 5 with HCl (3N), and extracted with ethyl acetate (3×80 mL). The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated in vacuo to give the residue, which was purified by Prep-HPLC under the following conditions [(Agilent 1200 prep HPLC): Column, SunFire Prep C18, 19*50 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (25% CH3CN up to 67% in 10 min); Detector, UV 220 nm] to afford 2-(4-fluorophenyl)-3-(methyl(o-tolyl)amino)quinoxaline-6-carboxylic acid as a light yellow solid (46.5 mg, 30%).
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:6][OH:7])[CH2:4][OH:5].[CH3:8][C:9]([CH3:11])=O.Cl(O)(=O)(=O)=O.N>>[CH3:8][C:9]1([CH3:11])[O:5][CH2:4][CH:3]([CH2:6][OH:7])[CH2:2][O:1]1
Reactant: OCC(CO)CO
Reactant: CC(C)=O
Agent: N
Agent: [O-][Cl+3]([O-])([O-])O
Product: CC1(C)OCC(CO)CO1
Temperature: 25 °C
Reaction time: 21 h
Yield: 85.8 %

Procedure:
A mixture of 2-(hydroxymethyl)-1,3-propanediol (4.09 g, 38.5 mmol), acetone (130 ml, 1768 mmol) and 70% perchloric acid (1.37 g, 9.55 mmol) was stirred at room temperature for 21 hours. After the pH of the reaction mixture was adjusted with concentrated aqueous ammonia to 9, the reaction mixture was concentrated. The residue was purified by silica gel column chromatography (silica gel: 100 g, elution solvent: heptane, heptane/ethyl acetate=1/3) to obtain the title compound (4.83 g, yield: 85.8%) as a colorless oil.
Reaction SMILES: C(OC([C:6]1[CH:33]=[CH:32][C:9]2[N:10]=[C:11]([C:13]3[CH:14]=[N:15][C:16]([N:19]4[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]4)=[CH:17][CH:18]=3)[S:12][C:8]=2[CH:7]=1)=O)C.[CH3:34][O:35]C1C=CC(B(O)O)=CN=1>>[CH3:34][O:35][C:6]1[CH:33]=[CH:32][C:9]2[N:10]=[C:11]([C:13]3[CH:14]=[N:15][C:16]([N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)=[CH:17][CH:18]=3)[S:12][C:8]=2[CH:7]=1
Reactant: CCOC(=O)c1ccc2nc(-c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)nc3)sc2c1
Reactant: COc1ccc(B(O)O)cn1
Product: COc1ccc2nc(-c3ccc(N4CCNCC4)nc3)sc2c1

Procedure:
The title compound was prepared according to the method used for the preparation of 2-[6-[4-[(1,1-dimethylethoxy)carbonyl]-1-piperazinyl]-3-pyridinyl]-6-benzothiazolecarboxylic acid ethyl ester, from 2-methoxy-5-pyridineboronic acid (0.48 g, 3.14 mmol), and obtained as a solid (0.29 g) after purification by flash column chromatography using 15% ethyl acetate in hexane. 1H NMR δ 8.94 (d, 1 H) 8.81 (s, 1 H) 8.40 (dd, 1 H) 8.00-8.19 (m, 2 H) 7.04 (d, 1 H) 4.37 (q, 2 H) 3.97 (s, 3 H) 1.36 (t, 3 H); MS m/z (M+H) 315.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[Cl:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=1[CH2:16][C:17](Cl)=[O:18]>C(OCC)(=O)C>[Cl:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=1[CH2:16][C:17]([N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[O:18]
Reactant: O=C(Cl)Cc1ccc([N+](=O)[O-])cc1Cl
Reactant: CCNCC
Solvent: CCOC(C)=O
Product: CCN(CC)C(=O)Cc1ccc([N+](=O)[O-])cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5.67 mL (54.0 mmol) of diethylamine is dissolved in 50 mL of ethyl acetate and 3.20 g (13.7 mmol) of (2-chloro-4-nitrophenyl)acetic acid chloride (VI.1.a) in 50 mL of ethyl acetate is slowly added dropwise at 0° C. Then the mixture is stirred for another 2 hours at ambient temperature. After this time, some more ethyl acetate is added and the mixture is washed twice with water and twice with saturated saline solution. The organic phase is dried over sodium sulfate, the solvent is eliminated and the residue is dried in vacuo. Yield: 3.70 g (100% of theory); Rf value: 0.45 (silica gel, petroleum ether/ethyl acetate=1:1); C12H15ClN2O3; EII mass spectrum: m/z=271/273 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[OH:13].C(O[CH:17]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)[CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])C>CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:3](=[O:13])[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10](=[O:12])[C:11]=1[CH:17]([C:25]1[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=1)[CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23]
Reactant: CCOC(CCCCC(=O)O)c1ccc(OC)cc1
Reactant: Cc1cc(O)c2ccccc2c1O
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Product: COc1ccc(C(CCCCC(=O)O)C2=C(C)C(=O)c3ccccc3C2=O)cc1
Temperature: 60 °C
Yield: 44.6 %

Procedure:
D-Camphor-10-sulfonic acid (0.1 g) was added to a toluene solution (50 ml) of 2-methyl-1,4-naphthohydroquinone (3.6 g, 0.02 mole) and 6-ethoxy-6-(4-methoxyphenyl)hexanoic acid (5.6 g, 0.021 mole), and the mixture was heated at 60° C. for 18 hours, with stirring. After cooling, the solvent was distilled off under reduced pressure, and then tetrahydrofuran (20 ml) was added to the residue. A 10% aqueous solution of ferric chloride was added to the solution, followed by stirring for 10 minutes, and the reaction product was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated under reduced pressure. The residue was chromatographed on a silica gel column, and elution was effected with isopropyl ether to give 6-(3-methyl-1,4-naphthoquinon -2-yl)-6-(4-methoxyphenyl)hexanoic acid (3.5 g, 45%). This product was recrystallized from isopropyl ether. Its typical physical properties and nuclear magnetic resonance spectrum data are shown in Table 1. By following the procedure of this Example, the Compound No. 21 was prepared.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:13]=[C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:15]=1[OH:16])[CH:8]=[CH:9][C:10](O)=O)([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:22][O:23][C:24](=[O:29])[C@H:25]([CH2:27][OH:28])[NH2:26].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>ClCCl>[CH3:22][O:23][C:24](=[O:29])[C@H:25]([CH2:27][OH:28])[NH:26][CH2:10][CH:9]=[CH:8][C:7]1[CH:6]=[C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[C:15]([OH:16])=[C:14]([C:17]([CH3:18])([CH3:20])[CH3:19])[CH:13]=1
Reactant: CC(C)(C)c1cc(C=CC(=O)O)cc(C(C)(C)C)c1O
Reactant: COC(=O)[C@@H](N)CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CO)NCC=Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Yield: 35.5 %

Procedure:
First, 20 g of 3,5-di-t-butyl-4-hydroxycinnamic acid, 11.2 g of serine methyl ester hydrochloride, 13.6 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, and 10 ml of triethylamine were added to 300 ml of dichloromethane, and then the mixture was allowed to react for 2 hours at room temperature. After completion of the reaction, this mixture was washed by addition of water, and the dichloromethane was distilled off under reduced pressure. The residue so obtained was separated and purified by column chromatography on silica gel using chloroform as an eluent, thereby obtaining 9.3 g of N-(3,5-di-t-butyl-4-hydroxycinnamyl)serine methyl ester.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:9]2[C:10]([F:24])=[N:11][CH:12]=[C:13](B3OC(C)(C)C(C)(C)O3)[CH:14]=2)[CH:3]=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29](OS(C(F)(F)F)(=O)=O)[CH:30]=[C:31]([O:40][CH3:41])[C:32]=1[CH2:33][N:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>[F-].[K+].C(#N)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:9]2[C:10]([F:24])=[N:11][CH:12]=[C:13]([C:29]3[CH:30]=[C:31]([O:40][CH3:41])[C:32]([CH2:33][N:34]4[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]4)=[C:27]([O:26][CH3:25])[CH:28]=3)[CH:14]=2)[CH:3]=1
Reactant: COc1cc(OS(=O)(=O)C(F)(F)F)cc(OC)c1CN1CCCCC1
Reactant: CC1(C)OB(c2cnc(F)c(-c3cc(Cl)ncc3N)c2)OC1(C)C
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(-c2cnc(F)c(-c3cc(Cl)ncc3N)c2)cc(OC)c1CN1CCCCC1
Temperature: 100 °C
Yield: 100.9 %

Procedure:
A degassed mixture of 6′-chloro-2-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-[3,4′]bipyridinyl-3′-ylamine (630 mg, 1.80 mmol), trifluoromethanesulfonic acid 3,5-dimethoxy-4-piperidin-1-ylmethylphenyl ester (1.06 g, 1.98 mmol), 1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (147 mg, 0.18 mmol) in 1N aqueous potassium fluoride solution (10 mL) and acetonitrile (8 mL) was heated under microwave irradiation at 100° C. for 30 minutes. The cooled reaction mixture was partitioned between DCM (50 mL) and brine (50 mL). The organic phase was separated, dried over sodium sulfate, filtered and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 20 g column, ISCO, 0-10% methanol in DCM) to afford the title compound as a white solid (830 mg, 76%). 1H NMR (CDCl3 plus CD3OD, 300 MHz): 8.52-8.57 (m, 1H), 8.12-8.19 (m, 1H), 7.98 (s, 1H), 7.19 (s, 1H), 6.91 (s, 2H), 4.34 (s, 2H), 4.01 (s, 6H), 2.87-3.64 (ν br m, 4H), 1.63-2.02 (s, 6H).
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15]O)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:19])=O.C(Cl)(Cl)Cl>O>[C:1]([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][Cl:19])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)N1CCC(CO)CC1
Reactant: O=S(Cl)Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(c1ccccc1)N1CCC(CCl)CC1
Yield: 90 %

Procedure:
4-Hydroxymethylpyridine is hydrogenated in methanol at 140° C. under 200 atmospheres of hydrogen pressure in the presence of ruthenium oxide, producing 4-hydroxymethylpiperidine, b.p. 126°-130° C./14 mm Hg; m.p. 55°-56° C. Reaction with benzoyl chloride produces N-benzoyl-4-hydroxymethylpiperidine (m.p. 83°-85° C.). A mixture of 135.0 g of N-benzoyl-4-hydroxymethyl-piperidine, 90 ml of thionyl chloride and 900 ml of chloroform is heated under reflux for 4 hours. Thereafter, the reaction mixture is mixed with water, while cooling with ice, and the organic phase is washed neutral with an aqueous solution of sodium bicarbonate, dried over anhydrous sodium sulfate and evaporated. There are obtained 132.0 g (90% of theory) of N-benzoyl-4-chloromethylpiperidine; m.p. 68°-70° C.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1>>[Cl:32][C:33]1[CH:38]=[C:37]([C:12]2[N:13]([CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]3)[N:14]=[C:15]3[C:11]=2[CH2:10][CH2:9][NH:8][CH2:17][CH2:16]3)[CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(C3CCCCC3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Reactant: OB(O)c1cccc(Cl)c1
Product: Clc1cccc(-c2c3c(nn2C2CCCCC2)CCNCC3)c1
Yield: 10.2 %

Procedure:
The title compound (14.4 mg) was prepared as in Example 177, Steps C and D, using 199.3 mg of 2-cyclohexyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 177, Step B) and 216.2 mg of 3-chlorophenylboronic acid. MS (ESI): exact mass calculated for C19H24ClN3, 329.87; found, m/z 330.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.57-7.54 (m, 2H), 7.35 (s, 1H), 7.28-7.25 (m, 1H), 3.91-3.84 (m, 1H), 3.43-3.38 (m, 2H), 3.19-3.14 (m, 2H), 2.79-2.74 (m, 2H), 1.97-1.80 (m, 6H), 1.71-1.64 (m, 1H), 1.28-1.19 (m, 3H).