Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].I[CH:13]([CH3:15])[CH3:14].C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>CN(C=O)C>[CH:13]([O:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])([CH3:15])[CH3:14]
Reactant: COc1ccc(C=O)c(O)c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(C=O)c(OC(C)C)c1
Temperature: 45 °C
Reaction time: 18 h

Procedure:
To the solution of 2-hydroxy-4-methoxybenzaldehyde 10 (6.6 mmol, 1 equiv.) and 2-iodopropane (7.23 mmol, 1.1 equiv.) in 7 mL of DMF was added K2CO3 (26.3 mmol, 4 equiv.). The reaction was stirred at 45° C. for 18 h. Next day, added DCM 5 mL, filtered off solid, and washed solid with DCM twice. The filtrate was washed by water. And then organic layer was dried over MgSO4, and concentrated. The remaining residues was purified by Biotage SP1:0-20% EtOAc in hexane over 7 CV, 20% EtOAc in hexane over 5 CV.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:12]([CH3:31])=[N:13][C:14]2[N:15]([N:18]=[C:19]([C:21]3[CH:30]=[CH:29][C:28]4[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=4[CH:22]=3)[CH:20]=2)[C:16]=1Cl)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:32][C:33]1([CH3:39])[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.Cl.CCN(C(C)C)C(C)C.[OH-].[Na+]>CN1C(=O)CCC1>[C:1]([O:5][C@@H:6]([C:11]1[C:12]([CH3:31])=[N:13][C:14]2[N:15]([N:18]=[C:19]([C:21]3[CH:30]=[CH:29][C:28]4[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=4[CH:22]=3)[CH:20]=2)[C:16]=1[N:36]1[CH2:37][CH2:38][C:33]([CH3:39])([CH3:32])[CH2:34][CH2:35]1)[C:7]([OH:9])=[O:8])([CH3:3])([CH3:2])[CH3:4]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(-c3ccc4c(c3)CCCC4)nn2c1Cl
Reactant: CC1(C)CCNCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1nc2cc(-c3ccc4c(c3)CCCC4)nn2c(N2CCC(C)(C)CC2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 50 °C
Yield: 29.6 %

Procedure:
To a solution of (S)-methyl 2-(tert-butoxy)-2-(7-chloro-5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)pyrazolo[1,5-a]pyrimidin-6-yl)acetate (40 mg, 0.091 mmol) and 4,4-dimethylpiperidine.HCl (13.55 mg, 0.091 mmol) in NMP (1 mL) was added DIEA (0.047 mL, 0.272 mmol) and the mixture was heated at 50° C. for 2 h. Then, 1N NaOH (0.272 mL, 0.272 mmol) was added to the reaction mixture and the contents were heated at 50° C. for 2 h. The reaction mixture was then filtered and purified by prep-HPLC to afford (S)-2-(tert-butoxy)-2-(7-(4,4-dimethylpiperidin-1-yl)-5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)pyrazolo[1,5-a]pyrimidin-6-yl)acetic acid (13.5 mg, 0.027 mmol, 29.6% yield) as white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.77-7.71 (m, 2H), 7.19 (s, 1H), 6.95 (s, 1H), 5.80 (s, 1H), 2.91 (s, 2H), 2.84-2.76 (m, 4H), 1.83-1.75 (m, 4H), 1.65-1.58 (m, 2H), 1.56-1.45 (m, 2H), 1.20 (s, 9H), 1.11 (s., 6H). LCMS (M+H)=506.5.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1>C(O)C>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:21][C:18]3[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=3)=[N:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: Clc1ccc2c(Cl)ncnc2c1
Reactant: COc1ccc(N)cc1
Solvent: CCO
Product: COc1ccc(Nc2ncnc3cc(Cl)ccc23)cc1
Yield: 58 %

Procedure:
5 ml of ethanol were added to a mixture of 4.8 g of 4,7-dichloroquinazoline and 3.0 g of p-anisidine. The resulting mixture was heated, whereupon the solids dissolved and then the mixture immediately solidified. After cooling, the solidified compound was collected and washed with, in turn, ethanol, dilute aqueous sodium hydroxide and water. The resulting crystals were recrystallized from ethanol to give 4.0 g (yield 51%) of the desired Compound No. 9 in the form of pale yellow plates melting at 177°-179° C.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[N:26]=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)[CH:24]=[C:23]([C:34]([F:37])([F:36])[F:35])[N:22]=3)[CH:16]=2)[CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:33][C:30]1[CH:31]=[CH:32][C:27]([C:25]2[CH:24]=[C:23]([C:34]([F:36])([F:35])[F:37])[N:22]=[C:21]([C:17]3[CH:16]=[C:15]([C:11]4[CH:12]=[CH:13][CH:14]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:10]=4)[CH:20]=[CH:19][CH:18]=3)[N:26]=2)=[CH:28][CH:29]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2cccc(-c3nc(-c4ccc(F)cc4)cc(C(F)(F)F)n3)c2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1cccc(-c2cccc(-c3nc(-c4ccc(F)cc4)cc(C(F)(F)F)n3)c2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 84.5 %

Procedure:
To a cooled and stirred solution of 3′-[4-(4-fluoro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-biphenyl-3-sulfonic acid tert-butylamide (0.49 g) in dichloromethane (6 ml) was added TFA (6 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into 2N NaHCO3 solution (20 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification by crystallization (ethyl acetate/heptane) yielded the title compound as a white solid (0.37 g, 78%). MS (ISP) 474.0 [(M+H)+]; mp 208° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][CH2:24][CH3:25])=[O:22])=[CH:16][CH:15]=2)[CH:3]=1.[CH3:26][S:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1B(O)O)(=[O:29])=[O:28]>>[CH2:24]([NH:23][C:21]([NH:20][C:17]1[CH:18]=[CH:19][C:14]([C:4]2[CH:3]=[C:2]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[S:27]([CH3:26])(=[O:29])=[O:28])[N:7]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:5]=2)=[CH:15][CH:16]=1)=[O:22])[CH3:25]
Reactant: CS(=O)(=O)c1ccccc1B(O)O
Reactant: CCNC(=O)Nc1ccc(-c2cc(Cl)nc(N3CCOCC3)n2)cc1
Product: CCNC(=O)Nc1ccc(-c2cc(-c3ccccc3S(C)(=O)=O)nc(N3CCOCC3)n2)cc1
Yield: 10 %

Procedure:
Method as described for Example 8 using 1-(4-(6-chloro-2-morpholinopyrimidin-4-yl)phenyl)-3-ethylurea and (2-methylsulfonylphenyl)boronic acid. The reaction mixture was concentrated in vacuo, and the residue dissolved in DMSO, filtered and purified by prep HPLC (low pH) to afford a white solid (13.2 mg, 10%).
Reaction SMILES: S(=O)(=O)(O)N.[CH2:6]([O:13][C:14]1[CH:28]=[CH:27][C:17]([O:18][C:19]2[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=2)=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl([O-])=[O:30].[Na+]>O.CC(C)=O>[CH2:6]([O:13][C:14]1[CH:28]=[CH:27][C:17]([O:18][C:19]2[CH:20]=[CH:21][C:22]([C:23]([OH:30])=[O:24])=[CH:25][CH:26]=2)=[CH:16][CH:15]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=Cc1ccc(Oc2ccc(OCc3ccccc3)cc2)cc1
Reactant: [O-][Cl+][O-]
Agent: NS(=O)(=O)O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)c1ccc(Oc2ccc(OCc3ccccc3)cc2)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 85.4 %

Procedure:
Sulphamic acid (0.526 g, 5.43 mmol) in 2 mL water was added at 0° C. to 4-(4-benzyloxy-phenoxy)-benzaldehyde (0.55 g, 1.81 mmol) in acetone (8 mL). After 5 minutes, sodium chlorite (0.654 g, 7.24 mmol) was added and the mixture was stirred at 0° C. for three hours. Water was added and the resulting solid was isolated by filtration to afford 495 mg (85% yield) of 4-(4-benzyloxy-phenoxy)-benzoic acid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[N:10]=2)[CH:3]=1.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCCCO.CO>[NH2:15][C:11]1[N:10]=[C:9]([NH:8][C:4]2[CH:3]=[C:2]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:7]=[CH:6][N:5]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ccccc1
Reactant: Nc1cccc(Nc2cc(Cl)ncn2)n1
Solvent: CCCCO
Solvent: CO
Product: Nc1cccc(Nc2cc(Nc3ccccc3)ncn2)n1
Yield: 84.9 %

Procedure:
Step-1 A solution of N2-(6-chloropyrimidin-4-yl)pyridine-2,6-diamine (1) (0.25 g, 1.1 mmol) and aniline (2) (0.16 g, 1.7 mmol) in n-BuOH (25 mL) was heated at 120° C. for 12 h in a pressure tube. The reaction mixture was cooled, was dissolved in methanol (10 mL) and was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (35 mL) and was washed successively with 10% sodium bicarbonate solution (20 mL), water (20 mL), and saturated brine (20 mL). The ethyl acetate extract was dried over Na2SO4 and was concentrated under reduced pressure to give a residue, which was triturated with diethyl ether to give (260 mg, 83%) N4-(6-aminopyridin-2-yl)-N6-phenylpyrimidine-4,6-diamine (3) as an off-white solid. Step-2 To a stirred solution of 3 (0.2 g, 0.7 mmol) in NMP (10 mL) was added acryloyl chloride (0.097 g, 1 mmol), drop wise at 0° C. The reaction mixture was allowed to stir at the same temperature for 20 min and then warmed to rt for 1.5 h. It was quenched with 10% sodium bicarbonate solution (4 mL) and was extracted with ethyl acetate (2×35 mL). The combined ethyl acetate layer was washed with water (20 mL), saturated brine (20 mL), was dried over Na2SO4 and was concentrated under reduced pressure. The residue was further purified by column chromatography (SiO2, 60-120, Petroleum ether/EtOAc: 90/10) to give N-6-(6-(phenylamino)pyrimidin-4-ylamino)pyridine-2-yl)acrylamide (I-72) as a brown solid. 1H NMR (DMSO-d6) δ ppm: 5.80 (dd, J=1.84 & 10.12 Hz, 1H), 6.31 (dd, J=1.8 & 16.96 Hz, 1H), 6.64 (dd, J=10.08 & 16.88 Hz, 1H), 6.96 (t, J=7.32 Hz, 1H), 7.15-7.20 (m, 1H), 7.28 (t, J=7.52 Hz, 2H), 7.34 (s, 1H), 7.60-7.70 (m, 4H), 8.30 (s, 1H), 9.08 (s, 1H), 9.66 (s, 1H), 10.06 (s, 1H); LCMS: m/e 332.6 (M+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[C:12](=NO)[CH:11]=[CH:10][C:9]2=[O:16])([O-:3])=[O:2].Cl.[OH2:18]>O.O.O.O.[Fe](Cl)Cl>[N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[C:12](=[O:18])[CH:11]=[CH:10][C:9]2=[O:16])([O-:3])=[O:2]
Reactant: O=C1C=CC(=NO)c2c1cccc2[N+](=O)[O-]
Reactant: O
Agent: Cl[Fe]Cl
Agent: Cl
Product: O=C1C=CC(=O)c2c1cccc2[N+](=O)[O-]
Temperature: 40 °C

Procedure:
42 g (0.21 mol) of iron (II) chloride tetrahydrate and 11 g (0.05 mol) of 8-nitro-1,4-naphthoquinone-1-oxime are introduced into 120 ml quantities of the solvents indicated in Table I below. While gaseous hydrogen chloride is slowly passed through them, the mixtures are left to react with continuous stirring at the temperatures indicated in Table I below until the respective reactions are complete. The increases in weight indicated in Table I below are obtained. After the reaction times specified in Table I, the mixtures are poured onto 500 ml of water heated to approximately 40°C, followed by stirring for 30 minutes. The 5-nitro-1,4-naphthoquinone formed is filtered off under suction, washed off under suction, washed with water until neutral and dried at 50°C. The yields of 5-nitro-1,4-naphthoquinone specified in Table I below in g and percent of the theoretical yield are obtained.
Reaction SMILES: C(O)(C(F)(F)F)=O.[N:8]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[CH:12]=[CH:11][CH:10]=[CH:9]1.[F:20][C:21]([F:34])([F:33])[C:22]([N:24]1[C@H:29]2[CH2:30][CH2:31][C@@H:25]1[CH2:26][C:27](=O)[CH2:28]2)=[O:23]>ClC(Cl)C>[F:34][C:21]([F:20])([F:33])[C:22]([N:24]1[CH:29]2[CH2:30][CH2:31][CH:25]1[CH2:26][C:27]1([O:19][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[N:8]3[CH:9]=[CH:10][CH:11]=[C:12]13)[CH2:28]2)=[O:23]
Reactant: O=C1C[C@H]2CC[C@@H](C1)N2C(=O)C(F)(F)F
Reactant: Oc1ccccc1-n1cccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(Cl)Cl
Product: O=C(N1C2CCC1CC1(C2)Oc2ccccc2-n2cccc21)C(F)(F)F
Temperature: 70 °C
Yield: 51.4 %

Procedure:
A solution of TFA (387 μL, 5.02 mmol) in dichloroethane (18 mL) was added to 2-pyrrol-1-ylphenol (401 mg, 2.52 mmol) and (1R,5S)-8-(2,2,2-trifluoroacetyl)-8-azabicyclo[3.2.1]octan-3-one (620 mg, 2.80 mmol). The solution was heated at 70° C. overnight. The solvent was evaporated and the crude residue was purified by column chromatography (silica gel: 0-10% EtOAc in hexanes) to afford 2,2,2-trifluoro-1-(8′-azaspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,3′-bicyclo[3.2.1]octane]-8′-yl)ethanone as a clear oil (469 mg, 46%). 1H NMR (400 MHz, CDCl3) δ 7.27 (d, J=7.5 Hz, 1H), 7.07-6.94 (m, 4H), 6.23 (t, J=3.2 Hz, 1H), 5.87 (d, J=3.4 Hz, 1H), 4.74 (d, J=7.4 Hz, 1H), 4.42 (s, 1H), 2.50-2.34 (m, 2H), 2.34-2.16 (m, 3H), 2.16-1.89 (m, 3H). ESI-MS m/z calc. 362.4. found 363.3 (M+1)+; Retention time: 2.07 minutes (3 min run).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].[F:13][C:14]1[CH:19]=[CH:18][C:17]([Mg]Br)=[CH:16][CH:15]=1>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([C:17]1[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=1)[OH:12]
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Reactant: Fc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1Nc2ccc(Br)cc2C1(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a solution of 5-bromoindoline-2,3-dione (120 g, 530 mmol, 1.0 eq) in THF (1 L) was added dropwise (4-fluorophenyl)magnesium bromide in THF (0.8 M, 1.6 L, 1280 mmol, 2.4 eq) at 0° C.˜15° C., the mixture was stirred for overnight at room temperature. Then mixture was cooled to 0° C., quenched with H2O (20 mL), concentrated to give crude product, which was dissolved in EtOAc (2 L), washed with 1N HCl.aq (2 L), brine (1 L×2), dried over Na2SO4, the organic phase was concentrated to give crude product. Then the crude product was stirred in PE, filtered to obtained yellow solid, and dried in air to give 136 g (yield 80%) product, which was used to the next step without further purification. 1H NMR (400 MHz, DMSO-d6): δH 10.58 (s, 1H), 7.44-7.46 (dd, 1H, J1=8.4 Hz, 2.0 Hz), 7.28-7.32 (m, 2H), 7.22-7.25 (m, 1H), 7.14-7.18 (t, 2H, J=8.8 Hz), 6.87-6.89 (d, 1H, J=8.4 Hz), 6.84 (s, 1H). MS (ESI) [M+1-18]+ 304, 306.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:21][OH:22])[CH2:10][O:11][C:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:21][O:22][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[CH2:10][O:11][C:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC(CO)COc1noc2ccccc12
Reactant: Oc1cccnc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(COc1cccnc1)COc1noc2ccccc12
Yield: 51.3 %

Procedure:
To a solution of 0.5 g of 3-(2-tert-butoxycarbonylamino-3-hydroxypropoxy)-1,2-benzoisoxazole in 5 ml of tetrahydrofuran are added 0.154 g of 3-hydroxypyridine, 0.553 g of triphenylphosphine and 0.33 ml of diethyl azodicarboxylate at room temperature with ice-cooling, and they are subjected to reaction at room temperature for eight hours. The solvent is removed from the reaction mixture by distillation under reduced pressure, and the residue obtained is purified by a silica gel column chromatography [eluant:n-hexane:ethyl acetate=4:1], to obtain 0.32 g of oily 3-[2-tert-butoxycarbonylamino-3-(3-pyridyloxy)propoxy]-1,2-benzoisoxazole.
Reaction SMILES: O.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)[CH2:5][CH2:4]1.[Cl:20][C:21]1[CH:22]=[C:23]([N:28]=[C:29]=[S:30])[CH:24]=[CH:25][C:26]=1[Cl:27]>>[Cl:20][C:21]1[CH:22]=[C:23]([NH:28][C:29]([NH:2][CH:3]2[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][CH:12]=3)[CH2:5][CH2:4]2)=[S:30])[CH:24]=[CH:25][C:26]=1[Cl:27]
Reactant: NC1CCN(CCc2c[nH]c3ccccc23)CC1
Reactant: S=C=Nc1ccc(Cl)c(Cl)c1
Solvent: O
Product: S=C(Nc1ccc(Cl)c(Cl)c1)NC1CCN(CCc2c[nH]c3ccccc23)CC1

Procedure:
4-Amino-1-[2-(3-indolyl)ethyl]piperidine hydrate is treated with 3,4-dichlorophenyl isothiocyanate in the manner described in Example 10 to obtain the title compound as the hydrochloride.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[Br:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][N:17]=[C:16]2[CH:22]=[O:23].[O:24]1[CH:29]=[CH:28][CH2:27][CH2:26][CH2:25]1>C1COCC1.C(Cl)Cl>[Br:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]([CH:25]1[CH2:26][CH2:27][CH2:28][CH2:29][O:24]1)[N:17]=[C:16]2[CH:22]=[O:23]
Reactant: O=Cc1n[nH]c2ccc(Br)cc12
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=Cc1nn(C2CCCCO2)c2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 80 %

Procedure:
p-Toluenesulfonic acid (10 mg, 0.052 mmol) was added to a solution of 5-bromo-indazole-3-carbaldehyde (100 mg, 0.444 mmol) and 3,4-dihydro-2H-pyran (75 mg, 0.891 mmol) in a mixture of THF/CH2Cl2 (1:1, 6 mL). The reaction mixture was stirred for 12 h at room temperature after which the solvent was removed in vacuo. The residue was dissolved in CH2Cl2 (20 mL) and poured in water (20 mL). The organic layer was separated, and the aqueous layer was extracted with CH2Cl2 (20 mL). The combined organic layers were washed with water (40 mL) and brine (40 mL), dried over Na2SO4 and concentrated. Purification by flash chromatography (CH2Cl2) afforded 110 mg, (80% yield) of the title compound as a solid. 1H NMR (400 MHz, CDCl3): δ 10.21 (s, 1H), 8.47 (s, 1H), 7.56 (m, 2H), 5.80 (dd, 1H, J=3.2 and 9.2 Hz), 3.98 (m, 1H), 3.79-3.74 (m, 1H), 2.57-2.49 (m, 1H), 2.20-2.12 (m, 2H), 1.83-1.57 (m, 3H).
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C@@H:6]1[CH2:11][CH2:10][CH2:9][C@H:8]([C:12]([OH:14])=[O:13])[CH2:7]1.[CH3:15]O>>[NH2:5][C@@H:6]1[CH2:11][CH2:10][CH2:9][C@H:8]([C:12]([O:14][CH3:15])=[O:13])[CH2:7]1
Reactant: N[C@@H]1CCC[C@H](C(=O)O)C1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@H]1CCC[C@@H](N)C1
Yield: 90.9 %

Procedure:
Thionyl chloride (0.6 ml) was added to solution of cis-3-amino-cyclohexanecarboxlic acid (bought from AMRI, USA, cat.-no.: A00342, 0.50 g, 2.80 mmol) in MeOH (20 ml) at 0° C. and stirred at reflux for 12 h. The volatiles were evaporated in vacuo and the resulting residue was partitioned between saturated sodium bicarbonate solution and ethyl acetate. The separated organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuo to afford 400 mg (90.9%) of cis-methyl 3-aminocyclohexanecarboxylate as colorless liquid.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([CH:10]2[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].C(C1C=C(C)C=C(C(C)(C)C)N=1)(C)(C)C.[F:32][C:33]([F:45])([F:44])[C:34](OS(C(F)(F)F)(=O)=O)=[O:35]>C(Cl)(Cl)(Cl)Cl>[CH2:1]([CH:4]1[CH2:5][CH2:6][CH:7]([CH:10]2[CH2:15][CH2:14][C:13]([O:16][C:34](=[O:35])[C:33]([F:45])([F:44])[F:32])=[CH:12][CH2:11]2)[CH2:8][CH2:9]1)[CH2:2][CH3:3]
Reactant: O=C(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCCC1CCC(C2CCC(=O)CC2)CC1
Agent: Cc1cc(C(C)(C)C)nc(C(C)(C)C)c1
Solvent: ClC(Cl)(Cl)Cl
Product: CCCC1CCC(C2CC=C(OC(=O)C(F)(F)F)CC2)CC1
Temperature: 25 °C
Yield: 22.8 %

Procedure:
To 50 ml of carbon tetrachloride were added 3.9 g (18 mmol) of 4-(4-propylcyclohexyl)cyclohexanone and 3.8 g (19 mmol) of 2,6-di-t-butyl-4-methylpyridine, and the mixture was stirred at room temperature. To this mixture was added dropwise 2 ml of solution of 4.5 g (18 mmol) of trifluoroacetyltriflate in carbon tetrachloride. Subsequently, 25 ml of carbon tetrachloride was added thereto and the mixture was stirred at room temperature for 1 hour. The reaction solution was filtered off and then the filtrate was concentrated under a reduced pressure. After the residue was purified by column chromatography on silica gel (eluent: heptane/toluene=3/1), the solvent was distilled off, and the residue was subjected twice to recrystallization by using heptane to give 1.3 g (4.1 mmol) of trifluoroacetic acid 4-(4-propylcyclohexyl)-1-cyclohexenyl ester. Yield of this compound based on 4-(4-propylcyclohexyl)cyclohexanone was 23%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[OH:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]2[N:40]=[C:39]3[CH2:41][O:42][C:43](=O)[C:38]3=[CH:37][CH:36]=2)[CH2:30][CH2:29]1.Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:43]1[C:38]2[C:39](=[N:40][C:35]([CH2:34][N:31]3[CH2:32][CH2:33][N:28]([CH2:27][CH2:26][O:25][CH2:24][CH2:23][OH:22])[CH2:29][CH2:30]3)=[CH:36][CH:37]=2)[CH2:41][O:42]1
Reactant: O=C1OCc2nc(CN3CCN(CCOCCO)CC3)ccc21
Reactant: O=C1Cc2cc(F)ccc2N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1Nc2ccc(F)cc2C1=C1OCc2nc(CN3CCN(CCOCCO)CC3)ccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 20.2 %

Procedure:
A solution of 5-fluoro-1,3-dihydro-indol-2-one (72 mg, 0.47 mmol) in THF (2 mL) is treated with a solution of lithium bis(trimethylsilyl)amide (1.2 mL of a 1M solution in THF, 1.2 mmol) dropwise. The resulting solution is stirred for 10 min at room temperature. A solution 2-{4-[2-(2-hydroxy-ethoxy)-ethyl]-piperazin-1-ylmethyl}-7H-furo[3,4-b]pyridin-5-one (77 mg, 0.24 mmol) in THF (1.5 mL) and added dropwise to the reaction mixture. The resulting solution is stirred for 4 h and is then treated with HCl (4M in dioxane, 5 mL) at 0° C. The reaction mixture is stirred at room temperature for 48 h. The reaction mixture is concentrated and the residue is treated with saturated aqueous NaHCO3. The aqueous solution is extracted with EtOAc (2×). The combined organic extracts are dried (MgSO4) and concentrated. The residue is purified by chromatography (silica gel, gradient elution 20:1 chloroform:MeOH to 10:1 chloroform:MeOH). The product containing fractions are concentrated and the residue is triturated from EtOAc-hexane and collected by filtration to give the title compound as a yellow solid (22 mg, 20%),
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].Br.CS(C)=[O:17]>O>[O:17]=[CH:2][C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)=[O:3]
Reactant: CS(C)=O
Reactant: COC(=O)c1ccc(C(C)=O)cc1
Agent: Br
Solvent: O
Product: COC(=O)c1ccc(C(=O)C=O)cc1

Procedure:
To a solution of methyl 4-acetylbenzoate (1.00 g, 5.61 mmol) in DMSO (5 mL) was slowly added 40% HBr (1.5 mL) at 20° C. under stirring. The mixture was stirred at 60° C. for 12 hours. The mixture was diluted with water (10 mL) and the resulting mixture was extracted with DCM (10 mL×3), washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give methyl 4-(2-oxoacetyl)benzoate (150 mg), which was taken forward without further purification. To a solution of 4-methoxybenzene-1,2-diamine (107 mg, 0.78 mmol) in 5 mL of acetic acid was added the crude methyl 4-(2-oxoacetyl)benzoate (150 mg). The mixture was refluxed for 2.5 hours. The solvent was removed in vacuo. The crude product was purified by prep-TLC (PE/EA: 1/1) to separate the desired methyl 4-(6-methoxyquinoxalin-2-yl)benzoate (more polar) from the undesired methyl 4-(7-methoxyquinoxalin-2-yl)benzoate. The two structures were confirmed by HMBC spectra.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C([O:11][C:12](=O)[CH2:13][C:14](=O)[CH2:15][Cl:16])C.S(=O)(=O)(O)O>O>[Cl:16][CH2:15][C:14]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([CH3:1])[CH:7]=2)[O:8][C:12](=[O:11])[CH:13]=1
Reactant: Cc1ccc(O)cc1
Reactant: CCOC(=O)CC(=O)CCl
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1ccc2oc(=O)cc(CCl)c2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86 %

Procedure:
To a mixture of 4-methylphenol (21.6 g, 200 mmol) and 4-chloro-3-oxo-butyric acid ethyl ester (32.9 g, 200 mmol) is added dropwise during 30 min. at 0° C. a mixture of concentrated sulfuric acid (180 mL) and water (60 mL). The resulting clear solution is stirred for 18 h at room temperature, during which time a white precipitate is formed. The reaction mixture is poured over crushed ice (1 kg) and the formed precipitate is collected, washed with water and dried in vacuo at 50° C. to yield the title compound as a white powder (35.8 g, 172 mmol, 86%). 1H NMR (400 MHz, CDCl3, 298 K): δ=7.45 (s, 1H), 7.40 (d, J=8.6 Hz, 1H), 7.29 (d, J=8.6 Hz, 1H), 6.58 (s, 1H), 4.69 (s, 1H), 2.46 (s, 3H).