Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]1[CH2:15][CH2:14][CH:13]([CH:16]=[CH:17][C:18](=[O:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[O:12]1.[BH4-].[Na+]>CO>[CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]1[CH2:15][CH2:14][CH:13]([CH:16]=[CH:17][CH:18]([OH:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[O:12]1
Reactant: CCCCCC(=O)C=CC1CCC(CCCCCCCC(=O)OC)O1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCCCC(O)C=CC1CCC(CCCCCCCC(=O)OC)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
III (3.17 g, 0.00900 mole) was dissolved in methanol (75 ml) and sodium tetrahydroborate (1.7 g, 0.045 mole) was added at 0° C with stirring. The stirring was continued for 1 hour. During this time the temperature was slowly raised to room temperature. The colourless solution was poured into ice-water (250 ml) and extracted with ether (100 + 50 + 50 ml). The combined ethereal extracts were washed with water (50 + 25 + 25 ml), dried over magnesium sulfate, and evaporated from a water bath (50° C, 10 mm Hg). The obtained light yellowish oil (3.38 g) was distilled under reduced pressure to give 2.90 g (91%) of IV as a colourless oil, b0.05 175°-188° C, nD25 1.4699.
Reaction SMILES: [CH2:1]([N:8]1[CH2:31][CH:30]([C:32]2[NH:33][CH:34]=[CH:35][N:36]=2)[O:29][C:10]2([CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH3:28])[CH:19]=3)=[O:17])[CH2:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:37]N(C=O)C.[H-].[Na+].CI>C1COCC1>[CH2:1]([N:8]1[CH2:31][CH:30]([C:32]2[N:36]([CH3:37])[CH:35]=[CH:34][N:33]=2)[O:29][C:10]2([CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:26])[CH3:27])=[C:20]([CH3:28])[CH:19]=3)=[O:17])[CH2:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(C(=O)N2CCC3(CC2)CN(Cc2ccccc2)CC(c2ncc[nH]2)O3)ccc1OC(C)C
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: Cc1cc(C(=O)N2CCC3(CC2)CN(Cc2ccccc2)CC(c2nccn2C)O3)ccc1OC(C)C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
[8-Benzyl-10-(1H-imidazol-2-yl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone (233 mg, 0.48 mmol) was suspended in a mixture of anhydrous DMF (1.5 mL)/THF (0.1 mL) under an atmosphere of nitrogen at 0° C. NaH (19 mg, 0.48 mmol) was added and the reaction mixture was stirred for 30 minutes, then MeI (68 mg, 30 μL, 0.48 mmol) was added and the reaction mixture was stirred for 10 minutes. The reaction mixture was quenched with water and diluted with EtOAc, the layers were separated and the aqueous layer was extracted once more with EtOAc. The combined organics were washed with brine solution (2×5 mL), dried over Na2SO4, filtered and concentrated in vacuo to an oil. The residue was purified by silica gel column chromatography using 0-5% MeOH in DCM to yield [8-benzyl-10-(1-methylimidazol-2-yl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone (205 mg, 86%) as a white foam. ESI-MS m/z calc. 502.3. Found 503.1 (M+1)+; Retention time: 1.51 minutes (3 min run); 1H NMR (400 MHz, DMSO) δ 7.38-7.30 (m, 4H), 7.25 (ddd, J=8.4, 5.9, 2.2 Hz, 1H), 7.19 (d, J=7.0 Hz, 2H), 7.10 (d, J=1.1 Hz, 1H), 6.96 (t, J=5.9 Hz, 1H), 6.75 (d, J=1.1 Hz, 1H), 4.96 (ddd, J=9.9, 6.7, 2.4 Hz, 1H), 4.68-4.59 (m, 1H), 3.70 (s, 3H), 3.53 (td, J=13.6, 9.0 Hz, 3H), 3.30-3.15 (m, 2H), 2.93 (dd, J=11.1, 0.7 Hz, 1H), 2.74-2.69 (m, 1H), 2.66-2.52 (m, 2H), 2.13 (s, 3H), 1.95-1.86 (m, 1H), 1.61-1.33 (m, 4H), 1.28 (d, J=6.9 Hz, 6H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:20])[CH:11]=1.C(=O)([O-])O.[Na+]>C(OC(C)(C)C)(=O)C.N(C(C)(C)C#N)=NC(C)(C)C#N>[Cl:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH2:20][Br:1])[CH:11]=1
Reactant: COC(=O)c1ccc(Cl)cc1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)(C)C
Product: COC(=O)c1ccc(Cl)cc1CBr
Temperature: 25 °C
Yield: 83.9 %

Procedure:
(Step 2) A solution of N-bromosuccinimide (6.33 g), 2,2′-azobis(isobutyronitrile) (0.27 g) and methyl 4-chloro-2-methylbenzoate obtained in Step 1 (5.05 g) in t-butyl acetate (80 ml) was stirred overnight at 90° C. The mixture was allowed to cool to room temperature, poured into aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate:hexane=0:1-3:17) to give methyl 4-chloro-2-bromomethylbenzoate (6.05 g) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:11]([NH:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Li+]>CO>[CH3:1][C:2]1[C:11]([NH:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CNc1cccc(C(=O)OC)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CNc1cccc(C(=O)O)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 43.4 %

Procedure:
To methyl 2-methyl-3-(methylamino)benzoate (125 mg, 0.698 mmol) in methanol (7 ml) was added 2M aqueous lithium hydroxide (1.8 ml, 3.63 mmol), and the solution was stirred at 25° C. for 3 h, at which point the volume was reduced by rotary evaporation. The aqueous mixture was diluted with water (3 ml) and the pH adjusted to 5 with 1 N hydrochloric acid. The resultant precipitate was collected by filtration and dried in vacuo to afford (50 mg, 42%) of 2-methyl-3-(methylamino)benzoic acid. MS (EI) for C9H11NO2: 166 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][CH:6]1[CH2:9][N:8]([C:10](Cl)=[O:11])[CH2:7]1.C(=O)([O-])[O-].[K+].[K+].[CH2:22]([NH2:25])[C:23]#[CH:24].O>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][CH:6]1[CH2:9][N:8]([C:10]([NH:25][CH2:22][C:23]#[CH:24])=[O:11])[CH2:7]1
Reactant: O=C(Cl)N1CC(Oc2cccc(Br)c2)C1
Reactant: C#CCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C#CCNC(=O)N1CC(Oc2cccc(Br)c2)C1
Reaction time: 42 h
Yield: 64.7 %

Procedure:
A stirred mixture of 5.8 g (0.02 mole) of 3-(3-bromophenoxy)-1-azetidinecarbonyl chloride and 2.8 g (0.02 mole) of potassium carbonate in 20 ml of tetrahydrofuran was treated with 1.1 g (0.02 mole) of 2-propynylamine added dropwise from a needle and syringe. A piece of ice was added and stirring was continued for 42 hr. The solid residue which remained was stirred with 100 ml of water then filtered, yielding 5.3 g of crude product. Recrystallization from ethanol yielded 4.0 g of fine beige crystals, m.p. 145°-147° C. After drying at 100° C. in vacuo, m.p. was 146°-147° C. (64.7%).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1)[CH2:7][OH:8])=[O:4].[H-].[Na+]>C1COCC1>[F:15][C:11]1[CH:10]=[C:9]([CH:6]2[NH:5][C:3](=[O:4])[CH2:2][O:8][CH2:7]2)[CH:14]=[CH:13][CH:12]=1
Reactant: O=C(CCl)NC(CO)c1cccc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1COCC(c2cccc(F)c2)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In step 2-3, a solution of 2-chloro-N-(1-(3-fluorophenyl)-2-hydroxyethyl)acetamide (5.5 g, 24 mmol) in THF (150 mL) was slowly added to a suspension of NaH (1.05 g, 26 mmol) in THF (600 mL) at 0° C. The heterogeneous solution was warmed to room temperature and stirred overnight. The reaction mixtures was quenched, concentrated and ethyl acetate was added to the residue. This solution was washed with water and brine and the organic phase was dried over MgSO4, filtered and concentrated to yield 5-(3-fluorophenyl)morpholin-3-one (2-3).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][O:13][CH3:14])=[C:6]([N+:15]([O-])=O)[CH:5]=1>CO.CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][O:13][CH3:14])=[C:6]([NH2:15])[CH:5]=1
Reactant: COCCNc1ccc(C(=O)OC)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COCCNc1ccc(C(=O)OC)cc1N
Yield: 94.5 %

Procedure:
3-Amino-4-(2-methoxy-ethylamino)-benzoic acid methyl ester (800.0 mg) was prepared by following General Procedure B starting from 4-(2-methoxy-ethylamino)-3-nitro-benzoic acid methyl ester (960.0 mg) and Pd/C (20% by weight, 190.0 mg) in MeOH:EtOAc (1:1, 10.0 mL). The crude product was used in the next step without further purification.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=O.P(Cl)(Cl)([Cl:13])=O>>[Cl:13][C:2]1[NH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c2ccccc2[nH]1
Product: Clc1nc2ccccc2[nH]1

Procedure:
Benzimidazolin-2-one (13.0 g) was added to phosphoryl chloride and the mixture was heated under reflux for a period of 3.5 hours. The excess phosphoryl chloride was removed by distillation and the residue was treated with water. The acidic solution was cooled, filtered and made basic by the addition of dilute ammonium hydroxide. The solid was collected and recrystallised from aqueous ethanol to give 2-chlorobenzimidazole (11.5 g) as colourless needles, mp 214° C.
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6](/[CH:10]=[C:11]2\[C:12](C)=[C:13]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=3)[CH:14]([CH2:17][N:18]([CH3:20])[CH3:19])[CH2:15][CH2:16]\2)[CH:5]=1.[OH-].[K+].Cl>CO>[CH3:19][N:18]([CH2:17][CH:14]1[CH2:15][CH2:16]/[C:11](=[CH:10]/[C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:30])=[O:2])/[CH:12]=[C:13]1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=1)[CH3:20]
Reactant: COC(=O)c1cccc(/C=C2/CCC(CN(C)C)C(c3cccc(OC)c3)=C2C)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1cccc(C2=C/C(=C\c3cccc(C(=O)O)c3)CCC2CN(C)C)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 96.7 %

Procedure:
3 g of the Z-3-[4-dimethylaminomethyl-3-(3-methoxy-phenyl)-2-methyl-cyclohex-2-enylidenemethyl]-benzoic acid methyl ester, as the base, prepared according to example 1 were dissolved in 30 ml methanol, and 30 ml 1 N potassium hydroxide solution were added. The mixture was stirred at 60° C. for 2 hours. After the reaction mixture had cooled to room temperature, 1 N hydrochloric acid was added to the mixture until a pH of 4 was established. The phases were separated and the aqueous phase was washed 3 times with 20 ml ethyl acetate each time. The combined organic phases were dried over magnesium sulfate and freed from the solvent in vacuo. 2.7 g Z-3-[4-dimethylaminomethyl-3-(3-methoxy-phenyl)-cyclohex-2-enylidenemethyl]-benzoic acid base were obtained in this way in the form of an orange-yellow oil. To prepare the hydrochloride, the base was dissolved in 10 ml acetone, and an equimolar amount of trimethylchlorosilane and water was added. 2.4 g (77% of theory) Z-3-[4-dimethylaminomethyl-3-(3-methoxy-phenyl)-cyclohex-2-enylidenemethyl]-benzoic acid hydrochloride (14) were obtained in this way in the form of white crystals.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[C:13]([C:33]([F:36])([F:35])[F:34])=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C:22]2([NH:26]S(C(C)(C)C)=O)[CH2:25][O:24][CH2:23]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.Cl.CCOCC>C1CCCCC1>[C:1]([C@H:5]1[CH2:6][CH2:7][C@H:8]([O:11][C:12]2[C:13]([C:33]([F:36])([F:34])[F:35])=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C:22]2([NH2:26])[CH2:23][O:24][CH2:25]2)[CH:16]=[CH:15]3)[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)S(=O)NC1(c2ccc3c(C(F)(F)F)c(O[C@H]4CC[C@H](C(C)(C)C)CC4)ccc3c2)COC1
Agent: Cl
Solvent: C1CCCCC1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(C4(N)COC4)ccc3c2C(F)(F)F)CC1
Reaction time: 0.17 h

Procedure:
To a solution of 2-methyl-propane-2-sulfinic acid {3-[6-(trans-4-tert-butyl-cyclohexyloxy)-5-trifluoromethyl-naphthalen-2-yl]-oxetan-3-yl}-amide (332 mg, 0.632 mmol) in methylene chloride (7 mL, 100 mmol) was added 2.0 M of hydrogen chloride in ether (0.632 mL, 1.26 mmol) and stirred for 10 min. A precipitate formed and cyclohexane was added to dilute the mixture. After removal of solvent, the residue was dissolved in methylene chloride, 1M aq. NH4OH was added, the extracted organic layer was dried and subjected to silica gel chromatography with MeOH/CH2Cl2 (20-40%) to give 3-(6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)oxetan-3-amine as a solid (213.7 mg, 80%). LCMS: Rf=1.67 min 405.20 ([M-16]). 1H NMR (400 MHz, CHLOROFORM-d) δ=8.27 (d, J=9.3 Hz, 1 H), 7.93 (d, J=9.2 Hz, 1 H), 7.91 (d, J=1.9 Hz, 1 H), 7.81 (dd, J=2.1, 9.3 Hz, 1 H), 7.33 (d, J=9.2 Hz, 1 H), 5.06 (d, J=6.5 Hz, 2 H), 4.82 (d, J=6.5 Hz, 2 H), 4.38-4.24 (m, 1 H), 2.20 (d, J=12.4 Hz, 2 H), 1.93-1.82 (m, 2 H), 1.55 (br. s., 2 H), 1.41-1.09 (m, 5 H), 0.89 (s, 9 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:13][CH3:14])[CH:9]=2)[CH:4]=1.[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:13]([Br:15])[CH3:14])[CH:9]=2)[CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1ccc2cc(OC)ccc2c1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc2cc(C(C)Br)ccc2c1
Temperature: 25 °C

Procedure:
A mixture of 1.0 gram of 2-methoxy-6-ethylnaphthalene and 1.05 grams of N-bromosuccinimide in 10.0 ml. of carbon tetrachloride was refluxed for 1 hour. During this time, the solids migrated from the bottom of the reaction flask to the top. The mixture was cooled to room temperature and the solids were separated from the liquid by filtration on a small suction filter funnel. The carbon tetrachloride solvent was removed using a rotary vacuum evaporator. The yield was 1.55 grams of a pale oil that solidified at room temperature. Based on 1H nuclear magnetic resonance data, the product had a structure consistent with that of 2-methoxy-6- (1-bromoethyl) naphthalene.
Reaction SMILES: C([Li])CCC.[Br-].[OH:7][C:8]1[CH:33]=[CH:32][CH:31]=[CH:30][C:9]=1[CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[F:34][C:35]1[CH:36]=[C:37]([CH:54]=[C:55]([F:68])[C:56]=1[O:57][Si:58]([CH:65]([CH3:67])[CH3:66])([CH:62]([CH3:64])[CH3:63])[CH:59]([CH3:61])[CH3:60])[CH2:38][CH:39]([CH:52]=O)[CH2:40][CH2:41][C:42]1[CH:51]=[CH:50][C:45]([C:46]([O:48][CH3:49])=[O:47])=[CH:44][CH:43]=1.[Cl-].[NH4+]>CCCCCC.C1COCC1>[F:34][C:35]1[CH:36]=[C:37]([CH:54]=[C:55]([F:68])[C:56]=1[O:57][Si:58]([CH:59]([CH3:61])[CH3:60])([CH:65]([CH3:67])[CH3:66])[CH:62]([CH3:63])[CH3:64])[CH2:38][CH:39](/[CH:52]=[CH:10]/[C:9]1[CH:30]=[CH:31][CH:32]=[CH:33][C:8]=1[OH:7])[CH2:40][CH2:41][C:42]1[CH:51]=[CH:50][C:45]([C:46]([O:48][CH3:49])=[O:47])=[CH:44][CH:43]=1
Reactant: COC(=O)c1ccc(CCC(C=O)Cc2cc(F)c(O[Si](C(C)C)(C(C)C)C(C)C)c(F)c2)cc1
Reactant: Oc1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)c1ccc(CCC(/C=C/c2ccccc2O)Cc2cc(F)c(O[Si](C(C)C)(C(C)C)C(C)C)c(F)c2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
7.49 ml (11.98 mmol) of a 1.6 M solution of n-butyllithium in hexane are slowly added to a solution of 2.38 g (5.14 mmol) of (2-hydroxybenzyl)triphenylphosphonium bromide in 50 ml of THF at 0° C. Then, at this temperature, 2.16 g (4.28 mmol) of methyl 4-[3-(3,5-difluoro-4-triisopropylsilanyloxybenzyl)-4-oxobutyl]benzoate are slowly metered in. The reaction solution is stirred at 0° C. for 2 hours and then mixed with 100 ml of saturated ammonium chloride solution and extracted with diethyl ether. The combined organic phases are washed with saturated sodium chloride solution and dried over sodium sulfate. After filtration, the solvent is concentrated to dryness. The resulting crude product is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 10:1). 2.37 g (90% of theory) of a colorless solid are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([NH2:15])[CH:12]=[CH:11][N:10]=1.I[C:17]1[C:18]2[C:19](=[CH:23][N:24]([CH:26]3[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]3)[N:25]=2)[N:20]=[CH:21][CH:22]=1.CC(C)([O-])C.N#N.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>C1(C)C(C)=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([NH:15][C:17]2[C:18]3[C:19](=[CH:23][N:24]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[N:25]=3)[N:20]=[CH:21][CH:22]=2)[CH:12]=[CH:11][N:10]=1
Reactant: Cc1ccc(F)c(-c2cc(N)ccn2)c1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc3nccc(I)c3n2)CC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1C
Product: Cc1ccc(F)c(-c2cc(Nc3ccnc4cn(C5CCNCC5)nc34)ccn2)c1
Temperature: 120 °C
Yield: 87 %

Procedure:
A solution of 2-(2-fluoro-5-methylphenyl)pyridin-4-amine (42.5 mg, 0.210 mmol), tert-butyl 4-(7-iodo-2H-pyrazolo[4,3-b]pyridin-2-yl)piperidine-1-carboxylate (60 mg, 0.140 mmol) and t-butoxide (18.85 mg, 0.196 mmol) in xylene (3 mL) was sparged with N2 and then 2-dicyclohexylphosphino-2′,4′,6′-tri-iso-propyl-1,1′-biphenyl (13.36 mg, 0.028 mmol) and tris(dibenzylideneacetone)dipalladium(0) (12.83 mg, 0.014 mmol) were added and the mixture was heated at 120° C. overnight. The reaction was cooled, concentrated, the residue treated with dichloromethane/TFA (1/1) and the solvent was removed in vacuo. The residue was dissolved with methanol and purified with preparative HPLC using a Sunfire Prep 5 μm C18, 75×30 mm column eluting with a gradient of 15-40% acetonitrile (containing 0.035% TFA) in water (containing 0.05% TFA) to give N-(2-(2-fluoro-5-methylphenyl)pyridin-4-yl)-2-(piperidin-4-yl)-2H-pyrazolo[4,3-b]pyridin-7-amine (49 mg, 87%)
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[C:16]([C:17](=[O:21])[C:18]=2[O:19]C)=[C:15]([OH:22])[CH:14]=[C:13]([OH:23])[CH:12]=3)=[CH:5][CH:4]=1.B(Br)(Br)Br>ClCCl>[F:25][C:2]([F:1])([F:24])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:10][C:11]3[C:16]([C:17](=[O:21])[C:18]=2[OH:19])=[C:15]([OH:22])[CH:14]=[C:13]([OH:23])[CH:12]=3)=[CH:7][CH:8]=1
Reactant: COc1c(-c2ccc(C(F)(F)F)cc2)oc2cc(O)cc(O)c2c1=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=c1c(O)c(-c2ccc(C(F)(F)F)cc2)oc2cc(O)cc(O)c12
Temperature: 25 °C
Yield: 70 %

Procedure:
2-(4-trifluoromethylphenyl)-3-methoxy-5,7-dihydroxy-4H-chromen-4-one (10 g, 28.3 mmol) was dissolved into 150 mL dichloromethane in a 250 ml three-necked flask. Boron tribromide (21.2 g, 84.9 mmol) was slowly dropped into the solution at 0° C. After that, the solution was heated to room temperature and reacted for 4 hours, and quenched with 80 mL ice water for terminating the chemical reaction. The solution was extracted with 500 mL ethyl acetate for 3 times. The extracts were combined, washed with saturated sodium chloride aqueous solution once and dried with anhydrous sodium sulfate. After filtration, crude product was mixed with 20 mL ethyl acetate/petroleum (1:10) and stirred, and target yellow compound was obtained after filtering and drying. (7 g, yield 70%).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[N:13]=[C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[S:15][CH:16]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:23][CH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31]C)=[O:30])=[CH:27][CH:26]=1.[OH-].[Na+]>C1COCC1.CO.O>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[N:13]=[C:14]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[S:15][CH:16]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:23][CH2:24][C:25]1[CH:26]=[CH:27][C:28]([C:29]([OH:31])=[O:30])=[CH:33][CH:34]=1
Reactant: COC(=O)c1ccc(COc2ccc3cc(-c4csc(-c5ccccc5)n4)ccc3c2Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(COc2ccc3cc(-c4csc(-c5ccccc5)n4)ccc3c2Br)cc1
Temperature: 25 °C
Yield: 73.1 %

Procedure:
A mixture of methyl 4-({[1-bromo-6-(2-phenyl-1,3-thiazol-4-yl)-2-naphthyl]oxy}methyl)benzoate (214.8 mg, 0.405 mmol), prepared in the previous step, and 1 N NaOH (608 μL, 0.608 mmol) in 40 mL of THF plus 40 mL of methanol plus 10 mL of water was refluxed for 24 h. By TLC starting material remained. An additional 608 μL (0.608 mmol) of 1 N NaOH was added and the mixture refluxed for 24 h. After cooling to room temperature the reaction was filtered, acidified by the addition of 5 mL of 1 N HCl and then concentrated under reduced pressure to remove the THF and methanol. The solid present was collected by filtration, washed with water and dried under reduced pressure to give the title compound (152.9 mg, 73%) as a white solid, mp 268-270° C. Elemental analysis for C27H18BrNO3S.0.20H2O Calc'd: C, 62.36; H, 3.57; N, 2.69. Found: C, 62.38; H, 3.54; N, 2.62.
Reaction SMILES: [OH-].[Na+].[CH2:3]([C:15]1[CH:19]=[N:18][N:17]([CH:20]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:21]([O:23]CC)=[O:22])[N:16]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>C(O)C>[CH2:3]([C:15]1[CH:19]=[N:18][N:17]([CH:20]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:21]([OH:23])=[O:22])[N:16]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCc1cnn(C(C(=O)OCC)c2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCCCc1cnn(C(C(=O)O)c2ccccc2)n1
Reaction time: 1 h

Procedure:
Solid NaOH (0.44 g, 11 mmol) was added to a solution of ethyl (±)-4-dodecyl-α-phenyl-2H-1,2,3-triazole-2-acetate (2.92 g, 7.3 mmol) in 100 mL 95% ethanol. The resulting yellow solution was stirred for 1 hour and then concentrated in vacuo. The residue was partitioned between water and ether, the aqueous layer was acidified with concentrated HCl and extracted with ethyl acetate. The ethyl acetate solution was dried over MgSO4, filtered, and concentrated to give an off-white solid (2.75 g, quant.); mp 94°-98° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH:13]([CH2:16][NH2:17])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS[C:20]1[C:29]2[C:24](=[N:25][CH:26]=[CH:27][N:28]=2)[N:23]=[CH:22][N:21]=1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH:13]([CH2:16][NH:17][C:20]2[C:29]3[C:24](=[N:25][CH:26]=[CH:27][N:28]=3)[N:23]=[CH:22][N:21]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCC1CCN(C(=O)OCc2ccccc2)C1
Reactant: CSc1ncnc2nccnc12
Product: O=C(OCc1ccccc1)N1CCC(CNc2ncnc3nccnc23)C1

Procedure:
EXAMPLE 101 was prepared from 3-aminomethyl-pyrrolidine-1-carboxylic acid benzyl ester (EXAMPLE 79, Step 3) and 4-methylthio-pteridine (A. A. Brown, D. J. Brown,h. C. S. Wood, J. Chem. Soc., 1954, 3832–3839): MS (m+1)=365.4.
Reaction SMILES: [S:1]([C:21]1[CH:26]=C(C2C(Cl)=CC(C(F)(F)F)=CC=2Cl)C=C[C:22]=1C)[C:2]1[CH:7]=[C:6]([C:8]2[C:13]([Cl:14])=[CH:12][C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=2[Cl:19])[CH:5]=[CH:4][C:3]=1[CH3:20].C(S([O-])=O)O.[Na+].C(I)(C)C.O>CN(C)C=O>[Cl:19][C:9]1[CH:10]=[C:11]([C:15]([F:17])([F:18])[F:16])[CH:12]=[C:13]([Cl:14])[C:8]=1[C:6]1[CH:5]=[CH:4][C:3]([CH3:20])=[C:2]([S:1][CH:21]([CH3:22])[CH3:26])[CH:7]=1
Reactant: Cc1ccc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1Sc1cc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)ccc1C
Agent: O=S([O-])CO
Agent: [Na+]
Solvent: O
Solvent: CC(C)I
Solvent: CN(C)C=O
Product: Cc1ccc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1SC(C)C
Yield: 75.3 %

Procedure:
3.3 g (4.9 mmol) of 1,1′-thiodi-[5-(2,6-dichloro-4-trifluoromethylphenyl)-2-methylbenzene], 3.0 g (19.5 mmol) of Rongalite and 3.0 g (17.6 mmol) of isopropyl iodide were stirred in 30 ml of N,N-dimethylformamide at room temperature for 3 hours. The resulting reaction mixture was poured into 300 ml of water and extracted with 50 ml of ethyl acetate twice. The ethyl acetate layer was washed with 50 ml of water twice and dried over anhydrous magnesium sulfate, and the ethyl acetate was distilled off under reduced pressure. Purification of the residue by silica gel column chromatography afforded 1.4 g of [5-(2,6-dichloro-4-trifluoromethylphenyl)-2-methylphenyl]isopropyl sulfide (yield 38.0%) as a yellow dough (nD20 1.5462).