Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH3:13])(=[O:12])=[O:11])=[CH:6][C:5]=1[C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH2:18][CH2:17]1)=[O:15])([CH3:3])=[CH2:2]>C(OC(=O)C)C.C(Cl)Cl.[Pd]>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH3:13])(=[O:11])=[O:12])=[CH:6][C:5]=1[C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:26][CH:27]=2)[CH2:18][CH2:17]1)=[O:15])([CH3:3])[CH3:2]
Reactant: C=C(C)c1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ccc(C(F)(F)F)cc2)CC1
Agent: [Pd]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)c1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ccc(C(F)(F)F)cc2)CC1
Reaction time: 1 h
Yield: 70 %

Procedure:
To a solution of (2-Isopropenyl-5-methanesulfonyl-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone, (Example 44, 20 mg, 0.0442 mmol) in Ethylacetate (1 ml) was added Pd/C 10% (1 mg). The mixture was hydrogenated at rt for 1 hour. Then, Pd/C 10% (10 mg) and Ethylacetate (5mL) were added and the mixture was hydrogenated at reflux temperature for 1 hour. The mixture was diluted with MeCl2 ,filtered and the filtrate was concentrated in vacuo. The crude mixture was purified on SiO2 Eluent: Heptane/AcOEt 0% to 40% (20 minutes) to provide the title compound (14 mg, 70%, yellow solid); M+H=455.2
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.C1(P(=[CH:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cccc(Cl)c1
Solvent: C1CCOC1
Product: CCOC(=O)C=Cc1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
In a 2 l three necked flask fitted with mechanical stirrer and dropping funnel under inert atmosphere, 106.2 g (755 mmoles, 1 eq) of 3-chlorobenzaldehyde are dissolved in 1 l of THF and cooled down to 0° C. 341.9 g (980 mmoles, 1.3 eq) of ethyl (triphenylphosphoranylidene)acetate are then added under efficient stirring, the temperature raising to 10° C. The mixture is kept under stirring one hour at 0° C., and then overnight at room temperature. The mixture is concentrated to dryness, the residue suspended in diethyl ether, the triphenylphosphine oxide is filtered off and the filtrate concentrated to dryness. The residue is purified by PrepLC (1 kg SiO2, pet. ether/EtOAc, 75:35) to give 191.8 g of pure 375, 92% yield. 1H NMR (250 MHz, (CD3)2SO): 1.30 (t, 3H), 4.25 (q, 2H), 6.70 (d, 1H), 7.40 (m, 2H), 7.50-7.70 (m, 2H), 7.85 (s(broad), 1H).
Reaction SMILES: [CH3:1][C:2]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=2)=[CH:9][C:5]2[N:6]=[CH:7][S:8][C:4]=2[CH:3]=1.[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:20]=1[C:21](Cl)=[O:22].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+].C(Cl)Cl>C(Cl)Cl>[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:20]=1[C:21]([NH:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]2[C:2]([CH3:1])=[CH:3][C:4]3[S:8][CH:7]=[N:6][C:5]=3[CH:9]=2)=[CH:16][N:15]=1)=[O:22]
Reactant: Cc1cc2scnc2cc1-c1ccc(N)nc1
Reactant: O=C(Cl)c1c(F)cccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2scnc2cc1-c1ccc(NC(=O)c2c(F)cccc2F)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
To a solution of 5-(6-methylbenzothiazol-5-yl)-2-pyridylamine (55) (24 mg, 0.1 mmol) in 2 ml DCM was added 2,6-difluorobenzoyl chloride (25 μl, 0.2 mmol) followed by addition of DIEA (105 μl). The resulting solution was stirred at r.t. for 2 h. The reaction mixture was worked up with aq. NaHCO3/DCM. DCM phase was washed with brine, concentrated to dryness. The residue was dissolved in 2 ml THF/MeOH/H2O (5:4:1) and stirred with 1N NaOH (200 μl) at r.t. for 1 h and then at 50° C. for 2 h before worked up with EA/aq. NaHCO3. Silica gel flash chromatography furnished (2,6-difluorophenyl)-N-[5-(6-methylbenzothiazol-5-yl)(2-pyridyl)]carboxamide (56) (29.6 mg, yield: 77.6%, purity>95%) as white solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([CH3:7])[N:6]=1.F[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[F:18].C(=O)(O)[O-].[Na+].O>CS(C)=O>[F:18][C:10]1[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=1[N:3]1[CH:4]=[C:5]([CH3:7])[N:6]=[C:2]1[CH3:1]
Reactant: Cc1c[nH]c(C)n1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cn(-c2ccc([N+](=O)[O-])cc2F)c(C)n1
Temperature: 80 °C
Reaction time: 72 h
Yield: 53.5 %

Procedure:
Step T (1): A mixture of 2,4-dimethyl-1H-imidazole (5.00 g, 52.0 mmol), 1,2-difluoro-4-nitrobenzene (8.27 g, 52.0 mmol), and sodium bicarbonate (4.37 g, 52.0 mmol) in DMSO (100 mL) was heated at 80° C. for 24 h. The reaction mixture was allowed to cool to rt and was poured into water (800 mL). The aqueous mixture was extracted with EtOAc (3×200 mL). The combined organic extracts were sequentially washed with water (500 mL) and brine solution (100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The dark residue was dissolved in ethyl acetate (200 mL). Hexane (50 mL) was added to the solution. The resulting mixture was allowed to age for 72 h at rt. The resulting solid was collected by vacuum filtration. The solid was dried under high vacuum to afford 1-(2-fluoro-4-nitrophenyl)-2,4-dimethyl-1H-imidazole (6.68 g, 27.8 mmol, 54% yield) as a yellow crystalline solid. LC-MS (M+H)+=236.1. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.13-8.22 (m, 2 H), 7.51 (dd, J=8.9, 7.3 Hz, 1 H), 6.72 (s, 1 H), 2.28-2.36 (m, 3 H), 2.22-2.28 (m, 3 H).
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][C:10]([CH2:14][CH2:15][CH:16]=[C:17]([CH3:29])[CH2:18][CH2:19][CH:20]=[C:21]([CH3:28])[CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])=[CH:11][CH2:12][OH:13].[OH-].[K+]>CCCCCC>[CH2:1]([O:13][CH2:12][CH:11]=[C:10]([CH3:9])[CH2:14][CH2:15][CH:16]=[C:17]([CH3:29])[CH2:18][CH2:19][CH:20]=[C:21]([CH3:28])[CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCO
Reactant: ClCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCCCCC
Product: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCOCc1ccccc1
Reaction time: 2 h
Yield: 61 %

Procedure:
To 100 ml of benzyl chloride were added 15 g of 3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraen-1-ol and 6.0 g of finely divided potassium hydroxide, and the resulting mixture was refluxed under stirring for 2 hours. The mixture was cooled and then to the mixture was added 1 liter of hexane. The hexane solution was then washed with water and concentrated. The concentrate was purified over a silica gel column to give 12 g of 1-benzyloxy-3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraene (yield 61%).
Reaction SMILES: [CH2:1]([N:3]([CH2:28][CH3:29])[C:4]([C:6]1[CH:7]=[CH:8][C:9]2[C:10](=[C:20]3[CH2:25][CH2:24][N:23]([CH:26]=S)[CH2:22][CH2:21]3)[C:11]3[C:16]([O:17][C:18]=2[CH:19]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2].S(C1C=CC(C)=CC=1)(OC)(=O)=O.[NH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.Cl>C(Cl)(Cl)Cl>[CH2:1]([N:3]([CH2:28][CH3:29])[C:4]([C:6]1[CH:7]=[CH:8][C:9]2[C:10](=[C:20]3[CH2:25][CH2:24][N:23]([CH:26]=[N:42][C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[CH2:22][CH2:21]3)[C:11]3[C:16]([O:17][C:18]=2[CH:19]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: Nc1ccccc1
Reactant: CCN(CC)C(=O)c1ccc2c(c1)Oc1ccccc1C2=C1CCN(C=S)CC1
Agent: COS(=O)(=O)c1ccc(C)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCN(CC)C(=O)c1ccc2c(c1)Oc1ccccc1C2=C1CCN(C=Nc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A sample of compound 11b (0.1 g, 0.25 mmol) in 1 mL of chloroform was placed in a pressure tube and treated with methyl tosylate (0.037 mL, 0.25 mmol). The reaction was heated for 1 h on a steam bath. At that time the reaction was cooled to room temperature and aniline (0.023 mL, 0.25 mmol) was added, and the reaction was heated again on a steam bath for another 2 h. After 2 h, the reaction was cooled, washed with 1 N NaOH, and evaporated. Flash chromatography on silica gel was used to purify the crude material, eluting the product with 5% methanol/CH2Cl2, followed by conversion to its hydrochloride salt with ethereal hydrogen chloride (0.004 g, 0.009 mmol). MS m/z (MH+) 466.3. 1H NMR 300 MHz (CDCl3) δ 1.2 (br s, 6H), 3.1 (m, 4H), 3.3 (d, 2H) 3.4-3.8 (m, 4H), 4.3 (s, 2H),) 7.1-7.4 (m, 10H), 7.7 (s, 2H), 8.0 (s, 1H), 13.6 (s, 1H).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4](=[O:17])[C:5]2[CH2:12][O:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[C:6]=2[O:7][CH:8]=1.[C-:18]#[N:19].[Na+]>O1CCCC1.O>[CH3:2][C:3]1[C:4](=[O:17])[C:5]2[CH2:12][O:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[C:6]=2[O:7][C:8]=1[C:18]#[N:19]
Reactant: O=c1c(CCl)coc2c1COc1ccccc1-2
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(C#N)oc2c(c1=O)COc1ccccc1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.1 %

Procedure:
A solution of 3-chloromethyl-4H,5H-[1]benzopyrano[4,3-b]pyran-4-one (2.65 g, 10.65 mmoles, described in Example 5) in tetrahydrofuran (130 ml) is combined with a solution of sodium cyanide (5.3 g) in water (27 ml). The mixture is stirred overnight at room temperature and poured into water. The solution is extracted with chloroform. The chloroform extract is dried and evaporated. The residue is chromatographed on silica gel using ethyl acetate-benzene (1:19), the eluates are evaporated, and the residue is crystallized from chloroform-diethyl ether to give the title compound (0.767 g), mp 179°-181° C.; nmr (CDCl3) δ 2.25(s, 3H), 5.2(s, 2H), and 6.8-7.7(m, 4H).
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([C:25](=[O:27])[CH3:26])[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[F:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][C:38](OC)=[O:39])=[CH:33][CH:32]=1>C1COCC1>[F:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][C:38](=[O:39])[CH2:26][C:25]([C:23]2[N:22]=[CH:21][N:20]([C:1]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:24]=2)=[O:27])=[CH:33][CH:32]=1
Reactant: COC(=O)Cc1ccc(F)cc1
Reactant: CC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(CC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.9 %

Procedure:
To a solution of 1-(1-trityl-1H-imidazol-4-yl)ethanone (1.5 g, 4.26 mmol) in anhydrous THF (25 mL) was added NaH (0.23 g, 8.52 mmol) at 0° C. The mixture was stirred at RT for 2 hours, and methyl (4-fluorophenyl)acetate (1.43 g, 12.78 mmol) was added at 0° C. The mixture was refluxed overnight. The mixture was evaporated and the residue was purified via column chromatography (silica gel, EtOAc/Petroleum ether 1:5) to yield the title compound (1.018 g, 48.0%) as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.[H-].[Na+].I[CH:15]([CH3:17])[CH3:16].C(OCC)C>CN(C=O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:15]([CH3:17])[CH3:16])=[C:4]([Cl:11])[N:3]=1
Reactant: CC(C)I
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)n1cnc2c(Cl)nc(Cl)nc21
Reaction time: 1 h

Procedure:
The 2,6-dichloropurine (5.00 g, 26.46 mmol) was suspended in 55 ml of dry DMF at room temperature and treated with sodium hydride, 60% dispersion (1.21 g, 31.75 mmol) added in portions. After stirring for 1 hr, 2-iodopropane (4.5 ml, 44.98 mmol) was added and the reaction stirred for 2 days. The reaction was poured into diethyl ether and washed once with saturated sodium bicarbonate solution and once with water. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. The concentrate was chromatographed over silica gel eluting with 10% acetone in dichloromethane solution to give the desired N-9 alkylation product as a white solid.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([NH:5][C@H:6]([CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:7][OH:8])=[O:4].[H-].[Na+].Br[CH2:18][CH:19]=[CH2:20]>C1COCC1>[CH2:20]([O:8][CH2:7][C@H:6]([NH:5][C:3](=[O:4])[C:2]([F:13])([F:14])[F:1])[CH2:9][CH:10]([CH3:12])[CH3:11])[CH:19]=[CH2:18]
Reactant: C=CCBr
Reactant: CC(C)C[C@H](CO)NC(=O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCOC[C@@H](CC(C)C)NC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.2 %

Procedure:
Step AK (2): (R)-2,2,2-trifluoro-N-(1-hydroxy-4-methylpentan-2-yl)-acetamide (200 mg, 0.94 mmol) was dissolved in THF (5 mL) under nitrogen atmosphere. Sodium hydride (80 mg, 1.9 mmol) was added to the reaction mixture in portions. 3-Bromoprop-1-ene (0.16 mL, 1.9 mmol) was added dropwise to the reaction mixture. The reaction mixture was stirred at rt for 3 h and was extracted with EtOAc. The combined organic phases were washed with water and brine and dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography to give (R)-N-(1-(allyloxy)-4-methylpentan-2-yl)-2,2,2-trifluoroacetamide (210 mg, 88%) as a colorless oil. LC-MS (M+H)+=254.06. 1H NMR (CD3OD, 500 MHz) δ 5.91 (m, 1H) 5.31-5.17 (m, 2H) 4.21 (m, 1H) 4.05-3.97 (m, 2H) 3.49-3.42 (m, 2H) 1.63 (m, 1H) 1.52 (m, 1H) 1.39 (m, 1H) 0.97-0.93 (m, 6H).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[N:15]=[C:16]([N:19]4[CH2:24][CH2:23][CH2:22][CH:21]([NH2:25])[CH2:20]4)[S:17][CH:18]=3)[CH:5]=[CH:4][C:3]1=2.Cl[CH2:28][CH2:29][CH2:30][OH:31].Cl>>[CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]3[N:15]=[C:16]([N:19]4[CH2:24][CH2:23][CH2:22][CH:21]([NH:25][CH2:28][CH2:29][CH2:30][OH:31])[CH2:20]4)[S:17][CH:18]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCCC(N)C4)n3)ccc21
Reactant: OCCCCl
Agent: Cl
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCCC(NCCCO)C4)n3)ccc21

Procedure:
The preparation is carried out as described starting from 50 mg (0.11 mmol) of 1-[4(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperidin-3-ylamine and 14 μl (0.16 mmol) of 3-chloropropan-1-ol. The product is in the form of the hydrochloride.
Reaction SMILES: OC1C=CC=CC=1C1SC=C(CC(O)=O)N=1.C([O:19][C:20](=[O:34])[CH2:21][C:22]1[N:23]=[C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=2)[S:25][CH:26]=1)C.[Li+].[OH-]>>[OH:33][C:29]1[CH:28]=[C:27]([C:24]2[S:25][CH:26]=[C:22]([CH2:21][C:20]([OH:34])=[O:19])[N:23]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: CCOC(=O)Cc1csc(-c2cccc(O)c2)n1
Agent: O=C(O)Cc1csc(-c2ccccc2O)n1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)Cc1csc(-c2cccc(O)c2)n1
Yield: 99 %

Procedure:
The procedure used for the preparation of 5a was repeated with 4d (1.84 g, 7.00 mmol) and 2N LiOH (14.0 mL) to provide 5d (1.63 g, 99%) as a white solid, which was recrystallized from EtOAc/toluene. mp 172.0°-174.0° C.; IR (KBr) 3500-2400 (br), 3336 (br), 1689, 1442, 1276, 1231 cm-1 ; 1H NMR (DMSO-d6) δ 3.72 (2H, s, CH2), 6.81 (1H, d, J=7.4 Hz, Ar), 7.19-7.30 (3H, m, Ar), 7.43 (1H, s), 9.67 (1H, br s, OH), 12.40 (1H, br s, CO2H); FDMS m/z 236 (M+ +1); Anal. Calcd for C11H9NO3S: C, 56.14; H, 3.86; N, 5.95. Found: C, 56.11; H, 3.73; N, 5.80.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:24]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:9]([C:11]3[C:19]4[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=4)[NH:13][CH:12]=3)=[CH:10][C:3]=12.Cl.Cl[CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:24]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:9]([C:11]3[C:19]4[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=4)[N:13]([CH2:36][CH2:37][N:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)[CH:12]=3)=[CH:10][C:3]=12
Reactant: COc1cc2[nH]cc(-c3cc4c(Cl)ccnc4n3S(=O)(=O)c3ccc(C)cc3)c2cc1OC
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(-c3cc4c(Cl)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(CCN3CCOCC3)c2cc1OC
Temperature: 95 °C
Yield: 43.7 %

Procedure:
A suspension of 1 g of 4-chloro-2-(5,6-dimethoxy-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine, 0.655 g of 4-(2-chloroethyl)morpholine hydrochloride and 1.11 g of potassium carbonate in 10 ml of dimethylformamide is heated at around 95° C. for approximately 3 hours. After cooling to a temperature in the region of 20° C., the reaction mixture is run into 20 ml of water, and extracted with three times 100 ml of ethyl acetate. The combined organic phases are washed with 100 ml of a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (13 kPa). The residue is purified by flash chromatography on a silica column [eluent: cyclohexane/ethyl acetate (90/10 by volume)]. 0.54 g of 4-chloro-2-[5,6-dimethoxy-1-(2-morpholin-4-ylethyl)-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine is obtained in the form of a solid, the characteristics of which are as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(c1ccc(Cl)nc1)N1CCOCC1
Reaction time: 0.5 h
Yield: 97.1 %

Procedure:
To a solution of 6-chloro nicotinic acid (1.11 g, 7.04 mmol) in CH2Cl2 at 0 C was added EDCI (2.70 g, 14.08 mmol) and HOBt and then the resulting mixture was stirred for 30 minutes at 0 C. After that, morpholine (2.46 ml, 28.17 mmol) was added, the ice-bath removed and the reaction was done in 15 minutes. Water was added, the mixture was extracted with CH2Cl2, dried over MgSO4 and concentrated to afford 1.55 g of product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[O:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.Cl[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N+:33]([O-:35])=[O:34]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[O:9][CH:10]1[CH2:11][CH2:12][N:13]([CH2:23][CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[N+:33]([O-:35])=[O:34])[CH2:14][CH2:15]1
Reactant: Cc1ccccc1C(OC1CCNCC1)c1ccccc1
Reactant: O=[N+]([O-])c1ccccc1OCCCCl
Product: Cc1ccccc1C(OC1CCN(CCCOc2ccccc2[N+](=O)[O-])CC1)c1ccccc1

Procedure:
The procedure of Example 24 (a) was repeated except for using 4-[(2-methylphenyl)-phenylmethoxy]piperidine and 1-chloro-3-(2-nitrophenoxy)propane instead of 4-[(2-chlorophenyl)-phenylmethoxy]piperidine and 1-chloro-3-(2-nitrophenoxy)propane to give oily 4-[(2-methylphenyl)-phenylmethoxy]-1-[3-(2-nitrophenoxy)propyl]piperidine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.CC(C)([O-])C.[K+].Cl[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[CH:17]=1>CC(N(C)C)=O.CCOC(C)=O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([O:8][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[CH:17]=2)=[CH:6][CH:7]=1
Reactant: Nc1ccc(O)cn1
Reactant: CC(C)NC(=O)c1cc(Cl)ccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CC(C)NC(=O)c1cc(Oc2ccc(N)nc2)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
A solution of 2-amino-5-hydroxypyridine (0.446 g, 4.05 mmol) in DMA (6.75 mL) was treated with potassium tert-butoxide (0.511 g, 4.55 mmol), stirred at RT for 1 h, treated with DMA (2 mL) and a solution of 4-chloro-N-isopropylpicolinamide (0.67 g, 3.37 mmol) in DMA (6.75 mL) and stirred at RT overnight under Ar. The mixture was diluted with EtOAc, washed with 1N NaOH, then brine and the organic layer was dried over Na2SO4, concentrated to dryness and purified by silica gel chromatography (MeOH/EtOAc) to afford 4-((6-aminopyridin-3-yl)oxy)-N-isopropylpicolinamide (0.523 g, 57%). 1H NMR (400 MHz, DMSO-d6): δ 8.46 (t, J=5.6 Hz, 2H), 7.82 (d, J=2.9 Hz, 1H), 7.33 (d, J=2.6 Hz, 1H), 7.30 (dd, J=8.9, 3.0 Hz, 1H), 7.12 (dd, J=5.6, 2.6 Hz, 1H), 6.53 (d, J=8.9 Hz, 1H), 6.08 (s, 2H), 4.05-4.04 (m, 1H), 1.14 (d, J=6.6 Hz, 6H); MS (ESI) m/z: 273.1 (M+H+).
Reaction SMILES: [OH:1][C:2]1([CH3:12])[C:7](=O)[CH2:6][CH:5]2[CH2:9][CH:3]1[C:4]2([CH3:11])[CH3:10].[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][NH2:20])[CH:14]=1.B(F)(F)F>C1C=CC=CC=1>[CH3:12][C:2]1([OH:1])[C:7](=[N:20][CH2:19][C:15]2[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=2)[CH2:6][CH:5]2[CH2:9][CH:3]1[C:4]2([CH3:11])[CH3:10]
Reactant: CC1(O)C(=O)CC2CC1C2(C)C
Reactant: NCc1cccnc1
Agent: FB(F)F
Solvent: c1ccccc1
Product: CC1(O)C(=NCc2cccnc2)CC2CC1C2(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 56 %

Procedure:
To a stirring solution of (+)-2-hydroxy-3-pinanone (10.00 g, 59.4 mmol) in benzene (500 mL) was added 3-pyridylmethylamine (6.66 mL, 65.4 mmol) in one portion. Boron trifluoride diethyletherate (0.7 mL, 5.9 mmol) was added in one portion and the reaction was refluxed under N2 for 5 h and then stirred at room temperature for an additional 16 h. The benzene was removed by rotary evaporation and the resulting residue was stirred in saturated NaHCO3 solution (100 mL) for 1 h. This was then extracted with chloroform (3×100 mL) and the combined extracts were dried (Na2SO4), filtered and concentrated by rotary evaporation. The resulting dark brown oil was purified by column chromatography, using a chloroform:methanol gradient (9:1 to 1:1, v/v) as eluent. The light yellow oil was then dissolved in hot ethyl acetate (50 mL) and placed in a −4° C. freezer for 16 h. After warming to room temperature, the resulting crystals were filtered, washed with cold ethyl acetate, and dried using a hi-vacuum pump to yield 8.59 g of white powder (52.4% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:13]O)[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH:10]([F:12])[F:11].[C:15]1(=[O:25])[NH:19][C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:13][N:19]2[C:15](=[O:25])[C:16]3[C:17](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:18]2=[O:20])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH:10]([F:11])[F:12]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCc1cnc(OCC(F)F)c(Cl)c1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1Cc1cnc(OCC(F)F)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.8 %

Procedure:
A mixture of (5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methanol (0.87 g, 3.88 mmol, Step-3), phthalimide (0.63 g, 4.26 mmol), di-tert-butyl azodicarboxylate (2.11 mL, 4.65 mmol, ca. 2.2 mol/L in toluene) and triphenylphosphine (1.53 g, 5.81 mmol) in THF (26 mL) is stirred at rt for 2 hours. The reaction mixture is concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane/EtOAc (10:1 to 3:1) to give 1.27 g (93% yield) of the title compound as white solid.