Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH2:35][CH3:36])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH3:37][C:38]1[C:39]([N:47]2[CH2:52][CH2:51][N:50]([CH2:53][CH2:54][S:55]([CH3:58])(=[O:57])=[O:56])[CH2:49][CH2:48]2)=[CH:40][C:41]([O:45][CH3:46])=[C:42]([CH:44]=1)[NH2:43].C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>C(Cl)Cl.CC(O)C>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:43][C:42]3[CH:44]=[C:38]([CH3:37])[C:39]([N:47]4[CH2:52][CH2:51][N:50]([CH2:53][CH2:54][S:55]([CH3:58])(=[O:57])=[O:56])[CH2:49][CH2:48]4)=[CH:40][C:41]=3[O:45][CH3:46])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH2:35][CH3:36]
Reactant: CCOc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Reactant: COc1cc(N2CCN(CCS(C)(=O)=O)CC2)c(C)cc1N
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClCCl
Product: CCOc1ccc(-c2nc3ccccn3c2-c2ccnc(Nc3cc(C)c(N4CCN(CCS(C)(=O)=O)CC4)cc3OC)n2)cc1C(=O)Nc1c(F)cccc1F
Temperature: 120 °C
Yield: 50.5 %

Procedure:
5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(ethyloxy)benzamide (Intermediate Example 6) (115 mg, 0.227 mmol), 5-methyl-2-(methyloxy)-4-{4-[2-(methylsulfonyl)ethyl]-1-piperazinyl}aniline (Example 148, step D) (67 mg, 0.204 mmol), and p-toluenesulfonic acid (93 mg, 0.49 mmol) were weighed into a 20 mL vial. 10 mL of iPrOH was added and the mixture was heated to 120° C. for 48 h. The mixture was transferred to a 50 mL round bottom and neutralized with 2 mL of 0.5 N sodium methoxide. The solvent was rotovaped down. The residue was taken up in 10 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography to give the title compound (82 mg, 0.103 mmol, 57%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.73 (s, 1H), 9.36 (s, 1H), 8.46 (s, 1H), 8.22 (d, J=5.31 Hz, 1H), 8.03 (d, J=2.01 Hz, 1H), 7.73 (dd, J=8.61, 2.01 Hz, 1H), 7.68 (d, J=8.97 Hz, 1H), 7.49 (s, 1H), 7.40-7.45 (m, 1H), 7.32-7.39 (m, 1H), 7.25 (d, J=8.61 Hz, 1H), 7.18 (t, J=8.15 Hz, 2H), 6.94 (t, J=6.87 Hz, 1H), 6.75 (s, 1H), 6.54 (d, J=5.31 Hz, 1H), 4.25 (q, J=6.78 Hz, 2H), 3.79 (s, 3H), 3.31-3.34 (m, 2H), 3.05 (s, 3H), 2.82-2.89 (m, 4H), 2.76 (t, J=6.68 Hz, 2H), 2.52-2.63 (m, 4H), 2.13 (s, 3H), 1.41 (t, J=6.87 Hz, 3H). MS (ESI): 797 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[C:5]([CH3:20])=[C:6]2[C:11](=[C:12]([CH3:14])[CH:13]=1)[S:10](=[O:16])(=[O:15])[CH2:9][C:8]([CH3:18])([CH3:17])[C:7]2=[O:19])([OH:3])=O.[CH2:21]([N:23]1[C:27]([OH:28])=[CH:26][CH:25]=[N:24]1)[CH3:22].C1(N=C=NC2CCCCC2)CCCCC1.C(=O)([O-])[O-].[K+].[K+]>C(O)(CC)(C)C>[CH2:21]([N:23]1[C:27]([OH:28])=[C:26]([C:1]([C:4]2[C:5]([CH3:20])=[C:6]3[C:11](=[C:12]([CH3:14])[CH:13]=2)[S:10](=[O:15])(=[O:16])[CH2:9][C:8]([CH3:18])([CH3:17])[C:7]3=[O:19])=[O:3])[CH:25]=[N:24]1)[CH3:22]
Reactant: Cc1cc(C(=O)O)c(C)c2c1S(=O)(=O)CC(C)(C)C2=O
Reactant: CCn1nccc1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)(C)O
Product: CCn1ncc(C(=O)c2cc(C)c3c(c2C)C(=O)C(C)(C)CS3(=O)=O)c1O
Temperature: 25 °C
Yield: 81.9 %

Procedure:
A 50-ml round-bottomed flask was charged with 0.51 g (1.72 mmol) of 6-carboxy-3,3,5,8-tetramethylthiochroman-4-one-1,1-dioxide, 0.21 g (1.88 mmol) of 1-ethyl-5-hydroxypyrazole and 5 ml of t-amyl alcohol, and while the mixture was stirred at room temperature, a solution of 0.42 g (2.04 mmol) of N,N'-dicyclohexylcarbodiimide in 2 ml of t-amyl alcohol was added. The mixture was further stirred at room temperature for 1 hour, and 0.18 g (1.30 mmol) of potassium carbonate was added to the reaction mixture. The mixture was heated at 80~90° C. for 8 hours. The solvent was distilled off under reduced pressure, and ethyl acetate and a 2 wt % sodium carbonate aqueous solution were added to the residue. An insoluble solid was removed by filtration. The mixture was separated into two phases, and an aqueous layer was neutralized and acidified with a 5 wt % hydrochloric acid aqueous solution, and a precipitated solid was extracted with ethyl acetate. An organic layer was washed with diluted hydrochloric acid and with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to give 0.55 g (yield 82%) of 6-(1-ethyl-5-hydroxypyrazol-4-yl)carbonyl-3,3,5,8-tetramethylthiochroman-4-one-1,1-dioxide in the form of a brown solid. This product was recrystallized from mixed solvents of ethyl acetate and n-hexane to give 0.36 g (yield 54%) of a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=O.[CH3:13][NH:14][C@H:15]1[CH2:34][N:19]2[C:20]3[C:25]([C:26]([CH2:27][C:28]([O:30]CCC)=[O:29])=[C:18]2[CH2:17][CH2:16]1)=[CH:24][CH:23]=[CH:22][CH:21]=3>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([N:14]([CH3:13])[C@H:15]1[CH2:34][N:19]2[C:20]3[C:25]([C:26]([CH2:27][C:28]([OH:30])=[O:29])=[C:18]2[CH2:17][CH2:16]1)=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:12]
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Reactant: O=C(O)Cc1ccc(F)cc1F
Product: CN(C(=O)Cc1ccc(F)cc1F)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using analogous procedures described in Example 1 (Method A) from (2,4-difluorophenyl)acetic acid and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 413.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]#[C:33][CH2:34][NH:35][CH:36]2[CH2:45][CH2:44][C:39]3(OCC[O:40]3)[CH2:38][CH2:37]2)=[CH:4][N:3]=1.Cl.C(=O)([O-])[O-].[Na+].[Na+].O>CC(C)=O.C(OCC)(=O)C>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]#[C:33][CH2:34][NH:35][CH:36]2[CH2:37][CH2:38][C:39](=[O:40])[CH2:44][CH2:45]2)=[CH:4][N:3]=1
Reactant: COc1cc(-c2csc3c(C#CCNC4CCC5(CC4)OCCO5)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(C)=O
Product: COc1cc(-c2csc3c(C#CCNC4CCC(=O)CC4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 42 %

Procedure:
N-(4-{4-Amino-7-[3-(1,4-dioxaspiro[4.5]dec-8-ylamino)prop-1-ynyl]thieno[3,2-c]pyridin-3-yl}-2-methoxyphenyl)-1-methyl-1H-indole-2-carboxamide (0.062 g, 0.099 mmol) in acetone was treated with 5N hydrochloric acid (5 mL). The reaction mixture was stirred for 15 hours at room temperature. Solid sodium carbonate and water were added to basify reaction mixture to pH 7. Ethyl acetate was added and the layers were partitioned. The aqueous layer was extracted with ethyl acetate. The organic layers were combined and dried over magnesium sulfate, filtered and evaporated under reduced pressure to give 0.024 g (41%) of the title compound. 1H NMR (DMSO-d6, 400 MHz) δ 9.51 (s, 1H), 8.01-7.98 (m, 2H), 7.70 (m, 1H), 7.62 (m, 2H), 7.35 (m, 2H), 7.21 (m, 1H), 7.19 (m, 1H), 7.10 (m, 1H), 5.85 (brs, 2H), 4.03 (s, 3H), 3.91 (s, 3H), 3.73 (s, 2H), 3.15 (m, 1H), 2.40-2.20 (m, 4H), 2.10 (m, 2H), 1.70 (m, 2H); LCMS (Conditions a) Rt 3.50 min (95%), M+ 578.4.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1.B(F)(F)F.[CH3:32]COCC>CO>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]([O:25][CH3:32])=[O:24])=[CH:26][CH:27]=1
Reactant: O=C(O)c1ccc(NCCCCCCCCCCCCCCCCBr)cc1
Reactant: CCOCC
Agent: FB(F)F
Solvent: CO
Product: COC(=O)c1ccc(NCCCCCCCCCCCCCCCCBr)cc1
Temperature: 0 °C

Procedure:
A solution of 50.5 g. of 4-(16-bromohexadecylamino)benzoic acid and 34.4 ml. of boron trifluoride etherate in 200 ml. of methanol is stirred under reflux for 44 hours, allowed to cool, and is poured into 1.20 liters of ice-cold 5% aqueous sodium carbonate solution. The white solid is collected by filtration and recrystallized from benzene-ethanol to yield methyl 4-(16-bromohexadecylamino)benzoate, m.p. 92°-93° C.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]1[C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[N:17][C:18]([O:24][CH3:25])=[CH:19][CH:20]=2)[N:15]=1.Cl[CH2:27][C:28](=[O:33])[CH2:29][CH:30]([CH3:32])[CH3:31].Cl>CN(C)C=O.C(OCC)(=O)C.O>[CH3:25][O:24][C:18]1[N:17]=[C:16]2[C:21]([CH:22]=[CH:23][C:14]([N:5]3[CH:4]([O:3][CH2:27][C:28](=[O:33])[CH2:29][CH:30]([CH3:32])[CH3:31])[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[C:6]3=[O:13])=[N:15]2)=[CH:20][CH:19]=1
Reactant: CC(C)CC(=O)CCl
Reactant: COc1ccc2ccc(N3C(=O)c4ccccc4C3O)nc2n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc2ccc(N3C(=O)c4ccccc4C3OCC(=O)CC(C)C)nc2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 24.4 %

Procedure:
An oily suspension (50% by weight; 1.8 g) of sodium hydride is added in small portions at a temperature in the region of -5° C. to a solution, maintained under an argon atmosphere, of 3-hydroxy-2-(7-methoxy-1,8-naphthyridin-2-yl)-1-isoindolinone (9.3 g) in anhydrous dimethylformamide (120 cc), and the suspension obtained is stirred for 30 minutes at a temperature in the region of 0° C. 1-Chloro-4-methyl-2-pentanone (8.1 g) is then added dropwise while the temperature is maintained at 0° C., and stirring is continued for a further 1 hour at 0° C. and then for 4 hours at a temperature in the region of 20° C. The reaction mixture is then poured into a mixture of ice (150 g) and water (350 cc), neutralized with 1N hydrochloric acid solution and extracted with dichloromethane (3×250 cc). The organic phases are combined, washed with water (4×75 cc), dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. The residue obtained is taken up with ethyl acetate (25 cc) and the insoluble product is separated by filtration, washed successively with ethyl acetate (10 cc) and diisopropyl ether (10 cc) and then discarded. The filtrate is concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. The residue obtained is purified by chromatography on silica (120 g) contained in a column 3 cm in diameter [eluant: dichloromethane/methanol (98.5:1.5 by volume)]. Elution is first performed with 170 cc of solvent: the corresponding eluate is discarded; elution is then performed with 800 cc of solvent and the corresponding eluate concentrated to dryness under reduced pressure (2.7 kPa). After recrystallization of the residue in ethyl acetate, 2-(7-methoxy-1,8-naphthyridin-2-yl)-3-(4-methyl-2-oxopentyloxy)-1isoindolinone (3 g), m.p. 120° C., is obtained. 1-Chloro-4-methyl-2-pentanone may be prepared by the method described by ASINGER F., et al., Ann. Chem., 1964, 672, 156.
Reaction SMILES: C[O:2][C:3](=[O:37])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C@H:10]([NH:13][C:14]([C:16]2[N:24]3[C:19]([CH2:20][O:21][CH2:22][CH2:23]3)=[C:18]([C:25](=[O:36])[NH:26][C@@H:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:28][CH3:29])[CH:17]=2)=[O:15])[CH2:11][CH3:12])[CH:5]=1.COC(=O)C1C=CC=C([C@H](N)CC)C=1.[OH-].[Na+]>CO>[C:30]1([C@H:27]([NH:26][C:25]([C:18]2[CH:17]=[C:16]([C:14]([NH:13][C@@H:10]([C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:37])=[O:2])[CH2:11][CH3:12])=[O:15])[N:24]3[CH2:23][CH2:22][O:21][CH2:20][C:19]=23)=[O:36])[CH2:28][CH3:29])[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC[C@@H](NC(=O)c1cc(C(=O)N[C@H](CC)c2cccc(C(=O)OC)c2)n2c1COCC2)c1ccccc1
Agent: CC[C@@H](N)c1cccc(C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC[C@@H](NC(=O)c1cc(C(=O)N[C@H](CC)c2cccc(C(=O)O)c2)n2c1COCC2)c1ccccc1
Yield: 73 %

Procedure:
A solution of 3-((R)-1-{[8-((R)-1-phenyl-propylcarbamoyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-6-carbonyl]-amino}-propyl)-benzoic acid methyl ester (synthesized from comp. no. 11a and 3-((R)-1-amino-propyl)-benzoic acid methyl ester) in methanol (0.5 ml) and 2 N aqueous sodium hydroxide (0.5 ml) was stirred at reflux for 1 h, the solvents were evaporated, water was added and the solution was acidified with excess aqueous hydrochloric acid. The solid formed was filtered off, washed with water and dried in vacuo to give 41 mg (73%) of 3-((R)-1-{[8-((R)-1-phenyl-propylcarbamoyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-6-carbonyl]-amino}-propyl)-benzoic acid. LC/MS (method 2): rt=1.1 min; m/z=490.4 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([N+:12]([O-])=O)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]>CCO.[Pd]>[NH2:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([F:1])[CH:11]=1
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1F
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1ccc(N)cc1F
Yield: 96.5 %

Procedure:
To a stirred solution of methyl 2-fluoro-4-nitrobenzoate (1 g, 4.9 mmol, 1.0 eq) in EtOH (15 mL) was added 10% Pd/C (300 mg) and stirred under hydrogen gas balloon pressure. The reaction mixture was passed through celite, washed with EtOAC, the filtrate was concentrated to obtain methyl 4-amino-2-fluorobenzoate (800 mg; 95%) as a pale yellow solid (TLC: EtOAc/PE (2:3); Rf: 0.2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([C:13]([O:15]C)=[O:14])[CH2:10]2)=[CH:5][CH:4]=1.[OH-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([C:13]([OH:15])=[O:14])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: COC(=O)C1CCc2ccc(OC)cc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc2c(c1)CC(C(=O)O)CC2
Reaction time: 3 h
Yield: 90.9 %

Procedure:
To a solution of methyl 7-methoxy-1,2,3,4-tetrahydronaphthalene-2-carboxylate (4.03 g, 18.3 mmol), in MeOH (180 mL), was added 1N NaOH solution (73.2 mL, 73.3 mmol). The reaction was allowed to stir for 3 h and then the solvents were evaporated until approximately 50 mL of water remained. The solution was washed with Et2O and then the aqueous phase was acidified to pH 1 by the addition of 1N HCl solution. A precipitate formed and was filtered, washed with water and hexane, and dried under vacuum to give 7-methoxy-1,2,3,4tetrahydronaphthalene-2-carboxylic acid as a white solid (3.43 g, 91%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:12]([N:19]1[C:23]2[N:24]=[C:25](F)[N:26]=[C:27]([S:28][C:29]3[C:34]([CH3:35])=[CH:33][C:32]([CH3:36])=[CH:31][C:30]=3[CH3:37])[C:22]=2[CH:21]=[CH:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN1C=CC=CC1=O>[CH2:12]([N:19]1[C:23]2[N:24]=[C:25]([NH:1][C:2]3[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=3)[N:26]=[C:27]([S:28][C:29]3[C:30]([CH3:37])=[CH:31][C:32]([CH3:36])=[CH:33][C:34]=3[CH3:35])[C:22]=2[CH:21]=[CH:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1cc(C)c(Sc2nc(F)nc3c2ccn3Cc2ccccc2)c(C)c1
Reactant: N#Cc1ccc(N)cc1
Agent: Cn1ccccc1=O
Agent: [H-]
Agent: [Na+]
Product: Cc1cc(C)c(Sc2nc(Nc3ccc(C#N)cc3)nc3c2ccn3Cc2ccccc2)c(C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83.4 %

Procedure:
To a solution of 4-aminobenzonitrile (184 mg, 1.56 mmol) in 1-methyl-2-pyridone (2 mL) was added NaH (62 mg, 1.56 mmol). The reaction mixture was stirred at room temperature for 15 min and a solution of 7-benzyl-2-fluoro-4-(2,4,6-trimethyl-phenylsulfanyl)-7H-pyrrolo[2,3-d]pyrimidine (118 mg, 0.31 mmol) in 1-methyl-2-pyridone (2 mL) was added to the mixture. The mixture was stirred at room temperature for 4 h, then poured into ice water and extracted with EtOAc (2×20 mL). The combined organic solution was washed with H2O (20 mL) and brine (20 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (Hexanes:EtOAc=75:25) yielded 123 mg (83%) of 4-[7-benzyl-4-(2,4,6-trimethyl-phenylsulfanyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino]-benzonitrile.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[O:6][C@H:5]([C:7]([O:9]C)=O)[CH2:4][O:3]1.[Cl:12][CH2:13]I.[Li+].CC([N-]C(C)C)C.[OH-].[Na+]>C1COCC1.CCOC(C)=O.C(O)(=O)C>[Cl:12][CH2:13][C:7]([C@@H:5]1[CH2:4][O:3][C:2]([CH3:1])([CH3:11])[O:6]1)=[O:9]
Reactant: ClCI
Reactant: COC(=O)[C@@H]1COC(C)(C)O1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(C)OC[C@@H](C(=O)CCl)O1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 42 %

Procedure:
To a solution of (S)-methyl 2,2-dimethyl-1,3-dioxolane-4-carboxylate (1.3 g, 8.1 mmol) and chloroiodomethane (4.3 g, 24 mmol) in THF (50 mL) at −78° C. was added a solution of LDA (16.2 mL, 24 mmol) in portions over 10 minutes. The reaction was stirred at −78° C. for 10 minutes. To this mixture was added a 10% solution of acetic acid (50 mL) in THF at −78° C. After addition, the slurry was warmed to ambient temperature. The reaction was poured into EtOAc (200 mL) and the aqueous layer basified using 1 N NaOH. The organics were separated and washed with brine, dried over MgSO4 and concentrated in vacuo. The material was purified by chromatography using DCM as eluent to give (S)-2-chloro-1-(2,2-dimethyl-1,3-dioxolane-4-yl)ethanone (0.60 g, 3.4 mmol, 42% yield) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][C:9]2[N:14]=[C:13]([CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[O:28])[CH:20]=[CH:21][C:22]3[CH:27]=[CH:26][N:25]=[CH:24][N:23]=3)[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9]2[N:14]=[C:13]([CH2:15][CH2:16][CH2:17][CH2:18][CH:19]([OH:28])[CH:20]=[CH:21][C:22]3[CH:27]=[CH:26][N:25]=[CH:24][N:23]=3)[CH:12]=[CH:11][CH:10]=2)=[CH:29][CH:30]=1
Reactant: COc1ccc(CNc2cccc(CCCCC(=O)C=Cc3ccncn3)n2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CNc2cccc(CCCCC(O)C=Cc3ccncn3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.4 %

Procedure:
A solution of the enone 6-8 (3.0 g, 7.45 mmol) in MeOH (30 mL) at 0° was treated with NaBH4. The ice bath was removed and the solution was stirred at room temperature for 1 hr. The reaction was quenched with water (25 mL) and extracted with EtOAc (3×125 mL). The organics were combined, dried (Na2SO4), concentrated in vacuo, and purified on silica gel (5% MeOH/CH2Cl2) to afford 1.94 g of 6-9.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]2[NH:15][CH:16]=[CH:17][N:18]=2)=[CH:9][CH:8]=1)C.[NH3:20]>C(O)C>[NH:18]1[CH:17]=[CH:16][N:15]=[C:14]1[CH2:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([NH2:20])=[O:3])=[CH:8][CH:9]=1
Reactant: N
Reactant: CCOC(=O)COc1ccc(Cc2ncc[nH]2)cc1
Solvent: CCO
Product: NC(=O)COc1ccc(Cc2ncc[nH]2)cc1

Procedure:
A solution of 4-(1-imidazolylmethyl)phenoxyacetic acid ethyl ester (2.0 g) in ethanol (10 ml) and concentrated aqueous ammonia (SG 0.880) were heated under reflux for 2 hours and then evaporated. The residue was crystallised from a mixture of methanol and 2-butanone to give 4-(1-imidazolylmethyl)phenoxyacetamide (1.31 g) m.p. 173°-174° C. Found: C, 62.42, H, 5.76, N, 17.40. C12H13N3O2 requires: C, 62.32, H, 5.67, N, 18.17%.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[C:6]([N+:12]([O-])=O)[CH:5]=1)[CH3:2].[NH2:15][C:16]1[CH:33]=[CH:32][C:19]([O:20][CH2:21][C@@H:22]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH3:23])=[CH:18][C:17]=1[F:34].S([O-])([O-])(=O)=O.[Mg+2]>C(O)C>[CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]2[C:6]([CH:5]=1)=[N:12][N:15]([C:16]1[CH:33]=[CH:32][C:19]([O:20][CH2:21][C@@H:22]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:28])[CH3:29])[CH3:23])=[CH:18][C:17]=1[F:34])[CH:8]=2)[CH3:2]
Reactant: CCOc1ccc(C=O)c([N+](=O)[O-])c1
Reactant: C[C@@H](COc1ccc(N)c(F)c1)NC(=O)OC(C)(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCO
Product: CCOc1ccc2cn(-c3ccc(OC[C@H](C)NC(=O)OC(C)(C)C)cc3F)nc2c1
Yield: 57.1 %

Procedure:
A mixture of 4-ethoxy-2-nitrobenzaldehyde (5.20 g), tert-butyl [(1S)-2-(4-amino-3-fluorophenoxy)-1-methylethyl]carbamate (7.58 g), magnesium sulfate (3.21 g) and ethanol (60 mL) was stirred under reflux overnight. The reaction mixture was concentrated under reduced pressure, triethyl phosphite (13.7 ml) was added to the residue, and the mixture was stirred at 130° C. for 3 hr. The reaction mixture was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as a yellow solid (6.53 g).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[C:12]/[CH:13]=[CH:14]\[CH2:15][CH3:16].C1(BC2CCCCC2)CCCCC1.B>C(O)(=O)C>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH:13]=[CH:14]/[CH2:15][CH3:16]
Reactant: CC/C=C\C#CCCCCCCCCCCl
Agent: B
Agent: B(C1CCCCC1)C1CCCCC1
Solvent: CC(=O)O
Product: CC/C=C\C=C/CCCCCCCCCCl

Procedure:
reducing the 15-chloro-(Z)-3-pentadecen-5-yne with dicyclohexyl borane followed by protonolysis of the product borane with acetic acid to obtain 15-chloro-(Z,Z)-3,5-pentadecadiene;
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:12][NH2:13]>O1CCOCC1>[Cl:11][C:8]1[CH:9]=[N:10][C:2]([NH:13][CH3:12])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: CN
Reactant: O=C(O)c1cc(Cl)cnc1Cl
Solvent: C1COCCO1
Product: CNc1ncc(Cl)cc1C(=O)O
Temperature: 160 °C
Yield: 92 %

Procedure:
A mixture of 2,5-dichloronicotinic acid (1.76 g, 9.17 mmol), 41% aq. methylamine solution (7 mL), and 1,4-dioxane (6 mL) was heated at 160° C. under microwave irradiation for 20 min. After cooling, volatile material was distilled off, and the residue was dissolved in water (30 mL) and acidified to pH 3 by addition of 37% aq. hydrochloric acid solution. The precipitate was collected by filtration and triturated in DCM to produce the title compound (1.60 g, 92%). Off-white solid, MS (ISP): 187.1 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].[CH:12]([NH2:15])([CH3:14])[CH3:13]>CO>[CH:12]([NH:15][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9])([CH3:14])[CH3:13]
Reactant: CC(C)N
Reactant: NS(=O)(=O)c1cnccc1Cl
Solvent: CO
Product: CC(C)Nc1ccncc1S(N)(=O)=O
Reaction time: 18 h

Procedure:
10 g of 4-chloropyridine-3-sulfonamide are dissolved in 50 cm3 of methanol and 50 cm3 of isopropylamine. The solution is introduced into a sealed tube and brought to 120° C. for 18 hours. After cooling, the reaction mixture is concentrated to dryness under vacuum (rotary evaporator) and the residue is taken up in 200 cm3 of water. The precipitate corresponding to the title compound is collected on a filter and washed with water. The precipitate is redissolved in 100 cm3 of dilute NaOH. The solution is decolored with charcoal, filtered and then acidified to a pH of 6.5-7. The crystalline precipitate obtained is collected on a filter, washed with water and dried.