Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.Cl.[C:9]1([CH:15]([NH2:25])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Cl:26][CH2:27][C:28](Cl)=[O:29]>C(Cl)(Cl)Cl.C1CCCCC1>[Cl:26][CH2:27][C:28]([NH:25][CH:15]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1)=[O:29]
Reactant: O=C(Cl)CCl
Reactant: COc1cccc(CC(N)c2ccccc2)c1
Agent: Cl
Solvent: C1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cccc(CC(NC(=O)CCl)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.5 %

Procedure:
Triethylamine (254.9 g, 2.5 mol) was added with stirring to a solution of 1-phenyl-2-(3-methoxyphenyl)ethylamine hydrochloride (166.0 g, 0.63 mol) in chloroform (4 L) under nitrogen at 0° C. Then chloroacetyl chloride (142.2 g, 1.26 mol) was added dropwise over a period of 2 hrs. The resulting mixture was stirred at ambient temperature (about 25° C.) for 16 hrs, washed with 10% HCl (3×1 L) and water (1 L), and then the organic phase was dried over MgSO4. Evaporation of the solvent gave a dark oily residue which was dissolved in cyclohexane (2 L). Upon standing, the resulting solution gave solid crystals which were collected by filtration and dried to give 142.5 g of N-chloroacetyl-1-phenyl-2-(3-methoxyphenyl)ethylamine. A sample recrystallized twice from cyclohexane had a mp. 104°-105° C.
Reaction SMILES: [N+:1]([C:4]1[CH:20]=[CH:19][CH:18]=[CH:17][C:5]=1[CH2:6][N:7]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]1[C:13]([O:15][CH3:16])=[O:14])([O-])=O>O1CCCC1.C(OCC)C.O.[Cl-].[Cl-].[Cl-].[Ti+3]>[NH2:1][C:4]1[CH:20]=[CH:19][CH:18]=[CH:17][C:5]=1[CH2:6][N:7]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]1[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1ccc(Cl)n1Cc1ccccc1[N+](=O)[O-]
Agent: [Ti+3]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: COC(=O)c1ccc(Cl)n1Cc1ccccc1N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 2.68 g of methyl 1-(2-nitrobenzyl)-5-chloropyrrole-2-carboxylate in 30 mL of anhydrous tetrahydrofuran is added 35 mL of titanium trichloride in a dropwise manner over a 15 minute period. The reaction is allowed to stir at room temperature for 18 hours and then is diluted with 150 mL of a 1:1 mixture of diethyl ether and water. The organic phase is separated, washed with brine and saturated sodium bicarbonate, dried over anhydrous sodium sulfate, and evaporated to dryness to yield methyl 1-(2-aminobenzyl)-5-chloropyrrole-2-carboxylate which is used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:9][CH:8]=1)[CH3:6])[CH3:2].[Li+].CC([N-]C(C)C)C.[Br:26][CH2:27][CH2:28][CH2:29][CH2:30]Br.O>C1COCC1>[CH2:1]([O:3][C:4](=[O:17])[C:5]([C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:11][CH:12]=1)([CH3:6])[CH2:30][CH2:29][CH2:28][CH2:27][Br:26])[CH3:2]
Reactant: CCOC(=O)C(C)c1ccc(CC(C)C)cc1
Reactant: BrCCCCBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(CCCCBr)c1ccc(CC(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
Under nitrogen atmosphere and at −78° C., to a solution of 204 (10.5 g, 44.8 mmol) in anhydrous THF (150 mL) was added a solution of LDA (2.0 M, 28 mL, 56 mmol) and the mixture was stirred for 1 h. 1,4-Dibromobutane (25 mL, 37.5 g, 175 mmol) was then added dropwise over 30 min and the solution allowed to warm to room temperature over 5 h. After stirring at room temperature for an additional 16 h, the reaction was hydrolyzed with water (100 mL) and extracted with Et2O (2×100 mL). The combined organic layers were washed with 10% HCl (2×100 mL), saturated aqueous NaHCO3 solution (100 mL) and water (100 mL). After drying with Na2SO4 (5 g), filtration and concentration, the crude product was purified by flash chromatography (silica gel; ethyl acetate/hexanes=5/95) and dried in high vacuo (0.5 mmHg) at 150° C. for 30 min, affording 205f (14.49 g, 88%) as a clear, viscous oil. 1H NMR (CDCl3): δ 7.19 (d, 2H, J=8.0), 7.08 (d, 2H, J=8.0), 4.11 (q, 2H, J=7.0), 3.35 (t, 2H, J=6.8), 2.43 (d, 2H, J=7.3), 2.10-1.92 (m, 1H), 1.92-1.78 (m, 4H), 1.53 (s, 3H), 1.40-1.28 (m, 2H), 1.17 (t, 3H, J=7.0), 0.88 (d, 6H, J=6.8). 13C NMR (CDCl3): δ 176.17, 141.12, 140.04, 129.14, 125.64, 60.77, 49.80, 44.99, 38.52, 33.51, 33.26, 30.22, 23.55, 22.69, 22.50, 14.19. HRMS (LSIMS, nba): Calcd for C19H30O2Br (MH+): 369.1429. found: 369.1445.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:12][CH3:13])=[C:9]([CH3:11])[CH:10]=1)(=[O:4])=[O:3].C1C(=O)N([Br:21])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:12][CH3:13])=[C:9]([CH:10]=1)[CH2:11][Br:21])(=[O:3])=[O:4]
Reactant: COc1ccc(S(C)(=O)=O)cc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(S(C)(=O)=O)cc1CBr
Temperature: 25 °C

Procedure:
A mixture of 5-methanesulfonyl-2-methoxytoluene (for preparation, see: U.S. Pat. No. 2,803,580 and Monatsh. Chem. 91, 57 (1960)) (298 mg), NBS (265 mg) and benzoylperoxide (catalytic amount) in CCl4 was irradiated with a sun lamp under reflux under a nitrogen atmosphere for 2 hours and cooled to room temperature. The solid was filtered off and the filtrate was concentrated and subjected to silica gel chromatogiraphy (hexanes/ethyl acetate 3:1) to give bromide 5 as a white solid.
Reaction SMILES: [CH3:1][C:2](O)([CH2:5][CH2:6][CH:7]=[C:8]([CH3:19])[CH2:9][CH2:10][CH:11]=[C:12]([CH3:18])[CH2:13][O:14][CH2:15][O:16][CH3:17])[C:3]#[CH:4].C(O)(=[O:28])C1C=CC=CC=1>C1(C)C(C)=CC=CC=1>[CH3:17][O:16][CH2:15][O:14][CH2:13][C:12]([CH3:18])=[CH:11][CH2:10][CH2:9][C:8]([CH3:19])=[CH:7][CH2:6][CH2:5][C:2]([CH3:1])=[CH:3][CH:4]=[O:28]
Reactant: C#CC(C)(O)CCC=C(C)CCC=C(C)COCOC
Reactant: O=C(O)c1ccccc1
Solvent: Cc1ccccc1C
Product: COCOCC(C)=CCCC(C)=CCCC(C)=CC=O
Temperature: 25 °C
Yield: 506.2 %

Procedure:
A solution of 3,7,11-trimethyl-12-(methoxymethyl)oxy-6,10-dodecadien-1-in-3-ol (175 mg, 0.62 mmol), tris (triphenylsilyl)vanadate (49 mg, 0.062 mmol), and benzoic acid (7.6 mg, 0.062 mmol) in xylene (2 ml) was stirred on an oil bath at 140° C. After two-hour-stirring, the solution was allowed to cool to room temperature and concentrated. The resultant residue was subjected to silica gel column chromatography to obtain 12-(methoxymethyl)oxy-3,7,11-trimethyl-2,6,10-dodecatrienal (88 mg, 50%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=O.[CH3:12][C:13]1[N:18]=[CH:17][C:16]([CH:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH2:20][NH2:21])=[CH:15][N:14]=1>>[F:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:2]([F:1])[C:3]=1[C:4]([NH:21][CH2:20][CH:19]([C:16]1[CH:17]=[N:18][C:13]([CH3:12])=[N:14][CH:15]=1)[N:22]1[CH2:23][CH2:24][O:25][CH2:26][CH2:27]1)=[O:6]
Reactant: O=C(O)c1c(F)cccc1F
Reactant: Cc1ncc(C(CN)N2CCOCC2)cn1
Product: Cc1ncc(C(CNC(=O)c2c(F)cccc2F)N2CCOCC2)cn1

Procedure:
From 2,6-difluorobenzoic acid and 2-(2-methylpyrimidin-5-yl)-2-morpholinoethanamine.
Reaction SMILES: [O:1]=[CH:2][C:3]([Cl:6])([Cl:5])[Cl:4].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[C:10]=1[OH:17].C(=O)([O-])[O-].[K+].[K+].P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+]>O>[CH3:16][O:15][C:11]1[CH:12]=[C:13]([CH:2]([OH:1])[C:3]([Cl:6])([Cl:5])[Cl:4])[CH:14]=[C:9]([O:8][CH3:7])[C:10]=1[OH:17]
Reactant: O=CC(Cl)(Cl)Cl
Reactant: COc1cccc(OC)c1O
Agent: O=C([O-])[O-]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Product: COc1cc(C(O)C(Cl)(Cl)Cl)cc(OC)c1O
Reaction time: 8 h

Procedure:
47 grams of anhydrous chloral and 50 grams of 2,6-dimethoxyphenol were introduced in a reactor thermostated at 45° C. Upon obtaining a homogeneous solution, a mixture of 6.4 grams of potassium carbonate and 1.6 grams of sodium phosphate was added thereto portionwise under stirring in a 3-hour period. At the end of the addition, the mixture was left under stirring at the same temperature until the mixture thickened. The stirring was stopped and the mixture was left stand overnight at 45° C. The mixture was kneaded a long time in water and filtered. A yellow-reddish solid product was obtained, which was crystallized from aqueous ethanol. Yield: 82 grams (83.9% calculated on dimethoxyphenol). Analysis: chlorine 34.7% theoretical 35.27%), melting point 160°-162° C.; purity 97.5% (GC).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].[NH:20]1[CH2:23][CH:22]([NH:24][CH2:25][C@H:26]2[O:30][C:29](=[O:31])[N:28]([C:32]3[CH:33]=[CH:34][C:35]4[S:40][CH2:39][C:38](=[O:41])[NH:37][C:36]=4[CH:42]=3)[CH2:27]2)[CH2:21]1>CC#N.O>[CH:12]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:19])=[C:2]([N:20]4[CH2:23][CH:22]([NH:24][CH2:25][C@H:26]5[O:30][C:29](=[O:31])[N:28]([C:32]6[CH:33]=[CH:34][C:35]7[S:40][CH2:39][C:38](=[O:41])[NH:37][C:36]=7[CH:42]=6)[CH2:27]5)[CH2:21]4)[N:11]=3)[C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8]2)[CH2:14][CH2:13]1
Reactant: O=C1CSc2ccc(N3C[C@@H](CNC4CNC4)OC3=O)cc2N1
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Solvent: O
Solvent: CC#N
Product: O=C1CSc2ccc(N3C[C@@H](CNC4CN(c5nc6c(cc5F)c(=O)c(C(=O)O)cn6C5CC5)C4)OC3=O)cc2N1
Temperature: 75 °C

Procedure:
A mixture of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid (commercial; 141 mg), 6-[(5R)-5-[(3-azetidinylamino)methyl]-2-oxo-3-oxazolidinyl]-2H-1,4-benzothiazin-3(4H)-one (prepared according to WO 2008/126034; 167 mg) and TEA (0.15 ml) in MeCN (4 ml) was heated at 75° C. for 2 h. The reaction mixture was allowed to reach rt, diluted with water, filtered and the solid was washed with MeOH and EA, affording a beige solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13]C(=O)C(C)(C)C)=[N:9]2)[CH2:4][O:3]1.O.[OH-].[Na+]>CO>[CH3:1][C:2]1([CH3:20])[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH2:13])=[N:9]2)[CH2:4][O:3]1
Reactant: CC1(C)OC[C@@H](Cn2ccc(NC(=O)C(C)(C)C)n2)O1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Temperature: 70 °C
Reaction time: 40 h

Procedure:
N-[1-((R)-2,2-Dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-2,2-dimethyl-propionamide (1.42 g, 5 mmol) was dissolved in methanol (15 ml), and water (3 ml) was added in one portion. NaOH (1.67 g, 40 mmol) was added in one portion. The mixture was stirred at 70° C. for 40 h. HPLC indicated the conversation was 2.8%. No further workup.
Reaction SMILES: [C:1]([O:4][CH:5]([C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][N:14]=1)[C:6]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])(=[O:3])[CH3:2].[H][H]>O1CCOCC1.[Pd]>[C:9]([NH:8][C:6](=[O:7])[CH:5]([C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][N:14]=1)[O:4][C:1](=[O:3])[CH3:2])([CH3:10])([CH3:11])[CH3:12]
Reactant: [H][H]
Reactant: CC(=O)OC(C(=O)NC(C)(C)C)c1ccc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: C1COCCO1
Product: CC(=O)OC(C(=O)NC(C)(C)C)c1ccc(N)cn1

Procedure:
5 g (16.9 mmol) of 2-acetoxy-2-(5-nitro-2-pyridyl)-N-tert.-butyl-acetamide are dissolved in 50 ml of 90% strength aqueous dioxane, 250 mg of 10% strength palladium-on-active charcoal are added and hydrogenation is carried out at room temperature until the uptake of hydrogen is complete. For working up, the catalyst is filtered off and the filtrate is evaporated. The residue is dried.
Reaction SMILES: ClC.[CH3:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[NH:11][CH2:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:25]([S:29](Cl)(=[O:31])=[O:30])[CH2:26][CH2:27][CH3:28]>C(=O)(O)[O-].[Na+]>[CH3:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[N:11]([CH2:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[S:29]([CH2:25][CH2:26][CH2:27][CH3:28])(=[O:31])=[O:30]
Reactant: CCCCS(=O)(=O)Cl
Reactant: Cc1ccc(NCc2cccnc2)c(C)c1
Agent: CCl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Product: CCCCS(=O)(=O)N(Cc1cccnc1)c1ccc(C)cc1C
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A 4.2 g. portion of 3-(2,4-dimethylphenylaminomethyl)pyridine chloromethane, and to it were added 4.1 g. of potassium carbonate and 4.7 g. of butanesulfonyl chloride. The mixture was stirred at ambient temperature for 4 days, and then was stirred under gentle reflux for several days more. It was then diluted with aqueous sodium bicarbonate and extracted with dichloromethane, and the organic layer was dried over magnesium sulfate and evaporated to an oil. The oil was applied to a silica gel column and eluted with dichloromethane and then with chloroform to obtain 0.75 g. of the desired product.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11]P(=O)(OCC)OCC.[H-].[Na+].[CH:22]([C:24]1[S:25][CH:26]=[C:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:28]=1)=O.O>C1COCC1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1/[CH:11]=[CH:22]/[C:24]1[S:25][CH:26]=[C:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:28]=1
Reactant: CCOC(=O)c1csc(C=O)n1
Reactant: CCOP(=O)(Cc1ccc2ccccc2n1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1csc(/C=C/c2ccc3ccccc3n2)n1
Reaction time: 0.17 h

Procedure:
Diethyl 2-quinolinylmethylphosphonate (0.580 g, 2.08 mmol; see Preparation 13(i) above) was dissolved in anhydrous THF (2 mL), NaH (0.273 g, 11 mmol) was then added in small portions and the resulting solution allowed to stir for 10 min. Ethyl 2-formyl-1,3-thiazole-4-carboxylate (0.387 g, 2.08 mmol; see step (v) above) in anhydrous THF (3 mL) was added dropwise and the solution allowed to stir for 16 h. Water (5 mL) was then added (dropwise initially), during which time the sub-title compound precipitated as a light brown/yellow solid.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]1[CH:23]=[CH:22][C:17]([C:18](OC)=[O:19])=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl.[CH3:27][C:28]1[CH:33]=[C:32]([CH3:34])[CH:31]=[CH:30][C:29]=1[N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>O1CCOCC1.CO>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]1[CH:15]=[CH:16][C:17]([C:18]([N:38]2[CH2:39][CH2:40][N:35]([C:29]3[CH:30]=[CH:31][C:32]([CH3:34])=[CH:33][C:28]=3[CH3:27])[CH2:36][CH2:37]2)=[O:19])=[CH:22][CH:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Reactant: COC(=O)c1ccc(N2C(=O)OC[C@H]2Cc2ccccc2)cc1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4Cc4ccccc4)cc3)CC2)c(C)c1
Temperature: 65 °C
Reaction time: 7 h
Yield: 61.3 %

Procedure:
To methyl (R)-4-(4-benzyl-2-oxooxazolidin-3-yl)benzoate (0.19 g) described in Preparation Example 22 were added 1N aqueous sodium hydroxide solution (0.92 mL), methanol (5 mL) and 1,4-dioxane (1 mL), and the mixture was stirred at 65° C. for 7 hr. 1N hydrochloric acid (0.92 mL) was added, 1-(2,4-dimethylphenyl)piperazine (0.116 g) and 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (0.17 g) were added, and the mixture was stirred at room temperature. After completion of the reaction, the mixture was extracted with ethyl acetate, washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (chloroform) to give the title compound (175.4 mg).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([N:20]([C:24]([C:26]2[CH:27]=[N:28][C:29](Br)=[CH:30][CH:31]=2)=[O:25])[CH:21]2[CH2:23][CH2:22]2)[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].[CH3:33][S:34]([C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1)(=[O:36])=[O:35]>CN(C)C=O>[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([N:20]([CH:21]2[CH2:23][CH2:22]2)[C:24]([C:26]2[CH:27]=[N:28][C:29]([C:40]3[CH:41]=[CH:42][C:37]([S:34]([CH3:33])(=[O:36])=[O:35])=[CH:38][CH:39]=3)=[CH:30][CH:31]=2)=[O:25])[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(N(C(=O)c2ccc(Br)nc2)C2CC2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(N(C(=O)c2ccc(-c3ccc(S(C)(=O)=O)cc3)nc2)C2CC2)CC1
Temperature: 90 °C
Reaction time: 6 h

Procedure:
2 M aqueous Na2CO3 solution (8.26 mL) is added to a mixture of 4-[(6-bromo-pyridine-3-carbonyl)-cyclopropyl-amino]-piperidine-1-carboxylic acid tert-butyl ester (500 mg) and 4-(methanesulfonyl)phenylboronic acid (259 mg) in N,N-dimethylformamide (5 mL). The mixture is sparged with argon for 10 min and [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium dichloromethane complex (96 mg) is added. The resulting mixture is stirred for 6 h at 90° C. After cooling to room temperature, water (50 mL) is added and the aqueous phase is extracted with ethyl acetate. The organic phase is dried over MgSO4, the solvent is evaporated, and the residue is chromatographed on silica gel (ethyl acetate/cyclohexane 3:1→1:0) to afford the title compound. LC (method 6): tR=1.17 min; Mass spectrum (ESI+): m/z=500 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:32]=[CH:31][C:19]4[CH2:20][CH2:21][N:22]([CH2:25][C:26]([O:28]CC)=[O:27])[CH2:23][CH2:24][C:18]=4[CH:17]=3)[N:12]=2)=[CH:7][C:6]=1[C:33]([F:36])([F:35])[F:34])[CH3:3].[OH-].[Na+]>C(O)C>[CH3:3][CH:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:32]=[CH:31][C:19]4[CH2:20][CH2:21][N:22]([CH2:25][C:26]([OH:28])=[O:27])[CH2:23][CH2:24][C:18]=4[CH:17]=3)[N:12]=2)=[CH:7][C:6]=1[C:33]([F:36])([F:35])[F:34])[CH3:1]
Reactant: CCOC(=O)CN1CCc2ccc(-c3noc(-c4ccc(OC(C)C)c(C(F)(F)F)c4)n3)cc2CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)CCN(CC(=O)O)CC4)no2)cc1C(F)(F)F
Temperature: 40 °C
Yield: 66.7 %

Procedure:
A mixture of ethyl (7-{5-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}-1,2,4,5-tetrahydro-3H-3-benzazepin-3-yl)acetate (Preparation 48) (59 mg, 0.12 mmol), aqueous sodium hydroxide (2M, 590 μL, 1.18 mmol) and ethanol (6 ml) was heated at 40° C. for 1 hr. The reaction mixture was cooled to room temperature and concentrated. The residue was taken up in water, which was then acidified to pH 6 with acetic acid. The aqueous phase was extracted with EtOAc (2×20 ml) before the combined organic fractions were concentrated and the residue was triturated with EtOAc and the title compound was filtered off and dried in a vacuum oven to give a white solid (36 mg, 0.08 mmol). δH (d6DMSO, 400 MHz): 8.41 (1H, dd), 8.30 (1H, d), 7.88-7.82 (2H, m), 7.58 (1H, d), 7.35 (1H, d), 4.98 (1H, septet), 3.25 (2H, s), 3.06-2.96 (4H, m), 2.89-2.81 (4H, m), 1.36 (6H, d); MS (ES−): C24H24F3N3O4 requires 475; found 474 [M−H+].
Reaction SMILES: [H-].[Na+].[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH2:8][OH:9].Br[CH2:11][C:12]#[CH:13].O>CN(C=O)C.C1(C)C=CC=CC=1>[CH2:13]([O:9][CH2:8][C:4]1[O:3][CH:7]=[CH:6][CH:5]=1)[C:12]#[CH:11]
Reactant: C#CCBr
Reactant: OCc1ccco1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: C#CCOCc1ccco1
Temperature: 0 °C
Yield: 33.5 %

Procedure:
To a suspension of sodium hydride (1.570 g, 39.2 mmol) in DMF (46 ml) stirred under argon at 0° C. was dropped a solution of 2-furanylmethanol (3.5 g, 35.7 mmol) in DMF (4 ml) in 20 minutes. The reaction mixture was stirred at 0° C. for 15 minutes. 3-bromo-1-propyne (4.24 g, 35.7 mmol) 80% in toluene was dropped in 10 minutes at 0° C., then the mixture was left stirring at room temperature overnight. Water was added and then the mixture was extracted with ethyl ether 3 times. The organic phase was dried over sodium sulphate and concentrated under vacuum. The residue was purified by flash chromatography on silica (Biotage SP1 instrument), eluting with a gradient cyclohexane/ethyl acetate 95/5 to 85/15. Evaporation afforded the title compound (1.63 g).
Reaction SMILES: C1(NN)C=CC=CC=1.[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][NH2:17].N1C=CC=CC=1NN.C(N(CC)C(C)C)(C)C.[C:35]12[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=1)[NH:40]C(=O)O[C:36]2=[O:37]>O1CCCC1.C(O)C.C(N(CC)CC)C>[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][NH:17][C:36](=[O:37])[C:35]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[NH2:40]
Reactant: NNc1ccccc1F
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Agent: NNc1ccccn1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: NNc1ccccc1
Product: Nc1ccccc1C(=O)NNc1ccccc1F

Procedure:
A phenylhydrazine b (e.g., 2-fluorophenylhydrazine) or pyridinylhydrazine (e.g., 2-hydrazinopyridine) that has been treated with or without a base such as N,N-diisopropylethylamine or triethylamine in a suitable solvent (e.g., ethanol or tetrahydrofuran (THF)) is reacted with the anhydride a (e.g., isatoic anhydride) to give the hydrazide c (e.g., 2-amino-benzoic acid N′-(2-fluoro-phenyl)-hydrazide). c is then acidified and reacted with sodium nitrite, followed by ethanol to generate the indazole d (e.g., 1-(2-fluoro-phenyl)-1H-indazol-3-ol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl.Cl[CH2:26][CH2:27][N:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1.CCOC(C)=O>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:26][CH2:27][N:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:6][CH:7]=1
Reactant: ClCCN1CCCC1
Reactant: Fc1ccc(Nc2nccs2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Fc1ccc(N(CCN2CCCC2)c2nccs2)cc1

Procedure:
A solution of 1.0 g (5.2 mmol) of N-(4-fluorophenyl)thiazol-2-amine in 25 mL of THF was treated with 10.3 mL (10.3 mmol) of a 1.0 M solution of NaHMDS in THF and 0.88 g (5.2 mmol) of 1-(2-chloroethyl)pyrrolidine hydrochloride and heated at reflux for 18 h. The reaction mixture was poured into 250 mL of EtOAc and extracted thrice with 1 M aqueous HCl. The combined acidic extracts were brought to pH 12 with a 10% (w/v) solution of Na2CO3 and extracted five times with CHCl3. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo, and the crude product was purified by flash chromatography eluting with a linear gradient of neat EtOAc to 20% MeOH in EtOAc to deliver the desired compound. MS (M+H)+ 292.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][C:10]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:9]=2[S:8][CH2:7][CH2:6]1.Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])[C:21]([Cl:35])=[CH:20][N:19]=1>>[Cl:35][C:21]1[C:22]([NH:24][C:25]2[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])=[N:23][C:18]([NH:16][C:13]2[CH:14]=[CH:15][C:9]3[S:8][CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][C:10]=3[CH:12]=2)=[N:19][CH:20]=1
Reactant: COCCN1CCSc2ccc(N)cc2C1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CN(CCOC)CCS3)ncc1Cl
Yield: 41.5 %

Procedure:
Following the procedure of 512f, 8-(2-methoxy-ethyl)-6,7,8,9-tetrahydro-5-thia-8-aza-benzocyclohepten-2-ylamine (0.07 g, 0.00029 mol) and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl benzamide (0.086 g, 0.00029 mol) were reacted. Purification was carried by SiO2 prep plate chromatography giving 2-{5-chloro-2-[8-(2-methoxy-ethyl)-6,7,8,9-tetrahydro-5-thia-8-aza-benzocyclohepten-2-ylamino]-pyrimidin-4-ylamino}-N-methyl-benzamide (0.06 g, 43%) as a grey solid. MP: 176-7° C.; 1H-NMR (DMSO-d6) 11.63 (s, 1H), 9.53 (s, 1H), 8.75 (d, 1H), 8.72 (d, 1H), 8.24 (s, 1H), 7.75-7 (d, 1H), 7.61 (s, 1H), 7.51-7 (m, 2H), 7.36-8 (d, 1H), 7.16-8 (t, 1H), 7.11-4 (d, 1H), 5.17 (s, 1H), 3.98 (s, 2H), 3.89 (s, 1H0, 2.80-1 (d, 2H), 2.67 (d, 2H); LC/MS (ESI+): 499 (M).