Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([O:6][C:7]([CH3:22])([CH:20]=[CH2:21])[C:8]#[C:9][C:10]1(O)[C:15]([CH3:17])([CH3:16])[CH2:14][CH2:13][CH:12]=[C:11]1[CH3:18])C)C.[C:23]([OH:26])(=[O:25])[CH3:24]>CCCCCC>[CH3:18][C:11]1[CH:12]([O:26][C:23](=[O:25])[CH3:24])[CH2:13][CH2:14][C:15]([CH3:16])([CH3:17])[C:10]=1[C:9]#[C:8][C:7]([CH3:22])([OH:6])[CH:20]=[CH2:21]
Reactant: C=CC(C)(C#CC1(O)C(C)=CCCC1(C)C)OC(C)OCC
Reactant: CC(=O)O
Solvent: CCCCCC
Product: C=CC(C)(O)C#CC1=C(C)C(OC(C)=O)CCC1(C)C

Procedure:
The compound 1-ethoxy-[1-(2,6,6-trimethyl-1-hydroxy-2-cyclohexen-1-yl)-3-methyl-4-penten-1-yn-3-oxy]ethane (9.5) in acetic acid (40 ml) was heated at 55° for 11/2 hr and then taken to dryness "in vacuo" (45° at .5 mmHg), dissolved in hexane, and chromatographed on silica gel (400 g). Elution with hexane-ether mixtures (4:1 parts by volume and 3:1 parts by volume 500 ml cuts, 2 liters) yielded 1-(2,6,6-trimethyl-3-acetoxycyclohexen-1-yl)-3-methyl-4-penten-1-yn-3-ol (4.3g) bp 165° (0.09 mmHg).
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][CH:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]=2[CH:18]=1)N.O.Cl.[NH:21]1[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1>C(O)(C)C>[C:12]1([C:9]2[C:8]3=[C:18]4[C:4](=[CH:5][CH:6]=[C:7]3[S:11][CH:10]=2)[NH:2][C:24]2[CH2:25][CH2:26][NH:21][CH2:22][C:23]4=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1CCNCC1
Reactant: NNc1ccc2scc(-c3ccccc3)c2c1
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: c1ccc(-c2csc3ccc4[nH]c5c(c4c23)CNCC5)cc1

Procedure:
28 g of 5-hydrazino-3-phenylbenzothiophene hydrochloride are dissolved in 300 ml of isopropanol and the solution is combined with 20 g of 4-piperidone hydrochloride monohydrate under an inert gas. After boiling the mixture for 3 hours, the solvent is evaporated off, the residue is taken up in isopropanol and the product is precipitated with the addition of isopropyl ether. The precipitate is filtered off and taken up in water; a layer of methylene chloride is introduced under the solution and the mixture is shaken with NaOH solution. The organic phase is separated off and worked up. Melting point: 228° C. (decomposition)
Reaction SMILES: [BH4-].[Na+].C(O)C.[N:6]1([CH2:24][C:25]([C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=2)=[O:26])[CH2:11][CH2:10][N:9]([CH2:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:14])[CH2:8][CH2:7]1>O>[N:6]1([CH2:24][CH:25]([C:27]2[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=2)[OH:26])[CH2:11][CH2:10][N:9]([CH2:12][CH:13]([C:15]2[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=2)[OH:14])[CH2:8][CH2:7]1
Reactant: O=C(CN1CCN(CC(=O)c2ccc([N+](=O)[O-])cc2)CC1)c1ccc([N+](=O)[O-])cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1ccc(C(O)CN2CCN(CC(O)c3ccc([N+](=O)[O-])cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
NaBH4 (308 mg, 8.15 mmol) was added to a 25 mL ethanol solution of 2,2′-piperazine-1,4-diylbis[1-(4-nitrophenyl)ethanone] (400 mg, 0.970 mmol) at 0° C. The reaction mixture was allowed to warm up to room temperature and stir overnight. The reaction mixture was poured into water and extracted twice with EtOAc. The combined organic layers were washed with brine twice, then dried over MgSO4, filtered, and evaporated to dryness. The residue was purified by preparative TLC using 5% methanol in DCM to yield 2,2′-piperazine-1,4-diylbis[1-(4-nitrophenyl)ethanol].
Reaction SMILES: F[C:2]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[F:10][C:9]1[C:2]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[C:3]([CH:6]=[CH:7][CH:8]=1)[CH:4]=[O:5]
Reactant: O=Cc1cccc(F)c1F
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=Cc1cccc(F)c1N1CCOCC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 28.5 %

Procedure:
A 100 mL round-bottom flask was charged with 2,3-difluorobenzaldehyde (2.00 g, 14.1 mmol, 1.00 equiv), morpholine (1.84 g, 21.1 mmol, 1.50 equiv), potassium carbonate (4.90 g, 35.4 mmol, 2.52 equiv), and dimethyl sulfoxide (20 mL). The resulting solution was stirred overnight at 100° C. in an oil bath and diluted with H2O (50 mL). The resulting solution was extracted with dichloromethane (3×20 mL) and the organic layers were combined, washed with H2O (3×50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/20) to yield 0.840 g (28% yield) of 3-fluoro-2-(morpholin-4-yl)benzaldehyde as a yellow solid. 1H NMR 300 MHz, (CDCl3) δ 10.54 (s, 1H), 7.63 (d, J=7.5 Hz, 1H), 7.18-7.34 (m, 2H), 3.85 (br, 4H), 3.23 (br, 4H). LCMS (ESI, m/z): 210 [M+H].
Reaction SMILES: Cl.C(OCC)(=O)C.C(OC([N:15]1[C@@H:19]([C@@H:20]([OH:22])[CH3:21])[CH2:18][CH2:17][C@H:16]1[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)=O)(C)(C)C>>[F:29][C:26]1[CH:27]=[CH:28][C:23]([C@H:16]2[NH:15][C@@H:19]([C@@H:20]([OH:22])[CH3:21])[CH2:18][CH2:17]2)=[CH:24][CH:25]=1
Reactant: C[C@H](O)[C@H]1CC[C@@H](c2ccc(F)cc2)N1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: C[C@H](O)[C@H]1CC[C@@H](c2ccc(F)cc2)N1
Yield: 100 %

Procedure:
A 4 N hydrochloric acid/ethyl acetate (6.8 mL) solution of (2S,5R)-2-(4-fluorophenyl)-5-((S)-1-hydroxyethyl)-pyrrolidine-1-carboxylic acid t-butyl ester (708 mg, high polarity compound) was stirred for 1 hour at room temperature. The solvent was removed under a vacuum, and 5 N sodium hydroxide was added, and extraction was conducted twice with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under a vacuum, and the title compound (479 mg) was obtained. The physical property values are as follows.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=1.CN(C)[CH:23]=[O:24]>O1CCCC1.C(OCC)(=O)C.O.C(O)(=O)C>[Cl:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([Br:13])[C:15]=1[CH:23]=[O:24]
Reactant: Clc1cccc(Br)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=Cc1c(Cl)cccc1Br
Temperature: 0 °C

Procedure:
A 1.6 molar solution of butyllithium in hexanes (4.5 mL, 2.8 mmol) was placed in a three-neck flask equipped with a stirrer, addition funnel, low-temperature thermometer and nitrogen inlet tube at 0° C. A solution of diisopropyl amine (1.13 mL, 8.1 mmol) in anhydrous tetrahydrofuran was added dropwise. The resulting solution was stirred at 0° C. for ten minutes, then cooled to −78° C. Upon cooling, a solution of 1-bromo-3-chlorobenzene (1.4 g, 7.3 mmol) in anhydrous tetrahydrofuran was added dropwise. The reaction was allowed to stir at −78° C. for one hour. Anhydrous dimethylformamide (636 μL) was added. The solution was allowed to slowly warm to room temperature, followed by the addition of acetic acid (50 mL) and water (50 mL). The aqueous mixture was extracted with ether twice and the ether layers were separated. The combined ether layers were successively washed with aqueous hydrochloric acid and brine. The separated organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel, eluting with 9:1 hexanes:ethyl acetate to yield 2-chloro-6-bromobenzaldehyde as an off white solid (850 mg, 53% yield). NMR (300 MHz, CDCl3): 10.4 (s, 1H), 7.6 (m, 1H), 7.45 (m, 1H), 7.3 ppm (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:29])=[C:4]([CH:26]=[CH:27][CH:28]=1)[CH2:5][N:6]1[C:10]2=[N:11][C:12]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[CH:13][C:14]([C:15]([O:17]C)=[O:16])=[C:9]2[N:8]=[C:7]1[CH3:25]>[Li+].[OH-].C1COCC1>[Cl:1][C:2]1[C:3]([CH3:29])=[C:4]([CH:26]=[CH:27][CH:28]=1)[CH2:5][N:6]1[C:10]2=[N:11][C:12]([N:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)=[CH:13][C:14]([C:15]([OH:17])=[O:16])=[C:9]2[N:8]=[C:7]1[CH3:25]
Reactant: COC(=O)c1cc(N2CCOCC2)nc2c1nc(C)n2Cc1cccc(Cl)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1c(Cl)cccc1Cn1c(C)nc2c(C(=O)O)cc(N3CCOCC3)nc21
Temperature: 60 °C
Reaction time: 5 h
Yield: 70.1 %

Procedure:
A mixture of methyl 3-(3-chloro-2-methylbenzyl)-2-methyl-5-morpholino-3H-imidazo[4,5-b]pyridine-7-carboxylate (239 mg, 0.58 mmol) in 2N LiOH (15 mL) and THF (15 mL) was stirred at 60° C. for 5 h. It was cooled to room temperature and the precipitate was collected by filtration. It was then poured into water (100 mL) and the suspension was acidified with formic acid to pH=1. It was filtered and the solid was washed with water to afford the desired product as a gray solid (163 mg, 71%). LC/MS: MS (ES+) m/e 401 (MH+); 1H NMR (300 MHz, DMSO-d6) δ ppm 2.36 (s, 3H), 2.44 (s, 3H), 3.41 (s, 4H), 3.69 (s, 4H), 5.44 (s, 2H), 6.40 (d, J=7.5 Hz, 1H), 7.05-7.11 (m, 2H), 7.35 (d, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][C:6](=O)[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.[CH2:12]([NH2:15])[CH2:13][NH2:14]>CO>[CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([NH:14][CH2:13][CH2:12][NH:15][CH:6]2[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3][C:2]([CH3:11])([CH3:1])[CH2:7]2)[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1
Reactant: NCCN
Reactant: CC1(C)CC(=O)CC(C)(C)N1
Solvent: CO
Product: CC1(C)CC(NCCNC2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1
Reaction time: 2 h

Procedure:
162.75 g (1.05 moles) of 2,2,6,6-tetramethyl-4-piperidone dissolved in 200 cc of methanol, 30 g (0.5 moles) of ethylenediamine dissolved in 40 cc of methanol, and 0.5 g of Pt (at 10% on carbon) were introduced into a 1 liter autoclave, and the mixture hydrogenated at 80° C and 50 atm pressure for 2 hours.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:8]=[C:9]([NH:14][C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([C@H:25]3[CH2:30][N:29]([CH2:31][CH3:32])[CH2:28][CH2:27][NH:26]3)=[O:24])[CH2:19][CH2:18]2)=[O:16])[CH:10]=[CH:11][C:12]=1[Cl:13]>>[Cl:6][C:7]1[CH:8]=[C:9]([NH:14][C:15]([N:17]2[CH2:18][CH2:19][N:20]([C:23]([C@H:25]3[CH2:30][N:29]([CH2:31][CH3:32])[CH2:28][CH2:27][N:26]3[S:2]([CH3:1])(=[O:4])=[O:3])=[O:24])[CH2:21][CH2:22]2)=[O:16])[CH:10]=[CH:11][C:12]=1[Cl:13]
Reactant: CCN1CCN[C@@H](C(=O)N2CCN(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Reactant: CS(=O)(=O)Cl
Product: CCN1CCN(S(C)(=O)=O)[C@@H](C(=O)N2CCN(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Yield: 64 %

Procedure:
In this way, using methane sulphonylchloride (13 μl), N-(3,4-Dichlorophenyl)-4-{[(2R)-4-ethylpiperazin-2-yl]carbonyl}piperazine-1-carboxamide (70 mg) gave the title compound (53 mg, 64%).
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=2)=[CH:10][CH:11]=1)[CH:2]([CH3:4])[CH3:3].[F:22][C:23]1[CH:24]=[CH:25][C:26]([CH3:33])=[C:27]([S:29](Cl)(=[O:31])=[O:30])[CH:28]=1.C(N(CC)C(C)C)(C)C>ClCCl>[F:22][C:23]1[CH:24]=[CH:25][C:26]([CH3:33])=[C:27]([S:29]([N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH2:6][C:7]2[S:8][C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=3)=[CH:10][CH:11]=2)(=[O:31])=[O:30])[CH:28]=1
Reactant: CC(C)CNCc1ccc(-c2cccc(S(C)(=O)=O)c2)s1
Reactant: Cc1ccc(F)cc1S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(F)cc1S(=O)(=O)N(Cc1ccc(-c2cccc(S(C)(=O)=O)c2)s1)CC(C)C

Procedure:
In analogy to example 13, step 2, isobutyl-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-amine (example 15, step 2) was reacted with 5-fluoro-2-methylbenzenesulfonyl chloride and N,N-diisopropyl ethyl amine in dichloromethane to give 5-fluoro-N-isobutyl-N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-2-methyl-benzenesulfonamide as a colorless oil. MS: 513.0 ([M+NH4]+)
Reaction SMILES: [CH3:1][C:2]1([C:7]2[C:8]([CH2:13][CH2:14][NH2:15])=[N:9][CH:10]=[CH:11][CH:12]=2)OCCO1.Cl.[OH-].[Na+]>>[CH3:1][C:2]1[C:7]2[CH:12]=[CH:11][CH:10]=[N:9][C:8]=2[CH2:13][CH2:14][N:15]=1
Reactant: CC1(c2cccnc2CCN)OCCO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC1=NCCc2ncccc21
Temperature: 100 °C

Procedure:
2-[3-(2-Methyl-[1,3]dioxolan-2-yl)-pyridin-2-yl]-ethylamine (490 mg, 2.35 mmol, 1.0 equiv) is dissolved in 1N HCl solution (47 mL, 47.0 mmol, 20.0 equiv) and heated at 100° C. for 2 hours. According to TLC analysis the reaction is completed. The mixture is cooled and 1N NaOH solution is added. The mixture is extracted twice with dichloromethane, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. This gave the title compound.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].[CH3:11][C:12]1([CH3:19])[C:16]([CH3:18])([CH3:17])[O:15][BH:14][O:13]1.CCN(CC)CC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[CH3:10][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[C:7]([CH3:8])[C:2]=1[B:14]1[O:15][C:16]([CH3:18])([CH3:17])[C:12]([CH3:19])([CH3:11])[O:13]1
Reactant: Cc1cc(O)cc(C)c1Br
Reactant: CC1(C)OBOC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cc1cc(O)cc(C)c1B1OC(C)(C)C(C)(C)O1
Yield: 180.3 %

Procedure:
Following the procedure described in Example 220, step a, reaction of 4-bromo-3,5-dimethyl-phenol (1.5 gm, 7.6 mmol), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.3 mL, 23 mmol, Aldrich Chemical Company), PdCl2(PPh3)2 (530 mg, 0.76 mmol, Strem Chemicals Inc, Newburyport, Mass.), Et3N (634 μL, 46 mmol), and dioxane (30 mL) afforded 3.4 gm of a tan glassy solid after chromatography (50 gm, silica SPE column) which was used without further purification. 1H-NMR (CDCl3; 400 MHz): δ 6.4 (s, 2H), 2.3 (s, 6H), 1.4 (s, 12H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[C:7]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)=[C:6]2[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.FC1C=C(C2C3C(=CC=C(OC)C=3)C(=O)C=2C2C=NC=CC=2)C=C(F)C=1>>[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[C:7]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)=[C:6]2[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COc1ccc2c(c1)C(c1ccccc1)=C(c1cccnc1)C2=O
Agent: COc1ccc2c(c1)C(c1cc(F)cc(F)c1)=C(c1cccnc1)C2=O
Product: O=C1C(c2cccnc2)=C(c2ccccc2)c2cc(O)ccc21
Yield: 93 %

Procedure:
The procedure of Step 5 of Example 128 was repeated except for using 5-methoxy-3-phenyl-2-(pyridin-3-yl)-1H-inden-1-one obtained in Step 5 as a starting material instead of 3-(3,5-difluorophenyl)-5-methoxy-2-(pyridin-3-yl)-1H-inden-1-one to obtain the title compound (93%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[NH:21][N:20]=[CH:19]4)=[C:11]([F:25])[CH:10]=2)[CH:5]=[C:4](Cl)[N:3]=1.[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[NH:21][N:20]=[CH:19]4)=[C:11]([F:25])[CH:10]=2)[CH:5]=[C:4]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:3]=1
Reactant: Nc1nc(Cl)cc(Nc2ccc(Oc3ccc4[nH]ncc4c3)c(F)c2)n1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Nc1nc(Nc2ccc(Oc3ccc4[nH]ncc4c3)c(F)c2)cc(-c2ccccc2)n1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
50 mg (130 μmol) of N-[2-amino-6-chloro-4-pyrimidinyl]-N-[3-fluoro-4-(1H-indazol-5-yloxy)phenyl]amine (from example 8) are suspended in 3 ml of toluene/ethanol (2:1), and 4.68 mg of tetrakis(triphenylphosphine)palladium(0) are added. After addition of 19.7 mg (160 μmol) of phenylboronic acid and 0.50 ml of 2M aqueous sodium carbonate solution, the mixture is stirred at 100° C. overnight. The mixture is evaporated to dryness using a rotary evaporator and purified by preparative HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[CH:9][C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[Cl:15][C:16]1[CH:21]=[C:20]([C:22]2[NH:26][N:25]=[N:24][N:23]=2)[CH:19]=[CH:18][C:17]=1[NH2:27]>C(#N)C>[Cl:1][C:2]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[CH:9][C:3]=1[C:4]([NH:6][C:7]([NH:27][C:17]1[CH:18]=[CH:19][C:20]([C:22]2[NH:26][N:25]=[N:24][N:23]=2)=[CH:21][C:16]=1[Cl:15])=[O:8])=[O:5]
Reactant: O=C=NC(=O)c1cc(F)c(F)cc1Cl
Reactant: Nc1ccc(-c2nnn[nH]2)cc1Cl
Solvent: CC#N
Product: O=C(NC(=O)c1cc(F)c(F)cc1Cl)Nc1ccc(-c2nnn[nH]2)cc1Cl
Temperature: 40 °C
Reaction time: 1 h

Procedure:
The solution of equivalent amounts of 2-chloro-4,5-difluorobenzoyl isocyanate was added dropwise to the solution of 100 mg of 2-chloro-4-(1H-tetrazol-5-yl)phenylamine in 3 ml of acetonitrile and the mixture was stirred at 40° C. for 60 minutes. The solid formed was filtered off with suction and dried under reduced pressure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[N:5]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[CH:6]1[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]1.C(O)(C(F)(F)F)=O>ClCCl>[F:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][N:5]([C:4]2[CH:27]=[CH:28][CH:29]=[C:2]([F:1])[CH:3]=2)[CH:6]2[CH2:7][CH2:8][NH:9][CH2:10][CH2:11]2)=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N(Cc2ccc(F)cc2)c2cccc(F)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1ccc(CN(c2cccc(F)c2)C2CCNCC2)cc1
Temperature: 0 °C
Yield: 96 %

Procedure:
Tert-butyl 4-[3-fluoro(4-fluorobenzyl)anilino]-1-piperidinecarboxylate 8 (25.5 g) was dissolved in dichloromethane and the solution was cooled to 0° C. TFA (30 ml) was added to the solution and the reaction mixture was stirred at room temperature. After 1 h 30, TFA (20 ml) was added and the reaction mixture was stirred for a further 30 minutes. The solvent was removed under vacuum and the residue was taken up in dichloromethane and water. The aqueous phase was alkalized by addition of NaOH and washed with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated. The crude was purified by chromatography (eluant: CH2Cl2/MeOH/NH4OH 95/5/0.5) to give N-(4-fluorobenzyl)-N-(3-fluorophenyl)-4-piperidinamine (18.4 g) as a free base.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[C:3](=[O:8])[NH:2]2.N1C=CC=CC=1.[C:15](Cl)(=[O:17])[CH3:16].O>C(#N)C>[C:15]([N:2]1[C:3](=[O:8])[CH:4]2[CH2:7][CH:1]1[CH:6]=[CH:5]2)(=[O:17])[CH3:16]
Reactant: O=C1NC2C=CC1C2
Reactant: CC(=O)Cl
Solvent: O
Solvent: CC#N
Solvent: c1ccncc1
Product: CC(=O)N1C(=O)C2C=CC1C2
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 77.8 %

Procedure:
100 g of (±)-2-azabicyclo[2.2.1]hept-5-en-3-one were dissolved in acetonitrile (800 ml) and pyridine (161.26 ml) under nitrogen. At 12° C., 104.5 g of acetyl chloride were added dropwise over the course of 2 hours. The mixture was then stirred at room temperature for 4.5 hours. 800 ml of water were added to the mixture, and the acetonitrile was evaporated off in vacuo. The aqueous phase was extracted 3 times with 400 ml of ethyl acetate. The combined org. phases were washed with 1N HCl (400 ml), water (400 ml), saturated NaCl (400 ml), dried with magnesium sulphate and completely evaporated. The residue was taken up in methylene chloride and filtered through silica gel. The filtrate was concentrated and the product was purified by distillation. 107.76 g of product were obtained as a clear liquid. The yield was 71%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:20])[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:18][OH:19])(=[O:11])=[O:10])=[CH:4][CH:3]=1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:20])[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH:18]=[O:19])(=[O:10])=[O:11])=[CH:4][CH:3]=1
Reactant: CN(c1ccc(F)cc1)S(=O)(=O)c1ccccc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CN(c1ccc(F)cc1)S(=O)(=O)c1ccccc1C=O
Temperature: 60 °C
Reaction time: 16 h
Yield: 66.2 %

Procedure:
A solution of N-(4-fluorophenyl)-2-hydroxymethyl-N-methylbenzenesulfonamide (0.35 g) in chloroform (20 mL) was treated with manganese dioxide (1.2 g), and the resulting mixture was stirred at 60° C. for 16 hours. The mixture was filtered through Celite and the filtrate concentrated under reduced pressure to afford the title compound as colourless oil (0.23 g).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[CH:9]=[CH:8][C:7]=1[NH:18][C:19](=O)[CH2:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1)[CH:2]([CH3:4])[CH3:3]>CC(O)=O>[CH2:1]([N:5]1[C:6]2[CH:11]=[C:10]([O:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[CH:9]=[CH:8][C:7]=2[N:18]=[C:19]1[CH2:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: COc1cccc(OCC(=O)Nc2ccc(OCCC(C)C)cc2NCC(C)C)c1
Solvent: CC(=O)O
Product: COc1cccc(OCc2nc3ccc(OCCC(C)C)cc3n2CC(C)C)c1
Yield: 87 %

Procedure:
A 250 mL flask fitted with a stir-bar, condenser, and an Ar inlet was charged with amine 50b (10.7 g, 25.8 mmol) and AcOH (110 mL). The resultant solution was heated in a 100° C. bath for 3 hr. The mixture was cooled and concentrated in vacuo to an orange solid. The solid was partitioned with EtOAc (150 mL) and saturated NaHCO3 (100 mL). The organic phase was then washed with brine (100 mL), filtered through phase separation paper, and concentrated in vacuo to 10.6 g of a red oil. The oil was chromatographed on silica gel eluting the product with 10-15% EtOAc in hexanes. The product fractions were concentrated in vacuo to give 8.9 g of Compound #2 as an orange oil, which slowly crystallized (87%). 1H NMR (300 MHz, CDCl3): δ 7.66 (d, 1H), 7.22 (t, 1H), 7.27 (t, 1H), 6.93 (dd, 1H), 6.82 (d, 1H), 6.69 (dd, 1H), 6.63 (t, 1H), 6.57 (dd, 1H), 5.32 (s, 2H), 4.06 (t, 2H), 4.04 (d, 2H), 3.81 (s, 3H), 2.36 (nonet, 1H), 1.90 (nonet, 1H), 1.74 (qt, 2H), 1.00 (d, 6H), 0.97 (d, 6H) ppm. HPLC analysis (0:10:90 H2O:A1:MeOH) showed a purity of 98% with a retention time of 5.8 min.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](=[O:23])[N:9]([CH2:11][CH2:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[N:10]=2)[CH:7]=1.C([Sn](CCCC)(CCCC)[C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1)CCC>CN(C=O)C.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[N:31]1[CH:32]=[CH:33][CH:34]=[C:29]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8](=[O:23])[N:9]([CH2:11][CH2:12][C:13]4[CH:22]=[CH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[N:14]=4)[N:10]=3)[CH:7]=2)[CH:30]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Reactant: O=c1n(CCc2ccc3ccccc3n2)nc2ccc(Br)cn12
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Solvent: CN(C)C=O
Product: O=c1n(CCc2ccc3ccccc3n2)nc2ccc(-c3cccnc3)cn12
Temperature: 135 °C
Yield: 33.2 %

Procedure:
In a 2 mL microwave vial were placed 3-4 (15 mg, 0.041 mmol), 3-(tributylstannyl)pyridine (16 mg, 0.045 mmol), and bis(tri-tert-butylphosphine)palladium (2 mg, 0.004 mmol) in anhydrous DMF (0.4 mL). The vial was sealed and the reaction was heated at 135° C. under microwave irradiation for 15 min. The reaction mixture was filtered, and the filtrate was directly purified by reversed phase HPLC to give 5.0 mg (35%) of 9-1. 1H NMR (500 MHz, DMSO-d6): δ 9.03 (s, 1H), 8.67 (d, J=5.0 Hz, 1H), 8.51 (d, J=8.4 Hz, 1H), 8.34 (d, J=8.0 Hz, 1H), 8.29 (s, 1H), 8.04 (d, J=8.1 Hz, 1H), 7.98 (d, J=8.5 Hz, 1H), 7.83 (t, J=7.6 Hz, 1H), 7.69-7.61 (m, 4H), 7.38 (d, J=9.8 Hz, 1H), 4.47 (t, J=6.9 Hz, 2H), 2.54 (t, J=6.9 Hz, 2H). HRMS (ES) 368.1502 (M+H) found, 368.1509 required.