Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.[F:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]=[CH:32][CH:33]([CH:37]([CH3:39])[CH3:38])[C:34](O)=[O:35])=[CH:27][CH:26]=1>CCOCC>[F:24][C:25]1[CH:26]=[CH:27][C:28]([CH:31]=[CH:32][CH:33]([CH:37]([CH3:39])[CH3:38])[C:34]([O:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[C:3]([O:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:4]=2)=[O:35])=[CH:29][CH:30]=1
Reactant: OCc1ccc(F)c(Oc2ccccc2)c1
Reactant: CC(C)C(C=Cc1ccc(F)cc1)C(=O)O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)C(C=Cc1ccc(F)cc1)C(=O)OCc1ccc(F)c(Oc2ccccc2)c1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-fluoro-3-phenoxybenzyl alcohol (0.22 g, 0.99 mmol) and triethylamine (0.14 g, 1.38 mmol) in ether (about 15 ml), under nitrogen, is added by syringe a solution of the acid chloride of 4-(4-fluorophenyl)-2-isopropyl-3-butenoic acid (1.5 mmol) in ether. The mixture is stirred for 30 minutes and then quenched with saturated aqueous sodium bicarbonate. The ether phase is washed with aqueous sodium bicarbonate, water and brine and filtered through silica. Evaporation of solvent, followed by thin layer chromatography using a circular chromatograph, eluting with 20 percent ether/hexane, gives 4-fluoro-3-phenoxybenzyl 4-(4-fluorophenyl)-2-isopropyl-3-butenoate.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:5]2[C:6]=1[C:7](=[O:13])[NH:8]3.[H-].[Na+].Br[CH2:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1.O>CN(C=O)C>[C:27]([O:26][C:24]([N:21]1[CH2:22][CH2:23][CH:18]([CH2:17][N:8]2[C:9]3[N:5]4[C:4](=[N:3][C:2]([CH3:1])=[C:6]4[C:7]2=[O:13])[CH:12]=[CH:11][CH:10]=3)[CH2:19][CH2:20]1)=[O:25])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Reactant: Cc1nc2cccc3[nH]c(=O)c1n23
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc2cccc3n(CC4CCN(C(=O)OC(C)(C)C)CC4)c(=O)c1n23
Yield: 62.9 %

Procedure:
To a suspension of 735 mg (4.24 mmol) of 1,2-dihydro-3-methyl-1,4,7b-triazacyclopent[cd]inden-2-one in 15 ml of DMF was added, while stirring under ice-cooling, 187 mg (4.68 mmol) of 60% sodium hydride (dispersion in oil). The mixture was stirred for 20 minutes at the same temperature. To the mixture was added a solution of 1.18 g (4.24 mmol) of 4-bromomethyl-1-tert-butoxycarbonylpiperidine in 5 ml of DMF. The mixture was stirred for one hour at 100° C. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and brine, dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent: ethyl acetate) to give 988 mg of the desired compound (62.8%, pale yellow solid).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:14]2[CH:15]=[N:16][CH:17]=[CH:18][C:13]2=[CH:12][C:11]=1[C:19]([OH:21])=O.[CH:22]([O:24][CH2:25][CH2:26][O:27][NH2:28])=[CH2:23].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:22]([O:24][CH2:25][CH2:26][O:27][NH:28][C:19]([C:11]1[CH:12]=[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][N:14]2[C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[F:1])=[O:21])=[CH2:23]
Reactant: C=COCCON
Reactant: O=C(O)c1cc2ccncn2c1Nc1ccc(I)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=COCCONC(=O)c1cc2ccncn2c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.2 %

Procedure:
7-(2-Fluoro-4-iodo-phenylamino)-pyrrolo[1,2-c]pyrimidine-6-carboxylic acid (67 mg, 0.18 mmol), O-(2-vinyloxy-ethyl)-hydroxylamine (18 mg, 0.18 mmol), HOBt (26 mg, 0.19 mmol), EDCI hydrochloride (37 mg, 0.19 mmol) and DIPEA (31 μL, 0.18 mmol) were suspended in DMF (3 mL). The reaction mixture was stirred at room temperature for 16 hours, during which time the reagents dissolved. The reaction mixture was concentrated in vacuo, the resultant residue dissolved in ethyl acetate (10 mL), washed with aqueous saturated sodium bicarbonate solution (10 mL) and the aqueous fraction extracted twice with ethyl acetate (2×10 mL). The combined organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0-100% ethylacetate in cyclohexane) to yield the title compound as a yellow solid (54 mg, 65%). LCMS (Method B): RT=3.38 min, M+H+=483.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C@@H:10]1[CH2:27][C:26]2[CH:25]=[C:24]([O:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][O:30]3)[CH:23]=[CH:22][C:21]=2[C@@H:20]2[C@@H:11]1[C@H:12]1[C@@:16]([CH2:18][C@@H:19]2[F:35])([CH3:17])[C:15](=[O:36])[CH2:14][CH2:13]1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.O>[F:35][C@H:19]1[CH2:18][C@@:16]2([CH3:17])[C@@H:12]([CH2:13][CH2:14][C:15]2=[O:36])[C@H:11]2[C@H:20]1[C:21]1[CH:22]=[CH:23][C:24]([O:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][O:30]3)=[CH:25][C:26]=1[CH2:27][C@H:10]2[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][OH:4]
Reactant: CC(=O)OCCCCC[C@@H]1Cc2cc(OC3CCCCO3)ccc2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: C[C@]12C[C@H](F)[C@@H]3c4ccc(OC5CCCCO5)cc4C[C@@H](CCCCCO)[C@H]3[C@@H]1CCC2=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 103.3 %

Procedure:
7.4 g of 7α- (5-acetoxypentyl)-11β-fluoro-3-(tetrahydro-pyran-2-yloxy)oestra-1,3,5(10)-trien-17-one are stirred with 1.8 g of potassium carbonate at room temperature in 370 ml of methanol and 37 ml of water. After 3 h, the reaction mixture is added to ice-water. The precipitated product is filtered off with suction, dissolved in ethyl acetate, and the solution is washed with water until neutral, dried and concentrated in vacuo. 7.0 g of 11β-fluoro-7α-(5-hydroxypentyl)-3-(tetrahydropyran-2-yloxy)oestra-1,3,5(10)-trien-17-one are obtained as a foam.
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].S(Cl)(Cl)(=O)=O.[C:13]1([OH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CC(N=NC(C#N)(C)C)(C#N)C.O1CCOCC1>[OH:19][C:13]1[CH:18]=[CH:17][C:16]([CH:7]2[NH:1][C:2](=[O:3])[NH:4][C:5]2=[O:6])=[CH:15][CH:14]=1
Reactant: Oc1ccccc1
Reactant: O=C1CNC(=O)N1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: O=S(=O)(Cl)Cl
Solvent: C1COCCO1
Product: O=C1NC(=O)C(c2ccc(O)cc2)N1
Temperature: 90 °C
Reaction time: 5 h
Yield: 5.3 %

Procedure:
4.0 g (40 mmol) of hydantoin, 50 ml of dioxane, 5.4 g (40 mmol) of sulfuryl chloride, and 0.01 g of azobisiso-butylonitrile were mixed. The reaction mixture was then stirred at a temperature of 90° C. for 5 hours. The reaction system was then allowed to cool to room temperature. To the reaction system was then added 7.6 g (80 mmol) of phenol. The reaction mixture was then allowed to undergo reaction at a temperature of 80° C. for 5 hours. The resulting precipitate was recovered by filtration, washed with water, recrystallized from water and then dried to obtain 0.41 g (yield: 5.3%) of 5-(p-hydroxyphenyl)hydantoin.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1[C:8](=[C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][C:13]1=[O:21])[C:9](O)=[O:10].[CH2:22]([N:24]([CH2:28][CH3:29])[CH2:25][CH2:26][NH2:27])[CH3:23]>>[CH2:22]([N:24]([CH2:28][CH3:29])[CH2:25][CH2:26][NH:27][C:9](=[O:10])[C:8]([C:3]1[NH:4][C:5]([CH3:7])=[CH:6][C:2]=1[CH3:1])=[C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][C:13]1=[O:21])[CH3:23]
Reactant: CCN(CC)CCN
Reactant: Cc1cc(C)c(C(C(=O)O)=C2C(=O)Nc3ccccc32)[nH]1
Product: CCN(CC)CCNC(=O)C(=C1C(=O)Nc2ccccc21)c1[nH]c(C)cc1C
Yield: 30.5 %

Procedure:
(3,5-Dimethyl-1H-pyrrol-2-yl)-(2-oxo-1,2-dihydroindol-3-ylidene)-acetic acid (90 mg) was reacted with N,N-diethylethylenediamine (48 mg) using method B to give 37 mg (46%) of the title compound.
Reaction SMILES: [N:1]1[NH:2][C:3](=[O:7])[CH:4]=[CH:5][CH:6]=1.[N+:8]1([O-])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>[Pd]>[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:6]1[CH:5]=[CH:4][C:3](=[O:7])[NH:2][N:1]=1
Reactant: O=c1cccn[nH]1
Reactant: [O-][n+]1ccccc1
Agent: [Pd]
Product: O=c1ccc(-c2ccccn2)n[nH]1

Procedure:
Haginiwa et al. [Yakugaku Zasshi 98 (1), 67-71 (1978); Chem. Abstrs. 88, 170,096v (1978)] reacted 3(2H)-pyridazinone with pyridine 1-oxide and platinized Pd-C catalyst to produce 6-(2-pyridinyl)-3(2H)-pyridazinone.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[CH3:27])=[C:9]([C:14]2[N:18]([CH3:19])[N:17]=[N:16][N:15]=2)[CH:10]=[CH:11][CH:12]=[O:13])=[C:4]([CH3:28])[CH:3]=1.[C:29]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])(=[O:34])[CH2:30][C:31]([CH3:33])=[O:32].[H-].[Na+].C([Li])CCC>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[CH3:27])=[C:9]([C:14]2[N:18]([CH3:19])[N:17]=[N:16][N:15]=2)[CH:10]=[CH:11][CH:12]([OH:13])[CH2:33][C:31](=[O:32])[CH2:30][C:29]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[C:4]([CH3:28])[CH:3]=1
Reactant: Cc1cc(F)ccc1C(=C(C=CC=O)c1nnnn1C)c1ccc(F)cc1C
Reactant: CC(=O)CC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1C(=C(C=CC(O)CC(=O)CC(=O)OC(C)(C)C)c1nnnn1C)c1ccc(F)cc1C
Temperature: -30 °C
Reaction time: 1.5 h

Procedure:
To a solution of 5,5-bis(4-fluoro-2-methylphenyl)-4-(1-methyl-1H-tetrazol-5-yl)-2,4-pentadienal (1.0 g, 2.5 mmoles) in tetrahydrofuran at -50° C. was added the dianion of t-butyl acetoacetate (2.5 mL of a 1M solution, 2.5 mmoles) prepared by adding t-butyl acetoacetate (4.0 g, 25.0 mmoles) in tetrahydrofuran (4 mL) to a suspension of sodium hydride (1.0 g of 60% dispersion, 25.0 mmoles) in tetrahydrofuran at -5° C. followed by cooling to -30° C. and the addition of butyl lithium (11.4 mL of 2.2M solution, 25 mmoles). After stirring for 1.5 hours, analytical TLC indicated starting aldehyde and another 0.5 mL of dianion solution was added. The solution was stirred an additional 0.5 hour and quenched with 1N hydrochloric acid. The mixture was extracted with methylene chloride. The extracts were dried and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with methanol in methylene chloride to produce 0.6 g of the title compound; m.p.=65°-72° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[S:11][CH2:12][CH2:13][C:14]([F:23])([F:22])[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)=[O:4].[OH-].[Na+].O>CCO>[F:23][C:14]([F:22])([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[CH2:13][CH2:12][S:11][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1ccncc1SCCC(F)(F)c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccncc1SCCC(F)(F)c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
To a solution of 3-[[3,3-difluoro-3-(4-fluorophenyl)-propyl]sulfanyl]-pyridine-4-carboxylic acid methyl ester (0.33 g, 0.96 mmol) in EtOH (10 ml) are added sodium hydroxide (0.15 g, 3.87 mmol) and water (10 ml). The reaction mixture is stirred at 80° C. for 1 h. After completion of the reaction, the solvent is evaporated and the residue is diluted with water (10 ml). The aqueous layer is acidified with 2M hydrochloric acid to pH 3 and extracted with EtOAc (3×20 ml). The combined organic layers are washed with water (20 ml), brine (20 ml), dried over anhydrous sodium sulfate and evaporated to get the crude 3-[[3,3-difluoro-3-(4-fluorophenyl)-propyl]sulfanyl]-pyridine-4-carboxylic acid (0.26 g, 0.8 mmol, 82%), which is used in the next step without further purification.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:20])([CH3:19])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH2:15])(=[O:14])=[O:13])=[CH:8][C:7]=1[N+:16]([O-:18])=[O:17].C(N(C(C)C)[P:25]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])(C)C.N1C=NN=N1.OO.S([O-])([O-])=[O:47].S([O-])([O-])=O.[Na+].[Na+].[Na+].[Na+]>O1CCCC1.ClCCl>[P:25]([O:1][CH2:2][C:3]([CH3:20])([CH3:19])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](=[O:13])(=[O:14])[NH2:15])=[CH:8][C:7]=1[N+:16]([O-:18])=[O:17])([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:47]
Reactant: O=S([O-])[O-]
Reactant: CC(C)(CO)CNc1ccc(S(N)(=O)=O)cc1[N+](=O)[O-]
Reactant: CC(C)N(C(C)C)P(OC(C)(C)C)OC(C)(C)C
Agent: OO
Agent: [Na+]
Agent: c1nnn[nH]1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(CNc1ccc(S(N)(=O)=O)cc1[N+](=O)[O-])COP(=O)(OC(C)(C)C)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of EXAMPLE 4A (540 mg) in tetrahydrofuran (5 ml) was added di-tert-butyl diisopropylphosphoramidite (0.84 ml) and 0.45 M 1H-tetrazole (7.91 ml) at 0° C. The mixture was stirred at room temperature for 1.5 hours and cooled to 0° C. 30% Hydrogen peroxide (0.82 ml) was added. The mixture was stirred at room temperature for 30 minutes. Ice water and sodium bissulfite (1.1 g) were added. The resulting mixture was diluted with dichloromethane and the organic layer was washed with water extensively until the water layer became pH neutral. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography, eluting with 0-66% ethyl acetate in dichloromethane to provide the title compound.
Reaction SMILES: Br[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH:7]([OH:12])[C:6]=2[CH:5]=[N:4][CH:3]=1.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1>>[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][C:18]([C:2]2[C:11]3[CH2:10][CH2:9][CH2:8][CH:7]([OH:12])[C:6]=3[CH:5]=[N:4][CH:3]=2)=[CH:17][CH:16]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: OC1CCCc2c(Br)cncc21
Product: OC1CCCc2c(-c3ccc(C(F)(F)F)cc3)cncc21
Yield: 86 %

Procedure:
In analogy to the procedure described for the preparation of example 1 (rac)-4-bromo-5,6,7,8-tetrahydroisoquinolin-8-ol (intermediate A-2) was reacted with 4-(trifluoromethyl)phenylboronic acid to give the title compound as white solid in 86% yield. MS: 294.1 (M+H+).
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([CH2:24]O)=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[N:28]=2)[N:4]=1)[CH3:2].CS(Cl)(=O)=O.C([O-])([O-])=O.[K+].[K+].[N:45]1([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1>C(Cl)Cl.CN(C=O)C>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([CH2:24][N:48]4[CH2:49][CH2:50][N:45]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:46][CH2:47]4)=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[N:28]=2)[N:4]=1)[CH3:2]
Reactant: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(CO)ccn34)c12
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(CN5CCN(C(=O)OC(C)(C)C)CC5)ccn34)c12
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 39.7 %

Procedure:
To N-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(hydroxymethyl)imidazo[1,2-a]pyridine-3-carboxamide (40 mg, 0.091 mmol) in DCM (3 mL) was added methanesulfonyl chloride (21 mg, 0.18 mmol). The reaction mixture was stirred for 30 minutes, diluted with DCM (10 mL), washed with saturated NaHCO3 aqueous solution (3 mL) and brine (3 mL). The organic phase was concentrated under reduced pressure to a residue, to which was added DMF (2 mL), K2CO3 (38 mg, 0.27 mmol) and tert-butyl piperazine-1-carboxylate (51 mg, 0.27 mmol). The reaction mixture was heated to 50° C. for 2 hours. The mixture was concentrated under reduced pressure to remove DMF. Silica gel chromatography (DCM/MeOH) gave the product (22 mg).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.[N:48]([CH2:51][CH3:52])=[C:49]=[O:50]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][N:43]([C:49]([NH:48][CH2:51][CH3:52])=[O:50])[CH2:42][CH2:41]1
Reactant: CCN=C=O
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: CCNC(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cccc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 77 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) and isocyanato-ethane as starting materials in 77% yield. 1H NMR (300 MHz, DMSO-d6): δ 9.65 (s, 1H), 9.60 (s, 1H), 9.30 (s, 1H), 8.20 (s, 1H), 7.92 (s, 1H), 7.73 (s, 1H), 7.24 (d, 1H), 7.12 (m, 1H), 7.04 (d, 1H), 6.87 (d, 1H), 6.80 (d, 1H), 6.40 (s, 1H), 3.92 (d, 2H), 3.01 (m, 2H), 2.90 (m, 4H), 2.62 (m, 2H), 2.28 (d, 2H), 1.92 (m, 1H), 1.61 (m, 2H), 1.12 (m, 2H), 1.00 (t, 3H). LCMS for C28H33ClN7O2 (M+H)+: m/z=534.2.
Reaction SMILES: [S-:1][C:2]#[N:3].[NH4+].[C:5](Cl)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH2:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]2[S:24][C:23]3[N:25]=[CH:26][CH:27]=[N:28][C:22]=3[N:21]([CH2:29][O:30][CH3:31])[C:20]=2[CH:32]=1.O>CC(C)=O.C(OCC)(=O)C>[CH3:31][O:30][CH2:29][N:21]1[C:20]2[CH:32]=[C:16]([CH2:15][NH:14][C:2]([NH:3][C:5](=[O:12])[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)=[S:1])[CH:17]=[CH:18][C:19]=2[S:24][C:23]2[N:25]=[CH:26][CH:27]=[N:28][C:22]1=2
Reactant: COCN1c2cc(CN)ccc2Sc2nccnc21
Reactant: O=C(Cl)c1ccccc1
Reactant: N#C[S-]
Agent: [NH4+]
Solvent: O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COCN1c2cc(CNC(=S)NC(=O)c3ccccc3)ccc2Sc2nccnc21

Procedure:
To 5 ml of a solution of 350 mg of ammonium thiocyanate in acetone was added in a nitrogen atmosphere 0.50 ml of benzoyl chloride and the resulting mixture was heated under reflux for 5 minutes. Then 5 ml of a solution of 890 mg of 8-aminomethyl-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine in acetone was added thereto and the resulting mixture was heated under reflux for additional 1.5 hours. Next, the reaction mixture was distributed into water and ethyl acetate, washed with water and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate) and recrystallized from diisopropyl ether to thereby give 710 mg of the title compound as yellow crystals.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][C:9]([CH2:19][NH2:20])([CH2:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].N=C=N.[Cl:24][C:25]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:26]=1[C:27](O)=[O:28]>ClCCl>[Cl:24][C:25]1[CH:33]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:31]=[CH:30][C:26]=1[C:27]([NH:20][CH2:19][C:9]1([CH2:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH2:10][CH2:11][N:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH2:7][CH2:8]1)=[O:28]
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1Cl
Reactant: CCS(=O)(=O)N1CCC(CN)(CC2CCOCC2)CC1
Agent: N=C=N
Solvent: ClCCl
Product: CCS(=O)(=O)N1CCC(CNC(=O)c2ccc(C(F)(F)F)cc2Cl)(CC2CCOCC2)CC1
Reaction time: 0.5 h

Procedure:
In a large glass container with a sealable lid was placed 1-[1-(ethylsulfonyl)-4-(tetrahydro-2H-pyran-4-ylmethyl)piperidin-4-yl]methanamine (11, 350 mg, 1.15 mmol). Dichloromethane (50 ml) and PS-carbodiimide resin (474 mg, 2.299 mmol) were added along with 2-chloro-4(trifluoromethyl)benzoic acid (336 mg, 1.495 mmol). The lid was sealed and the bottle was shaken for 0.5 hours. The resin was filtered off and washed with EtOAc (3×25 ml) and the organics concentrated in vacuo to give an off-white solid. The residue was purified by column chromatography on silica gel, eluting with EtOAc/Hexanes to give 2-chloro-N-{[1-(ethylsulfonyl)-4-(tetrahydro-2H-pyran-4-ylmethyl)piperidin-4-yl]methyl}-4-(trifluoromethyl)benzamide (12) as a white solid. Calculated HRMS 511.164 Found 511.1649. 1H NMR (300 MHz D6DMSO): δ 8.51 (s, 1 H)), 7.96 (s, 1 H), 7.80 (d, J=8.1 Hz, 1 H), 7.61 (d, J=7.8 Hz, 1 H), 3.77 (d, J=9.3 Hz, 2 H), 3.41 (s, 2 H), 3.32 (m, 2 H), 3.29 (s, 2H), 3.21 (s, 4 H), 3.45 (q, J=9 Hz, 2 H), 1.66 (m, 1 H), 1.61 (m, 2 H), 1.564 (s, 2 H), 1.47 (m, 2 H), 1.30 (d, J=4.5 Hz, 2 H), 1.21 (t, J=7.5 Hz, 3 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][OH:10].Cl[C:12]1[CH:17]=[C:16](I)[CH:15]=[CH:14][N:13]=1.C([O-])([O-])=[O:20].[Cs+].[Cs+].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1>C1(C)C=CC=CC=1.[Cu]I.C(O)=O.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][O:10][C:16]1[CH:15]=[CH:14][NH:13][C:12](=[O:20])[CH:17]=1
Reactant: OCc1ccc(F)cc1F
Reactant: O=C([O-])[O-]
Reactant: Clc1cc(I)ccn1
Agent: [Cu]I
Agent: [Cs+]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: Cc1ccccc1
Solvent: O=CO
Solvent: O
Product: O=c1cc(OCc2ccc(F)cc2F)cc[nH]1
Temperature: 105 °C
Reaction time: 96 h
Yield: 43.4 %

Procedure:
A suspension of (2,4-difluorophenyl)methanol (4.86 g, 33.7 mmol), 2-chloro-4-iodopyridine (7.35 g, 30.7 mmol), Cs2CO3 (14.3 g, 43.8 mmol), CuI (5.83 g, 30.7 mmol) and 1,10-phenanthroline (1.11 g, 6.14 mmol) in toluene (20 mL) was degassed by bubbling N2 through the suspension for 15 min. The suspension was put under N2, and heated at 105° C. for 18 h. The suspension was cooled, EtOAc (50 mL) was added, and the resulting suspension was passed through a plug of SiO2. The resulting solution was concentrated under reduced pressure. Flash chromatography on silica gel (hexanes/(1:1 EtOAc/hexanes), 100:0 to 0:100) afforded a white solid. A suspension of the white solid and NH4OAc (8.21 g, 107 mmol) in 1:1 HCO2H/H2O (40 mL) was heated at reflux with stirring for 4 d. The solution was cooled and concentrated under reduced pressure. The resulting residue was made basic with saturated NaHCO3 solution, and the resulting suspension was filtered. The solid was washed with H2O and dried under reduced pressure to afford 3.16 g (44%) of the title compound as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 11.14 (br s, 1H), 7.62 (br dd, J=15.3, 8.7 Hz, 1H), 7.33 (ddd, J=10.5, 10.5, 2.4 Hz, 1H), 7.25 (d, J=7.2 Hz, 1H), 7.12 (ddd, J=8.4, 8.4, 1.8 Hz, 1H), 5.91-5.82 (m, 2H), 5.06 (s, 2H).