Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[N:9]2[CH:10]=[CH:11][N:12]=[C:8]2[CH:7]=[CH:6][CH:5]=1.Cl[CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[C:29](=[O:30])[C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:21]2[S:22](=[O:27])(=[O:26])[CH2:23][CH2:24][CH2:25][N:20]2[C:19]1=[O:37].[I-].[Na+]>CN(C)C=O.O>[N:12]1[CH:11]=[CH:10][N:9]2[C:4]([S:3][CH2:14][CH2:15][CH2:16][CH2:17][N:18]3[C:29](=[O:30])[C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[C:21]4[S:22](=[O:27])(=[O:26])[CH2:23][CH2:24][CH2:25][N:20]4[C:19]3=[O:37])=[CH:5][CH:6]=[CH:7][C:8]=12
Reactant: O=c1c(-c2ccccc2)c2n(c(=O)n1CCCCCl)CCCS2(=O)=O
Reactant: Sc1cccc2nccn12
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c(-c2ccccc2)c2n(c(=O)n1CCCCSc1cccc3nccn13)CCCS2(=O)=O
Reaction time: 0.17 h

Procedure:
To a suspension of 0.24 g (6.0 mmol) of 60% oily sodium hydride in 40 ml of N,N-dimethylformamide, 0.98 g (6.0 mmol) of 5-mercaptoimidazo[1,2-a]pyridine was added at room temperature, followed by stirring for 10 minutes. To this mixture, 2.87 g (5.97 mmol) of 7-(4-chlorobutyl)-1,1-dioxo-9-phenyl-3,4-dihydro-2H,6H-pyrimido[6,1-b][1,3]-thiazine-6,8(7H)-dione and 0.90 g (6.0 mmol) of sodium iodide were added, followed by stirring at 80° C. for 3 hours. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate 3 times. The organic layer was washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, ethyl acetate/ethanol=10/1) to yield 1.26 g (43.7%, white foamy substance) of the desired product.
Reaction SMILES: O.[CH3:2][C:3]1([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:12][CH2:11][C:6]2(OCC[O:7]2)[CH2:5][CH2:4]1>C(O)=O>[CH3:2][C:3]1([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:4][CH2:5][C:6](=[O:7])[CH2:11][CH2:12]1
Reactant: CCOC(=O)CC1(C)CCC2(CC1)OCCO2
Solvent: O
Solvent: O=CO
Product: CCOC(=O)CC1(C)CCC(=O)CC1

Procedure:
Water (0.5 mL) was added to a stirring solution of ethyl 2-(8-methyl-1,4-dioxaspiro[4.5]decan-8-yl)acetate (1.6 g, 6.60 mmol) and formic acid (10 mL) at room temperature. Analysis of the reaction mixture by LCMS indicated that the starting material was consumed and the desired product had formed. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between EtOAc and brine, the layers were separated, the organic material washed with brine (2×), dried (Na2SO4), filtered, and the filtrate was concentrated under reduced pressure to give a pale yellow liquid ethyl 2-(1-methyl-4-oxocyclohexyl)acetate (1.6 g, 8.07 mmol, 86% yield): 1H NMR (500 MHz, CDCl3) δ 1.22-1.31 (m, 6H), 1.77-1.91 (m, 4H), 2.39-2.43 (m, 6H), 4.12-4.23 (m, 2H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:31])=[CH:5][C:6]([F:30])=[C:7]([C@:9]23[CH2:18][O:17][C@@H:16]([CH2:19][F:20])[CH2:15][C@H:14]2[CH2:13][S:12][C:11]([NH:21][C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:10]3)[CH:8]=1.C(N(CC)CC)C.FC(F)(F)S(O[CH2:45][C:46]([F:49])([F:48])[F:47])(=O)=O>C(#N)C>[F:30][C:6]1[CH:5]=[C:4]([F:31])[C:3]([CH2:2][NH:1][CH2:45][C:46]([F:49])([F:48])[F:47])=[CH:8][C:7]=1[C@:9]12[CH2:18][O:17][C@@H:16]([CH2:19][F:20])[CH2:15][C@H:14]1[CH2:13][S:12][C:11]([NH:21][C:22](=[O:29])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[N:10]2
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: NCc1cc([C@]23CO[C@@H](CF)C[C@H]2CSC(NC(=O)c2ccccc2)=N3)c(F)cc1F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(NC1=N[C@@]2(c3cc(CNCC(F)(F)F)c(F)cc3F)CO[C@@H](CF)C[C@H]2CS1)c1ccccc1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
A solution of N-[(4aR,6R,8aS)-8a-[5-(aminomethyl)-2,4-difluorophenyl]-6-(fluoromethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C26) (0.598 g, 1.33 mmol) in acetonitrile (13 mL) was treated with triethylamine (0.277 mL, 2.00 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.288 mL, 2.00 mmol). The reaction vial was sealed and the resulting solution was stirred at 70° C. for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to yield a brown solid. The solid was partitioned between water (100 mL) and ethyl acetate (100 mL). The organics were isolated and the aqueous layer was extracted further with ethyl acetate (2×50 mL). The combined organics were then washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel chromatography (Gradient: 0% to 60% ethyl acetate in heptane) afforded the product as a white solid. Yield: 0.4064 g, 57%. LCMS m/z 532.0 [M+H+]. 1H NMR (400 MHz, CD3OD) δ 8.12 (br d, J=8 Hz, 2H), 7.45-7.59 (m, 3H), 7.08 (dd, J=12.3, 9.6 Hz, 1H), 4.50-4.52 (m, 1H), 4.38-4.40 (m, 1H), 4.15 (dd, J=12.1, 2 Hz, 1H), 3.90-3.94 (m, 3H), 3.00 (dd, J=13.4, 4.0 Hz, 1H), 2.77 (dd, J=13.1, 2.9 Hz, 1H), 1.87-1.96 (m, 1H), 1.69-1.72 (m, 1H).
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:5][CH2:6][C:7]1[N:8]([CH2:20][C:21]([CH3:28])([CH3:27])[C:22]([O:24]CC)=[O:23])[C:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[CH:11][C:10]=2[N:19]=1)[CH3:4].C(O)C>O>[CH2:3]([O:5][CH2:6][C:7]1[N:8]([CH2:20][C:21]([CH3:27])([CH3:28])[C:22]([OH:24])=[O:23])[C:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[CH:11][C:10]=2[N:19]=1)[CH3:4]
Reactant: CCOCc1nc2cnc3ccccc3c2n1CC(C)(C)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOCc1nc2cnc3ccccc3c2n1CC(C)(C)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Aqueous sodium hydroxide (1.5 mL of 50%, 19 mmol) was added to a mixture of ethyl 3-[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2,2-dimethylpropanoate (5.0 g, 14 mmol), ethanol (50 mL), and water (5 mL). The reaction was stirred for two hours at ambient temperature; an analysis by TLC indicated that starting material was present. Additional aqueous sodium hydroxide (0.5 mL of 50%) was added, and the reaction was heated at reflux for two hours and concentrated under reduced pressure. Ethanol (100 mL) was added to the residue and then removed under reduced pressure to provide 3-[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2,2-dimethylpropanoic acid, which was dried overnight under vacuum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[CH:4]=1.[NH:17]1[CH2:21][CH2:20][CH2:19][C:18]1=O.P(Cl)(Cl)(Cl)=O>ClCCCl>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]([C:18]3[N:17]([C:18]4[CH2:19][CH2:20][CH2:21][N:17]=4)[CH2:21][CH2:20][CH:19]=3)[C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)Nc1ccccc1S2
Reactant: O=C1CCCN1
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(c1)N(C1=CCCN1C1=NCCC1)c1ccccc1S2

Procedure:
Reaction of 2-methoxyphenothiazine, 2-pyrrolidinone and phosphorus oxychloride in 1,2-dichloroethane according to the procedure of Example 1 affords 2-METHOXY-10-[1-(1-PYRROLIN-2-YL)-2-PYRROLIN-2-YL]PHENOTHIAZINE free base, m.p. 151°-153° C. (corr.), from isopropyl alcohol.
Reaction SMILES: [C:1]([CH:6]1[CH2:10][CH2:9][CH2:8][C:7]1=[O:11])([O:3][CH2:4][CH3:5])=[O:2].[CH2:12](I)[CH3:13].[H-]>>[C:1]([C:6]1([CH2:12][CH3:13])[CH2:10][CH2:9][CH2:8][C:7]1=[O:11])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCI
Reactant: CCOC(=O)C1CCCC1=O
Agent: [H-]
Product: CCOC(=O)C1(CC)CCCC1=O

Procedure:
2-Carboethoxycyclopentanone is reacted with ethyl iodide in the presence ofsodium hydride to produce 2-carboethoxy-2-ethyl-cyclopentanone.
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH2:20][CH2:21][OH:22])=[CH:16][CH:17]=3)[N:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-])=O.C(O[K])=O>O.C1COCC1.CCOC(C)=O.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH2:20][CH2:21][OH:22])=[CH:16][CH:17]=3)[N:12]=[CH:11][CH:10]=2)=[CH:23][CH:24]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(OCCO)ccc23)cc1
Agent: [Pd]
Agent: O=CO[K]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(Oc2ccnc3cc(OCCO)ccc23)cc1
Temperature: 45 °C
Reaction time: 4 h
Yield: 47.2 %

Procedure:
To a suspension of 2-((4-(4-nitrophenoxy)quinolin-7-yl)oxy)ethanol (0.32 g, 1 mmol), HCOOK (0.59 g, 7 mmol) in water (1 mL) and THF (3 mL) was added 10% Pd/C (0.03 g). The reaction was stirred at 45° C. for 4 hours. The mixture was diluted with EtOAc (5 mL), filtered through a Celite pad. The filtrate was concentrated in vacuo, washed with a mixture of 95% ethanol (1 mL) and water (5 mL). The solid was collected by filtration and dried in vacuo at 50° C. overnight to give the title compound as a pale yellow solid (140 mg, 47.3%).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=1)[O:11][C:12]1[C:17]([C:18]#N)=[CH:16][CH:15]=[CH:14][N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)=[O:24]>[Ni].O>[O:1]([C:8]1[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=1)[O:11][C:12]1[C:17]([CH:18]=[O:24])=[CH:16][CH:15]=[CH:14][N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cccnc1Oc1cccc(Oc2ccccc2)c1
Reactant: O=CO
Agent: [Ni]
Solvent: O
Product: O=Cc1cccnc1Oc1cccc(Oc2ccccc2)c1

Procedure:
Crude 2-(3-phenoxyphenoxy)-3-cyanopyridine (15 g) was stirred with Raney nickel alloy (15 g, 50:50) in refluxing 75% formic acid (200 ml) for 2 hours. The reaction mixture was diluted with water and then extracted repeatedly with ether. The combined ether extracts were dried, filtered and evaporated to give an orange oil. Filtration through a plug of silica (eluent hexane-ether, 1:1) afforded 2-(3-phenoxyphenoxy)-3-formylpyridine (3.03 g), infrared max. 1685 cm-1.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:3]([NH:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1)=[O:4].[C:18]([O:22][C:23](=[O:28])[NH:24][CH2:25][CH:26]=O)([CH3:21])([CH3:20])[CH3:19].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CCOC(C)=O>[C:18]([O:22][C:23](=[O:28])[NH:24][CH2:25][CH2:26][NH:1][C@H:2]([C:3](=[O:4])[NH:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1)[CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)NCC=O
Reactant: N[C@@H](CC1CCCCC1)C(=O)Nc1nccs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCN[C@@H](CC1CCCCC1)C(=O)Nc1nccs1
Temperature: 50 °C
Reaction time: 3 h
Yield: 34.7 %

Procedure:
A solution of compound 12B (2.03 g, 8 mmol), (2-oxo-ethyl)-carbamic acid tert-butyl ester (1.27 g, 8 mmol) and NaBH(OAc)3 (1.70 g, 8 mmol) in DCM (30 ml) was maintained at ambient temperature overnight followed by the addition of NaBH(OAc)3 (3.39 g, 16 mmol). Reaction mixture was stirred at 50° C. for 3 hours, diluted with EtOAc (200 ml) and extracted with water (200 ml), 5% aq. bicarbonate (200 ml) and brine (200 ml). Organic layer was dried over anh. MgSO4 and evaporated in vacuum. Residue was dissolved in DMSO (5 ml) and subjected to HPLC purification. [Phenomenex Gemini C-18 column, 110 Å (30×100 mm); flow rate=45 ml/min; mobile phase A: 100% water, 0.1% TFA; mobile phase B: 100% ACN, 0.1% TFA; gradient elution from 25% B to 70% B in 70 min., detection 254 nm]. Fractions containing the desired product were combined and neutralized with 1 M NaOH. ACN was evaporated. Residual solution was extracted with EtOAc (2×100 ml). Organic layer was dried over anh. MgSO4 and evaporated in vacuum to provide target product (1.10 g, 35%) as light yellow oil. LC-MS [M+H] 397.2 (C19H32N4O3S+H, requires 397.56).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][NH2:19])[CH2:14][CH2:13]2)[N:5]2[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[C:6]=12.C(N(CC)CC)C.[C:27](Cl)(=[O:29])[CH3:28].O>ClCCl>[Br:1][C:2]1[N:3]=[C:4]([C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][NH:19][C:27](=[O:29])[CH3:28])[CH2:14][CH2:13]2)[N:5]2[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[C:6]=12
Reactant: Cc1nccn2c1c(Br)nc2[C@H]1CC[C@H](CN)CC1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CC[C@H](c2nc(Br)c3c(C)nccn32)CC1

Procedure:
To ((trans)-4-(1-bromo-8-methylimidazo[1,5-a]pyrazin-3-yl)cyclohexyl)methanamine (0.464 mmol, 150 mg) in dichloromethane (5 ml) at 0° C. were added triethylamine (0.466 mmol, 65 μl) and acetyl chloride (0.510 mmol, 36.4 μl). After stirring at room temperature for one hour water was added. The organic layer separated, dried (Na2SO4) and concentrated in vacuo to give N-(((trans)-4-(1-bromo-8-methylimidazo[1,5-a]pyrazin-3-yl)cyclohexyl)methyl)acetamide (96 mg)
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:14]2[C:9](=[N:10][CH:11]=[N:12][C:13]=2[NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[C:18]([Cl:30])[CH:17]=2)[NH:8][N:7]=1.[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>>[Cl:30][C:18]1[CH:17]=[C:16]([NH:15][C:13]2[N:12]=[CH:11][N:10]=[C:9]3[NH:8][N:7]=[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)[C:14]=23)[CH:21]=[CH:20][C:19]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: C1CCNC1
Reactant: ClCCCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Product: Clc1cc(Nc2ncnc3[nH]nc(OCCCN4CCCC4)c23)ccc1OCc1ccccn1
Yield: 39 %

Procedure:
The procedure described in Example 23 was repeated using 3-(3-chloropropoxy)-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (prepared as described in Example 17) and pyrrolidine to give the title compound in 39% yield; NMR Spectrum: 1.66 (br s, 4H), 1.95-2.01 (m, 2H), 2.42 (br s, 4H), 2.53 (t, 2H), 4.35 (t, 2H), 5.29 (s, 2H), 7.23 (d, 1H), 7.35-7.38 (t, 1H), 7.54-7.58 (m, 2H), 7.86-7.89 (m, 2H), 8.27 (s, 1H), 8.44 (s, 1H), 8.59 (d, 1H); Mass Spectrum: 480 (MH+).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:13][CH2:12][C@@H:11]([C:14](=[O:27])[NH:15][C:16]2[CH:17]=[CH:18][CH:19]=[C:20]3[C:25]=2[N:24]=[C:23]([CH3:26])[CH:22]=[CH:21]3)[CH2:10][C@H:9]1[O:28][CH3:29])(C)(C)C>ClCCl>[CH3:26][C:23]1[CH:22]=[CH:21][C:20]2[C:25](=[C:16]([NH:15][C:14]([C@@H:11]3[CH2:12][CH2:13][C@@H:8]([NH2:7])[C@H:9]([O:28][CH3:29])[CH2:10]3)=[O:27])[CH:17]=[CH:18][CH:19]=2)[N:24]=1
Reactant: CO[C@@H]1C[C@H](C(=O)Nc2cccc3ccc(C)nc23)CC[C@H]1NC(=O)OC(C)(C)C
Solvent: ClCCl
Product: CO[C@@H]1C[C@H](C(=O)Nc2cccc3ccc(C)nc23)CC[C@H]1N
Yield: 94.5 %

Procedure:
Carbamate (h) (110 mg, 0.27 mmol) was dissolved in dichloromethane/triluoroacetic acid (2 ml/2 ml). After 1 hour the mixture was evaporated to dryness and the residue triturated with ether. The residue was then redissolved in 10% methanol in dichloromethane (20 ml) and treated with macroporous triethylammonium methylpolystyrene carbonate resin (2.8 mmol/g; 2.7 g, Argonaut Technologies). After 1 hour the mixture was filtered and the resin washed several times alternately with 10% methanol in dichloromethane then methanol. The combined filtrate and washings were evaporated affording a white solid (80 mg, 95%).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].N#N.[C:9]([NH:28][CH2:29][CH2:30][OH:31])(=O)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]=[CH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].[OH-].[K+]>O1CCCC1>[CH2:9]([NH:28][CH2:29][CH2:30][OH:31])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]=[CH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCC=CCCCCCCCC(=O)NCCO
Agent: N#N
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CCCCCCCCC=CCCCCCCCCNCCO
Temperature: 60 °C
Reaction time: 16 h
Yield: 60.2 %

Procedure:
A 100-ml eggplant type flask equipped with a stirrer was charged with 1.40 g (37.2 mmol) of LiAlH4 and 30 ml of tetrahydrofuran. While heating and stirring the contents at room temperature in an N2 atmosphere, a tetrahydrofuran solution of 1.67 g (5.12 mmol) of N-(9-octadecenoyl)ethanolamine was added dropwise over 10 minutes. After the mixture was heated to 60° C. and stirred for 16 hours, the resultant reaction mixture was cooled to room temperature, and 14 g of 5% aqueous KOH. After a salt deposited was separated by filtration, the filtrate was concentrated under reduced pressure, and the resultant residue was purified by column chromatography on silica gel, thereby obtaining 0.96 g (yield: 65%) of the title compound (IIc-6).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([C:18]3[CH:23]=[CH:22][N:21]=[C:20](Cl)[CH:19]=3)[N:9]=2)=[CH:4][CH:3]=1.[C:25]([NH:29][S:30]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)(=[O:32])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([NH:29][S:30]([C:33]1[CH:34]=[CH:35][CH:36]=[C:37]([C:20]2[CH:19]=[C:18]([C:10]3[N:9]=[C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=3)[CH:23]=[CH:22][N:21]=2)[CH:38]=1)(=[O:32])=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc(-c2ccnc(Cl)c2)n1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2cc(-c3nc(-c4ccc(Cl)cc4)cc(C(F)(F)F)n3)ccn2)c1

Procedure:
3-{4-[4-(4-Chloro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonic acid tert-butylamide was prepared from 4-(4-chloro-phenyl)-2-(2-chloro-pyridin-4-yl)-6-trifluoromethyl-pyrimidine (example E.5) (0.37 g, 1.0 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.31 g, 1.2 mmol) according to the general procedure VI. Obtained as a light brown solid (0.41 g), which was subsequently deprotected.
Reaction SMILES: [C:1]([C:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1)#[CH:2].Br[C:19]1[S:23][C:22]2[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=2[CH:20]=1>>[S:23]1[C:19]([C:2]#[C:1][C:3]2([CH3:17])[CH2:8][CH2:7][C:6]3[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=3[O:4]2)=[CH:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]1=2
Reactant: C#CC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Reactant: Brc1cc2ccccc2s1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C#Cc1cc3ccccc3s1)O2

Procedure:
Reaction of rac-3,4-dihydro-2-ethynyl-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol with 2-bromobenzo[b]thiophene under the conditions described in example 16 gave after chromatographic isolation and crystallization from ether/hexane colorless crystals with m.p. 120°-123° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]1[C:19]2[C:14](=[C:15]([O:20][CH3:21])[CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:22][C:23]2[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=2)[N:11]=1>>[CH3:28][C:26]1[NH:25][N:24]=[C:23]([NH:22][C:12]2[N:11]=[C:10]([O:8][C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)[C:19]3[C:14]([CH:13]=2)=[C:15]([O:20][CH3:21])[CH:16]=[CH:17][CH:18]=3)[CH:27]=1
Reactant: COc1cccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc12
Reactant: Cc1ccc(O)cc1
Product: COc1cccc2c(Oc3ccc(C)cc3)nc(Nc3cc(C)[nH]n3)cc12

Procedure:
Similar procedure as described in example 10 was used, starting from 4-methyl-phenol and (1-chloro-5-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give (5-methyl-1H-pyrazol-3-yl)-(1-p-tolyloxy-5-methoxy-isoquinolin-3-yl)-amine. LC-MS m/e 361(MH+).
Reaction SMILES: [NH:1]1C[CH2:4][CH2:3][CH:2]1[CH2:6][S:7]([OH:10])(=[O:9])=[O:8].[OH2:11]>>[NH2:1][CH:2]([CH:3]([OH:11])[CH3:4])[CH2:6][S:7]([OH:10])(=[O:9])=[O:8]
Reactant: O
Reactant: O=S(=O)(O)CC1CCCN1
Product: CC(O)C(N)CS(=O)(=O)O

Procedure:
NMR (0.2 NaOD, t-BuOD, δ=1.23 ppm): δ1.17(3H,d,J=6.5 Hz), 2.83(1H,dd,J=9 Hz, 14 Hz), 3.10(1H,dd,J=2.5 Hz, 14 Hz), 3.11-3.17(1H,m), 3.77-3.84(1 H,m) 2-Pyrrolidinylmethanesulfonic acid (compound 23) m.p.: 307°-308° C. (decomposition) [α]24 : +33.4° (c=1.0, H2O) Elementary Analysis: C5H11NO3S
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([C:13]2[N:14]=[CH:15][N:16]([C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:17]=2)([OH:12])[CH:9]([CH3:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:42]1[O:43][CH:44]=[CH:45][CH:46]=1)CCC>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>[O:43]1[CH:44]=[CH:45][CH:46]=[C:42]1[C:2]1[CH:3]=[C:4]([C:8]([C:13]2[N:14]=[CH:15][N:16]([C:18]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:17]=2)([OH:12])[CH:9]([CH3:10])[CH3:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C(O)(c1cccc(Br)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CC(C)C(O)(c1cccc(-c2ccco2)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1

Procedure:
By the reaction in the same manner as in Example 28-(i) using 1-(3-bromophenyl)-1-(1-trityl-1H-imidazol-4-yl)-2-methyl-1-propanol (1.70 g), tri-n-butyl(2-furyl)tin (1.29 ml) and tetrakis(triphenylphosphine)palladium((0) (110 mg), the title compound (1.62 g) was obtained as colorless powder crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:18][CH:17]2[O:19][CH:13]([CH2:14][NH:15][CH2:16]2)[CH2:12]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:22][CH2:23][CH2:24][OH:25].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[OH:25][CH2:24][CH2:23][CH2:22][N:15]1[CH2:14][CH:13]2[O:19][CH:17]([CH2:18][N:11]([CH2:10][CH2:9][CH2:8][NH:7][C:6](=[O:20])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:12]2)[CH2:16]1
Reactant: OCCCBr
Reactant: CC(C)(C)OC(=O)NCCCN1CC2CNCC(C1)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCCN1CC2CN(CCCO)CC(C1)O2
Temperature: 60 °C
Reaction time: 8 h
Yield: 69.2 %

Procedure:
To tert-butyl[3-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)propyl]carbamate (0.300 g; 1.05 mmol; see Preparation A above), 3-bromo-1-propanol (0.153 mg; 1.10 mmol) and potassium carbonate (0.218 mg; 1.58 mmol) was added acetonitrile (10 mL). The resulting mixture was heated to 60° C. and stirred overnight. The mixture was then filtered and the filtrate was concentrated in vacuo. The crude product was purified by filtration through silica gel (10 g, Isolute®, eluent: DCM (30 mL), acetonitrile (30 mL), DCM/MeOH 80:20 (140 mL) and DCM/MeOH(NH3-satd.) (40 mL), 10 mL/fraction, product in fractions 8-22), which afforded 250 mg (69.2%) of the title compound.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[CH:8][C:7]([NH:10][S:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]4[C:23]([CH3:28])=[N:24][O:25][C:26]=4[CH3:27])=[CH:16][CH:15]=3)(=[O:13])=[O:12])=[CH:6][N:5]=2)[CH2:3][CH2:2]1.[C:29](N=C(N(C)C)N(C)C)([CH3:32])([CH3:31])[CH3:30].BrCC(C)C>C(#N)C.O>[CH:1]1([C:4]2[N:9]=[CH:8][C:7]([N:10]([CH2:30][CH:29]([CH3:32])[CH3:31])[S:11]([C:14]3[CH:15]=[CH:16][C:17]([O:20][CH2:21][C:22]4[C:23]([CH3:28])=[N:24][O:25][C:26]=4[CH3:27])=[CH:18][CH:19]=3)(=[O:12])=[O:13])=[CH:6][N:5]=2)[CH2:2][CH2:3]1
Reactant: CN(C)C(=NC(C)(C)C)N(C)C
Reactant: Cc1noc(C)c1COc1ccc(S(=O)(=O)Nc2cnc(C3CC3)nc2)cc1
Solvent: CC#N
Solvent: O
Solvent: CC(C)CBr
Product: Cc1noc(C)c1COc1ccc(S(=O)(=O)N(CC(C)C)c2cnc(C3CC3)nc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.8 %

Procedure:
To a solution of N-(2-cyclopropylpyrimidin-5-yl)-4-((3,5-dimethylisoxazol-4-yl)methoxy)benzenesulfonamide (74 mg, 0.185 mmol) in acetonitrile (0.1 mL) stirred at room temperature, was added 2-(tert-butyl)-1,1,3,3-tetramethylguanidine (0.074 mL, 0.370 mmol). The mixture was stirred at room temperature for 1 hour, then 1-bromo-2-methylpropane (0.04 mL, 0.370 mmol) added. The reaction was then heated by microwaves to 150° C., for 30 minutes. After cooling the reaction was diluted with acetonitrile (0.5 mL) and water (0.5 mL) and the crude sample purified by mass directed autoprep (formic acid modifier) to give the title product (43.75 mg). LCMS (2 min, High pH) Rt 1.27 min, m/z (ES+) 457 (M+H).