Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=O.[CH2:14]([O:16][CH2:17][CH2:18][NH2:19])[CH3:15].C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>Cl.C(#N)C>[CH2:14]([O:16][CH2:17][CH2:18][NH:19][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([N+:11]([O-:13])=[O:12])=[C:2]([F:1])[CH:3]=1)[CH3:15]
Reactant: CCOCCN
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOCCNC(=O)c1ccc([N+](=O)[O-])c(F)c1
Reaction time: 19 h

Procedure:
3-Fluoro-4-nitrobenzoic acid 5.55 g, 2-ethoxyethylamine 3.15 mL, N,N-diisopropylethylamine 5.23 mL, 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride 8.63 g, 1-hydroxybenzotriazole monohydrate 5.96 g and acetonitrile 77 mL were mixed and stirred for 19 hours. The reaction liquid was poured in diluted hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated brine, saturated aqueous sodium hydrogencarbonate solution and saturated brine, by the order stated, and dried over magnesium sulfate. Distilling the solvent off, 6.86 g of the title compound was obtained.
Reaction SMILES: CS([O:5][CH2:6][CH2:7][N:8]1[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:15][C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)(=O)=O.[OH:22][CH:23]([CH2:29][C:30]1[CH:35]=[CH:34][C:33](O)=[CH:32][CH:31]=1)[C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[CH:20]1[C:21]2[N:8]([CH2:7][CH2:6][O:5][C:33]3[CH:32]=[CH:31][C:30]([CH2:29][CH:23]([OH:22])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:35][CH:34]=3)[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[O:15][C:16]=2[CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)C(O)Cc1ccc(O)cc1
Reactant: CS(=O)(=O)OCCN1c2ccccc2Oc2ccccc21
Product: CCOC(=O)C(O)Cc1ccc(OCCN2c3ccccc3Oc3ccccc32)cc1
Yield: 42.8 %

Procedure:
The title compound (1.06 g, 43%) was prepared as a pale yellow liquid from 2-(phenoxazin-10-yl)ethyl methanesulfonate (1.8 g, 5.9 mmol) and ethyl 2-hydroxy-3-(4-hydroxyphenyl)propanoate (1.36 g, 6.49 mmol) by an analogous procedure to that described in example 6 (Method B).
Reaction SMILES: [F:1][CH2:2][C:3]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[C:11](=[O:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:21]([O-])=O)[CH:9]=2)[N:4]=1.C(O)(=O)C>[H][H].C(Cl)(Cl)Cl.[C].[Pd]>[F:1][CH2:2][C:3]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[C:11](=[O:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH2:21])[CH:9]=2)[N:4]=1
Reactant: [H][H]
Reactant: Cc1ccccc1-n1c(CF)nc2ccc([N+](=O)[O-])cc2c1=O
Agent: [Pd]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: Cc1ccccc1-n1c(CF)nc2ccc(N)cc2c1=O
Yield: 5.2 %

Procedure:
A mixture of 2.0 g(0.064 mol) of 2-fluoromethyl-3-(o-tolyl)-6-nitro-4(3H)-quinazolinone, 0.2 g of 5 % palladium-carbon and 100 ml of acetic acid is shaken for 30 minutes in hydrogen gas. The initial pressure of hydrogen gas is adjusted to 46 lb and the mixture is heated with an infrared lamp during the reaction. After 30 minutes of said reaction, the pressure of hydrogen gas decreases to 6 lb. After the mixture is cooled, said mixture is filtered to remove the catalyst. The filtrate is evaporated to remove acetic acid, and the residue is dissolved in chloroform. The chloroform solution is washed with 5 % aqueous sodium hydroxide and water, successively. Then, the solution is dried and evaporated to remove solvent. The oily residue thus obtained is dissolved in 2 ml of chloroform, and the chloroform solution is passed through a column of 200 g of silica gel. The silical gel column is eluted with ethyl acetate-benzene(1 : 1). Then, the eluate is evaporated to remove solvent. The crude crystal obtained is washed with isopropylether and recrystallized from isopropanol. 0.95 g of 2-fluoromethyl-3-(o-tolyl)-6-amino-4(3H)-quinazolinone is obtained.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([Mg]Cl)[CH:6]=[CH:7][CH:8]=1.BrC1C=C(C(F)(F)F)C=CC=1.C([Mg]Cl)(C)C.C(OC([N:34]1[CH2:56][CH2:55][C:38]2[C:39]3[C:40](O)(C4C=CC=CC=4)[C:41]([F:47])([F:46])[CH2:42][C:43]=3[CH:44]=[CH:45][C:37]=2[CH2:36][CH2:35]1)=O)C>C1COCC1>[F:47][C:41]1([F:46])[CH:40]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:12])([F:11])[F:1])[CH:4]=2)[C:39]2[C:38]3[CH2:55][CH2:56][NH:34][CH2:35][CH2:36][C:37]=3[CH:45]=[CH:44][C:43]=2[CH2:42]1
Reactant: FC(F)(F)c1cccc([Mg]Cl)c1
Reactant: CCOC(=O)N1CCc2ccc3c(c2CC1)C(O)(c1ccccc1)C(F)(F)C3
Agent: CC(C)[Mg]Cl
Agent: FC(F)(F)c1cccc(Br)c1
Solvent: C1CCOC1
Product: FC(F)(F)c1cccc(C2c3c(ccc4c3CCNCC4)CC2(F)F)c1
Reaction time: 16 h

Procedure:
Example 18 was prepared in a similar fashion to Example 14, except (3-(trifluoromethyl)phenyl)magnesium chloride (prepared from 3-bromobenzotrifluoride (1 eq) in THF, followed by addition of isopropyl magnesium chloride (2M in THF, 1 eq) at room temperature and stirring for 16 hours was used instead of phenylmagnesium bromide (example 14, step (c)) 1H NMR (300 MHz, CDCl3) δ 7.55-7.53 (m, 1H); 7.42 (t, J=7.8 Hz, 1H); 7.29 (bs, 1H); 7.20-7.17 (m, 1H); 7.13-7.07 (m, 2H); 4.70 (d, J=19.2, 1H); 3.51-3.36 (m, 2H); 3.01-2.84 (m, 4H); 2.74-2.61 (m, 2H); 2.54-2.49 (m, 2H); 2.01 (bs, 1H); MS: ESI (positive): 368 (M+1).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]([O:9][CH3:10])=[O:8].[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][C:13]=1[CH3:20].C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO.C(OCC)(=O)C.C(O)(=O)C>[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH:1][C@H:2]2[CH2:6][CH2:5][CH2:4][C@H:3]2[C:7]([O:9][CH3:10])=[O:8])=[CH:14][C:13]=1[CH3:20]
Reactant: Cc1cc(C=O)ccc1F
Reactant: COC(=O)[C@@H]1CCC[C@@H]1N
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)[C@@H]1CCC[C@@H]1NCc1ccc(F)c(C)c1
Reaction time: 0.17 h
Yield: 79.7 %

Procedure:
To a stirred solution of methyl (1R,2S)-2-aminocyclopentanecarboxylate (310 mg, 2.17 mmol) in methanol (10 mL) under a nitrogen atmosphere, 4-fluoro-3-methyl-benzaldehyde (0.27 mL, 2.17 mmol) was added. The mixture was stirred for 10 min, and then acetic acid (0.4 mL) was added followed by sodium cyanoborohydride (340 mg, 5.42 mmol). The resulting mixture was stirred at 25° C. for 16 h, and then poured into a mixture of saturated aqueous sodium bicarbonate solution (50 mL) and ethyl acetate (100 mL). Two layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous brine solution, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to afford the desired product, methyl (1R,2S)-2-[(4-fluoro-3-methylbenzyl)amino]cyclopentanecarboxylate (460 mg, 1.73 mmol, 80%), as a clear oil. 1H NMR (400 MHz, CDCl3) δ: 1.68 (2H, m), 1.89 (3H, m), 2.04 (1H, m), 2.28 (3H, d, J=2.0 Hz), 2.97 (1H, m), 3.31 (1H, m), 3.71 (3H, s), 3.72 (2H, m), 6.93 (1H, t, J=8.4 Hz), 7.07 (1H, m), 7.11 (1H, m).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH:8]2[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]2)[CH:5]=[C:4]([Cl:19])[N:3]=1.Cl.[F:21][C:22]1([F:27])[CH2:26][CH2:25][NH:24][CH2:23]1.CN1C(=O)CCC1.CCN(C(C)C)C(C)C>>[Cl:19][C:4]1[CH:5]=[C:6]([CH:8]2[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]2)[CH:7]=[C:2]([N:24]2[CH2:25][CH2:26][C:22]([F:27])([F:21])[CH2:23]2)[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CC(c2cc(Cl)nc(Cl)c2)C1
Reactant: FC1(F)CCNC1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC(c2cc(Cl)nc(N3CCC(F)(F)C3)c2)C1
Temperature: 140 °C
Reaction time: 0.5 h

Procedure:
To a suspension of tert-butyl 3-(2,6-dichloro-4-pyridyl)azetidine-1-carboxylate (1-a, 472 mg, 1.557 mmol), 3,3-difluoropyrrolidine hydrochloride (1.12 g, 5.0 equiv., 7.784 mmol) in NMP (3.0 mL, 31 mmol) in a microwave vial was added DIPEA (1.90 mL, 7.0 equiv., 10.90 mmol)), and the reaction was maintained at 140° C. for 30 min and then at 150° C. for 30 min in the microwave machine. LCMS showed more than 95% conversion. The crude was used without further treatment. LCMS: m/z 374 (M+H).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH3:12][O:13][C:14]1[CH:49]=[CH:48][C:17]2[NH:18][C:19](=[O:47])[N:20]([CH:23]3[CH2:28][CH2:27][N:26]([C:29]4[CH:34]=[C:33]([S:35][C:36]5[CH:45]=[C:44]([CH3:46])[C:39]6[NH:40][C:41](=[O:43])[O:42][C:38]=6[CH:37]=5)[N:32]=[CH:31][N:30]=4)[CH2:25][CH2:24]3)[CH2:21][CH2:22][C:16]=2[CH:15]=1>ClCCl.CO>[CH3:12][O:13][C:14]1[CH:49]=[CH:48][C:17]2[NH:18][C:19](=[O:47])[N:20]([CH:23]3[CH2:24][CH2:25][N:26]([C:29]4[CH:34]=[C:33]([S:35]([C:36]5[CH:45]=[C:44]([CH3:46])[C:39]6[NH:40][C:41](=[O:43])[O:42][C:38]=6[CH:37]=5)=[O:6])[N:32]=[CH:31][N:30]=4)[CH2:27][CH2:28]3)[CH2:21][CH2:22][C:16]=2[CH:15]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(Sc4cc(C)c5[nH]c(=O)oc5c4)ncn3)CC1)C(=O)N2
Solvent: CO
Solvent: ClCCl
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(S(=O)c4cc(C)c5[nH]c(=O)oc5c4)ncn3)CC1)C(=O)N2

Procedure:
Under a nitrogen atmosphere 28 mg (0.11 mmol) 3-chloroperoxybenzoic acid (70%) in 5 mL dichloromethane was added dropwise to 60 mg (0.11 mmol) 7-methoxy-3-{1-[6-(4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-ylsulphanyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one in 5 mL dichloromethane and 1 mL methanol. After the reaction had ended the reaction mixture was evaporated down, dissolved in MeOH/DMF and purified by preparative HPLC-MS. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH:13]([F:15])[F:14])[C:8]1[N:16]([CH3:29])[C:17](=[O:28])[C:18]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=3[Cl:27])=[CH:19][C:7]2=1)(=[O:3])[CH3:2].CC(O[CH:35](N(C)C)[N:36]([CH3:38])[CH3:37])(C)C>>[Cl:27][C:21]1[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:20]=1[C:18]1[C:17](=[O:28])[N:16]([CH3:29])[C:8]2[N:9]([CH:13]([F:15])[F:14])[C:10]3[C:6]([C:7]=2[CH:19]=1)=[CH:5][C:4]([C:1](=[O:3])/[CH:2]=[CH:35]/[N:36]([CH3:38])[CH3:37])=[CH:12][CH:11]=3
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: CC(=O)c1ccc2c(c1)c1cc(-c3ccc(Cl)cc3Cl)c(=O)n(C)c1n2C(F)F
Product: CN(C)/C=C/C(=O)c1ccc2c(c1)c1cc(-c3ccc(Cl)cc3Cl)c(=O)n(C)c1n2C(F)F

Procedure:
The process is carried out as for preparation 1.10 above, using compound A: 6-acetyl-3-(2,4-dichlorophenyl)-9-difluoromethyl-1-methyl-1,9-dihydropyrido[2,3-b]indol-2-one and Bredereck's reagent.
Reaction SMILES: [CH3:1][S:2]([C:4]1[S:8][C:7]([N:9]2[CH:14]([OH:15])[CH2:13][CH2:12][N:11]([CH2:16][C:17]#[CH:18])[C:10]2=[O:19])=[N:6][N:5]=1)=[O:3].ClC(OC1CC1)=[S:22].N1[CH:32]=[CH:31][CH:30]=[CH:29]C=1>>[CH3:1][S:2]([C:4]1[S:8][C:7]([N:9]2[CH:14]([O:15][C:29]([CH:30]3[CH2:32][CH2:31]3)=[S:22])[CH2:13][CH2:12][N:11]([CH2:16][C:17]#[CH:18])[C:10]2=[O:19])=[N:6][N:5]=1)=[O:3]
Reactant: C#CCN1CCC(O)N(c2nnc(S(C)=O)s2)C1=O
Reactant: c1ccncc1
Reactant: S=C(Cl)OC1CC1
Product: C#CCN1CCC(OC(=S)C2CC2)N(c2nnc(S(C)=O)s2)C1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Tetrahydro-1-(5-methylsulfinyl-1,3,4-thiadiazol-2-yl)-3-propargyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole) dissolved in pyridine (80 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The solution is cooled to a temperature of about 10° C. and cyclopropyl chlorothioformate (0.06 mole) dissolved in pyridine (25 ml) is slowly added with stirring over a period of about 15 minutes. After the addition is completed, the reaction mixture is warmed to room temperature and is stirred for an additional period of about 20 minutes to ensure completion of the reaction. After this time the reaction mixture is filtered. The filtrate is then combined with water (100 ml) resulting in the formation of a precipitate. This precipitate is recovered by filtration and is dissolved in ether. The ether solution is washed with dilute aqueous sodium carbonate, is dried over anhydrous magnesium sulfate and is filtered. The filtrate is then stripped of ether to yield the desired product tetrahydro-1-(5-methylsulfinyl-1,3,4-thiadiazol-2-yl)-3-propargyl-6-cyclopropylthiocarbonyloxy-2(1H)-pyrimidinone as the residue. EXAMPLE 48
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=2[F:29])[C:12]2[C:13]([CH3:21])=[CH:14][C:15]([C:18](O)=[O:19])=[N:16][CH:17]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[CH3:31][NH:32][CH3:33].ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]([C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=2[F:29])[C:12]2[C:13]([CH3:21])=[CH:14][C:15]([C:18]([N:32]([CH3:33])[CH3:31])=[O:19])=[N:16][CH:17]=2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CNC
Reactant: Cc1cc(C(=O)O)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: Cc1cc(C(=O)N(C)C)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 90 %

Procedure:
To a solution of 5-[[(4-chlorophenyl)sulfonyl](2,5-difluorophenyl)methyl]-4-methylpyridine-2-carboxylic acid (88 mg, 0.20 mmol) obtained in Example 3 in methylene chloride (2 ml), dimethylamine hydrochloride (18 mg, 0.22 mmol), 1-hydroxybenzotriazole (30 mg, 0.22 mmol), 4-methylmorpholine (0.048 ml, 0.44 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (42 mg, 0.22 mmol) were added at room temperature. After stirring for 6 hours at room temperature, the reaction mixture was washed with saturated aqueous sodium hydrogencarbonate. The organic layer was dried over anhydrous sodium sulfate and filtered then the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to flash silica gel chromatography. The fraction obtained from an elution with hexane:ethyl acetate=1:1 was concentrated under reduced pressure, and the resulting residue was washed with a mixed solvent of diethyl ether and hexane, and collected by filtration to obtain the title compound (83 mg, 0.18 mmol, 89%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5](=[CH:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]2)=[CH:14][CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[NH2:26][CH2:27][C@@H:28]([C:30]1[CH:31]=[CH:32][C:33]([OH:41])=[C:34]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[CH:35]=1)[OH:29]>>[CH2:1]([O:3][C:4](=[O:25])[C:5](=[CH:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:19][CH2:20][CH:21]([NH:26][CH2:27][C@H:28]([OH:29])[C:30]3[CH:31]=[CH:32][C:33]([OH:41])=[C:34]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[CH:35]=3)[CH2:22][CH2:23]2)=[CH:14][CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: CCOC(=O)C(=Cc1ccc(N2CCC(=O)CC2)cc1)C(=O)OCC
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Product: CCOC(=O)C(=Cc1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1)C(=O)OCC

Procedure:
2-(4-{4-[(2R)-2-Hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidine-1-yl}-benzylidene)-malonic acid diethyl ester was prepared from 2-[4-(4-oxo-piperidin-1-yl)-benzylidene]-malonic acid diethyl ester (which was obtained in Example 153) and N-[5-(-2-amino-(1R)-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 10) according to the procedure of Example 180 as a yellowish solid; 1H NMR (300 MHz, DMSO-d6) δ 1.21 (t, J=7.0 Hz, 3 H), 1.23 (t, J=7.0 Hz, 3 H), 1.75–1.95 (m, 2 H), 2.50–3.50 (m, 7 H), 2.90 (s, 3 H), 3.75–3.90 (m, 2 H), 4.16 (q, J=7.0 Hz, 2 H), 4.29 (q, J=7.0 Hz, 2 H), 4.47 (dd, J=8.0, 4.2 Hz, 1 H), 6.84 (d, J=8.2 Hz, 1 H), 6.94 (d, J=9.0 Hz, 2 H), 7.00 (dd, J=8.2, 2.0 Hz, 1 H), 7.17 (d, J=2.0 Hz, 1 H), 7.33 (d, J=9.0 Hz, 2 H), 7.52 (s, 1 H); MS (ES) m/z: 576.0 (MH+); HRMS Calcd. for C28H38N3O8S(MH+): 576.2374. Found: 576.2373.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([N:9]2[CH2:27][CH2:26][C:13]3([CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)[O:12][CH2:11][CH2:10]2)=[O:8])[N:6]=1.[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31].C1(C)C=CC=CC=1>C(Cl)Cl>[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31].[CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([N:9]2[CH2:27][CH2:26][C:13]3([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[O:12][CH2:11][CH2:10]2)=[O:8])[N:6]=1
Reactant: Cc1nc(C(=O)N2CCOC3(CCN(C(=O)OC(C)(C)C)CC3)CC2)cs1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1nc(C(=O)N2CCOC3(CCNCC3)CC2)cs1
Reaction time: 0.42 h

Procedure:
A solution of tert-butyl 10-(2-methylthiazole-4-carbonyl)-7-oxa-3,10-diazaspiro[5.6]dodecane-3-carboxylate (example 89, step f) (0.21 g) in DCM (10 mL) was treated with trifluoroacetic acid (10 mL) and the solution allowed to stand at 20° C. for 25 minutes. Toluene (40 mL) was added and the solvents evaporated under reduced pressure. The residue was azeotroped with acetonitrile to afford the subtitled compound. Yield 0.21 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[C:5]([CH:6]=O)[C:4]=1[OH:14].[N+:15]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1)([O-:17])=[O:16].N12CCCN=C1CCCCC2>O1CCOCC1>[N+:15]([C:18]1[CH:25]=[CH:24][C:21]([C:22]2[O:14][C:4]3[C:3]([O:2][CH3:1])=[CH:10][C:9]([N+:11]([O-:13])=[O:12])=[CH:8][C:5]=3[CH:6]=2)=[CH:20][CH:19]=1)([O-:17])=[O:16]
Reactant: COc1cc([N+](=O)[O-])cc(C=O)c1O
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cc([N+](=O)[O-])cc2cc(-c3ccc([N+](=O)[O-])cc3)oc12
Temperature: 100 °C
Yield: 57.1 %

Procedure:
5.0 g (1.0 equivalent) of 3-methoxy-5-nitrosalicylaldehyde and 6.03 g (1.1 equivalents) of p-nitrobenzyl bromide were dissolved in 15 ml of 1,4-dioxane, and then 13.5 g (3.5 equivalents) of 1,8-diazabicyclo[5.4.0]undeca-7-ene was added thereto. The resulting mixture was heated at about 100° C. for three hours with stirring, and then cooled to room temperature. Thereafter, the resulting solid substance was filtered off and sufficiently washed with ethanol. Thus, 4.55 g of 2-(p-nitrophenyl)-5-nitro-7-methoxybenzo[b]furan was obtained (yield: 70%).
Reaction SMILES: [C:1]([C:3]1[CH:30]=[CH:29][C:6]([C:7]([CH:9]([CH:15]2[C:28]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[S:22][C:21]3[C:16]2=[CH:17][CH:18]=[CH:19][CH:20]=3)C(OCC)=O)=[O:8])=[CH:5][CH:4]=1)#[N:2].C(OCC)C>CS(C)=O.O>[CH:27]1[C:28]2[CH:15]([CH2:9][C:7]([C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:30][CH:29]=3)=[O:8])[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:22][C:23]=2[CH:24]=[CH:25][CH:26]=1
Reactant: CCOC(=O)C(C(=O)c1ccc(C#N)cc1)C1c2ccccc2Sc2ccccc21
Solvent: O
Solvent: CS(C)=O
Solvent: CCOCC
Product: N#Cc1ccc(C(=O)CC2c3ccccc3Sc3ccccc32)cc1

Procedure:
A solution of ethyl 2-(4-cyanobenzoyl)-2-(9H-thioxanthen-9-yl)acetate (5 g, 12.0 mmol) in dimethylsulphoxide (50 ml) and water (0.45 ml) was reacted as described in Example 1 (iv) and the product was isolated in a similar manner except the extraction used diethyl ether to give 4-[2-(9H-thioxanthen-9-yl)acetyl]benzonitrile as a yellow oil which solidified on standing.
Reaction SMILES: [C@@H:1]1([O:12][C:13]2[C:17]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[OH:25])=[C:16]([CH:26]([CH3:28])[CH3:27])[NH:15][N:14]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].[F:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33]Br>>[F:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33][O:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][C:17]1[C:13]([O:12][C@@H:1]2[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]2[OH:3])=[N:14][NH:15][C:16]=1[CH:26]([CH3:28])[CH3:27]
Reactant: Fc1cccc(CBr)c1
Reactant: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccccc1O
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccccc1OCc1cccc(F)c1

Procedure:
The title compound was prepared in a similar manner to that described in Example 11 using 3-(β-D-glucopyranosyloxy)-4-(2-hydroxybenzyl)-5-isopropyl-1H-pyrazole instead of 3-(β-D-glucopyranosyloxy)-4-(2-hydroxybenzyl)-1-(2-hydroxyethyl)-5-trifluoromethyl-1H-pyrazole and using 3-fluorobenzyl bromide instead of benzyl bromide.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C(OC(=O)[NH:27][C@H:28]1[C@@H:33]([F:34])[CH2:32][CH2:31][NH:30][CH2:29]1)C1C=CC=CC=1.CCN(C(C)C)C(C)C.[Si](I)(C)(C)C.C(Cl)[Cl:51]>CCCCO>[ClH:51].[NH2:27][C@H:28]1[C@@H:33]([F:34])[CH2:32][CH2:31][N:30]([C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]3[NH:8][CH:9]=[C:10]([NH:11][C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])[C:4]=23)[CH2:29]1
Reactant: CC(C)C(=O)Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: ClCCl
Reactant: O=C(N[C@@H]1CNCC[C@@H]1F)OCc1ccccc1
Agent: C[Si](C)(C)I
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C(=O)Nc1c[nH]c2ncc(Br)c(N3CC[C@H](F)[C@H](N)C3)c12
Product: Cl
Temperature: 155 °C
Reaction time: 22 h
Yield: 21 %

Procedure:
A mixture of N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramide (0.11 g, 0.37 mmol; Example 15, Step A), benzyl-cis-4-fluoropiperidin-3-ylcarbamate (0.19 g, 0.75 mmol; Example F) and DIEA (0.26 mL, 1.49 mmol) in n-BuOH (2 mL) was stirred at 155° C. (bath) for 22 hours. The solvent was removed, and the residue was dissolved in ethyl acetate (20 mL), washed with water (10 mL), brine (10 mL), dried (sodium sulfate) and concentrated in vacuo. The residue was purified by reverse phase chromatography (Biotage SP4, C-18 25M+, 10-80% CH3CN/water, 30 CV). The product isolated was dissolved in DCM (3 mL), and TMS-I (0.16 mL, 1.12 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed in vacuo, water (10 mL) and ether (30 mL) were added. The aqueous layer was separated, basified with 30% potassium carbonate to a pH of about 9, and extracted with DCM (2×20 mL). The combined organic layers were dried (sodium sulfate) and concentrated in vacuo. The residue was dissolved in DCM (3 mL), and 2N HCl in ether (2 mL) was added. The solid formed was collected to give N-(4-(cis-3-amino-4-fluoropiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramide hydrochloride (36 mg, 21%) as a solid. 1H NMR (400 MHz, D2O) δ 8.25 (s, 1H), 7.27 (s, 1H), 3.86 (m, 1H), 3.62 (m, 1H), 3.41 (m, 2H), 3.20 (m, 1H), 2.64 (m, 1H), 2.12 (m, 2H), 1.96 (m 1H), 1.11 (t, 6H). LCMS (APCI+) m/z 398 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH2:8][CH2:9][NH2:10])[CH2:5][CH2:6][NH2:7].[C:11]([O:15][CH3:16])(=[O:14])[CH:12]=[CH2:13]>CO>[CH3:16][O:15][C:11]([CH2:12][CH2:13][N:1]([CH2:13][CH2:12][C:11]([O:15][CH3:16])=[O:14])[CH2:2][CH2:3][N:4]([CH2:8][CH2:9][N:10]([CH2:13][CH2:12][C:11]([O:15][CH3:16])=[O:14])[CH2:13][CH2:12][C:11]([O:15][CH3:16])=[O:14])[CH2:5][CH2:6][N:7]([CH2:13][CH2:12][C:11]([O:15][CH3:16])=[O:14])[CH2:13][CH2:12][C:11]([O:15][CH3:16])=[O:14])=[O:14]
Reactant: NCCN(CCN)CCN
Reactant: C=CC(=O)OC
Solvent: CO
Product: COC(=O)CCN(CCC(=O)OC)CCN(CCN(CCC(=O)OC)CCC(=O)OC)CCN(CCC(=O)OC)CCC(=O)OC
Temperature: 20 °C

Procedure:
14.69 g (0.100 mol) of tris-(2-aminoethyl)-amine, dissolved in 20 ml of methanol, is instilled in 103.3 g (1.20 mol) of methyl acrylate with stirring at 20° C. The batch is stirred under argon atmosphere for 5 days at room temperature and for 2 days at 50° C. Then, it is concentrated by evaporation in a vacuum and excess methyl acrylate is removed by azeotropic distillation with toluene. The residue is taken up in 150 ml of methanol and 30 ml of diethyl ether, absorptively precipitated with 150 ml of hexane and, after separation of the hexane phase, concentrated by evaporation in a vacuum. The product is obtained as yellowish liquid, which is further reacted without purification.