Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:14][C@H:15]([CH2:41][O:42][C:43](=[O:55])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:16][S:17][CH2:18][C@@H:19]([C:38](O)=[O:39])[NH:20][C:21](=[O:37])[O:22][CH2:23][CH:24]1[C:36]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].Cl.[NH2:57][CH2:58][CH2:59][O:60][CH2:61][CH2:62][O:63][CH2:64][CH2:65][C:66]([P:69](=[O:76])([O:73][CH2:74][CH3:75])[O:70][CH2:71][CH3:72])([F:68])[F:67].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH:35]1[C:36]2[CH:24]([CH2:23][O:22][C:21]([NH:20][C@@H:19]([CH2:18][S:17][CH2:16][C@H:15]([O:14][C:1](=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:41][O:42][C:43](=[O:55])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[C:38](=[O:39])[NH:57][CH2:58][CH2:59][O:60][CH2:61][CH2:62][O:63][CH2:64][CH2:65][C:66]([P:69](=[O:76])([O:73][CH2:74][CH3:75])[O:70][CH2:71][CH3:72])([F:68])[F:67])=[O:37])[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:31]=2[CH:32]=[CH:33][CH:34]=1
Reactant: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)OC(=O)CCCCCCCCCCC
Reactant: CCOP(=O)(OCC)C(F)(F)CCOCCOCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCCOCCOCCC(F)(F)P(=O)(OCC)OCC)OC(=O)CCCCCCCCCCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (5R,9R)-9-(dodecanoyloxy)-1-(9H-fluoren-9-yl)-3,12-dioxo-2,11-dioxa-7-thia-4-azatricosane-5-carboxylic acid (6, 1 eq) in DCM (0.1M) was added diethyl 3-(2-(2-aminoethoxy)ethoxy)-1,1-difluoropropylphosphonate hydrochloride (1.3 eq), DIEA (3.5 eq) and HBTU (1.2 eq). The reaction mixture was then stirred at room temperature for 2 hours. The mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 30-80% EtOAc/Hex to give the product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:34])=[C:23](B4OC(C)(C)C(C)(C)O4)[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:35][C:36]1[CH:37]=[CH:38][C:39]([CH3:54])=[C:40]2[C:45]=1[CH:44]=[N:43][C:42](OS(C(F)(F)F)(=O)=O)=[CH:41]2.O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].O>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:34])=[C:23]([C:42]4[N:43]=[CH:44][C:45]5[C:40]([CH:41]=4)=[C:39]([CH3:54])[CH:38]=[CH:37][C:36]=5[F:35])[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(B4OC(C)(C)C(C)(C)O4)c3)cn2)CC1
Reactant: Cc1ccc(F)c2cnc(OS(=O)(=O)C(F)(F)F)cc12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(F)c2cnc(-c3cc(-c4cnn(C5CCN(C(=O)OC(C)(C)C)CC5)c4)cnc3N)cc12
Temperature: 105 °C

Procedure:
To a solution of 4-{4-[6-amino-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (BB3) (56.1 mg, 0.120 mmol), trifluoromethanesulfonic acid 8-fluoro-5-methylisoquinolin-3-yl ester (40.2 mg, 0.130 mmol), and PS-PPh3-Pd (0.10 mmol/g loading; 83 mg, 0.0083 mmol; Argonaut) in 1,4-dioxane (2.0 mL, 26 mmol) in a sealable microwave tube was added a solution of Cs2CO3 (80.5 mg, 0.247 mmol) in H2O (0.60 mL, 33 mmol). The tube was sealed, evacuated and refilled with nitrogen (3×), and heated in the microwave reactor to 105° C. for 30 minutes. The resin was filtered off and washed with DCM. The combined filtrate and washings were washed with water and brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by preparative TLC [20×20 cm plate, 500 μm layer of silica gel, eluting with 3% MeOH in DCM (2×)]. Material from the main band was collected and dried in vacuo overnight giving the title compound as a yellow glassy solid. 1H NMR (400 MHz, CDCl3): δ=9.57 (s, 1H), 8.21 (d, J=2.4 Hz, 1H), 8.05 (s, 1H), 7.96 (d, J=2.4 Hz, 1H), 7.77 (s, 1H), 7.66 (d, J=0.4 Hz, 1H), 7.49 (ddd, J=1.0, 5.2, 7.8 Hz, 1H), 7.15 (dd, J=7.8, 9.8 Hz, 1H), 6.89 (brs, 2H), 4.39-4.19 (brm, 3H), 2.92 (brt, J=11.6 Hz, 2H), 2.70 (s, 3H), 2.19 (brdd, J=2.0, 12.4 Hz, 2H), 1.97 (brdq, J=4.2, 12.4 Hz, 2H), 1.49 (s, 9H). MS(ES+): m/z=503.19 (100) [MH+], 447.13 (2) [MH+-isobutene]. HPLC: tR=3.08 min (polar—5 min, ZQ2).
Reaction SMILES: [CH3:1][C:2]1[CH:33]=[C:32]([NH:34][C:35](=[O:37])[CH3:36])[CH:31]=[CH:30][C:3]=1[O:4][CH2:5][CH:6]([OH:29])[CH2:7][N:8]([CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:28])[CH3:27])=[CH:21][CH:20]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:38](OC(=O)C)(=[O:40])[CH3:39].[OH-].[Na+]>N1C=CC=CC=1>[CH3:1][C:2]1[CH:33]=[C:32]([NH:34][C:35](=[O:37])[CH3:36])[CH:31]=[CH:30][C:3]=1[O:4][CH2:5][CH:6]([O:29][C:38](=[O:40])[CH3:39])[CH2:7][N:8]([CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:28])[CH3:27])=[CH:21][CH:20]=1)[CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(=O)Nc1ccc(OCCN(Cc2ccccc2)CC(O)COc2ccc(NC(C)=O)cc2C)cc1
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(OCCN(Cc2ccccc2)CC(COc2ccc(NC(C)=O)cc2C)OC(C)=O)cc1
Temperature: 0 °C

Procedure:
Two grams of 1-(2-methyl-4-acetamidophenoxy)-3-{N-[2-(4-acetamidophenoxy)ethyl]-N-benzylamino}propan-2-ol are added to 20 ml. of anhydrous pyridine, followed by the immediate addition of 8.0 g. of acetic anhydride to the mixture with stirring. The resulting solution is then refluxed for a period of five minutes, cooled and subsequently poured into 50 ml. of ice water. The latter aqueous soltuion is then basified with 2N aqueous sodium hydroxide solution and extracted with chloroform, and the chloroform extract is thereafter washed with water and dried over anhydrous sodium sulfate prior to concentration in vacuo. The crude product obtained in this manner is then recrystallized from ethanol to afford pure 1-(2-methyl-4-acetamidophenoxy)-3-{N-[2-(4-acetamidophenoxy)ethyl]-N-benzylamino}-2-acetoxypropane. On subsequent treatment with hydrogen in the presence of palladium-on-carbon, the latter compound then gave 1-(2-methyl-4-acetamidophenoxy)-3-[2-(4-acetamidophenoxy)ethylamino]-2-acetoxypropane.
Reaction SMILES: [S:1]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8](O)=[O:9])(=[O:4])(=[O:3])[NH2:2].S(Cl)([Cl:16])=O>>[S:1]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([Cl:16])=[O:9])(=[O:4])(=[O:3])[NH2:2]
Reactant: NS(=O)(=O)c1cccc(C(=O)O)c1
Reactant: O=S(Cl)Cl
Product: NS(=O)(=O)c1cccc(C(=O)Cl)c1

Procedure:
10 g of ground 3-sulfamoylbenzoic acid were reacted as prescribed in Example 70b), the thionyl chloride was distilled off and the residue was crystallized under a mixture of petroleum ether and diethyl ether (1:1). Melting point: 123° C.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH2:18][C@H:19]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)[CH2:20][OH:21]>C(#N)C>[Cl:11][C:4]1[N:3]=[C:2]([NH:18][C@H:19]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:20][OH:21])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: N[C@@H](CO)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(Cl)nc1N[C@@H](CO)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.1 %

Procedure:
To a mixture of 2,6-dichloro-3-nitropyridine (0.933 g, 4.83 mmol) and potassium carbonate (0.58 g, 4.19 mmol) in anhydrous acetonitrile (10 ml) was added (R)-2-amino-2-(4-fluoro phenyl)ethanol (1.00 g, 7.19 mmol) at 0° C. The resulting reaction mixture was stirred at 25° C. for 18 hours. The solid was removed by filtration and washed with EtOAc (20 ml). After evaporation of the solvent, the resulting residue was purified by column chromatography (hexane-EtOAc=5:1) to give the title compound as a yellow solid (0.77 g, 61%). 1H NMR (400 MHz) δ 8.96 (d, J=7.6 Hz, 1H), 8.46 (d, J=8.4 Hz, 1H), 7.45 (m, 2H), 7.15 (m, 2H), 6.81 (d, J=8.8 Hz, 1H), 5.27 (m, 2H), 3.80 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C:8]([C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=2[NH:20][C:21](=[O:24])[CH2:22]Cl)=O)[CH:7]=1.[N:27]1C=CC=CC=1>C1C=CC=CC=1>[NH2:27][C:22]1[C:21](=[O:24])[NH:20][C:11]2[C:10]([C:8]=1[C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[O:25][CH3:26])=[CH:15][C:14]([C:16]([F:18])([F:17])[F:19])=[CH:13][CH:12]=2
Reactant: c1ccncc1
Reactant: COc1ccc(Cl)cc1C(=O)c1cc(C(F)(F)F)ccc1NC(=O)CCl
Solvent: c1ccccc1
Product: COc1ccc(Cl)cc1-c1c(N)c(=O)[nH]c2ccc(C(F)(F)F)cc12
Yield: 98 %

Procedure:
A mechanically stirred solution of N-[2-[(5-chloro-2-methoxyphenyl)carbonyl]-4-(trifluoromethyl)phenyl]chloroacetamide (12.2 g, 0.03 mol) in anhydrous pyridine (150 mL) was heated to reflux for 20-25 min. The resultant suspension of the pyridinium salt was allowed to cool and then diluted with benzene (100 mL). The pyridinium salt was filtered, washed with benzene and then dried in vacuo to afford the desired titled compound (13.75 g, 98%): mp 325-330° C. (dec.); IR (KBr, cm-1) 1678,1322,1270,1118; 1H NMR (300 MHz, DMSO-d6)δ 3.59 (3H, s), 7.09 (1H, d, J=9.0 Hz), 7.38 (1H, s), 7.44 (1H, d, J=2.6 Hz), 7.52 (1H, dd, J=8.9 and 2.6 Hz), 7.83 (1H, d, J=8.7 Hz), 8.11 (1H, dd, J=8.7 and 1.8 Hz), 8.19-8.27 (2H, m), 8.70-8.75 (1H, m), 9.05-9.07 (2H, m), 13.54 (1H, brd s); MS m/e 431 (MH)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C:10](=[N:15]O)[C:9]=2[CH:8]=[N:7]1)[CH3:2].C([BH3-])#N.[Na+].C([O-])(=O)C.[NH4+].N.[Cl-].[NH4+]>CO.[Cl-].[Ti+3].[Cl-].[Cl-].O>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH:10]([NH2:15])[C:9]=2[CH:8]=[N:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ncc2c1CCCC2=NO
Agent: [Ti+3]
Agent: CC(=O)[O-]
Agent: N
Solvent: CO
Solvent: O
Product: CCOC(=O)Cn1ncc2c1CCCC2N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (4-hydroxyimino-4,5,6,7-tetrahydro-indazol-1-yl)-acetic acid ethyl ester (132 mg, 0.59 mmol), sodium cyanoborohydride (110 mg, 1.76 mmol), and ammonium acetate (0.5 g, 7.2 mmol) in methanol (10 mL) was added titanium (III) chloride (0.99 mL, 20% wt in water, 1.68 mmol) dropwise. The reaction mixture was stirred at room temperature for 2 hours under an argon atmosphere. To the above mixture were added water (10 mL) and a solution of concentrated ammonia and saturated ammonium chloride (10 mL, 1:5, v/v). The resulting mixture was filtered through a pad of Celite® (a diatomite filter from World Minerals Inc.) with dichloromethane (30 mL). The separated aqueous layer was extracted with dichloromethane (20 mL×3). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate and concentrated in vacuo to afford 4-amino-4,5,6,7-tetrahydro-indazol-1-yl)-acetic acid ethyl ester (131 mg, 99%) as a viscous light brown oil. 1H NMR (400 MHz, CD3OD) δ ppm 7.76 (s, 1 H), 5.34 (s, 2 H), 4.60 (m, 2 H), 4.34 (m, 2 H), 2.70 (m, 2 H), 2.20 (m, 1 H), 1.98 (m, 3 H), 1.32 (t, J=7.2 Hz, 3 H). MS calcd. for C11H17N3O2 223, obsd. (ESI+) [(M+H)+] 224.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[NH:12][NH:11][C:10](=[S:13])[N:9]1[CH2:14][CH3:15].[C:16](OC(=O)C)(=[O:18])[CH3:17]>O1CCCC1.O.C(OCC)(=O)C>[C:16]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[NH:12][NH:11][C:10](=[S:13])[N:9]1[CH2:14][CH3:15])(=[O:18])[CH3:17]
Reactant: CCN1C(=S)NNC1c1ccccc1N
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCN1C(=S)NNC1c1ccccc1NC(C)=O

Procedure:
A solution of 0.25 g of 5-(2-aminophenyl)-2,4-dihydro-4-ethyl-1H-[1,2,4]triazol-3-thione and 0.13 mL of acetic anhydride in 1.5 mL of tetrahydrofuran and 0.7 mL of water was stirred at 24° C. for 4 hours. The solution was diluted with 25 mL of ethyl acetate, washed with brine, and dried over MgSO4. The mixture was filtered and the filtrate was concentrated to dryness and then dissolved in 20 mL of 1N sodium hydroxide. The aqueous mixture was extracted twice with 20 mL portions of ethyl acetate. The extracts were combined, washed with brine, dried, and concentrated to dryness to give a solid. The solid was triturated with ethyl acetate:hexane (1:1 v/v) to give 140 mg of 5-(2-acetamidophenyl)-2,4-dihydro-4-ethyl-1H-[1,2,4]triazol-3-thione, mp 193°-194° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:33])/[CH:16]=[CH:17]/[C:18]1[CH:22]=[CH:21][N:20]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH:19]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:33])/[CH:16]=[CH:17]/[C:18]1[CH:22]=[CH:21][N:20]([S:23]([C:26]2[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=2)(=[O:25])=[O:24])[CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc(/C=C/C(=O)Nc3ccccc3NC(=O)OC(C)(C)C)c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccc(/C=C/C(=O)Nc3ccccc3N)c2)cc1
Reaction time: 93 h
Yield: 54.4 %

Procedure:
0.116 g of (2-{(E)-3-[1-(toluene-4-sulfonyl)-1-H-pyrrol-3-yl]-allanoylamino}-phenyl)-carbamic acid tert-butyl ester (compound A5) are dissolved in 20 ml of dichloromethane at ambient temperature. 2 ml of trifluoroacetic acid (TFA) are added and the solution is stirred for 93 hour. The solvent is evaporated to dryness and to the residue are added 25 ml of water. The water phase is extracted exhaustively with ethyl acetate. Afterwards the combined organic phases are dried over sodium sulfate and filtered. The filtrate is evaporated under vacuo. Then the residue is crystallized from methanol to give 0.050 g of the title compound as white crystals.
Reaction SMILES: [C:1]([N:5]1[C:13]2[CH:12]=[CH:11][NH:10][C:9](=[O:14])[C:8]=2[C:7]([NH:15]CC2C=CC(OC)=CC=2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].C([SiH](CC)CC)C>C(O)(C(F)(F)F)=O>[NH2:15][C:7]1[C:8]2[C:9](=[O:14])[NH:10][CH:11]=[CH:12][C:13]=2[N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[N:6]=1
Reactant: COc1ccc(CNc2nn(C(C)(C)C)c3cc[nH]c(=O)c23)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)n1nc(N)c2c(=O)[nH]ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.1 %

Procedure:
To a solution of 1-tert-butyl-3-((4-methoxybenzyl)amino)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one (250 mg) obtained in Example 249 in TFA (5 ml) was added triethylsilane (0.306 ml), and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give the title compound (155 mg).
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][N:4]([CH3:9])[C:3]=1[CH3:10].NC[CH2:13][C:14]([OH:16])=[O:15]>>[C:14]([CH2:13][CH2:9][N:4]1[CH:5]=[CH:6][C:7](=[O:8])[C:2]([OH:1])=[C:3]1[CH3:10])([OH:16])=[O:15]
Reactant: Cc1c(O)c(=O)ccn1C
Reactant: NCCC(=O)O
Product: Cc1c(O)c(=O)ccn1CCC(=O)O

Procedure:
A reaction analogous to that used for the synthesis of 3-hydroxy-1,2-dimethyl-4-pyridinone was employed starting with β-alanine (2.5 g). No precipitate was observed after concentration and, at this point, the pH was set to 4 with hydrochloric acid. Following extraction with dichloromethane, the solvent was removed by rotary evaporation. Hydrogenolysis was performed as before, although the final product was not recrystallized. An off-white powder was obtained (2.3 g). Proton NMR (D20): 7.89 (d, 1H), 6.88 (d, 1H), 4.39 (t, 2H), 2.76 (t, 2H), 2.38 (s, 3H).
Reaction SMILES: C[C:2](C)([C:4](=[O:14])[CH2:5][C:6](=[N:8][CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])[CH3:7])C.CC(CC(C)=O)=O.[O-]S([O-])(=O)=O.[Na+].[Na+]>>[CH3:12][N:11]([CH2:10][CH2:9][N:8]=[C:6]([CH3:7])[CH2:5][C:4](=[O:14])[CH3:2])[CH3:13]
Reactant: CC(CC(=O)C(C)(C)C)=NCCN(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)=O
Product: CC(=O)CC(C)=NCCN(C)C
Yield: 83 %

Procedure:
In a procedure analogously to 2,2-dimethyl-5-(dimethylaminoethyl-imino)-3-hexanone, starting with starting with 2,4-pentadione (8.00 g, 80.7 mmol), Na2SO4 (14 g, 98.64 mmol), and 3-(dimethylamino)ethylamine (7.83 g, 88.8 mmol). A green liquid was obtained via vacuum distillation at an oil bath of 95-105° C. under 150 mTorr. The yield was 83%. GC analysis indicated one peak.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:11]([O-])=O)=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6]>[Pd].C1COCC1>[NH2:11][C:3]1[C:2]([CH3:1])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: Cc1cccc(C(=O)O)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1cccc(C(=O)O)c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
Pd/C catalyst (ISO mg) was suspended in a solution of 3-methyl-2-nitrobenzoic acid (1.50 g, 8.28 mmol, 1.0 eq) in THF (60 mL), the mixture was stirred under H2 atmosphere at room temperature overnight. The Pd/C was removed by filtration over Celite and the THF was removed in vacuo to give 1.23 g of Iv-a as a white solid (yield 98%). LCMS m/z=152.1 (M+1) (Method B) (retention time=0.73 min). The product was used further without purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([O:9][CH3:10])=[CH:4][N:3]=1.[C:11]([O-])([O-])=[O:12].[K+].[K+]>CO>[Cl:1][C:2]1[N:7]=[C:6]([O:12][CH3:11])[C:5]([O:9][CH3:10])=[CH:4][N:3]=1
Reactant: COc1cnc(Cl)nc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COc1cnc(Cl)nc1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.2 %

Procedure:
To a solution of 10 g (55.9 mmol) 2,4-dichloro-5-methoxy-pyrimidine in 200 mL MeOH was added 7.7 g (55.9 mmol) K2CO3. The reaction mixture was stirred at room temperature for 24 h, then the volatiles were removed in vacuo. The residue was diluted with EtOAc (200 mL) and water (100 mL). The organic layer was separated, dried (Na2SO4), and evaporated affording 9.0 g (92%) 2-chloro-4,5-dimethoxy-pyrimidine as a fluffy white solid which was used in subsequent steps without further purification. LCMS [M+H]+=175.0.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]([NH:8][CH2:9][CH2:10]O)=[O:7])=[C:4]([N+:14]([O-:16])=[O:15])[CH:3]=1.S(Cl)([Cl:19])=O>ClC(Cl)Cl>[Cl:19][CH2:10][CH2:9][NH:8][C:6](=[O:7])[C:5]1[CH:12]=[CH:13][C:2]([F:1])=[CH:3][C:4]=1[N+:14]([O-:16])=[O:15]
Reactant: O=C(NCCO)c1ccc(F)cc1[N+](=O)[O-]
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=C(NCCCl)c1ccc(F)cc1[N+](=O)[O-]
Yield: 83 %

Procedure:
A mixture of 28 parts of 4-fluoro-N-(2-hydroxyethyl)-2-nitrobenzamide, 40 parts of thionyl chloride and 150 parts of trichloromethane is stirred and refluxed for 2 hours. After cooling, the precipitated product is filtered off and dried, yielding 24.5 parts (83%) of N-(2-chloroethyl)-4-fluoro-2-nitrobenzamide.
Reaction SMILES: [C:1]([NH:4][CH:5]1[C:14](=[O:15])[C:13]2[C:8](=[C:9]([CH3:20])[CH:10]=[CH:11][C:12]=2[NH:16]C(=O)C)[S:7][CH2:6]1)(=[O:3])[CH3:2].[OH-].[Na+]>Cl>[C:1]([NH:4][CH:5]1[C:14](=[O:15])[C:13]2[C:8](=[C:9]([CH3:20])[CH:10]=[CH:11][C:12]=2[NH2:16])[S:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(C)c2c1C(=O)C(NC(C)=O)CS2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)NC1CSc2c(C)ccc(N)c2C1=O
Temperature: 90 °C
Reaction time: 0.33 h

Procedure:
109 mg of the compound prepared in (1) above was added to 10 ml of 6N hydrochloric acid, and the mixture was stirred at 90° C. for 20 minutes. After cooling, the mixture was alkalinized by the addition of sodium hydroxide and extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate. The residue obtained after removal of the solvent was subjected to silica gel column chromatography using a chloroform-ethyl acetate (4:1) mixed solvent as an eluant to obtain fractions containing the target compound. The fractions were concentrated to produce 51 mg of the title compound.
Reaction SMILES: N1C2C(=CC(O)=CC=2)C=N1.[NH:11]1[C:19]2[C:14](=[CH:15][C:16]([O:20][C@H:21]3[CH2:26][CH2:25][CH2:24][C@H:23]([N:27]4C(=O)C5C(=CC=CC=5)C4=O)[CH2:22]3)=[CH:17][CH:18]=2)[CH:13]=[N:12]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC1C=CC=CC=1)=O)=NC(OCC1C=CC=CC=1)=O.ClCCl.CN.C(O)C>O1CCCC1>[NH:11]1[C:19]2[C:14](=[CH:15][C:16]([O:20][C@@H:21]3[CH2:26][CH2:25][CH2:24][C@H:23]([NH2:27])[CH2:22]3)=[CH:17][CH:18]=2)[CH:13]=[N:12]1
Reactant: O=C1c2ccccc2C(=O)N1[C@H]1CCC[C@H](Oc2ccc3[nH]ncc3c2)C1
Agent: CN
Agent: O=C(N=NC(=O)OCc1ccccc1)OCc1ccccc1
Agent: Oc1ccc2[nH]ncc2c1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCO
Product: N[C@H]1CCC[C@@H](Oc2ccc3[nH]ncc3c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.4 %

Procedure:
To a solution of the 1H-indazol-5-ol (200 mg, 1.49 mmol) obtained in Reference Example 4 in tetrahydrofuran (15 ml) were added dropwise trans-2-[3-(1H-indazol-5-yloxy)cyclohexyl]-1H-isoindole-1,3(2H)-dione (366 mg, 1.49 mmol), triphenylphosphine (430 mg, 1.64 mmol) and a 40%-dibenzyl azodicarboxylate-dichloromethane solution (1.03 ml, 1.79 mmol) at 0° C. After 1 hour, the mixture thus obtained was warmed up to room temperature. After stirring overnight, the reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in chloroform (50 ml) and washed with a 1M-aqueous sodium hydroxide solution (20 ml). Extraction with chloroform (20 ml) was carried out again and the organic layer was dried over anhydrous magnesium sulfate. The organic layer dried was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain a mixture. To this mixture was added 30%-methylamine/ethanol (6 ml) under a nitrogen atmosphere at room temperature, after 15 minutes, then the resulting mixture was refluxed. After 3 hours, the reaction mixture was concentrated under reduced pressure at room temperature and the resulting residue was purified by a silica gel column chromatography (eluent: chloroform/methanol→chloroform/methanol/(1% aqueous ammonia)) to obtain cis-3-(1H-indazol-5-yloxy)cyclohexanamine (98 mg, 29%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24]Br)=[CH:20][C:19]=2[CH3:26])=[O:17])[C:11](=[O:27])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:28][C:29]1([CH3:34])[CH2:33][CH2:32][NH:31][CH2:30]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][N:31]3[CH2:32][CH2:33][C:29]([OH:28])([CH3:34])[CH2:30]3)=[CH:20][C:19]=2[CH3:26])=[O:17])[C:11](=[O:27])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(CBr)ccc1C(=O)Cn1ccc(OCc2ccccc2)cc1=O
Reactant: CC1(O)CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(CN2CCC(C)(O)C2)ccc1C(=O)Cn1ccc(OCc2ccccc2)cc1=O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of 4-benzyloxy-1-[2-(4-bromomethyl-2-methyl-phenyl)-2-oxo-ethyl]-1H-pyridin-2-one (preparation 1d, 100 mg, 0.24 mmol) in DMF (2 mL) is added 3-hydroxy-3-methylpyrrolidine (28 mg, 0.28 mmol) and K2CO3 (65 mg, 0.47 mmol). The reaction mixture is stirred overnight at 50° C. The mixture is purified via reverse phase HPLC chromatography (Phenomenex Gemini-C18 10 μm, gradient 5% 90% acetonitrile in water+0.3% NH4OH, 120 mL/min).