Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.I[C:55]1[C:63]2[C:58](=[CH:59][CH:60]=[C:61]([N+:64]([O-:66])=[O:65])[CH:62]=2)[N:57]([CH3:67])[N:56]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C.O1CCOCC1>[CH3:67][N:57]1[C:58]2[C:63](=[CH:62][C:61]([N+:64]([O-:66])=[O:65])=[CH:60][CH:59]=2)[C:55]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:56]1
Reactant: Cn1nc(I)c2cc([N+](=O)[O-])ccc21
Reactant: C1CCNC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cn1nc(N2CCCC2)c2cc([N+](=O)[O-])ccc21
Yield: 20.3 %

Procedure:
Pyrrolidine (90 mg), cesium carbonate (500 mg), Pd2(dba)3 (46 mg), and Xantphos (58 mg) were added to a dioxane solution (4 ml) containing 3-iodo-1-methyl-5-nitro-1H-indazole (303 mg) obtained in the 1st step, followed by microwave irradiation (Initiator™, 160° C., 15 minutes, 2.45 GHz, 0-240 W). Then, ethyl acetate was added to the obtained residue, insoluble matter was removed by filtration, and the solvent was distilled away under reduced pressure. 1-Methyl-5-nitro-3-(pyrrolidine-1-yl)-1H-indazole (50 mg) was thus obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:31][CH3:32])[CH2:22][NH:23][S:24]([C:27]3([CH3:30])[CH2:29][CH2:28]3)(=[O:26])=[O:25])[C:11](=[O:33])[C@:10]([CH2:35][C:36]([O:38][CH3:39])=[O:37])([CH3:34])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH2:40](P(CCCC)(CCCC)=CC#N)CCC>CO.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[N:12]([C@@H:21]([CH2:31][CH3:32])[CH2:22][N:23]([CH3:40])[S:24]([C:27]3([CH3:30])[CH2:28][CH2:29]3)(=[O:26])=[O:25])[C:11](=[O:33])[C@:10]([CH2:35][C:36]([O:38][CH3:39])=[O:37])([CH3:34])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@@H](CNS(=O)(=O)C1(C)CC1)N1C(=O)[C@@](C)(CC(=O)OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: CO
Product: CC[C@@H](CN(C)S(=O)(=O)C1(C)CC1)N1C(=O)[C@@](C)(CC(=O)OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1

Procedure:
A solution of methyl 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(1-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetate (21.7 mg, 0.036 mmol; Example 193), 2-(tributylphosphoranylidene)acetonitrile (8.8 mg, 0.036 mmol) and one drop of MeOH in toluene (0.5 mL) was stirred at 110° C. for 1 h. Flash column purification on silica gel (0 to 60% EtOAc in hexanes) gave methyl 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N,1-dimethylcyclopropanesulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetate. This was hydrolyzed with LiOH (1N solution in water, 0.3 mL) in ethanol (0.5 mL) for 3 h at rt. HPLC purification (C18 column, eluted with 10 to 95% CH3CN in water, with 0.1% TFA) gave the title compound.
Reaction SMILES: [F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[N:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)[S:8][CH:9]=1)([F:4])[CH3:3].[C:17]1([CH3:31])[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[O:27][CH:26]=[N:25][C:24]=2[C:28](O)=[O:29])[CH:18]=1>>[F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[N:15]=[C:14]([NH:16][C:28]([C:24]3[N:25]=[CH:26][O:27][C:23]=3[C:19]3[CH:18]=[C:17]([CH3:31])[CH:22]=[CH:21][CH:20]=3)=[O:29])[CH:13]=[N:12]2)[S:8][CH:9]=1)([F:4])[CH3:3]
Reactant: CC(F)(F)c1csc(Cn2ncc(N)n2)n1
Reactant: Cc1cccc(-c2ocnc2C(=O)O)c1
Product: Cc1cccc(-c2ocnc2C(=O)Nc2cnn(Cc3nc(C(C)(F)F)cs3)n2)c1

Procedure:
Following general procedure Z2, starting from 2-[4-(1,1-difluoro-ethyl)-thiazol-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-m-tolyl-oxazole-4-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:15][N:16]([CH3:30])[C:17]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:2]1([NH:1][CH:20]2[CH2:19][CH2:18][C:17]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)([N:16]([CH3:30])[CH3:15])[CH2:22][CH2:21]2)[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Reactant: Nc1cccc2c1Cc1ccccc1-2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN(C)C1(c2ccccc2)CCC(Nc2cccc3c2Cc2ccccc2-3)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 52.3 %

Procedure:
1-Aminofluorene (181 mg, 1 mmol) and 4-dimethylamino-4-phenylcyclohexanone (217 mg, 1 mmol) were dissolved in dry 1,2-dichloroethane (10 ml) under argon. Glacial acetic acid (1 mmol) and sodium triacetoxyborohydride (300 mg) were added to this mixture and the mixture was stirred for 24 hours at RT. For working up, the mixture was concentrated and the residue was adjusted to pH 11 with five molar sodium hydroxide solution. The alkaline phase was diluted with water (10 ml) and extracted with ethyl acetate (4×20 ml). The combined extracts were dried over sodium sulfate and filtered and the filtrate was concentrated. The crude product was chromatographed over silica gel with ethyl acetate/ethanol (1:1). 200 mg N′-(9H-fluoren-1-yl)-N,N-dimethyl-1-phenyl-cyclohexane-1,4-diamine were obtained as a colorless oil, which, for preparation of the hydrochloride, was dissolved in 2-butanone (5 ml), and 1.85 M ethanolic HCl (0.7 ml) was added. The N′-(9H-fluoren-1-yl)-N,N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride obtained was filtered off with suction and dried (220 mg, m.p. 223-225° C.).
Reaction SMILES: [CH2:1]([N:8]1[C:14](=[O:15])[C@H:13]2[CH2:16][CH2:17][CH2:18][C@H:12]2[N:11]([C:19](=[O:22])[CH2:20]Cl)[C:10]2[CH:23]=[CH:24][CH:25]=[CH:26][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:1]([N:8]1[C:14](=[O:15])[C@H:13]2[CH2:16][CH2:17][CH2:18][C@H:12]2[N:11]([C:19](=[O:22])[CH2:20][NH:34][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:10]2[CH:23]=[CH:24][CH:25]=[CH:26][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1[C@H]2CCC[C@H]2N(C(=O)CCl)c2ccccc2N1Cc1ccccc1
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C1[C@H]2CCC[C@H]2N(C(=O)CNCc2ccccc2)c2ccccc2N1Cc1ccccc1
Yield: 30 %

Procedure:
To a solution of (3aR*,10aS*)-9-benzyl-4-(chloroacetyl)-2,3,3a,4,9,10a-hexahydrobenzo[b]-cyclopenta[e][1,4]diazepin-10(1H)-one (1.0 g, 2.7 mmol) and benzylamine (1.45 g, 13.6 mmol) in ethanol (30 mL) was added potassium carbonate (560 mg, 4.1 mmol), and the mixture was refluxed for 17 hours. The solvent was distilled off. To the residue was added water, which was subjected to extraction with dichloromethane. The extract was washed with water, dried and, then, the solvent was distilled off. The residue was purified by silica-gel column chromatography (ethyl acetate-hexane 1:1), followed by crystallization from diethyl-ether to give 0.36 g (yield 30%), m.p. 95-98° C.
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[C:8]3[CH2:15][CH2:14][O:13][C:9]3=[CH:10][CH:11]=2)[NH:6][CH:5]=1)(=O)[CH3:2].B.CC(C)=O>O1CCCC1>[CH2:1]([C:4]1[C:12]2[C:7](=[C:8]3[CH2:15][CH2:14][O:13][C:9]3=[CH:10][CH:11]=2)[NH:6][CH:5]=1)[CH3:2]
Reactant: CC(=O)c1c[nH]c2c3c(ccc12)OCC3
Agent: B
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CCc1c[nH]c2c3c(ccc12)OCC3
Temperature: 25 °C
Yield: 45.1 %

Procedure:
To a stirred mixture of 3-acetyl-7,8-dihydrofuro[2,3-g]indole (721 mg, 3.58 mmol) in tetrahydrofuran (25 mL) under an atmosphere of Ar at ambient temperature was added, over 5 min, borane (1.0 M in THF; 18 mL, 18 mmol). The resultant mixture was stirred at ambient temperature for 30 min, then heated to reflux for 2 h before cooling to room temperature. Acetone (25 mL) was added and the mixture was heated to reflux for a further 30 min. The mixture was cooled to room temperature then all solvent was removed in vacuo. Methanol (40 mL) was added, and the mixture was again heated to reflux for 30 min, then cooled to room temperature followed by solvent removal in vacuo. Purification by flash column chromatography [SiO2; ethyl acetate-heptane (1:4)] afforded the product (302 mg, 45%) as a white solid: m.p. 91–92.5° C.; Found: C, 76.90; H, 7.02; N, 7.44%. C12H13NO requires: C, 76.98; H, 7.00; N, 7.48%.
Reaction SMILES: C[N:2](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.[Br:30][C:31]1[CH:32]=[C:33]2[C:37](=[C:38]([C:40](O)=[O:41])[CH:39]=1)[NH:36][CH:35]=[C:34]2[CH2:43][CH:44]1[CH2:48][CH2:47][S:46](=[O:50])(=[O:49])[CH2:45]1.N.CO>ClCCl>[Br:30][C:31]1[CH:32]=[C:33]2[C:37](=[C:38]([C:40]([NH2:2])=[O:41])[CH:39]=1)[NH:36][CH:35]=[C:34]2[CH2:43][CH:44]1[CH2:48][CH2:47][S:46](=[O:50])(=[O:49])[CH2:45]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)c1cc(Br)cc2c(CC3CCS(=O)(=O)C3)c[nH]c12
Agent: F[B-](F)(F)F
Agent: N
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NC(=O)c1cc(Br)cc2c(CC3CCS(=O)(=O)C3)c[nH]c12
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 33.5 %

Procedure:
TBTU (5.68 g, 17.68 mmol) and triethylamine (1.79 g, 17.68 mmol) were added to a solution of 5-bromo-3-[(1,1-dioxidotetrahydro-3-thienyl)methyl]-1H-indole-7-carboxylic acid (3.28 g, 8.84 mmol) in dichloromethane (100 mL). After the mixture was stirred for 0.5 h at 20° C., NH3/MeOH was added into the solution, and stirring continued for 2 h. The mixture was washed with water and extracted with EtOAc. The organic phase was dried (Na2SO4) and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (petroleum: ethyl acetate=10:1 to 5:1 to 2:1), giving 1.1 g (33.6%) of the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1.COC1C=CC(C[O:23][NH:24][C:25](=[O:33])[CH2:26][N:27]2[C:31]([SH:32])=[N:30][N:29]=[N:28]2)=CC=1>>[SH:32][C:31]1[N:27]([CH2:26][C:25]([NH:24][OH:23])=[O:33])[N:28]=[N:29][N:30]=1
Reactant: COc1ccc(CONC(=O)Cn2nnnc2S)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Cn1nnnc1S)NO
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.8 %

Procedure:
To a mixed solvent of trifluoroacetic acid (15 ml) and anisole (15 ml) is added 5-mercapto-1H-tetrazole-1-acetohydroxamic acid p-methoxybenzyl ester (3 g), and the mixture is stirred at room temperature for 2 hours under nitrogen gas. The reaction mixture is concentrated under reduced pressure, and the resultant material is dissolved in water and passed through a column of synthetic resin adsorbent (Diaion HP-20 distributed by Mitsubishi Chemical K.K.) (95 ml). The resin is washed with water. The fractions containing the main product are combined and concentrated under reduced pressure. The resultant solid is crystallized from a mixture of ether and hexane to give the title compound (1.83 g). mp. 105°-107° C.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30]C)[CH:25]=3)(=[O:23])=[O:22])[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].B(Br)(Br)Br>C(Cl)Cl>[F:33][C:2]([F:1])([F:32])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([S:21]([C:24]3[CH:25]=[C:26]([OH:30])[CH:27]=[CH:28][CH:29]=3)(=[O:23])=[O:22])[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5]
Reactant: COc1cccc(S(=O)(=O)N2CCN(c3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=S(=O)(c1cccc(O)c1)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 25 ml, round-bottomed flask was charged with 1,1,1,3,3,3-hexafluoro-2-(4-(4-((3-methoxyphenyl)sulfonyl)-1-piperazinyl)phenyl)-2-propanol (80 mg, 0.16 mmol) and CH2Cl2 (5 mL). BBr3 (1M in CH2Cl2, 0.48 mL, 0.48 mmol) was added at room temperature. The reaction was stirred at room temperature for 1 h. The mixture was quenched with MeOH (20 mL), concentrated onto silica gel and purified via column chromatography (12 g silica gel, 0 to 10% MeOH in CH2Cl2) to give 3-((4-(4-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)phenyl)-1-piperazinyl)sulfonyl)phenol. 1H NMR (400 MHz, CD3OD) δ=7.57 (d, J=9.0 Hz, 2H), 7.44 (t, J=8.0 Hz, 1H), 7.25 (d, J=7.4 Hz, 1H), 7.18 (s, 1H), 7.10-7.06 (m, 1H), 7.04 (d, J=9.2 Hz, 2H), 3.37-3.33 (m, 4H), 3.21-3.07 (m, 4H). m/z (ESI, +ve ion) 485.1 (M+H)+. GK-GKRP IC50 (Binding)=0.949 μM; GK-GKRP EC50 (LC MS/MS-2)=0.74 μM.
Reaction SMILES: [CH:1]([NH:4][CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].Cl[CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:19]=[C:20]3[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]3[CH:27]=2)=[CH:14][CH:13]=1.BrCCCl>>[CH:1]([N:4]([CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:19]=[C:20]3[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]3[CH:27]=2)=[CH:14][CH:13]=1)[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: Cc1cccn2cc(-c3ccc(OCCCl)cc3)nc12
Reactant: CC(C)NC(C)C
Solvent: ClCCBr
Product: Cc1cccn2cc(-c3ccc(OCCN(C(C)C)C(C)C)cc3)nc12

Procedure:
The title compound was prepared by condensing di-iso-propylamine with 2-(4-chloroethoxyphenyl)-8-methylimidazo[1,2-a]pyridine. 2-(4-Chloroethoxyphenyl)-8-methylimidazo[1,2-1]pyridine was prepared according the procedure described in Example 1 above using 1-bromo-2-chloroethane in place of 1-bromo-3-chloropropane. Analysis Calc'd for C22H29N3O 3HCl; C, 7.16; H, 55.18; N, 8.77. Found: C, 7.13; H, 55.56; N, 8.8.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12]O[C:10]=1[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:18][NH2:19].[OH-].[Na+].Cl>O.C(O)C>[CH3:18][N:19]1[CH:12]=[CH:13][C:14](=[O:15])[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:10]1[CH3:16]
Reactant: Cc1occc(=O)c1OCc1ccccc1
Reactant: CN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1c(OCc2ccccc2)c(=O)ccn1C
Temperature: 25 °C
Reaction time: 144 h
Yield: 62.9 %

Procedure:
3-Benzyloxy-2-methyl-4-pyrone (4.8 g) and methylamine hydrochloride (1.56 g) are dissolved in water (200 ml) and ethanol (100 ml) containing sodium hydroxide (2 g) is added. The mixture is stirred at room temperature for 6 days and is then acidified with concentrated hydrochloric acid to pH 2, and evaporated to dryness. The resulting colourless solid is washed with water and extracted into chloroform (2×50 ml). The chloroform extracts are combined, dried over magnesium sulphate, and evaporated to yield 1,2-dimethyl-3-benzyloxypyrid-4-one (3.2 g).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH2:7][N:8]([C:16]2[C:17](=[O:35])[N:18]([CH3:34])[N:19]=[C:20]([O:22][CH2:23][C@H:24]3[CH2:26][C@@H:25]3[C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][N:28]=3)[CH:21]=2)C(=O)OC(C)(C)C)=[N:4][N:3]=1>C(O)(C(F)(F)F)=O>[CH3:34][N:18]1[C:17](=[O:35])[C:16]([NH:8][CH2:7][C:5]2[S:6][C:2]([CH3:1])=[N:3][N:4]=2)=[CH:21][C:20]([O:22][CH2:23][C@H:24]2[CH2:26][C@@H:25]2[C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][N:28]=2)=[N:19]1
Reactant: Cc1ccc([C@H]2C[C@@H]2COc2cc(N(Cc3nnc(C)s3)C(=O)OC(C)(C)C)c(=O)n(C)n2)nc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc([C@H]2C[C@@H]2COc2cc(NCc3nnc(C)s3)c(=O)n(C)n2)nc1

Procedure:
A solution of tert-butyl (5-methyl-1,3,4-thiadiazol-2-yl)methyl(2-methyl-6-(((1S,2S)-2-(5-methyl pyridin-2-yl)cyclopropyl)methoxy)-3-oxo-2,3-dihydropyridazin-4-yl)carbamate (7) (95 mg, 0.19 mmol) in TFA (1 mL) was stirred at room temperature for 1 h. The reaction mixture was concentrated and 10 mL sat. aq. NaHCO3 was added, extracted with EA (3×10 mL). The organic phase was dried with anhydrous Na2SO4, filtered and concentrated. The residue was purified by Prep-TLC using PE/EtOAc=1/2 to give title compound as a oil. 1H NMR (400 MHz, DMSO) δ 8.23 (s, 1H), 7.55 (t, 1H), 7.45 (d, 1H), 7.18 (d, 1H), 5.86 (s, 1H), 4.73-4.71 (m, 2H), 4.09-4.04 (m, 1H), 3.97-3.97 (m, 1H), 3.51 (s, 3H), 2.66 (s, 3H), 2.22 (s, 3H), 2.11-2.05 (m, 1H), 1.72-1.68 (m, 1H), 1.14-1.09 (m, 1H), 0.99-0.94 (m, 1H); LRMS m/z (M+H) 399.2 found, 399.15 required.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH:12]=[N:11][C:10]2[C:5]1=[N:6][CH:7]=[N:8][C:9]=2[NH2:13].CC(C)[O-].[Mg+2].CC(C)[O-].CC(C)([O-])C.[Mg+2].CC(C)([O-])C.C1(C)C=CC(S(O[CH2:44][P:45](=[O:52])([O:49]CC)[O:46]CC)(=O)=O)=CC=1.Br[Si](C)(C)C>CN(C=O)C.O>[P:45]([CH2:44][O:1][CH2:2][CH2:3][N:4]1[CH:12]=[N:11][C:10]2[C:5]1=[N:6][CH:7]=[N:8][C:9]=2[NH2:13])([OH:52])([OH:49])=[O:46]
Reactant: Nc1ncnc2c1ncn2CCO
Reactant: CCOP(=O)(COS(=O)(=O)c1ccc(C)cc1)OCC
Agent: CC(C)(C)[O-]
Agent: CC(C)[O-]
Agent: C[Si](C)(C)Br
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncnc2c1ncn2CCOCP(=O)(O)O
Temperature: 80 °C
Reaction time: 7 h
Yield: 65.4 %

Procedure:
9-(2-Hydroxyethyl)adenine (HEA) (20.0 g, 0.112 mol) was suspended in DMF (125 ml) and heated to 80° C. Magnesium isopropoxide (11.2 g, 0.0784 mol), or alternatively magnesium t-butoxide, was added to the mixture followed by diethyl p-toluenesulfonyloxymethylphosphonate (66.0 g, 0.162 mol) over one hour. The mixture was stirred at 80° C. for 7 hours. 30 ml of volatiles were removed via vacuum distillation and the reaction was recharged with 30 ml of fresh DMF. After cooling to room temperature, bromotrimethylsilane (69.6 g, 0.450 mol) was added and the mixture heated to 80° C. for 6 hours. The reaction was concentrated to yield a thick gum. The gum was dissolved into 360 ml water, extracted with 120 ml dichloromethane, adjusted to pH 3.2 with sodium hydroxide, and the resulting slurry stirred at room temperature overnight. The slurry was cooled to 4° C. for one hour. The solids were isolated by filtration, washed with water (2×), and dried in vacuo at 56° C. to yield 20 g (65.4%) of 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA) as a white solid. Mp:>200° C. dec. 1H NMR (D2O) δ 3.49 (t, 2H); 3.94 (t, 2H); 4.39 (t, 2H); 8.13 (s, 1H); 8.22 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:11](=[O:12])[NH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:13]([O-])=O)[CH:8]=2)[NH:3]1>[Pd]>[NH2:13][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[NH:3][C:2]([CH3:1])([CH3:16])[C:11](=[O:12])[NH:10]2
Reactant: CC1(C)Nc2ccc([N+](=O)[O-])cc2NC1=O
Agent: [Pd]
Product: CC1(C)Nc2ccc(N)cc2NC1=O

Procedure:
A solution of 1,2-dihydro-2,2-dimethyl-6-nitro-3-(4H)-quinoxalinone(663 mg, 3 mmol) in CH30H (10 ml) is hydrogenated with 50 psi H2 (g) at room temperature in the presence of a catalyst of 10% by weight palladium on charcoal (50 mg). After the starting material is consumed, the solution is filtered and concentrated in vacuo to yield 6-amino-1,2-dihydro-2,2-dimethyl-3-(4H)quinoxalinone.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]([CH2:4][C:5](OC)=[O:6])=[CH2:3].[CH:12]1([NH2:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>CO>[CH3:11][O:10][C:1]([CH:2]1[CH2:4][C:5](=[O:6])[N:19]([CH:12]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:3]1)=[O:9]
Reactant: C=C(CC(=O)OC)C(=O)OC
Reactant: NC1CCCCCC1
Solvent: CO
Product: COC(=O)C1CC(=O)N(C2CCCCCC2)C1

Procedure:
A solution of dimethyl itaconate (0.5 g, 3.16 mmoles), cycloheptylamine (0.357 g, 3.16 mmoles) in methanol (5 mL) was heated at 85° C. for eighteen hours. The solvent was evaporated in vacuo and the resulting crude product was purified by flash chromatography (hexanes/ethyl acetate 80:20 to 20:80) to give the title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:11])=[CH:4][C:3]=1[CH:12]([C:14]1[N:18]2[N:19]=[C:20]([C:23](=O)[CH3:24])[CH:21]=[CH:22][C:17]2=[N:16][CH:15]=1)[CH3:13].Cl.[NH2:27][O:28][CH2:29][CH2:30][OH:31].C(N(CC)CC)C>CO>[OH:31][CH2:30][CH2:29][O:28]/[N:27]=[C:23](/[C:20]1[CH:21]=[CH:22][C:17]2[N:18]([C:14]([CH:12]([C:3]3[CH:4]=[C:5]4[C:9](=[CH:10][C:2]=3[F:1])[N:8]([CH3:11])[N:7]=[CH:6]4)[CH3:13])=[CH:15][N:16]=2)[N:19]=1)\[CH3:24]
Reactant: CC(=O)c1ccc2ncc(C(C)c3cc4cnn(C)c4cc3F)n2n1
Reactant: NOCCO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: C/C(=N\OCCO)c1ccc2ncc(C(C)c3cc4cnn(C)c4cc3F)n2n1
Temperature: 30 °C
Reaction time: 20 h
Yield: 18 %

Procedure:
To a solution of 1-(3-(1-(6-fluoro-1-methyl-1H-indazol-5-yl)ethyl)imidazo[1,2-b]pyridazin-6-yl)ethanone (100 mg, 0.267 mmol) in methanol (10 mL) was added 2-(aminooxy)ethanol hydrochloride (30.3 mg, 0.267 mmol). Triethyl amine was added dropwise to adjust the pH to 5˜6. The reaction mixture was stirred at 30° C. for 20 h. The solvent was removed in vacuo and the residue was dissolved in DCM, washed with NaHCO3 (aq) and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to afford the crude product which was purified by chromatography on silica gel to afford 19 mg (17%) of the title compound. 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.01 (d, 1H), 7.91 (s, 1H), 7.77 (s, 1H), 7.58 (d, 1H), 7.50 (s, 1H), 7.49 (d, 1H), 4.91 (q, 1H), 4.76 (t, 1H), 4.20 (t, 2H), 3.95 (s, 3H), 3.65 (m, 2H), 2.13 (s, 3H), 1.76 (d, 3H). LCMS (method B): [MH]+=397, tR=2.50 min. Chiral separation (method K) provided enantiomeric pure compounds example 39-R and example 39-S.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([N:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([F:26])[CH:24]=4)[CH:19]=[N:18]3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([N:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([F:26])[CH:24]=4)[CH:19]=[N:18]3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-n3ncc4ccc(F)cc43)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(-n3ncc4ccc(F)cc43)nc12
Reaction time: 15 h
Yield: 42.1 %

Procedure:
To a stirred solution of N-tert-butyl-2-(6-fluoro-1H-indazol-1-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (101 mg, 209 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL). After 15 h, the mixture was concentrated in vacuo then 25 mL of a Jan. 10, 1960 mixture of ammonium hydroxide/methanol/dichloromethane added. After 1 h the mixture was concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0-4% methanol containing 10% ammonium hydroxide in dichloromethane) gave 2-(6-Fluoro-indazol-1-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (31 mg, 42%). MS (M+H)+=351; 1H NMR (DMSO-d6) δ: 9.02 (s, 1H), 8.56 (d, J=1.0 Hz, 1H), 8.42 (s, 1H), 8.32 (dd, J=9.4, 2.1 Hz, 1H), 8.02 (dd, J=8.8, 5.3 Hz, 1H), 7.58 (s, 1H), 7.28 (d, J=2.3 Hz, 1H), 1.50 (s, 9H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][C:12]([OH:14])=O)=[CH:9][C:4]=2[O:3][CH2:2]1.S(Cl)([Cl:17])=O>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][C:12]([Cl:17])=[O:14])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCc1ccc2c(c1)OCO2
Product: O=C(Cl)CCc1ccc2c(c1)OCO2

Procedure:
3-Benzo[1,3]dioxol-5-yl-propionic acid (2.50 g, 12.9 mmol) and thionyl chloride (20 mL, 274 mmol) were heated to 79° C. for 4 h then concentrated to afford 3-(benzo[d][1,3]dioxol-5-yl)propanoyl chloride as a brown oil. 2-(2-Imidazol-1-yl-6-methyl-pyrimidin-4-yl)-2-methyl-propylamine (100 mg, 0.432 mmol) and methylene chloride (20 mL) were added and the reaction mixture stirred at rt for about 2 h. The reaction mixture was filtered, filtrate washed with K2CO3 (100 mL, sat. aq.), and the organic layer was dried over Na2SO4. Filtration, concentration and purification using column chromatography gave 40 mg of 3-benzo[1,3]dioxol-5-yl-N-[2-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-2-methyl-propyl]-propionamide as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.90 (s, 1H), 7.92 (s, 1H), 7.05 (s, 1H), 6.90 (s, 1H), 6.70 (m, 3H), 5.90 (s, 2H), 3.59 (d, 2H), 2.94 (t, 2H), 2.57 (s, 3H), 2.40 (t, 2H), 1.28 (s, 6H).