Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]([CH:42]([CH3:44])[CH3:43])[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2([C:35]3[CH:40]=[CH:39][C:38]([Br:41])=[CH:37][CH:36]=3)[CH2:34][CH2:33][CH2:32][CH2:31]2)[N:15]=1)=[O:13])(C(C)(C)C)(C)C.Cl>O1CCCC1.C(OCC)(=O)C>[OH:8][CH2:9][CH2:10][N:11]([CH:42]([CH3:44])[CH3:43])[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2([C:35]3[CH:40]=[CH:39][C:38]([Br:41])=[CH:37][CH:36]=3)[CH2:34][CH2:33][CH2:32][CH2:31]2)[N:15]=1)=[O:13]
Reactant: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(c3ccc(Br)cc3)CCCC2)nc(O)c1OCc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)N(CCO)C(=O)c1nc(CC2(c3ccc(Br)cc3)CCCC2)nc(O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.3 %

Procedure:
To a stirred solution of 5-benzyloxy-2-[1-(4-bromophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]isopropylamide (232) (1.0 g, 1.46 mmol) in tetrahydrofuran (10 mL) was added HCl (37% aqueous, 1.70 mmol) and the reaction mixture was stirred at room temperature for 1.5 h. After completion of the reaction, the mixture was diluted with ethyl acetate (30 mL), washed with water, separated and the organic phase dried over Na2SO4. After evaporation of the solvent, the crude product was purified by 100-200 silica gel column chromatography using 60% ethyl acetate in hexane followed by 5% methanol in dichloromethane as the eluent to obtain 5-benzyloxy-2-[1-(4-bromophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid (2-hydroxyethyl)-isopropylamide (233) (0.7 g, 84%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([NH:14][C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[C:11]3=[C:27]([CH3:31])[N:28]=[C:29]([CH3:30])[N:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:32](O)(=[O:35])[CH2:33][OH:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(Cl)CCl>CN(C=O)C>[CH3:31][C:27]1[N:28]=[C:29]([CH3:30])[N:10]2[C:11]=1[C:12]([NH:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=1)=[N:13][C:8]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:33](=[O:34])[CH2:32][OH:35])=[CH:7][CH:6]=1)=[N:9]2
Reactant: O=C(O)CO
Reactant: COc1cc(Nc2nc(-c3ccc(N)cc3)nn3c(C)nc(C)c23)cc(OC)c1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COc1cc(Nc2nc(-c3ccc(NC(=O)CO)cc3)nn3c(C)nc(C)c23)cc(OC)c1OC
Temperature: 20 °C
Reaction time: 8 h

Procedure:
A solution of are 50 mg (0.12 mmol) of N-[2-(4-aminophenyl)-5,7-dimethyl-imidazo[5,1-f][1,2,4]triazin-4-yl]-N-(3,4,5-trimethoxyphenyl)amine from example 3 in DMF is treated with 18 mg (0.24 mmol) of glycolic acid, 90 mg (0.24 mmol) of HATU and 46 mg (0.24 mmol) of EDC. It is stirred overnight at 20° C. The solvent is removed under reduced pressure and the residue is purified by HPLC.
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[C:12]([NH:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1)(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: NC1CCc2ccccc2C1
Product: CC(=O)NC1CCc2ccccc2C1
Yield: 65 %

Procedure:
Using a procedure similar to that described in Example 1, 1.50 g of 2-amino-tetralin yielded 1.01 g (65%) of 2-acetamido-tetralin following treatment with acetic anhydride.
Reaction SMILES: [CH:1]1([C:4]2[C:12]([N:13]([CH2:18][CH2:19][OH:20])[S:14]([CH3:17])(=[O:16])=[O:15])=[CH:11][C:10]3[C:6](=[C:7]([C:28]([NH:30][CH3:31])=[O:29])[N:8]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[N:9]=3)[CH:5]=2)[CH2:3][CH2:2]1.[C:32]1(=[O:42])[O:37][C:35](=[O:36])[C:34]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:33]12>N1C=CC=CC=1>[CH:1]1([C:4]2[C:12]([N:13]([S:14]([CH3:17])(=[O:16])=[O:15])[CH2:18][CH2:19][O:20][C:32]([C:33]3[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=3[C:35]([OH:37])=[O:36])=[O:42])=[CH:11][C:10]3[C:6](=[C:7]([C:28](=[O:29])[NH:30][CH3:31])[N:8]([C:21]4[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=4)[N:9]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CNC(=O)c1c2cc(C3CC3)c(N(CCO)S(C)(=O)=O)cc2nn1-c1ccc(F)cc1
Solvent: c1ccncc1
Product: CNC(=O)c1c2cc(C3CC3)c(N(CCOC(=O)c3ccccc3C(=O)O)S(C)(=O)=O)cc2nn1-c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-cyclopropyl-2-(4-fluorophenyl)-6-[(2-hydroxyethyl)(methylsulfonyl)amino]-N-methyl-2H-indazole-3-carboxamide (14) (5.00 mg, 0.0112 mmol) in pyridine (0.200 mL) at RT was added phthalic anhydride (8.29 mg, 0.560 mmol). The reaction mixture was heated under microwave irradiation at 100° C. for 15 min. A further portion of phthalic anhydride (8.29 mg, 0.560 mmol) was added and the reaction mixture reheated at 100° C. for 30 min and 110° C. for 30 min. A further portion of phthalic anhydride (16.6 mg, 1.12 mmol) was added and the reaction mixture was heated at 120° C. for 15 min. The reaction mixture was concentrated in vacuo, the residue redissolved in MeOH (1 mL) and purified by preparative LCMS (40-80% ACN in 0.1% aqueous formic acid). 2-[(2-{[5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)-2H-indazol-6-yl](methylsulfonyl)amino}ethoxy)carbonyl]benzoic acid (15) was isolated as a white solid (4.29 mg, 64%). ESI-MS rniz calculated for [M+H]+: 595.16; found: 594.98; 1H NMR (400 MHz, d4-MeOH) δ 7.85 (s, 1H), 7.75 (brd, J=7.4 Hz, 2H), 7.63-7.58 (m, 2H), 7.53 (ddd, J=19.3, 15.5, 6.6 Hz, 1H), 7.48-7.42 (m, 2H), 7.34 (brs, 1H), 7.33-7.26 (m, 1H), 4.51-4.37 (m, 2H), 4.32-4.23 (m, 1H), 4.11-4.02 (m, 1H), 3.10 (s, 3H), 2.92 (s, 3H), 2.39-2.30 (m, 1H), 1.06-0.94 (m, 3H), 0.66-0.59 (m, 1H).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:13]([Cl:14])=[CH:12][C:7]([C:8]([O:10]C)=[O:9])=[C:6]([OH:15])[CH:5]=1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]Br.O>CN(C)C=O>[NH2:3][C:4]1[C:13]([Cl:14])=[CH:12][C:7]([C:8]([OH:10])=[O:9])=[C:6]([O:15][CH2:20][C:19]2[CH:22]=[CH:23][CH:24]=[C:17]([Cl:16])[CH:18]=2)[CH:5]=1
Reactant: Clc1cccc(CBr)c1
Reactant: COC(=O)c1cc(Cl)c(N)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(OCc2cccc(Cl)c2)c(C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.6 %

Procedure:
A cooled (0° C.) suspension of 60% sodium hydride/oil dispersion (7.2 g, 180 mmol) in anhydrous N,N-dimethylformamide (200 mL) under nitrogen was treated in portions with 4-amino-5-chloro-2-hydroxybenzoic acid, methyl ester (30.24 g, 150 mmol) so as to keep the pot temperature below 20° C. After one hour at 40° C., the mixture was treated with 3-chlorobenzyl bromide (37.0 g, 180 mmol) and heated to 100°±5° C. for one hour, then cooled to room temperature and added to water (600 mL). A solid precipitate soon formed, which was collected, washed with water, partially air dried, and dissolved in methylene chloride. The solution was filtered through alumina (eluted with methylene chloride) and the filtrate was concentrated in vacuo. The residue was taken up in a mixture of 50% sodium hydroxide (50 mL), water (50 mL), and ethanol (100 mL), and refluxed for one hour. Most of the ethanol was removed in vacuo and water (400 mL) was added to dissolve all solid. The aqueous solution was extracted with ether (100 mL), then with petroleum ethers (30°-60° C., 100 mL), cooled (0° C.), and acidified to pH 3 with concentrated hydrochloric acid (about 90 mL). The resultant precipitate was collected and the solid was washed with water, dried, and recrystallized (2 crops) from ethanol to afford 28.36 g (61%) of pale tan solid; mp 182.5°-184.0° C.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].C(#N)C.Br[CH2:21][CH:22]=[CH2:23]>O>[CH2:23]([N:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)[CH:22]=[CH2:21]
Reactant: C1CC2(CCN1)OCCO2
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: C=CCN1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
To a mixture of 15 g (0.015 mol) of 1,4-dioxa-8-azaspiro[4.5]decane, 15.93 g (0.115 mol)of K2CO3, and 100 ml of acetonitrile is added dropwise 9.07 ml (0.105 mol) of ;b 3-bromopropene. The mixture is stirred overnight at room temperature and then at 65° C. for 2 hours. After cooling, the mixture is diluted with water and extracted with methylene chloride. The combined extracts are washed with brine, dried over Na2SO4, and concentrated in vacuo to afford 9.48 g (49%) of title compound as an oil: ir (neat) 2955 and 1090 cm-1 ; NMR (CDCl3) δ5.91 (m, 1H), 5.21 (m, 2H), 3.97 (s, 4H), 3.05 (d, 2H), 2.56 (t, 4H), 1.76 (t, 4H).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:40])[CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([C:21]([C:23]3[N:27]([CH2:28][C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)[C:26]4[CH:36]=[CH:37][CH:38]=[CH:39][C:25]=4[N:24]=3)=[O:22])[CH2:17][CH2:16]2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[BH4-].[Na+]>CO>[CH3:4][C:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([OH:40])[CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([CH:21]([C:23]3[N:27]([CH2:28][C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)[C:26]4[CH:36]=[CH:37][CH:38]=[CH:39][C:25]=4[N:24]=3)[OH:22])[CH2:17][CH2:16]2)=[CH:7][CH:6]=1)([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1ccc(C(=O)CCCN2CCC(C(=O)c3nc4ccccc4n3Cc3ccc(F)cc3)CC2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)c1ccc(C(O)CCCN2CCC(C(O)c3nc4ccccc4n3Cc3ccc(F)cc3)CC2)cc1
Reaction time: 8 h

Procedure:
To a stirred, room temperature, solution of 1-[4-(1,1-dimethylethyl)phenyl]-4-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]carbonyl]-1-piperidinyl]-1-butanone (2.1 g, 3.9×10-3 mole) and methanol (80 ml) was added NaBH4 (0.42 g, 1.1×10-2 mole). After stirring overnight, the methanol was evaporated at reduced pressure. The concentrate was dissolved in a two phase mixture of EtOAc/H2O. The layers were separated and the aqueous layer was re-extracted with EtOAc. The EtOAc extracts were combined, washed with saturated aqueous NaCl, and dried over anhydrous MgSO4. The drying agent was removed by filtration and the filtrate was evaporated at reduced pressure leaving a solid. Crystallization from cyclohexane/hexane afforded α-[1-[4-[4-(1,1-dimethylethyl)phenyl]-4-hydroxybutyl]-4-piperidinyl]-1-[(4-fluorophenyl)methyl]-1H-benzimidazole-2-methanol as a colorless solid: 1.6 g (75%), m.p. 87-90° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=O)[CH2:23][CH3:24])[C:13]=2[C:14]([O:16][CH3:17])=[O:15])[N:4]=1.Cl.[CH3:27][O:28][NH2:29].C([O-])(=O)C.[K+]>CO>[CH3:27][O:28][N:29]=[C:22]([C:18]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([O:11][C:5]2[N:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[N:4]=2)[CH:21]=[CH:20][CH:19]=1)[CH2:23][CH3:24]
Reactant: CCC(=O)c1cccc(Oc2nc(OC)cc(OC)n2)c1C(=O)OC
Reactant: CON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Product: CCC(=NOC)c1cccc(Oc2nc(OC)cc(OC)n2)c1C(=O)OC
Yield: 89.3 %

Procedure:
0.62 g of methyl 2-[(4,6-dimethoxypyrimidin-2-yl)oxy]-6-propionylbenzoate, 0.45 g of methoxyamine hydrochloride and 0.53 g of potassium acetate were added to 80 ml of methanol, and were heat-refluxed for 6 hours. The precipitated product was filtered out, and the solvent was distilled off. Water was added to the product, and the product was extracted with ethyl acetate. The product was then washed with water, and was dried with magnesium sulfate anhydride. After distilling off the solvent, the mixture was purified by column chromatography, and the purified product was crystallized with isopropyl ether/ethyl acetate to obtain 0.60 g of the aimed compound (melting point=75° to 77° C.) at a yield of 89.5%.
Reaction SMILES: [CH2:1]([C:3]1[S:17][C:6]2[S:7][CH2:8][CH2:9][CH:10]3[CH2:15][C:14](=[O:16])[NH:13][N:12]=[C:11]3[C:5]=2[CH:4]=1)[CH3:2].BrBr>C(O)(=O)C>[CH2:1]([C:3]1[S:17][C:6]2[S:7][CH2:8][CH2:9][C:10]3[C:11](=[N:12][NH:13][C:14](=[O:16])[CH:15]=3)[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc2c(s1)SCCC1CC(=O)NN=C21
Agent: BrBr
Solvent: CC(=O)O
Product: CCc1cc2c(s1)SCCc1cc(=O)[nH]nc1-2
Reaction time: 0.25 h
Yield: 49 %

Procedure:
To a solution of 3.7 g of 9-ethyl-4,4a,5,6-tetrahydrothieno[2',3':2,3]-thiepino[4,5-c]pyridazin-3(2H)-one in 40 ml of acetic acid is added dropwise a solution of 2.3 g of bromine in 10 ml of acetic acid with stirring for 15 minutes at 45°-50° C. and the mixture is stirred for 30 minutes at the same temperature. Then, the mixture is poured into ice-cold water and the precipitated crystals are collected by filtration and washed with water. The resulting crude crystals are dissolved in chloroform, subjected to column chromatography on silica gel and eluted with a mixed solvent of chloroform and ethanol (100:0.5). The crystals obtained from the fraction are recrystallized from a mixed solvent of chloroform and ethanol to give 1.8 g of 9-ethyl-5,6-dihydrothieno[2',3':2,3]thiepino[4,5-c]pyridazin-3(2H)-one as white crystals, melting at 256°-258° C.
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH3:9])=[C:5]([Br:8])[C:6]=1[CH3:7].C[CH2:11][O:12]CC.C([Li])CCC>CN(C)C=O>[Br:8][C:5]1[C:6]([CH3:7])=[C:2]([CH:11]=[O:12])[S:3][C:4]=1[CH3:9]
Reactant: CCOCC
Reactant: Cc1sc(Br)c(C)c1Br
Agent: [Li]CCCC
Solvent: CN(C)C=O
Product: Cc1sc(C=O)c(C)c1Br
Temperature: -35 °C

Procedure:
15.0 G. of 2,4-dibromo-3,5-dimethylthiophene was dissolved in 250 ml. of anhydrous ether and cooled to -70° C. with stirring under argon. 24 Ml. of a 2.4 M solution of n-butyl lithium was slowly added to the solution and the mixture was warmed to -35° C. for 10 minutes, and then cooled again to -70° C. 7.3 G. of dimethylformamide was added slowly to the mixture and the reaction mixture was warmed to room temperature for 14 hours. The resulting solution was poured into ice water, stirred for 20 minutes and extracted with ethyl ether. The ether extracts were combined, washed with an aqueous solution of 5% sodium carbonate, saturated sodium chloride solution, dried with sodium sulfate, filtered and evaporated to yield 4-bromo-3,5-dimethylthiophene-2-carboxaldehyde, m.p. 44°-45° C
Reaction SMILES: [CH3:1][C:2]12[O:9][CH:6]([CH2:7][CH2:8]1)[C:5](=O)[CH2:4][C:3]2=[O:11].P(Cl)(Cl)(Cl)(Cl)[Cl:13]>C(Cl)(Cl)Cl>[Cl:13][C:5]1[CH:6]2[O:9][C:2]([CH3:1])([CH2:8][CH2:7]2)[C:3](=[O:11])[CH:4]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CC12CCC(O1)C(=O)CC2=O
Solvent: ClC(Cl)Cl
Product: CC12CCC(O1)C(Cl)=CC2=O
Yield: 82.9 %

Procedure:
To a solution of 1-methyl-8-oxa-bicyclo[3.2.1]octane-2,4-dione (175 mg, 1.14 mmol) in chloroform (2 ml) is added, under N2, in one portion, the phosphorous pentachloride (135 mg, 0.65 mmol). The reaction mixture is stirred for reflux for 5 hours. Silica gel is added to the cooled crude reaction mixture, the solvent is evaporated under reduced pressure and the residue is purified by flash chromatography on silica gel to give 4-chloro-1-methyl-8-oxa-bicyclo[3.2.1]oct-3-en-2-one (93 mg).
Reaction SMILES: [C:1]([C:4]1[N:9]=[N:8][C:7]([NH:10][C@@H:11]2[CH2:16][CH2:15][O:14][CH2:13][C@@H:12]2[NH:17]C(=O)OC(C)(C)C)=[CH:6][C:5]=1[NH:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([CH2:34][CH2:35][CH3:36])[N:27]=1)(=[O:3])[NH2:2].FC(F)(F)C(O)=O>ClCCl>[NH2:17][C@@H:12]1[C@H:11]([NH:10][C:7]2[N:8]=[N:9][C:4]([C:1]([NH2:2])=[O:3])=[C:5]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([CH2:34][CH2:35][CH3:36])[N:27]=3)[CH:6]=2)[CH2:16][CH2:15][O:14][CH2:13]1
Reactant: CCCc1nc(Nc2cc(N[C@@H]3CCOC[C@@H]3NC(=O)OC(C)(C)C)nnc2C(N)=O)ccc1OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCc1nc(Nc2cc(N[C@@H]3CCOC[C@@H]3N)nnc2C(N)=O)ccc1OC
Temperature: 25 °C
Yield: 53.4 %

Procedure:
To a solution of tert-butyl (3R,4R)-4-(6-carbamoyl-5-(5-methoxy-6-propylpyridin-2-ylamino)pyridazin-3-ylamino)tetrahydro-2H-pyran-3-ylcarbamate (77 mg, 154 μmol) in dichloromethane (2.4 mL) was added trifluoroacetic acid (350 mg, 237 μL, 3.07 mmol) and the mixture stirred at room temperature. After 16 h the mixture was concentrated in vacuo then diluted with 25% aqueous NH4OH and dichloromethane. The mixture was washed with water, then the organic phase was concentrated in vacuo and purified by chromatography (silica, 3 to 10% methanol in dichloromethane) to give 6-((3R,4R)-3-aminotetrahydro-2H-pyran-4-ylamino)-4-(5-methoxy-6-propylpyridin-2-ylamino)pyridazine-3-carboxamide (33 mg, 82.2 μmol, 54%) as a an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.37 (s, 1H), 8.33 (s, 1H), 7.74 (s, 1H), 7.58 (s, 1H), 7.41 (d, J=8.7 Hz, 1H), 6.87 (d, J=8.8 Hz, 1H), 6.76 (d, J=7.6 Hz, 1H), 3.98 (br. s, 1H), 3.84 (m, 1H), 3.79 (s, 3H), 3.70 (d, J=11.3 Hz, 1H), 3.51 (d, J=11.5 Hz, 1H), 3.40 (t, J=11.2 Hz, 1H), 2.99 (s, 1H), 2.72 (t, J=7.4 Hz, 2H), 1.81 (m, 1H), 1.72 (m, 2H), 1.72 (m, 3H), 0.94 (t, J=7.3 Hz, 3H); MS (EI/CI) m/z: 402.2 [M+H].
Reaction SMILES: C1(S(Cl)(=O)=[O:8])C=CC=CC=1.[F:11][C:12]1[C:17]([CH:18]2[CH2:23][CH2:22][C:21](=[N:24]O)[CH2:20][CH2:19]2)=[CH:16][CH:15]=[CH:14][N:13]=1>N1C=CC=CC=1>[F:11][C:12]1[C:17]([CH:18]2[CH2:23][CH2:22][NH:24][C:21](=[O:8])[CH2:20][CH2:19]2)=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: ON=C1CCC(c2cccnc2F)CC1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: O=C1CCC(c2cccnc2F)CCN1
Temperature: 100 °C
Reaction time: 0.75 h

Procedure:
Benzenesulfonyl chloride (0.05 mL, 0.40 mmol) was added to a solution of 4-(2-fluoropyridin-3-yl)cyclohexanone oxime (0.075 g, 0.36 mmol) in pyridine (1 mL) at 0° C. The ice bath was removed and the mixture was stirred for 45 min before being heated to 100° C. for 30 minutes. After cooling to room temperature the pyridine was removed in vacuo and the residue was dissolved in 1:1 dioxane/water (5 mL) and stirred overnight. Ammonium chloride (50 mg) was added and stirring continued for 30 minutes. The mixture was extracted with ethyl acetate (3×), the combined extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel chromatography to 5-(2-fluoropyridin-3-yl)azepan-2-one. [M+1]=209.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:51])[CH2:4][CH2:5][NH:6][CH2:7][CH2:8][NH:9][C:10]([C@:12]12[CH2:47][CH2:46][C@@H:45]([C:48]([CH3:50])=[CH2:49])[C@@H:13]1[C@@H:14]1[C@@:27]([CH3:30])([CH2:28][CH2:29]2)[C@@:26]2([CH3:31])[C@@H:17]([C@:18]3([CH3:44])[C@@H:23]([CH2:24][CH2:25]2)[C:22]([CH3:33])([CH3:32])[C:21]([C:34]2[CH:43]=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][CH:35]=2)=[CH:20][CH2:19]3)[CH2:16][CH2:15]1)=[O:11].I[CH2:53][CH3:54].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O1CCOCC1>[CH2:53]([N:6]([CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:51])[CH2:7][CH2:8][NH:9][C:10]([C@:12]12[CH2:47][CH2:46][C@@H:45]([C:48]([CH3:50])=[CH2:49])[C@@H:13]1[C@@H:14]1[C@@:27]([CH3:30])([CH2:28][CH2:29]2)[C@@:26]2([CH3:31])[C@@H:17]([C@:18]3([CH3:44])[C@@H:23]([CH2:24][CH2:25]2)[C:22]([CH3:33])([CH3:32])[C:21]([C:34]2[CH:35]=[CH:36][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:42][CH:43]=2)=[CH:20][CH2:19]3)[CH2:16][CH2:15]1)=[O:11])[CH3:54]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCNCCC(=O)OC)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CC#N
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCN(CC)CCC(=O)OC)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 75.7 %

Procedure:
A mixture of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(3-methoxy-3-oxopropylamino)ethylcarbamoyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (20 mg, 0.029 mmol), iodoethane (0.019 mL, 0.228 mmol) and potassium carbonate (7.89 mg, 0.057 mmol) in acetonitrile (2 mL) and dioxane (2 mL) was refluxed for 8 hours. LCMS indicated the formation of desired product and consumption of starting material. The reaction mixture was quenched with distilled water, extracted with DCM (3×3 mL). All the extracts were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the title compound as white solid (16 mg, 77%). LCMS: m/e 729.45 (M+H)+, 2.76 min (method 1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[CH:12][NH:11][C:8]2=[N:9][CH:10]=1)=[O:4].[I:14]N1C(=O)CCC1=O>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:13]([I:14])=[CH:12][NH:11][C:8]2=[N:9][CH:10]=1)=[O:4]
Reactant: O=C1CCC(=O)N1I
Reactant: COC(=O)c1cnc2[nH]ccc2c1
Solvent: CN(C)C=O
Product: COC(=O)c1cnc2[nH]cc(I)c2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of Example 235a (1.04 g, 5.9 mmol) in 12 mL anhydrous DMF was added N-iodosuccinimide (1.46 g, 6.49 mmol) and the solution stirred at room temperature for 16 hours. The solvent was evaporated and the residue suspended in water and filtered. The collected solid was triturated with dichloromethane and the mixture filtered. The dichloromethane filtrate was concentrated to a brown powder that was carried on without purification.
Reaction SMILES: O(P(O[C:18]1[N:19]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=1)(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[OH:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1>>[OH:31][C:32]1[CH:37]=[C:36]([C:18]2[N:19]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=2)[CH:35]=[CH:34][CH:33]=1
Reactant: OB(O)c1cccc(O)c1
Reactant: CC(C)(C)OC(=O)N1CCOC=C1OP(=O)(Oc1ccccc1)Oc1ccccc1
Product: CC(C)(C)OC(=O)N1CCOC=C1c1cccc(O)c1
Yield: 35 %

Procedure:
This compound was prepared from tert-butyl 5-((diphenoxyphosphoryl)oxy)-2H-1,4-oxazine-4(3H)-carboxylate and 3-hydroxyphenylboronic acid using a procedure similar to that described in Example 2 (Steps 1-3a) above. The product was isolated as an off-white solid (35% yield); 1H-NMR (d6-DMSO) 1.08 (9H, s), 3.65 (2H, t), 4.07 (2H, t), 6.34 (1H, s), 6.58-6.63 (3H, m), 7.06 (1H, m), 9.23 (1H, s); MS ES(+) 222.1 (M+-tBu); Anal. Calcd for C15H19NO4: C, 64.97; H, 6.91; N, 5.05. Found: C, 64.77; H, 7.08; N, 4.85. IR λmax=3365, 1666 cm−1.
Reaction SMILES: [OH-].[Na+].C1(C[O:10][C:11]([C:13]2([NH:19][C:20]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[N:29]=[C:30]([N:33]5[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]5)[S:31][CH:32]=4)=[CH:24][CH:23]=3)=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])C=CC=CC=1.CCOCC>O1CCCC1>[CH3:39][N:36]1[CH2:35][CH2:34][N:33]([C:30]2[S:31][CH:32]=[C:28]([C:25]3[CH:24]=[CH:23][C:22]([C:20]([NH:19][C:13]4([C:11]([OH:12])=[O:10])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]4)=[O:21])=[CH:27][CH:26]=3)[N:29]=2)[CH2:38][CH2:37]1
Reactant: CN1CCN(c2nc(-c3ccc(C(=O)NC4(C(=O)OCc5ccccc5)CCCCC4)cc3)cs2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN1CCN(c2nc(-c3ccc(C(=O)NC4(C(=O)O)CCCCC4)cc3)cs2)CC1
Yield: 67 %

Procedure:
35 ml of 2N aqueous sodium hydroxide solution was added to a solution of 11.8 g (23.0 mmol) of 1-[[[4-[2-(4-methyl-1-piperazinyl)-4-thiazolyl]phenyl]carbonyl]amino]cyclohexanecarboxylic acid phenylmethyl ester in 120 ml of tetrahydrofuran, and the mixture was heated under reflux for 15 hours. Ether was added to the reaction solution to separate the aqueous layer. Concentrated hydrochloric acid was added to the separated aqueous layer to neutralize it, and the precipitated crystal was collected by filtration to obtain 6.60 g (67%) of the title compound.