Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C@H:6]([NH2:7])[C@@H:5]([O:8][C@@H:9]2[O:14][C@H:13]([CH2:15][NH2:16])[C@H:12]([OH:17])[C@@H:11]([OH:18])[C@H:10]2[NH2:19])[C@H:4]([O:20][C@@H:21]2[O:25][C@H:24]([CH2:26][OH:27])[C@@H:23]([O:28][C@H:29]3[O:34][C@@H:33]([CH2:35][NH2:36])[C@@H:32]([OH:37])[C@H:31]([OH:38])[C@H:30]3[NH2:39])[C@H:22]2[OH:40])[C@@H:3]([OH:41])[C@@H:2]1[NH2:42].[NH2:43][CH2:44][CH2:45][CH2:46][C:47]([OH:49])=[O:48].CO[C:52](=[NH:54])[NH2:53].CSC(=N)N>O>[CH2:1]1[C@H:6]([NH2:7])[C@@H:5]([O:8][C@@H:9]2[O:14][C@H:13]([CH2:15][NH2:16])[C@H:12]([OH:17])[C@@H:11]([OH:18])[C@H:10]2[NH2:19])[C@H:4]([O:20][C@@H:21]2[O:25][C@H:24]([CH2:26][OH:27])[C@@H:23]([O:28][C@H:29]3[O:34][C@@H:33]([CH2:35][NH2:36])[C@@H:32]([OH:37])[C@H:31]([OH:38])[C@H:30]3[NH2:39])[C@H:22]2[OH:40])[C@@H:3]([OH:41])[C@@H:2]1[NH2:42].[NH:43]([CH2:44][CH2:45][CH2:46][C:47]([OH:49])=[O:48])[C:52]([NH2:54])=[NH:53]
Reactant: NCCCC(=O)O
Reactant: COC(=N)N
Agent: CSC(=N)N
Agent: NC[C@@H]1O[C@H](O[C@H]2[C@@H](O)[C@H](O[C@@H]3[C@@H](O)[C@H](N)C[C@H](N)[C@H]3O[C@@H]3O[C@H](CN)[C@H](O)[C@@H](O)[C@H]3N)O[C@@H]2CO)[C@H](N)[C@@H](O)[C@@H]1O
Solvent: O
Product: N=C(N)NCCCC(=O)O

Procedure:
For guanylation, the neomycin B/γ-amino butyric acid conjugate obtained in Example 9a above is treated with O-methyl isourea or S-methyl isothiourea in water at basic pH for 34 days, resulting in guanylation of the terminal amino groups. The product is purified by ion exchange chromatography, yielding the neomycin B/γ-guanidino butyric acid conjugate 17.
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[N:7]([C:9]1[N:17]=[CH:16][N:15]=[C:14]2[C:10]=1[N:11]=[CH:12][N:13]2[C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][OH:36])=[C:30]([C:37]([F:40])([F:39])[F:38])[CH:29]=2)=[O:26])=[CH:20][CH:19]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[C:1]([O:5][C:6](=[O:41])[N:7]([CH3:8])[C:9]1[N:17]=[CH:16][N:15]=[C:14]2[C:10]=1[N:11]=[CH:12][N:13]2[C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([CH2:34][CH:35]=[O:36])=[C:30]([C:37]([F:40])([F:39])[F:38])[CH:29]=2)=[O:26])=[CH:20][CH:19]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CN(C(=O)OC(C)(C)C)c1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(CCO)c(C(F)(F)F)c2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CN(C(=O)OC(C)(C)C)c1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(CC=O)c(C(F)(F)F)c2)cc1
Temperature: 0 °C
Reaction time: 20 h
Yield: 47.3 %

Procedure:
In 50 ml of dichloromethane, 300 mg (0.52 mmol) of [9-(4-{3-[4-(2-hydroxyethyl)-3-(trifluoromethyl)phenyl]-ureido}phenyl)-9H-purin-6-yl]-methyl-carbamic acid tert-butyl ester was dissolved, and 270 mg (0.64 mmol) of Dess-Martin periodinane was added thereto under cooling with ice and the solution was stirred at 0° C. for 20 hours. The reaction solution was partitioned between water and ethyl acetate and the organic layer was washed with a saturated sodium chloride solution and concentrated under reduced pressure. The product was purified by a silica gel column (ethyl acetate) to obtain 140 mg (47%) of a target product as a colorless amorphous substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]2C=C[O:16][C:12]=2[CH:11]=[C:10]2[C:4]=1C=CC([O:9]2)=O.C1(C=C(O)C=C(O)C=1)O>>[CH3:1][O:2][C:3]1[CH:13]=[C:12]([OH:16])[CH:11]=[C:10]([OH:9])[CH:4]=1
Reactant: COc1c2ccoc2cc2oc(=O)ccc12
Agent: Oc1cc(O)cc(O)c1
Product: COc1cc(O)cc(O)c1

Procedure:
The present invention also relates to a new synthesis of 5-methoxy-psoralen of the formula: ##STR3## starting from phloroglucinol of the formula: ##STR4## In this synthesis the phloroglucinol is methylated to obtain phloroglucinol mono-methyl ether, which is in turn cyclicized to obtain 6-hydroxy-4-methoxy-3-coumaranone; the coumaranone is reduced in one step to obtain 6-hydroxy-4-methoxy coumaran; the coumaran is then cyclicized to obtain 3,4,4',5'-tetrahydro-5 methoxy psoralen; and that product is hydrogenated to yield 5-methoxy-psoralen.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([Br:17])=[CH:7][CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.ClC1C=CC=C(C(OO)=[O:28])C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([Br:17])=[CH:7][CH2:8][N+:9]([O-:28])=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Clc1ccc2c(c1)C(c1ccccc1)=NCC=C2Br
Solvent: ClCCl
Product: [O-][N+]1=C(c2ccccc2)c2cc(Cl)ccc2C(Br)=CC1

Procedure:
A solution of 6.9 g (20.7 mmole) of 8-chloro-5-bromo-1-phenyl-3H-2-benzazepine and 6 g (29 mmole) of 85% m-chloroperbenzoic acid in 100 ml of methylene chloride was stirred at room temperature for 1 hr. The mixture was washed with cold dilute sodium hydroxide, dried over anhydrous sodium sulfate and concentrated at reduced pressure to dryness. The residue was crystallized from ether to give a white solid, mp 184°-185° C. Recrystallization from ether gave colorless prisms, mp 185°-186° C. dec.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[N:6]1[C:10](=[O:11])[C:9]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[NH:8][C:7]1=[O:17].[H-].[Na+].I[CH2:21][CH2:22][CH3:23]>CN(C)C=O.O>[CH2:21]([N:8]1[C:9]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:10](=[O:11])[N:6]([C:2]2[S:1][CH:5]=[CH:4][N:3]=2)[C:7]1=[O:17])[CH2:22][CH3:23]
Reactant: CCCI
Reactant: O=C1NC2(CCCCC2)C(=O)N1c1nccs1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCN1C(=O)N(c2nccs2)C(=O)C12CCCCC2
Reaction time: 1 h
Yield: 67 %

Procedure:
5.05 g of the product from Example 2, stage 2 were dissolved in 20 ml of dimethylformamide. 1.10 g of sodium hydride (50% suspension in mineral oil) were added in portions with stirring at 200C. After 1 hour's stirring, 4 ml of 1-iodopropane were added. Stirring was continued for a further 3 hours. The mixture was then diluted with 100 ml of distilled water, extracted three times with 30 ml portions of ethyl acetate, washed with saturated sodium chloride solution and dried over sodium sulphate. Once the solvent had been removed by distillation, the residue was purified by passage through a silica gel column with ethyl acetate/n-hexane=8/5. 3.95 g of l-propyl-3-thiazol-2-yl-1,3-diazaspiro[4.5]decane-2,4-dione (67% of th.) were obtained in the form of white crystals (mp 135-138° C.).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:8])=[CH:4][CH:5]=[CH:6][CH:7]=1.[C:9]([O:17]CC)(=O)[CH2:10][C:11]([O:13]CC)=O>>[CH3:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:11](=[O:13])[CH2:10][C:9]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8])=[O:17]
Reactant: Cc1ccccc1N
Reactant: CCOC(=O)CC(=O)OCC
Product: Cc1ccccc1NC(=O)CC(=O)Nc1ccccc1C
Temperature: 170 °C
Reaction time: 8 h

Procedure:
329 mmol o-toluidine and 165 mmol diethyl malonate were put together and stirred overnight at 170° C. The formed ethanol was distilled off directly on a stream of nitrogen. N1,N3-di(2-methylphenyl)malonamide was formed as one solid block. The reaction was cooled and EtOAc was added. The product had to be crushed with a mortar, because it resembled very hard brick. The crushed material was stirred in EtOAc and filtered. EtOAc added was added twice and the mixture was stirred and filtered each time. 38.1 g N1,N3-di(2-methylphenyl) malonamide (yield 82%) was obtained.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[O:8])[C@H:4]([C:20]([O:22][CH3:23])=[O:21])[CH2:3]1.N1C=CN=C1.[Si:29](Cl)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]>CN(C)C=O.C(OCC)(=O)C>[Si:29]([O:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=2)=[O:8])[C@H:4]([C:20]([O:22][CH3:23])=[O:21])[CH2:3]1)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 108 %

Procedure:
To a solution of (2S,4R)-4-hydroxy-2-methoxycarbonyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (178 g) in N,N-dimethylformamide (500 ml) were added imidazole (93.9 g) and t-butyldimethylsilyl chloride (93.9 g), and the mixture was stirred at ambient temperature for 14 hours. The reaction mixture was diluted with ethyl acetate (2.0 l) and washed in turn with water and brine, and then dried over magnesium sulfate. Removal of the solvent gave (2S,4R)-4-t-butyldimethylsilyloxy-2-methoxycarbonyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (260 g).
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[H-].[Na+].Cl[CH2:7][C:8]1[C:9]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:11]([CH:17]([CH3:19])[CH3:18])=[N:12][C:13]=1[CH:14]([CH3:16])[CH3:15]>O1CCCC1>[CH:17]([C:11]1[C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:9]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:8]([CH2:7][O:3][CH2:1][CH3:2])=[C:13]([CH:14]([CH3:15])[CH3:16])[N:12]=1)([CH3:18])[CH3:19]
Reactant: CCOC(=O)c1c(C(C)C)nc(C(C)C)c(CCl)c1-c1ccc(F)cc1
Reactant: CCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOCc1c(C(C)C)nc(C(C)C)c(C(=O)OCC)c1-c1ccc(F)cc1
Reaction time: 0.5 h

Procedure:
4.4 ml (76 mmol) of absolution ethanol are added dropwise at room temperature to a suspension of 2.29 g (76 mmol) of sodium hydride (80% strength) in 30 ml of absolute tetrahydrofuran and the mixture is stirred for 30 minutes. A solution of 2.7 g (7.6 mmol) of the compound from Example 86 are then added dropwise in 20 ml of absolute tetrahydrofuran and the mixture is heated overnight under reflux. The reaction batch is subsequently poured onto ice water and, after the pH has been adjusted to 8, extracted several times using ether. The organic phase is washed with sodium chloride solution, dried over sodium sulphate, concentrated and chromatographed over silica gel (eluent ethyl acetate/petroleum ether 5195).
Reaction SMILES: COC1C=CC(B2OC(C)(C)C(C)(C)O2)=CC=1[CH2:18][S:19](N)(=[O:21])=[O:20].[F:23][C:24]1[CH:25]=[C:26]([CH:64]=[CH:65][CH:66]=1)[CH2:27][N:28]1[CH:32]=[C:31]([C:33]2[C:41]3[C:36](=[N:37][CH:38]=[C:39]([C:42]4[CH:43]=[N:44][C:45]([N:48]5[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]5)=[CH:46][CH:47]=4)[CH:40]=3)[N:35]([S:54]([C:57]3[CH:63]=[CH:62][C:60]([CH3:61])=[CH:59][CH:58]=3)(=[O:56])=[O:55])[CH:34]=2)[CH:30]=[N:29]1.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=NC(N5CCN(C)CC5)=CC=4)C=3)NC=2)C=N1.CS(Cl)(=O)=O.C(N(CC)CC)C>C(Cl)Cl>[F:23][C:24]1[CH:25]=[C:26]([CH:64]=[CH:65][CH:66]=1)[CH2:27][N:28]1[CH:32]=[C:31]([C:33]2[C:41]3[C:36](=[N:37][CH:38]=[C:39]([C:42]4[CH:43]=[N:44][C:45]([N:48]5[CH2:53][CH2:52][N:51]([S:19]([CH3:18])(=[O:21])=[O:20])[CH2:50][CH2:49]5)=[CH:46][CH:47]=4)[CH:40]=3)[N:35]([S:54]([C:57]3[CH:63]=[CH:62][C:60]([CH3:61])=[CH:59][CH:58]=3)(=[O:56])=[O:55])[CH:34]=2)[CH:30]=[N:29]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCNCC5)nc4)cnc32)cc1
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1CS(N)(=O)=O
Agent: CN1CCN(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccc(F)c6)c5)c4c3)cn2)CC1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(S(C)(=O)=O)CC5)nc4)cnc32)cc1
Yield: 100 %

Procedure:
Using similar reaction conditions as described in step i of intermediate 17, 3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-5-(6-(piperazin-1-yl)pyridin-3-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (step 1 compound of example 137) (80 mg, 0.13 mmol) was mesylated with methanesulfonyl chloride (23 mg, 0.196 mmol) using triethylamine (40 mg, 0.39 mmol) in DCM (3 mL) to afford 100 mg (100% yield) of the titled compound. MS: m/z=686.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([C:15]2[CH:16]([CH3:22])[NH:17][C:18](=[O:21])[NH:19][N:20]=2)[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8]CC)=O.[NH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>C(O)C>[Cl:1][C:2]1[CH:14]=[C:13]([C:15]2[CH:16]([CH3:22])[NH:17][C:18](=[O:21])[NH:19][N:20]=2)[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([NH:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:8]
Reactant: NCCN1CCNCC1
Reactant: CCOC(=O)COc1ccc(C2=NNC(=O)NC2C)cc1Cl
Solvent: CCO
Product: CC1NC(=O)NN=C1c1ccc(OCC(=O)NCCN2CCNCC2)c(Cl)c1
Yield: 68.5 %

Procedure:
4.0 g of ethyl α-[2-chloro-4-(2,3,4,5-tetrahydro-5-methyl-3-oxo-1,2,4-triazin-6-yl)phenoxy]acetate (prepared as described in Example 5) and 1.59 g of N-(2-aminoethyl)piperazine were added to 50 ml of ethanol, and the mixture was heated under reflux for 60 hours. The mixture was then cooled, after which the crystals which precipitated were collected by filtration and then recrystallized from ethanol to give 3.44 g of the title compound as pale yellow prisms melting at 208°-210° C.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:5]=[C:6]([CH3:9])[S:7][CH:8]=1.[Cl:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([OH:23])=[C:18]([O:21][CH3:22])[CH:19]=2)[N:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:23][CH2:3][C:4]3[N:5]=[C:6]([CH3:9])[S:7][CH:8]=3)=[C:18]([O:21][CH3:22])[CH:19]=2)[N:14]=[CH:13][CH:12]=1
Reactant: Cc1nc(CCl)cs1
Reactant: COc1cc2c(Cl)ccnc2cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)ccnc2cc1OCc1csc(C)n1
Temperature: 70 °C
Reaction time: 2.5 h
Yield: 109.7 %

Procedure:
4-Chloromethyl-2-methylthiazole hydrochloride (226 mg, 1.23 mmol) was added to a suspension of 4-chloro-7-hydroxy-6-methoxyquinoline (216 mg, 1 mmol), (prepared as described for the starting material in Example 3), and potassium carbonate (483 mg, 3.5 mmol) in DMF (10 ml). The mixture was stirred for 2.5 hours at 70° C. The volatiles were removed by evaporation and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4), the insoluble materials were removed by filtration and the volatiles were removed by evaporation. The residue was triturated with ether, collected by filtration, washed with ether and dried under vacuum to give 4-chloro-6-methoxy-7-(2-methylthiazol-4-ylmethoxy)quinoline (352 mg, 55%).
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:47])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:46])[CH2:12][CH2:13][C@@:14]3([C:30](=[O:45])[NH:31][C@H:32]4[CH2:35][C@@H:34]([C:36]([N:38]5[CH2:42][CH2:41][CH2:40][CH2:39]5)=[O:37])[C:33]4([CH3:44])[CH3:43])[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:49])[CH3:48])(=O)C.[OH-].[Na+]>CO.C1COCC1>[CH3:43][C:33]1([CH3:44])[C@H:34]([C:36]([N:38]2[CH2:39][CH2:40][CH2:41][CH2:42]2)=[O:37])[CH2:35][C@@H:32]1[NH:31][C:30]([C@:14]12[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]1[C@@H:16]1[C@@:11]([CH3:46])([CH2:12][CH2:13]2)[C@@:10]2([CH3:47])[C@@H:19]([C@:20]3([CH3:23])[C@@H:7]([CH2:8][CH2:9]2)[C:6]([CH3:48])([CH3:49])[C@@H:5]([OH:4])[CH2:22][CH2:21]3)[CH2:18][CH2:17]1)=[O:45]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@H]3C[C@@H](C(=O)N4CCCC4)C3(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@H]3C[C@@H](C(=O)N4CCCC4)C3(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.5 %

Procedure:
To a stirred solution of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((1S,3R)-2,2-dimethyl-3-(pyrrolidine-1-carbonyl)cyclobutylcarbamoyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl acetate (Example 13, 0.230 g, 0.340 mmol) in MeOH:THF (2:1) (9 ml) NaOH (2N, 3 ml) was added at about 0° C. and allowed to stir at room temperature for about 16 hours. After completion of the reaction (monitored by TLC), the volatiles were evaporated and the aqueous layer was extracted with ethyl acetate and the organic layer was washed with water, brine and dried with Na2SO4. The solvent was evaporated and purified by silica gel column (100-200 mesh, elution 15% EtOAc in hexane) to afford the title compound as an off white solid. Wt: 0.150 g: Yield: 69.5%; 1H NMR (300 MHz, CDCl3): δ 6.39 (d, 1H, J=8.4 Hz), 4.73 (s, 1H), 4.57 (s, 1H), 4.13-4.03 (m, 1H), 3.58-3.28 (m, 4H), 3.21-3.07 (m, 2H), 2.79 (t, 1H, J=7.2 Hz), 2.57-2.33 (m, 2H), 2.27-2.18 (m, 1H), 2.04-1.72 (m, 8H), 1.70-1.10 (m, 23H), 0.95, 0.92, 0.88, 0.83, 0.80, 0.75 (s, 21H); Mass: [M+1]+ 635 (100%), [M+Na]+ 657 (90%); IR (KBr, cm−1): 3489, 2947, 2869, 1637, 1615, 1441, 1376, 1357, 1250, 1194, 1050, 881, 717; M.R: 172.4° C.-173.8° C.; HPLC: 96.79%.
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[CH:6][C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:4][N:3]=1.[CH3:15][O:16][C:17]1[CH:22]=[C:21]([CH3:23])[C:20](B(O)O)=[C:19]([CH3:27])[CH:18]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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].O.O1CCOCC1>[CH3:15][O:16][C:17]1[CH:22]=[C:21]([CH3:23])[C:20]([C:2]2[C:7]([NH2:8])=[CH:6][C:5]([N:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)=[CH:4][N:3]=2)=[C:19]([CH3:27])[CH:18]=1
Reactant: Nc1cc(N2CCOCC2)cnc1Cl
Reactant: COc1cc(C)c(B(O)O)c(C)c1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(C)c(-c2ncc(N3CCOCC3)cc2N)c(C)c1
Temperature: 90 °C
Reaction time: 19 h

Procedure:
2-Chloro-5-morpholinopyridin-3-amine (62 mg, 0.29 mmol), 4-methoxy-2,6-dimethylphenylboronic acid (0.07 g, 0.39 mmol), tricyclohexylphosphine (12 mg, 0.042 mmol), and tris(dibenzylideneacetone)dipalladium (0) (19 mg, 0.02 mmol) were added to a flask then degassed and backfilled with argon. To the flask, 1,4-dioxane (3 mL) and aq. 1.3M potassium phosphate tribasic (0.67 mL, 0.87 mmol) were added by syringe. The resulting reaction was heated to 90° C. and monitored with TLC and LC-MS. After 19 h, the reaction was cooled to rt then poured into water. After extracting twice with EtOAc and twice with DCM, the combined organic extractions were dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified on silica gel (0-30% of a premixed solution of 89:9:1 DCM:MeOH:ammonium hydroxide in DCM) to afford a light yellow solid as 2-(4-methoxy-2,6-dimethylphenyl)-5-morpholinopyridin-3-amine. 1H NMR (500 MHz, CDCl3) δ ppm 7.75 (1H, br. s.), 6.75 (3H, m), 3.95 (4H, m), 3.85 (3H, m), 3.54 (2H, br. s.), 3.28 (4H, m), 2.04 (6H, s). Mass Spectrum (pos.) m/e: 314.2 (M+1).
Reaction SMILES: [C-]#N.[Na+].O.[N:5]12CCN(CC1)C[CH2:6]2.[N:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:24]=[C:23](SC)[N:22]([CH3:27])[C:21](=[O:28])[C:20]=2[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=2)=[CH:15][CH:14]=1>CN1CCCC1=O>[CH3:27][N:22]1[C:21](=[O:28])[C:20]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=2)=[C:19]([C:16]2[CH:17]=[CH:18][N:13]=[CH:14][CH:15]=2)[N:24]=[C:23]1[C:6]#[N:5]
Reactant: CSc1nc(-c2ccncc2)c(-c2cccc(C(F)(F)F)c2)c(=O)n1C
Reactant: C1CN2CCN1CC2
Agent: [C-]#N
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cn1c(C#N)nc(-c2ccncc2)c(-c2cccc(C(F)(F)F)c2)c1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of NaCN (55 mg), water (0.1 ml) in 1-methyl-2-pyrrolidone (50 mL) was added 1,4-diazabicyclo[2,2,2]octane (220 mg, 2 mmole) and a solution of 365 mg of 6-(4-pyridyl)-3-methyl-2-methylthio-5-(3-(trifluoromethyl)phenyl)-(3H)-pyrimidin-4-one in 1-methyl-2-pyrrolidone (2 mL) at room temperature. The resulting mixture was stirred at room temperature for 5 minutes. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was dried over Na2SO4 and then concentrated. The residue was purified by flash chromatography (20% EtOAc:Hexanes) to provide the product as a colorless oil; MS (m/z) 357 (M+H)+; C18H11F3N4O requir. 356.3.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:13]=2)=[N:5][C:4]([CH2:25][OH:26])=[N:3]1.[H-].[Na+].[CH2:29]([O:31][CH2:32]Cl)[CH3:30]>O1CCCC1.CN(C)C=O>[CH2:29]([O:31][CH2:32][O:26][CH2:25][C:4]1[N:5]=[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]3[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]3)[CH:13]=2)[N:2]([CH3:1])[N:3]=1)[CH3:30]
Reactant: CCOCCl
Reactant: Cn1nc(CO)nc1NCCCOc1cccc(CN2CCCCC2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOCOCc1nc(NCCCOc2cccc(CN3CCCCC3)c2)n(C)n1
Temperature: 25 °C

Procedure:
A solution of 1-methyl-5-[[3-[3-(1-piperidinylmethyl)phenoxy]propyl]amino]-1H-1,2,4-triazole-3-methanol (3.6 g) in dry tetrahydrofuran (30 ml) and dry dimethylformamide (3 ml), was added to a suspension of an 80% dispersion of sodium hydride in mineral oil (0.31 g), in dry tetrahydrofuran (10 ml).The suspension was heated under reflux for 0.5 h. and cooled to room temperature. Chloromethyl ethyl ether (1.0 ml) was added dropwise, and thesuspension was heated at reflux for 1 h. The solvent was removed under reduced pressure, and the residual yellow oil was partitioned between aqueous sodium carbonate and ethyl acetate. The organic phase was chromatographed on silica using a mixture of dichloromethane:ethanol:0.880ammonia (100:8:1) to give an oil (0.7 g). This oil was distilled to give the title compound (0.44 g) as a pale yellow oil b.p. 220°/0.06 mm Hg.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:16]1[C:21]([C:22]#[C:23][Si](C)(C)C)=[N:20][C:19]([C:28]2[CH:33]=[CH:32][C:31]([S:34]([CH:37]([CH3:39])[CH3:38])(=[O:36])=[O:35])=[CH:30][CH:29]=2)=[CH:18][N:17]=1)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+]>CO>[C:1]([O:5][C:6]([N:8]([C:16]1[C:21]([C:22]#[CH:23])=[N:20][C:19]([C:28]2[CH:29]=[CH:30][C:31]([S:34]([CH:37]([CH3:39])[CH3:38])(=[O:36])=[O:35])=[CH:32][CH:33]=2)=[CH:18][N:17]=1)[C:9](=[O:15])[O:10][C:11]([CH3:13])([CH3:14])[CH3:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(C#C[Si](C)(C)C)n2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: C#Cc1nc(-c2ccc(S(=O)(=O)C(C)C)cc2)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.9 %

Procedure:
tert-Butyl N-tert-butoxycarbonyl-N-[5-(4-isopropylsulfonylphenyl)-3-(2-trimethylsilyl ethynyl)pyrazin-2-yl]carbamate (42.6 g, 74.25 mmol) was dissolved/suspended in methanol (510 mL) and 2M aqueous sodium carbonate (425.8 mL, 851.6 mmol) was added to the rapidly stirred mixture. An oil separated out and more methanol (100 mL) was added to dissolve. The mixture was stirred at ambient temperature for 1 hour. The slurry was poured into a mixture of EtOAc/water (800 mL/1 L). The organic phase was separated and the aqueous extracted with EtOAc (2×250 mL). The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was slurried in 5% EtOAc/Petroleum Ether and stirred for 90 minutes at ambient temperature. The precipitate was isolated by filtration, washed with Petroleum Ether and dried to give the sub-title product as a white solid (33.1 g, 89% Yield). 1H NMR (400.0 MHz, DMSO) δ 1.18 (d, 6H), 1.37 (s, 18H), 3.50 (sept, 1H), 4.99 (s, 1H), 8.03 (d, 2H), 8.44 (d, 2H) and 9.35 (s, 1H) ppm; MS (ES+) 502.1.