Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:10][N:9]([C:11](=[O:21])[NH:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH:8]([CH3:22])[C:7](=[O:23])[N:6]1[CH2:24][CH2:25][CH2:26][C:27]([N:29]1[CH2:36][CH2:35][C:32]2([CH2:34][CH2:33]2)[C@H:31]([OH:37])[CH2:30]1)=[O:28])=[O:4].O.[OH-].[Li+]>CO>[Cl:20][C:15]1[CH:14]=[C:13]([NH:12][C:11]([N:9]2[C@@H:8]([CH3:22])[C:7](=[O:23])[N:6]([CH2:24][CH2:25][CH2:26][C:27]([N:29]3[CH2:36][CH2:35][C:32]4([CH2:33][CH2:34]4)[C@H:31]([OH:37])[CH2:30]3)=[O:28])[CH:5]([C:3]([OH:4])=[O:2])[CH2:10]2)=[O:21])[CH:18]=[CH:17][C:16]=1[Cl:19]
Reactant: COC(=O)[C@@H]1CN(C(=O)Nc2ccc(Cl)c(Cl)c2)C(C)C(=O)N1CCCC(=O)N1CCC2(CC2)[C@H](O)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[C@H]1C(=O)N(CCCC(=O)N2CCC3(CC3)[C@H](O)C2)C(C(=O)O)CN1C(=O)Nc1ccc(Cl)c(Cl)c1
Reaction time: 16 h
Yield: 73 %

Procedure:
To 0.15 g (0.26 mmol) of (S)-4-(3,4-dichloro-phenylcarbamoyl)-1-[4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-4-oxo-butyl]-5-methyl-6-oxo-piperazine-2-carboxylic acid methyl ester in 2 ml of MeOH was added 0.01 g (0.26 mmol) of lithium hydroxide monohydrate. The reaction was stirred for 16 h after which time Amberlite IR120 resin was added until the pH was 5 and the reaction filtered and concentrated to afford the titled compound in 73% yield, a 6:4 mixture of diasteriomers as a colorless gum. MS: 541.3 (MH+, 2Cl).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:23]=[CH:22][C:8]([CH:9]=[C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12]/[C:11]/2=[N:20]\[OH:21])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>ClCCl.O>[CH2:24]([O:21]/[N:20]=[C:11]1/[C:10](=[CH:9][C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:23][CH:22]=2)[C:19]2[C:14]([CH2:13][CH2:12]/1)=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: CS(=O)(=O)c1ccc(C=C2/C(=N/O)CCc3ccccc32)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(C=C2/C(=N/OCc3ccccc3)CCc3ccccc32)cc1
Temperature: 97.5 °C
Reaction time: 48 h
Yield: 81.9 %

Procedure:
(E)-1-(4-methanesulfonyl-benzylidene)-3,4-dihydro-1H-naphthalene-2-one oxime (25 mg, 0.076 mmol), benzyl bromide (0.022 ml, 0.18 mmol) and potassium carbonate (0.032 g, 0.23 mmol) were added into dimethylformamide (1.0 ml). Then, the solution was stirred at 95-100° C. for 48 hours, and cooled to room temperature. Again, water and dichloromethane were added, and an organic layer was separated, washed with water and brine, and dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to remove organic solvent. The residue was purified through silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/3, v/v). As a result, 26 mg of the present compound (productive yield 82%) was obtained as a white solid crystal.
Reaction SMILES: Cl[C:2]1[S:3][C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.[C:16]([NH2:20])([CH3:19])([CH3:18])[CH3:17]>C(OCC)C>[CH3:17][C:16]([NH:20][C:2]1[S:3][C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1)([CH3:19])[CH3:18]
Reactant: CCOC(=O)c1sc(Cl)nc1C(F)(F)F
Reactant: CC(C)(C)N
Solvent: CCOCC
Product: CCOC(=O)c1sc(NC(C)(C)C)nc1C(F)(F)F

Procedure:
A stirred mixture of 2.6 g (10 mmol) of ethyl 2-chloro-4-trifluoromethyl-5-thiazolecarboxylate and ml of tert-butylamine was heated at reflux for 20 hours. The mixture was diluted with ethyl ether and washed twice with water. The ether phase was dried with magnesium sulfate and concentrated under reduced pressure to yield 2.85 g of a beige solid material which was recrystallized from methylcyclohexane to yield 2.4 g of a white plate crystal product (m.p.=104°-106° C.) identified in Table 1.
Reaction SMILES: CS([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])(=O)=O>CN1CCCC1=O>[CH2:6]([O:5][CH2:8][CH2:7][CH2:6][OH:5])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCCCCCCCCCOS(C)(=O)=O
Solvent: CN1CCCC1=O
Product: CCCCCCCCCCCCCCCCOCCCO

Procedure:
adding a solution of hexadecyl methanesulfonate dissolved in N-methylpyrrolidinone to form the 3-(hexadecyloxy)propan-1-ol.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](I)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].C(=O)(O)[O-].[Na+].O.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][N:30]=[CH:29][C:28]=1B(O)O>COCCOC.C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:28]3[CH:29]=[N:30][CH:31]=[CH:32][C:27]=3[O:26][CH3:25])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: CCCNC(=O)c1nnc2c(I)cccc2c1N
Reactant: COc1ccncc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: ClCCl
Product: CCCNC(=O)c1nnc2c(-c3cnccc3OC)cccc2c1N
Yield: 60.2 %

Procedure:
To a stirred solution of 4-amino-8-iodo-N-propyl-cinnoline-3-carboxamide (1.00 g, 2.81 mmol), sodium bicarbonate (473 mg, 5.62 mmol) and tetrakis(triphenylphosphine)palladium(0) (974 mg, 0.84 mmol) in 1,2-dimethoxyethane (180 mL)/water (30 mL) at 85° C. under nitrogen was added the aqueous solution of 4-methoxy-pyridine-3-boronic acid (25 mg/mL) dropwise, maintaining the internal temperature between 80° C. and 85° C. The reaction was monitored by HPLC until completed. Upon the completion, 2.42 equivalents of 4-methoxy-pyridine-3-boronic acid (1.16 g, 6.80 mmol) were applied. The reaction mixture was diluted with methylene chloride (300 mL), washed with water twice, dried through MgSO4, and then the solvent was evaporated. The residual was purified by flash chromatography using a gradient of methanol in methylene chloride to give a yellow solid. The yellow solid was crystallized from methylene chloride/methanol (2/1) to give an off-white needle crystal as the title compound (570 mg, 60.2% yield). 1H NMR (300 MHz, CDCl3) δ 8.58 (d, J=5.8 Hz, 1H), 8.53 (br, 1H), 5.11 (m, 6H), 8.46 (s, 1H), 7.94 (t, J=4.9 Hz, 1H), 7.74 (d, J=4.8 Hz, 2H), 6.96 (d, J=5.8 Hz, 1H), 3.78 (s, 3H), 3.45 (q, J=6.7 Hz, 2H), 1.66 (m, overlapped with H2O), 1.00 (t, J=7.4 Hz, 3H) MS APCI, m/z=338 (M+H) HPLC 1.28 min.
Reaction SMILES: [CH:1]1([C:4](=[O:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1.C(O)[C:13]1[CH:18]=[CH:17]C=[CH:15][CH:14]=1.O(Cl)[Li]>C1(C)C=CC=CC=1>[CH:1]1([C:4](=[O:11])[CH2:5][C:6]([O:8][CH2:9][C:10]2[CH:17]=[CH:18][CH:13]=[CH:14][CH:15]=2)=[O:7])[CH2:3][CH2:2]1
Reactant: OCc1ccccc1
Reactant: CCOC(=O)CC(=O)C1CC1
Agent: [Li]OCl
Solvent: Cc1ccccc1
Product: O=C(CC(=O)C1CC1)OCc1ccccc1
Temperature: 25 °C

Procedure:
A mixture of ethyl 3-cyclopropyl-3-oxopropanoate (5.0 g, 32.0 mmol), benzyl alcohol (8.2 mL, 80.0 mmol) and LiOCl (680 mg, 6.4 mmol) in toluene (50 mL) was refluxed for 48 h in flask equipped with a Dean-stark apparatus. The reaction mixture was cooled to room temperature and solvent was removed under reduced pressure to provide compound D20-1 (5.2 g, crude) as a brown oil.
Reaction SMILES: [CH3:1]/[C:2](/[CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])=[CH:3]\[CH2:4][O:5][C:6](=[O:12])[CH2:7][CH2:8][C:9]([OH:11])=[O:10].[OH-].[OH:20][CH2:21][CH2:22][N+:23]([CH3:26])([CH3:25])[CH3:24]>CO>[CH3:1]/[C:2](/[CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])=[CH:3]\[CH2:4][O:5][C:6](=[O:12])[CH2:7][CH2:8][C:9]([O-:11])=[O:10].[OH:20][CH2:21][CH2:22][N+:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)=CCC/C(C)=C/COC(=O)CCC(=O)O
Agent: C[N+](C)(C)CCO
Agent: [OH-]
Solvent: CO
Product: CC(C)=CCC/C(C)=C/COC(=O)CCC(=O)[O-]
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Hemisuccinate [5] (1.0173 g, 4 mmol) was dissolved in 10 ml of methanol and chilled to 0° C. Choline hydroxide in (1.13 ml, 40% sol. in methanol, 4 mmol) was added dropwise and the reaction mixture was stirred for 5 min at 0° C. The solvent was evaporated and remaining volatile material was removed under reduced pressure (0.01 mbar) to yield product [6] as yellow liquid in quantitative yield. The product was pure according to 1H NMR without further purification. 1H-NMR (300 MHz, d6-DMSO) δ(ppm)=5.28 (t, J=7.0 Hz, 1H), 5.07 (t, J=6.8 Hz, 1H), 4.49 (d, J=7.0 Hz, 2H), 3.85 (m, 2H), 3.44 (m, 2H), 3.13 (s, 9H), 2.36 (t, J=7.2 Hz, 2H), 2.10 (t, J=7.2 Hz, 2H), 2.03 (m, 4H, 1.65 (s, 6H), 1.57 (s, 3H). 13C-NMR (75 MHz, d6-DMSO) δ(ppm)=174.0, 173.6, 140.7, 131.1, 123.8, 119.0, 67.3, 60.2, 55.0, 53.1, 39.3, 32.8, 31.2, 25.8, 25.5, 17.6, 16.2. Tg−65° C., T5%onset 170° C.
Reaction SMILES: C([O-])(=O)C.[K+].CC1(C)C(C)(C)OB(B2OC(C)(C)C(C)(C)O2)O1.Br[C:25]1[CH:30]=[CH:29][C:28]([S:31][CH2:32][C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)=[CH:27][CH:26]=1.[CH2:39]([O:41][C:42](=[O:51])/[C:43](/Br)=[CH:44]/[CH:45]1[CH2:49][CH2:48][CH2:47][CH2:46]1)[CH3:40].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:39]([O:41][C:42](=[O:51])/[C:43](/[C:25]1[CH:30]=[CH:29][C:28]([S:31][CH2:32][C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)=[CH:27][CH:26]=1)=[CH:44]/[CH:45]1[CH2:49][CH2:48][CH2:47][CH2:46]1)[CH3:40]
Reactant: Brc1ccc(SCc2cccnc2)cc1
Reactant: CCOC(=O)/C(Br)=C/C1CCCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)/C(=C/C1CCCC1)c1ccc(SCc2cccnc2)cc1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 60.5 %

Procedure:
Following the method of example 6a, reaction of potassium acetate (1.1 g, 10.7 mmol), 4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl] (1 g, 3.9 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (0.28 g, 0.35 mmol) and 3-(4-bromo-phenylsulfanylmethyl)-pyridine (1 g, 3.6 mmol) in DMF (8.9 ml), stirred for 2.5 h at 80° C., and addition of (Z)-2-bromo-3-cyclopentyl-acrylic acid ethyl ester (1.8 g, 7.1 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (0.14 g, 0.18 mmol) and 2 M aqueous sodium carbonate solution (8.9 ml), stirred at 80° C. over night affords the title compound as a yellow oil (0.8 g). MS (m/e): 368 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[C:4]([CH3:16])=[N:3]1.[Cl-].[Li+].Br[C:20]1[N:21]=[C:22]2[C:28]([CH:29]=[O:30])=[CH:27][N:26]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:23]2=[N:24][CH:25]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1.C(O)C>[CH3:1][N:2]1[CH:6]=[C:5]([C:20]2[N:21]=[C:22]3[C:28]([CH:29]=[O:30])=[CH:27][N:26]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:23]3=[N:24][CH:25]=2)[C:4]([CH3:16])=[N:3]1
Reactant: Cc1nn(C)cc1B1OC(C)(C)C(C)(C)O1
Reactant: C[Si](C)(C)CCOCn1cc(C=O)c2nc(Br)cnc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1nn(C)cc1-c1cnc2c(n1)c(C=O)cn2COCC[Si](C)(C)C
Temperature: 62.5 °C
Reaction time: 20 h
Yield: 78.8 %

Procedure:
In a 25 mL pressure vessel, 1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (439 mg, 1.98 mmol), lithium chloride (52 mg, 1.23 mmol) and 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (440 mg, 1.23 mmol) were combined with ethanol (7 mL) and toluene (7 mL) and the mixture was purged with N2. Potassium phosphate tribasic (917 mg, 4.32 mmol) was dissolved in 4 mL water and added to the mixture. After more purging with N2 bis(triphenylphosphine)palladium (II) dichloride (87 mg, 0.12 mmol) was added, the vessel capped and stirred at 60-65° C. for 20 h. The reaction was cooled, then diluted with ethyl acetate and water. The organic layer was washed with brine, dried and evaporated. The crude material was purified by flash chromatography (silica gel, 80 g, 100% EtOAc to 20% THF/EtOAc) to give 360 mg (71% yield; 90% purity) of 2-(1,3-dimethyl-1H-pyrazol-4-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.Br.BrCC1[C:51]([Cl:52])=[C:50]([Cl:53])[CH:49]=[CH:48][N:47]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[C:51]([Cl:52])=[C:50]([Cl:53])[CH:49]=[CH:48][N:47]=3)[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Clc1ccnc(CBr)c1Cl
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Agent: Br
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(Cc3nccc(Cl)c3Cl)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-(bromomethyl)-3,4-dichloropyridine hydrobromide and isolated as light yellow gum. MS (m/e): 442.3 (MH+).
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[CH2:5]=[C:6]1[O:10][C:8](=[O:9])[CH2:7]1>O1CCCC1>[O:10]=[C:6]([CH3:5])[CH2:7][C:8]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:9]
Reactant: C=C1CC(=O)O1
Reactant: CC(C)N
Solvent: C1CCOC1
Product: CC(=O)CC(=O)NC(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 73684.2 %

Procedure:
32 ml (0.38 mmol) of isopropylamine were added dropwise to a solution of 30 g of diketene (0.36 mol) in 300 ml tetrahydrofuran at −5 to 0° C. After 1 h stirring at 0° C. no more starting material was detected by thin layer chromatography. The reaction mixture was evaporated and the residue purified by column chromatography. This gave 40.36 g (0.28 mol, 79% yield) of a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].[NH2:14][CH2:15][CH2:16][C:17]1[NH:18][CH:19]=[CH:20][N:21]=1.Cl>ClCCl.N1C=CC=CC=1.O.CO>[NH:18]1[CH:19]=[CH:20][N:21]=[C:17]1[CH2:16][CH2:15][NH:14][S:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11]
Reactant: NCCc1ncc[nH]1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: Cl
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)NCCc1ncc[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.9 %

Procedure:
A solution of 105 g (0.472 mol) of o-nitrobenzenesulfonyl chloride in 100 ml of dichloromethane was added slowly to a cold (0° C.) solution of 26.2 g (0.236 mol) of 2-(2-aminoethyl)imidazole in 300 ml of pyridine, under nitrogen. The reaction mixture was gradually warmed to room temperature and allowed to react overnight. When the reaction was complete, as determined by thin layer chromatography, the solution was reduced to dryness under reduced pressure. The resultant residue was dissolved in a water/methanol/5N sodium hydroxide solution and stirred for 3 hours. The solution was then acidified with concentrated hydrochloric acid and filtered to remove inorganic impurities. The methanol was removed under reduced pressure from the reaction mixture and the remaining solution was basicified by addition of aqueous sodium bicarbonate. The desired product was extracted from this solution with a solution consisting of ethyl acetate and a small amount of ethanol. The organic extract was washed with water, dried with anhydrous sodium sulfate and reduced to dryness under reduced pressure to provide an oil. This oil was then purified using standard purification techniques to provide 37.7 g of the desired subtitled intermediate.
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[C:9]([C:11]3[C:12]([NH:25][C@@H:26]4[CH2:31][CH2:30][CH2:29][N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27]4)=[N:13][C:14]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[N:15][C:16]=3[O:17][CH3:18])[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[NH2:39][C@@H:40]1[CH2:45][CH2:44][CH2:43][CH2:42][C@@H:41]1[NH2:46].CC([O-])(C)C.[Na+]>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].C1(C)C=CC=CC=1>[NH2:39][C@H:40]1[CH2:45][CH2:44][CH2:43][CH2:42][C@H:41]1[NH:46][C:2]1[C:7]2[N:8]=[C:9]([C:11]3[C:12]([NH:25][C@@H:26]4[CH2:31][CH2:30][CH2:29][N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27]4)=[N:13][C:14]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[N:15][C:16]=3[O:17][CH3:18])[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: N[C@@H]1CCCC[C@@H]1N
Reactant: COc1nc(N2CCOCC2)nc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1-c1nc2c(Cl)cccc2s1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COc1nc(N2CCOCC2)nc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1-c1nc2c(N[C@@H]3CCCC[C@@H]3N)cccc2s1
Temperature: 95 °C
Reaction time: 12 h

Procedure:
Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed tert-butyl (3R)-3-[[5-(4-chloro-1,3-benzothiazol-2-yl)-6-methoxy-2-(morpholin-4-yl)pyrimidin-4-yl]amino]piperidine-1-carboxylate (180.0 mg, 0.32 mmol, 1.00 equiv), cis-1,2-diaminocyclohexane (109.9 mg, 0.96 mmol, 3.00 equiv), sodium 2-methylpropan-2-olate (61.5 mg, 0.64 mmol, 2.00 equiv) and toluene (8.0 mL). tris(dibenzylideneacetone)dipalladium (30.0 mg, 0.03 mmol, 0.10 equiv), and o-biphenyl(t-Bu)2P (19.1 mg, 0.06 mmol, 0.20 equiv) were added. And nitrogen was bubbled in for 5 min. The resulting mixture was stirred for 12 h at 95° C. in an oil bath. After cooled down, the reaction mixture was quenched by the addition of 30.0 mL of water, and extracted with ethyl acetate (3×30.0 mL). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtered and concentrated under reduced pressure, the residue was purified by flash chromatography on silica gel, eluting with a mixture of 10-100% ethyl acetate in petroleum ether to give the title compounds as a white solid. MS m/z [M+H]+ (ESI): 639.
Reaction SMILES: [CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:33])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:34]([C:37]([CH3:39])=[CH2:38])[CH2:35][CH2:36][C@:5]1([NH:40][CH2:41][C:42]1[CH:46]=[CH:45][S:44][CH:43]=1)[CH2:4][CH2:3]2.[OH-].[Na+]>O1CCOCC1>[CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:33])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:21])([CH3:22])[C:14]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:34]([C:37]([CH3:39])=[CH2:38])[CH2:35][CH2:36][C@:5]1([NH:40][CH2:41][C:42]1[CH:46]=[CH:45][S:44][CH:43]=1)[CH2:4][CH2:3]2
Reactant: C=C(C)[C@@H]1CC[C@]2(NCc3ccsc3)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
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C=C(C)[C@@H]1CC[C@]2(NCc3ccsc3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 85 °C
Yield: 54 %

Procedure:
To a solution of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-(thiophen-3-ylmethylamino)-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 (32 mg, 0.050 mmol) in dioxane (1 mL) was added NaOH (1N) (0.250 mL, 0.250 mmol). The mixture was heated to 85° C. for 15 h. The mixture was cooled to rt and was purified by prep HPLC to give the title compound (18 mg, 0.027 mmol, 53.5% yield) as a white solid. LCMS: m/e 626.5 (M+H)+, 1.82 min (method 2). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.00 (2H, d, J=8.3 Hz), 7.30 (1H, dd, J=4.8, 3.0 Hz), 7.24 (2H, d, J=8.3 Hz), 7.20 (1H, d, J=2.0 Hz), 7.12 (1H, dd, J=5.0, 1.0 Hz), 5.30-5.34 (1H, m), 4.72 (1H, d, J=1.8 Hz), 4.61 (1H, s), 2.61 (1H, td, J=10.7, 5.4 Hz), 1.89-2.17 (5H, m), 1.77-1.88 (1H, m), 1.72 (3H, s), 1.14 (3H, s), 1.02 (3H, s), 1.00 (3H, s), 0.94-1.74 (18H, m), 0.96 (6H, s).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([CH3:9])=[CH:4][N:3]=1.[CH2:10]([O:12][C:13](=[O:19])[C:14](=O)[CH:15](Br)[CH3:16])[CH3:11].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[NH2:8][C:7]1[C:2]2[N:3]([C:15]([CH3:16])=[C:14]([C:13]([O:12][CH2:10][CH3:11])=[O:19])[N:1]=2)[CH:4]=[C:5]([CH3:9])[CH:6]=1
Reactant: Cc1cnc(N)c(N)c1
Reactant: CCOC(=O)C(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1nc2c(N)cc(C)cn2c1C
Yield: 29.3 %

Procedure:
A solution of 2,3-diamino-5-methyl-pyridine (2.3 g, 19 mmol) and 3-bromo-2-oxo-butyric acid ethyl ester (4.3 g, 21 mmol) in ethanol (25 ml) was refluxed for 20 h. Sodium carbonate (2.6 g, 25 mmol) was added and the mixture was filtrated and the solids were washed with ethanol. The filtrate and washings were combined and evaporated under reduced pressure. The residue was dissolved in methylene chloride, washed twice with a sodium carbonate solution and twice with water. The organic layer was separated dried (Na2SO4) and evaporated under reduced pressure. Purification of the residue by column chromatography on silica gel using methylene chloride:methanol (9:1) as eluent gave 1.3 g (30%) of the title compound as an oil.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[C:15]3[S:16][CH:17]=[CH:18][C:14]=3[O:13][N:12]=2)[CH:8]=[CH:9][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[F:25][C:26]([F:36])([F:35])[C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29][NH2:30]>C(#N)C>[O:13]1[C:14]2[CH:18]=[CH:17][S:16][C:15]=2[C:11]([C:7]2[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=2)[O:4][CH2:3][CH2:2][NH:30][CH2:29][C:28]2[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=2[C:26]([F:25])([F:35])[F:36])=[N:12]1
Reactant: BrCCOc1cccc(-c2noc3ccsc23)c1
Reactant: NCc1ccccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: FC(F)(F)c1ccccc1CNCCOc1cccc(-c2noc3ccsc23)c1
Reaction time: 8 h
Yield: 96.4 %

Procedure:
The title compound is prepared from 3-[3-(2-bromo-ethoxy)-phenyl]-thieno[2,3-d]isoxazole (0.250 g, 0.771 mmol), potassium carbonate (0.205 g, 1.48 mmol), 2-(trifluoromethyl)benzylamine (0.676 mg, 3.86 mmol) and acetonitrile (4 mL) essentially as described above in example 18 except that the reaction is run overnight and the compound is purified by column using a solvent gradient of 5% ethyl acetate in dichloromethane to 10% methanol in ethyl acetate to give the title compound (0.311 g, 96% Yield). Purity by LC/MS (APCI)=99%, [M+H]+=419.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[O-:18][C:19]#[N:20].[Na+].[OH-].[Na+]>C(O)(=O)C.O>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([N:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[C:19]([NH2:20])=[O:18])=[CH:11][CH:12]=1
Reactant: COc1ccc(Nc2ccc(OC)cc2)cc1
Reactant: N#C[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(N(C(N)=O)c2ccc(OC)cc2)cc1

Procedure:
A solution of 423 mg (1.85 mmol) bis-(4-methoxy-phenyl)-amine in 8 ml acetic acid is treated with 120 mg (1.85 mmol)sodium cyanate. After 4.5 h the reaction mixture is poured onto a solution of 8 g sodium hydroxide in 100 ml water. The resultant precipitate is filtered off and dried.