Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][C@H:15]1[CH2:17][O:16]1)[N:9]=[CH:8][N:7]=[C:6]2[O:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=[C:22]2[CH3:28].[NH2:29][CH2:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>CN(C=O)C>[OH:16][C@H:15]([CH2:17][NH:29][CH2:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)[CH2:14][O:13][C:12]1[CH:11]=[C:10]2[C:5]([C:6]([O:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[NH:24][CH:23]=[C:22]4[CH3:28])=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: NCCCN1CCOCC1
Reactant: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1OC[C@H]1CO1
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1OC[C@H](O)CNCCCN1CCOCC1
Temperature: 70 °C
Yield: 45.9 %

Procedure:
A mixture of (2R)-6-methoxy-4-(3-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazoline (100 mg, 0.28 mmol), (prepared as described in Example 278), and 4-(3-aminopropyl)morpholine (0.12 ml, 0.84 mmol) in DMF (5 ml) was heated to 70° C. for 3 hours. The solvents were removed in vacuo and the residue taken up in dichloromethane. This was washed with water, dried (MgSO3), filtered and evaporated. The residue was purified by silica column chromatography using gradient elution (dichloromethane, 5% methanol/95% dichloromethane, 20% methanolic ammonia (7M)/80% dichloromethane) to give (2R)-7-(2-hydroxy-3-(3-morpholinopropylamino)propoxy)-6-methoxy-4-(3-methylindol-5-yloxy)quinazoline (67 mg, 46%).
Reaction SMILES: [OH:1][C:2]1[CH:36]=[CH:35][C:5]([C:6]([CH2:8][NH:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=2[CH:18]2[CH2:27][CH2:26][C:25]3[CH:24]=[C:23]([O:28]C(=O)C(C)(C)C)[CH:22]=[CH:21][C:20]=3[CH2:19]2)=O)=[CH:4][CH:3]=1.Cl[CH2:38][C:39]([N:41]1[CH2:50][CH2:49][C:44]2([O:48][CH2:47][CH2:46][O:45]2)[CH2:43][CH2:42]1)=O>>[O:48]1[C:44]2([CH2:49][CH2:50][N:41]([CH2:39][CH2:38][O:1][C:2]3[CH:36]=[CH:35][C:5]([CH2:6][CH2:8][NH:9][C:10]4[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=4[CH:18]4[CH2:27][CH2:26][C:25]5[CH:24]=[C:23]([OH:28])[CH:22]=[CH:21][C:20]=5[CH2:19]4)=[CH:4][CH:3]=3)[CH2:42][CH2:43]2)[O:45][CH2:46][CH2:47]1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCC(=O)c2ccc(O)cc2)c1
Reactant: O=C(CCl)N1CCC2(CC1)OCCO2
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCc2ccc(OCCN3CCC4(CC3)OCCO4)cc2)c1
Yield: 45.4 %

Procedure:
Synthesized from pivalic acid 6-{2-[(4-hydroxybenzoyl)methylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg) and 2-chloro-1-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)ethanone (22 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (13 mg) was obtained.
Reaction SMILES: Br.Br.[N:3]1([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[C:16](OC(=O)C)(=[O:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[C:16]([N:6]1[CH2:5][CH2:4][N:3]([C:9]2[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: Oc1ccc(N2CCNCC2)cc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(=O)N1CCN(c2ccc(O)cc2)CC1

Procedure:
A mixture of 33.8 parts of 4-(1-piperazinyl)-phenol dihydrobromide, 11.2 parts of acetic acid anhydride, 42 parts of potassium carbonate and 300 parts of 1,4-dioxane is stirred and refluxed for 3 days. The reaction mixture is filtered and the filtrate is evaporated. The solid residue is stirred in water and sodium hydrogen carbonate is added. The whole is stirred for 30 minutes. The precipitated product is filtered off and dissolved in a diluted hydrochloric acid solution. The solution is extracted with trichloromethane. The acid aqueous phase is separated and neutralized with ammonium hydroxide. The product is filtered off and crystallized from ethanol, yielding 5.7 parts of 1-acetyl-4-(4-hydroxyphenyl)piperazine; mp. 181.3° C.
Reaction SMILES: [CH3:1][C@@H:2]1[O:7][C@@H:6]([O:8][C@H:9]2[C@H:14]([O:15][C:16]3[CH:17]=[C:18]([OH:36])[C:19]4[C:25](=[O:26])[CH2:24][C@@H:23]([C:27]5[CH:28]=[CH:29][C:30]([O:34][CH3:35])=[C:31]([OH:33])[CH:32]=5)[O:22][C:20]=4[CH:21]=3)[O:13][C@H:12]([CH2:37][OH:38])[C@@H:11]([OH:39])[C@@H:10]2[OH:40])[C@H:5]([OH:41])[C@H:4]([OH:42])[C@H:3]1[OH:43].[H][H]>[OH-].[Na+].[Ni]>[CH3:1][C@@H:2]1[O:7][C@@H:6]([O:8][C@H:9]2[C@H:14]([O:15][C:16]3[CH:17]=[C:18]([OH:36])[C:19]([C:25]([CH2:24][CH2:23][C:27]4[CH:28]=[CH:29][C:30]([O:34][CH3:35])=[C:31]([OH:33])[CH:32]=4)=[O:26])=[C:20]([OH:22])[CH:21]=3)[O:13][C@H:12]([CH2:37][OH:38])[C@@H:11]([OH:39])[C@@H:10]2[OH:40])[C@H:5]([OH:41])[C@H:4]([OH:42])[C@H:3]1[OH:43]
Reactant: COc1ccc([C@@H]2CC(=O)c3c(O)cc(O[C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O[C@@H]4O[C@@H](C)[C@H](O)[C@@H](O)[C@H]4O)cc3O2)cc1O
Reactant: [H][H]
Agent: [Ni]
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(CCC(=O)c2c(O)cc(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O[C@@H]3O[C@@H](C)[C@H](O)[C@@H](O)[C@H]3O)cc2O)cc1O
Reaction time: 15 h
Yield: 94.7 %

Procedure:
18.9 g (0.030 mol) of neohesperidin are dissolved in 90 ml of 2-N sodium hydroxide and treated with 1.2 g of Raney-nickel. The mixture is hydrogenated under normal pressure for 15 hours. The hydrogen uptake corresponds to 30 mmol. The solution is filtered and adjusted to pH 6 with 36 ml of 5-N hydrochloric acid while cooling with ice and stirring. The resulting clear yellow solution is left in a refrigerator for 48 hours and then filtered under suction. The white residue is washed with cold water and dried overnight in a high vacuum. There are obtained 17.4 g (95% yield) of neohesperidin dihydrochalcone of melting point 150°C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[N:10]([C:20](=[O:22])[CH3:21])[C:11]3[C:16]([C:17]=2[C:18]=1[CH3:19])=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2].[Br:23]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.C1(=O)NC(=O)CC1>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[N:10]([C:20](=[O:22])[CH3:21])[C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][Br:23])=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1ncc2c(c1C)c1ccccc1n2C(C)=O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ncc2c(c1CBr)c1ccccc1n2C(C)=O

Procedure:
10 g (33.8 mmol) of 9-acetyl-4-methyl-β-carboline-3carboxylic acid ethyl ester is combined in 500 ml of carbon tetrachloride with 12 g (67.4 mmol) of N-bromosuccinimide and one spatula tip of azobisisobutyronitril and heated to reflux for 1.5 hours while simultaneously exposing the reaction mixture to light. After cooling, the mixture is suctioned off from the succinimide, concentrated, and the residue is extracted by stirring with hot water and suctioned off. Yield: 10.64 g (84%) of 9-acetyl-4-bromomethyl-β-carboline-β-carboxylic acid ethyl ester, mp 188°-189° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH:23]([CH3:25])[CH3:24])/[CH:9]=[C:10](\[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)/[C:11]([O:13]CC)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Na+]>CCO>[C:1]([O:5][C:6]([N:8]([CH:23]([CH3:25])[CH3:24])/[CH:9]=[C:10](\[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)/[C:11]([OH:13])=[O:12])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)/C(=C/N(C(=O)OC(C)(C)C)C(C)C)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)N(/C=C(/C(=O)O)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 89.8 %

Procedure:
(E)-ethyl 3-((tert-butoxycarbonyl)(isopropyl)amino)-2-(4-chlorophenyl)acrylate (133.5 kg, 362.9 mol) was added into a mixture of H2O (252 L), NaOH (58.25 kg, 1456 mol) and EtOH (383.5 L) stirred at room temperature. The mixture was warmed to 40-45° C. for 2.5 h until a clear solution was formed. The mixture was concentrated to a minimum working volume maintaining the temperature below 50° C. The mixture was then cooled to 10-25° C. and a solution of HCl was added (842 L of 2N HCl and 11 L of 35% HCl) until a final pH=2˜4 was obtained. The aqueous layer was separated and the organic layer was washed with 25% aqueous NaCl (810 L). n-Heptane was added while distilling to form a suspension. The product was collected and washed with n-heptane and dried at 40-45° C. for ˜10 h to afford 110.7 kg (90.5% yield) of (E)-3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)acrylic acid having 99.9 A % purity by HPLC. E-configuration was confirmed using single crystal x-ray analysis (See FIG. 1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([C:20]#[C:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:17]=[C:16]([OH:29])[CH:15]=2)=[CH:9][C:8]=1[CH3:30])[CH3:2].[CH:32]1([CH2:38]O)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([C:20]#[C:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:17]=[C:16]([O:29][CH2:38][CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)[CH:15]=2)=[CH:9][C:8]=1[CH3:30])[CH3:2]
Reactant: OCC1CCCCC1
Reactant: CCOC(=O)COc1ccc(Sc2cc(O)cc(C#CCN3CCOCC3)c2)cc1C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(Sc2cc(C#CCN3CCOCC3)cc(OCC3CCCCC3)c2)cc1C
Reaction time: 1 h

Procedure:
{4-[3-Hydroxy-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (200 mg; 0.45 mmol), cyclohexylmethanol (77.6 mg; 0.68 mmol), tributylphosphine (0.27 mL; 1.36 mmol) and 1,1′-(azodicarbonyl)dipiperidine (0.34 g; 1.36 mmol) were dissolved in THF (15 mL) in a dried reaction flask under an atmosphere of nitrogen. After stirring for 1 h the reaction mixture was purified by prep. HPLC (method A). Yield: 200 mg. HPLC-MS: m/z: 538.1 (M+H); Rt: 2.24 min.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6](O)[N:5]=2.[F-].[Cs+].[CH2:14](I)[CH3:15].CN(C)C=[O:20]>O>[CH2:14]([O:20][NH:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[CH:6][N:5]=2)[CH3:15]
Reactant: Nc1nc2ccc(O)nc2s1
Reactant: CN(C)C=O
Reactant: CCI
Agent: [Cs+]
Agent: [F-]
Solvent: O
Product: CCONc1nc2cccnc2s1
Reaction time: 8 h

Procedure:
To a solution of 2-Amino-thiazolo[5,4-b]pyridin-5-ol (4.7 g, 28.1 mmol) in Dimethylformamide (50 ml) was added cesium fluoride (12.8 g, 84.4 mmol) under argon atmosphere. Ethyl iodide ((2.7 ml, 33.7 mmol) was added in drop wise manner at room temperature and stirred overnight. Completion of reaction was confirmed by TLC, reaction mixture was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×3),combined organic extracts were washed with water and brine (100 ml each) dried over Na2SO4, filtered and concentrated under vaccum to afford ethoxy-thiazolo[5,4-b]pyridin-2-ylamine (2.1 g).
Reaction SMILES: [CH3:1][O:2][C:3]([O:19][CH3:20])([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)[NH2:5].[N:21]([CH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[C:22]=[O:23]>C1COCC1>[C:27]1([CH2:26][CH2:25][CH2:24][NH:21][C:22]([NH:5][CH:4]([C:6]2[CH:7]=[CH:8][C:9]([F:12])=[CH:10][CH:11]=2)[C:3]([O:2][CH3:1])([O:19][CH3:20])[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[O:23])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COC(OC)(c1ccncc1)C(N)c1ccc(F)cc1
Reactant: O=C=NCCCc1ccccc1
Solvent: C1CCOC1
Product: COC(OC)(c1ccncc1)C(NC(=O)NCCCc1ccccc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2,2-dimethoxy-2-(4-pyridyl)-1-(4-fluorophenyl)ethanamine (1.22 g, 4.4 mmol) in THF (10 mL) was added a solution of (3-isocyanatopropyl)-benzene (1.61 g, 10 mmol) in THF (10 mL). The resulting mixture was stirred at room temperature for 30 minutes. The reaction was quenched by addition of water (50 mL) and extracted with ethyl acetate (2×50 mL). The combined ethyl acetate extract was washed with water (50 mL), brine (50 mL) and dried with Na2SO4. After removal of solvent, the crude product was purified by column chromatography to yield the product as a light brown solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:21])=[C:17]([F:20])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[O:23]=[C:24]1[CH2:29][O:28][C:27]2[CH:30]=[CH:31][C:32]([CH:34]=O)=[N:33][C:26]=2[NH:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[F:21][C:16]1[CH:15]=[C:14]2[C:19](=[CH:18][C:17]=1[F:20])[N:10]([CH2:9][CH2:8][N:5]1[CH2:6][CH2:7][CH:2]([NH:1][CH2:34][C:32]3[CH:31]=[CH:30][C:27]4[O:28][CH2:29][C:24](=[O:23])[NH:25][C:26]=4[N:33]=3)[CH2:3][CH2:4]1)[C:11](=[O:22])[CH:12]=[N:13]2
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Reactant: NC1CCN(CCn2c(=O)cnc3cc(F)c(F)cc32)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: O=C1COc2ccc(CNC3CCN(CCn4c(=O)cnc5cc(F)c(F)cc54)CC3)nc2N1
Yield: 61.7 %

Procedure:
1-[2-(4-Aminopiperidin-1-yl)ethyl]-6,7-difluoro quinoxalin-2(1H)-one (Intermediate 150, 190 mg, 0.62 mmol), 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) (110 mg, 0.62 mmol), and sodium triacetoxy borohydride (390 mg, 1.90 mmol) were reacted as described according to Example 69 to give 180 mg (62%) of the free base of the product as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]2[C:12](=[C:13]([CH3:19])[CH:14]=[C:15]([CH3:18])[CH:16]=2)[NH:11][C:10](=[O:20])[C:9]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22].[C:26](=O)([O-])[O-].[K+].[K+].CN(C=O)C.CI>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]2[C:12](=[C:13]([CH3:19])[CH:14]=[C:15]([CH3:18])[CH:16]=2)[N:11]=[C:10]([O:20][CH3:26])[C:9]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)c1c(-c2ccccc2Cl)c2cc(C)cc(C)c2[nH]c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)c1c(OC)nc2c(C)cc(C)cc2c1-c1ccccc1Cl
Yield: 90.3 %

Procedure:
To a mixture of ethyl 4-(2-chlorophenyl)-1,2-dihydro-6,8-dimethyl -2-oxo-3-quinolinecarboxylate (0.71 g), potassium carbonate (0.28 g) and DMF (8 ml) was dropwise added methyl iodide (0.15 ml) under stirring, followed by stirring for 15 minutes at room temperature. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried (MgSO4) and concentrated to obtain ethyl 4-(2-chlorophenyl)-2-methoxy-6,8-dimethyl-3-quinolinecarboxylate. Yield 90.3% mp 135°-136° C. (from ethanol)
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([C:13](OC(C)(C)C)=O)[CH2:9][CH2:8]2)[N:3]=[CH:2]1.C(O)(C(F)(F)F)=O.[Br:27][C:28]1C(Cl)=[C:30]([N+:35]([O-:37])=[O:36])[C:31]([NH2:34])=[N:32][CH:33]=1>C(Cl)Cl>[Br:27][C:28]1[C:13]([N:10]2[CH2:9][CH2:8][N:7]([CH2:6][C:4]3[N:3]=[CH:2][S:1][CH:5]=3)[CH2:12][CH2:11]2)=[C:30]([N+:35]([O-:37])=[O:36])[C:31]([NH2:34])=[N:32][CH:33]=1
Reactant: Nc1ncc(Br)c(Cl)c1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cscn2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncc(Br)c(N2CCN(Cc3cscn3)CC2)c1[N+](=O)[O-]
Reaction time: 1 h
Yield: 58.9 %

Procedure:
tert-Butyl 4-(thiazol-4-ylmethyl)piperazine-1-carboxylate (0.160 g, 0.56 mmol, 1.0 eq) was dissolved in DCM (1.8 mL) and the reaction mixture cooled in a ice-water bath before the dropwise addition of TFA (1.8 mL). Stirring was continued at this temperature for 1 h, the solvents were removed in vacuo. The resulting crude material was azeotroped with toluene and dried. The resulting 4-(piperazin-1-ylmethyl)thiazole (supposedly 0.10 g, 0.56 mmol, 1.1 eq) was suspended in iPrOH (0.55 mL) and DIPEA (0.22 mL). To this solution, 5-bromo-4-chloro-3-nitropyridin-2-amine (0.130 g, 0.51 mmol, 1 eq) was added and the reaction mixture was heated and stirred for 17 h at 65° C. The mixture was filtered, washed with iPrOH (3×3 mL), Et2O (2×3 mL) and dried to give the title compound as a bright yellow powder (0.120 g, 55%); 1H-NMR (500 MHz, DMSO-d6): δ 2.58 (br s, 4H, piperazine N(CH2)2), 3.06 (m, 4H, piperazine N(CH2)2), 3.72 (s, 2H, NCH2), 6.96 (s, 2H, NH2), 7.54 (br d, 1H, J=1.2 Hz, thiazole 5-H), 8.15 (s, 1H, pyridine 6-H), 9.04 (d, 1H, J=1.7 Hz, thiazole 2-H); LC (Method B)-MS (ESI, m/z): Rt=1.83 min—398/400 [(M+H)+, Br isotopic pattern, 100%].
Reaction SMILES: C[Si](C)(C)[O:3][C@H:4]1[CH2:27][C@@:26]2([CH3:28])[C@@H:15]([CH2:16][CH2:17][C@:18]2([OH:29])[C:19](=[O:25])[CH2:20][O:21][C:22](=[O:24])[CH3:23])[C@H:14]2[C@H:5]1[C@:6]1([CH3:31])[C:11]([CH2:12][CH2:13]2)=[CH:10][C:9](=[O:30])[CH:8]=[CH:7]1.[C:34]([O-])(=[O:36])[CH3:35].[Na+].[SiH3]O[SiH3]>C(OC(C)=C)(=O)C>[CH3:23][C:22]([O:21][CH2:20][C:19]([C@:18]1([O:29][C:34]([CH3:35])=[O:36])[C@@:26]2([CH3:28])[CH2:27][C@H:4]([OH:3])[C@@H:5]3[C@:6]4([CH3:31])[C:11](=[CH:10][C:9]([CH:8]=[CH:7]4)=[O:30])[CH2:12][CH2:13][C@H:14]3[C@@H:15]2[CH2:16][CH2:17]1)=[O:25])=[O:24]
Reactant: CC(=O)OCC(=O)[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O[Si](C)(C)C)C[C@@]21C
Reactant: CC(=O)[O-]
Agent: C=C(C)OC(C)=O
Agent: [Na+]
Agent: [SiH3]O[SiH3]
Product: CC(=O)OCC(=O)[C@@]1(OC(C)=O)CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C

Procedure:
A mixture of 8 g of 11β -trimethylsiloxy-17α-hydroxy-21-acetoxy-pregna-1,4-diene-3,20 -dione (from Example 29), 8 g of paratoluenesulfonic acid monohydrate and 800 ml of isopropenyl acetate was allowed to stand for one week at room temperature. By this time TLC control indicated that almost all the starting material had reacted. 15 g of anhydrous sodium acetate was added and the mixture left stirring for another day. The supernatant was decanted from the salt crystals and the resulting solution -- after addition of 400 ml methyl-isobutyl ketone -- was washed twice, each time with 500 ml of water, then with 200 ml of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to dryness. This residue was found to be 11β-trimethylsiloxy-17α,21-diacetoxypregna-1,4-diene-3,20-dione, about 90% pure, there was about 10% of a less polar artifact believed to be the result of a slight aromatization side reaction about ring A, followed by acetylation. The identity was proved by hydrolyzing off the silyl ether blocking group to give prednisolone 17,21-diacetate, identified by TLC with a sample obtained by the Ortho ester route.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C@@:9]([F:16])([CH:14]=[CH2:15])[CH2:8][N:7]([CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[C:6]=2[N:22]=1.[NH2:23][C:24]1[C:33]([O:34][CH3:35])=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]([F:36])[CH:25]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[CH:17]1([N:7]2[CH2:8][C@:9]([F:16])([CH:14]=[CH2:15])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:23][C:24]4[C:33]([O:34][CH3:35])=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]([F:36])[CH:25]=4)=[N:22][C:6]2=3)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: COC(=O)c1cc(OC)c(N)cc1F
Reactant: C=C[C@@]1(F)CN(C2CCCC2)c2nc(Cl)ncc2N(C)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Solvent: O
Product: C=C[C@@]1(F)CN(C2CCCC2)c2nc(Nc3cc(F)c(C(=O)OC)cc3OC)ncc2N(C)C1=O
Temperature: 95 °C
Reaction time: 36 h
Yield: 26.6 %

Procedure:
A mixture of (R)-2-chloro-9-cyclopentyl-7-fluoro-5-methyl-7-vinyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (1.0 g, 3.086 mmol), and methyl 4-amino-2-fluoro-5-methoxybenzoate (3.07 g, 15.43 mmol) was dissolved in dioxane (20 ml), and p-toluenesulfonic acid, monohydrate (2.99 g, 15.74 mmol) was added. The mixture was stirred at 95° C. for 24-48 h. The final compound was purified by reverse phase HPLC to give 400 mg product as white solid (40%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.48-1.82 (m, 4 H) 1.93-1.98 (m, 4 H) 3.29 (s, 3 H) 3.51 (br. s., 2 H) 3.61 (m, 3 H), 3.86 (m, 3 H) 3.94 (s, 3 H) 4.88 (t, J=8.08 Hz, 1 H) 5.30-5.47 (m, 2 H) 6.01 (ddd, J=17.43, 12.63, 10.86 Hz, 1 H) 7.41-7.57 (m, 1 H) 7.82 (s, 1 H) 8.12 (s, 1 H) 8.31 (d, J=8.08 Hz, 1 H). [M+H] calc'd for C24H27F2N5O4, 488; found 488.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[C:6]1([C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:20]=2[CH2:19][CH:18]=[CH:17]3)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:21][Si:22]([CH3:25])(Cl)Cl>C1(C)C=CC=CC=1.O=O>[CH3:21][Si:22]([CH3:25])([CH:17]1[C:16]2[C:20](=[C:12]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:13]=[CH:14][CH:15]=2)[CH:19]=[CH:18]1)[CH:1]1[C:17]2[C:4](=[C:12]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:20]=[CH:19][CH:18]=2)[CH:3]=[CH:2]1
Reactant: C1=Cc2cccc(-c3ccccc3)c2C1
Reactant: [Li]CCCC
Reactant: C[Si](C)(Cl)Cl
Agent: O=O
Solvent: Cc1ccccc1
Product: C[Si](C)(C1C=Cc2c(-c3ccccc3)cccc21)C1C=Cc2c(-c3ccccc3)cccc21
Temperature: 80 °C
Yield: 62 %

Procedure:
18.7 cm3 (50 mmol) of a 20% strength solution of butyllithium in toluene were added at room temperature to a solution of 10 g (50 mmol) of 10 in 100 cm3 of H2O- and O2-free toluene and 5 ml of H2O- and O2-free THF, and the mixture was heated at 80° C. for 2 hours. The yellow suspension was subsequently cooled to 0° C., and 3.2 g (25 mmol) of dimethyldichlorosilane were added. The reaction mixture was heated at 80° C. for a further 1 hour and subsequently washed with 50 cm3 of H2O. The solvent was removed in vacuo, and the residue was recrystallized from heptane at −20° C., giving 6.7 g (62%) of 11 as colorless crystals (m.p. 109-110° C.).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[CH2:25]([O:27][C:28]1[N:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)[CH3:26].O1CCOCC1>CO.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl>[CH2:25]([O:27][C:28]1[N:33]=[CH:32][C:31]([C:2]2[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]3[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=3)[CH:3]=2)=[CH:30][CH:29]=1)[CH3:26]
Reactant: CCOc1ccc(B(O)O)cn1
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: CO
Product: CCOc1ccc(-c2cc(NC(=O)c3ccc(C(C)(C)O)cc3)nc3cc(C)nn23)cn1
Temperature: 110 °C
Yield: 40.1 %

Procedure:
A suspension of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 100 mg, 0.290 mmol), 6-ethoxypyridin-3-ylboronic acid (63 mg, 0.377 mmol), and 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (21 mg, 29 μmol) in 2:1 1,4-dioxane/saturated aqueous NaHCO3 (0.966 mL of 1,4-dioxane and 0.483 mL of saturated aqueous NaHCO3) was prepared in a 10 mL microwave reaction vessel and the sealed reaction vessel warmed to 110° C. for 10 minutes in a CEM microwave reactor. The reaction mixture was cooled to rt, diluted with methanol, filtered, and purified via preparative HPLC (50-60% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a yellow solid (50.2 mg, 40%). Melting point (183.5-185.5° C.). 1H NMR (DMSO-d6) δ: 11.13 (s, 1H), 8.85 (dd, J=2.5, 0.5 Hz, 1H), 8.34 (dd, J=8.6, 2.5 Hz, 1H), 7.95 (d, J=8.8 Hz, 2H), 7.92 (s, 1H), 7.55 (d, J=8.6 Hz, 2H), 6.98 (dd, J=8.8, 0.8 Hz, 1H), 6.32 (s, 1H), 5.11 (br. s., 1H), 4.37 (q, J=6.9 Hz, 2H), 2.34 (s, 3H), 1.39 (s, 6H), 1.31 (t, 3H); ESI-MS: m/z 432.2 (M+H)+. Melting point (183.5-185.5° C.).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.O[C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1>>[C:9]([C:8]1[CH:11]=[CH:12][C:5]([N:4]([CH2:17][C:18]([F:19])([F:20])[F:21])[CH2:3][CH2:2][O:1][C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=2)=[CH:6][C:7]=1[C:13]([F:15])([F:16])[F:14])#[N:10]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: N#Cc1ccc(N(CCO)CC(F)(F)F)cc1C(F)(F)F
Product: COC(=O)c1ccc(OCCN(CC(F)(F)F)c2ccc(C#N)c(C(F)(F)F)c2)cc1

Procedure:
Synthesized as described in Example 1C from 4-[(2-hydroxyethyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile and methyl 4-hydroxybenzoate: MS (APCI) m/z 446 (M+).