Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[NH2:2][C:3]1[CH:8]=[C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:6]([C:16]#[N:17])=[C:5]([Cl:18])[N+:4]=1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C(N(CC)CC)C.[CH2:32]([NH2:36])[CH2:33][CH2:34][CH3:35]>CO>[Cl-:18].[NH2:2][C:3]1[CH:8]=[C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:6]([C:16]#[N:17])=[C:5]([NH:36][CH2:32][CH2:33][CH2:34][CH3:35])[N+:4]=1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCN
Reactant: CCCCCCNc1cc(N)[n+](CCCCCC)c(Cl)c1C#N
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CO
Product: CCCCCCNc1cc(N)[n+](CCCCCC)c(NCCCC)c1C#N
Yield: 61 %

Procedure:
3.37 gms (.01 mole) of 2-amino-6-chloro-5-cyano-1-n-hexyl-4-n-hexylamino pyridinium chloride (compound II - Table 1) was dissolved in methanol and 1.0 gm (0.01 mole) of triethylamine and 0.8 gms (0.011 mole) of n-butylamine added. The solution was refluxed for 1 hour and on cooling 2.5 gms (60% yield) of 2-amino-6-n-butylamino-5-cyano-1-n-hexyl-4-n-hexylamino pyridinium chloride (compound 42 - Table 2) crystallised out. [m.p. 179° - 180°C. c 64.88 (64.6) H 9.81 (9.78) N17.11 (17.1)].
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]3[CH:14]=[CH:15][O:16][C:12]=3[C:11](=[O:17])[C:10]([C:18]3[N:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:21]=[CH:20][CH:19]=3)=[N:9]2)=[CH:4][C:3]=1[O:29][C:30]([F:33])([F:32])[F:31].N1C=CC=N1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[C:23]1([N:22]2[C:18]([C:10]3[C:11](=[O:17])[C:12]4[O:16][CH:15]=[CH:14][C:13]=4[N:8]([C:5]4[CH:6]=[CH:7][CH:2]=[C:3]([O:29][C:30]([F:33])([F:32])[F:31])[CH:4]=4)[N:9]=3)=[CH:19][CH:20]=[N:21]2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=c1c(-c2ccnn2-c2ccccc2)nn(-c2ccc(I)c(OC(F)(F)F)c2)c2ccoc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1cn[nH]c1
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c(-c2ccnn2-c2ccccc2)nn(-c2cccc(OC(F)(F)F)c2)c2ccoc12
Temperature: 50 °C
Reaction time: 12 h
Yield: 10.7 %

Procedure:
A suspension of 1-[4-iodo-3-(trifluoromethoxy)phenyl]-3-(1-phenyl-1H-pyrazol-5-yl)furo[3,2-c]pyridazin-4(1H)-one (300 mg), pyrazole (72 mg), copper oxide(I) (7.6 mg), 2-hydroxybenzaldehydeoxime (29 mg) and cesium carbonate (346 mg) in DMF (5 mL) was stirred at 50° C. for 12 hr, and water was added. The reaction mixture was extracted with ethyl acetate, the extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (25 mg).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:16]=[N:17][C:18]([NH2:21])=[N:19][CH:20]=3)=[N:13][CH:14]=2)O1.Br[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30]([NH:33][CH2:34][C@H:35]([OH:37])[CH3:36])(=[O:32])=[O:31]>>[NH2:21][C:18]1[N:19]=[CH:20][C:15]([C:12]2[N:13]=[CH:14][C:9]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[S:30]([NH:33][CH2:34][C@H:35]([OH:37])[CH3:36])(=[O:32])=[O:31])=[CH:10][CH:11]=2)=[CH:16][N:17]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)nc2)OC1(C)C
Reactant: C[C@@H](O)CNS(=O)(=O)c1ccccc1Br
Product: C[C@@H](O)CNS(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)nc2)nc1

Procedure:
The title compound was prepared in a manner similar to that described in Example 427 using 5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pyrimidin-2-amine and (R)-2-bromo-N-(2-hydroxypropyl)benzenesulfonamide. MS (ESI): mass calcd. for C18H19N5O3S, 385.12; m/z found, 386.1 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.92 (s, 2H), 8.60 (dd, J=2.3, 0.8, 1H), 8.09 (dd, J=8.0, 1.3, 1H), 7.91 (dd, J=8.2, 2.3, 1H), 7.82 (dd, J=8.2, 0.9, 1H), 7.70 (m, 1H), 7.62 (m, 1H), 7.41 (dd, J=7.6, 1.4, 1H), 3.70-3.59 (m, 1H), 2.79-2.67 (m, 2H), 1.04 (d, J=6.3, 3H).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:5]2=[N:4][CH:3]=1.[Cl:12][C:13]1[CH:18]=[C:17](B2OC(C)(C)C(C)(C)O2)[CH:16]=[C:15]([Cl:28])[N:14]=1.O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[Cl:11][C:9]1[CH:8]=[CH:7][N:6]2[C:2]([C:17]3[CH:16]=[C:15]([Cl:28])[N:14]=[C:13]([Cl:12])[CH:18]=3)=[CH:3][N:4]=[C:5]2[CH:10]=1
Reactant: CC1(C)OB(c2cc(Cl)nc(Cl)c2)OC1(C)C
Reactant: Clc1ccn2c(Br)cnc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Clc1ccn2c(-c3cc(Cl)nc(Cl)c3)cnc2c1

Procedure:
3-Bromo-7-chloro-imidazo[1,2-a]pyridine (1 eq, 3.02 mmol, 700 mg) and 2,6-dichloro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (1.1 eq, 3.32 mmol, 1.01 g) are dissolved in DME (4 ml) and water (1 ml) and Na2CO3 (1.5 eq, 5.53 mmol, 562 mg) is added. PdCl2(PPh3)2 (0.1 eq, 0.3 mmol, 212 mg) is added and the reaction mixture is heated using microwave radiation at 120° C. for 15 min. At the completion of this time the solvent is removed in vacuo and the reaction mixture is purified by flash column chromatography eluting with 9:1 DCM/MeOH to yield 7-chloro-3-(2,6-dichloro-pyridin-4-yl)-imidazo[1,2-a]pyridine as a yellow solid; [M+H]+=299
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]2[O:6][C:7]3[CH:30]=[CH:29][CH:28]=[CH:27][C:8]=3[CH2:9][N:10]([C:11](=[O:26])/[CH:12]=[CH:13]/[CH2:14][C:15]([CH3:25])([O:20][Si](C)(C)C)[CH2:16][CH2:17][CH2:18][CH3:19])[C:4]=2[CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]2[O:6][C:7]3[CH:30]=[CH:29][CH:28]=[CH:27][C:8]=3[CH2:9][N:10]([C:11](=[O:26])/[CH:12]=[CH:13]/[CH2:14][C:15]([OH:20])([CH3:25])[CH2:16][CH2:17][CH2:18][CH3:19])[C:4]=2[CH:3]=1
Reactant: CCCCC(C)(C/C=C/C(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21)O[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CCCCC(C)(O)C/C=C/C(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 3 %

Procedure:
To a stirring solution of 5 (2.0 g), was added tetrabutyl ammonium fluoride (22 mL, 22 mmol in THF). The crude product was used due to the difficulty of separating compounds 1 and 5. The reaction mixture was stirred for 45 minutes at room temperature. The solvent was removed under reduced pressure and the residue was taken up in CHCl3, extracted with brine and dried (K2CO3). The product was purified by MPLC (silica gel, 3:7 EtOAc:hexane) to yield 6 as a yellow oil (50 mg). Analysis calculated for C23H26ClNO3 : C: 69.08; H: 6.55; N: 3.50. Found C: 69.33; H: 6.64; N: 3.45.
Reaction SMILES: [CH:1](=O)[C:2]([CH3:4])=[O:3].[NH2:6][CH:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][CH2:8]1>CCOCC>[CH2:13]([N:10]1[CH2:11][CH2:12][CH:7]([N:6]=[CH:1][C:2](=[O:3])[CH3:4])[CH2:8][CH2:9]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(=O)C=O
Reactant: NC1CCN(Cc2ccccc2)CC1
Solvent: CCOCC
Product: CC(=O)C=NC1CCN(Cc2ccccc2)CC1
Reaction time: 0.33 h

Procedure:
To a solution of pyruvaldehyde (40% w/w solution in water, 0.49 mL, 0.57 g, 3.19 mmol) in 10 mL of Et2O at room temperature was added dropwise 4-amino-1-benzylpiperidine (0.5 mL, 0.46 g, 2.45 mmol). After 20 min, the solution was diluted with 40 mL of Et2O and washed with 2×5 mL of water. The solution was concentrated in vacuo to yield the imine product which was used as such in the subsequent step: 1H NMR (CDCl3) δ7.62 (1H, s), 7.29 (5H, m), 3.53 (2H, s), 3.28 (1H, m), 2.91 (2H, m), 2.38 (3H, s), 2.15 (2H, m), 1.84 (2H, m), 1.69 (2H, m)
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=1)=O.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][CH:30]=O>>[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[CH:30]=[N:1][C:2]2[C:3]([C:12]=1[C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1)=[CH:4][CH:5]=[CH:6][C:7]=2[C:8]([F:11])([F:10])[F:9]
Reactant: COc1ccccc1CC=O
Reactant: Nc1c(C(=O)c2cccc(O)c2)cccc1C(F)(F)F
Product: COc1ccccc1-c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1

Procedure:
The title compound was prepared from [2-amino-3-(trifluoromethyl)phenyl]-(3-hydroxy-phenyl)methanone and (2-Methoxy-phenyl)-acetaldehyde following the procedure of Example 457: MS (ESI) m/z 396; HRMS: calcd for C23H16F3NO2+H+, 396.12059; found (ESI, [M+H]+), 396.1223.
Reaction SMILES: [N:1]1([CH2:10][C:11]2[N:15]3[CH2:16][CH2:17][O:18][C:19]4[CH:24]=[CH:23][C:22](Br)=[CH:21][C:20]=4[C:14]3=[N:13][C:12]=2[C:26]([NH2:28])=[O:27])[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[N:2]1.BrC1C=CC2OCCN3C(CN4C=CN=C4C)=C(C(N)=O)N=C3C=2C=1.N1C2C(=CC=NC=2)C=N1.[CH3:63][C:64]([OH:68])([C:66]#[CH:67])[CH3:65]>>[N:1]1([CH2:10][C:11]2[N:15]3[CH2:16][CH2:17][O:18][C:19]4[CH:24]=[CH:23][C:22]([C:67]#[C:66][C:64]([OH:68])([CH3:65])[CH3:63])=[CH:21][C:20]=4[C:14]3=[N:13][C:12]=2[C:26]([NH2:28])=[O:27])[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[N:2]1
Reactant: NC(=O)c1nc2n(c1Cn1ncc3cccnc31)CCOc1ccc(Br)cc1-2
Reactant: C#CC(C)(C)O
Agent: Cc1nccn1Cc1c(C(N)=O)nc2n1CCOc1ccc(Br)cc1-2
Agent: c1cc2cn[nH]c2cn1
Product: CC(C)(O)C#Cc1ccc2c(c1)-c1nc(C(N)=O)c(Cn3ncc4cccnc43)n1CCO2
Yield: 40 %

Procedure:
Similar to as described in General Procedure G, 3-((1H-pyrazolo[3,4-b]pyridin-1-yl)methyl)-10-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide (prepared similarly as described in the synthesis of 10-bromo-3-((2-methyl-1H-imidazol-1-yl)methyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide replacing 2-methylimidazole with 6-azaindazole) was reacted with 2-methylbut-3-yn-2-ol to give the titled compound as a colorless solid (21 mg, 40%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:26][C:25]4[C:24]5[N:34]=[C:35]([CH3:38])[N:36](O)[C:23]=5[CH2:22][CH2:21][C:20]=4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].P(OCC)(OCC)OCC>CN(C=O)C.O>[C:1]([O:5][C:6](=[O:39])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:27]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:26][C:25]4[C:24]5[N:34]=[C:35]([CH3:38])[NH:36][C:23]=5[CH2:22][CH2:21][C:20]=4[N:19]=3)=[CH:16][CH:17]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nc2c(n1O)CCc1nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc1-2
Agent: CCOP(OCC)OCC
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc2c([nH]1)CCc1nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc1-2
Temperature: 100 °C
Yield: 37.4 %

Procedure:
To a solution of tert-butyl(1-(4-(3-hydroxy-2-methyl-8-phenyl-4,5-dihydro-3H-imidazo[4,5-f]quinolin-7-yl)phenyl)cyclobutyl)carbamate (276 mg, 0.528 mmol) in anhydrous DMF (1.4 mL) was added triethyl phosphite (181 μl, 1.056 mmol) and heated to 100° C. under a nitrogen atmosphere overnight. The reaction mixture was allowed to cool to room temperature, diluted with 50:50 water:brine (10 mL) and extracted into ethyl acetate (3×5 mL). The combined organic phases were washed with 50:50 water:brine (2×10 mL), brine (10 mL) dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. The residue was purified via Biotage chromatography (silica, DCM:MeOH, gradient elution from 100:0 to 90:10) to give the desired product as a pale brown solid (100 mg, 37% yield). 1H-NMR (500 MHz, CDCl3) δ 7.74 (1H, s), 7.28 (2H, d), 7.23 (2H, d), 7.13-7.17 (3H, m), 7.06-7.11 (2H, m), 5.09 (1H, br s), 3.25 (2H, t), 2.92 (2H, t), 2.16-2.59 (4H, br m), 2.41 (3H, s), 1.95-2.08 (1H, m), 1.70-1.82 (1H, m), 1.05-1.47 (9H, br m). LCMS (Method A) RT=4.66 min, M+H+=507.20.
Reaction SMILES: CN1CCOCC1.C(Cl)(=O)OCC(C)C.[C:16]([NH:23][C@H:24]([C:33](O)=[O:34])[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].[BH4-].[Na+]>C(COC)OC.O>[C:19]([O:18][C:16]([NH:23][C@H:24]([CH2:33][OH:34])[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N[C@H](CO)CCc1ccccc1
Reaction time: 1 h
Yield: 78.5 %

Procedure:
N-Methylmorpholine (7.2 g, 72 mmol) and isobutyl chlorocarbonate (9.8 g, 72 mmol) were added to a solution of Boc-L-homophenylalanine (20 g, 72 mmol) in dimethoxyethane (100 mL) under ice-cold conditions. After one hour stirring, the reaction solution was filtered, and the filtrate was cooled in an ice bath. Thereafter, an aqueous solution (10 mL) of sodium borohydride (4.1 g, 107 mmol) was added thereto, followed by further addition of water (300 mL). The resulting precipitate was collected by filtration and washed with water and methanol to yield N-(tert-butoxycarbonyl)-L-homophenylalaninol (15 g, 79%) as a colorless crystal.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5](Br)=[CH:4][C:3]=1[S:19]([OH:22])(=[O:21])=[O:20].C(=O)([O-])[O-].[Na+].[Na+].C([NH:32][C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[C:35]([NH2:40])[CH:34]=1)(=O)C.Cl>O.C(O)(C)C>[NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([NH:40][C:35]2[CH:34]=[C:33]([NH2:32])[CH:38]=[CH:37][C:36]=2[CH3:39])=[CH:4][C:3]=1[S:19]([OH:22])(=[O:21])=[O:20]
Reactant: CC(=O)Nc1ccc(C)c(N)c1
Reactant: Nc1c(S(=O)(=O)O)cc(Br)c2c1C(=O)c1ccccc1C2=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: Cc1ccc(N)cc1Nc1cc(S(=O)(=O)O)c(N)c2c1C(=O)c1ccccc1C2=O
Temperature: 80 °C
Reaction time: 4 h

Procedure:
38.2 Parts 1-amino-4-bromoanthraquinone-2-sulphonic acid are dissolved in 200 parts water/100 parts i-propanol and the pH adjusted to 8.5-9.0 with sodium carbonate. After addition of 18 parts 4-acetylamino-2-aminotoluene the mixture is warmed to 80° C. and treated with 1 part cuprous chloride and 12 parts sodium carbonate. After 4 hours the reaction is over. Finally 25 parts 30% hydrochloric acid are added to the reaction mixture, which is then heated to reflux. After 18 hours the suspension is cooled to room temperature, filtered and washed with 1% hydrochloric acid, to give 1-amino-4-(5'-amino-2'-methylphenylamino)-anthraquinone-2-sulphonic acid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[S:8][C:9]([O:11][C:12]3[CH:25]=[CH:24][C:15]([O:16][CH:17]([CH3:23])[C:18]([O:20]CC)=[O:19])=[CH:14][CH:13]=3)=[N:10][C:5]2=[CH:4][CH:3]=1.[OH-].[Na+]>O>[Cl:1][C:2]1[N:7]=[C:6]2[S:8][C:9]([O:11][C:12]3[CH:25]=[CH:24][C:15]([O:16][CH:17]([CH3:23])[C:18]([OH:20])=[O:19])=[CH:14][CH:13]=3)=[N:10][C:5]2=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)Oc1ccc(Oc2nc3ccc(Cl)nc3s2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(Oc1ccc(Oc2nc3ccc(Cl)nc3s2)cc1)C(=O)O
Temperature: 80 °C

Procedure:
37.8 g (0.1 mole) of ethyl 2-[4-(5- chlorothiazolo[5,4-b]pyridin-2-yloxy)-phenoxy]-propionate from Example 1 were stirred with 4.4 g (0.11 mole) of sodium hyroxide in 250 ml of water for 24 hours at approximately 30° C. The slightly cloudy solution was filtered, 500 ml of toluene were then added and the mixture was warmed to 80° C. and its pH was adjusted to 1 with concentrated hydrochloric acid. The phases were separated while hot, the water phase was again stirred thoroughly with 250 ml of toluene under hot conditions, and the combined toluene phases were dried azeotropically and concentrated to a volume of approximately 250 ml.
Reaction SMILES: C(OC1C=C(F)C=C2C=1C(CC(N1CC3C(=CC=CC=3)C1)=O)=[CH:12][N:13]2CC)C1C=CC=CC=1.[CH2:33]([O:40][C:41]1[C:49]([F:50])=[CH:48][C:47]([Br:51])=[C:46]2[C:42]=1[C:43]([CH2:53][C:54]([OH:56])=O)=[CH:44][N:45]2[CH3:52])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH2:33]([O:40][C:41]1[C:49]([F:50])=[CH:48][C:47]([Br:51])=[C:46]2[C:42]=1[C:43]([CH2:53][C:54]([NH:13][CH3:12])=[O:56])=[CH:44][N:45]2[CH3:52])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CCn1cc(CC(=O)N2Cc3ccccc3C2)c2c(OCc3ccccc3)cc(F)cc21
Reactant: Cn1cc(CC(=O)O)c2c(OCc3ccccc3)c(F)cc(Br)c21
Product: CNC(=O)Cc1cn(C)c2c(Br)cc(F)c(OCc3ccccc3)c12
Yield: 96 %

Procedure:
Following the procedure (step 1, scheme 31) used to prepare compound 31-2, compound 33-4 gave compound 33-5 in 96% yield as a yellow solid. LRMS: calc 404.0 and found: 405.0 [M+1].
Reaction SMILES: F[C:2]([F:17])(S(F)(=O)=O)[C:3](F)(F)[C:4](F)(F)[C:5](F)(F)F.O[C@H]1C[C@@]2(C)[C@@H:30]([CH2:31][CH2:32][C:33]2=[O:37])[C@H:29]2[C@H:20]1[C@@H:21]1[C:26]([CH2:27][CH2:28]2)=[CH:25][C:24](=[O:38])[CH2:23][CH2:22]1>C1(C)C=CC=CC=1.N12CCCN=C1CCCCC2.C(OCC)(=O)C>[F:17][C@H:2]1[CH2:3][C@@:4]2([CH3:5])[C@@H:30]([CH2:31][CH2:32][C:33]2=[O:37])[C@H:29]2[C@H:20]1[C@@H:21]1[C:26]([CH2:27][CH2:28]2)=[CH:25][C:24](=[O:38])[CH2:23][CH2:22]1
Reactant: C[C@]12C[C@H](O)[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: C[C@]12C[C@H](F)[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Reaction time: 0.5 h

Procedure:
4.6 ml of perfluorobutane-1-sulphonyl fluoride are added dropwise at 0° C. to 5.0 g of 11β-hydroxyoestr-4-ene-3,17-dione in 100 ml of toluene and 7.3 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene. After 30 min, the solution is diluted with ethyl acetate, washed with saturated sodium chloride solution, dried and concentrated in vacuo. After chromatographing the crude product on silica gel using a hexane-ethyl acetate gradient, 3.8 g of 11β-fluorooestr-4-ene-3,17-dione of melting point 173-174° C. are obtained.
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[NH:6][N:5]=1)(=[O:3])[CH3:2].[C:14](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O.C(OCC)(=O)C>[C:1]([C:4]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:6]([CH3:14])[N:5]=1)(=[O:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1cc(C(C)=O)n[nH]1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: CCOC(=O)c1cc(C(C)=O)nn1C
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 65.1 %

Procedure:
Ethyl 3-acetyl-1H-pyrazole-5-carboxylate (Chem. Commun., 2004, 394-395) (4.82 g) was dissolved in N,N-dimethylformamide (80 ml). To the solution, potassium carbonate (4.39 g) and iodomethane (1.98 ml) were added under ice cooling, and the mixture was stirred at room temperature for 3 hours and 50 minutes. The reaction solution was diluted with ethyl acetate. The organic layer was washed with saturated saline, water, and saturated saline in this order and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain the title compound (3.38 g).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1[N:7]([CH3:13])[C:8]([CH2:11]Cl)=[N:9][CH:10]=1)=[O:5].[CH3:14][O:15][CH2:16][CH2:17][NH:18][CH3:19]>>[CH3:2][O:3][C:4]([C:6]1[N:7]([CH3:13])[C:8]([CH2:11][N:18]([CH2:17][CH2:16][O:15][CH3:14])[CH3:19])=[N:9][CH:10]=1)=[O:5]
Reactant: COC(=O)c1cnc(CCl)n1C
Reactant: CNCCOC
Agent: Cl
Product: COCCN(C)Cc1ncc(C(=O)OC)n1C

Procedure:
Using 2-chloromethyl-3-methyl-3H-imidazole-4-carboxylic acid methyl ester hydrochloride and (2-methoxy-ethyl)-methyl-amine, the title compound was obtained as light brown viscous oil (92% yield). MS: m/e=242(M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([NH:13][C@H:14]([C:16]([OH:18])=O)[CH3:15])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[NH2:19][C@H:20]([C:25]([N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)=[O:26])[C@H:21]([CH2:23][CH3:24])[CH3:22].C(N[C@H](C(O)=O)[C@H](CC)C)(OC(C)(C)C)=O.N1CCOCC1>C(Cl)(Cl)Cl.CO>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([NH:13][C@H:14]([C:16]([NH:19][C@H:20]([C:25]([N:27]2[CH2:28][CH2:29][O:30][CH2:31][CH2:32]2)=[O:26])[C@H:21]([CH2:23][CH3:24])[CH3:22])=[O:18])[CH3:15])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC[C@H](C)[C@H](N)C(=O)N1CCOCC1
Reactant: C[C@H](NC(=O)Cc1cccc([N+](=O)[O-])c1)C(=O)O
Agent: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: ClC(Cl)Cl
Solvent: C1COCCN1
Solvent: CO
Product: CC[C@H](C)[C@H](NC(=O)[C@H](C)NC(=O)Cc1cccc([N+](=O)[O-])c1)C(=O)N1CCOCC1

Procedure:
Following General Procedure C and using N-(3-nitrophenylacetyl)-L-alanine (from Example D 1 above) and 4-(L-isoleucinyl)morpholine (prepared from N-BOC-L-isoleucine (Aldrich) and morpholine (Aldrich) using General Procedure M, followed by removal of the BOC-group using General Procedure P), the title compound was prepared as a solid (mp=156-160° C.). The reaction was monitored by tlc (Rf=0.45 in 9:1 CHCl3/MeOH) and the product was purified by silica gel chromatography using 98:2 CHCl3/MeOH as the eluent.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=O)[C@@H:10]([NH:12][C:13]2[N:21]=[CH:20][N:19]=[C:18]3[C:14]=2[N:15]=[CH:16][N:17]3C2CCCCO2)[CH3:11])=[C:4]([NH:29][C:30]2[CH:35]=[N:34][CH:33]=[CH:32][N:31]=2)[CH:3]=1.[OH-].[Na+]>C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]=[C:9]([CH:10]([NH:12][C:13]3[N:21]=[CH:20][N:19]=[C:18]4[C:14]=3[NH:15][CH:16]=[N:17]4)[CH3:11])[N:29]([C:30]3[CH:35]=[N:34][CH:33]=[CH:32][N:31]=3)[C:4]=2[CH:3]=1
Reactant: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)C(=O)Nc1ccc(F)cc1Nc1cnccn1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(Nc1ncnc2nc[nH]c12)c1nc2ccc(F)cc2n1-c1cnccn1
Temperature: 80 °C
Yield: 38.1 %

Procedure:
(S)—N-[4-Fluoro-2-(pyrazin-2-ylamino)phenyl]-2-[9-(tetrahydropyran-2-yl)-9H-purin-6-ylamino]propionamide (100 mg, 0.21 mmol) was dissolved in acetic acid (6.0 ml) and heated to 80° C. overnight. The reaction was cooled and neutralized with sodium hydroxide (1.0M aqueous) and the aqueous layer extracted with EtOAc (×3). The combined organic fractions were washed with brine, dried over sodium sulfate and concentrated in vacuo. The product was purified by chromatography (SiO2, 0-10% methanol in DCM) to yield 243 (30.0 mg, 39%). LCMS (Method C): RT 2.85 min [M+H]+ 376.0. 1H NMR (MeOD, 400 MHz): δ 8.94 (1H, s), 8.60 (2H, m), 7.98 (2H, s), 7.67 (1H, dd, J=8.7, 4.6 Hz), 7.10 (2H, m), 5.83 (1H, br s), 1.81 (3H, d, J=7.0 Hz)
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16](O)=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.CN([CH:27]=[O:28])C>ClCCl>[F:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([NH:14][CH2:13][CH2:12][C:16]([O:28][CH3:27])=[O:17])=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: CN(C)C=O
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)O
Solvent: ClCCl
Product: COC(=O)CCNC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cccn12

Procedure:
The example compounds shown in Table 6A were prepared analogously to Example Compound 78A by reacting 8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid with the appropriate commercially available amines in DMF or dichloromethane under the reaction conditions described in the Representative Working Procedure 2a:
Reaction SMILES: [Cl:1][C@@:2]1([CH3:34])[C@H:7]([C:8]([O:10]CC(Cl)(Cl)Cl)=[O:9])[N:6]2[C:16](=[O:33])[C@@H:17]([NH:18][C:19]([C:21]3[C:22]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[N:23][O:24][C:25]=3[CH3:26])=[O:20])[C@H:5]2[S:4][CH2:3]1.C(O)(=O)C>C(OCC)(=O)C.[Zn]>[Cl:1][C@@:2]1([CH3:34])[C@H:7]([C:8]([OH:10])=[O:9])[N:6]2[C:16](=[O:33])[C@@H:17]([NH:18][C:19]([C:21]3[C:22]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)=[N:23][O:24][C:25]=3[CH3:26])=[O:20])[C@H:5]2[S:4][CH2:3]1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)N[C@@H]1C(=O)N2[C@@H]1SC[C@@](C)(Cl)[C@@H]2C(=O)OCC(Cl)(Cl)Cl
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1onc(-c2ccccc2)c1C(=O)N[C@@H]1C(=O)N2[C@@H]1SC[C@@](C)(Cl)[C@@H]2C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 55.2 %

Procedure:
A mixture of 2,2,2-trichloroethyl 3β-chloro-3α-methyl-7β-(5-methyl-3-phenylisoxazol-4-carboxamido)cepham-4α-carboxylate (210 mg), zinc metal (250 mg), and acetic acid (3 ml) is stirred at room temperature for 3 hours. The reaction mixture is filtered to remove solid, and the filtrate is evaporated to give a residue, which is dissolved in ethyl acetate and washed with aqueous sodium hydrogen carbonate. The water layer is acidified with hydrochloric acid and extracted with ethyl acetate. The extract solution is washed with water, dried, and evaporated to give 3β-chloro-3α-methyl-7β-(5-methyl-3-phenylisoxazol-4-carboxamido)cepham-4α-carboxylic acid (89 mg). m.p. 210°C.