Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[O:19][C:18]([CH:20]=[CH:21][C:22]4[CH:29]=CC(C#N)=CC=4)=[N:17][CH:16]=3)[CH:12]=[CH:11][CH:10]=2)[CH:3]=1.CC1C=C[N:34]=[C:33](NC2C=CC=C(C3OC=NC=3)N=2)C=1.BrC1C=NC=CC=1.O(C(C)(C)C)[Li]>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.O1CCOCC1>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([C:15]3[O:19][C:18]([C:20]4[CH:33]=[N:34][CH:29]=[CH:22][CH:21]=4)=[N:17][CH:16]=3)[N:14]=2)[CH:3]=1
Reactant: Cc1ccnc(Nc2cccc(-c3cnc(C=Cc4ccc(C#N)cc4)o3)n2)c1
Reactant: Cc1ccnc(Nc2cccc(-c3cnco3)n2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Li]OC(C)(C)C
Solvent: C1COCCO1
Solvent: Brc1cccnc1
Product: Cc1ccnc(Nc2cccc(-c3cnc(-c4cccnc4)o3)n2)c1
Yield: 8 %

Procedure:
Prepared as for 4-(2-{5-[6-(4-methyl-pyridin-2-ylamino)-pyridin-2-yl]-oxazol-2-yl}-vinyl)-benzonitrile above using (4-methyl-pyridin-2-yl)-(6-oxazol-5-yl-pyridin-2-yl)-amine, 3-bromopyridine, Pd(PPh3)4, LiOtBu and anhydrous 1,4-dioxane to afford the title compound as a pale yellow solid (8%). 1H NMR (300 MHz, DMSO-d6) δ=9.81 (s, 1H), 9.31 (s, 1H), 8.76 (d, J=4.8 Hz, 1H), 8.46 (d, J=8.1 Hz, 1H), 8.12 (d, J=5.0 Hz, 1H), 7.91 (s, 2H), 7.84-7.76 (m, 1H), 7.69-7.52 (m, 2H), 7.45 (d, J=7.4 Hz, 1H), 6.79 (d, J=5.0 Hz, 1H), 2.36 (s, 3H). (ESI+) m/z 330 (M+H).
Reaction SMILES: [C:1]1([CH3:60])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:23][CH2:22][CH2:21][CH2:20][N:19](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:18][CH2:17][N:16]([S:43]([C:46]3[CH:51]=[CH:50][C:49]([CH3:52])=[CH:48][CH:47]=3)(=[O:45])=[O:44])[CH2:15][CH2:14][N:13](CC3C=CC=CC=3)[CH2:12][CH2:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1>[Pd]>[C:1]1([CH3:60])[CH:2]=[CH:3][C:4]([S:7]([N:10]2[CH2:23][CH2:22][CH2:21][CH2:20][NH:19][CH2:18][CH2:17][N:16]([S:43]([C:46]3[CH:51]=[CH:50][C:49]([CH3:52])=[CH:48][CH:47]=3)(=[O:44])=[O:45])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)(=[O:9])=[O:8])=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCCCN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CCN(S(=O)(=O)c3ccc(C)cc3)CCN(Cc3ccccc3)CC2)cc1
Agent: [Pd]
Product: Cc1ccc(S(=O)(=O)N2CCCCNCCN(S(=O)(=O)c3ccc(C)cc3)CCNCC2)cc1

Procedure:
From 1,7-di-(p-toluenesulfonyl)-4-benzyl-10-trityl-1,4,7,10-tetraazacyclotetradecane (1.3.13.24) reduced by H2 and Pd/C.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26](B5OC(C)(C)C(C)(C)O5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:40]1[CH:45]=[CH:44][C:43]([F:46])=[CH:42][N:41]=1.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+]>C(COC)OC.O.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>[Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:24]=[CH:25][C:26]([C:40]5[CH:45]=[CH:44][C:43]([F:46])=[CH:42][N:41]=5)=[CH:27][CH:28]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2]
Reactant: Fc1ccc(Br)nc1
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(B5OC(C)(C)C(C)(C)O5)cc4)CC3)n2CCS1
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: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(-c5ccc(F)cn5)cc4)CC3)n2CCS1
Temperature: 25 °C
Yield: 72.8 %

Procedure:
A solution of the compound (555 mg, 1.0 mmol) obtained in Example 16-5), 2-bromo-5-fluoropyridine (263 mg, 1.5 mmol), tetrakis(triphenylphosphine)palladium(0) (231 mg, 0.2 mmol), and potassium carbonate (276 mg, 2 mmol) in dimethoxyethane (4 mL) and water (1 mL) was stirred at 130° C. for 1.5 h under microwave irradiation. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 40 g, methanol:ethyl acetate=0:100 to 20:80, gradient) to obtain the title compound (382 mg, 73%) as a light yellow oily substance.
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:17]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]4[NH:28][CH:29]=[CH:30][C:23]=34)[CH:19]=[N:18]2)[CH2:7][N:6]([C:8]2[N:9]=[CH:10][C:11]([C:14](O)=[O:15])=[N:12][CH:13]=2)[CH2:5]1)#[N:2].Cl.[CH:32]1([C@H:35]([NH2:40])[C:36]([F:39])([F:38])[F:37])[CH2:34][CH2:33]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O.CO>[C:1]([CH2:3][C:4]1([N:17]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]4[NH:28][CH:29]=[CH:30][C:23]=34)[CH:19]=[N:18]2)[CH2:5][N:6]([C:8]2[N:9]=[CH:10][C:11]([C:14]([NH:40][C@@H:35]([CH:32]3[CH2:34][CH2:33]3)[C:36]([F:39])([F:38])[F:37])=[O:15])=[N:12][CH:13]=2)[CH2:7]1)#[N:2]
Reactant: N#CCC1(n2cc(-c3ccnc4[nH]ccc34)cn2)CN(c2cnc(C(=O)O)cn2)C1
Reactant: N[C@@H](C1CC1)C(F)(F)F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#CCC1(n2cc(-c3ccnc4[nH]ccc34)cn2)CN(c2cnc(C(=O)N[C@@H](C3CC3)C(F)(F)F)cn2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 27.8 %

Procedure:
A mixture of 5-{3-(cyanomethyl)-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}pyrazine-2-carboxylic acid (10 mg, 0.02 mmol), (1S)-1-cyclopropyl-2,2,2-trifluoroethanamine HCl salt (6.6 mg, 0.037 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (12 mg, 0.027 mmol) and triethylamine (16 μL, 0.11 mmol) in N,N-dimethylformamide (0.3 mL) was stirred at room temperature for 3 h. It was diluted with methanol, purified by RP-HPLC (pH=2) to afford the desired product (2.9 mg) as TFA salt. LCMS (M+H)+: m/z=522.4. 1H NMR (500 MHz, DMSO-d6): δ 12.01 (s, 1H), 8.92 (s, 1H), 8.90 (d, J=9.4 Hz, 1H), 8.69 (d, J=1.1 Hz, 1H), 8.41 (s, 1H), 8.27 (d, J=5.3 Hz, 1H), 8.04 (d, J=1.0 Hz, 1H), 7.65-7.57 (m, 1H), 7.46 (d, J=5.3 Hz, 1H), 7.01 (s, 1H), 4.84 (d, J=9.8 Hz, 2H), 4.58 (d, J=9.8 Hz, 2H), 4.10-3.97 (m, 1H), 3.78 (s, 2H), 1.46-1.33 (m, 1H), 0.73-0.61 (m, 1H), 0.61-0.53 (m, 1H), 0.53-0.44 (m, 1H), 0.27-0.17 (m, 1H).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][CH:6]=1)([F:4])[F:3].[OH:13]O.[OH-].[Na+]>>[F:4][C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([NH2:12])=[O:13])=[CH:7][CH:6]=1)([F:3])[CH3:1]
Reactant: OO
Reactant: CC(F)(F)c1ccc(C#N)cc1
Agent: [Na+]
Agent: [OH-]
Product: CC(F)(F)c1ccc(C(N)=O)cc1

Procedure:
5 gm of p-CH3CF2C6H4CN, 200 ml of an aqueous solution of H2O2 at 3% and 10 ml of an aqueous solution of NaOH at 25% were reacted at 60° C. during 4 hours. A white precipitate was progressively formed. The reaction medium was then cooled, filtered, washed with water and dried under vacuum. 5.5 gm of ##STR45## were obtained.
Reaction SMILES: [CH2:1]([N:3]([CH2:11][CH3:12])[C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)[CH3:2].[N:13](OCCC(C)C)=[O:14].C(OCC)C.[ClH:26]>C(O)CC>[ClH:26].[CH2:11]([N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[CH:8][C:7]([N:13]=[O:14])=[C:6]([OH:10])[CH:5]=1)[CH3:12]
Reactant: CCN(CC)c1cccc(O)c1
Reactant: CC(C)CCON=O
Agent: Cl
Solvent: CCOCC
Solvent: CCCO
Product: CCN(CC)c1ccc(N=O)c(O)c1

Procedure:
0.1 mol of 3-diethylaminophenol are dissolved in 50 ml of n-propanol saturated with gaseous hydrogen chloride and, at 0° C., admixed dropwise and with stirring with 0.1 mol of isoamyl nitrite. Stirring is continued for another hour and the reaction solution is then admixed with diethyl ether, and the product which is formed is isolated by filtration with suction.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([CH3:9])=[CH:6][C:7]=1[CH3:8].C(N(C(C)C)CC)(C)C.Cl[CH:20]([CH3:29])[C:21]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=O>C(Cl)Cl>[CH2:20]([C:21]1[N:1]=[C:2]2[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[N:4][N:3]2[C:23]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:29]
Reactant: Cc1cc(C)c(N)nn1
Reactant: CCOC(=O)CC(=O)C(C)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1c(CC)nc2c(C)cc(C)nn12
Temperature: 75 °C
Reaction time: 16 h
Yield: 72.7 %

Procedure:
To a suspension of 0.598 g (4.86 mmol) of 3-amino-4,6-dimethylpyridazine in 10 mL of CH2Cl2 in a high pressure vessel was added 0.941 g (1.27 mL; 7.28 mmol) of diisopropylethylamine and 1.301 g (7.28 mmol) of ethyl a-chloropropionylacetate. The reaction mixture was equipped with a magnetic stir bar, tightly sealed, then heated and stirred in an oil bath at 75° C. for 16 hours. The flask was then cooled to room temperature, opened and the reaction mixture was evaporated in vacuo. The residue was partitioned between EtOAc and water, and the organic layer was separated. The organic layer was washed with brine, dried (MgSO4), filtered and evaporated. The residual brown solid was purified on a silica gel flash chromatography column eluted with 50% EtOAc-hexane. Combination of the purified fractions and evaporation in vacuo afforded 0.874 g (73%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[NH:12][C:11](=O)[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:11]1[N:10]=[C:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1nc(-c2ccc(Cl)c(Cl)c2)cc(C(F)(F)F)[nH]1
Product: FC(F)(F)c1cc(-c2ccc(Cl)c(Cl)c2)nc(Cl)n1

Procedure:
The title compound was prepared from 4-(3,4-dichloro-phenyl)-6-trifluoromethyl-1H-pyrimidin-2-one (5.72 g, 18.5 mmol) and phosphoryl chloride (60 mL) according to the general procedure I. Obtained as a white solid (6.04 g, 99%). MS (EI) 326.0 [(M)+]; mp 82° C.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][CH2:10][C:9](=[N:13]O)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1.CCOC(C)=O>[C:1]1([CH:7]2[CH2:12][CH2:11][CH2:10][CH:9]([NH2:13])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ON=C1CCCC(c2ccccc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: NC1CCCC(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 73.1 %

Procedure:
To a solution of 3-phenylcyclohexanone oxime (0.060 g, 0.32 mmol) in THF (2 ml) was added 1M lithium aluminum hydride in THF (0.67 ml, 0.67 mmol), and the reaction was heated to reflux for 3 hours. The reaction was cooled to ambient temperature and water (0.0254 ml), 1M sodium hydroxide (0.0254 ml), and additional water (0.0762 ml) were added sequentially, and the reaction was stirred for 15 minutes. The reaction was diluted with EtOAc and filtered. The filtrate was concentrated to yield 41 mg of the title compound (74% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14][CH2:15]CC(N)=O)=[C:10]([C:20]([F:23])([F:22])[F:21])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.CC(C)([O-])C.[Na+].[C:30]([C:32]1([NH:35][C:36]([C@H:38]2[N:42]([C:43]([C:45]3([CH3:48])[CH2:47][CH2:46]3)=[O:44])[CH2:41][C@@H](OS(C3C=CC=CC=3)(=O)=O)[CH2:39]2)=[O:37])[CH2:34][CH2:33]1)#[N:31]>O1CCCC1.CN(C)C(=O)C.O>[C:30]([C:32]1([NH:35][C:36]([C@@H:38]2[CH2:39][C@@H:15]([S:14][C:11]3[CH:12]=[CH:13][C:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=4)=[CH:9][C:10]=3[C:20]([F:22])([F:21])[F:23])[CH2:41][N:42]2[C:43]([C:45]2([CH3:48])[CH2:46][CH2:47]2)=[O:44])=[O:37])[CH2:33][CH2:34]1)#[N:31]
Reactant: CC1(C(=O)N2C[C@@H](OS(=O)(=O)c3ccccc3)C[C@H]2C(=O)NC2(C#N)CC2)CC1
Reactant: Cc1cc(-c2ccc(SCCC(N)=O)c(C(F)(F)F)c2)ccn1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(S[C@@H]3C[C@@H](C(=O)NC4(C#N)CC4)N(C(=O)C4(C)CC4)C3)c(C(F)(F)F)c2)ccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 110.6 %

Procedure:
3-[4-(2-Methyl-pyridin-4-yl)-2-trifluoromethyl-phenylsulfanyl]-propionamide (15.0 g, 44.1 mmol) was dissolved in tetrahydrofuran (75 mL), before sodium tert-butoxide (4.15 g, 43.2 mmol) was added and the fine suspension was stirred for 2 h at room temperature. N,N-dimethylacetamide (37 mL) was added and the solution was stirred for further 2 h. A solution of benzenesulfonic acid (3S,5S)-5-(1-cyano-cyclopropylcarbamoyl)-1-(1-methyl-cyclo-propanecarbonyl)-pyrrolidin-3-yl ester (15.7 g, 37.7 mmol) in N,N-dimethylacetamide (37 mL) was added and the brown, clear solution was stirred for 65 h at room temperature. After that, the mixture was diluted with cold water (240 mL) and extracted with tert-butyl methyl ether (1×180 mL, 5×90 mL). The combined organic extracts were washed with aqueous sodium carbonate solution (1 M, 90 mL) and brine (90 mL), dried over sodium sulfate and concentrated in vacuo to yield the title compound as a brown gum (22.05 g). The crude product (containing dimethylacetamide) was used in the next step without further purification. MS (EI): m/z=529.1 [M+H]+. 1H NMR (CDCl3, 400 MHz): δ 0.56-0.66 (m, 2H), 0.87-0.93 (m, 1H), 1.04-1.09 (m, 1H), 1.18-1.22 (m, 2H), 1.31 (s, 3H), 1.45-1.57 (m, 2H), 1.95-2.04 (m, 1H), 2.65 (s, 3H), 2.95-3.01 (m, 1H), 3.91 & 4.02 (ABX, JAB=11.3 Hz, JAX=5.6 Hz, JBX=6.5 Hz, each 1H), 4.14-4.22 (m, 1H), 4.66 (dd, J=4.3 Hz, 8.1 Hz, 1H), 7.31 (dd, J=1.5 Hz, 5.3 Hz, 1H), 7.37 (bs, 1H), 7.69 & 7.80 (ABX, JAB=8.2 Hz, JAX=0 Hz, JBX=2.0 Hz, each 1H), 7.93 (d, J=1.9 Hz, 1H), 8.06 (bs, 1H), 8.60 (d, J=5.1 Hz, 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([NH:13][C:14]([N:16]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:15])[S:9][C:10]=1[S:11][CH3:12])=[O:5])C.C(OC(C1N=C(NC(N(C2CCCCC2)C2CCCCC2)=O)SC=1SC#N)=O)C.CI>>[CH:23]1([N:16]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:14](=[O:15])[NH:13][C:8]2[S:9][C:10]([S:11][CH3:12])=[C:6]([C:4]([OH:5])=[O:3])[N:7]=2)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: CCOC(=O)c1nc(NC(=O)N(C2CCCCC2)C2CCCCC2)sc1SC
Agent: CCOC(=O)c1nc(NC(=O)N(C2CCCCC2)C2CCCCC2)sc1SC#N
Solvent: CI
Product: CSc1sc(NC(=O)N(C2CCCCC2)C2CCCCC2)nc1C(=O)O

Procedure:
2-(3,3-Dicyclohexyl-ureido)-5-methylsulfanyl-thiazole-4-carboxylic acid ethyl ester was pre-pared as described in general procedure (H) using 2-(3,3-dicyclohexyl-ureido)-5-thiocyanato-thiazole-4-carboxylic acid ethyl ester and methyl iodide. Hydrolysis using general procedure (F) gave the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[N:11][CH:12]=[CH:13][N:14]=3)[C:9]2=[O:18])=[N:6][CH:7]=1.[BH4-].[Na+].[OH-].[Na+]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:9]([OH:18])[C:10]3[C:15](=[N:14][CH:13]=[CH:12][N:11]=3)[C:16]2=[O:17])=[N:6][CH:7]=1
Reactant: O=C1c2nccnc2C(=O)N1c1ccc(Cl)cn1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C1c2nccnc2C(O)N1c1ccc(Cl)cn1
Temperature: 2.5 °C
Reaction time: 4.5 h

Procedure:
6-(5-Chloropyridin-2-yl)-5,7-dioxo-5,6-dihydropyrrolo-[3,4-b]-pyrazine (100g) was suspended in 900 ml water. The slurry was cooled to 0-5° C. and 100 ml (7.2%) of aqueous sodium borohydride solution stabilized with 0.1 g sodium hydroxide was added in 3 hrs under vigorous stirring. Reaction mixture was stirred at 0-5° C. for 4 to 5 hrs. After completion of reaction solid was filtered and washed with 2×300 ml water. The filtered solid was refluxed in 215 ml dichloromethane for 30 min and cooled to 25-30° C. The solid was filtered, washed with 100 ml dichloromethane and dried at 50-60° C. to obtain 82 g of title compound.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.[NH2:13][CH2:14][C:15]1[N:16]([C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:17]=[CH:18][N:19]=1>C(Cl)Cl.C(O)(C)C.C(OCC)(=O)C>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:13][CH2:14][C:15]1[N:16]([C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:17]=[CH:18][N:19]=1)=[O:4]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: NCc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: Nc1ccccc1C(=O)NCc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 80.1 %

Procedure:
Isatoic anhydride (2.65 g; 0.0162 mol) was slowly added to a room temperature solution of 5.51 g (0.0162 mol) of 2-(aminomethyl)-1-tritylimidazole in 30 ml of methylene chloride and 65 ml of isopropanol. The reaction mixture was then allowed to react overnight. The next morning the solution was reduced to dryness under reduced pressure and the resultant residue was redissolved in an ethyl acetate/aqueous sodium bicarbonate mixture. The resulting layers were separated, the organic layer was washed with water and then a saturated sodium chloride solution, dried over anhydrous sodium sulfate and finally reduced to dryness to provide a yellow solid. This solid was filtered through silica gel using 1000 ml of methylene chloride followed by 1000 ml of a 2% methanol in methylene chloride solution. The resulting filtrate was reduced to dryness to provide a white solid. This solid was recrystallized from a 1:1 ethyl acetate/hexanes solution to provide 5.95 g of the desired subtitled intermediate (m.p 171°-175° C.).
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]([C:13]1[C:14]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=2[F:31])=[C:15]([F:22])[C:16]2[N:17]([CH:19]=[CH:20][N:21]=2)[CH:18]=1)=[O:12]>C(#N)C.C(OCC)(=O)C>[CH3:9][O:10][C:11]([C:13]1[C:14]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=2[F:31])=[C:15]([F:22])[C:16]2[N:17]([C:19]([I:1])=[CH:20][N:21]=2)[CH:18]=1)=[O:12]
Reactant: COC(=O)c1cn2ccnc2c(F)c1Nc1ccc(C)cc1F
Reactant: O=C1CCC(=O)N1I
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)c1cn2c(I)cnc2c(F)c1Nc1ccc(C)cc1F
Yield: 100.7 %

Procedure:
N-iodosuccinimide (134 mg, 0.60 mmol) was added in a single portion to a solution of 8-fluoro-7-(2-fluoro-4-methylphenylamino)-imidazo[1,2-a]pyridine-6-carboxylic acid methyl ester (172 mg, 0.54 mmol) in acetonitrile (10 mL) resulting in a thick precipitate after ten minutes of stirring. The suspension was diluted with ethyl acetate, washed with NaHSO3, saturated NaHCO3, water, brine, and dried over Na2SO4. Concentration provided the desired product as a yellow solid (241 mg, 100%). MS APCI (+) m/z 444 (M+1) detected. 1H NMR (400 MHz, CD3OD) δ 8.78 (s, 1H), 7.62 (s, 1H), 6.95 (m, 3H), 4.00 (s, 3H), 2.33 (s, 3H). 19F NMR (376 MHz, CD3OD)−131.11 (s, 1F), −146.71 (s, 1F).
Reaction SMILES: C([O:5][C:6](=[O:38])[C@H:7]([CH2:29][CH2:30][C:31]([O:33]C(C)(C)C)=[O:32])[NH:8][NH:9][C:10](=[O:28])[C:11]1[CH:16]=[CH:15][C:14]([NH:17]C(OC(C)(C)C)=O)=[CH:13][C:12]=1[N+:25]([O-:27])=[O:26])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]([NH:9][NH:8][C@H:7]([C:6]([OH:38])=[O:5])[CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:28])=[C:12]([N+:25]([O-:27])=[O:26])[CH:13]=1
Reactant: CC(C)(C)OC(=O)CC[C@H](NNC(=O)c1ccc(NC(=O)OC(C)(C)C)cc1[N+](=O)[O-])C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(C(=O)NN[C@@H](CCC(=O)O)C(=O)O)c([N+](=O)[O-])c1

Procedure:
To a solution of di-tert.-butyl-N-(4-(tert-butoxycarbonylamino)-2-nitrobenzamido)-L-glutamate in 53 ml dichloromethane were added 53 ml of trifluoroacetic acid at 0° C. under argon. After 1 hour at room temperature the mixture was concentrated to dryness to give 3.54 g of N-(4-amino-2-nitrobenzamido)-L-glutamic acid as a yellow foam.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH:16]([OH:34])[CH2:17][CH2:18][NH:19][C:20](=[O:33])[C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)=[CH:23][CH:22]=2)[CH2:11][CH2:10]1.[C:35](OC(=O)C)(=[O:37])[CH3:36].C(N(CC)CC)C>C(Cl)Cl>[C:35]([O:34][CH:16]([CH2:17][CH2:18][NH:19][C:20](=[O:33])[C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)=[CH:23][CH:22]=1)[CH2:15][N:12]1[CH2:11][CH2:10][N:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=2[Cl:1])[CH2:14][CH2:13]1)(=[O:37])[CH3:36]
Reactant: O=C(NCCC(O)CN1CCN(c2cccc(Cl)c2Cl)CC1)c1ccc(-c2ccccn2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OC(CCNC(=O)c1ccc(-c2ccccn2)cc1)CN1CCN(c2cccc(Cl)c2Cl)CC1
Reaction time: 16 h

Procedure:
A solution of 16 (0.25 g, 0.5 mmol) in 10 mL of CH2Cl2 was treated with 70 μL (0.75 mmol) acetic anhydride followed by 140 μL (1.0 mmol) triethylamine. After stirring for 16 h, the mixture was washed with sodium bicarbonate solution, dried with sodium sulphate and purified by flash chromatography. Yield: 0.22 g (82%). Mp. (oxalate): foam. 1H NMR (CDCl3): δ 1.84 (m, 1H), 2.05 (m, 1H), 2.12 (s, 3H), 2.52 (dd, J 13.2, 5.2, 1H), 2.65 (m, 5H), 2.99 (s, 4H), 3.25 (dq, J 9.7, 5.00, 1H), 3.81 (dt, J 12.3, 5.7, 1H), 5.19 (m, 1H), 6.89 (dd, J 7.7, 1.8, 1H), 7.06-7.17 (m, 3H), 7.26 (ddd, J 6.1, 4.8, 2.44, 1H), 7.73-7.76 (m, 2H), 7.93 (d, J 8.6, 2H), 8.07 (d, J 8.6, 2H), 8.70 (td, J 4.83, 1.50, 1.50, 1H). 13C NMR (CDCl3): δ 21.0, 32.4, 36.1, 51.3, 53.7, 61.5, 69.6, 118.6, 120.8, 122.7, 124.5, 127.0, 127.4, 127.5, 133.9, 134.7, 136.9, 142.1, 149.8, 151.1, 156.2, 167.1, 171.5, Anal. (C26H30Cl2N4O3.1.5(COOH)2.H2O) C, H, N.
Reaction SMILES: [CH3:1][O-:2].[Na+].[OH:4][C@@:5]1([CH3:26])[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C:14](=[CH:15][C:16](=[O:24])[CH2:17][CH2:18]1)[C:13](=[CH2:25])[CH2:12]3.Cl>N1C=CC=CC=1.COC=O.C(OCC)(=O)C>[OH:4][C@@:5]1([CH3:26])[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C:14](=[CH:15][C:16](=[O:24])/[C:17](=[CH:1]\[OH:2])/[CH2:18]1)[C:13](=[CH2:25])[CH2:12]3
Reactant: C=C1C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC[C@]3(C)O)[C@@]2(C)CCC(=O)C=C12
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: COC=O
Solvent: CCOC(C)=O
Product: C=C1C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC[C@]3(C)O)[C@@]2(C)C/C(=C/O)C(=O)C=C12
Temperature: 0 °C
Reaction time: 18 h
Yield: 64.3 %

Procedure:
At room temperature, 2.2 g of sodium methylate is added to 3.0 g of 17β-hydroxy-17α-methyl-6-methyleneandrost-4-en-3-one (Tetrahedron 20: 597, 1964) in 70 ml of pyridine and 10.2 ml of formic acid methyl ester. After 18 hours, the reaction mixture is stirred into ice/water which contains hydrochloric acid. The precipitated product is suctioned off, dissolved in ethyl acetate, washed with water, and dried over sodium sulfate. Chromatography of the crude product on silica gel with a methylene chloride-(tert-butyl methyl ether) gradient yields 2.1 g of (Z)-17β-hydroxy-2-hydroxymethylene-17α-methyl-6-methyleneandrost-4-en-3-one as a foam.