Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[F:32][C:33]([F:42])([F:41])[C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=1.O[CH2:44][C@@H:45]([NH:50][C:51]([C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[C:46]([O:48][CH3:49])=[O:47]>C1COCC1>[F:32][C:33]([F:41])([F:42])[C:34]1[CH:35]=[CH:36][C:37]([O:40][CH2:44][C@@H:45]([NH:50][C:51]([C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)([C:58]2[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=2)[C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C:46]([O:48][CH3:49])=[O:47])=[CH:38][CH:39]=1
Reactant: COC(=O)[C@@H](CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@@H](COc1ccc(C(F)(F)F)cc1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of triphenylphosphine (3 eq) in dry THF under Argon was added diethylazodicarboxylate (3 eq) dropwise. The reaction mixture was stirred at room temperature for 15 minutes before adding a solution of 4-(trifluoromethyl)phenol (3 eq in dry THF) dropwise. The reaction mixture was stirred at room temperature for 1 hour before adding (R)-methyl 3-hydroxy-2-(tritylamino)propanoate (LXXXIX) in dry THF in one portion. The reaction mixture was stirred at room temperature ovenight. The mixture was concentrated to dryness, treated with hexane and filtered. The residue was concentrated to dryness and purified by silica flash chromatography (EtOAc/hexane=1:5). Pure (R)-methyl 3-(4-(trifluoromethyl)phenoxy)-2-(tritylamino)propanoate (XC) was obtained as an off-white solid (50% yield).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH:8]([O:9][CH3:10])[CH2:7][CH:6]([N:11](C)[CH2:12]C2C=CC=CC=2)[CH:5]([N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:4]1>C(O)C.[OH-].[OH-].[Pd+2]>[CH3:12][NH:11][CH:6]1[CH2:7][CH:8]([O:9][CH3:10])[CH:3]([O:2][CH3:1])[CH2:4][CH:5]1[N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: COC1CC(N(C)Cc2ccccc2)C(N2CCCC2)CC1OC
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CNC1CC(OC)C(OC)CC1N1CCCC1
Reaction time: 12 h

Procedure:
The N-benzylated amine from Step 5 (2.7 mmol) was dissolved in 30 mL of ethanol and treated with 1 mass equivalent of palladium hydroxide on carbon. This mixture was placed under an atmosphere of hydrogen gas, initially at 50 psi (445 kPa) for 12 hours.
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[CH3:14][O:15][C:16]([C:18]1[O:19][C:20]([CH3:25])=[C:21]([CH2:23][OH:24])[CH:22]=1)=[O:17]>CC(C)=O.C(OCC)C>[CH3:14][O:15][C:16]([C:18]1[O:19][C:20]([CH3:25])=[C:21]([C:23]([OH:3])=[O:24])[CH:22]=1)=[O:17]
Reactant: COC(=O)c1cc(CO)c(C)o1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: COC(=O)c1cc(C(=O)O)c(C)o1
Reaction time: 5 h

Procedure:
Jones' reagent (Prepared according to Fieser and Fieser, Reagents for Organic Synthesis, Volume 1, page 142, 1967) was added drop-wise to a stirred solution of 4-hydroxymethyl-5-methyl-furan-2-carboxylic acid methyl ester (16) (100 mg) in acetone (10 mL) until the orange colouration just remained. Stirring was continued for a further 5 hours then the reaction mixture was diluted with diethyl ether (20 mL) and filtered. The filtrate was dried and concentrated in vacuo to afford compound 23 as a buff coloured solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:29](=[O:30])[N:28]([CH3:31])[C:12]2[N:13]([CH3:27])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20](=O)[CH:21]=[CH:22]N(C)C)=[CH:16][CH:15]=3.Cl.[CH:33]1([NH:39][NH2:40])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>>[CH:33]1([N:39]2[C:20]([C:17]3[CH:18]=[C:19]4[C:14](=[CH:15][CH:16]=3)[N:13]([CH3:27])[C:12]3[N:28]([CH3:31])[C:29](=[O:30])[C:9]([C:3]5[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=5[Cl:1])=[CH:10][C:11]4=3)=[CH:21][CH:22]=[N:40]2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: CN(C)C=CC(=O)c1ccc2c(c1)c1cc(-c3ccc(Cl)cc3Cl)c(=O)n(C)c1n2C
Reactant: NNC1CCCCC1
Agent: Cl
Product: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4ccnn4C4CCCCC4)ccc3n(C)c21

Procedure:
The process is carried out as in Example 37 above, with the compound from preparation 1.10, 3-(2,4-dichlorophenyl)-6-[3-(dimethylamino)prop-2-enoyl]-1,9-dimethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one and cyclohexylhydrazine hydrochloride.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][CH:23]=1)[CH:11]1[CH2:16][CH2:15][CH:14]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:13][CH2:12]1.[NH:31]1[C:35]([CH2:36][NH2:37])=[N:34][N:33]=[N:32]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:37][CH2:36][C:35]2[NH:34][N:33]=[N:32][N:31]=2)=[O:28])=[CH:24][CH:23]=1)[CH:11]1[CH2:12][CH2:13][CH:14]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:15][CH2:16]1
Reactant: CC(C)(C)C1CCC(N(Cc2ccc(C(=O)O)cc2)c2nc3ccccc3[nH]2)CC1
Reactant: NCc1nnn[nH]1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C1CCC(N(Cc2ccc(C(=O)NCc3nnn[nH]3)cc2)c2nc3ccccc3[nH]2)CC1

Procedure:
To a solution of the title compound of Example 1 Step D (0.04 mmol, 16 mg), 1H-tetraazol-5-ylmethylamine (0.06 mmol, 8 mg), HOBt (0.1 mmol, 15 mg) and EDC (0.12 mmol, 23 mg) in 0.4 mL of DMF was added DIEA (0.2 mmol, 35 μL). After 3 h the reaction mixture was concentrated under reduced pressure. The product was purified by reverse-phase chromatography (Condition A) and lyophilized, affording the title compound as a white solid. MS (ESI): m/z 487 (M+H). HPLC A: 1.58 min.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[C:16]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:15][C:9]2[C:10](=[O:14])[CH2:11][CH2:12][O:13][C:8]=2[CH:7]=1)(=[O:4])=[O:3].C([Li])CCC.[CH3:29][S:30]S(C)(=O)=O.Cl>O1CCCC1.CN(C)P(=O)(N(C)C)N(C)C.O1CCCC1>[CH3:1][S:2]([NH:5][C:6]1[C:16]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:15][C:9]2[C:10](=[O:14])[CH:11]([S:30][CH3:29])[CH2:12][O:13][C:8]=2[CH:7]=1)(=[O:3])=[O:4]
Reactant: CSS(C)(=O)=O
Reactant: CS(=O)(=O)Nc1cc2c(cc1Oc1ccccc1)C(=O)CCO2
Agent: Cl
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CSC1COc2cc(NS(C)(=O)=O)c(Oc3ccccc3)cc2C1=O
Reaction time: 0.67 h
Yield: 42.2 %

Procedure:
In 10 ml of a mixture of anhydrous tetrahydrofuran-hexamethylphosphoric acid triamide (7:3) was dissolved 1.00 g of 2,3-dihydro-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one. To the resulting solution was added 10 ml of a tetrahydrofuran solution of 1,1,1,3, 3,3-hexamethylsilazane lithium salt consisting of 1.17 g of 1,1,1,3,3,3-hexamethylsilazane and 6.6 millimoles of n-butyllithium at -78° C., and the resulting mixture was stirred for 40 minutes, after which 500 mg of methyl methanethiolsulfate was added at the same temperature and the mixture was stirred for 15 minutes. Subsequently, the temperature of the reaction mixture was elevated to room temperature. The reaction mixture was introduced into 80 ml of 2N hydrochloric acid with ice-cooling and the resulting mixture was extracted with two 40-ml portions of ethyl acetate. The extracts were combined and washed with water and saturated aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure and the oily product obtained was purified by a column chromatography (eluant: toluene:ethyl acetate=50:1) to obtain 480 mg (yield: 39.6%) of 2,3-dihydro-7-methylsulfonylamino-3-methylthio-6-phenoxy-4H-1-benzopyran-4-one.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([SH:11])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].[CH:26]1([CH2:32]Br)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:32][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCC1CCCCC1
Reactant: Nc1nc(S)nc2c1nc(O)n2Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc(SCC2CCCCC2)nc2c1nc(O)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 9 h
Yield: 51.4 %

Procedure:
Crude 6-amino-9-benzyl-8-hydroxy-2-mercaptopurine (134 mg, 0.49 mmol) was suspended in dimethylformamide (60 ml). To the suspension were added potassium carbonate (100 mg, 0.72 mmol) and cyclohexylmethyl bromide (0.1 ml, 0.7 mmol) in order. The mixture was stirred at room temperature for 9 hours. The solvent was removed in vacuo, and the residue was purified by silica gel chromatography (3% methanol/chloroform) to give the subject compound (93 mg, yield 51%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.[C:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([CH3:19])[CH:13]=1)#[CH:11]>C(NC(C)C)(C)C.C1(C)C=CC=CC=1.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.[Cu]I>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]#[C:11][C:2]2[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=2)=[CH:13][C:14]=1[CH3:19]
Reactant: C#Cc1ccc(F)c(C)c1
Reactant: COc1cncc(Br)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CC(C)NC(C)C
Product: COc1cncc(C#Cc2ccc(F)c(C)c2)c1
Temperature: 60 °C
Yield: 51.1 %

Procedure:
Dissolve 3-bromo-5-methoxypyridine (1.0 g, 5.35 mmol) in diisopropylamine (17 mL) and toluene (10 mL) under nitrogen. Add tetrakis(triphenylphosphine)palladium (0.200 g, 0.16 mmol). Heat at 60° C. and add 4-ethynyl-1-fluoro-2-methylbenzene (717 mg, 5.35 mmol) and copper (I) iodide (20 mg, 0.11 mmol). After 20 h add additional 4-ethynyl-1-fluoro-2-methylbenzene (100 mg, 0.75 mmol) and heat at 60° C. for 5 h. Concentrate and purify using silica gel chromatography, eluting with 30:70 to 40:60 ethyl acetate:hexanes, to give the title compound (660 mg, 51%).
Reaction SMILES: C[O:2][C:3](=[O:36])[C@H:4]([CH2:16][NH:17][C:18](=[O:35])[CH2:19][C@H:20]1[O:24][N:23]([CH3:25])[C@@H:22]([C:26]2[CH:31]=[CH:30][C:29]([CH:32]=[N:33][NH2:34])=[CH:28][CH:27]=2)[CH2:21]1)[NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=1)(=[O:8])=[O:7].[ClH:37]>>[ClH:37].[CH3:25][N:23]1[C@@H:22]([C:26]2[CH:27]=[CH:28][C:29]([CH:32]=[N:33][NH2:34])=[CH:30][CH:31]=2)[CH2:21][C@@H:20]([CH2:19][C:18]([NH:17][CH2:16][C@@H:4]([C:3]([OH:36])=[O:2])[NH:5][S:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=2)(=[O:8])=[O:7])=[O:35])[O:24]1
Reactant: COC(=O)[C@H](CNC(=O)C[C@@H]1C[C@H](c2ccc(C=NN)cc2)N(C)O1)NS(=O)(=O)c1cccc(C)c1
Agent: Cl
Product: Cc1cccc(S(=O)(=O)N[C@@H](CNC(=O)C[C@@H]2C[C@H](c3ccc(C=NN)cc3)N(C)O2)C(=O)O)c1
Temperature: 25 °C
Reaction time: 36 h
Yield: 90 %

Procedure:
Cis-3-[2-[2-methyl-3-[4-(aminoiminomethyl)phenyl]-isoxazolidin-5-yl] -acetyl] amino-N-(3-methylphenylsulfonyl)-L-alanine methyl ester(100 mg, 0.19 mmol) was dissolved in 3N HCl(3 ml). The resulting solution was stirred at rt for 36 hrs and then concentrated to yield the acid as an amorphous solid(90 mg, 90% yield). The acid was further purified by reverse HPLC using water and 0.1% TFA in acetonitrile as eluent. 1H NMR(300 MHz, DMSO-d6)δ2.24(m, 1H), 2.38(s, 3H), 2.54(s, 3H), 2.60(m, 1H), 2.98(m, 1H), 3.08(m, 1H), 3.22(m,1H), 3.36(m, 1H), 3.86(m, 1H), 4.40(m,1H), 4.74(m, 1H), 7.43(m, 2H), 7.38(m, 2H), 7.80(d, J=7, 1H), 7.94(d, J=7, 2H), 8.20(m, 2H); MS(ESI) Calc. for (M+1)+ : 504. Found: 504.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].Cl[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]([NH:21][C:22]2[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=2)[N:12]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]([NH:21][C:22]2[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=2)[N:12]=1
Reactant: COc1ccccc1O
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Product: COc1ccccc1Oc1nc(Nc2cc(C)[nH]n2)cc2ccccc12

Procedure:
Similar procedure as described in example 10 was used, starting from 2-methoxy-phenol and (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give [1-(2-methoxy-phenoxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 347(MH+).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:11][CH2:10][CH:9]=[CH:8][CH2:7][CH2:6]1)(=[O:4])=[O:3].ClC1C=CC=C(C(OO)=[O:20])C=1>C(Cl)Cl>[CH3:1][S:2]([N:5]1[CH2:6][CH2:7][CH:8]2[O:20][CH:9]2[CH2:10][CH2:11]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)N1CCC=CCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)(=O)N1CCC2OC2CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
11.7 g (0.067 mol) of 1-methanesulphonyl-2,3,6,7-tetrahydro-1H-azepine are dissolved in 230 ml of methylene chloride and the solution is treated with 23 g (0.13 mol) of m-chloro-perbenzoic acid in portions. A white suspension soon forms and this is stirred for a further 24 hours at room temperature. The m-chlorobenzoic acid which has precipitated is filtered off and the filtrate is washed with a saturated aqueous solution of sodium carbonate, then with aqueous iron-II sulphate solution, then with 0.1 N sodium hydroxide solution and finally with water and dried over sodium sulphate. On concentrating the solution under a water pump vacuum, while crystals of 1-methanesulphonyl-hexahydro-4,5-epoxy-1H-azepine are obtained and these are isolated by filtration; melting point 133°-134°.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]=[CH:10][CH2:11]Cl)=[N:7][CH:8]=1.[NH2:13][C:14]1[S:15][C:16]2[CH2:17][CH2:18][NH:19][CH2:20][CH2:21][C:22]=2[N:23]=1.C(O)(C)C>C(Cl)(Cl)Cl>[NH2:13][C:14]1[S:15][C:16]2[CH2:17][CH2:18][N:19]([CH2:11][CH:10]=[CH:9][C:6]3[CH:5]=[CH:4][C:3]([CH3:2])=[CH:8][N:7]=3)[CH2:20][CH2:21][C:22]=2[N:23]=1
Reactant: Nc1nc2c(s1)CCNCC2
Reactant: Cc1ccc(C=CCCl)nc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Product: Cc1ccc(C=CCN2CCc3nc(N)sc3CC2)nc1
Yield: 22 %

Procedure:
Prepared from 3-(5-methyl-2-pyridyl)allyl chloride hydrochloride and 3 equivalents of 2-amino-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine in chloroform. Yield: 22% of theory, Melting point: 172°-175° C. (isopropanol).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10](Br)[C:9]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[S:15][C:8]=2[C:7]=1[OH:23])=[O:5])[CH3:2].[CH3:24][Sn](C)(C)C>CN(C)C=O.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>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([CH3:24])[C:9]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[S:15][C:8]=2[C:7]=1[OH:23])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Br)c2nc(-c3ccc(F)cc3)sc2c1O
Reactant: C[Sn](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(C)c2nc(-c3ccc(F)cc3)sc2c1O
Temperature: 130 °C
Reaction time: 0.75 h
Yield: 56.7 %

Procedure:
A mixture of 4-bromo-2-(4-fluoro-phenyl)-7-hydroxy-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (140 mg, 0.35 mmol), tetramethyltin (98 μL, 0.70 mmol) and bis(triphenylphosphine)palladium(II) dichloride (25 mg, 0.03 mmol) in dimethylformamide (2.5 mL) was stirred at 130° C. for 45 min before it was cooled to room temperature, quenched with water, filtered. The filtrate was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and hexanes to give the title compound as a white solid (66 mg): MS: (+) m/z 333.0 (M+1).
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[C@@H:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:11]O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].S(Cl)(C)(=O)=O.CC([O-])(C)C.[K+]>C(Cl)Cl>[Si:1]([O:8][C@@H:9]([CH:10]1[CH2:11][N@@:13]1[C:14]([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:20])[CH2:21][O:22][Si:23]([C:26]([CH3:27])([CH3:29])[CH3:28])([CH3:25])[CH3:24])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)[C@@H](CO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: CS(=O)(=O)Cl
Agent: [K+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC1[C@@H](CO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of tert-butyl (2S,3S)-3,4-bis(tert-butyldimethylsilyloxy)-1-hydroxybutan-2-ylcarbamate (1.025 g, 2.3 mmol) in 20 mL DCM was cooled to 0° C., treated with N,N-DIPEA (0.60 ml, 3.4 mmol) followed by Ms-Cl (0.18 ml, 2.3 mmol). After stirring at 0° C. for 2 hours, the reaction mixture was concentrated in vacuo and the crude residue was dissolved in 20 mL THF. KOt-Bu (0.51 g, 4.6 mmol) was added, and the reaction mixture was allowed to stir at RT for 10 minutes. The reaction mixture was then diluted with EtAOc, washed with water then brine. The organics dried over MgSO4 and concentrated in vacuo. Purification of the crude residue by column chromatography gave (S)-tert-butyl 2-((S)-1,2-bis(tert-butyldimethylsilyloxy)ethyl)aziridine-1-carboxylate as a clear oil.
Reaction SMILES: CS(O[C@H:6]1[C:25]2[C@:20]([CH3:27])([CH2:21][CH2:22][C:23](=[O:26])[CH:24]=2)[C@@H:19]2[C@H:8]([C@H:9]3[C@:16]([CH3:28])([CH2:17][CH2:18]2)[C@@:12]([O:29][C:30](=[O:32])[CH3:31])([C:13](=[O:15])[CH3:14])[CH2:11][CH2:10]3)[C@H:7]1OS(C)(=O)=O)(=O)=O.[N-:38]=[N+:39]=[N-:40].[Na+].C(O)(=O)C>CO>[N:38]([C:6]1[C:25]2[C@:20]([CH3:27])([CH2:21][CH2:22][C:23](=[O:26])[CH:24]=2)[C@@H:19]2[C@H:8]([C@H:9]3[C@:16]([CH3:28])([CH2:17][CH2:18]2)[C@@:12]([O:29][C:30](=[O:32])[CH3:31])([C:13](=[O:15])[CH3:14])[CH2:11][CH2:10]3)[CH:7]=1)=[N+:39]=[N-:40]
Reactant: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3[C@@H](OS(C)(=O)=O)[C@@H](OS(C)(=O)=O)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3C=C(N=[N+]=[N-])C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C

Procedure:
In a manner similar to that described in Example 6C, treat 6β,7β-dimethanesulfonyloxy-17α-acetoxy-4-pregnene-3,20-dione with sodium azide in aqueous methanol in the presence of acetic acid. Isolate and purify the resultant product in a manner similar to that described to obtain 6-azido-17α-acetoxy-4,6-pregnadiene-3,20-dione.
Reaction SMILES: CC([O-])(C)C.[K+].C1OCCOCCOCCOCCOCCOC1.[CH3:25][O:26][N:27]=[C:28]([C:33]1[NH:34][CH:35]=[CH:36][CH:37]=1)[C:29]([O:31][CH3:32])=[O:30].[CH3:38][C:39]1[CH:46]=[CH:45][CH:44]=[CH:43][C:40]=1[CH2:41]Br>CCOCC>[CH3:25][O:26][N:27]=[C:28]([C:33]1[N:34]([CH2:38][C:39]2[CH:46]=[CH:45][CH:44]=[CH:43][C:40]=2[CH3:41])[CH:35]=[CH:36][CH:37]=1)[C:29]([O:31][CH3:32])=[O:30]
Reactant: Cc1ccccc1CBr
Reactant: CON=C(C(=O)OC)c1ccc[nH]1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Product: CON=C(C(=O)OC)c1cccn1Cc1ccccc1C
Reaction time: 0.5 h
Yield: 52.1 %

Procedure:
4 g (35.7 mmol) of potassium tert-butylate are added to a solution of 730 mg (2.7 mmol) of 18-crown-6 in 50 ml of ether, after which a solution of 5 g (27.5 mmol) of the pyrrole from Example 18 in 50 ml of ether are added dropwise and stirring is carried out for 30 minutes at room temperature. Thereafter, a solution of 6.6 g (37.5 mmol) of o-methylbenzyl bromide in 25 ml of ether is added and stirring is carried out overnight at room temperature. The mixture is poured onto water and extracted with ether, and the organic phase is dried and evaporated down. Chromatography over silica gel using hexane/ethyl acetate gives 4.1 g (52%) of the product as a yellow oil.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=1[F:17].[CH2:18](Cl)Cl.C[Zn]C>O1CCOCC1.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]>[F:17][C:8]1[CH:9]=[C:10]([C:13]([F:16])([F:15])[F:14])[CH:11]=[CH:12][C:7]=1[C:6]1[O:5][CH:4]=[N:3][C:2]=1[CH3:18]
Reactant: ClCCl
Reactant: Fc1cc(C(F)(F)F)ccc1-c1ocnc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: C[Zn]C
Solvent: C1COCCO1
Product: Cc1ncoc1-c1ccc(C(F)(F)F)cc1F
Temperature: 25 °C
Yield: 2596.4 %

Procedure:
A mixture of Example 5B (4.58 g, 14.8 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II), 1:1 complex with CH2Cl2 (0.362 g, 0.443 mmol) in dioxane (49 mL) was treated carefully with dimethyl zinc (2M in toluene, 14.8 mL, 29.6 mmol). The reaction was heated to reflux for 2 hours, then cooled to room temperature and carefully quenched with a few milliliters of methanol. The mixture was diluted with ether and washed twice with 1N HCl and once with brine. The organic phase was dried over Na2SO4 and evaporated, then chromatographed (5 to 15% ethyl acetate-hexane) to afford the title compound as an orange oil (2.82 g, 78% yield). 1H NMR (300 MHz, DMSO-d6) δ 8.52 (s, 1H), 7.87 (m, 2H), 7.74 (m, 1H), 2.27 (s, 3H). MS (DCI+) m/z 246 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH2:31])[C:5]([NH:8][CH:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=3)=[C:13]([O:29][CH3:30])[CH:12]=2)[CH3:10])=[CH:6][CH:7]=1.Cl[CH2:33]C1C=CC(C(F)(F)F)=NC=1.C(OCC)(OCC)OCC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[I:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]([CH:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]4[CH:20]=[N:21][C:22]([C:25]([F:26])([F:28])[F:27])=[CH:23][CH:24]=4)=[C:13]([O:29][CH3:30])[CH:12]=3)[CH3:10])[CH:33]=[N:31][C:4]=2[CH:3]=1
Reactant: FC(F)(F)c1ccc(CCl)cn1
Reactant: COc1cc(C(C)Nc2ccc(I)cc2N)ccc1OCc1ccc(C(F)(F)F)nc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Solvent: CCOC(OCC)OCC
Product: COc1cc(C(C)n2cnc3cc(I)ccc32)ccc1OCc1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
To stirred solution of 4-iodo-N1-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)ethyl)benzene-1,2-diamine [prepared from 5-(chloromethyl)-2-(trifluoromethyl)pyridine using the procedures described in Example 3-45-1 through Example 3-45-5] (1.04 g, 1.91 mmol) in ethanol (30 mL) was added triethyl orthoformate (1.0 mL, 5.89 mmol) and p-toluenesulfonic acid monohydrate (0.025 g, 0.13 mmol). The yellow solution was heated to reflux. After 30 min, the mixture was allowed to cool to room temperature and was concentrated to provide a yellow oil. Chromatographic purification (CombiFlash, 24 g SiO2 gold column, 1-5% methanol/dichloromethane elute) afforded 0.803 g (76%) of 5-iodo-1-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)ethyl)-1H-benzo[d]imidazole as a yellow solid.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH:6]=[O:7])[N:3]=[CH:2]1.[H-].[Na+].Br[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O1CCCC1>[C:13]1([CH2:12][CH2:11][N:1]2[CH:5]=[C:4]([CH:6]=[O:7])[N:3]=[CH:2]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1c[nH]cn1
Reactant: BrCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=Cc1cn(CCc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Imidazole-4-carboxaldehyde (6.73 g, 70 mmol) was added portionwise to a suspension of sodium hydride (1.68 g, 60% dispersion in mineral oil, 70 mmol) in tetrahydrofuran (280 ml), and the mixture was then stirred at room temperature for 30 minutes. (2-Bromoethyl)benzene (9.56 ml, 70 mmol) was added, and the mixture was stirred at room temperature for 72 hours. The mixture was evaporated under reduced pressure and the residue was partitioned between water (300 ml) and dichloromethane (500 ml), and the layers were separated. The organic phase was dried (MgSO4) and evaporated under reduced pressure. The crude product was pre-adsorbed onto silica gel, and purified by column chromatography on silica gel using an elution gradient of ethyl acetate:pentane (50:50 to 100:0) to afford the title compound, 1.44 g. 1H-NMR (CDCl3, 400 MHz) δ: 3.16 (t, 2H), 4.23 (t, 2H), 7.02 (d, 2H), 7.28 (m, 3H), 7.36 (s, 1H), 7.50 (s, 1H), 9.83 (s, 1H). LRMS: m/z (ES+) 223 [MNa+].