Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[N+:9]([O-])[CH:10]=1.C(Cl)(=O)C1C=CC=CC=1.C[Si]([C:30]#[N:31])(C)C.CCOC(C)=O.CCCCCC>C(Cl)Cl>[CH3:1][O:2][CH2:3][O:4][C:5]1[C:10]([C:30]#[N:31])=[N:9][C:8]([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:7][CH:6]=1
Reactant: C[Si](C)(C)C#N
Reactant: COCOc1ccc(CC(C)(C)C)[n+]([O-])c1
Solvent: ClCCl
Solvent: CCCCCC
Solvent: O=C(Cl)c1ccccc1
Product: COCOc1ccc(CC(C)(C)C)nc1C#N
Reaction time: 4 h
Yield: 73.6 %

Procedure:
5-(Methoxymethoxy)-2-neopentylpyridine-N-oxide (11.5 g, 51 mmol) was dissolved in CH2Cl2 (50 mL) to which benzoyl chloride (12 ml, 102 mmol) and (trimethylsilyl)formonitrile (14 ml, 102 mmol) were added. The mixture was stirred under N2 4 h, quenched with saturated NaHCO3 (150 mL), and extracted with CH2Cl2 (3×100 mL). The combined organic layers were washed with saturated NaHCO3 (2×50 mL), dried (MgSO4), and evaporated to give the crude product as a brown oil, which was purified by ISCO (330 g SiO2, O-40% EtOAc/Hexane) to give 3-(methoxymethoxy)-6-neopentylpicolinonitrile (8.8 g, 74% yield) as a clear oil.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][OH:7].[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17](F)[C:14]=1[C:15]#[N:16]>CN(C=O)C>[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([O:7][CH2:6][C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[Br:3])[C:14]=1[C:15]#[N:16]
Reactant: OCc1ccccc1Br
Reactant: N#Cc1c(F)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1c(F)cccc1OCc1ccccc1Br
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 83 %

Procedure:
To a cold (ice water) suspension of sodium hydride (222 mg; 5.0 mmol) in anhydrous DMF (4 mL) is added a solution of 2-bromobenzyl alcohol (941 mg; 5.0 mmol) in anhydrous DMF (5 mL) over 10 minutes. After allowing to room temperature over 45 minutes, this solution is added to a cold (ice water) stirred solution of 2,6-difluorobenzonitrile (703 mg; 5.0 mmol) in anhydrous DMF (3 mL), and allowed to room temperature over 4 hours. The reaction mixture is poured into ice water with vigorous stirring and the resulting solid is filtered, washed with water, and dried under vacuum at 40° C. for 3 hours to give 1.27 grams of 2-fluoro-6-(2-bromobenzyloxy)-benzonitrile.
Reaction SMILES: [H-].[Na+].[CH:3]([O:6][C:7]([N:9]1[CH2:14][CH2:13][CH:12]([O:15][N:16]=[C:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[C:27]([F:29])[C:26]([CH2:30][OH:31])=[CH:25][C:24]=3[F:32])[CH2:19][CH2:18]2)[CH2:11][CH2:10]1)=[O:8])([CH3:5])[CH3:4].CI.[CH3:35]C(OC)(C)C>CN(C=O)C.CO>[CH:3]([O:6][C:7]([N:9]1[CH2:14][CH2:13][CH:12]([O:15][N:16]=[C:17]2[CH2:18][CH2:19][N:20]([C:23]3[CH:28]=[C:27]([F:29])[C:26]([CH2:30][O:31][CH3:35])=[CH:25][C:24]=3[F:32])[CH2:21][CH2:22]2)[CH2:11][CH2:10]1)=[O:8])([CH3:5])[CH3:4]
Reactant: CC(C)OC(=O)N1CCC(ON=C2CCN(c3cc(F)c(CO)cc3F)CC2)CC1
Reactant: COC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CO
Solvent: CN(C)C=O
Product: COCc1cc(F)c(N2CCC(=NOC3CCN(C(=O)OC(C)C)CC3)CC2)cc1F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
NaH (60%, 10 mg, 0.25 mmol) was added to a solution of 48-1 (36 mg, 0.085 mmol) in 0.3 mL of DMF at 0° C. After 10 minutes, methyl iodide in MTBE (2M, 0.6 mL, 1.2 mmol) was added and the reaction was stirred at room temperature for 2 h. The mixture was quenched with water (2 mL) and extracted with 1 mL of ethyl acetate. The organic extract was dried under a stream of nitrogen and the residue was purified by preparative TLC(eluent: 30% EtOAc in hexane) to afford 49-1: LC-MS 408.1 (MH+-MeOH), tR=8.77 (Method 2). EC50: 265 nM.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=2)[NH:12][CH:11]=[C:10]3[CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[O:32]=[C:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35](=[O:42])[N:34]1[CH2:43][CH2:44][S:45](Cl)(=[O:47])=[O:46]>C(Cl)Cl>[O:42]=[C:35]1[C:36]2[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:33](=[O:32])[N:34]1[CH2:43][CH2:44][S:45]([N:22]1[CH2:23][CH2:24][CH:19]([C:10]2[C:9]3[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:8]=3)[NH:12][CH:11]=2)[CH2:20][CH2:21]1)(=[O:47])=[O:46]
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCNCC3)c[nH]c12
Reactant: O=C1c2ccccc2C(=O)N1CCS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CCN4C(=O)c5ccccc5C4=O)CC3)c[nH]c12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
To a solution of 5-phenyl-3-(4-piperidinyl)-1H-indole-7-carboxamide (84.8 mg, 0.265 mmol) in CH2Cl2 at 0° C., triethylamine (0.15 mL, 1.06 mmol) and 2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethanesulfonyl chloride (87.03 mg, 0.32 mmol) were added. The reaction mixture was stirred at 0° C. for 30 min. The reaction mixture was partitioned between CH2Cl2 and water. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (2×). The combined organic phase washed with brine, dried over magnesium sulfate and filtered. The solvent was removed under reduced pressure to give the crude product (90 mg, 61%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].C(O)C.[CH3:8][N:9]([CH3:43])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[O:26][C:27](=[O:42])/[C:28](=[CH:30]/[C:31]4[CH:36]=[CH:35][C:34]([O:37][C:38]([F:41])([F:40])[F:39])=[CH:33][CH:32]=4)/[N:29]=3)=[CH:21][CH:20]=2)=[CH:12][CH:11]=1>CO>[CH3:8][N:9]([CH3:43])[C:10]1[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([NH:29]/[C:28](/[C:27]([NH:1][CH2:2][CH2:3][OH:4])=[O:42])=[CH:30]\[C:31]3[CH:32]=[CH:33][C:34]([O:37][C:38]([F:40])([F:39])[F:41])=[CH:35][CH:36]=3)=[O:26])=[CH:21][CH:20]=2)=[CH:14][CH:15]=1
Reactant: NCCO
Reactant: CN(C)c1ccc(CCOc2ccc(C3=N/C(=C\c4ccc(OC(F)(F)F)cc4)C(=O)O3)cc2)cc1
Solvent: CCO
Solvent: CO
Product: CN(C)c1ccc(CCOc2ccc(C(=O)N/C(=C\c3ccc(OC(F)(F)F)cc3)C(=O)NCCO)cc2)cc1
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 63.6 %

Procedure:
2-Aminoethanol (57 μL, 0.944 mmol) was added to a solution of ethanol (0.5 mL) containing (4Z)-2-(4-{2-[4-(dimethylamino)phenyl]ethoxy}phenyl)-4-[4-(trifluoromethoxy)benzylidene]-1,3-oxazol-5(4H)-one (234 mg, 0.471 mmol) prepared in Example 23 (23c). The mixture was stirred at 60° C. for 2.5 hours, and then the solvent was evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:methanol, 50:1, v/v) to give 167 mg of the title compound (white amorphous solid, yield: 64%).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[N:5][N:6]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:7]=1.CCN(C(C)C)C(C)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>CC#N>[Br:2][C:3]1[CH:4]=[N:5][N:6]([CH:8]2[CH2:13][CH2:12][N:11]([S:24]([CH3:23])(=[O:26])=[O:25])[CH2:10][CH2:9]2)[CH:7]=1
Reactant: Brc1cnn(C2CCNCC2)c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CS(=O)(=O)N1CCC(n2cc(Br)cn2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.2 %

Procedure:
To a solution of 4-(4-bromopyrazol-1-yl)piperidine hydrochloride (380 mg, 1.43 mmol) in CH3CN (10 ml) at 0° C. was added DIPEA (0.75 mlml, 4.3 mmol) followed by methanesulphonyl chloride (0.11 ml, 1.43 mmol), stirred at 0° C. for 1 hour then allowed to warm up to RT over 1 hour. The reaction then partitioned between water and EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to give the product (380 mg), which was used without further purification 1H NMR (400 MHz, Me-d3-OD): 7.84 (1H, s), 7.50 (1H, s), 4.40-4.27 (1H, m), 3.86 (2H, d), 3.05-2.93 (2H, m), 2.90 (3H, s), 2.25-2.01 (4H, m).
Reaction SMILES: [S:1](=[O:33])(=[O:32])([O:3][CH2:4][C@@H:5]1[CH2:9][C@@H:8]([N:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([NH:19][CH2:20][CH:21]4[CH2:23][CH2:22]4)[C:13]=3[CH:12]=[CH:11]2)[CH2:7][C@@H:6]1[O:24][Si](C(C)(C)C)(C)C)[NH2:2]>C1COCC1.N1C=CC=CC=1.F.N1C=CC=CC=1>[S:1](=[O:32])(=[O:33])([O:3][CH2:4][C@@H:5]1[CH2:9][C@@H:8]([N:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([NH:19][CH2:20][CH:21]4[CH2:22][CH2:23]4)[C:13]=3[CH:12]=[CH:11]2)[CH2:7][C@@H:6]1[OH:24])[NH2:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](n2ccc3c(NCC4CC4)ncnc32)C[C@H]1COS(N)(=O)=O
Agent: F
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: NS(=O)(=O)OC[C@@H]1C[C@@H](n2ccc3c(NCC4CC4)ncnc32)C[C@@H]1O
Reaction time: 3 h
Yield: 4.4 %

Procedure:
((1S,2S,4R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-4-{4-[(cyclopropylmethyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)methyl sulfamate (88.0 mg, 0.178 mmol) was dissolved in THF (1.00 mL) and pyridine (3.00 mL). Pyridine hydrofluoride (12 drops) was added and the reaction was stirred for 3 h. The reaction was quenched using saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted with EtOAc (3×10 mL), and the combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 5% MeOH in DCM. The compound was re-purified via silica gel chromatography eluting with 10% MeOH in DCM to afford the title compound (3.00 mg, 4.4%). 1H NMR (400 MHz, CD3OD, δ): 8.05 (s, 1H), 7.15 (d, J=3.6 Hz, 1H), 6.59 (d, J=3.6 Hz, 1H), 5.45-5.32 (m, 1H), 4.56 (br s, 1H), 4.45 (br s, 1H), 4.33 (dd, J=7.6, 7.6 Hz, 1H), 4.15 (dd, J=7.4, 7.4 Hz, 1H), 3.34 (d, J=6.9 Hz, 2H), 2.83-2.68 (m, 1H), 2.35-2.08 (m, 3H), 2.05-1.93 (m, 1H), 1.33-1.03 (m, 3H), 0.93-0.77 (m, 1H) ppm. LC/MS: Rt=0.85 min, ES+ 382 (FA standard).
Reaction SMILES: [CH:1]1([CH:6]2[C:15]3[C:14](=[O:16])[CH2:13][C:12]([CH3:18])([CH3:17])[CH2:11][C:10]=3[NH:9][C:8](=[O:19])[CH:7]2[C:20]#[N:21])[CH2:5][CH2:4][CH2:3][CH2:2]1>C(#N)C.O.ClCCl>[CH:1]1([C:6]2[C:15]3[C:14](=[O:16])[CH2:13][C:12]([CH3:17])([CH3:18])[CH2:11][C:10]=3[NH:9][C:8](=[O:19])[C:7]=2[C:20]#[N:21])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC1(C)CC(=O)C2=C(C1)NC(=O)C(C#N)C2C1CCCC1
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: CC1(C)CC(=O)c2c([nH]c(=O)c(C#N)c2C2CCCC2)C1
Temperature: 60 °C

Procedure:
11.0 g 4-Cyclopentyl-7,7-dimethyl-2,5-dioxo-1,2,3,4,5,6,7,8-octahydro-quinoline-3-carbonitrile are suspended in 160 ml acetonitrile, heated to 60° C. and mixed dropwise with a solution of 85 g ammonium cer-(IV)-nitrate in 80 ml water. After heating for 1 h the mixture is diluted with 1200 ml dichloromethane and vigorously stirred. The aqueous bottom phase is discarded and the organic phase is washed successively with saturated sodium bicarbonate and brine. After drying with magnesium sulphate the solvents are evaporated in vacuo and the residue is triturated with diethylether. The solid is isolated by filtration, washed with diethylether and dried in vacuo.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.CO.[S:13]([O-])([O-:16])(=[O:15])=[S:14].[Na+].[Na+].S(OOS([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+]>O>[NH2:9][C:6]1[CH:7]=[CH:8][C:3]([N:2]([CH3:10])[CH3:1])=[CH:4][C:5]=1[S:13]([OH:16])(=[O:15])=[S:14]
Reactant: CN(C)c1ccc(N)cc1
Reactant: O=S([O-])([O-])=S
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN(C)c1ccc(N)c(S(=O)(O)=S)c1
Temperature: 5 °C
Reaction time: 3 h

Procedure:
N′,N′-dimethyl-p-phenylene diamine (10 g, 0.0735 mols) was added to a round bottom flask. To this was added de-ionised water (160 ml) and methanol (40 ml) and the solution was then cooled to 5° C. Sodium thiosulfate (20 g, 0.0808 mols) in water (20 ml) was added to the solution in one aliquot. Sodium persulfate (17.5 g, 0.0735 mols) in water (40 ml) was added drop-wise over a 15 minute period. The reaction mixture was stirred for 3 hours at 5° C. and then warmed to 22° C. over a period of 1 hour. The dark solid which precipitated was collected via filtration. The black solid was washed with water (50 ml) then dried at 40° C. for 16 hours, 7.88 g (43%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:24])[CH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:23])[CH2:20][CH2:21][NH2:22])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1.CCN=C=NCCCN(C)C.[Cl:36][C:37]1[CH:42]=[C:41]([Cl:43])[CH:40]=[CH:39][C:38]=1[C:44]1[O:45][C:46]([C:52]([F:55])([F:54])[F:53])=[C:47]([C:49](O)=[O:50])[N:48]=1.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)C(C)C)C>ClCCl.C([O-])(O)=O.[Na+]>[CH3:2][O:3][C:4](=[O:24])[CH2:5][C@H:6]1[CH2:7][CH2:8][C@H:9]([C:12]2[CH:13]=[CH:14][C:15]([NH:18][C:19](=[O:23])[CH2:20][CH2:21][NH:22][C:49]([C:47]3[N:48]=[C:44]([C:38]4[CH:39]=[CH:40][C:41]([Cl:43])=[CH:42][C:37]=4[Cl:36])[O:45][C:46]=3[C:52]([F:55])([F:54])[F:53])=[O:50])=[CH:16][CH:17]=2)[CH2:10][CH2:11]1
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)CCN)cc2)CC1
Reactant: O=C(O)c1nc(-c2ccc(Cl)cc2Cl)oc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)CCNC(=O)c3nc(-c4ccc(Cl)cc4Cl)oc3C(F)(F)F)cc2)CC1
Reaction time: 24 h

Procedure:
A mixture of trans-{4-[4-(3-aminopropionylamino)phenyl]cyclohexyl}acetic acid methyl ester HCl salt (60 mg, 0.17 mmol), EDCI (81 mg, 0.42 mmol), 2-(2,4-dichloro-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid (66.14 mg, 0.2 mmol), HOBt (34.27 mg, 0.25 mmol) and ethyldiisopropylamine (76.7 mg, 0.6 mmol) dissolved in dichloromethane solvent (10 mL) were stirred for 24 hours. The reaction mixture was diluted with aqueous NaHCO3 and extracted with dichloromethane. The extract was washed with brine and dried with anhydrous sodium sulfate and concentrated under vacuum. The residue was purified with silica gel column chromatography to obtain the desired compound (80 mg, 75%) as a white solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:30]=[CH:29][C:9]([O:10][C:11]3[CH:16]=[CH:15][C:14]([S:17]([CH:20]4[CH:25]([C:26]([OH:28])=O)[NH:24][CH2:23][CH2:22][S:21]4)(=[O:19])=[O:18])=[CH:13][CH:12]=3)=[CH:8][CH:7]=2)=[CH:2]1.[Si](O[NH2:49])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.C(Cl)CCl>ClCCl>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:30]=[CH:29][C:9]([O:10][C:11]3[CH:12]=[CH:13][C:14]([S:17]([CH:20]4[CH:25]([C:26]([NH2:49])=[O:28])[NH:24][CH2:23][CH2:22][S:21]4)(=[O:18])=[O:19])=[CH:15][CH:16]=3)=[CH:8][CH:7]=2)=[CH:2]1
Reactant: O=C(O)C1NCCSC1S(=O)(=O)c1ccc(Oc2ccc(-c3ccoc3)cc2)cc1
Reactant: CC(C)(C)[Si](ON)(c1ccccc1)c1ccccc1
Solvent: ClCCCl
Solvent: ClCCl
Product: NC(=O)C1NCCSC1S(=O)(=O)c1ccc(Oc2ccc(-c3ccoc3)cc2)cc1
Reaction time: 18 h
Yield: 14.5 %

Procedure:
To a solution of 3(S)-4-(4-(4-(furan-3-yl)phenoxy)benzenesulfonyl-tetrahydro-2H-1,4-thiazine-3-carboxylic acid (293 mg, 0.62 mmol) and O-(tert-butyldiphenylsilyl)hydroxylamine (0.22 g, 0.8 mmol) in 5 mL of dichloromethane was added EDC (132 mg, 0.69 mmol). After 18 hours at 25° C., the mixture was partitioned between 1 N aq. sodium bisulfate and dichloromethane. The aqueous layer was extracted twice with dichloromethane, and the combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by chromatography on silica gel, eluting with a gradient from dichloromethane to 5% methanol in dichloromethane, to provide 3(S)-N-(tert-butyldiphenylsilyl)oxy-4-(4-(4-(furan-3-yl)phenoxy)benzenesulfonyl-tetrahydro-2H-1,4-thiazine-3-carboxamide (40 mg, 8%). FAB+MS Calcd for M+Cs+=859.1308 Obs 859.1274; 1HNMR (d6-DMSO): δ 10.81 (s, 1H), 8.17 (s, 1H), 7.74 (s, 1H), 7.67-7.61 (m, 8H), 7.45-7.30 (m, 6H), 7.10 (d, 2H, J=8.83 Hz), 7.00 (d, 2H, J=8.46 Hz), 6.94 (s, 1H), 4.06 (s, 1H), 3.95-3.89 (bm, 1H), 3.77-3.73 (bm, 1H), 2.87-2.78 (bm, 1H), 1.28 (s, 3H), 0.99 (s, 9H), 0.61 (s, 3H)
Reaction SMILES: N#N.[Cl:3][C:4]1[CH:9]=[CH:8][N:7]2[C:10](I)=[CH:11][N:12]=[C:6]2[CH:5]=1.[OH:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>>[Cl:3][C:4]1[CH:9]=[CH:8][N:7]2[C:10]([C:19]3[CH:20]=[CH:21][C:16]([CH2:15][OH:14])=[CH:17][CH:18]=3)=[CH:11][N:12]=[C:6]2[CH:5]=1
Reactant: Clc1ccn2c(I)cnc2c1
Reactant: OCc1ccc(B(O)O)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Product: OCc1ccc(-c2cnc3cc(Cl)ccn23)cc1

Procedure:
Charge a 50 mL round bottom flask equipped with: a magnetic stirrer, temperature controlled heating mantle, N2 atmosphere, condenser, with 7-chloro-3-iodo-imidazo[1,2-a]pyridine (1.0 g, 3.6 mmol), 4-(hydroxymethyl)phenyl boronic acid (570 mg, 3.75 mmol), 2 M K2CO3 (7 mL), dimethoxy ethane DME (25 mL). Deoxygenate with a nitrogen purge and add Pd(TPP)4 (200 mg, 0.17 mmol 5 mol %) and heat the reaction to 65° C. for 48 hours. Cool the reaction and siphon off the lower aqueous phase (5 mL). Evaporate the reaction under vacuum at 42° C. to remove DME. Take up the residue in CH2Cl2 and wash with water (15 mL). Concentrate the CH2Cl2 and chromatograph giving an oil that solidified on standing to an ivory solid 670 mg (72%) MS (ES), m/z 259.1 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][C@@H:17]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[C:34]([Cl:39])[CH:35]=3)[N:30]=2)=[CH:24][CH:23]=1)[C:18]([OH:20])=[O:19]>CS(C)=O>[C:18]([C@@H:17]([NH:16][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[C:34]([Cl:39])[CH:35]=3)[N:30]=2)=[CH:26][CH:27]=1)([OH:20])=[O:19]
Reactant: N[C@@H](Cc1ccc(Oc2ccc3cc(Cl)ccc3n2)cc1)C(=O)O
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Solvent: CS(C)=O
Product: O=C(O)c1cc2cc(Cl)ccc2nc1N[C@@H](Cc1ccc(Oc2ccc3cc(Cl)ccc3n2)cc1)C(=O)O

Procedure:
In close analogy to the procedure described in Example 109c, 2,6-dichloroquinoline-3-carboxylic acid is reacted with (S)-2-amino-3-[4-(6-chloro-quinolin-2-yloxy)-phenyl]-propionic acid (prepared by analogy to Example 109a,b) in DMSO to provide the title compound in good yield.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][CH:15]3[CH2:17][CH2:16]3)=[N:6][CH:7]=[C:8]([CH:12]=2)[C:9]([OH:11])=O)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl.[F:50][C:51]1[CH:56]=[CH:55][C:54]([N:57]([CH3:59])[NH2:58])=[CH:53][CH:52]=1>CN(C=O)C.O1CCCC1>[F:50][C:51]1[CH:56]=[CH:55][C:54]([N:57]([CH3:59])[NH:58][C:9](=[O:11])[C:8]2[CH:12]=[C:4]([CH:1]3[CH2:2][CH2:3]3)[C:5]([O:13][CH2:14][CH:15]3[CH2:17][CH2:16]3)=[N:6][CH:7]=2)=[CH:53][CH:52]=1
Reactant: CN(N)c1ccc(F)cc1
Reactant: O=C(O)c1cnc(OCC2CC2)c(C2CC2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(NC(=O)c1cnc(OCC2CC2)c(C2CC2)c1)c1ccc(F)cc1
Reaction time: 8 h
Yield: 97.5 %

Procedure:
In a 10 mL two-necked flask, the above prepared 5-cyclopropyl-6-cyclopropylmethoxy-nicotinic acid (70 mg, 300 μmol, Eq: 1.00) was combined with tetrahydrofuran (3 mL) and DMF (1 mL) to give a colorless solution. TBTU (145 mg, 450 μmol, Eq: 1.5) and N,N-diisopropylethylamine (194 mg, 262 μl, 1.5 mmol, Eq: 5) were added and the reaction mixture stirred for 10 min at rt, before 1-(4-fluorophenyl)-1-methylhydrazine hydrochloride (63.6 mg, 360 μmol, Eq: 1.2, CAN 1978-54-7) was added and the reaction mixture kept overnight at rt. The reaction mixture was quenched with 1 M HCl (10 mL) and extracted with EtOAc (2×20 mL). The organic layers were washed with 1 M NaOH, then with H2O/NaCl solution, combined, dried over Na2SO4 and concentrated in vacuo. The crude material was eventually purified by flash chromatography (silica gel, 20 g, 15% to 40% EtOAc in heptane) to provide 104 mg of the title product as colorless oil; MS (EI) 354.6 (M−H)−.
Reaction SMILES: C[Mg+].[Br-].[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5]1.[Cl:13][C:14]1[N:19]=[C:18](Cl)[C:17]([Cl:21])=[CH:16][N:15]=1.C(O)(=O)C>C1COCC1.O>[Cl:13][C:14]1[N:19]=[C:18]([C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[NH:4][CH:5]=2)[C:17]([Cl:21])=[CH:16][N:15]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: C[Mg+]
Agent: [Br-]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: Clc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Temperature: 1 °C
Reaction time: 0.5 h
Yield: 71.2 %

Procedure:
CH3MgBr (3.2M in 2-methyltetrahydrofuran, 3.37 mL, 10.79 mmol) was added dropwise over 10 minutes to a solution of indole (1.28 g, 10.79 mmol) in THF (6 mL) at 0° C. The solution was then stirred at 0-2° C. for 0.5 h. 2,4,5-Trichloropyrimidine (1 g, 5.40 mmol) was then added dropwise, resulting in a yellow solution. The ice bath was removed, then the solution was stirred at r.t. for 1 h, resulting in a red solution. The mixture was heated to 60° C. and then stirred at 60° C. for 1.5 h. The mixture was then cooled to r.t. and acetic acid (634 μL, 11.06 mmol) was added dropwise. Water (9.90 mL) and THF (2 mL) were added, then the mixture was stirred for 20 minutes at 60° C., resulting in a bi-phasic solution. The layers were separated and heptane (11 mL) was added to the organic solution, resulting in the crystallisation of a solid. The solid was collected by filtration, washed with heptane (2 mL), and dried in a vacuum oven to give the title compound (1.015 g, 66%) as a yellow solid; 1H NMR: 7.24-7.32 (2H, m), 7.55-7.58 (1H, m), 8.52-8.55 (1H, m), 8.71-8.73 (2H, m), 12.24 (1H, s); m/z: ES+ MH+ 264, 266.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)=[CH:9][C:8]=1[O:22][CH3:23])(=O)=O.O.C([O-])([O-])=O.[K+].[K+].[N:33]1[CH:38]=[CH:37][CH:36]=[C:35](B(O)O)[CH:34]=1>CN(C=O)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[Br-].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>[CH3:23][O:22][C:8]1[CH:9]=[C:10]([C:13]2[O:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)[CH:11]=[CH:12][C:7]=1[C:35]1[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=1
Reactant: OB(O)c1cccnc1
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1OS(=O)(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(-c2nc3ccccc3o2)ccc1-c1cccnc1
Temperature: 75 °C

Procedure:
The solution of 4-(1,3-benzoxazol-2-yl)-2-methoxyphenyl trifluoromethanesulfonate (148 mg, 0.4 mmol) in 6 mL of 2:1 DMF:H2O was degassed via Argon for 10 min. Then K2CO3 (137 mg, 0.99 mmol), Pd(Ph3P)4 (23 mg, 0.02 mmol), n-Bu4NBr (128 mg, 0.40 mmol) and 3-Pyridylboronic acid (73 mg, 0.60 mmol) were added at 22° C. The resulting mixture was then heated at 75° C. for 1 h under Argon. Cooled the reaction mixture to 22° C., then filtered through a pad of Celite. The filtrate was concentrated under reduced pressure to give after purification by flash chromatography (silica gel, 3:1; hexanes:EtOAc) the desired compound as a yellow solid. 1H NMR (CDCl3, 300 MHz) δ 8.83 (d, 1H), 8.60 (dd, 1H), 7.92 (m, 3H), 7.81 (m, 1H), 7.62 (m, 1H), 7.48 (d, 1H), 7.39 (m, 3H), 3.98 (s, 3H). MS (ESI) 303 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CN(C)[P:15](N(C)C)N(C)C.Cl.CNC>C1(C)C=CC=CC=1>[N:1]12[P:15]3[N:4]([CH2:5][CH2:6][N:7]3[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]1)[CH2:3][CH2:2]2
Reactant: CN(C)P(N(C)C)N(C)C
Reactant: C1CNCCNCCNCCN1
Agent: CNC
Agent: Cl
Solvent: Cc1ccccc1
Product: C1CN2CCN3CCN(CCN1)P23
Yield: 100 %

Procedure:
A solution of 1.75 g of 1,4,7,10-tetraazacyclododecane and 1.63 g of hexamethylphosphorous triamide in 50 ml of toluene is refluxed for 12 hours. Titration of the off-gases with 1 N HCl indicates that 97% of the theoretical amount of dimethylamine is evolved in this time. The toluene is removed under reduced pressure to give 2.0 g of 1,4,7,10-tetraaza-13-phosphatricyclo[5.5.1.04,13 ]tridecane as a white solid which melts at 109°-111° C with sintering from 90° C (possibly because of the presence of a trace of toluene). Sublimation of this product at 75° C and 0.55 mm gives large colorless crystals, which melt at 111°-113° C. The mass spectrum shows an M+ ion at 200; measured mass, 200.1194; calc'd, 200.1190.