Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:6]2[C:13](=[O:17])[NH:14][CH2:15][CH2:16][C:5]1=2.Cl[CH2:19][C:20]1[O:24][CH:23]=[N:22][C:21]=1[CH3:25].O>COCCOC>[CH3:3][N:4]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:6]2[C:13](=[O:17])[N:14]([CH2:19][C:20]3[O:24][CH:23]=[N:22][C:21]=3[CH3:25])[CH2:15][CH2:16][C:5]1=2
Reactant: Cn1c2c(c3ccccc31)C(=O)NCC2
Reactant: Cc1ncoc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ncoc1CN1CCc2c(c3ccccc3n2C)C1=O
Reaction time: 5 h
Yield: 13.6 %

Procedure:
Sodium hydride (60% dispersion in oil; 600 mg) was added to a stirred suspension of 2,3,4,5-tetrahydro-5-methyl-1H-pyrido[4,3-b]indol-1-one (1.5 g) in dry DME (150 ml) and then the mixture was stirred at 60° for 5 h under nitrogen. 5-Chloromethyl-4-methyloxazole (1.2 g) was added and the mixture was stirred overnight. A further quantity of sodium hydride (60% dispersion in oil; 600 mg) was added and the mixture was stirred at 60° for 4 h, then cautiously treated with water (100 ml). The mixture was extracted with dichloromethane containing methanol (ca. 1%) (3×100 ml) and the combined extracts were evaporated. The residue was purified by FCC eluting with System A (100:8:1) to give the title compound (300 mg) as a solid, t.l.c. (System A, 100:8:1) Rf 0.4.
Reaction SMILES: [CH2:1]([C:5]1[C:9](/[CH:10]=[CH:11]/[C:12]2[S:13][C:14]([C:18]([OH:20])=O)=[C:15]([CH3:17])[N:16]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[F:22][C:23]([F:27])([F:26])[CH2:24][NH2:25]>>[F:22][C:23]([F:27])([F:26])[CH2:24][NH:25][C:18]([C:14]1[S:13][C:12](/[CH:11]=[CH:10]/[C:9]2[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6][O:7][C:8]=2[CH3:21])=[N:16][C:15]=1[CH3:17])=[O:20]
Reactant: NCC(F)(F)F
Reactant: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)O)s1
Product: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)NCC(F)(F)F)s1
Yield: 68 %

Procedure:
As described for example 104, 2-[(E)-2-(3-butyl-5-methyl-isoxazol-4-yl)-vinyl]-4-methyl-thiazole-5-carboxylic acid (153 mg, 0.5 mmol) was converted, using 2,2,2-trifluoroethylamine instead of rac-2-amino-1-butanol, to the title compound (131 mg, 68%) which was obtained as a white solid after purification by chromatography (silica, 50 to 100% ethyl acetate in heptane) and recrystallization from ethyl acetate/heptane. MS: m/e=388.2 [M+H]+.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][O:9][CH2:10][C:11]([CH3:14])([OH:13])[CH3:12])[CH:5]=[CH:4][CH:3]=1.[C:15](=[O:25])([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[NH2:16].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:13][C:11]([CH3:14])([CH3:12])[CH2:10][O:9][CH2:8][C:6]1[N:7]=[C:2]([NH:16][C:15](=[O:25])[O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:3]=[CH:4][CH:5]=1
Reactant: NC(=O)OCc1ccccc1
Reactant: CC(C)(O)COCc1cccc(Br)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC(C)(O)COCc1cccc(NC(=O)OCc2ccccc2)n1
Temperature: 80 °C

Procedure:
To a flask containing 1-[(6-bromopyridin-2-yl)methoxy]-2-methylpropan-2-ol (500 mg, 1.92 mmol), benzyl carbamate (349 mg, 2.31 mmol), Pd2(dba)3 (88 mg, 0.096 mmol), Xantphos (111 mg, 0.192 mmol) and cesium carbonate (939 mg, 2.88 mmol) was added degassed dioxane (15 mL). The flask was evacuated/purged with argon 5 times. The reaction mixture was heated to 80° C. for 18 hours. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate, washed with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (0-50% ethyl acetate/hexanes, linear gradient) to afford benzyl {6-[(2-hydroxy-2-methylpropoxy)methyl]pyridin-2-yl}carbamate. MS ESI calc'd. for C18H23N2O4 [M+H]+ 331. found 331. 1H NMR (500 MHz, CDCl3) δ 7.88 (d, J=8.4 Hz, 1H), 7.69 (t, J=7.9 Hz, 1H), 7.46-7.30 (m, 5H), 7.07 (d, J=7.5 Hz, 1H), 5.22 (s, 2H), 4.57 (s, 2H), 3.39 (s, 2H), 1.24 (s, 6H).
Reaction SMILES: C1(C)C=CC(S(O[CH:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)=[O:21])=[CH:16][CH:15]=2)[C:12]#[N:13])(=O)=O)=CC=1.[Na].[SH:29][C:30]1[S:31][C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=1.O>COCCOC>[S:31]1[C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=[C:30]1[S:29][CH:11]([C:14]1[CH:15]=[CH:16][C:17]([C:20]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)=[O:21])=[CH:18][CH:19]=1)[C:12]#[N:13]
Reactant: Sc1nc2ccccc2s1
Reactant: Cc1ccc(S(=O)(=O)OC(C#N)c2ccc(C(=O)c3cccs3)cc2)cc1
Agent: [Na]
Solvent: COCCOC
Solvent: O
Product: N#CC(Sc1nc2ccccc2s1)c1ccc(C(=O)c2cccs2)cc1
Reaction time: 0.5 h
Yield: 67 %

Procedure:
1.191 g of O-(p-toluenesulfonyl)-p-(2-thienylcarbonyl)mandelonitrile was dissolved in 5 ml of DME, and the solution was stirred in an argon atmosphere under ice cooling. Sodium salt of 2-mercaptobenzothiazole (567 mg) was added, and the mixture was stirred under ice cooling for 45 minutes, and then at room temperature for 30 minutes. Water (30 ml) was added, and the mixture was extracted with 30 ml of methylene chloride three times. The extract was washed with 20 ml of water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography (silica gel; methylene chloride) to afford 788 mg (yield 67%) of alpha-(2-benzothiazolylthio)[p-(2-thienylcarbonyl)phenyl] acetonitrile as a viscous oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][CH3:14])[C:5]([OH:7])=O.C(OC1C=C(C2O[N:32]=[C:31]([C:34]3[CH:42]=[CH:41][CH:40]=[C:39]4[C:35]=3[CH:36]=[CH:37][NH:38]4)[N:30]=2)C=CC=1OCCC)CC>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:7][N:32]=[C:31]([C:34]3[CH:42]=[CH:41][CH:40]=[C:39]4[C:35]=3[CH:36]=[CH:37][NH:38]4)[N:30]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCOc1ccc(-c2nc(-c3cccc4[nH]ccc34)no2)cc1OCCC
Reactant: CCCOc1ccc(C(=O)O)cc1Cl
Product: CCCOc1ccc(-c2nc(-c3cccc4[nH]ccc34)no2)cc1Cl
Yield: 35 %

Procedure:
When the product of Step C was substituted for 5-(3,4-dipropoxyphenyl)-3-(1H-indol-4-yl)-1,2,4-oxadiazole in Example 43 Step C, the similar process afforded the title compound in 35% yield, as off white solid. 1H-NMR (CDCl3) 1.1 (tr, 3H, J=7.37 Hz); 1.78-1.95 (m, 2H); 4.09 (t, 2H, J=6.47 Hz); 7.03 (d, 1H, J=8.66 Hz); 7.34-7.39 (m, 3H); 7.56 (d, 1H, J=8.14 Hz); 8.04 (d, 1H, J=6.8 Hz); 8.1 (dd, 1H, J=8.6, 2.1 Hz); 8.28 (d, 1H, J=3.21 Hz); 8.38 (broad s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[N:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:21]=[CH:20][CH:19]=2)=[N:10]1.Cl.[F:30][C:31]1([F:38])[C:35]([F:37])([F:36])[CH2:34][NH:33][CH2:32]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC([O-])(C)C.[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[F:1][C:2]1[CH:7]=[C:6]([N:33]2[CH2:34][C:35]([F:37])([F:36])[C:31]([F:38])([F:30])[CH2:32]2)[CH:5]=[CH:4][C:3]=1[N:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:21]=[CH:20][CH:19]=2)=[N:10]1
Reactant: COc1cn(-c2ccc(I)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Reactant: FC1(F)CNCC1(F)F
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Solvent: O
Product: COc1cn(-c2ccc(N3CC(F)(F)C(F)(F)C3)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 90 °C
Reaction time: 6 h
Yield: 72.7 %

Procedure:
A suspension of 1-(2-fluoro-4-iodophenyl)-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (488 mg, 1.0 mmol), 3,3,4,4-tetrafluoropyrrolidine hydrochloride (215 mg, 1.2 mmol), Pd2(dba)3 (18.3 mg, 0.02 mmol), Xantphos (46.3 mg, 0.08 mmol), and NaOtBu (250 mg, 2.6 mmol) in 1,4-dioxane (5 mL) was stirred for 6 h at 90° C. under Ar atmosphere. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography eluting with hexane/AcOEt (1/1-0/1) and crystallized from hexane/AcOEt to give the title compound (366 mg, 73% yield) as a white solid: mp 175-177° C.; 1H NMR (300 MHz, CDCl3): δ ppm 3.75-3.89 (7H, m), 6.10 (1H, ddd, J=0.8, 2.6, 9.0 Hz), 6.26 (1H, dd, J=2.6, 13.6 Hz), 6.35 (1H, t, J=9.0 Hz), 7.27 (1H, d, J=1.9 Hz), 7.34-7.46 (5H, m), 7.71 (1H, d, J=2.6 Hz), 7.78 (1H, d, J=1.9. Hz). LC-MS (ESI) m/z 504 [M+H]+. Anal. Calcd for C24H18F5N5O2: C, 57.26; H, 3.60; N, 13.91. Found: C, 57.17; H, 3.61; N, 13.79.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([CH:19]3[CH2:24][CH2:23][N:22]([CH2:25][C@H:26]4[C@@H:31]([CH3:32])[O:30][CH2:29][CH2:28][NH:27]4)[CH2:21][CH2:20]3)=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C=O.[CH3:35]N(CCO)C>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10]([CH:19]3[CH2:24][CH2:23][N:22]([CH2:25][C@H:26]4[C@@H:31]([CH3:32])[O:30][CH2:29][CH2:28][N:27]4[CH3:35])[CH2:21][CH2:20]3)=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: CN(C)CCO
Reactant: C[C@H]1OCCN[C@H]1CN1CCC(c2cc(-c3ccncc3)c(-c3ccc(F)cc3)[nH]2)CC1
Agent: C=O
Solvent: CCO
Product: C[C@H]1OCCN(C)[C@H]1CN1CCC(c2cc(-c3ccncc3)c(-c3ccc(F)cc3)[nH]2)CC1
Reaction time: 8 h
Yield: 83 %

Procedure:
To a stirred solution of the product of Step C (21 mg, 0.048 mmol) in 2 mL ethanol was added formaldehyde (37% in H2O, 20 ul, 0.24 mmol), followed by borane-pyridine complex (12 ul, 0.097 mmol). After stirring overnight, the reaction was treated with dimethylaminoethanol (1 mL) and heated for 2 hours. Solvent was removed in vacuo. Purification by prep-TLC afforded the desired product (120 mg, 83%).1.2(d, J=6.3 Hz, 3H), 1.9(m, 1H), 2.1(m, 2H), 2.4(s, 3H), 2.5(m, 1H), 2.7(m, 1H), 3.4(m, 1H), 3.6(m, 1H), 3.8(m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[O:11][CH2:12][CH:13]1[CH2:15][CH2:14]1.[Cl-].[NH4+].O.C(O)C>C1COCC1.[Fe]>[Br:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[O:11][CH2:12][CH:13]1[CH2:14][CH2:15]1)[NH2:8]
Reactant: O=[N+]([O-])c1ccc(OCC2CC2)c(Br)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(OCC2CC2)c(Br)c1
Yield: 99.4 %

Procedure:
A mixture of 2-bromo-1-(cyclopropylmethoxy)-4-nitrobenzene (1.07 g, 3.9 mmol), ammonium chloride (421 mg, 7.8 mmol), and iron powder (1.1 g, 20 mmol) suspended in THF (6.5 mL), water (2.5 mL) and ethanol (6.5 mL) was heated to 95° C. using microwave irradiation (normal) for 3 h. The crude reaction mixture was filtered through a short plug of celite; the celite plug was washed with MeOH (˜10 mL). The resulting filtrate was concentrated in vacuo. The resulting residue was diluted with EtOAc (50 ml) and washed with saturated bicarbonate solution (aq), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford the title compound, (939 mg, 90%). The material was carried forward without any further purification. LCMS (M+H)+=242.
Reaction SMILES: [C:1]1([C:12]([O:14][CH3:15])=[O:13])([C:8]([O:10]C)=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]C1.[H-].C([Al+]CC(C)C)C(C)C>C(OCC)C>[CH3:15][O:14][C:12]([C:1]1([CH:8]=[O:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1)=[O:13]
Reactant: COC(=O)C1(C(=O)OC)CCCCCC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCOCC
Product: COC(=O)C1(C=O)CCCCC1
Reaction time: 1.5 h

Procedure:
To a solution of dimethyl cycloheptane-1,1-dicarboxylate (7.62 g, 35.6 mmol) in diethyl ether (250 mL) at −78° C. under an argon atmosphere was added diisobutylaluminum hydride (1.5M in toluene, 48 mL, 72 mmol) dropwise. After 1.5 h, the reaction mixture was quenched with a mixutre of methanol (100 mL) and water (100 mL), was filtered through Celite@ and was extracted with diethyl ether (100 mL×3). The combined organic extracts were dried (MgSO4), were filtered and were evaporated in vacuo to yield the title compound which was used without further purification. MH+185.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1[C:10]([F:29])=[C:11]([C:16]2[C:20]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:27][CH3:28])[CH:22]=3)=[CH:19][NH:18][N:17]=2)[C:12]([F:15])=[CH:13][CH:14]=1)C1C=CC=CC=1.O>C1(C)C=CC=CC=1>[NH2:8][C:9]1[C:10]([F:29])=[C:11]([C:16]2[C:20]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:27][CH3:28])[CH:22]=3)=[CH:19][NH:18][N:17]=2)[C:12]([F:15])=[CH:13][CH:14]=1
Reactant: CNc1cc(-c2c[nH]nc2-c2c(F)ccc(N(Cc3ccccc3)Cc3ccccc3)c2F)ccn1
Solvent: Cc1ccccc1
Solvent: O
Product: CNc1cc(-c2c[nH]nc2-c2c(F)ccc(N)c2F)ccn1

Procedure:
To a solution of {4-[3-(3-dibenzylamino-2,6-difluoro-phenyl)-1H-pyrazol-4-yl]-pyridin-2-yl}-methyl-amine (408 mg, 0.849 mmol) in toluene (4.30 mL) trifluoro-methanesulfonic acid (4.30 mL) was added and the mixture was irradiated in the microwave oven at 120° C. for 30 minutes. The reaction was then poured into water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous NaHCO3 and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography eluting with 5% methanol in methylene chloride (60% over 4 steps).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[NH2:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][N:11]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[Br:8][C:4]1[N:3]=[C:2]([NH:9][C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][N:11]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)n1
Reactant: Cc1ccnc(N)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccnc(Nc2cccc(Br)n2)c1
Temperature: 80 °C
Reaction time: 12 h
Yield: 110.5 %

Procedure:
A suspension of 2,6-dibromopyridine (12.5 g), 2-amino-4-picoline (32.8 g, 139 mmol), palladium acetate (2.59 g, 11.6 mmol), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (8.64 g, 13.9 mmol), sodium tert-butoxide (13.3 g, 139 mmol) in toluene (200 ml) was heated and stirred in an Ar stream at 80° C. for 12 hours. Water was added to the reaction solution and the solution was extracted with ethyl acetate. After the organic layer was washed with a saturated brine and dried over anhydrous magnesium sulfate, the residue obtained by vacuum concentration was purified by flash chromatography on silica gel (n-hexane:ethyl acetate=3:1) and subsequently washed with isopropyl ether and the title compound (15.4 g, 51%) was obtained.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[N:8]=[CH:7][C:6]([CH2:9][S:10]([CH2:13][C:14]#[N:15])(=[O:12])=[O:11])=[CH:5][CH:4]=1.[F:18][C:19]([S:22][CH2:23][CH2:24]OS(C(F)(F)F)(=O)=O)([F:21])[F:20]>>[F:17][C:2]([F:1])([F:16])[C:3]1[N:8]=[CH:7][C:6]([CH2:9][S:10]([CH:13]([CH2:24][CH2:23][S:22][C:19]([F:21])([F:20])[F:18])[C:14]#[N:15])(=[O:11])=[O:12])=[CH:5][CH:4]=1
Reactant: O=S(=O)(OCCSC(F)(F)F)C(F)(F)F
Reactant: N#CCS(=O)(=O)Cc1ccc(C(F)(F)F)nc1
Product: N#CC(CCSC(F)(F)F)S(=O)(=O)Cc1ccc(C(F)(F)F)nc1

Procedure:
Compound II-9 was prepared from (6-trifluoromethyl-pyridin-3-ylmethanesulfonyl)-acetonitrile and trifluoro-methanesulfonic acid 2-trifluoromethylsulfanyl-ethyl ester as described for compound II-1.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][C:15]1=[O:20])(=[O:13])=[O:12])([O-:4])=[O:3].[N:21]1([CH2:30][C:31](O)=[O:32])[CH:29]=[C:27]([CH3:28])[C:25](=[O:26])[NH:24][C:22]1=[O:23].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.C(O)C>[N+:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([N:14]1[CH2:19][CH2:18][N:17]([C:31](=[O:32])[CH2:30][N:21]2[CH:29]=[C:27]([CH3:28])[C:25](=[O:26])[NH:24][C:22]2=[O:23])[CH2:16][C:15]1=[O:20])(=[O:12])=[O:13])([O-:4])=[O:3]
Reactant: O=C1CNCCN1S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: Cc1cn(CC(=O)O)c(=O)[nH]c1=O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cn(CC(=O)N2CCN(S(=O)(=O)c3ccccc3[N+](=O)[O-])C(=O)C2)c(=O)[nH]c1=O
Reaction time: 2 h
Yield: 94.9 %

Procedure:
To a mixture of 1-(2-nitro-benzenesulfonyl)-piperazin-2-one HCl salt (1.13 g, 3.5 mmol), (thymin-1-yl)-acetic acid (0.64 g, 3.5 mmol), and PyBOP (2.00 g, 3.85 mmol) in DMF (11 mL) was addeed N,N-diisopropylethylamine (0.91 mL) at room temperature. After stirring for additional 2 h, the reaction mixture was slowly added to a solution of aqueous ethyl alcohol to precipitate solid. The solid was filtered off, washed with ethanol and ethyl ether, and dried in vacuo to give the titled compound (1.50 g, 95%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20]O)=[CH:16][CH:15]=2)=[CH:9][C:8]=1[CH3:22])[CH3:2].S(Cl)([Cl:26])=O>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][Cl:26])=[CH:16][CH:15]=2)=[CH:9][C:8]=1[CH3:22])[CH3:2]
Reactant: CCOC(=O)COc1ccc(Sc2ccc(CO)cc2)cc1C
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)COc1ccc(Sc2ccc(CCl)cc2)cc1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 105.9 %

Procedure:
An oven-dried 1 L round-bottomed flask was charged with compound 7.2 (30.0 g, 90.2 mmol) and chloroform (300 mL) and the mixture was cooled to 0° C. Thionyl chloride (7.90 mL, 107 mmol) was added dropwise at 0° C., and the reaction was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo to give 7.3 as a slightly yellow oil (33.5 g), which was used in the next step without further purification. 1H NMR (400 MHz) (CDCl3) δ 7.30-7.20 (4H, m); 7.12 (2H, d, J=8.3 Hz); 6.68 (1H, d, J=8.4 Hz); 4.65 (2H, s) ; 4.53 (2H, s); 4.27 (2H, q, J=7.1 Hz); 2.27 (3H, s); 1.30 (3H, t, J=7.1 Hz).
Reaction SMILES: [CH2:1]([C:4]1[C:5]([O:13][C:14](=[O:16])[CH3:15])=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][N:10]=[CH:9]2)[CH:2]=[CH2:3].[CH2:17]([N:19]=[C:20]=[O:21])[CH3:18]>C1COCC1>[CH2:1]([C:4]1[C:5]([O:13][C:14](=[O:16])[CH3:15])=[CH:6][CH:7]=[C:8]2[C:12]=1[N:11]([C:20](=[O:21])[NH:19][CH2:17][CH3:18])[N:10]=[CH:9]2)[CH:2]=[CH2:3]
Reactant: CCN=C=O
Reactant: C=CCc1c(OC(C)=O)ccc2cn[nH]c12
Solvent: C1CCOC1
Product: C=CCc1c(OC(C)=O)ccc2cnn(C(=O)NCC)c12
Temperature: 70 °C
Yield: 81 %

Procedure:
To a solution of the product from Step C (2.5 g, 11.6 mmol) in THF (10 mL) was added ethylisocyanate (1.01 ml, 13 mmol) and the mixture heated at 70° C. for 18 h. The reaction mixture was evaporated to a residue which was purified by chromatography (silica, 10% to 50% EtOAc/hexane) to give a colorless oil (2.70 g, 81%): LC/MS (+APCI) m/z 288 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([CH3:14])=[CH:9][C:8]=2[N+:15]([O-:17])=[O:16])=[O:4].[Br:25]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([CH2:14][Br:25])=[CH:9][C:8]=2[N+:15]([O-:17])=[O:16])=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc2cc(C)cc([N+](=O)[O-])c2n1C(=O)OC(C)(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc2cc(CBr)cc([N+](=O)[O-])c2n1C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 5 h
Yield: 114.2 %

Procedure:
1-BOC-5-methyl-7-nitro-indole-2-carboxylic acid methyl ester (34 g, 101.7 mmol) prepared in Step A was dissolved in carbon tetrachloride (100 mL). N-bromosuccinimide (27.2 g, 152.6 mmol) and AIBN (1.7 g, 10.2 mmol) were added thereto, and the mixture was stirred for 5 h at 80° C. After completion of the reaction, the reaction mixture was distilled under reduced pressure, and purified by column chromatography to give the title compound (48.0 g, Yield 100%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([C:10]2[CH:19]=[C:18]([CH3:20])[C:13]3[NH:14][C:15](=[O:17])[O:16][C:12]=3[CH:11]=2)=[O:9])[CH:3]=1.[NH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]2([CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[NH:23][C:22]1=[O:36].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:20][C:18]1[C:13]2[NH:14][C:15](=[O:17])[O:16][C:12]=2[CH:11]=[C:10]([C:8]([C:4]2[CH:3]=[C:2]([N:33]3[CH2:32][CH2:31][C:24]4([C:25]5[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=5)[NH:21][C:22](=[O:36])[NH:23]4)[CH2:35][CH2:34]3)[N:7]=[CH:6][N:5]=2)=[O:9])[CH:19]=1
Reactant: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2oc(=O)[nH]c12
Reactant: O=C1Nc2ccccc2C2(CCNCC2)N1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)c2cc(N3CCC4(CC3)NC(=O)Nc3ccccc34)ncn2)cc2oc(=O)[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
144 mg (0.500 mmol) 6-(6-chloropyrimidine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one, 108 mg (0.500 mmol) 1′H-spiro[piperidin-4,4′-quinazolin]-2′(3′H)-one and 0.174 mL (1.00 mmol) DIPEA were combined in 5.0 mL DMF and stirred overnight at RT. The reaction mixture was purified by preparative HPLC, the fractions containing the product were combined and the organic solvent was eliminated i.vac. The aqueous phase was neutralised by the addition of 4N aqueous NaOH solution. The product precipitated as a solid was filtered off, washed with water and dried.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][NH:9][CH:10]=1)=[O:5])C.[I:11][C:12]1[CH:13]=[CH:14][C:15](F)=[N:16][CH:17]=1.CNC1CCCCC1NC.C(=O)([O-])[O-].[K+].[K+]>[Cu]I.O>[I:11][C:12]1[CH:13]=[CH:14][C:15]([N:9]2[CH:10]=[C:6]([C:4]([OH:3])=[O:5])[CH:7]=[N:8]2)=[N:16][CH:17]=1
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: Fc1ccc(I)cn1
Agent: [Cu]I
Agent: CNC1CCCCC1NC
Agent: O=C([O-])[O-]
Solvent: O
Product: O=C(O)c1cnn(-c2ccc(I)cn2)c1
Temperature: 120 °C
Reaction time: 48 h
Yield: 8.7 %

Procedure:
A mixture of 1H-pyrazole-4-carboxylic acid ethyl ester (2.00 g), 5-iodo-2-fluoropyridine (1.68 g), copper (I) iodide (136 mg), N,N′-dimethyl-1,2-cyclohexanediamine (5 ml) and potassium carbonate (4.06 g) was stirred at 120° C. for 48 hours. After completion of the reaction, water was added and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was dissolved in ethanol (10 ml), sodium hydroxide (568 mg) was added and the mixture was stirred at room temperature overnight. The reaction solution was concentrated by an evaporator, the aqueous solution was acidified by the addition of 1N hydrochloric acid aqueous solution and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated to give the titled compound (207 mg) as a dark brown solid.