Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[N:13]=[C:14]=[O:15].[Br:16][C:17]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:18]=1[NH2:19]>C(#N)C>[Br:16][C:17]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:18]=1[NH:19][C:14]([NH:13][C:4]1[CH:5]=[C:6]([C:9]([F:12])([F:11])[F:10])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])=[O:15]
Reactant: COc1ccc(C(F)(F)F)cc1N=C=O
Reactant: Nc1c(F)cccc1Br
Solvent: CC#N
Product: COc1ccc(C(F)(F)F)cc1NC(=O)Nc1c(F)cccc1Br
Temperature: 85 °C
Yield: 99 %

Procedure:
2-Methoxy-5-trifluoromethylphenyl isocyanate (274.3 g) is dissolved in acetonitrile (1 l), then 2-bromo-6-fluoroaniline (200 g) is added and rinsed out with acetonitrile (50 ml). The resulting clear solution is stirred under reflux (ca. 85° C.) for 38 h, then concentrated in vacuo at 40° C. to a viscous magma. This is filtered off with suction, washed with acetonitrile (260 ml, cooled to 0-5° C.) and dried overnight at 45° C. in the VDO using entraining nitrogen. A total of 424.3 g of N-(2-bromo-6-fluorophenyl)-N′-[2-methoxy-5-(trifluoromethyl)phenyl]urea are obtained as a solid, corresponding to 99.2% of theory.
Reaction SMILES: [N:1]([CH2:4][C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)([F:7])[F:6])=[N+:2]=[N-:3].C(C1C=C(SC2C=C(C)C(O)=C(C(C)(C)C)C=2)C=C(C)C=1[OH:24])(C)(C)C.C1C=C(Cl)C=C(C(OO)=O)C=1>ClCCCl>[N:1]([CH2:4][C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N+:9]=1[O-:24])([F:7])[F:6])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCC(F)(F)c1ccccn1
Reactant: Cc1cc(Sc2cc(C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCCl
Product: [N-]=[N+]=NCC(F)(F)c1cccc[n+]1[O-]
Temperature: 55 °C
Reaction time: 12 h
Yield: 96 %

Procedure:
To the solution of 2-(2-azido-1,1-difluoro-ethyl)-pyridine (example 59c), 2.6 g, 14 mmol) and 3-tert-butyl-4-hydroxy-5-methylphenyl sulfide (0.5 g, 1.4 mmol) in 1,2-dichloroethane (40 mL) was added MCPBA (77%, 4.2 g, 18.2 mmol). The reaction mixture was stirred at 55° C. for 12 h. After cooling to room temperature, the reaction mixture was poured into a saturated aqueous NaHCO3/NaS2O3 solution (100 mL) and extracted with methylene chloride (3×100 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 50%-100% ethyl acetate in hexane in 30 min) afforded 2-(2-azido-1,1-difluoro-ethyl)-pyridine N-oxide (2.7 g, 96%) as a clear oil. LC-MS m/e 201 (MH+).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:13]3[CH:12]=[C:11]([NH:14][C:15](=[O:26])[C:16]4[CH:21]=[CH:20][C:19]([C:22]([OH:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=4)[N:10]=[CH:9][C:8]=3[CH:7]=[CH:6]2)[CH2:3][CH2:2]1.C1C(=O)N([Br:34])C(=O)C1.CCOC(C)=O>C(Cl)Cl>[Br:34][C:7]1[C:8]2[CH:9]=[N:10][C:11]([NH:14][C:15](=[O:26])[C:16]3[CH:17]=[CH:18][C:19]([C:22]([OH:25])([CH3:23])[CH3:24])=[CH:20][CH:21]=3)=[CH:12][C:13]=2[N:5]([CH2:4][CH:1]2[CH2:3][CH2:2]2)[CH:6]=1
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc3c(ccn3CC3CC3)cn2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(O)c1ccc(C(=O)Nc2cc3c(cn2)c(Br)cn3CC2CC2)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 65.1 %

Procedure:
To an ice-cooled solution of N-(1-(cyclopropylmethyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)-4-(2-hydroxypropan-2-yl)benzamide (Example 9, 75 mg, 0.215 mmol) in DCM (4 ml) was added NBS (38.2 mg, 0.215 mmol). The reaction mixture was stirred at 50° C. for 1 h, and then subjected to chromatography (NH—SiO2, EtOAc). The fractions were concentrated in vacuo and purified by preparatory HPLC to give the title compound N-(3-bromo-1-(cyclopropylmethyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)-4-(2-hydroxypropan-2-yl)benzamide (60 mg, 0.14 mmol, 65% yield) as a white powder. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.40-0.48 (m, 2 H) 0.52-0.59 (m, 2 H) 1.20-1.32 (m, 1 H) 1.46 (s, 6 H) 4.05 (d, J=7.07 Hz, 2 H) 5.17 (s, 1 H) 7.59 (d, J=8.59 Hz, 2 H) 7.74 (s, 1 H) 8.02 (d, J=8.59 Hz, 2 H) 8.40 (s, 1 H) 8.51 (s, 1 H) 10.69 (s, 1 H); m.p. 193-194° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([NH2:26])=[O:25])[CH:19]=2)=[C:14]([CH3:27])[CH:13]=1.[CH3:28][C:29]1([CH3:36])[CH2:34][CH2:33][C:32](=O)[CH2:31][CH2:30]1.CCN(CC)CC>CO.C(Cl)Cl.CC(O)=O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:28][C:29]1([CH3:36])[CH2:34][CH2:33][CH:32]([NH:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([NH2:26])=[O:25])[CH:19]=3)=[C:14]([CH3:27])[CH:13]=2)[CH2:31][CH2:30]1
Reactant: Cc1cc(OCCN)ccc1-c1cccc(C(N)=O)c1
Reactant: CC1(C)CCC(=O)CC1
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: Cc1cc(OCCNC2CCC(C)(C)CC2)ccc1-c1cccc(C(N)=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4′-[(2-aminoethyl)oxy]-2′-methyl-3-biphenylcarboxamide trifluoroacetate (0.105 g; 0.273 mmol; Intermediate VII-1) and 4,4-dimethylcyclohexanone (0.038 g; 0.30 mmol; Intermediate Step 1 of III-1) in MeOH/CH2Cl2/HOAc (3 mL; 1:1 MeOH/CH2Cl2 with 5% HOAc) was added Et3N (0.040 mL; 0.27 mmol), followed by PS-BH3CN (0.32 g; ca. 4.2 mmol/g; ca. 1.35 mmol BH3CN). The mixture was agitated overnight at rt using an orbital shaker, and the resin was removed by filtration. The filtrate was concentrated in vacuo, and the residue was purified by RP-HPLC (C18 column, MeCN/H2O gradient with TFA additive) affording the title compound as a colorless foam. (LC/MS Method C) 2.24 min, m/z 381 (M+1, freebase).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[C@@H:6]([CH2:14][CH3:15])[N:5]([CH:16]3[CH2:18][CH2:17]3)[C:4]=2[N:3]=1.[NH:19]1[CH:23]=[CH:22][N:21]=[C:20]1[C:24]1[CH:29]=[N:28][CH:27]=[CH:26][N:25]=1>>[CH:16]1([N:5]2[C:4]3[N:3]=[C:2]([N:19]4[CH:23]=[CH:22][N:21]=[C:20]4[C:24]4[CH:29]=[N:28][CH:27]=[CH:26][N:25]=4)[N:11]=[CH:10][C:9]=3[N:8]([CH3:12])[C:7](=[O:13])[C@H:6]2[CH2:14][CH3:15])[CH2:18][CH2:17]1
Reactant: c1cnc(-c2ncc[nH]2)cn1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Cl)nc2N1C1CC1
Product: CC[C@@H]1C(=O)N(C)c2cnc(-n3ccnc3-c3cnccn3)nc2N1C1CC1

Procedure:
The title compound was prepared similarly to the methods described in Example 77, with Intermediate O instead of Intermediate C and with 2-(1H-imidazol-2-yl)pyrazine instead of 2-phenyl-1H-imidazole. LCMS: 377.2 m/z (M+H)+; ret. Time: 4.07 min (Analytical Method C).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:31])[CH2:15][CH:16]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C(C1C=C(C(C)C)C=C(C(C)C)C=1S([N:60]=[N+:61]=[N-:62])(=O)=O)(C)C.CC(O)=O>C1COCC1>[N:60]([C@@H:15]([CH:16]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[C:14]([N:9]1[C@@H:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:12][O:11][C:10]1=[O:13])=[O:31])=[N+:61]=[N-:62]
Reactant: O=C(CC(c1ccc(Cl)cc1)c1ccc(Cl)cc1)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)N=[N+]=[N-])c(C(C)C)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: [N-]=[N+]=N[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.5 %

Procedure:
A solution of 4-(S)-benzyl-3-[3,3-bis-(4-chloro-phenyl)-propionyl]-oxazolidin-2-one (2.0 g, 4.4 mmol) in THF (25 mL) was cooled to −78° C. and added via cannula to a solution of potassium bis(trimethylsilyl)amide (0.5 M in toluene, 9.7 mL, 4.8 mmol) in THF (15 mL) at −78° C. After 30 min at −78° C., a solution of 2,4,6-triisopropylbenzenesulfonyl azide (1.77 g, 5.7 mmol) in THF (15 mL) was cooled to −78° C. and added via cannula. After 1 min, the reaction was quenched by addition of AcOH (1.2 mL, 21 mmol). The cooling bath was removed, and the mixture was allowed to warm to rt and stir overnight. The reaction mixture was diluted with water and extracted with DCM (3×). The combined organic extracts were dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (EtOAc/hexanes) to provide 1.58 g (72%) of the desired azide as a white foam. 1H NMR (400 MHz, CDCl3): 7.38-7.15 (m, 13H), 5.94 (d, J=11.0, 1H), 4.50 (d, J=11.0, 1H), 4.34-4.25 (m, 1H), 4.08 (dd, J=9.2, 2.4, 1H), 3.76 (dd, J=8.8, 8.1, 1H), 3.22 (dd, J=13.5, 3.3, 1H), 2.77 (dd, J=13.5, 9.5, 1H).
Reaction SMILES: C1COCC1.[C:6]1([Mg]Br)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1.Cl[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH3:26].[Cl-].C(C1C=CC=C(C(C)C)C=1[NH+]1CCN(C2C(C(C)C)=CC=CC=2C(C)C)C1)(C)C>CCCCCC.C1(C)C=CC=CC=1>[CH3:26][O:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: COc1ccccc1Cl
Reactant: Br[Mg]c1cccc2ccccc12
Agent: CC(C)c1cccc(C(C)C)c1N1CC[NH+](c2c(C(C)C)cccc2C(C)C)C1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: COc1ccccc1-c1cccc2ccccc12
Reaction time: 48 h
Yield: 92 %

Procedure:
Using a THF solution of 1-naphthylmagnesium bromide (4.62 mL, 0.26 M, 1.2 mmol), 1-chloro-2-methoxybenzene (142.6 mg, 1.0 mmol), FeF3.3H2O (8.34 mg, 0.05 mmol) and 1,3-bis(2,6-diisopropylphenyl)imidazolinium chloride (64.1 mg, 0.15 mmol) as starting materials, the reaction was performed at a scale of 1.0 mmol at 70° C. for 48 hours in the same manner as in Example 2. After performing silica gel column chromatography (toluene=10, 20 and 40% in hexane), the above compound was obtained as a white solid (0.215 g, yield=92%, purity=>99% (GC analysis)).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][CH:9]=2)[N:5]=[C:4]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:23][CH:22]=2)[N:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:38]1([CH:45]=[CH:44][CH:43]=[C:41]([OH:42])[CH:40]=1)[OH:39]>ClC1C=CC=CC=1>[OH:39][C:38]1[CH:40]=[C:41]([OH:42])[CH:43]=[CH:44][C:45]=1[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][CH:9]=2)[N:5]=[C:4]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:23][CH:22]=2)[N:3]=1
Reactant: Clc1nc(-c2ccc(Oc3ccccc3)cc2)nc(-c2ccc(Oc3ccccc3)cc2)n1
Reactant: Oc1cccc(O)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Product: Oc1ccc(-c2nc(-c3ccc(Oc4ccccc4)cc3)nc(-c3ccc(Oc4ccccc4)cc3)n2)c(O)c1
Temperature: 85 °C
Reaction time: 1 h
Yield: 74.3 %

Procedure:
A mixture of 5.9 gm of 2-chloro-4,6-bis(4-phenoxyphenyl)-1,3,5-triazine, 2.6 gm aluminum chloride and 1.6 gm of resorcinol in 25 ml chlorobenzene was heated under nitrogen at 85° C. for 3 hr. An additional 0.17 gm resorcinol was added, and the heating continued for another 1 hr. The reaction mixture was cooled to room temperature, and quenched with water. The precipitated product was filtered, washed with water, and dried to give 5.1 gm of crude 2-(2,4-dihydroxyphenyl)-4,6-bis(4-phenoxyphenyl)-1,3,5-triazine.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[O:14][C:13](=[O:15])[NH:12][CH2:11]2)=[CH:6][CH:5]=1.Br[CH2:17][C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:19]=1[C:28]1[CH:33]=[C:32]([CH:34]([CH3:36])[CH3:35])[CH:31]=[CH:30][C:29]=1[O:37][CH3:38]>C1COCC1>[CH:34]([C:32]1[CH:31]=[CH:30][C:29]([O:37][CH3:38])=[C:28]([C:19]2[CH:20]=[CH:21][C:22]([C:24]([F:27])([F:25])[F:26])=[CH:23][C:18]=2[CH2:17][N:12]2[CH2:11][CH:10]([C:7]3[CH:6]=[CH:5][C:4]([CH3:3])=[CH:9][CH:8]=3)[O:14][C:13]2=[O:15])[CH:33]=1)([CH3:36])[CH3:35]
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CBr
Reactant: Cc1ccc(C2CNC(=O)O2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN1CC(c2ccc(C)cc2)OC1=O
Reaction time: 0.5 h

Procedure:
Sodium hydride (6.4 mg of a 60% dispersion in mineral oil, 0.161 mmol) was added to a stirred solution of 5-(4-methylphenyl)-1,3-oxazolidin-2-one (37.7 mg, 0.0973 mmol) in dry THF (1 mL) at room temperature under N2. The reaction was stirred for 30 min and a solution of 2-(bromomethyl)-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl (19.0 mg, 0.107 mmol) in dry THF (2 mL) was added by cannula. The reaction was stirred at room temperature for 3 days. The reaction was quenched with saturated NH4Cl (10 mL) and extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine (10 mL), dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 12×160 mm, 0-80% EtOAc in hexanes gradient) to afford 3-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-5-(4-methylphenyl)-1,3-oxazolidin-2-one as a colorless oil. Rf=0.37 (20% EtOAc/hexanes). LCMS calc.=484.21; found=484.2 (M+1)+. 1H NMR (benzene-d6, 500 MHz, 1:1 mixture of atropisomers) δ 7.76 (s, 0.5H), 7.65 (s, 0.5H), 7.31 (d, J=7.7 Hz, 1H), 7.08 (dd, J=8.4, 2.4 Hz, 1H), 7.05 (br d, J=7.8 Hz, 1H), 6.95-6.86 (m, 5H), 6.58 (t, J=7.7 Hz, 1H), 4.74 (t, J=8.0 Hz, 0.5H), 4.70 (t, J=8.0 Hz, 0.5H), 4.50 (d, J=15.7 Hz, 0.5H), 4.42 (d, J=15.7 Hz, 0.5H), 4.25 (d, J=15.7 Hz, 0.5H), 4.11 (d, J=15.7 Hz, 0.5H), 3.26 (s, 1.5H), 3.21 (s, 1.5H), 2.81 (t, J=8.6 Hz, 0.5H), 2.76 (septet, J=7.0 Hz, 1H), 2.68 (t, J=8.6 Hz, 0.5H), 2.55 (t, J=8.6 Hz, 0.5H), 2.53 (t, J=8.6 Hz, 0.5H), 2.04 (s, 3H), 1.20 (t, J=7.0 Hz, 3H), 1.19 (t, J=7.0 Hz, 3H).
Reaction SMILES: S([O-])([O-])(=O)=O.[Na+].[Na+].[Br:8][C:9]1[CH:10]=[C:11]([O:19][CH3:20])[CH:12]=[C:13]2[C:18]=1[CH2:17][NH:16][CH2:15][CH2:14]2>[O-2].[O-2].[Mn+4].C1(C)C=CC=CC=1>[Br:8][C:9]1[CH:10]=[C:11]([O:19][CH3:20])[CH:12]=[C:13]2[C:18]=1[CH:17]=[N:16][CH:15]=[CH:14]2
Reactant: COc1cc(Br)c2c(c1)CCNC2
Agent: [Mn+4]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cc(Br)c2cnccc2c1
Temperature: 140 °C
Reaction time: 24 h
Yield: 35.7 %

Procedure:
Sodium sulfate (2.8 g) and manganese dioxide (7.1 g; Ald) were added to a toluene (60 mL) solution of Intermediate 5 (1.99 g) and the resulting mixture was stirred at 140° C. for 24 hours. The reaction mixture was filtrated through celite followed by the addition of 2 N hydrochloric acid and the resulting mixture was washed with ether. The resulting mixture was neutralized with 5 N aqueous sodium hydroxide solution and then extracted with dichloromethane to give the title compound (698 mg).
Reaction SMILES: N1C=CN=C1.CN(C)C=O.[OH:11][CH:12]([C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)[CH2:13][C:14]#[N:15].[C:22]([Si:26]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)Cl)([CH3:25])([CH3:24])[CH3:23]>CCOCC.C(OCC)(=O)C>[O:11]([CH:12]([C:16]1[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=1)[CH2:13][C:14]#[N:15])[Si:26]([C:22]([CH3:25])([CH3:24])[CH3:23])([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: N#CCC(O)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](OC(CC#N)c1ccncc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 98.9 %

Procedure:
Next, imidazole (4.60 g, 67.5 mmol) and N,N-dimethylformamide (30 ml) were added to the obtained 3-hydroxy-3-(4-pyridyl)propionitrile (1.00 g, 6.75 mmol), and the mixture was stirred at room temperature. t-Butyldiphenylchlorosilane (2.23 g, 8.10 mmol) was added to the mixture, and the whole was stirred for one day and further stirred at an external temperature of 50° C. for three hours. Ethyl acetate (50 ml) and ether (50 ml) were added to the reaction mixture, the whole was washed with water (20 ml) three times and saturated brine (30 ml) successively, and the organic layer was dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give 2.58 g (98.9%) of 3-(t-butyldiphenylsiloxy)-3-(4-pyridyl)propionitrile as a colorless oily matter.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[Br:7][C:8]1[S:12][C:11]([C:13]([C@H:15]2[CH2:20][CH2:19][C@H:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]2)=O)=[N:10][CH:9]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)C.O.C(OCC)(=O)C>[Br:7][C:8]1[S:12][C:11]([C:13]([C@H:15]2[CH2:20][CH2:19][C@H:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]2)=[CH2:1])=[N:10][CH:9]=1
Reactant: CC(C)(C)[O-]
Reactant: CCOC(=O)[C@H]1CC[C@H](C(=O)c2ncc(Br)s2)CC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCOCC
Product: C=C(c1ncc(Br)s1)[C@H]1CC[C@H](C(=O)OCC)CC1
Reaction time: 0.42 h

Procedure:
Methyl(triphenyl)phosphonium bromide (774 mg, 2.166 mmol) was suspended in anhydrous diethyl ether (5 mL) and potassium tert-butoxide (2.311 mmol, 1.78 M in THF, 1.29 mL) was added at 0° C. dropwise. The suspension was left 25 min at the same temperature (solution became orange-brown). A solution of diethyl ether (1 ml) and ethyl trans-4-[(5-bromo-1,3-thiazol-2-yl)carbonyl]cyclohexanecarboxylate (500 mg, 1.444 mmol) was added dropwise at 0° C. The mixture was left at the same temperature for 30 min, allowed to reach room temperature, left under stirring additional 90 min, diluted with water and taken up in ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (0% to 10% EtOAc in hexanes) to afford ethyl trans-4-[1-(5-bromo-1,3-thiazol-2-yl)ethenyl]-cyclohexanecarboxylate (62%) as an oil. MS ESI calc'd. for C14H18BrNO2S for [M+H]+ 344, 346. found 344, 346. 1H NMR (500 MHz, CDCl3) δ 7.55 (s, 1H), 5.60 (s, 1H), 5.19 (s, 1H), 4.04 (q, J=7.0, 2H), 2.62-2.78 (m, 1H), 2.20-2.30 (m, 1H), 1.90-2.02 (m, 3H), 1.50-1.60 (m, 2H), 1.10-1.30 (m, 2H), 1.17 (t, J=7.0, 3H), 0.72-0.82 (m, 1H).
Reaction SMILES: [C:1]1([CH2:7][NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:15]=[C:16](Cl)OC(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[C:1]1([CH2:7][N:8]2[C:16](=[O:15])[N:11]3[CH2:10][CH:9]2[CH2:14][CH2:13][CH2:12]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: c1ccc(CNC2CCCNC2)cc1
Solvent: Cc1ccccc1
Product: O=C1N2CCCC(C2)N1Cc1ccccc1
Temperature: 0 °C
Yield: 30 %

Procedure:
1.06 g of the product obtained in stage C is dissolved in 28 cm3 of toluene, then cooled down to 0° C. and 337 μl of diphosgene is added under an inert gas. Then the temperature is left to rise and maintained for 2 hours at 20° C. The reaction medium is concentrated under reduced pressure then the residue is, chromatographed on silica eluting successively with methylene chloride-acetone 95/5 then 80/20 and finally methylene chloride-methanol, triethylamine; 92/8/3 and 362 mg of expected product C13H16N2O (M=216.85 g) is obtained i.e. a yield of 30%.
Reaction SMILES: Cl.O1CCOCC1.C(O[C:13](=O)[N:14]([CH2:16][CH2:17][O:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[C:26]([N:28]1[CH2:42][C:31]2=[C:32]3[N:37]([N:38]=[C:30]2[CH2:29]1)[C:36]([CH3:39])=[C:35]([Cl:40])[C:34]([CH3:41])=[N:33]3)=[O:27])C)(C)(C)C>C(Cl)Cl.CC(OC)(C)C>[ClH:40].[Cl:40][C:35]1[C:34]([CH3:41])=[N:33][C:32]2[N:37]([N:38]=[C:30]3[CH2:29][N:28]([C:26]([C:20]4[CH:21]=[CH:22][C:23]([F:25])=[CH:24][C:19]=4[O:18][CH2:17][CH2:16][NH:14][CH3:13])=[O:27])[CH2:42][C:31]3=2)[C:36]=1[CH3:39]
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccc(F)cc1OCCN(C)C(=O)OC(C)(C)C)C3
Agent: Cl
Solvent: COC(C)(C)C
Solvent: ClCCl
Solvent: C1COCCO1
Product: CNCCOc1cc(F)ccc1C(=O)N1Cc2nn3c(C)c(Cl)c(C)nc3c2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 139 %

Procedure:
A 4M solution of HCl in 1,4-dioxane (0.72 mL; 2.9 mmol; 15 eq.) was added to a solution of {2-[2-(6-chloro-5,7-dimethyl-1H,3H-2,4,7a,8-tetraaza-cyclopenta[a]indene-2-carbonyl)-5-fluoro-phenoxy]-ethyl}-methyl-carbamic acid tert-butyl ester (100 mg; 0.19 mmol; 1 eq.) in DCM (5 mL) and the reaction mixture was stirred at room temperature for 2 hours. The residue was suspended in hot MTBE, filtered and dried to afford the title compound (60 mg, 68%) as a pale yellow solid. 1H NMR (DMSO-d6) δ 8.92-8.69 (m, 2H), 7.50-7.38 (m, 1H), 7.24-7.13 (m, 1H), 7.00-6.90 (td, J=8.5, 8.0, 2.2 Hz, 1H), 4.89-4.77 (d, J=8.6 Hz, 2H), 4.65-4.51 (m, 2H), 4.41-4.32 (m, 2H), 3.27 (br s, 2H), 2.85 (s, 1.7H), 2.81 (s, 1.3H), 2.62 (s, 1.3H), 2.57 (s, 1.7H), 2.53 (s, 3H). HPLC (max plot) 97.0%, Rt 2.73 min. UPLC/MS: (MS+) 418.3 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:9])=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Br[CH2:11][CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>>[Br:1][C:2]1[C:3]([F:9])=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:11][CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: Oc1cccc(Br)c1F
Reactant: BrCC1CCOCC1
Product: Fc1c(Br)cccc1OCC1CCOCC1

Procedure:
Prepared as described for 1-bromo-2-fluoro-3-isopropoxy-benzene SM23 starting from 3-bromo-2-fluorophenol and 4-bromomethyltetrahydropyran. MS m/z: 290 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[CH:24]=[C:25]([C:28](O)=[O:29])[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:64][N:65]([CH3:71])[C@H:66]1[CH2:70][CH2:69][NH:68][CH2:67]1>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[CH:24]=[C:25]([C:28]([N:68]5[CH2:69][CH2:70][C@H:66]([N:65]([CH3:71])[CH3:64])[CH2:67]5)=[O:29])[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1
Reactant: O=C(O)c1ccc2c(c1)-c1sc(-c3ncnn3-c3ccc(F)cc3F)cc1CCO2
Reactant: CN(C)[C@H]1CCNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CN(C)[C@H]1CCN(C(=O)c2ccc3c(c2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.9 %

Procedure:
To a stirred solution of 2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-9-carboxylic acid (70 mg; 0.16 mmol) in DMF (5 ml) was added HATU (103 mg; 0.27 mmol), DIPEA (50 μl; 0.27 mmol) and (S)-(−)-3-(dimethylamino)pyrrolidine (50 μl; 0.38 mmol). The reaction mixture was stirred at r.t. for 4 h upon which time it was diluted with EtOAc (20 ml) and washed successively with satd. NaHCO3 (20 ml) and brine (2 20 ml). The organic layer was dried (Na2SO4), concentrated and purified by prep. LCMS to give 420 as an off-white solid (50 mg; 58%). δH (400 MHz, CDCl3) 1.77-1.92 (br m, 1H), 2.06-2.17 (m, 1H), 2.24 (br s, 3H), 2.35 (br s, 3H), 2.60-2.83 (m, 1H), 3.16 (br s, 2H), 3.29-3.98 (m, 4H), 4.33 (br s, 2H), 6.94-7.20 (m, 4H), 7.32-7.39 (m, 1H), 7.50-7.60 (m, 1H), 7.77 (s, 1H), 8.11 (s, 1H). [M+H]+: 522
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([SH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].[OH-].[Na+].Cl[CH2:13][C:14]#[N:15]>O>[Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH2:13][C:14]#[N:15])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: N#CCCl
Reactant: Sc1ccc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N#CCSc1ccc(Cl)c(Cl)c1

Procedure:
17.9 g (0.10 mol) of 3,4-dichlorobenzenethiol are mixed in the cold with a solution of 4.1 g of sodium hydroxide (about 0.1 mol) in 50 ml of water. The mixture is heated to 60°-70° C. and 7.5 ml (0.12 mol; 20% excess relative to the 3,4-dichlorobenzenethiol) of chloroacetonitrile are added dropwise. The whole is then heated under reflux for about 30 minutes and cooled, the oil which has formed is extracted with ether, the ether solution is washed with dilute sodium hydroxide solution and water, until the pH of the wash waters is neutral, and dried over SO4Mg, the SO4Mg is filtered off, the ether is evaporated off and the expected nitrile, which is in the form of a chromatographically pure oil, is collected.