Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@H:5]([C@H:8]([C@H:13]([C@@H:18]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[O:19][C:20](=[O:22])[CH3:21])[O:14][C:15](=[O:17])[CH3:16])[O:9][C:10](=O)C)C=O)(=[O:3])[CH3:2].[C:28]1([SH:34])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(Cl)Cl>[C:28]1([S:34][C@@H:10]2[O:9][C@H:8]([CH2:5][O:4][C:1](=[O:3])[CH3:2])[C@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:23]2[O:24][C:25](=[O:27])[CH3:26])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Sc1ccccc1
Reactant: CC(=O)OC[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H](OC(C)=O)[C@H](C=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](Sc2ccccc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 95.8 %

Procedure:
To a solution of galactose pentaacetate (5.00 g, 12.8 mmol) in 125 mL of CH2Cl2 is added thiophenol (1.49 mL, 14.1 mmol) and boron trifluoride diethyl ether complex (4.73 mL, 38.4 mmol). The reaction mixture is stirred at room temperature for 5 h and then poured into 200 mL of ice water. The organic layer is washed with saturated NaHCO3 (200 ml), dried over Na2SO4, filtered, concentrated and purified by flash chromatography (35% EtOAc/hexane) to give 5.4 g (96%) of 1-deoxy-1-(phenylthio)-2,3,4,6-tetra-O-acetyl-β-D-galactopyranose 39: Rf 0.22 (35% EtOAc/hexane); 1H NMR (CDCl3, 270 MHz) δ 7.35-7.65 (m, 5 H, ArH), 5.50 (br d, J=3.3 Hz, 1 H, H-4), 5.32 (t, J=9.8 Hz, 1 H, H-2), 5.13 (dd, J=9.8, 3.3 Hz, 1 H, H-3), 4.80 (d, J=9.8 Hz, 1 H, H-1), 4.13-4.32 (m, 2 H, H-6, H-6'), 4.02 (br t, J=6.5 Hz, 1 H, H-5), 2.02-2.23 (4s, 12 H, OAc).
Reaction SMILES: [CH:1]1([C:4]2(O)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[CH2:8][CH2:7][C:6]3[CH:15]=[CH:16][CH:17]=[CH:18][C:5]2=3)[CH2:3][CH2:2]1.C(O)(=O)C.[BrH:24]>C(Cl)Cl>[Br:24][CH2:3][CH2:2][CH:1]=[C:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]1=2
Reactant: OC1(C2CC2)c2ccccc2CCc2ccccc21
Reactant: Br
Solvent: CC(=O)O
Solvent: ClCCl
Product: BrCCC=C1c2ccccc2CCc2ccccc21
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
In a 100-mL round bottom flask, 5-cyclopropyl-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-ol (0.130 g, 0.0006 mol) was added with 1 mL acetic acid. The solid was allowed to dissolve at which point the reaction mixture was chilled to 10° C. Then a solution of 33% hydrobromic acid (0.5 mL hydrobromic acid and 0.5 mL acetic acid; total 1 mL) was added to the flask. The reaction was allowed to stir for an additional 30 min. while reaction progress was monitored by HPLC. Then the reaction mixture was transferred to a separatory funnel and DCM (100 mL) added. The organic layer collected and washed with H2O (1×100 mL) and dried over Na2SO4 for 2 hrs. The resulting product was purified by flash column chromatography on silica gel using MeOH/DCM (Biotage 25M column). The product was confirmed by 1H NMR and LC/MS. (Yield ˜62%)
Reaction SMILES: [CH2:1]([N:26]1[C:30]([CH3:32])([CH3:31])[C:29](=[O:33])[N:28]([C:34]2[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[C:36]([C:42]([F:45])([F:44])[F:43])[CH:35]=2)[C:27]1=[O:46])/[CH:2]=[CH:3]\[CH2:4][N:5]1[C:9]([CH3:11])([CH3:10])[C:8](=[O:12])[N:7]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([C:21]([F:24])([F:23])[F:22])[CH:14]=2)[C:6]1=[O:25].C(Cl)Cl.CC[OH:52].ClC1C=CC=C(C(OO)=O)C=1>ClCCl>[O:52]1[C@@H:2]([CH2:1][N:26]2[C:30]([CH3:32])([CH3:31])[C:29](=[O:33])[N:28]([C:34]3[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[C:36]([C:42]([F:45])([F:44])[F:43])[CH:35]=3)[C:27]2=[O:46])[C@H:3]1[CH2:4][N:5]1[C:9]([CH3:11])([CH3:10])[C:8](=[O:12])[N:7]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([C:21]([F:23])([F:24])[F:22])[CH:14]=2)[C:6]1=[O:25]
Reactant: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1C/C=C\CN1C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)C1(C)C
Reactant: CCO
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1C[C@@H]1O[C@@H]1CN1C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)C1(C)C
Temperature: 25 °C
Reaction time: 96 h
Yield: 50 %

Procedure:
The compound of Example 21 (90 mg, 0.139 mmol) is mixed under argon with 3-metachloroperbenzoic acid (72.5 mg, 0.210 mmol) in anhydrous dichloromethane (10 ml). The mixture is stirred at ambient temperature. The progression of the reaction is monitored by TLC (eluent DCM/EtOH: 95/05). After 4 days, starting compound remains. A fresh quantity of metachloroperbenzoic acid (0.124 g, 0.36 mmol) is added to the reaction medium and the reaction medium is stirred at ambient temperature for another 4 days. The solvent is evaporated off under reduced pressure and the residue is purified by flash chromatography (BIOTAGE 25+M column, gradient dichloromethane/acetone: 0% to 8% of acetone). The expected compound is obtained in the form of a white solid, with a yield of 50%. Melting point: 108-110° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:8]=[CH:9][NH:10][CH:11]=2)[CH:2]=1.C(O)C.[CH:15](=[O:19])/[CH:16]=[CH:17]/[CH3:18]>C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:8]=[CH:9][N:10]([CH:17]([CH3:18])[CH2:16][CH:15]=[O:19])[CH:11]=2)[CH:2]=1
Reactant: C/C=C/C=O
Reactant: c1cncc(-c2c[nH]cn2)c1
Solvent: C1CCOC1
Solvent: CCO
Product: CC(CC=O)n1cnc(-c2cccnc2)c1

Procedure:
To a solution 4pyridin-3-yl-imidazole (10 g, 68.88 mmol) in THF (300 ml) were added ethanol (4.04 ml, 68.88 mmol) and crotonaldehyde (22.83 ml, 275.52 mmol). The resulting mixture was heated under reflux for 18 hours. At this point of time, an additional 2 equiv of crotonaldehyde was added and contiuned to reflux for another 20 hours. TLC analysis indicated the reaction was complete. Solvent was removed in vacuo and the crude aldehyde of formula 18, wherein R7 is methyl and R3 is pyridin-3-yl, which was used without purification.
Reaction SMILES: [C:1]1([CH3:10])[C:2]([C:7](Cl)=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.O.[C-:12]#[N:13].[Na+]>ClCCl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:10][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:12]#[N:13])=[O:8]
Reactant: [C-]#N
Reactant: Cc1ccccc1C(=O)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1ccccc1C(=O)C#N
Reaction time: 2 h

Procedure:
To a stirred solution of o-toluoyl chloride (38.86 g) in dichloromethane (250 ml) at room temperature was added water (20.0 ml) followed immediately by tetrabutylammonium bromide (0.15 g) and sodium cyanide (13.0 g). The reaction mixture was stirred vigorously for 11/2 hours, then filtered. The filtrate was washed with water (2×100 ml) then dried (MgSO4) and evaporated under reduced pressure to give a golden oil. Distillation under vacuum gave 2-methylbenzoyl cyanide, as a colourless oil, bp 47°-50°/0.05 mm. To 85% w/w sulphuric acid (140 ml) at room temperature was added sodium bromide (20 g) followed immediately by the dropwise addition of 2-methylbenzoyl cyanide (34.8 g). The reaction mixture was then heated gently until the exothermic reaction started and then maintained at 70° C. for 10 minutes by cooling. Methanol (400 ml) was added and the mixture heated under reflux for 1 hour, cooled and diluted with ice/water (500 ml). Extraction with diethyl ether gave a golden oil which was distilled under vacuum to give methyl oxo(o-tolyl)acetate, as B colourless oil, bp 75°-85°/0.4 mm.
Reaction SMILES: [CH2:1]([S:8][CH2:9][CH:10]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:11]([OH:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:27])C=1>ClCCl>[CH2:1]([S:8]([CH2:9][CH:10]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:11]([OH:13])=[O:12])=[O:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(O)CCC(CSCc1ccccc1)C(=O)O
Solvent: ClCCl
Product: O=C(O)CCC(CS(=O)Cc1ccccc1)C(=O)O
Temperature: 25 °C
Yield: 68.9 %

Procedure:
To a cooled mixture (-78° C.) of 2-[(benzylsulfanyl)methyl]pentanedioic acid (5.2 g, 19.4 mmol) in dichloromethane (100 ml) was added 3-chloroperbenzoic acid (85%, 3.9 g, 19.4 mmol) with stirring. The reaction mixture was allowed to stir for 1 hour at -78° C., then allowed to warm to room temperature. If starting material was still present according to analysis by TLC, the reaction was cooled again to -78° C. and additional 3-chloroperbenzoic acid (2-4 mmol depending on the intensity of the starting material spot) added and the reaction mixture allowed to warm at room temperature. This was repeated until no more starting material was detected by TLC. The dichloromethane was removed under reduced pressure and the resulting residue was purified by column chromatography to yield 3.8 g (69%) of white solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([O:9][CH2:10][CH2:11][CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:6]=[C:5]([CH2:17][CH3:18])[C:4]=1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]=[O:26])[CH:20]=1)[CH3:2].CO.[BH4-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[CH2:17]([C:5]1[CH:6]=[C:7]([O:9][CH2:10][CH2:11][CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:8]=[C:3]([CH2:1][CH3:2])[C:4]=1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][OH:26])[CH:20]=1)[CH3:18]
Reactant: CCc1cc(OCCCS(C)(=O)=O)cc(CC)c1-c1cccc(C=O)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1cc(OCCCS(C)(=O)=O)cc(CC)c1-c1cccc(CO)c1
Reaction time: 2 h
Yield: 83.8 %

Procedure:
A solution of 2′,6′-diethyl-4′-[3-(methylsulfonyl)propoxy]biphenyl-3-carbaldehyde (2.86 g, 7.64 mmol) in a mixed solvent of methanol (8 mL) and tetrahydrofuran (16 mL) was ice-cooled, sodium borohydride (90%, 0.161 g, 3.82 mmol) was added, and the mixture was stirred for 2 hr under nitrogen atmosphere. The reaction mixture was treated with 10% aqueous citric acid solution, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate hexane=40:80-80:20), and the obtained crystals were recrystallized from heptane-ethyl acetate to give the title compound (2.41 g, yield 84%) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[H-].[Na+].[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Br)=[CH:11][CH:10]=1>CN(C=O)C.O>[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:11][CH:10]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: COCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOCc1ccc(Br)cc1
Temperature: 60 °C
Reaction time: 12 h
Yield: 66.6 %

Procedure:
2-Methoxyethanol (5.0 g) was added to a stirred suspension of sodium hydride (2.64 g of a 60% mineral oil suspension) in DMF (200 ml) at ambient temperature and under an atmosphere of argon. The stirred mixture was heated to 60° C. and then cooled to 5° C. Solid 4-bromobenzyl bromide (15 g) was added in one portion. The mixture was stirred for 12 hours at ambient temperature, then for 1 hour at 60° C. and cooled. The mixture was diluted with iced water (600 ml) and extracted with ethyl acetate (3×200 ml). The ethyl acetate extracts were combined, washed with 2M aqueous hydrochloric acid (100 ml), water (2×100 ml), saturated brine (100 ml), dried (MgSO4) and evaporated. The residue, an oil, was distilled using a short path distillation apparatus (furnace temperature 125° C./0.05 bar) to give 1-(4-bromobenzyloxy)-2-methoxyethane (9.8 g); NMR (CDCl3): 3.39(3H,s), 3.51(4H,m), 4.51(2H,s), 7.21(2H,d) and 7.44(2H,d).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:4][CH:3]=1.F[C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][N:15]2[CH2:16][CH2:17][N:18]([C:22]3[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=3)[CH2:19][CH2:20]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2ccccc2CN2CCNCC2)cc1
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#Cc1ccc(N2CCN(Cc3ccccc3-c3ccc(Cl)cc3)CC2)cc1
Temperature: 130 °C

Procedure:
A solution of EXAMPLE 22C (932 mg, 2.591 mmol) in DMSO (13 mL) was treated with 4-fluorobenzonitrile (408 mg, 3.368 mmol) and K2CO3 (1.788 g, 12.955 mmol), heated at 130° C. for 4 hours, and filtered. The filtrate was partitioned between aqueous NaHCO3 and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined extracts were dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel column chromatography with 20% ethyl acetate/hexanes to provide the desired product. MS (ESI) m/e 388, 390 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[C:6]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18](=[O:25])[N:17]([CH3:26])[CH:16]=2)=[N:7][C:8](S(C)(=O)=O)=[N:9][CH:10]=1.[CH3:32][S:33]([NH2:36])(=[O:35])=[O:34]>>[F:1][C:2]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[C:6]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18](=[O:25])[N:17]([CH3:26])[CH:16]=2)=[N:7][C:8]([NH:36][S:33]([CH3:32])(=[O:35])=[O:34])=[N:9][CH:10]=1
Reactant: CS(N)(=O)=O
Reactant: Cn1cc(-c2nc(S(C)(=O)=O)ncc2Oc2ccc(F)cc2F)c2ccccc2c1=O
Product: Cn1cc(-c2nc(NS(C)(=O)=O)ncc2Oc2ccc(F)cc2F)c2ccccc2c1=O

Procedure:
The title compound of Example 151 was treated with MeSO2NH2 in a manner similar to Example 152, step 6 to give the title compound. 1H NMR (DMSO-d6, 400 MHz) δ 11.50 (s, 1H), 8.59 (s, 1H), 8.25 (s, J=8.0 Hz, 1H), 7.87 (s, 1H), 7.77 (d, J=8.0 Hz, 1H), 7.67 (t, J=8.0 Hz, 1H), 7.54 (t, J=7.2 Hz, 1H), 7.34-7.28 (m, 1H), 7.20-7.13 (m, 1H), 6.90 (t, J=8.8 Hz, 1H), 3.54 (s, 3H), 3.35 (s, 3H). LCMS: 459.0 (M+1)+
Reaction SMILES: [C:1]1([CH:7]([CH3:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:10]Br>>[Br:10][C:4]1[CH:5]=[CH:6][C:1]([CH:7]([CH3:9])[CH3:8])=[CH:2][CH:3]=1
Reactant: CC(C)c1ccccc1
Reactant: BrBr
Product: CC(C)c1ccc(Br)cc1

Procedure:
This example describes the reaction of cumene with liquid bromine to give 4-bromocumene. 10 g of cumene, 5 g of catalyst composite material, zeolite K-L and 2.14 ml bromine were mixed in a batch reactor. The reaction mixture was stirred and heated up to 70° C. After completion of the reaction, the mixture was let to cool to room temperature and analysed by gas-chromatography. The conversion of cumene and the selectivity for 4-bromocumene were found to be 10.7 wt. % and 78.8%, respectiveley.
Reaction SMILES: [C:1]([C:4]([C:18](=O)[CH3:19])=[CH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]#[N:17])=[CH:8][CH:7]=1)(=[O:3])[CH3:2].[NH2:21][C:22]1[CH:27]=[CH:26][NH:25][C:24](=[O:28])[CH:23]=1>C(O)(C)C>[C:1]([C:4]1[CH:5]([C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16]#[N:17])=[CH:8][CH:7]=2)[C:23]2[C:24](=[O:28])[NH:25][CH:26]=[CH:27][C:22]=2[NH:21][C:18]=1[CH3:19])(=[O:3])[CH3:2]
Reactant: CC(=O)C(=Cc1ccc(C#N)c2ccccc12)C(C)=O
Reactant: Nc1cc[nH]c(=O)c1
Solvent: CC(C)O
Product: CC(=O)C1=C(C)Nc2cc[nH]c(=O)c2C1c1ccc(C#N)c2ccccc12

Procedure:
325 mg (1.23 mmol) of 4-(2-acetyl-3-oxobut-1-en-1-yl)-1-naphthonitrile are taken up in 20 ml of isopropanol and, after addition of 151 mg (1.23 mmol) of 4-aminopyridin-2(1H)-one, heated at the reflux temperature for 72 h. The mixture is then concentrated and the residue is purified by preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→95:5). The product fractions are combined, the solvent is removed, and the residue is stirred with diethyl ether. The precipitated product is filtered off and dried under high vacuum. 91 mg (21.2% of theory) of the title compound are obtained.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][C:13]1[N:17]2[N:18]=[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[CH:26]=3)[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1.[CH2:33](I)[CH3:34].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CCOC(C)=O>[CH2:33]([N:30]1[CH2:31][CH2:32][CH:27]([N:25]2[CH:26]=[C:22]([C:19]3[CH:20]=[CH:21][C:16]4[N:17]([C:13]([CH2:12][C:3]5[CH:4]=[C:5]6[C:10](=[CH:11][C:2]=5[F:1])[N:9]=[CH:8][CH:7]=[CH:6]6)=[CH:14][N:15]=4)[N:18]=3)[CH:23]=[N:24]2)[CH2:28][CH2:29]1)[CH3:34]
Reactant: CCI
Reactant: Fc1cc2ncccc2cc1Cc1cnc2ccc(-c3cnn(C4CCNCC4)c3)nn12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCN1CCC(n2cc(-c3ccc4ncc(Cc5cc6cccnc6cc5F)n4n3)cn2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 7-fluoro-6-[6-(1-piperidin-4-yl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-3-ylmethyl]-quinoline (Example 180, 50 mg, 0.117 mmol) and ethyliodide (19 μL, 0.234 mmol) in dioxane (1 mL) was stirred at rt for 2 h. Cs2CO3 (19 mg, 0.059 mmol) was then added and the RM was stirred at rt for 5 h more. The mixture was diluted with EtOAc and washed with NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (CombiFlash® Companion System®, with a 4 g RediSep® silica gel column, DCM/(DCM/MeOH 9:1+NH3)=100:0→0:100) to afford the title compound as a foam (tR 3.10 min (conditions 3), MH+=456.2, 1H-NMR in DMSO-d6: 8.84 (m, 1H); 8.50 (s, 1H); 8.34 (m, 1H); 8.08 (m, 2H); 8.04 (d, 1H); 7.76 (d, 1H); 7.60 (s, 1H); 7.53 (d, 1H); 7.47 (dd, 1H); 4.55 (s, 2H); 4.18 (m, 1H); 2.96 (m, 2H); 2.35 (q, 2H); 1.97 (m, 6H); 1.01 (t, 3H)).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8](=O)[NH:9][CH:10]=[N:11]2)=[CH:6][C:5]=1[O:15][CH3:16])[CH3:2].O=P(Cl)(Cl)[Cl:19]>C1(C)C=CC=CC=1>[Cl:19][C:8]1[C:7]2[C:12](=[CH:13][C:4]([O:3][CH2:1][CH3:2])=[C:5]([O:15][CH3:16])[CH:6]=2)[N:11]=[CH:10][N:9]=1
Reactant: CCOc1cc2nc[nH]c(=O)c2cc1OC
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOc1cc2ncnc(Cl)c2cc1OC
Yield: 96 %

Procedure:
A mixture of 7-ethoxy-6-methoxyquinazolin-4(3H)-one (1.20 g, 5.45 mmol) and POCl3 (3 mL), in toluene (10 mL) was heated at 125° C. for 5 hours. It was concentrated under reduced pressure to dryness. To it was added CH2Cl2 and it was washed with saturated NaHCO3. The organic layer was dried over MgSO4 and concentrated to give 4-chloro-7-ethoxy-6-methoxyquinazoline as solid (1.254 g, 96%). 1H NMR (300 MHz, CDCl3) δ 8.91 (s, 1H), 7.52 (s, 1H), 7.42 (s, 1H), 4.34 (q, 2H), 4.08 (s, 3H), 1.59 (t, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[N+:20]([O-])=O)[CH2:8][CH2:7]1)=[O:5])[CH3:2]>C1COCC1.C(O)C.[Pt]>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][CH:9]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[NH2:20])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(Nc2ccc(F)cc2[N+](=O)[O-])CC1
Agent: [Pt]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC(Nc2ccc(F)cc2N)CC1
Reaction time: 4 h

Procedure:
This 1-ethoxycarbonyl-4-(4-fluoro-2-nitroanilino)piperidine (5.7 g, 18.3 mmol.) was dissolved in THF (50 mL) and diluted with ethanol (100 mL). After addition of 5% platinum/carbon catalyst (1.2 g), the hydrogenation of the nitro functional group was carried out at atmospheric pressure via a balloon over a four hour period. The catalyst was removed and the solvents evaporated to give 1-ethoxycarbonyl-4-(2-amino-4-fluoroanilino)-piperidine as a viscous oil which was used as is.
Reaction SMILES: [CH2:1]1[CH2:23][O:22][C:3]2([CH2:8][CH2:7][C:6](O)([C:9]3[CH:14]=[C:13]([F:15])[C:12]([C:16]([F:19])([F:18])[F:17])=[C:11]([F:20])[CH:10]=3)[CH2:5][CH2:4]2)[O:2]1.CC1C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH2:23]1[CH2:1][O:2][C:3]2([CH2:8][CH2:7][C:6]([C:9]3[CH:14]=[C:13]([F:15])[C:12]([C:16]([F:17])([F:18])[F:19])=[C:11]([F:20])[CH:10]=3)=[CH:5][CH2:4]2)[O:22]1
Reactant: OC1(c2cc(F)c(C(F)(F)F)c(F)c2)CCC2(CC1)OCCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Fc1cc(C2=CCC3(CC2)OCCO3)cc(F)c1C(F)(F)F
Yield: 79.4 %

Procedure:
1,1-Ethylenedioxy-4-hydroxy-4-(3',5'-difluoro-4'-trifluoromethylphenyl)cyclohexane (23 g) was dissolved in toluene (200 ml), followed by adding p-toluenesulfonic acidmonohydrate (5 g) to the solution, stirring the mixture under reflux for one hour, allowing the mixture to cool down, washing the reaction solution with water (200 ml), drying the organic layer over anhydrous MgSO4, and distilling off the solvent, to obtain 1,1-ethylenedioxy-4-(3',5'-difluoro-4'-trifluoromethylphenyl)-3-cyclohexene (17.3 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[N:14][CH:15]=2)=[CH:5][CH:4]=1)#[N:2].[F:16][C:17]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:18]=1[CH2:19]Br>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:10]2[CH:15]=[N:14][CH:13]=[N:12][CH:11]=2)[CH2:19][C:18]2[CH:21]=[CH:22][C:23]([F:25])=[CH:24][C:17]=2[F:16])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(Nc2cncnc2)cc1
Reactant: Fc1ccc(CBr)c(F)c1
Product: N#Cc1ccc(N(Cc2ccc(F)cc2F)c2cncnc2)cc1

Procedure:
Starting compounds: 5-[N-(4-cyanophenyl)amino]pyrimidine and 2,4-difluorobenzyl bromide
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([CH:19]2[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][CH3:28])=[O:26])[CH2:20]2)=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([O:16]C)=[O:15])=[C:10]([F:18])[CH:9]=1.[Li+].[OH-].Cl>C1COCC1.CO>[NH2:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[C:10]([F:18])[CH:9]=2)=[N:6][C:5]([CH:19]2[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][CH3:28])=[O:26])[CH2:20]2)=[CH:4][N:3]=1
Reactant: COC(=O)c1ccc(-c2nc(C3CCCN(C(=O)OC)C3)cnc2N)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)N1CCCC(c2cnc(N)c(-c3ccc(C(=O)O)c(F)c3)n2)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To methyl 3-(5-amino-6-(3-fluoro-4-(methoxycarbonyl)phenyl)pyrazin-2-yl)piperidine-1-carboxylate (50 mg, 0.129 mmol) in THF (4 mL) and MeOH (2 mL) was added 1 M LiOH (0.500 mL, 0.500 mmol). The reaction mixture was stirred at room temperature for 4 h. The reaction mixture pH was adjusted to ˜3 with 2 N HCl, and product was extracted with ethyl acetate. The EtOAc layer was separated, washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was proceeded to next step without purification (40 mg, 83%). LCMS (m/z): 375.2 (MH+), 0.637 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C@H:4]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1)[NH:5][C:6]([C:8]1([CH2:13][CH2:14][CH2:15][CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:12][CH2:11][CH2:10][CH2:9]1)=O.C1COCC1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:46])=CC=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:31])[C@H:4]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1)[NH:5][C:6]([C:8]1([CH2:13][CH2:14][CH2:15][CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[S:46]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)C1(CCCCS(C)(=O)=O)CCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=S)C1(CCCCS(C)(=O)=O)CCCC1
Temperature: 62.5 °C
Reaction time: 48 h
Yield: 44.2 %

Procedure:
To a solution of N-[[1-[4-(methylsulfonyl)butyl]cyclopentyl]carbonyl]-4-nitro-L-phenylalanine methyl ester (33 mmol, 15 g) in toluene (100 mL, stored over 4 Å molecular sieves) and freshly distilled THF (50 mL) was added Lawesson's reagent (33 mmol, 13.35 g, 1.0 equiv.) at room temperature. The solution was heated to 60-65° C. and was stirred for 48 h at which time TLC analysis of the mixture indicated the absence of starting material. The reaction mixture was cooled to room temperature and was poured into saturated sodium bicarbonate solution (200 mL) and extracted with ethyl acetate (3×150 mL). An oil formed in the aqueous layer, which was separated, diluted with water and extracted with ethyl acetate (2×50 mL). The combined ethyl acetate extracts were washed with saturated sodium bicarbonate solution (200 mL), with brine (300 mL), dried (MgSO4), filtered and the solution was concentrated in vacuo. The residual light brown syrup was purified by silica gel column chromatography (hexane:ethyl acetate, 1:1) to obtain 6.87 g (44%) of N-[[1-[4-(methylsulfonyl)butyl]cyclopentyl]thioxo-methyl]-4-nitro-L-phenylalanine methyl ester as a fluffy yellow solid. HRMS: Obs. mass, 493.1438. Calcd. mass, 493.1443 (M+Na).