Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([CH:10]([CH3:12])[CH3:11])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[C:13]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[C:17]([F:23])[CH:16]=1)#[N:14].C([O-])(O)=O.[Na+].O>CN(C=O)C>[C:13]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH:1][CH:2]([CH:10]([CH3:12])[CH3:11])[C:3]([O:5][C:6]([CH3:7])([CH3:9])[CH3:8])=[O:4])=[C:17]([F:23])[CH:16]=1)#[N:14]
Reactant: N#Cc1ccc(CBr)c(F)c1
Reactant: CC(C)C(N)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)C(NCc1ccc(C#N)cc1F)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of tert-butyl 2-amino-3-methylbutanoate (8.5 g, 0.05 mol) in dry DMF (50 mL) under nitrogen, was added 4-cyano-2-fluoro-benzyl bromide (FluoroChem Ltd, 9.4 g, 0.044 mol) and NaHCO3 (10.2 g, 0.12 mol). The resulting mixture was stirred at RT for 16 h. Water (70 mL) was added and the desired product was extracted with ethyl acetate (2×100 mL). The organic layer was washed with water (3×100 mL) and the solvent was dried over Na2SO4 and concentrated under vacuum. The resulted residue was purified by column chromatography using petroleum ether/ethyl acetate as eluent, affording of the title compound as colorless liquid. 1H NMR (DMSO-d6, 400 MHz) δ 7.77 (d, J=10.2 Hz, 1H), 7.67 (t, J=1.5 Hz, 1H), 3.85-3.79 (m, 2H), 2.72 (m, 1H), 2.49 (m, 1H), 1.81 (m, 1H), 1.37 (s, 9H), 0.86 (m, 6H).
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[C:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:23]([Li])[CH2:24][CH2:25]C.C(Br)C=C>C1COCC1>[CH2:25]([C:6]1([C:16]2[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH:21]=2)[C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[CH2:9][CH2:10][C:11]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]1=2)[CH:24]=[CH2:23]
Reactant: [Li]CCCC
Reactant: CN1CCC(=C2c3ccccc3CCc3ccccc32)CC1
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCC1(C2=CCN(C)CC2)c2ccccc2CCc2ccccc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 70.2 %

Procedure:
Dissolved 4-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-methylpiperidine (10 g, 34.6 mmol) in 200 mL of dry THF, and cooled to -78° C. under a nitrogen atmosphere. Added n-butyl lithium (15.2 mL of 2.5M in hexane, 38.0 mmol) dropwise via syringe. Warmed to 0° C, and stirred for 60 mins. Recooled to -78° C, and added allyl bromide (4.6 g, 3.3 mL, 38.0 mmol) dropwise via syringe. Warmed to room temperature slowly, and stirred for 5 hours. Added saturated NH4Cl, and extracted with ether. Dried the combined organic extracts with MgSO4, filtered, and evaporated. Purified the crude product by flash chromatography on silica gel eluting with 5:95:0.1MeOH:EtOAc:NH4OH. Combined appropriate fractions, and evaporated to give 8.0 g (70% yield) of 4-[10,11-dihydro-5-(2-propenyl)-5H-dibenzo[a,d]cyclohepten-5-yl]-1-methyl-1,2,5,6-tetrahydropyridine as an oil. Dissolved free base in ether, and added 19 weight % HCl-EtOH until acidic. Added additional ether, and let stand to precipitate hydrochloride salt. Recrystallized salt from acetonitrile-ether.
Reaction SMILES: [O:1]1[C:5](=[O:6])[CH2:4][C@@H:3]2[CH2:7][C:8]3[C:13]([CH2:14][C@@H:2]12)=[CH:12][CH:11]=[CH:10][CH:9]=3.[CH3:15][NH:16][CH3:17]>C1COCC1>[CH3:15][N:16]([CH3:17])[C:5](=[O:6])[CH2:4][C@@H:3]1[CH2:7][C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:14][C@H:2]1[OH:1]
Reactant: O=C1C[C@@H]2Cc3ccccc3C[C@H]2O1
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)C(=O)C[C@@H]1Cc2ccccc2C[C@H]1O
Yield: 97 %

Procedure:
A mixture of 18.8 (0.10 mol) of trans-3a, 4,9,9a-tetrahydronaphtho[2,3-b]furan-2(3H)-one, 35 ml of anhydrous dimethylamine, and 35 ml of dry THF is heated in a small Parr bomb at 100° for 3 days. The cooled reaction mixture is then taken to dryness in vacuo, and the residue triturated with ether to give 22.5 g (97%) of crystalline solid after drying in vacuo.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9]([OH:10])=[C:8]([C:11]([O:13]CC)=[O:12])[CH:7]=[N:6][N:5]2[CH:16]=1.[OH-].[Na+]>CO.C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:9]([OH:10])=[C:8]([C:11]([OH:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:16]=1
Reactant: CCOC(=O)c1cnn2cc(F)cc2c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cnn2cc(F)cc2c1O
Temperature: 65 °C
Reaction time: 3 h
Yield: 89.9 %

Procedure:
To a solution of ethyl 6-fluoro-4-hydroxypyrrolo[1,2-b]pyridazine-3-carboxylate (700 mg, 3.12 mmol) in MeOH (3 mL) and THF (3 mL) was added 3 N aq. sodium hydroxide (5.20 mL, 15.61 mmol) and the resulting mixture was stirred at 65° C. for 3 h. The mixture was cooled and concentrated to remove the MeOH and THF and the obtained residue was cooled in an ice bath and 3N aq. HCl was added dropwise with stirring until pH of the mixture was ˜2. The resulting slurry was stirred for 30 min, and filtered to collect the solid. The solid was rinsed with water and dried to afford 550 mg (90%) of the title compound as a white solid. HPLC (condition B): retention time=2.37 min. LCMS (condition B): m/z 197 +ve.
Reaction SMILES: Cl[C:2]1[N:3]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][OH:20])[CH:14]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[OH:20][CH2:19][C:15]1[CH:14]=[C:13]([N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]([CH:11]=[O:12])=[C:2]2[N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:18]=[CH:17][CH:16]=1
Reactant: C1CNCCN1
Reactant: O=Cc1c(Cl)n(-c2cccc(CO)c2)c2ccccc12
Product: O=Cc1c(N2CCNCC2)n(-c2cccc(CO)c2)c2ccccc12
Yield: 32 %

Procedure:
2-Chloro-1-(3-hydroxymethylphenyl)-1H-indole-3-carboxaldehyde is reacted with piperazine as described in Step 2 of Example 29 to afford 1-(3-hydroxymethylphenyl)-2-(piperazin-1-yl)-1H-indole-3-carboxaldehyde (32% yield) as a red solid. ESI/MS 336 (M+H); RT 2.37 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([OH:24])=O)[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6].[CH2:25]([NH:27][CH2:28][CH3:29])[CH3:26].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([N:27]([CH2:28][CH3:29])[CH2:25][CH3:26])=[O:24])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6]
Reactant: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)O)c(Cl)c1
Reactant: CCNCC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCN(CC)C(=O)c1ccc(C(=O)NCc2nc3cc(Cl)ccc3[nH]2)cc1Cl

Procedure:
Prepared analogously to Example 1d from 3-chloro-N-(5-chloro-1H-benzimidazol-2-ylmethyl)-4-carboxybenzamide, diethylamine, TBTU, and triethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.59 minutes; C20H20Cl2N4O2 (419.31); mass spectrum: (M+H)+=419.2.
Reaction SMILES: [CH:1]1[CH:10]=[C:9]2[C:11]([O:13][C:14](=O)[C:7]3=[C:8]2[C:3](=[C:4]([S:16]([O-:19])(=[O:18])=[O:17])[CH:5]=[CH:6]3)[CH:2]=1)=[O:12].[K+:20].Cl.[NH2:22][OH:23]>N1C=CC=CC=1>[OH:23][N:22]1[C:14](=[O:13])[C:7]2[CH:6]=[CH:5][C:4]([S:16]([O-:19])(=[O:18])=[O:17])=[C:3]3[C:8]=2[C:9](=[CH:10][CH:1]=[CH:2]3)[C:11]1=[O:12].[K+:20]
Reactant: O=C1OC(=O)c2ccc(S(=O)(=O)[O-])c3cccc1c23
Reactant: NO
Agent: Cl
Agent: [K+]
Solvent: c1ccncc1
Product: O=C1c2cccc3c(S(=O)(=O)[O-])ccc(c23)C(=O)N1O
Yield: 102.2 %

Procedure:
4-Sulfo-1,8-naphthalic anhydride potassium salt (2.0 g, 6.2 mmol) and hydroxylamine hydrochloride (0.9 g, 12.4 mmol) were reacted in pyridine (50 mL) following the procedure of Example 1. The solids formed were filtered, washed with ethanol, and dried to give 2.1 g of the title compound, mp>380° C.;
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][NH2:10].C(N(CC)CC)C.[C:18](OC(=O)C)(=[O:20])[CH3:19]>C(Cl)Cl.Cl>[Br:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][NH:10][C:18](=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: NCc1ccccc1Br
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCc1ccccc1Br
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of commercially available 1-(2-bromophenyl)methanamine hydrochloride salt (1 eq.) in CH2Cl2 (0.3M) at room temperature was added triethylamine (2.1 eq) then acetic anhydride (1.1 eq.). The mixture was stirred at room temperature for 6 h, poured in aqueous HCl (0.5N) and extracted with CH2Cl2. The organic extract was dried over MgSO4 filtered and concentrated to afford the desired compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([NH2:12])[CH:10]=2)[N:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:4]=1.[Cl:22][C:23]1[C:28]([C:29](O)=[O:30])=[C:27]([F:32])[C:26]([NH:33][S:34]([CH2:37][CH2:38][CH3:39])(=[O:36])=[O:35])=[CH:25][CH:24]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[Cl:22][C:23]1[C:28]([C:29]([NH:12][C:9]2[CH:10]=[C:11]3[C:3]([O:2][CH3:1])=[N:4][N:5]([CH2:13][C:14]4[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=4)[C:6]3=[N:7][CH:8]=2)=[O:30])=[C:27]([F:32])[C:26]([NH:33][S:34]([CH2:37][CH2:38][CH3:39])(=[O:36])=[O:35])=[CH:25][CH:24]=1
Reactant: COc1ccc(Cn2nc(OC)c3cc(N)cnc32)cc1
Reactant: CCCS(=O)(=O)Nc1ccc(Cl)c(C(=O)O)c1F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)Nc1ccc(Cl)c(C(=O)Nc2cnc3c(c2)c(OC)nn3Cc2ccc(OC)cc2)c1F
Temperature: 25 °C
Reaction time: 48 h
Yield: 68.6 %

Procedure:
3-Methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-5-amine (0.020 g, 0.070 mmol), 6-chloro-2-fluoro-3-(propylsulfonamido)benzoic acid (0.023 g, 0.077 mmol), EDCI (0.015 g, 0.077 mmol), and HOBt (0.010 g, 0.077 mmol) were dissolved in DMF (1.0 mL) and stirred for two days at room temperature. The solution was partitioned between water and EtOAc. The organic layers were washed with water (3×), brine, dried over Na2SO4 and concentrated to an oil. The residue was purified by column chromatography (2:1 hexanes/EtOAc) giving 6-chloro-2-fluoro-N-(3-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide (0.027 g, 68%) as a solid.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][N:9]2[C:22]=1I)=[O:4].[OH-].[K+].O.[CH3:29][S:30]SC>N1C=CC=CC=1.[Cu]>[F:1][C:2]([F:25])([F:24])[C:3]([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][N:9]2[C:22]=1[S:30][CH3:29])=[O:4]
Reactant: O=C(c1ccccc1)c1ccc2nc(NC(=O)C(F)(F)F)c(I)n2c1
Reactant: CSSC
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Product: CSc1c(NC(=O)C(F)(F)F)nc2ccc(C(=O)c3ccccc3)cn12
Temperature: 104 °C
Reaction time: 0.25 h
Yield: 81.4 %

Procedure:
The 2-trifluoroacetamido-3-iodo-6-benzoyl-imidazo[1,2-a]pyridine (1.00 g, 2.17 mmol) was dissolved in 20 ml of pyridine (predried over KOH and then molecular sieve 3A , 0.04% H2O) under argon atmosphere. Copper bronze (207 mg, 3.25 mmol) was added. To the golden suspension in brown solution was added methyldisulfide (160 μl, 2.17 mmol) via syringe. The reaction mixture was heated for 1 hour at 104° C. then 68 hours at 100° C. The evolution of the reaction was followed by NMR (in each case, a sample was taken, hydrolized and washed with ammonia/NH4Cl (1:9) before checking by NMR). When the reaction was complete, the reaction mixture was diluted in 3 L of EtOAc and stirred for 15 minutes. Two liters of NH4OH/NH4Cl 1:9 were added and the mixture was strongly stirred for 30 minutes in a 10 L funnel. The layers were separated and 2 L of NH4OH/NH4Cl (1:9) were added to the organic layer. The mixture was again stirred for 30 minutes and then left without stirring for 5 to 10 minutes. The layers were separated and the organic layer was washed with brine. The organic layers were removed in vacuo and the resulting brown solid was subjected to a vary rapid column chromatography (MeOH/CH2Cl2, 2:98) to give 670 mg (81%) of a yellow solid. NMR
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([Cl:9])[CH:3]=1.[Li]CCCC.[CH3:15][C:16]([CH3:18])=[O:17]>C1COCC1>[Cl:9][C:4]1[CH:3]=[C:2]([C:16]([OH:17])([CH3:18])[CH3:15])[CH:7]=[CH:6][C:5]=1[CH3:8]
Reactant: Cc1ccc(Br)cc1Cl
Reactant: CC(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(C(C)(C)O)cc1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a solution of 4-bromo-2-chlorotoluene (10 g, 48.7 mmol) in THF was added n-BuLi at −78° C. After the reaction mixture was stirred at −78° C. for 30 minutes, dry acetone was slowly added. The resulting content was maintained at −78° C. for 3 hours and slowly warmed up to RT overnight. The reaction mixture was then partitioned between ethyl acetate and water. The ethyl acetate layer was then washed with brine, dried over Na2SO4, filtered, and the solvent evaporated in vacuo to yield a crude oil. The crude solid was purified via flash chromatography (30% EtOAc in n-hexane) yielded the title compound as an oil (7.2 g, 80%)
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[C:3]=1[F:13].C([O-])([O-])=O.[Cs+].[Cs+].[Cl:20][CH2:21][CH2:22][CH2:23]I>>[Cl:20][CH2:21][CH2:22][CH2:23][N:6]1[C:5]2[CH:11]=[CH:12][C:2]([F:1])=[C:3]([F:13])[C:4]=2[O:9][CH2:8][C:7]1=[O:10]
Reactant: O=C1COc2c(ccc(F)c2F)N1
Reactant: ClCCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=C1COc2c(ccc(F)c2F)N1CCCCl
Yield: 93.2 %

Procedure:
7,8-Difluoro-4H-benzo[1,4]oxazin-3-one (81MF2082a) (0.119 g, 0.64 mmol), Cs2CO3 (0.314 g, 0.96 mmol) and 3-chloro-1-iodopropane (0.144 g, 0.70 mmol) were mixed according to GP5 giving the crude title compound (0.156 g); 1H NMR (CDCl3) d 6.89-6.82 (m, 1H), 6.78-6.74 (m, 1H), 4.68 (s, 2H), 4.08 (t, J=7.2 Hz, 2H), 3.63 (t, J=6.4 Hz, 2H), 2.18-2.10 (m, 2H); 13CNMR (CDCl3) d 163.5, 147.7 (q, J=245.6 Hz, J=10.4 Hz), 141.0 (q, J=249.4 Hz, J=15.7 Hz), 135.5, 126.2, 109.9 (d, J=18.4 Hz), 108.6 (q, J=7.6 Hz, J=4.2 Hz), 67.8, 42.3, 39.4, 30.0.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]([C:6](=O)[CH2:7][NH:8][C:9](=O)[O:10]CC)=[CH:4][CH:3]=1.O.[NH2:18][NH2:19]>C(O)CCC>[OH:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]2[CH2:7][NH:8][C:9](=[O:10])[NH:18][N:19]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)NCC(=O)c1ccc(O)cc1
Reactant: NN
Solvent: CCCCO
Solvent: O
Product: O=C1NCC(c2ccc(O)cc2)=NN1
Yield: 54 %

Procedure:
A mixture of 20 g of ethyl N-(p-hydroxyphenacyl)carbamate (prepared as described in Preparation 6), 56 g of 80% hydrazine hydrate and 100 ml of butanol was heated under reflux for 30 hours, whilst stirring. The reaction mixture was then concentrated by evaporation under reduced pressure, and the residue was washed with ethanol to give 9.25 g of the title compound as crystals, melting at 266°-269° C. (with decomposition).
Reaction SMILES: [C:1]([O:9][CH2:10][C:11]([OH:13])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:16])=O>>[C:1]([O:9][CH2:10][C:11]([Cl:16])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)COC(=O)c1ccccc1
Product: O=C(Cl)COC(=O)c1ccccc1

Procedure:
A mixture of benzoyloxyacetic acid (5.4 g.) and thionyl chloride (50 ml.) was stirred at 70°-80° C. for an hour and then excess thionyl chloride was distilled off under reduced pressure to give benzoyloxyacetyl chloride. A solution of benzoyloxyacetylchloride obtained above in acetone (10 ml.) was added dropwise to a solution of 3-(N-hydroxyamino)propylphosphonic acid (1.64 g.) in a mixture of water (16 ml.) and acetone (20 ml.) over 30 minutes interval with stirring under ice-cooling and maintaining carefully the pH at around 7-8, together with by adding dropwise a 5% aqueous sodium bicarbonate solution and stirring was continued for additional 30 minutes.
Reaction SMILES: [Cl:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([CH2:30][CH3:31])=[C:12]([C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21]Cl)=[CH:15][CH:14]=3)=[CH:7][C:5]=2[CH:6]=1.[N:32]1(C(OC(C)(C)C)=O)[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>CO>[Cl:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([CH2:30][CH3:31])=[C:12]([C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][N:32]4[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]4)=[CH:17][CH:18]=3)=[CH:7][C:5]=2[CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCC(=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1)c1ccc2oc(Cl)cc2c1
Solvent: CO
Product: CCC(=C(c1ccc(O)cc1)c1ccc(OCCN2CCNCC2)cc1)c1ccc2oc(Cl)cc2c1

Procedure:
According to the same procedure as example 1, step E described, 4-(2-(2-chlorobenzofuran-5-yl)-1-(4-(2-chloroethoxy)phenyl)but-1-enyl)phenol (70 mg, 1.0 eq, made by example 11, step D) was reacted with tert-butyl piperazine-1-carboxylate (500 mg) in MeOH (3 mL) under reflux and separated via column chromatography, followed by treatment with 1 mL trifluoroacetic acid in 3 mL CH2Cl2 and then purified by column chromatography to give the desired product (Z/E=1/1) as a white solid. m/z=503[M+1]+.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:43]([O:47][CH2:48][CH3:49])(=[O:46])[CH:44]=[CH2:45]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:4][C:3]1[CH:5]=[CH:6][C:7]([O:9][C:10]([F:13])([F:12])[F:11])=[CH:8][C:2]=1/[CH:45]=[CH:44]/[C:43]([O:47][CH2:48][CH3:49])=[O:46]
Reactant: Nc1ccc(OC(F)(F)F)cc1Br
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1cc(OC(F)(F)F)ccc1N
Temperature: 120 °C

Procedure:
To a mixture of 2-bromo-4-(trifluoromethoxy)aniline (1.00 mmol), triethylamine (1.5 mmol) and P(o-tol)3 (0.40 mmol) in DMF (0.5 M) in a glass pressure tube under nitrogen gas were added ethyl acrylate (1.0 mmol) and palladium acetate (0.20 mmol). The tube was sealed and heated to 120° C. for 18 h. The resulting solution was concentrated under vacuum and purified by column chromatography. Retention time (min)=2.467, method [1], MS (ESI) 276.1 (M+H).
Reaction SMILES: Br[CH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=1.[C:13]([O-:16])(=[O:15])[CH3:14].[K+]>C(#N)C>[C:13]([O:16][CH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=1)(=[O:15])[CH3:14]
Reactant: CCOC(=O)c1csc(CBr)n1
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1csc(COC(C)=O)n1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
2.7 g (10.80 mmol) of ethyl 2-(bromomethyl)thiazole-4-carboxylate are dissolved in 108 mL of acetonitrile. 2.225 g (22.67 mmol) of potassium acetate are added and the medium is stirred at room temperature for 14 hours.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=2)[CH2:11][N:12]2[C:17](=[O:18])[CH:16]=[CH:15][C:14]([C:19]3[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=3)=[N:13]2)=[N:6][CH:7]=1.[O:28]1CCC[CH2:30][CH:29]1OCCO.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl.C1COCC1>[OH:28][CH2:29][CH2:30][O:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=2)[CH2:11][N:12]2[C:17](=[O:18])[CH:16]=[CH:15][C:14]([C:19]3[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=3)=[N:13]2)=[N:6][CH:7]=1
Reactant: Cn1cc(-c2ccc(=O)n(Cc3cccc(-c4ncc(O)cn4)c3)n2)cn1
Reactant: OCCOC1CCCCO1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cn1cc(-c2ccc(=O)n(Cc3cccc(-c4ncc(OCCO)cn4)c3)n2)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
252 mg of 2-[3-(5-hydroxypyrimidin-2-yl)benzyl]-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one (0.7 mmol) are suspended in abs. THF under a protective-gas atmosphere in a 25 ml three-necked flask, 0.19 ml of 2-(tetrahydropyran-2-yloxy)ethanol (1.4 mmol) and 367 mg of triphenylphosphine (1.4 mmol) are added, and the mixture is stirred at RT for 30 min. 275 μl of diisopropyl azodicarboxylate (1.4 mmol) are subsequently added dropwise, and the reaction mixture is stirred at RT for a further 2 h. For work-up, the reaction mixture is diluted with 20 ml of dichloromethane, washed with 10 ml of water, dried over sodium sulfate, evaporated to dryness and purified by chromatography. (silica gel: MTB ether->DCM->DCM: 30% of MeOH). The THP-protected product is stirred at RT for 20 h in 5 ml of 4 N HCl in dioxane. The reaction solution is evaporated to dryness and crystallised from methanol/diethyl ether, giving “A294”; ESI 405; m.p. 182-3° C.
Reaction SMILES: [CH2:1]([N:4]1[C:9]([CH3:10])=[CH:8][C:7]([OH:11])=[CH:6][C:5]1=[O:12])[CH:2]=[CH2:3].C1C(=O)N(Br)C(=O)C1.[Cl:21]C(Cl)C(O)=O>CC#N>[CH2:1]([N:4]1[C:9]([CH3:10])=[CH:8][C:7]([OH:11])=[C:6]([Cl:21])[C:5]1=[O:12])[CH:2]=[CH2:3]
Reactant: O=C(O)C(Cl)Cl
Reactant: C=CCn1c(C)cc(O)cc1=O
Agent: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: C=CCn1c(C)cc(O)c(Cl)c1=O
Reaction time: 2 h
Yield: 58.4 %

Procedure:
To a stirred solution of 1-allyl-4-hydroxy-6-methylpyridin-2(1H)-one (500 mg, 3.0 mmol) in CH3CN (10 ml), at rt, was added sequentially n-bromosuccinimide (440 mg, 3.3 mmol) and dichloroacetic acid (546 μl, 6.62 mmol). The resulting mixture was stirred for 2 h. The heterogeneous mixture was filtered and the solid was washed with additional CH3CN to give 350 mg (59%) of the desired product as a tan solid. 1H-NMR (DMSOd6/300 MHz) δ 11.16 (s, 1H), 5.98-5.86 (m, 2H), 5.12 (dd, J=10.5, 1.5 Hz, 1H), 4.89 (dd, J=17.1, 1.5 Hz, 1H), 4.63-4.61 (m, 2H), 2.29 (s, 3H). ES-HRMS m/z 200.050 (M+H calcd for C9H11ClNO2=200.0470)
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[C:6]([F:9])[C:5]([CH3:10])=[CH:4][CH:3]=1.C1OCCOCCOCCOCCOCCOC1.CC(C)([O-])C.[K+].F[C:36]1[CH:37]=[C:38]([CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1)[C:39]#[N:40]>CS(C)=O.O>[Cl:1][C:2]1[C:7]([O:8][C:36]2[CH:37]=[C:38]([CH:41]=[C:42]([C:44]([F:45])([F:47])[F:46])[CH:43]=2)[C:39]#[N:40])=[C:6]([F:9])[C:5]([CH3:10])=[CH:4][CH:3]=1
Reactant: N#Cc1cc(F)cc(C(F)(F)F)c1
Reactant: Cc1ccc(Cl)c(O)c1F
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc(Cl)c(Oc2cc(C#N)cc(C(F)(F)F)c2)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.2 %

Procedure:
To a solution of 6-chloro-2-fluoro-3-methylphenol (8.49 g, 52.9 mmol) and 18-crown-6 (13.98 g, 52.9 mmol) in dimethyl sulfoxide (80 ml) was added potassium t-butoxide (20% wt solution in THF) (31.2 g, 55.5 mmol) (31.2 mL) and the mixture was stirred at rt for 30 minutes. Next, 3-fluoro-5-(trifluoromethyl)benzonitrile (10.00 g, 52.9 mmol) was added and the mixture was heated with stirring for 5 hours at 135° C. The reaction mixture was cooled to 0° C., poured into 700 mL water, and the precipitate was filtered off to give the title compound (12.6 g, 38.2 mmol, 72% yield) as a grey solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.10 (s, 1H), 7.80 (s, 1H), 7.74 (s, 1H), 7.39-7.49 (m, 1H), 7.34 (t, 1H), 2.28 (s, 3H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[F:12].[F:13][C:14]1[CH:15]=[C:16]([C:30]2([OH:34])[CH2:33][CH2:32][CH2:31]2)[CH:17]=[C:18]([F:29])[C:19]=1B1OC(C)(C)C(C)(C)O1>>[F:13][C:14]1[CH:15]=[C:16]([C:30]2([OH:34])[CH2:31][CH2:32][CH2:33]2)[CH:17]=[C:18]([F:29])[C:19]=1[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[F:12]
Reactant: CC1(C)OB(c2c(F)cc(C3(O)CCC3)cc2F)OC1(C)C
Reactant: COC(=O)c1ccc(F)c(Br)n1
Product: COC(=O)c1ccc(F)c(-c2c(F)cc(C3(O)CCC3)cc2F)n1
Yield: 71 %

Procedure:
Method 1 was followed using methyl 6-bromo-5-fluoropicolinate (1.0 equiv.) and 1-(3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobutanol (1.6 equiv.) at 100° C. for 30 min in microwave to give methyl 6-(2,6-difluoro-4-(1-hydroxycyclobutyl)phenyl)-5-fluoropicolinate in 71% yield. LC/MS=338.0 (MH+), Rt=0.85 min.