Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)[O:3]1.C(=O)([O-])[O-].[K+].[K+].[CH2:25]([O:27][CH2:28]Cl)[CH3:26]>C(#N)C>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:18])([CH3:1])[O:3][B:4]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([O:15][CH2:28][O:27][CH2:25][CH3:26])=[O:14])=[CH:11][CH:10]=2)[O:5]1
Reactant: CCOCCl
Reactant: CC1(C)OB(c2ccc(C(=O)O)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOCOC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 65 °C
Yield: 84 %

Procedure:
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (0.50 g, 2.02 mmol) was dissolved in 20 mls of dry acetonitrile. To this solution was added powdered potassium carbonate (0.42 g, 3.02 mmol) followed by chloromethyl ethyl ether (0.24 mls, 2.42 mmol). This mixture was warmed to 65° C. for 2 hours, then allowed to cool to room temperature, filtered and the filtrate concentrated to give ethoxymethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate as a solid (84%). This material was taken onto the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)=[C:5]([C:7]([O:9]C)=[O:8])[N:6]=1.[OH-].[Na+]>O1CCCC1.O>[Cl:1][C:2]1[S:3][C:4]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)=[C:5]([C:7]([OH:9])=[O:8])[N:6]=1
Reactant: COC(=O)c1nc(Cl)sc1CCc1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1nc(Cl)sc1CCc1cccc(Cl)c1

Procedure:
The product from step (ii) (3.46 g) was treated with sodium hydroxide (0.7 g) in tetrahydrofuran (15 ml) and water (15 m) at room temperature. After 3 h the mixture was partitioned between 2M HCl and ethyl acetate. The organic phase was collected, dried (MgSO4) and solvent evaporated under reduced pressure to leave a colourless solid.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[I:20]I.N1C=CN=C1.[C:27]([O:31][C:32](=[O:39])[NH:33][CH2:34][CH2:35][CH2:36][CH2:37]O)([CH3:30])([CH3:29])[CH3:28]>C(Cl)Cl>[C:27]([O:31][C:32](=[O:39])[NH:33][CH2:34][CH2:35][CH2:36][CH2:37][I:20])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)NCCCCO
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCCI
Reaction time: 0.75 h

Procedure:
To a suspension of PPh3-resin (16.4 g, 21.1 mmol) in methylene chloride (150 mL) at 0° C. is added iodine (5.4 g, 21.2 mmol) and imidazole (1.66 g, 24.4 mmol) then stirring is continued at 0° C. for 45 min. To this is added (4-hydroxybutyl)-carbamic acid tert-butyl ester (2.0 g, 10.6 mmol) and the suspension is refluxed for 2 h. The suspension is filtered and the organic layer is washed with a saturated sodium bisulfite solution, water and brine, and dried over sodium sulfate. The solvent is removed under reduced pressure to afford the title compound as pale yellow liquid: 1H NMR (CDCl3) δ 4.51 (s, 1H), 3.21-3.17 (t, J=6.82 Hz, 2H), 3.16-3.11 (q, J=6.82 Hz, 2H), 1.88-1.81 (m, 2H), 1.62-1.55 (m, 2H), 1.43 (s, 9H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][C:7]1[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]2[C:8]=1[CH:9]=[C:10]([C:17]([O:19][CH3:20])=[O:18])[NH:11]2.[OH-].[Na+].CN([CH:26]=[O:27])C>>[CH:26]([C:9]1[C:8]2[C:12](=[C:13]([CH3:16])[CH:14]=[CH:15][C:7]=2[CH3:6])[NH:11][C:10]=1[C:17]([O:19][CH3:20])=[O:18])=[O:27]
Reactant: COC(=O)c1cc2c(C)ccc(C)c2[nH]1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1[nH]c2c(C)ccc(C)c2c1C=O
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 26 %

Procedure:
A 500-ml 3-necked flask dried with heating was charged with 71 ml of anhydrous DMF. Then 21.5 ml (230 mmol) of phosphorus oxychloride was added dropwise at O° C. over a period of 40 minutes and stirring was continued until the solution turned red. A solution of 50 g (246 mmol) of methyl 4,7-dimethylindole-2-carboxylate in 200 ml of anhydrous DMF was added dropwise at 20°-30° C. over a period of at least 30 minutes, and the reaction mixture was stirred at 90° C. for 2 hours. The reaction mixture was poured upon 500 g of ice and made basic by gradually adding 225 ml of aqueous solution of 40 g of sodium hydroxide. The solution thus obtained was refluxed for 1 minute and immediately filtered. The crystals precipitated were washed with 100 ml of water four times and dried under reduced pressure. The crude product was purified by silica gel column chromatography to provide 29.5 g of light yellow crystals. Yield: 26%
Reaction SMILES: [CH2:1]([O:3][C:4](=O)[CH2:5][N:6]([CH3:8])[CH3:7])[CH3:2].Br[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1>>[CH3:7][N:6]([CH2:5][CH:4]1[CH2:14][CH:15]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[C:16]2[C:1](=[CH:2][CH:13]=[CH:12][CH:11]=2)[O:3]1)[CH3:8]
Reactant: CCOC(=O)CN(C)C
Reactant: Cc1ccc(Br)cc1
Product: Cc1ccc(C2CC(CN(C)C)Oc3ccccc32)cc1

Procedure:
The process of example 4 was repeated using N,N-dimethylglycine ethyl ester in place of the N,N-dimethylalanine ethyl ester in part (a), and using 4-bromotoluene in place of the 4-bromochlorobenzene in part (c) to yield the title compound, m.p. 114°-116° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:33][CH2:32][C:14]2([C:18](=[O:19])[N:17]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]4NN=[N:29][N:28]=4)=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)[CH2:13][CH2:12]1)(=[O:10])=[O:9].[C:34](OC(=O)C)(=[O:36])[CH3:35]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:33][CH2:32][C:14]2([C:18](=[O:19])[N:17]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]4[O:36][C:34]([CH3:35])=[N:29][N:28]=4)=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)[CH2:13][CH2:12]1)(=[O:9])=[O:10]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1N(c2ccc(Cc3nnn[nH]3)cc2)CCC12CCN(S(=O)(=O)c1ccccc1Cl)CC2
Solvent: ClCCl
Product: Cc1nnc(Cc2ccc(N3CCC4(CCN(S(=O)(=O)c5ccccc5Cl)CC4)C3=O)cc2)o1

Procedure:
This material was obtained essentially following a procedure described in the literature (Jurisic et al, Synth. Comm. 1994, p 1575) from above 8-(2-chloro-benzenesulfonyl)-2-[4-(1H-tetrazol-5-ylmethyl)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one (135 mg) on treatment with acetic anhydride (2 ml), in CH2Cl2 (2 ml), heating at reflux for 30 minutes and subsequent usual aqueous work-up to give the desired 8-(2-chloro-benzenesulfonyl)-2-[4-(5-methyl-[1,3,4]oxadiazol-2-ylmethyl)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one (133 mg) as a light brown crystalline solid. MS (ESI): 501.1 (MH+).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:41])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([CH:38]([CH3:40])[CH3:39])[CH:33]=2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:38]([C:34]1[CH:33]=[C:32]([C:28]2[CH:27]=[C:26]([C:24]3[CH2:23][C:22](=[O:41])[NH:21][C:9]4[CH:10]=[C:11]([C:17]([F:19])([F:20])[F:18])[C:12]([O:14][CH2:15][CH3:16])=[CH:13][C:8]=4[N:7]=3)[CH:31]=[CH:30][CH:29]=2)[CH:37]=[CH:36][N:35]=1)([CH3:39])[CH3:40]
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(C(C)C)c3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccnc(C(C)C)c3)c1)=N2

Procedure:
The title compound was prepared from [2-{3-[3-(2-isopropyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-ethoxy-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M254) (0.32 g, 0.55 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (200 mg, 78%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([C:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>CN(C)C=O>[NH2:1][C:2]1[CH:11]=[C:10]([C:12]([O:14][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1ccc(C(=O)[O-])cc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(=O)OCc2ccccc2)cc1N
Temperature: 25 °C
Reaction time: 15.5 h
Yield: 70 %

Procedure:
After dissolving 1-methyl 2-aminoterephthalate (8.00 g, 41.1 mmol) in dimethylformamide (80 ml), anhydrous potassium carbonate (6.25 g, 45.1 mmol) and benzyl bromide (4.12 ml, 43.1 mmol) were added and the mixture was stirred at room temperature for 15.5 hours. An excess of triethylamine was added, and after stirring for an additional 10 minutes at room temperature, ice water was added and extraction was performed with ethyl acetate. The ethyl acetate layer was washed with water and brine and then dried over anhydrous magnesium sulfate. Filtration was performed with silica gel-alumina and the solvent was distilled off under reduced pressure. IPE was added to the obtained oil for crystallization, and the crystals were filtered off. The filtrate was concentrated and then the same procedure was repeated twice to yield the title compound (8.21 g) as a light yellow powder.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[B-](F)(F)F.NC1O[C:22]([CH:33]([CH3:35])[CH3:34])=[N+:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]=12>C(#N)C>[CH:33]([C:22]1[N:23]2[CH:32]=[CH:31][C:30]3[C:25]([C:24]2=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:26][CH:27]=[CH:28][CH:29]=3)([CH3:35])[CH3:34]
Reactant: CC(C)c1oc(N)c2c3ccccc3cc[n+]12
Reactant: CCOC(=O)C#Cc1ccccc1
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: CCOC(=O)c1c(-c2ccccc2)c2c3ccccc3ccn2c1C(C)C
Yield: 16.4 %

Procedure:
Ethyl phenylpropiolate (10.1 g, 0.058 mol) was added with stirring to a solution of 1-amino-3-isopropyloxazolo[4,3-a]isoquinolinium tetrafluoroborate (9.1 g) in acetonitrile (90 ml) at 50° C. The solution was then heated at reflux for 30 minutes and it was then evaporated in vacuo to give a viscous orange-brown oil, which was extracted with hot petroleum ether (b.p. 60°-80° C.)(4×100 ml). The petroleum extract was evaporated in vacuo and the residue was subjected to flash chromatography on silica gel using as eluent a mixture of petroleum ether (b.p. 40°-60° C.) and diethyl ether (19:1 v/v), giving an oil, which crystallised on standing, to give ethyl 3-isopropyl-1-phenylpyrrolo-[ 2,1-a]isoquinoline-2-carboxylate (1.7 g), in the form of a colourless solid, m.p. 82°-84° C. [N.M.R. (in CDCl3): 0.88 (3H, t, J=7 Hz), 1.52 (6H, d, J=7 Hz), 4.01 (2H, q, J=7 Hz), 4.14 (1H, septet, J=7 Hz), 6.75 (1H, d, J=8 Hz), 7.00-7.50 (9H, m), and 7.85 (1H, d, J=8 Hz)].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2N3N=CC=[C:13]3[N:12]=[CH:11][C:10]=2[C:18](OCC)=O)=[C:4](C)[CH:3]=1.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:9][C:10]3([CH2:11][NH:12][CH2:13]3)[CH2:18]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cnc2ccnn2c1Nc1ccc(F)cc1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1ccc(N2CC3(CNC3)C2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 69 %

Procedure:
tert-Butyl 6-(4-fluorophenyl)-2,6-diazaspiro[3,3]heptane-2-carboxylate (0.029 g, 0.098 mmol) obtained in step 1 was dissolved in dichloromethane (0.3 mL), and trifluoroacetic acid (0.11 mL, 1.467 mmol) was added. The mixture was stirred at room temperature for 5 hr, and saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (0.013 g, 68%).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[O:3][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[CH2:7][NH:8][CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.[Br:20][C:21]1[N:22]([CH3:29])[CH:23]=[C:24]([C:26](O)=[O:27])[N:25]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(#N)C>[Br:20][C:21]1[N:22]([CH3:29])[CH:23]=[C:24]([C:26]([N:8]([CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH2:7][C:6]2[CH:15]=[CH:16][CH:17]=[C:4]([O:3][C:2]([F:18])([F:1])[F:19])[CH:5]=2)=[O:27])[N:25]=1
Reactant: FC(F)(F)Oc1cccc(CNC2CCOCC2)c1
Reactant: Cn1cc(C(=O)O)nc1Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(C(=O)N(Cc2cccc(OC(F)(F)F)c2)C2CCOCC2)nc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.7 %

Procedure:
A mixture of N-[3-(trifluoromethoxy)benzyl]tetrahydro-2H-pyran-4-amine (190 mg), 2-bromo-1-methyl-1H-imidazole-4-carboxylic acid (100 mg), HATU, diisopropylethylamine (190 mg) and acetonitrile (3 mL) was stirred overnight at room temperature. Acetonitrile was distilled off under reduced pressure and the residue was purified by column chromatography (NH silica gel cartridge; hexane/ethyl acetate=3:1 to 1:2) to give the titled compound (130 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:9]/[CH:10]=O)=[CH:4][CH:3]=1.[C:17]([CH:21]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:19][CH3:20])=[O:18]>ClCCl>[CH3:20][O:19][C:17](=[O:18])/[CH:21]=[CH:10]/[CH:9]=[C:8](/[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)\[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCC/C(=C\C=O)c1ccc(F)cc1
Solvent: ClCCl
Product: CCCCC/C(=C\C=C\C(=O)OC)c1ccc(F)cc1

Procedure:
As described in Example 99, (E)-3-(4-fluorophenyl)-2-octenal (7.4 g) was treated with (carbomethoxymethylene)triphenylphosphorane (13.5 g) in dichloromethane (60 mL) for 4 days at room temperature. The ester was isolated in the normal manner and purified by HPLC (ether-hexane; 1:9) to yield 7.04 g of (E,E)-5-(4-fluorophenyl)-2,4-decadienoic acid methyl ester as an oil.
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][C:21]1=[O:26])(=[O:19])=[O:18].[CH3:27][O:28][C:29]1[CH:52]=[CH:51][C:32]([CH2:33][O:34][C:35]([NH:37][C:38]2[N:46]=[CH:45][N:44]=[C:43]3[C:39]=2[N:40]=[CH:41][N:42]3[CH2:47][C:48](O)=[O:49])=[O:36])=[CH:31][CH:30]=1>>[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([N:20]1[CH2:25][CH2:24][N:23]([C:48](=[O:49])[CH2:47][N:42]2[CH:41]=[N:40][C:39]3[C:43]2=[N:44][CH:45]=[N:46][C:38]=3[NH:37][C:35]([O:34][CH2:33][C:32]2[CH:51]=[CH:52][C:29]([O:28][CH3:27])=[CH:30][CH:31]=2)=[O:36])[CH2:22][C:21]1=[O:26])(=[O:19])=[O:18]
Reactant: O=C1CNCCN1S(=O)(=O)c1nc2ccccc2s1
Reactant: COc1ccc(COC(=O)Nc2ncnc3c2ncn3CC(=O)O)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(COC(=O)Nc2ncnc3c2ncn3CC(=O)N2CCN(S(=O)(=O)c3nc4ccccc4s3)C(=O)C2)cc1

Procedure:
The title compound was synthesized by the reaction of 1-(benzothiazole-2-sulfonyl)-piperazin-2-one trifluoroacetic acid salt with [6-N-(4-methoxybenzyloxycarbonyl)-adenine-9-yl]-acetic acid as per the procedure of Example 52. 1H NMR (500 MHz; DMSO-d6) δ 10.60 (bs, 1H), 8.59 (d, 1H), 8.34 (m, 2H), 8.27 (m, 1H), 7.72 (m, 2H), 7.38 (d, 2H), 6.94 (d, 2H), 5.40 (s, 1.2H), 5.28 (s, 0.8H), 5.14 (s, 2H), 4.56 (s, 0.8H), 4.28 (m, 2.4H), 4.09 (t, 2H), 3.87 (t, 0.8H), 3.75 (s, 3H).
Reaction SMILES: O.[CH3:2][CH:3]([OH:10])[CH2:4][NH:5][CH2:6][CH:7]([OH:9])[CH3:8].[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1C=CC=CC=1>[C:12]1([CH:11]2[N:5]([CH2:6][CH:7]([OH:9])[CH3:8])[CH2:4][CH:3]([CH3:2])[O:10]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(O)CNCC(C)O
Reactant: O=Cc1ccccc1
Solvent: c1ccccc1
Solvent: O
Product: CC(O)CN1CC(C)OC1c1ccccc1
Yield: 96.8 %

Procedure:
A reaction vessel equipped with a thermometer, a dropping funnel, a stirrer and a condenser having a water separator was charged with 133 g of diisopropanolamine and 100 g of benzene, to which 107 g of benzaldehyde was added dropwise at room temperature for one hour. The content was heated to reflux and, after removing water produced during reacting, reacted for another 5 hours. Benzene was removed under a reduced pressure and then distilled at 125° to 127° C./1 mmHg to obtain 214 g of 2-phenyl-3-(2-hydroxypropyl)-5-methyloxazolidine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)=[CH:17][C:15]=3[N:16]=2)[C:5]([NH:8][CH2:9][CH2:10][CH3:11])=[CH:6][CH:7]=1.[CH:28]1[C:33]([C:34]([OH:36])=[O:35])=[CH:32][C:31]2[C:37]([O:39][C:40](=O)[C:30]=2[CH:29]=1)=[O:38]>>[CH2:9]([NH:8][C:5]1[C:4]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)=[CH:17][C:15]=3[N:16]=2)=[CH:3][C:2]([N:1]2[C:37](=[O:38])[C:31]3[C:30](=[CH:29][CH:28]=[C:33]([C:34]([OH:36])=[O:35])[CH:32]=3)[C:40]2=[O:39])=[CH:7][CH:6]=1)[CH2:10][CH3:11]
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: CCCNc1ccc(N)cc1-c1nc2cc(-c3ccc(F)cc3)ccc2o1
Product: CCCNc1ccc(N2C(=O)c3ccc(C(=O)O)cc3C2=O)cc1-c1nc2cc(-c3ccc(F)cc3)ccc2o1

Procedure:
Prepared by the method of Example 15f), from 2-(3-amino-6-propylaminophenyl)-5-(4-fluorophenyl)benzoxazole (108 mg, 0.30 mmol) and 1,2,4-benzenetricarboxylic anhydride (57 mg, 0.30 mmol) the title compound was obtained. (74 mg, 46%). 1H NMR (DMSO) δ 13.63(s, 1H), 8.49(t, 1H), 8.42(dd, 1H), 8.31(s, 1H), 8.12(d, 1H), 8.08(m, 2H), 7.81(m, 3H), 7.68(dd, 1H), 7.47(dd, 1H), 7.32(t, 2H), 7.03(d, 1H), 3.34(m, 2H), 1.76(m, 2H), 1.07(t, 3H). MS 536.2 m/z (M+H)+.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH2:13][C@@H:14]2[CH2:19][N:18]([C:20](=[O:24])[CH:21]([F:23])[F:22])[CH2:17][CH2:16][O:15]2)[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([C:38]2[CH:43]=[CH:42][C:41](B3OC(C)(C)C(C)(C)O3)=[CH:40][CH:39]=2)[CH2:34][CH2:33]1>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:22][CH:21]([F:23])[C:20]([N:18]1[CH2:17][CH2:16][O:15][C@H:14]([CH2:13][NH:12][C:10]2[C:9]3[C:4](=[N:5][CH:6]=[CH:7][N:8]=3)[CH:3]=[C:2]([C:41]3[CH:40]=[CH:39][C:38]([N:35]4[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]4)=[CH:43][CH:42]=3)[N:11]=2)[CH2:19]1)=[O:24]
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: O=C(C(F)F)N1CCO[C@H](CNc2nc(Cl)cc3nccnc23)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CN1CCN(c2ccc(-c3cc4nccnc4c(NC[C@@H]4CN(C(=O)C(F)F)CCO4)n3)cc2)CC1
Temperature: 110 °C
Reaction time: 24 h

Procedure:
To a solution of (R)-1-(2-((7-chloropyrido[4,3-b]pyrazin-5-ylamino)methyl)morpholino)-2,2-difluoroethanone (72 mg, 0.2 mmol) in dioxane/H2O (5 mL/0.5 mL) was added Cs2CO3 (98 mg, 0.3 mmol), Pd (PPh3)4 (46.2 mg, 0.04 mmol) and 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine (72.5 mg, 0.24 mmol). The mixture was stirred at 110° C. for 24 hours under N2. The reaction was filtered, concentrated and purified on column (CH2Cl2:MeOH=20:1) to give yellow solid. MS (m/z): 498 (M+H)+
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:5]=1[NH2:6].S([O-])([O-])(=O)=S.[Na+].[Na+].C([O-])(=O)C.[Na+]>C(O)(=O)C.O>[Br:1][C:9]1[CH:10]=[C:4]([F:3])[C:5]([NH2:6])=[C:7]([F:11])[CH:8]=1
Reactant: BrBr
Reactant: Nc1c(F)cccc1F
Agent: CC(=O)[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Nc1c(F)cc(Br)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
A solution of bromine (127.0 g, 0.79 mol) in glacial acetic acid (200 ml) was added slowly, dropwise to a stirred solution of 2,6-difluoroaniline (101.5 g, 0.79 mol) in glacial acetic acid (550 ml) keeping the temperature below 25° C. The mixture was stirred at room temperature for 2 h, and then sodium thiosulphate (50 g), sodium acetate (125 g) and water (700 ml) were added and the mixture was cooled in a refrigerator overnight. The product was filtered off, dissolved in ether, and the ether phase was washed with water, 10% sodium hydroxide, water and dried (MgSO4). The solvent was removed in vacuo to yield a pale yellow solid (134 g) which was steam distilled to give a colourless solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[C:13]([CH3:18])[C:12]=2[F:19])[CH:9]=1)[C:5]#[N:6].C1C(=O)N([Br:27])C(=O)C1>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[C:13]([CH2:18][Br:27])[C:12]=2[F:19])[CH:9]=1)[C:5]#[N:6]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(Cl)c(Oc2cc(Br)cc(C#N)c2)c1F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1cc(Br)cc(Oc2c(Cl)ccc(CBr)c2F)c1
Yield: 60.4 %

Procedure:
3-bromo-5-[(6-chloro-2-fluoro-3-methylphenyl)oxy]benzonitrile (6.05 g, 17.76 mmol) and NBS (3.16 g, 17.76 mmol) were combined in carbon tetrachloride (100 mL) with a catalytic amount of AIBN (0.146 g, 0.888 mmol) and stirred at reflux for 16 h. The reaction mixture was washed with water, dried over MgSO4, filtered and concentrated to dryness. The residue was purified on silica gel (eluted with 0 to 10% Et2O in hexanes) to give 3-bromo-5-{[3-(bromomethyl)-6-chloro-2-fluorophenyl]oxy}benzonitrile (4.5 g, 10.73 mmol, 60.4% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.92-7.95 (m, 1H), 7.52-7.61 (m, 4H), 4.75 (s, 2H).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[C:7](/[CH:10]=[C:11](\[CH2:17][C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)/[CH:12]([CH3:16])[C:13]([OH:15])=[O:14])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].ClC[C:33]1[S:34][CH:35]=[CH:36][CH:37]=1>>[CH2:1]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[C:7](/[CH:10]=[C:11](\[CH2:17][C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)/[CH:12]([CH2:16][C:33]2[S:34][CH:35]=[CH:36][CH:37]=2)[C:13]([OH:15])=[O:14])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: ClCc1cccs1
Reactant: CCCCc1ncc(/C=C(\Cc2cccs2)C(C)C(=O)O)n1Cc1ccccc1Cl
Product: CCCCc1ncc(/C=C(\Cc2cccs2)C(Cc2cccs2)C(=O)O)n1Cc1ccccc1Cl

Procedure:
This compound is prepared according to the procedure of Example 14(i, ii) using less than one equivalent of 2-chloromethylthiophene in place of methyl iodide.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[C:11]([CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)#[N:12]>>[CH3:7][N:6]1[C:2]([N:16]2[CH2:17][CH2:18][CH:13]([C:11]#[N:12])[CH2:14][CH2:15]2)=[C:3]([N+:8]([O-:10])=[O:9])[CH:4]=[N:5]1
Reactant: N#CC1CCNCC1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Product: Cn1ncc([N+](=O)[O-])c1N1CCC(C#N)CC1
Yield: 79 %

Procedure:
Reaction of 5-chloro-1-methyl-4-nitro-1H-pyrazole and 4-cyanopiperidine gave 1-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperidine-4-carbonitrile as an off-white solid (0.23 g, 79%). 1H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 3.78 (s, 3H), 3.35-3.19 (m, 4H), 2.88-2.79 (m, 1H), 2.19-2.11 (m, 2H), 2.06-1.95 (m, 2H)
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[Br:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33](Cl)(=[O:35])=[O:34]>>[Br:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33]([N:20]1[CH2:21][CH2:22][CH:17]([N:15]2[C:14](=[O:23])[C:13]([CH3:25])([CH3:24])[C:12]([C:6]3[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:2])[CH:5]=3)=[N:16]2)[CH2:18][CH2:19]1)(=[O:35])=[O:34]
Reactant: O=S(=O)(Cl)c1ccccc1Br
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(S(=O)(=O)c4ccccc4Br)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) and 2-bromobenzenesulfonyl chloride as starting compounds. The crude product is purified by crystallization from methanol to yield the title compound.