Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH:6]([CH:16](O)[C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[O:8])[CH:5]=[N:4][CH:3]=[N:2]1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.Cl>N1C=CC=CC=1>[N:1]1([C:6](=[CH:16][C:17](=[O:22])[C:18]([CH3:20])([CH3:19])[CH3:21])[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[O:8])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: CC(C)(C)C(=O)C(O)C(C(=O)c1ccc(Cl)cc1)n1cncn1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)C=C(C(=O)c1ccc(Cl)cc1)n1cncn1
Reaction time: 48 h
Yield: 60 %

Procedure:
The product (4.9 g, 0.015 mol) of Stage 1 and p-toluenesulphonyl chloride (3.0 g, 0.06 mol) were mixed together in pyridine (50 ml) at 20°. After standing at room temperature for 48 hours, the solution was poured into crushed ice (50 ml)/concentrated hydrochloric acid (50 ml). The mixture was extracted with diethyl ether (100 ml), and the extract washed with water (3×100 ml) and dried over anhydrous sodiumsulphate. Removal of the ether gave a brown gum which was further purified by column chromatography (silica gel eluted with diethyl ether) to give 2-(1,2,4-triazol-1-yl)-1-p-chlorophenyl-5,5-dimethyl-hex-2-en-1,4-dione asa gum (2.8 g; yield 60%).
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][N:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:11]([NH2:13])=[O:12])C.CCOCC.[OH-].[Na+]>C(O)(=O)C>[C:11]1(=[O:12])[NH:13][CH:4]=[CH:5][N:6]2[CH:10]=[CH:9][CH:8]=[C:7]12
Reactant: CCOC(Cn1cccc1C(N)=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOCC
Product: O=c1[nH]ccn2cccc12
Yield: 80 %

Procedure:
1-(2,2-diethoxyethyl)pyrrole-2-carboxamide (3.0 g, 13.2 mmol) was dissolved in glacial acetic acid. The reaction mixture was allowed to reflux and the reaction was continued by thin layer chromatography in a 100% ether system. At the end of the reaction, the reaction mixture was made basic with a 2N solution of sodium hydroxide. The reaction mixture was then extracted with ethyl acetate, washed with a saturated sodium bicarbonate solution, dried over MgSO4 and evaporated. The product was purified by recrystallization in CH2Cl2 -hexane to give the title compound, pyrrolo[1,2-a]pyrazin-1(2H)-one (80%), m.p. 227°-228° C.
Reaction SMILES: C1([C@H]([NH:9][C@H:10]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][CH2:11]2)C)C=CC=CC=1.C([O-])=O.[NH4+]>CO.[OH-].[OH-].[Pd+2]>[NH2:9][C@H:10]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][CH2:11]1
Reactant: C[C@@H](N[C@H]1CCCN(C(=O)OC(C)(C)C)CC1)c1ccccc1
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@H](N)CC1
Temperature: 25 °C
Yield: 86.3 %

Procedure:
A suspension of Pd(OH)2/C (10%, 550 mg), tert-butyl (4S)-4-{[(1R)-1-phenylethyl]amino}azepane-1-carboxylate (5.5 g, 17.3 mmol) and HCOONH4 (3.3 g, 51.9 mmol) in MeOH (80 mL) was heated at reflux for 1.5 h. The reaction mixture was cooled to rt and filtered, the solvents of the filtrate were removed in vacuo. The residue was purified by column chromatography (gradient 0% to 10% MeOH in DCM) to give tert-butyl (4S)-4-aminoazepane-1-carboxylate (3.2 g, 87.3%).
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3]1[N:25]=[C:6]2[CH:7]=[C:8]([NH:11][C:12]([C:14]3[N:18]([CH3:19])[N:17]=[CH:16][C:15]=3[C:20]([O:22]CC)=[O:21])=[O:13])[CH:9]=[CH:10][N:5]2[N:4]=1.O.[OH-].[Li+]>CO.O>[CH3:1][N:2]([CH3:26])[C:3]1[N:25]=[C:6]2[CH:7]=[C:8]([NH:11][C:12]([C:14]3[N:18]([CH3:19])[N:17]=[CH:16][C:15]=3[C:20]([OH:22])=[O:21])=[O:13])[CH:9]=[CH:10][N:5]2[N:4]=1
Reactant: CCOC(=O)c1cnn(C)c1C(=O)Nc1ccn2nc(N(C)C)nc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN(C)c1nc2cc(NC(=O)c3c(C(=O)O)cnn3C)ccn2n1
Temperature: 50 °C
Reaction time: 4 h
Yield: 95.4 %

Procedure:
A mixture of ethyl 5-(2-(dimethylamino)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylate (1.24 g, 3.47 mmol) and lithium hydroxide monohydrate (291 mg, 6.94 mmol) in methanol (20 ml) and water (5 ml) is stirred for 4 hours at 50° C. The solvent is evaporated. The brown oily residue is dissolved in water and acidified to pH=5 with 2N aqueous hydrochloric acid (3.47 ml). The precipitated off-white solid is collected by filtration, dissolved in methanol and evaporated affording 5-(2-(dimethylamino)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid (1.09 g, 95.3%) as an off-white solid. Mp.: >250° C. MS: m/z=328.0 (M−H+).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[C:18]1([C:24]#[CH:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>N1CCCCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([C:25]#[C:24][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3]
Reactant: C#Cc1ccccc1
Reactant: CS(=O)(=O)N1CCN(c2ccc(Br)cc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: CS(=O)(=O)N1CCN(c2ccc(C#Cc3ccccc3)cc2)CC1
Temperature: 105 °C
Reaction time: 14 h
Yield: 32.4 %

Procedure:
To a stirred suspension of 1-(methylsulfonyl)-4-(4-bromophenyl)piperazine (5.77 g, 18.1 mmol), phenyl acetylene (3.97 mL, 36.1 mmol), Copper (I) iodide (38 mg, 0.2 mmol) and triphenylphosphine (95 mg, 0.36 mmol) in piperidine (72 mL) at 20° C. was added dichlorobis(triphenylphosphine)palladium(II) (38 mg, 54 mmol). The reaction was warmed to 105° C. and stirred for 14 hours under an inert atmosphere. Volatiles were removed in vacuo, and the solid residue was dissolved in CH2Cl2 (200 mL) and washed with aqueous hydrochloric acid (2M) to pH 2. The layers were then separated and the organic extract dried, (sat. Brine and MgSO4), filtered and evaporated to dryness in vacuo. The residue was triturated in CH2Cl2, and filtered to give 1-(methylsulfonyl)-4-[4-(phenylethynyl)phenyl]piperazine as a flaky white solid (1.99 g, 5.86 mmol, 32%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CO[CH:26]1[CH2:30][CH2:29][CH:28](OC)O1.C(O)(=O)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([N:23]3[CH:26]=[CH:30][CH:29]=[CH:28]3)=[CH:21][CH:22]=2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: COC1CCC(OC)O1
Reactant: Cc1ccc(S(=O)(=O)NCCCCOc2ccc(N)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NCCCCOc2ccc(-n3cccc3)cc2)cc1
Temperature: -10 °C

Procedure:
A mixture of 3.2 g of 4-methyl-N-[4-(4-aminophenyl-oxy)butyl]benzenesulfonamide (Example 36), 1.5 g of 2,5-dimethoxytetrahydrofuran, and 50 ml of acetic acid is stirred and heated on the steam bath for 16 hours. The reaction mixture is taken to dryness in vacuo. The residue is shaken with 150 ml of dichloromethane and 150 ml of saturated sodium bicarbonate solution. The dichloromethane layer is separated, dried over Na2SO4, and diluted with 100 ml of hexane. The solution is concentrated until turbid, then cooled at -10° C. The precipitate that forms is collected, washed with hexane, and air dried; m.p. 124°-126° C.; yield, 0.2 g.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[N:15][C:14]=2F)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[NH:23]1[C:27]2=[N:28][C:29]([CH2:32][NH2:33])=[CH:30][CH:31]=[C:26]2[CH:25]=[CH:24]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[N:15][C:14]=2[NH:33][CH2:32][C:29]2[N:28]=[C:27]3[NH:23][CH:24]=[CH:25][C:26]3=[CH:31][CH:30]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCc1ccc2cc[nH]c2n1
Reactant: CC(C)(C)c1ccc(NC(=O)c2cccnc2F)cc1
Agent: Cl
Product: CC(C)(C)c1ccc(NC(=O)c2cccnc2NCc2ccc3cc[nH]c3n2)cc1

Procedure:
The titled compound was prepared from N-(4-tert-butyl-phenyl)-2-fluoro-nicotinamide and C-(1H-pyrrolo[2,3-b]pyridin-6-yl)-methylamine dihydrochloride by the method described in Step A of Example 1. MS (ES+): 400 (M+H). Calc'd. for C24H25N5O—399.50.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][CH2:8][CH2:9]O)[CH:2]=1.C(Br)(Br)(Br)[Br:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:12][CH2:9][CH2:8][O:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: OCCOc1cccnc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCOc1cccnc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.2 %

Procedure:
A solution of 2-(pyridin-3-yloxy)-ethanol (200 mg) in 5 mL dichloromethane was cooled to 0° C. and treated with carbon tetrabromide (524 mg) followed by triphenylphosphine (415 mg) portionwise. The reaction mixture was stirred at 0° C. for 30 mins then at room temperature for 45 mins. The volatiles were evaporated and the residue purified by silica gel chromatography eluting with 0-100% EtOAc/pentane to give the title compound (204 mg) as a colourless liquid which was used without further purification.
Reaction SMILES: [C:1]12([CH2:11][CH2:12][O:13][C:14]3[CH:15]=[C:16]([CH2:20][CH2:21][NH:22][CH2:23][C@@H:24]([C:33]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=5)=[C:39]5[C:34]=4[CH:35]=[CH:36][C:37](=[O:51])[NH:38]5)[O:25][Si](C(C)(C)C)(C)C)[CH:17]=[CH:18][CH:19]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:1]12([CH2:11][CH2:12][O:13][C:14]3[CH:15]=[C:16]([CH2:20][CH2:21][NH:22][CH2:23][C@@H:24]([C:33]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=5)=[C:39]5[C:34]=4[CH:35]=[CH:36][C:37](=[O:51])[NH:38]5)[OH:25])[CH:17]=[CH:18][CH:19]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CNCCc1cccc(OCCC23CC4CC(CC(C4)C2)C3)c1)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: O=c1ccc2c([C@@H](O)CNCCc3cccc(OCCC45CC6CC(CC(C6)C4)C5)c3)ccc(OCc3ccccc3)c2[nH]1
Temperature: 45 °C
Reaction time: 3.5 h
Yield: 93 %

Procedure:
To a solution of Intermediate 32 (0.48 g, 0.68 mmol) in tetrahydrofuran (12 mL) was added tetrabutylammonium fluoride trihydrate (0.284 g, 1.09 mmol). The reaction mixture was stirred at 45° C. for 3.5 hours. The solvent was removed under reduced pressure and the crude was partitioned between ethyl acetate and water. The organic layer was washed several times with water and the solvent was removed under reduced pressure to give the title compound as a yellow solid (0.375 g, 88%). MS (M+): 593.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C@H:8]([C:10](=O)[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][CH:19]1[CH2:24][CH2:23][CH2:22][O:21][CH2:20]1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]>CC(O)=O>[C:1]([O:5][C:6](=[O:26])[NH:7][C@H:8]([C:10]1[N:18]([CH:19]2[CH2:24][CH2:23][CH2:22][O:21][CH2:20]2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccccc1NC1CCCOC1
Solvent: CC(=O)O
Product: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccccc2n1C1CCCOC1
Temperature: 70 °C
Yield: 81 %

Procedure:
{(S)-1-[2-(Tetrahydropyran-3-ylamino)phenylcarbamoyl]ethyl}carbamic acid tertbutyl ester (0.95 g, 2.61 mmol) was dissolved in AcOH (20 mL) and heated to 70° C. for 38 h. Volatiles were then removed in vacuo and the residue was partitioned between DCM and a saturated solution of NaHCO3. The aqueous phase was further extracted with DCM (×2) and the combined organic layers were then washed with brine, dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-4% 2M NH3/MeOH in DCM) affording {(S)-1-[1-(Tetrahydropyran-3-yl)-1H-benzoimidazol-2-yl]ethyl}carbamic acid tertbutyl ester as a light brown solid (0.73 g, 81%). LCMS: RT 2.35 min [M+H-tBu]+ 290.0.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[C:5](=[O:14])[N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1.BrC1C=C(I)C(=O)N([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)C=1.ClC1C=CC=CC=1B(O)O.C1([Mg]Cl)CCCCC1.[Cl-].[NH4+]>O1CCCC1.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:4]1[C:5](=[O:14])[N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=[C:2]([CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH:3]=1
Reactant: O=c1c(-c2ccccc2Cl)cc(Br)cn1-c1ccccc1
Reactant: O=c1c(I)cc(Br)cn1-c1ccccc1
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: Cl[Mg]C1CCCCC1
Agent: OB(O)c1ccccc1Cl
Solvent: C1CCOC1
Product: O=c1c(-c2ccccc2Cl)cc(C2CCCCC2)cn1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
30 mg of 5-bromo-3-(2-chlorophenyl)-1-phenyl-1,2-dihydropyridin-2-one synthesized from 5-bromo-1-phenyl-3-iodo-1,2-dihydropyridin-2-one and 2-chlorophenyl boronic acid in accordance with the method of Referential Example 3 was dissolved in 20 ml of tetrahydrofuran, followed by adding 1 mg of [1,3-bis(diphenylphosphino)propane]nickel (II) chloride. Under stirring in nitrogen atmosphere, 0.1 ml of cyclohexyl magnesium chloride (2.0M ether solution) was added dropwise thereinto. After stirring at room temperature in nitrogen atmosphere overnight, the mixture was heated under reflux for 1 hour. After cooling to room temperature, a saturated aqueous solution of ammonium chloride was added thereto, followed by extracting with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel chromatography (chloroform/methanol system), to give 6 mg of the title compound.
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=[O:4].[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14][S:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]2[O:24]C(C(NC3C=C4C(=CC=3)NC(C(OC(C)(C)C)=O)=C4)=O)=[CH:22][C:21]=2[CH:44]=1>>[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14][S:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]2[O:24][C:2]([C:3]([OH:5])=[O:4])=[CH:22][C:21]=2[CH:44]=1
Reactant: CC(C)(C)OC(=O)c1cc2cc(NC(=O)c3cc4cc(CSSc5ccccn5)ccc4o3)ccc2[nH]1
Reactant: O=C(O)C(F)(F)F
Product: O=C(O)c1cc2cc(CSSc3ccccn3)ccc2o1
Reaction time: 2 h

Procedure:
To 4 mL trifluoroacetic acid, cooled to 0° C. and stirred under argon, was added 16 (120 mg, 0.23 mmol). After 2 h, trifluoroacetic acid was removed under reduced pressure to give 15 as an off-white solid: NMR (acetone-d6) d 4.3 (2,2H), δ7.3-8.7 (m, 12H).
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[C:4]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][C:5]=1[C:6]([OH:8])=O)[CH3:2].Cl.[N:20]1([C:26]2[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[S:28][N:27]=2)[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(OCC)(=O)C>C(#N)C>[S:28]1[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:26]([N:20]2[CH2:21][CH2:22][N:23]([C:6]([C:5]3[CH:9]=[C:10]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:11]=[CH:12][C:4]=3[N:3]([CH2:1][CH3:2])[CH2:17][CH3:18])=[O:8])[CH2:24][CH2:25]2)=[N:27]1
Reactant: CCN(CC)c1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Agent: Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCN(CC)c1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2nsc3ccccc23)CC1

Procedure:
Prepared in analogy to example 1.1 b) from 2-diethylamino-5-methanesulfonyl-benzoic acid (Example 2.5) and 3-piperazin-1-yl-benzo[d]isothiazole hydrochloride (CA=87691-88-1) in acetonitrile. Chromatography (SiO2; ethyl acetate) yields the title compound as a colorless solid. MS (m/e): 473.4 (M+H+; 100%)
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([OH:10])=[O:9])[C:3]1=O.[F:12][C:13]([F:22])([F:21])[C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17]>>[F:12][C:13]([F:21])([F:22])[C:14]1[CH:15]=[C:16]2[C:18]([C:2]3[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([OH:10])=[O:9])[C:3]=3[NH:17]2)=[CH:19][CH:20]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: O=C(O)C1CCCC(Br)C1=O
Product: O=C(O)C1CCCc2c1[nH]c1cc(C(F)(F)F)ccc21

Procedure:
Under the conditions as described in Example 1(a), 10 g. of the ethyl ester of 3-bromo-2-oxocyclohexanecarboxylic acid is reacted with 3-trifluoromethylaniline to obtain the ethyl ester of 7-trifluoromethyl-1,2,3,4-tetrahydrocarbazole-1-carboxylic acid.
Reaction SMILES: [C:1]([C:4]([N:6]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]#[C:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[CH:21][CH:20]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1)=[O:5])([OH:3])=[O:2]>CCOC(C)=O>[C:1]([C:4]([N:6]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[CH:23][CH:24]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:15])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:5])([OH:3])=[O:2]
Reactant: O=C(O)CCCCCCCCC#Cc1ccc(CN(Cc2ccc(C(F)(F)F)cc2)C(=O)C(=O)O)cc1
Solvent: CCOC(C)=O
Product: O=C(O)CCCCCCCCCCc1ccc(CN(Cc2ccc(C(F)(F)F)cc2)C(=O)C(=O)O)cc1
Yield: 20 %

Procedure:
The same procedure as employed in the preparation of Example 1 (step c) but using 11-[4-({(carboxycarbonyl)[4-(trifluoromethyl)benzyl]amino}methyl)phenyl]undec-10-ynoic acid in EtOAc gave the title compound as a colorless oil (20%). M−(LC/MS(ESI)): 520. HPLC (Condition A), Rt: 5.03 min (HPLC purity: 96.1%).
Reaction SMILES: [CH2:1]1[O:20][C:4]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14]CC(O)=O)[C:10](=[O:19])[CH2:9]2)([O:5][CH2:6][CH3:7])[O:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[O:27]1CCCC1>>[CH2:1]1[O:20][C:4]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][OH:27])[C:10](=[O:19])[CH2:9]2)([O:5][CH2:6][CH3:7])[O:3][CH2:2]1
Reactant: C1CCOC1
Reactant: CCOC1(N2CCC(CCC(=O)O)C(=O)C2)OCCO1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCOC1(N2CCC(CO)C(=O)C2)OCCO1
Temperature: 0 °C
Yield: 84 %

Procedure:
To an ice cooled solution of ethyl 4-carboxyethyl-3-oxopiperidine-1-carboxylate ethylene ketal (38 g, 0.132 mol, U.S. Pat. No. 4,278,676) in tetrahydrofurane (100 ml) is added lithium aluminium hydride pellets (2.51 g, 0.066 mol). The ice bath is removed and the reaction mixture is allowed to reach reflux temperature and is then kept at reflux temperature for 3 hours. The mixture is quenched with dilute hydrochloric acid and is diluted with dichloromethane. The mixture is washed twice with saturated brine, dried over magnesium sulphate and evaporated in vacuo to give 27.3 g (0.111 mol, 84%) of oily title product.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH3:12])[CH2:11][N:6]2[CH2:7][CH2:8][NH:9][CH2:10][CH:5]2[CH2:4]1.Cl[C:14]1[N:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[OH:1][CH2:2][C:3]1([CH3:12])[CH2:11][N:6]2[CH2:7][CH2:8][N:9]([C:14]3[N:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=3)[CH2:10][CH:5]2[CH2:4]1
Reactant: Fc1cnc(Cl)nc1
Reactant: CC1(CO)CC2CNCCN2C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC1(CO)CC2CN(c3ncc(F)cn3)CCN2C1
Yield: 47.3 %

Procedure:
A mixture of (7RS,8aSR)-7-hydroxymethyl-7-methyl-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine (1.08 g, 6.35 mmol), 0.925 g (6.98 mmol) of 2-chloro-5-fluoropyrimidine (Dunaiskis, A.; et al. Org. Prep. Proc. Int., 1995, 27, 600-602), and 1.48 g (13.96 mmol) of sodium carbonate and 65 mL of water was heated at 90° C. for 72 h. the solution was cooled and extracted with chloroform (3×). The combined organic layers were dried (magnesium sulfate), filtered and evaporated. Purification by flash silica gel chromatography eluting with chloroform:methanol (95:5) gave 0.80 g (47%) of the title compound. 13C NMR (CDCl3): a 25.5, 39.5, 41.7, 43.3, 48.7, 51.2, 62.3, 63.8, 71.0, 144.9, 145.2, 149.8, 153.1, 158.9. m/z (MH+) 267.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]3[CH:15]=[N:16][N:17]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:18]=3)[N:11]3[CH:27]=[CH:28][N:29]=[C:10]3[CH:9]=2)=[CH:4][CH:3]=1.[CH3:30][N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.O>C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(O)(C)C>[CH3:30][N:31]1[CH:35]=[C:34]([C:2]2[CH:3]=[CH:4][C:5]([C:8]3[N:13]=[C:12]([C:14]4[CH:15]=[N:16][N:17]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:25])([CH3:24])[CH3:26])[CH:18]=4)[N:11]4[CH:27]=[CH:28][N:29]=[C:10]4[CH:9]=3)=[CH:6][CH:7]=2)[CH:33]=[N:32]1
Reactant: C[Si](C)(C)CCOCn1cc(-c2nc(-c3ccc(Br)cc3)cc3nccn23)cn1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(C)O
Solvent: O
Solvent: ClCCl
Product: Cn1cc(-c2ccc(-c3cc4nccn4c(-c4cnn(COCC[Si](C)(C)C)c4)n3)cc2)cn1
Reaction time: 4 h
Yield: 85.9 %

Procedure:
A flask charged with 7-(4-bromophenyl)-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine (Preparation L; 0.200 g, 0.425 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.195 g, 0.935 mmol), potassium phosphate (0.271 g, 1.28 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.0507 g, 0.106 mmol), and tris(dibenzylideneacetone)dipalladium (0.0389 g, 0.0425 mmol) was evacuated and backfilled with argon. To the reaction was added 4 mL of isopropanol (degassed with argon for 30 minutes) and water (0.0460 mL, 2.55 mmol). The reaction was sealed and allowed to proceed at 100° C. for 4 hours. The reaction was then diluted with DCM (100 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting crude was then purified by means of silica gel chromatography eluting with a linear gradient of 1-5% methanol in DCM to afford 7-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine (0.174 g, 0.365 mmol, 85.9% yield). MS (apci) m/z=472.2 (M+H).
Reaction SMILES: S(=O)(=O)(O)[O-].[K+].[K+].C(OC([C:13]1[C:17](=[O:18])[O:16][CH2:15][C:14]=1[O-])=O)C.[Cl:20][C:21]1[N:26]=[CH:25][C:24]([CH2:27][NH:28][CH2:29][CH:30]([F:32])[F:31])=[CH:23][CH:22]=1.O>C(#N)CCC.ClCCl>[Cl:20][C:21]1[N:26]=[CH:25][C:24]([CH2:27][N:28]([CH2:29][CH:30]([F:32])[F:31])[C:14]2[CH2:15][O:16][C:17](=[O:18])[CH:13]=2)=[CH:23][CH:22]=1
Reactant: FC(F)CNCc1ccc(Cl)nc1
Reactant: CCOC(=O)C1=C([O-])COC1=O
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCCC#N
Solvent: ClCCl
Solvent: O
Product: O=C1C=C(N(Cc2ccc(Cl)nc2)CC(F)F)CO1
Temperature: 92.5 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
At room temperature, 11.5 g of potassium bisulphate are added to a suspension of 10.4 g of 4-(ethoxycarbonyl)-5-oxo-2,5-dihydrofuran-3-olate potassium salt and 7.5 g of N-[(6-chloropyridin-3-yl)methyl)-2,2-difluoroethylamine in 68 ml of butyronitrile. The mixture is stirred at a temperature of from 90 to 95° C. for 3 hours. The mixture is then cooled to room temperature, 120 ml of water and 120 ml of dichloromethane are added, the organic phase is separated off and the aqueous phase is extracted twice with in each case 120 ml of methylene chloride. The combined organic phases are concentrated to dryness. This gives 11.4 g of amorphous 4-[[(6-chloropyridin-3-yl)methyl](2,2-difluoroethyl)amino]furan-2(5H)-one in a purity of 84% (this corresponds to a yield of 92%).