Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH3:13])=[N:10][CH:9]=2)=[C:4]([O:14][CH3:15])[CH:3]=1.[Cl:16][CH2:17][CH2:18][CH2:19][C:20]#[CH:21].C(N(CC)CC)C>C(OCC)(=O)C.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.[Cu]I>[Cl:16][CH2:17][CH2:18][CH2:19][C:20]#[C:21][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH3:13])=[N:10][CH:9]=2)=[C:4]([O:14][CH3:15])[CH:3]=1
Reactant: C#CCCCCl
Reactant: COc1cc(Br)ccc1-c1cnc(C)o1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1cc(C#CCCCCl)ccc1-c1cnc(C)o1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
A mixture of 5-(4-bromo-2-methoxyphenyl)-2-methyl-1,3-oxazole (6.00 g), 5-chloropent-1-yne (4.74 mL), dichlorobis(triphenylphosphine)palladium(II) (1.57 g), copper(I) iodide (426 mg) and triethylamine (60 mL) was stirred at 70° C. for 3 hr, and diluted with ethyl acetate, and the mixture was filtered through celite. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (4.85 g).
Reaction SMILES: C([Cl:4])(=O)C.C(OC([NH:12][N:13]([CH2:18][CH:19]=[CH2:20])[CH:14]1[CH2:17][CH2:16][CH2:15]1)=O)(C)(C)C>CO>[ClH:4].[CH2:18]([N:13]([CH:14]1[CH2:17][CH2:16][CH2:15]1)[NH2:12])[CH:19]=[CH2:20]
Reactant: C=CCN(NC(=O)OC(C)(C)C)C1CCC1
Reactant: CC(=O)Cl
Solvent: CO
Product: C=CCN(N)C1CCC1
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Acetyl chloride (1.45 mL, 20.41 mmol) was added dropwise into methanol (10 mL) at 0° C. The resulting mixture was stirred at 25° C. for 30 min. N′-allyl-N′-cyclobutyl-hydrazinecarboxylic acid tert-butyl ester (0.40 g, 1.77 mmol) was added in one portion. The reaction was stirred at 25° C. for 18 h. The mixture was concentrated in vacuo and used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.Cl.Cl.[Cl:13][C:14]1[CH:30]=[CH:29][C:17]([CH2:18][N:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][CH2:27][SH:28])[CH2:21][CH2:20]2)=[CH:16][CH:15]=1.C(N(CC)CC)C>C(Cl)Cl>[OH2:10].[ClH:1].[ClH:13].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[SH:28][CH2:27][CH2:26][CH2:25][N:22]2[CH2:23][CH2:24][N:19]([CH2:18][C:17]3[CH:16]=[CH:15][C:14]([Cl:13])=[CH:30][CH:29]=3)[CH2:20][CH2:21]2)[OH:10])=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: SCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O
Product: OC(Nc1ccc(Cl)cc1)=[SH]CCCN1CCN(Cc2ccc(Cl)cc2)CC1
Yield: 42.4 %

Procedure:
The procedure described in Example 2 was followed, using 1.5 g of 4-chlorophenyl isocyanate, 3.5 g of 3-[4-(4-chlorobenzyl)piperazin-1-yl]propanethiol dihydrochloride, 1.2 g of triethylamine and 50 ml of methylene chloride, to give 1.1 g (21% of theory) of N-(4-chlorophenyl)-S-{3-[4-(4-chlorobenzyl)piperazin-1-yl]propyl}thiocarbamate dihydrochloride monohydrate as an off-white crystalline solid, M.p. 243°-245° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH:14]=[CH:13][C:12]3=[N:15][C:16]([CH2:18][O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:17][N:11]3[C:10]2=[O:26])=[N:6][C:7]=1[CH3:8].[H][H]>CN(C=O)C.CO.[Ni]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:14][CH2:13][C:12]3=[N:15][C:16]([CH2:18][O:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:17][N:11]3[C:10]2=[O:26])=[N:6][C:7]=1[CH3:8]
Reactant: [H][H]
Reactant: Cc1nc(-n2ccc3nc(COc4ccccc4)cn3c2=O)ccc1F
Agent: [Ni]
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1nc(N2CCc3nc(COc4ccccc4)cn3C2=O)ccc1F
Yield: 40.8 %

Procedure:
A solution of 6-(5-fluoro-6-methyl-pyridin-2-yl)-2-phenoxymethyl-6H-imidazo[1,2-c]pyrimidin-5-one (20 mg, 0.057 mmol) in a mixture of DMF (0.6 mL) and MeOH (0.6 mL) was hydrogenated in a H-cube reactor (1 mL/min, 30 mm Raney nickel cartridge, 80° C., full hydrogen mode, 1 cycle). The solvents were evaporated in vacuo and the crude product was purified by RP HPLC (C18 XBridge 19×100 5 um, gradient from 80% of 0.1% solution of ammonium formate/ammonium hydroxide buffer pH 9 solution in water and 20% CH3CN to 0% of 0.1% solution of ammonium formate/ammonium hydroxide buffer pH 9 solution in water and 100% ACN) to yield 6-(5-fluoro-6-methyl-pyridin-2-yl)-2-phenoxymethyl-7,8-dihydro-6H-imidazo[1,2-c]pyrimidin-5-one (8.2 mg, 41% yield). 1H NMR (400 MHz, CDCl3) δ ppm 2.49 (d, J=3.0 Hz, 3H), 3.24 (t, J=6.7 Hz, 2H), 4.35 (t, J=6.7 Hz, 2H), 5.02 (s, 2H), 6.97 (br. t, J=7.4, 7.4 Hz, 1H), 7.00-7.05 (m, 2H), 7.27-7.33 (m, 2H), 7.39 (t, J=8.6 Hz, 1H), 7.59 (s, 1H), 7.65 (dd, J=8.8, 3.2 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][C@H:15]3[CH3:20])[N:11]=[C:10]([N:21]3[CH2:25][CH2:24][CH2:23][C@H:22]3[CH3:26])[N:9]=2)=[CH:4][CH:3]=1.Br[C:28]1[C:33]([CH3:34])=[CH:32][C:31]([Br:35])=[CH:30][N:29]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O.O>[Br:35][C:31]1[CH:32]=[C:33]([CH3:34])[C:28]([N:17]2[CH2:18][CH2:19][N:14]([C:12]3[CH:13]=[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[N:9]=[C:10]([N:21]4[CH2:25][CH2:24][CH2:23][C@H:22]4[CH3:26])[N:11]=3)[C@H:15]([CH3:20])[CH2:16]2)=[N:29][CH:30]=1
Reactant: Cc1cc(Br)cnc1Br
Reactant: C[C@@H]1CNCCN1c1cc(-c2ccc(F)cc2)nc(N2CCC[C@H]2C)n1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1cc(Br)cnc1N1CCN(c2cc(-c3ccc(F)cc3)nc(N3CCC[C@H]3C)n2)[C@H](C)C1

Procedure:
Heat a mixture of 4-(4-fluoro-phenyl)-6-(2-(R)-methyl-piperazin-1-yl)-2-(2-(R)-methyl-pyrrolidin-1-yl)-pyrimidine (400 mg, 1.13 mmol), 2,5-dibromo-3-methyl-pyridine (367 mg, 1.46 mmol), and DIEA (218 mg, 1.69 mmol) in DMA at 135° C. for 96 h. Dilute with water, extract with EtOAc, and wash with brine. Dry the organic layer (Na2SO4) and concentrate under reduced pressure. Purify the residue by flash column chromatography eluting with EtOAc-Hexanes (1:10) to afford the title compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][C@H:9]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])=[O:11])[CH:5]=[CH:6][CH:7]=1.[CH3:30][C:31]1(C)C(C)(C)OB(C=C)O1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.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>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([N:12]([CH3:13])[C:10](=[O:11])[C@@H:9]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH:30]=[CH2:31])[CH:3]=2)=[CH:15][CH:16]=1
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: COc1ccc(N(C)C(=O)[C@H](Cc2cccc(Br)c2)NC(=O)OC(C)(C)C)cc1
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: [K+]
Solvent: COCCOC
Product: C=Cc1cccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)c2ccc(OC)cc2)c1
Yield: 98 %

Procedure:
A suspension of (S)-tert-butyl 3-(3-bromophenyl)-1-((4-methoxyphenyl)(methyl)amino)-1-oxopropan-2-ylcarbamate (6.3 g, 13.6 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (3.3 g, 20.4 mmol), potassium carbonate (54 ml, 0.4 M) and tetrakis(triphenylphosphine)palladium(0) (0.79 g, 0.68 mmol) in 50 ml of DME, was heated at reflux overnight. The suspension was cooled and filtered through celite. The filtrate was washed with brine and filtered through celite. The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was introduced to a silica gel loading column and purified by column chromatography (15-35% EtOAc/hexanes) to provide the desired product (5.47 g, 13.33 mmol), 94%. MS (m/z) 411 [M+H]+.
Reaction SMILES: [C:1](OCC12CC3CC(CC(O)(C3)C1)C2)(=[O:4])[CH:2]=[CH2:3].[OH:18][C:19]12[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][CH:21]([C:22]3=[O:29])[CH2:20]1)[CH2:26]2>>[C:1]([O:18][C:19]12[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][CH:21]([C:22]3=[O:29])[CH2:20]1)[CH2:26]2)(=[O:4])[CH:2]=[CH2:3]
Reactant: O=C1C2CC3CC1CC(O)(C3)C2
Reactant: C=CC(=O)OCC12CC3CC(CC(O)(C3)C1)C2
Product: C=CC(=O)OC12CC3CC(C1)C(=O)C(C3)C2
Yield: 95 %

Procedure:
The reaction was conducted in the same manner as said (2) except that 1-hydroxyadamantane-4-one was used instead of the 1-hydroxyadamantane-2-one, and, as a result, a 1-acryloyloxyadamantane-4-one (yield: 95%, white solid) was obtained.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[S:4][CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)[CH:11]([CH3:13])[CH3:12].[CH2:17](Br)[CH:18]=[CH2:19]>>[CH2:13]([N:1]([CH2:19][CH:18]=[CH2:17])[CH2:2][C:3]1[S:4][CH:5]=[CH:6][CH:7]=1)[CH:11]=[CH2:12]
Reactant: C=CCBr
Reactant: NCc1cccs1
Reactant: CCN(C(C)C)C(C)C
Product: C=CCN(CC=C)Cc1cccs1
Reaction time: 16 h
Yield: 80.1 %

Procedure:
A solution of 2-aminomethyl-thiophene (51.4 g, 956 mmol) and i-Pr2NEt (140 g, 1081 mmol) in CH2C2 (1 l) was placed in a 3-1 flask equipped with a condenser and an efficient magnetic agitation. Allyl bromide (115.7 g, 454 mmol) was added, whereupon the moderately exothermic reaction spontaneously reached the reflux temperature after 2 h. The mixture was stirred overnight (16 h), washed (NaHCO3 sat; brine), dried (MgSO4), and concentrated. The resulting oil was filtered over silica gel (EtOAc:hexane 1:4). The filtrate was concentrated and the filtration was repeated to afford 70.3 g (80%) of the title diallylamine as a brown-yellow oil, clean by NMR: 1H NMR (CDCl3) p7.25 (br. d, J=5.9 Hz, 1H), 6.98 (br. dd, J=5.1, 2.8 Hz, 1H), 6.94-6.92 (m, 1H), 5.99-5.86 (m, 2H), 5.29-5.18 (m, 4H), 3.85 (s, 2H), 3.16 (dd, J=6.3, 0.9 Hz, 4H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[N:4][O:5][C:6]=1[CH3:7].C(=O)([O-])[O-].[Na+].[Na+].C(=O)(O)[O-].[Na+].[Cl:27][CH2:28][C:29](Cl)=[O:30]>ClCCl.O>[C:8]([C:3]1[C:2]([NH:1][C:29](=[O:30])[CH2:28][Cl:27])=[C:6]([CH3:7])[O:5][N:4]=1)(=[O:9])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)CCl
Reactant: Cc1onc(C(=O)c2ccccc2)c1N
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1onc(C(=O)c2ccccc2)c1NC(=O)CCl
Reaction time: 1 h

Procedure:
To a chilled (5° C.) mixture of 6.5 g of (4-amino-5-methylisoxazol-3-yl)phenylmethanone, 65 ml of 2N sodium carbonate, 163 ml of a saturated solution of sodium bicarbonate, and 150 ml of dichloromethane was added, dropwise, 5.1 ml of chloroacetyl chloride. The resulting mixture was stirred for one hour, diluted with dichloromethane and water, and separated. The organic phase was washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated to an oil. Flash chromatography of the oil (20% ethyl acetate/hexane as the eluent) afforded 7.15 g of N-(3-benzoyl-5-methylisoxazol-4-yl)chloroacetamide, m.p. 86°-88° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=[O:11].[CH3:13][Si:14]([CH3:19])([CH3:18])[CH2:15][CH2:16]O.Cl.CN(C)CCCN=C=NCC.C(OCC)(=O)C>ClCCl.CN(C)C1C=CN=CC=1.CCCCCC>[CH3:13][Si:14]([CH3:19])([CH3:18])[CH2:15][CH2:16][O:11][C:10](=[O:12])[CH2:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[F:1]
Reactant: O=C(O)Cc1ccc(I)cc1F
Reactant: C[Si](C)(C)CCO
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: C[Si](C)(C)CCOC(=O)Cc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
A solution of 2-fluoro-4-iodo phenyl acetic acid (0.3 g, 1.07 mmol) and 2-(trimethylsilyl)ethanol (0.28 mL, 1.95 mmol) in anhydrous dichloromethane (5 mL) was treated with 4-(dimethylamino)pyridine (0.275 g, 2.3 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.37 g, 1.95 mmol) and the resulting reaction mixture was stirred at ambient temperature overnight. The reaction mixture was then subjected to flash column chromatography using 5% ethyl acetate in hexane as the eluent to afford the title compound as a white solid (0.37 g, 91%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[C:14]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=[C:13]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[NH:12][C:11]2=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Br)(Br)([Br:31])=O.S1(CCCC1)(=O)=O.[OH-].[Na+]>>[F:27][C:24]1[CH:25]=[CH:26][C:21]([C:13]2[N:12]=[C:11]([Br:31])[N:10]([CH2:9][CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:14]=2[C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[CH:22][CH:23]=1
Reactant: O=P(Br)(Br)Br
Reactant: O=c1[nH]c(-c2ccc(F)cc2)c(-c2ccncc2)n1CCCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=S1(=O)CCCC1
Product: Fc1ccc(-c2nc(Br)n(CCCc3ccccc3)c2-c2ccncc2)cc1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
1,3-Dihydro-1-(3-phenylpropyl)-4-(4-fluorophenyl)-5(4-pyridyl)-2H-imidazol-2-one (100 g, 0.26 mol) was mixed with POBr3 (268.7 g, 0.93 mol) and sulfolane (200 g) and the reaction mixture was heated to a temperature of 120–125° C. for 1–2 h. Upon completion, the reaction mixture was cooled to 40° C. Cautiously, over about 30 min, 2N NaOH solution (53 g) was added. Additional 2N NaOH solution (53 g) was then added at faster rate. The reaction mixture was then cooled to 15–20° C. and 4N NaOH solution (802 g) was added to adjust the solution to pH 7–8. The aqueous phase was extracted with t-butylmethyl ether (3×143 g) and the organic phases combined. To the combined organic phase was added t-butylmethyl ether (107 g). The solution was washed with water (2×150 g), resulting in the precipitation of a solid, which was collected by filtration.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15]([C:17]2[C:21]([NH:22][C:23]([NH2:25])=[O:24])=[CH:20][N:19]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)[CH:18]=2)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:33][C:34]([F:38])([F:37])[CH2:35]N.C(OCC)(=O)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15]([C:17]2[C:21]([NH:22][C:23]([NH:25][CH2:35][C:34]([F:38])([F:37])[F:33])=[O:24])=[CH:20][N:19]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)[CH:18]=2)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: NCC(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](NC(=O)c2cn(-c3cccc(F)c3)cc2NC(N)=O)C1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H](NC(=O)c2cn(-c3cccc(F)c3)cc2NC(=O)NCC(F)(F)F)C1
Yield: 39 %

Procedure:
Following general method 7, employing (S)-3-{[1-(3-fluorophenyl)-4-ureido-1H-pyrrole-3-carbonyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester and 2,2,2-trifluoroethylamine, afforded the crude desired product. Column chromatography (silica, 12 g column, ISCO, 0-100% ethyl acetate in DCM) afforded the title compound as a glass (70 mg, 39%). LCMS (method B): RT=4.00 min, M+H+=528.
Reaction SMILES: [CH3:1][C:2]1([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C@H:18]4[CH2:19][CH2:20][CH2:21][CH2:22][C@@H:17]4[NH:16][C:15]3=[O:23])[CH2:10][CH2:9]2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[C:25]([O:27][CH2:28][C:29]#[CH:30])=[O:26]>>[O:23]=[C:15]1[N:14]([CH:11]2[CH2:12][CH2:13][N:8]([C:2]3([CH3:1])[CH2:7][CH2:6][N:5]([C:25]([O:27][CH2:28][C:29]#[CH:30])=[O:26])[CH2:4][CH2:3]3)[CH2:9][CH2:10]2)[C@H:18]2[CH2:19][CH2:20][CH2:21][CH2:22][C@@H:17]2[NH:16]1
Reactant: CC1(N2CCC(N3C(=O)N[C@H]4CCCC[C@@H]43)CC2)CCNCC1
Reactant: C#CCOC(=O)Cl
Product: C#CCOC(=O)N1CCC(C)(N2CCC(N3C(=O)N[C@H]4CCCC[C@@H]43)CC2)CC1
Yield: 9.5 %

Procedure:
Following the procedure used in example 16 and starting from (3aS,7aS)-3-[1-(4-methyl-4-piperidyl)-4-piperidyl]-3a,4,5,6,7,7a-hexahydro-1H-benzimidazol-2-one (HCl salt, 181 mg, 0.51 mmol) and prop-2-ynyl chloroformate (0.050 mL, 0.51 mmol), the title compound (19.40 mg, 9.50%) was obtained after purification by preparative LC/MS (high pH). 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.29-1.47 (m, 5H), 1.49 (s, 3H), 1.76-2.01 (m, 8H), 2.29-2.44 (m, 2H), 2.82 (t, J=9.96 Hz, 5H), 2.90 (d, J=10.55 Hz, 2H), 3.03 (d, J=6.64 Hz, 1H), 3.68 (t, J=9.57 Hz, 2H), 4.06-4.17 (m, 1H), 4.27 (d, J=19.53 Hz, 2H), 4.52 (s, 1H), 4.69 (s, 1H), 4.76 (s, 1H). MS (M+1): 403.3.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8](Cl)=[O:9])[CH:3]=1.CCN(C(C)C)C(C)C.[NH:20]1[CH:28]2[CH:23]([CH2:24][CH2:25][CH2:26][CH2:27]2)[CH2:22][CH2:21]1>ClCCl>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([N:20]2[CH:28]3[CH:23]([CH2:24][CH2:25][CH2:26][CH2:27]3)[CH2:22][CH2:21]2)=[O:9])[CH:3]=1
Reactant: O=C(Cl)c1cc(Cl)ncn1
Reactant: C1CCC2NCCC2C1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(c1cc(Cl)ncn1)N1CCC2CCCCC21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.517 g (2.92 mmol) 6-chloropyrimidine-4-carboxylic acid chloride in 10 mL dichloromethane were combined with 1.07 mL (6.00 mmol) DIPEA. 0.73 g (2.92 mmol) octahydroindole in 10 mL DCM was slowly added dropwise. After 2 h stirring at RT the mixture was diluted with dichloromethane and extracted with water. The organic phase was separated off, dried on sodium sulphate, filtered, evaporated down i. vac. and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH:11]([CH3:25])[C:12]([C:18]1[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[CH:19]=1)([OH:17])[C:13]([F:16])([F:15])[F:14])[C:5](O)=[O:6].[CH3:26][O:27][C:28](=[O:37])[C:29]1[CH:34]=[CH:33][C:32]([NH:35][CH3:36])=[CH:31][CH:30]=1.C(N(C(C)C)C(C)C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>ClCCl>[CH3:26][O:27][C:28](=[O:37])[C:29]1[CH:34]=[CH:33][C:32]([N:35]([C:5](=[O:6])[C:4]2[CH:8]=[CH:9][C:10]([CH:11]([CH3:25])[C:12]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[CH:19]=3)([OH:17])[C:13]([F:16])([F:14])[F:15])=[C:2]([Cl:1])[CH:3]=2)[CH3:36])=[CH:31][CH:30]=1
Reactant: CC(c1ccc(C(=O)O)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Reactant: CNc1ccc(C(=O)OC)cc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(N(C)C(=O)c2ccc(C(C)C(O)(c3ccnc(Cl)c3)C(F)(F)F)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 34.2 %

Procedure:
To a solution of 3-chloro-4-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-benzoic acid (Example 26, step 3, 80 mg, 0.2 mmol) and 4-methylamino-benzoic acid methylester (35 mg, 0.21 mmol) in dichloromethane (4 ml) were added N-ethyldiisopropylamine (29 mg, 0.22 mmol) and PyBroP (95 mg, 0.2 mmol). The mixture was stirred for 17 h at room temperature. The reaction solution was extracted with brine/water, dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (5 g silica gel, heptane/AcOEt 8:2=>7:3) to give the title compound (37 mg) as a white solid. MS (m/e)=541.3 [M+H+].
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19](C(F)(F)F)=[CH:18][C:17]([CH2:24][OH:25])=[CH:16][N:15]=2)[CH2:10][C@H:9]1[CH3:26])=O)(C)(C)C.FC(F)(F)C(O)=O.[Cl:34]CCl>C1(C)C=CC=CC=1>[Cl:34][C:19]1[CH:18]=[C:17]([CH2:24][OH:25])[CH:16]=[N:15][C:14]=1[N:11]1[CH2:12][CH2:13][NH:8][C@H:9]([CH3:26])[CH2:10]1
Reactant: C[C@@H]1CN(c2ncc(CO)cc2C(F)(F)F)CCN1C(=O)OC(C)(C)C
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: C[C@@H]1CN(c2ncc(CO)cc2Cl)CCN1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 4-(5-hydroxymethyl-3-trifluoromethyl-pyridin-2-yl)-2-methyl-piperazine-1-carboxylic acid tert-butyl ester from step (f) above (3.75 g, 10 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (10 mL, Aldrich) dropwise at 0° C. over a period of 10 min. The mixture was stirred at room temperature for 16 h and diluted with toluene (20 mL). The solvents were removed in vacuo and the residue was dissolved in EtOAc (100 mL), washed with saturated aqueous solution of NaHCO3 (2×30 mL) and brine (20 mL), dried over Na2SO4, and filtered. The solvent was evaporated in vacuo and the residue was purified by silica gel column chromatography, eluting with 90:10:1 mixture of MeOH/CH2Cl2/ammonium hydroxide to give the title compound as a white solid. MS (ESI, pos. ion) m/e: 276 (M+1).
Reaction SMILES: [OH-:1].[Na+].[Br:3][C:4]1[N:5]([C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]([CH:35]3[CH2:37][CH2:36]3)=[CH:27][CH:26]=2)[C:6]([S:9][CH2:10][C:11](NC2C=CC(S(=O)(=O)N)=CC=2Cl)=[O:12])=[N:7][N:8]=1.C>C(O)C>[Br:3][C:4]1[N:5]([C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]([CH:35]3[CH2:37][CH2:36]3)=[CH:27][CH:26]=2)[C:6]([S:9][CH2:10][C:11]([OH:1])=[O:12])=[N:7][N:8]=1
Reactant: [OH-]
Reactant: NS(=O)(=O)c1ccc(NC(=O)CSc2nnc(Br)n2-c2ccc(C3CC3)c3ccccc23)c(Cl)c1
Agent: [Na+]
Solvent: CCO
Product: O=C(O)CSc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Sodium hydroxide solution (2M aqueous, 33.7 mL, 67 mmol, 2 eq) was added to a suspension of 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)-N-(2-chloro-4-sulfamoylphenyl)acetamide (prepared by previously published procedures; 20 g, 34 mmol) in ethanol (200 mL) and the mixture heated at reflux for 4 hours. Charcoal (10 g) was added, the mixture stirred at room temperature for 12 hours and the charcoal removed by filtration. The charcoal was washed several times with ethanol and the filtrate then concentrated. Water (200 mL) was added and then concentrated to approx. one third volume, to remove all ethanol. Water (200 mL) and ethyl acetate (250 mL) were added, the mixture stirred vigorously for 15 mins and the organic layer removed. The aqueous layer was cooled to 0° C. and acidified by treatment with HCl (1N) resulting in the formation of a cloudy oily precipitate. The mixture was extracted with ethyl acetate (3×) and the combined organic extracts dried over sodium sulfate and concentrated to give 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid as an off white solid (11.2 g, 82%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13]1[CH:21]=[CH:20][C:16]([C:17](=[S:19])[NH2:18])=[CH:15][CH:14]=1)[CH:7]=[CH:6]2.[C:22](Cl)(=[O:26])C(Cl)=O.[Si]([N:32]=[N+]=[N-])(C)(C)C.O>ClCCCl.CC(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13]1[CH:21]=[CH:20][C:16]([C:17]3[S:19][NH:32][C:22](=[O:26])[N:18]=3)=[CH:15][CH:14]=1)[CH:7]=[CH:6]2
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc2nc(-c3ccc(C(N)=S)cc3)ccc2c1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Solvent: ClCCCl
Solvent: O
Solvent: CC(C)O
Product: COc1ccc2nc(-c3ccc(-c4nc(=O)[nH]s4)cc3)ccc2c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
To a solution of 4-(6-methoxyquinolin-2-yl)benzothioamide (500 mg, 1.07 mmol) in DCE (10 mL) was added oxalylchloride (0.3 mL, 3.9 mmol) dropwise at 0° C. The mixture was heated to 90° C. for 2 hours. TMSN3 (0.8 mL, 5.7 mmol) was added dropwise. The mixture was stirred at 100° C. for 2 hours. Water (10 mL) was added to the mixture. The mixture was filtered and the filter cake was washed with IPA (20 mL) to product (280 mg, yield 49%).
Reaction SMILES: [CH3:1][C:2]([CH3:13])([CH3:12])[C:3]#[C:4][C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][CH:11]=1)[NH2:8].[H][H]>O1CCCC1.[Ru]>[CH3:1][C:2]([CH3:13])([CH3:12])[CH2:3][CH2:4][CH:5]1[CH2:11][CH2:10][CH2:9][CH:7]([NH2:8])[CH2:6]1
Reactant: CC(C)(C)C#Cc1cccc(N)c1
Reactant: [H][H]
Agent: [Ru]
Solvent: C1CCOC1
Product: CC(C)(C)CCC1CCCC(N)C1
Temperature: 25 °C

Procedure:
0.5 g of Ru/C 5% is added to a solution consisting of 1.04 g (0.6 mol) of 3-(3,3-dimethylbut-1-yn-1-yl)aniline in 20 ml of tetrahydrofuran, and the mixture is hydrogenated with 100 bar of hydrogen at 120° C. for 40 hours. After cooling to room temperature, the catalyst is filtered off through kieselguhr and the product is concentrated under reduced pressure. This gives 0.9 g (81% of theory) of 3-(3,3-dimethylbutyl)cyclohexanamine as main component according to MSD-HPLC.