Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][S:14][C:15]3[C:20]([C:21]#[N:22])=[C:19]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][OH:32])=[CH:25][CH:24]=4)[C:18]([C:33]#[N:34])=[CH:17][N:16]=3)[N:12]=2)=[CH:4][CH:3]=1.[CH2:35]([NH:37][CH2:38][CH3:39])[CH3:36].O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][S:14][C:15]3[C:20]([C:21]#[N:22])=[C:19]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][OH:32])=[CH:25][CH:24]=4)[C:18]([C:33]#[N:34])=[C:17]([N:37]([CH2:38][CH3:39])[CH2:35][CH3:36])[N:16]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: CCNCC
Reactant: N#Cc1cnc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCN(CC)c1nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N

Procedure:
At RT, 60 mg (0.11 mmol) of 2-chloro-6-({(2-(4-chlorophenyl)-1,3-thiazol-4-ylmethyl}sulfanyl)-4-(4-(2-hydroxyethoxy)phenyl)pyridine-3,5-dicarbonitrile (Example 2A) and 0.023 ml (0.22 mmol) of diethylamine were stirred in 1.5 ml of THF for 30 min. About 15 ml of water were added to the reaction mixture, and the aqueous phase was extracted 3× with ethyl acetate. The combined organic phases were washed once with saturated aqueous sodium chloride solution, dried over sodium sulfate, concentrated by evaporation and dried under high vacuum. This gave 67 mg (99% of theory, purity 95%) of the desired target compound.
Reaction SMILES: [C:1]([C:9]1[C:10](=[O:20])[N:11]([CH3:19])[C:12](=[O:18])[N:13]([CH3:17])[C:14]=1[CH2:15]Br)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[CH:24](OCC)[CH2:25][CH2:26][CH2:27][NH2:28])C>CCO>[CH3:17][N:13]1[C:14]2=[C:15]3[N:28]([C:1]([C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[C:9]2[C:10](=[O:20])[N:11]([CH3:19])[C:12]1=[O:18])[CH2:27][CH2:26][CH:25]=[CH:24]3
Reactant: Cn1c(CBr)c(C(=O)c2ccccc2)c(=O)n(C)c1=O
Reactant: CCOC(CCCN)OCC
Solvent: CCO
Product: Cn1c(=O)c2c(-c3ccccc3)n3c(c2n(C)c1=O)C=CCC3
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
5-Benzoyl-6-(bromomethyl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione (Intermediate C), (1.169 g, 3.47 mmol) in EtOH (20 mL) was treated with 4,4-diethoxybutan-1-amine (0.659 mL, 3.81 mmol) and TEA (0.966 mL, 6.93 mmol) and the mixture heated at reflux for 50 min. The reaction mixture was cooled to RT and evaporated under reduced pressure. The residue was re-dissolved in THF (20 mL), 1M hydrochloric acid (3.47 mL) was added and the mixture stirred at RT for 1.5 h. The reaction mixture was diluted with EtOAc, washed with water, brine and the organic phase was dried over sodium sulphate and evaporated under reduced pressure. The residue was triturated with DCM/hexane and the precipitate collected by filtration to give the title product as a pale pink solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8]Cl)=[C:6]([CH3:10])[CH:5]=[C:4]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:3]=1[OH:15].[SH:16][CH2:17][CH2:18][OH:19].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(C(C)=O)C(C)C>[CH3:1][C:2]1[C:7]([CH2:8][S:16][CH2:17][CH2:18][OH:19])=[C:6]([CH3:10])[CH:5]=[C:4]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:3]=1[OH:15]
Reactant: OCCS
Reactant: Cc1cc(C(C)(C)C)c(O)c(C)c1CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: Cc1cc(C(C)(C)C)c(O)c(C)c1CSCCO

Procedure:
This material was prepared according to the procedure of Example III using 2,4-dimethyl-3-chloromethyl-6-t-butylphenol (160.8 g, 0.71 m), 2-mercaptoethanol (52.5 g, 0.71 m), potassium carbonate (110.4 g, 0.8 m), potassium iodide (5.0 g), and methyl isobutyl ketone (500 ml). Work-up afforded a dark colored oil. This material can be distilled under a very good vacuum. The nmr spectrum was consistent with the desired structure.
Reaction SMILES: Br[C:2]([CH3:6])([CH3:5])[CH:3]=[O:4].[O:7]1[CH2:10][CH:9]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH2:8]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:5][C:2]([N:14]1[CH2:15][CH2:16][N:11]([CH:9]2[CH2:10][O:7][CH2:8]2)[CH2:12][CH2:13]1)([CH3:6])[CH:3]=[O:4]
Reactant: C1CN(C2COC2)CCN1
Reactant: CC(C)(Br)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C=O)N1CCN(C2COC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-bromo-2-methyl-propanal (696.6 mg, 4.61 mmol) in DCM (10 mL) was cooled with an ice bath and 1-(oxetan-3-yl)piperazine (328 mg, 2.31 mmol), diluted with 5-10 mL of DCM, was slowly added via addition funnel over a 15 min period. Next, Hunig's base (0.4 mL, 2.31 mmol) was added and then the cooling bath was removed. The reaction mixture was stirred at room temperature overnight and the DCM layer was washed three times with 0.5N HCl. The combined aqueous layer was neutralized with NaOH to pH 10-11 and extracted with DCM. The combined organic layer was washed with brine and dried over Na2SO4. Filtration and removal of solvent afforded 2-methyl-2-[4-(oxetan-3-yl)piperazin-1-yl]propanal as a light yellow liquid, which was used directly in the next step without further purification.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[Br:8][C:9]1[S:13][C:12]([S:14](Cl)(=[O:16])=[O:15])=[CH:11][CH:10]=1.C(N(CC)CC)C>C1COCC1>[OH:4][CH2:3][CH2:2][N:1]([CH2:5][CH2:6][OH:7])[S:14]([C:12]1[S:13][C:9]([Br:8])=[CH:10][CH:11]=1)(=[O:16])=[O:15]
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Reactant: OCCNCCO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(Br)s1)N(CCO)CCO
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.7 %

Procedure:
To a stirred solution of diethanolamine (1.45 g, 13.8 mmol) in THF (20 ml) was added at 0° C. (ice water bath) commercially available 5-bromo-thiophene-2-sulfonyl chloride (1.0 g, 3.82 mmol) and triethylamine (0.71 ml, 5.07 mmol). The reaction mixture was stirred at room temperature for 16 h and evaporated. The crude product was further purified by flash chromatography (ethyl acetate/heptane) to yield the title compound (0.98 g, 77%) as a white solid. MS (ISP) 330.0 [(M+H)+], mp 70° C.
Reaction SMILES: [CH:1]([P:3](=[O:14])([CH:12]=[CH2:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=[CH2:2].[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1.O>[CH2:15]([N:22]1[CH2:13][CH2:12][P:3](=[O:14])([CH2:4][C:5]2[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=2)[CH2:1][CH2:2]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCc1ccccc1
Reactant: C=CP(=O)(C=C)Cc1ccc(F)cc1
Solvent: C1CCOC1
Solvent: O
Product: O=P1(Cc2ccc(F)cc2)CCN(Cc2ccccc2)CC1
Temperature: 82 °C
Yield: 77.5 %

Procedure:
Divinyl-(4-Fluorophenylmethyl)-phosphine oxide (0.719 g, 3.42 mmol) and benzylamine (0.45 mL, 4.11 mmol) were dissolved in a mixture of THF (15 mL) and deionized water (15 mL). The reaction mixture was heated at 82° C. for 22 hours. The reaction was not complete and so an additional 0.04 mL of benzylamine was added and the reaction mixture was heated for an additional six hours at 90° C. The reaction mixture was concentrated by rotary evaporation and the product was extracted into dichloromethane and washed with saturated brine. The organic phase was dried with sodium sulfate, filtered, and concentrated by rotary evaporation. The crude product was taken up in 1:1 ethyl acetate:dichloromethane and passed through a plug of silica. The product was then eluted from the silica with a solution of 10% methanol in ethyl acetate. The solvents were removed by rotary evaporation to yield 0.84 g of 1-benzyl-4-(4-fluorophenylmethyl)-[1,4]azaphosphinane 4-oxide (2.65 mmol, 77%). 1H NMR (400 MHz, CDCl3) δ 7.34-7.25 (m, 5H); 7.25-7.20 (m, 2H); 7.04-6.98. (m, 2H); 3.6 (s, 2H); 3.17-3.12 (d, 2H); 3.00-2.85 (m, 2H); 2.81-2.66 (m, 2H); 1.98-1.75 (m, 4H).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[CH2:14][C@@H:13]([OH:15])[CH2:12][N:11]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].[F:25][C:26]1[CH:27]=[C:28]([N+:33]([O-:35])=[O:34])[CH:29]=[C:30](F)[CH:31]=1>CN(C=O)C>[Si:1]([O:8][CH2:9][C@@H:10]1[CH2:14][C@@H:13]([O:15][C:30]2[CH:29]=[C:28]([N+:33]([O-:35])=[O:34])[CH:27]=[C:26]([F:25])[CH:31]=2)[CH2:12][N:11]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1CO[Si](C)(C)C(C)(C)C
Reactant: O=[N+]([O-])c1cc(F)cc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@H](Oc2cc(F)cc([N+](=O)[O-])c2)C[C@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
To a 0° C. solution of (2S,4R)-tert-butyl 2-((tert-butyldimethylsilyloxy)methyl)-4-hydroxypyrrolidine-1-carboxylate (1 equiv) in DMF (0.5 M) was added NaH (1.3 equiv) as a solid. After stirring for 30 minutes at 0° C., 3,5-difluoronitrobenzene (1.2 equiv) was added by syringe. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched by the addition of water, and the mixture was diluted with EtOAc. The organic layer was washed four times with water and once with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification by flash chromatography (10-20% EtOAc/Hexanes) provided the title compound in 66% yield.
Reaction SMILES: [CH2:1]([CH:6]1[CH2:12][CH:11]2[CH2:13][CH:8]([CH:9]=[CH:10]2)[C:7]1=[O:14])[CH2:2][CH2:3][CH2:4][CH3:5].[H][H]>[Pd].C(O)(C)C>[CH2:1]([CH:6]1[CH2:12][CH:11]2[CH2:13][CH:8]([CH2:9][CH2:10]2)[C:7]1=[O:14])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCC1CC2C=CC(C2)C1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(C)O
Product: CCCCCC1CC2CCC(C2)C1=O
Temperature: 100 °C
Yield: 53.3 %

Procedure:
3-Pentylbicyclo [3.2.1]oct-6-en-2-one (130 g, synthesized as above) was placed in a stainless steel autoclave with isopropanol (30 g) and Pd/C (1.5 g). The mixture was placed under 300 psi of hydrogen gas, and heated at 100° C. until gas uptake ceased. The resulting material was then removed from the autoclave, filtered, and distilled to yield 3-pentylbicyclo[3.2.1]octan-2-one 70 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([N:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:5]([Cl:21])=[CH:4][N:3]=1.[NH2:22][C:23]1[C:42]([O:43][CH3:44])=[CH:41][C:26]2[CH2:27][CH2:28][N:29]([CH2:32][C:33]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[O:34])[CH2:30][CH2:31][C:25]=2[CH:24]=1>>[Cl:21][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([N:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])=[N:7][C:2]([NH:22][C:23]2[C:42]([O:43][CH3:44])=[CH:41][C:26]3[CH2:27][CH2:28][N:29]([CH2:32][C:33]([N:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)=[O:34])[CH2:30][CH2:31][C:25]=3[CH:24]=2)=[N:3][CH:4]=1
Reactant: COc1cc2c(cc1N)CCN(CC(=O)N1CCOCC1)CC2
Reactant: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)N(C)C)n1)CCN(CC(=O)N1CCOCC1)CC2
Yield: 55 %

Procedure:
In an analogous manner to Example 1503, the product was prepared from 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N,N-dimethyl-benzenesulfonamide and 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-1-morpholin-4-yl-ethanone. Product was isolated as an off-white foam (60 mg, 55%). MS (ESI+): 630.6 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 9.36 (s, 1H), 8.54 (d, J=8 Hz, 1H), 8.16 (s, 1H), 8.02 (s, 1H), 7.90 (d, J=8 Hz, 1H), 7.58 (t, 1H), 7.52 (s, 1H), 7.25 (t, 1H), 6.67 (s, 1H), 3.89 (s, 3H), 3.74 (s, 7H), 3.67 (m, 2H), 3.30 (s, 2H), 2.87 (m, 2H), 2.76 (s, 8H), 2.68 (m, 5H).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([O:10][CH2:11][CH2:12][O:13][CH3:14])[N:7]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH2:21])[N:16]=3)[C:6]=2[CH:22]=1.N1CCCCC1.[N:29]1[CH:34]=[CH:33][CH:32]=[N:31][C:30]=1[C:35]([OH:39])([C:37]#[CH:38])[CH3:36]>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.[Cu]I>[NH2:21][C:17]1[N:16]=[C:15]([N:7]2[C:6]3[CH:22]=[C:2]([C:38]#[C:37][C:35]([C:30]4[N:29]=[CH:34][CH:33]=[CH:32][N:31]=4)([OH:39])[CH3:36])[CH:3]=[CH:4][C:5]=3[N:9]=[C:8]2[O:10][CH2:11][CH2:12][O:13][CH3:14])[CH:20]=[CH:19][N:18]=1
Reactant: C#CC(C)(O)c1ncccn1
Reactant: COCCOc1nc2ccc(I)cc2n1-c1ccnc(N)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: COCCOc1nc2ccc(C#CC(C)(O)c3ncccn3)cc2n1-c1ccnc(N)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a pressure tube was added 4-[6-iodo-2-(2-methoxyethoxy)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine (70%, 120 mg, 0.2 mmol) followed by piperidine (1.0 mL), tetrakis(triphenylphosphine)palladium(0) (23.61 mg, 0.02 mmol), copper(I) iodide (3.89 mg, 0.02 mmol) and 2-(pyrimidin-2-yl)but-3-yn-2-ol (60.53 mg, 0.41 mmol). The reaction was capped and stirred at RT for 1 h. The reaction mixture was concentrated in vacuo. The crude material was purified by flash column chromatography (1-10% MeOH gradient in DCM), followed by trituration with EtOAc/heptanes/DCM to give the title compound: 1H NMR (500 MHz, DMSO) delta 1.88 (3H, s), 3.92-3.64 (2H, m), 4.84-4.59 (2H, m), 6.13 (1H, s), 6.97 (1H, d, J=5.5 Hz), 7.10 (2H, s), 7.23 (1H, dd, J=8.2, 1.5 Hz), 7.44 (1H, d, J=8.1 Hz), 7.49 (1H, t, J=4.8 Hz), 8.13 (1H, s), 8.39 (1H, d, J=5.5 Hz), 8.89 (2H, d, J=4.9 Hz); LC-MS: m/z=+432.05 (M+H)+.
Reaction SMILES: [CH3:1][S:2][C:3](=[S:8])[NH:4][CH2:5][CH2:6]O.[CH2:9]([O:13][CH:14]=[CH2:15])[CH:10]([CH3:12])[CH3:11].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(N(CC)CC)C>[CH3:1][S:2][C:3](=[S:8])[NH:4][CH2:5][CH2:6][CH:14]([O:13][CH2:9][CH:10]([CH3:12])[CH3:11])[CH3:15]
Reactant: C=COCC(C)C
Reactant: CSC(=S)NCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCN(CC)CC
Product: CSC(=S)NCCC(C)OCC(C)C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a mixture of N-(2-hydroxyethyl)dithiocarbamic acid methyl ester (1.513 g) and isobutoxyethylene (2.59 ml) is added toluene-p-sulfonic acid monohydrate (9.5 mg). After stirring for 30 minutes, triethylamine (8 μl) is added to the mixture, and the resulting solution is concentrated under reduced pressure to give N-[2-(1-isobutoxyethyl)ethyl]dithiocarbamic acid methyl ester (3.2 g). Yield: 95%.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[S:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[S:11](Cl)(=[O:13])=[O:12]>O1CCCC1>[CH3:2][C:1]([NH:5][S:11]([C:7]1[S:6][CH:10]=[CH:9][CH:8]=1)(=[O:13])=[O:12])([CH3:4])[CH3:3]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: CC(C)(C)N
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.5 %

Procedure:
To a solution of t-butylamine (8.35 g, 0.114 mol) in dry tetrahydrofuran (THF) (20 mL) cooled to 0° C. was added dropwise 2-thiophenesulfonyl chloride (5.0 g, 27.4 mmol). After the addition was completed, the reaction mixture was warmed to ambient temperature and stirred overnight. The mixture was extracted with ethyl acetate (3×80 mL) and the combined extracts were washed with water, dried over molecular sieves and concentrated. The residue was chromatographed on silica, eluting with 25% ethyl acetate-hexane, to yield 5.62 g (94%) of solid: mp 80°-82° C.
Reaction SMILES: [NH2:1][C:2]1[C:32]([Cl:33])=[CH:31][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:34][CH3:35])[CH:3]=1.[CH:36](=O)[CH3:37].C([BH3-])#N.[Na+]>>[NH2:1][C:2]1[C:32]([Cl:33])=[CH:31][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:36][CH3:37])[CH2:23][C:24]3[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=3)[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:34][CH3:35])[CH:3]=1
Reactant: CC=O
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCCNCc2ccc(C)cc2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCN(CCCCCCN1CCC(CNC(=O)c2cc(Cl)c(N)cc2OC)CC1)Cc1ccc(C)cc1

Procedure:
4-Amino-5-chloro-2-methoxy-N-((1-(6-(4-methylbenzylamino)hexyl)-piperidin-4-yl)methyl)benzamide (0.77 g) as starting compound, acetaldehyde (0.1 ml) and sodium cyanoborohydride (0.23 g) were reacted and treated in the same manner as in Example 136 to give 0.42 g of 4-amino-5-chloro-N-((1-(6-(N-ethyl-N-(4-methylbenzyl)amino)hexyl)-piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[C:12]([CH3:16])[S:13][C:14]=2[CH3:15])[CH:5]=1.[Br:18]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[C:12]([CH3:16])[S:13][C:14]=2[CH2:15][Br:18])[CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cccc(-c2nc(C)sc2C)c1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cccc(-c2nc(C)sc2CBr)c1
Yield: 118.7 %

Procedure:
A mixture of 3-(2,5-dimethyl-thiazol-4-yl)-benzoic acid methyl ester (3.96 g), N-bromosuccinimid (3.13 g) and α,α′-bis(isobutyronitrile) (0.02 g) in CCl4 (60 mL) was heated at reflux for 30 min. The cooled mixture was filtered and the solvent was evaporated to give crude 3-(5-bromomethyl-2-methyl-thiazol-4-yl)-benzoic acid methyl ester (6.2 g) as an oil.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([CH:7]=[O:8])=[CH:5][N:6]=1.[F-].[Cs+].[C:11]([Si](C)(C)C)([F:14])([F:13])[F:12]>COCCOC>[Br:1][C:2]1[S:3][C:4]([CH:7]([OH:8])[C:11]([F:14])([F:13])[F:12])=[CH:5][N:6]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=Cc1cnc(Br)s1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Product: OC(c1cnc(Br)s1)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution (0.52 M) of 2-bromo-5-formylthiazole (1.0 eq.) and CsF (0.2 eq.) in DME was treated with CF3SiMe3 (2.0 eq.) and then stirred for 2 h at RT. The reaction mixture was quenched by adding water and stirred for 15 min. Then, it was diluted with EtOAc and the organic phase was separated. The aqueous phase was extracted twice with EtOAc. The combined organic phase was dried (Na2SO4) and solvents were removed under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with 5-25% EtOAc/petroleum ether to afford the title compound as a yellow solid. 1H NMR (300 MHz, CDCl3, 300K) δ 4.04 (1H, d, J=5.9 Hz), 5.32 (1H, dq, J=5.9 Hz, J=5.9 Hz), 7.59 (1H, s). MS (ES+) C5H3BrF3NOS requires: 261/263, found: 262/264 (M+H)+.
Reaction SMILES: [F:1][C@@:2]([CH3:25])([C:6]([NH:8][C@@H:9]1[C:15](=[O:16])[NH:14][C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[C:11]2[CH:21]=[CH:22][CH:23]=[CH:24][C:10]1=2)=[O:7])[C:3](O)=[O:4].[F:26][C:27]([F:34])([C:30]([F:33])([F:32])[F:31])[CH2:28][NH2:29]>>[F:1][C@:2]([CH3:25])([C:3]([NH:29][CH2:28][C:27]([F:34])([F:26])[C:30]([F:33])([F:32])[F:31])=[O:4])[C:6]([NH:8][C@@H:9]1[C:15](=[O:16])[NH:14][C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[C:11]2[CH:21]=[CH:22][CH:23]=[CH:24][C:10]1=2)=[O:7]
Reactant: NCC(F)(F)C(F)(F)F
Reactant: C[C@@](F)(C(=O)O)C(=O)N[C@@H]1C(=O)Nc2ccccc2-c2ccccc21
Product: C[C@@](F)(C(=O)NCC(F)(F)C(F)(F)F)C(=O)N[C@@H]1C(=O)Nc2ccccc2-c2ccccc21

Procedure:
In an analogous manner to that described in Example 1 c), the condensation of (2S)-2-fluoro-2-methyl-N-[(S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-malonamic acid and 2,2,3,3,3-pentafluoro-propylamine yielded the title compound as a white solid; MS: m/e=474 (M+H)+; optical integrity 96.4% d.e.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11](=[C:14](SC)[NH:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[C:12]#[N:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:24][CH:25]([NH2:30])[C:26]([CH3:29])([CH3:28])[CH3:27]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11](=[C:14]([NH:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[NH:30][CH:25]([CH3:24])[C:26]([CH3:29])([CH3:28])[CH3:27])[C:12]#[N:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CSC(Nc1cccnc1)=C(C#N)S(=O)(=O)c1ccc(Cl)cc1
Reactant: CC(N)C(C)(C)C
Product: CC(NC(Nc1cccnc1)=C(C#N)S(=O)(=O)c1ccc(Cl)cc1)C(C)(C)C
Yield: 58 %

Procedure:
2-(4-Chloro-phenylsulfonyl)-3-methylsulfanyl-3-(pyridin-3-ylamino)-2-propenenitrile (0.186 g, 0.5 mmol) was stirred in 1,2,2-trimethylpropylamine (1 ml) for 22 h at 100° C. under nitrogen. The reaction mixture was concentrated. The residue was dissolved in DCM, washed with water, dried (sodium sulfate) and concentrated. The crude product was purified by flash chromatography using ethyl acetate as eluent to give 124 mg (58%) of the title compound as a syrup, which could be crystallised from ethyl acetate/heptane 2:1 to give 65 mg (30%). Mp 172-174° C. 1H NMR (300 MHz, CDCl3): δ=0.85 (s, 9H), 0.9 (d, 3H), 3.03 (m, 1H), 7.35 (m, 2H), 7.48 (d, 2H), 7.80 (d, 2H), 8.33 (br s, 1H), 8.5 (br s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([I:12])[C:9]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:15][C:8]=2[C:7]=1[OH:22])=[O:5])[CH3:2].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([I:12])[C:9]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:15][C:8]=2[C:7]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(I)c2nc(-c3ccccc3)sc2c1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(I)c2nc(-c3ccccc3)sc2c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.9 %

Procedure:
A mixture of 7-hydroxy-4-iodo-2-phenyl-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (405 mg, 0.95 mmole), benzyl bromide (170 μl, 1.43 mmole), potassium carbonate (329 mg, 2.38 mmole) in dimethylformamide (5 ml) was stirred at room temperature for four hours before it was partitioned between ethyl acetate and water, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and hexanes to give the title compound as a white solid (451 mg). MS: (+) m/z 517.04 (M+1).
Reaction SMILES: [C:1]1(=[O:27])[N:5]([CH2:6][C:7]2[NH:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[CH:10]=[C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]=23)[C:4](=[O:22])[C:3]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:2]12.C(O)=O.[H][H]>CN(C)C=O.[Pd]>[C:4]1(=[O:22])[N:5]([CH2:6][CH:7]2[NH:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[CH2:10][C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]2=3)[C:1](=[O:27])[C:2]2=[CH:26][CH:25]=[CH:24][CH:23]=[C:3]12
Reactant: O=C1c2ccccc2C(=O)N1CC1=c2ccccc2=Cc2ccccc2N1
Reactant: [H][H]
Agent: [Pd]
Solvent: O=CO
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CC1Nc2ccccc2Cc2ccccc21
Temperature: 50 °C

Procedure:
A suspension of 110.0 kg of 6-phthalimidomethyl-5H-dibenz[b,e]azepine in 911.4 liters of dimethylformamide, 28.7 kg of formic acid and a suspension of 12.5 kg of 10% palladium charcoal in 25 liters of dimethylformamide is fed into a 1200 liter VA-propulsive jet loop reactor. The reaction mixture is heated to 70° C. and hydrogenated under 7 bar of absolute hydrogen pressure. After the catalyst has been filtered off and the reaction equipment and catalyst have been washed with 80 liters of dimethylformamide, 960 liters of dimethylformamide are distilled off from the combined filtrates at 70° to 80° C. After cooling to 50° C., 150 liters of acetone are added, then after further cooling to 15° C. the precipitated crystals are centrifuged off, washed with acetone and dried.