Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.C(N(CC)C(C)C)(C)C.[O:32]1[CH2:38][CH2:37][CH2:36][O:35][C:34]2[CH:39]=[C:40](B(O)O)[CH:41]=[CH:42][C:33]1=2>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[O:32]1[CH2:38][CH2:37][CH2:36][O:35][C:34]2[CH:39]=[C:40]([C:2]3[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:3]=3)[CH:41]=[CH:42][C:33]1=2
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1Cl
Reactant: OB(O)c1ccc2c(c1)OCCCO2
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: COCCOC
Product: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1-c1ccc2c(c1)OCCCO2
Yield: 85.1 %

Procedure:
This compound was prepared according to general method E from methyl 2-(4-chloro-6-methyl-2-phenylpyrimidin-5-yl)pentanoate (0.08 g; 0.25 mmol), tetrakis(triphenylphosphine) palladium(0) (0.029 mg; 0.025 mmol), N,N-diisopropylethylamine (0.173 mL; 1 mmol) and 3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-ylboronic acid (0.097 g; 0.5 mmol) in DME-water (2 mL) for 30 min. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (2-40%) in heptane furnished 0.092 g (75%) of the title compound.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[CH:8]1[CH2:17][C:16]2[CH:15]=[C:14]([C:18]#[N:19])[CH:13]=[CH:12][C:11]=2[CH2:10][CH2:9]1.[O:20]=[C:21]1[C:25]2[CH:26]=[CH:27][C:28]([CH2:30][CH:31]=O)=[CH:29][C:24]=2[CH2:23][O:22]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[O:1]=[C:2]1[CH2:7][N:6]([CH2:31][CH2:30][C:28]2[CH:27]=[CH:26][C:25]3[C:21](=[O:20])[O:22][CH2:23][C:24]=3[CH:29]=2)[CH2:5][CH2:4][N:3]1[CH:8]1[CH2:17][C:16]2[CH:15]=[C:14]([C:18]#[N:19])[CH:13]=[CH:12][C:11]=2[CH2:10][CH2:9]1
Reactant: N#Cc1ccc2c(c1)CC(N1CCNCC1=O)CC2
Reactant: O=CCc1ccc2c(c1)COC2=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)CC(N1CCN(CCc3ccc4c(c3)COC4=O)CC1=O)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 7-(2-Oxopiperazin-1-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (100 mg, 0.39 mmol) in 10 mL of anhydrous DCM was added (1-Oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde (69 mg, 0.39 mmol), NaBH(OAc)3 (330 mg, 1.56 mmol) and the mixture was stirred at room temperature overnight. DCM was added, and the mixture was washed with brine. The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep-TLC to give the desired product. 1H-NMR (400 MHz, CDCl3) δ ppm 7.79 (d, J=7.5 Hz, 1H), 7.27-7.35 (m, 4H), 7.12 (d, J=8.3 Hz, 1H), 5.23 (s, 2H), 4.74-4.85 (m, 1H), 3.17-3.34 (m, 4H), 2.64-2.95 (m, 10H), 1.74-1.95 (m, 2H).
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][C:29]=1[CH3:30])[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:13]=[C:12]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[C:11]=1[O:25][CH3:26])=[O:8])=[N+:2]=[N-:3].[C:31]([C:33]1[N:37]([CH3:38])[C:36]([N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=[N:35][CH:34]=1)#[CH:32]>>[C:16]([C:14]1[CH:13]=[C:12]([NH:20][S:21]([CH3:24])(=[O:22])=[O:23])[C:11]([O:25][CH3:26])=[C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:27]=[CH:28][C:29]([CH3:30])=[C:4]([N:1]3[CH:32]=[C:31]([C:33]4[N:37]([CH3:38])[C:36]([N:39]5[CH2:40][CH2:41][O:42][CH2:43][CH2:44]5)=[N:35][CH:34]=4)[N:3]=[N:2]3)[CH:5]=2)[CH:15]=1)([CH3:18])([CH3:19])[CH3:17]
Reactant: COc1c(NC(=O)c2ccc(C)c(N=[N+]=[N-])c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reactant: C#Cc1cnc(N2CCOCC2)n1C
Product: COc1c(NC(=O)c2ccc(C)c(-n3cc(-c4cnc(N5CCOCC5)n4C)nn3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O

Procedure:
Example 29 was prepared from 3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide and 4-(5-ethynyl-1-methyl-1H-imidazol-2-yl)-morpholine in the same manner as Example 15. ESI MS m/z 623 [C30H38N8O5S+H]+.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][N:5]=1)[NH2:3].CN(C)/[CH:14]=[CH:15]/[C:16]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]([O:25][CH3:26])[CH:19]=1)=O>>[CH3:26][O:25][C:20]1[CH:19]=[C:18]([C:16]2[N:2]([C:4]3[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][N:5]=3)[N:3]=[CH:14][CH:15]=2)[CH:23]=[CH:22][C:21]=1[CH3:24]
Reactant: COc1cc(C(=O)/C=C/N(C)C)ccc1C
Reactant: N#Cc1ccnc(NN)c1
Agent: Cl
Product: COc1cc(-c2ccnn2-c2cc(C#N)ccn2)ccc1C
Yield: 100 %

Procedure:
The title compound was prepared in 100% yield from 2-hydrazinylpyridine-4-carbonitrile hydrochloride salt (PREPARATION 3) and (2E)-3-(dimethylamino)-1-(3-methoxy-4-methylphenyl)prop-2-en-1-one according to the procedure for the preparation of Example 12, part B. 1H NMR (400 MHz, CDCl3): δ 2.24 (3H, s), 3.73 (3H, s), 6.51 (1H, d, J=1.6 Hz), 6.71-6.75 (2H, m), 7.08 (1H, d, J=8.0 Hz), 7.39 (1H, dd, J=5.2, 1.2 Hz), 7.77 (1H, d, J=1.2 Hz), 7.90 (1H, s), 8.47(1H, d, J=5.2 Hz). [M+H] Calc'd for C17H14N4O, 291; Found, 291.
Reaction SMILES: C(OC([C:6]1[NH:7][C:8]([CH3:18])=[C:9]([CH2:12][CH2:13][C:14]([O:16]C)=[O:15])[C:10]=1[CH3:11])=O)C.[OH-].[Na+]>Cl>[CH3:18][C:8]1[NH:7][CH:6]=[C:10]([CH3:11])[C:9]=1[CH2:12][CH2:13][C:14]([OH:16])=[O:15]
Reactant: CCOC(=O)c1[nH]c(C)c(CCC(=O)OC)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1c[nH]c(C)c1CCC(=O)O
Temperature: 50 °C
Yield: 43.7 %

Procedure:
4-(2-Methoxycarbonyl-ethyl)-3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester (Aldrich, 228 g, 0.9 mol) and 720 mL of 5 N sodium hydroxide were refluxed for one hour. Thin layer chromatography showed the hydrolysis to be complete. The stirred mixture was cooled to 50° C. and hydrochloric acid (10 N, 390 mL) was slowly added to give a pH of 2-3. The oil which separated solidified. The mixture was stirred and cooled to 4° C. The solids were collected by vacuum filtration, washed thoroughly with water and dried under vacuum at 40° C. to give 65.7 g (49% yield) of 3-(2,4-dimethyl-1H-pyrrol-3-yl)-propionic acid as a reddish solid.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([C:15]([S:27][C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25]O)[CH:20]=2)[C:16]#[N:17])[CH:10]=[CH:11][C:12]=1OC.O.CN(C)[CH:38]=[O:39]>>[Cl:3][CH2:25][C:21]1[CH:20]=[C:19]([CH2:18][C:15]([C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([O:6][CH3:5])[C:8]=2[O:39][CH3:38])([S:27][C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)[C:16]#[N:17])[CH:24]=[CH:23][CH:22]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(C(C#N)(Cc2cccc(CO)c2)Sc2ccc(C)cc2)cc1OC
Reactant: CN(C)C=O
Solvent: O
Product: COc1cccc(C(C#N)(Cc2cccc(CCl)c2)Sc2ccc(C)cc2)c1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 0.1 mL of thionyl chloride and 0.12 mL of N,N-dimethyl formamide is stirred at room temperature for 30 minutes. A solution of 0.34 g of α-(3,4-dimethoxyphenyl)-3-(hydroxymethyl)-α-[(4-methylphenyl)thio]benzene propane nitrile in 1.0 mL of N,N-dimethylformamide is added to the above mixture and the resulting mixture is heated at 70° C. for 17 hours, cooled, poured into water and extracted with diethyl ether. The diethyl ether extract is washed with brine, dried and filtered. The filtrate is evaporated in vacuo to yield an oil. This oil is purified by flash chromatography using 10% ethyl acetate in hexane to yield 0.27 g of the desired product as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[CH:5]=[N:6][CH:7]=1.FC(F)(F)C(O)=O.ClCCl>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][NH2:9])[CH:5]=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N(Cc1cncc(Br)c1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: NCc1cncc(Br)c1
Yield: 87.7 %

Procedure:
The product of Example 18A (0.98 g, 2.53 mmol) was treated with trifluoroacetic acid and dichloromethane (1:1 v/v, 20 mL) for 2 hours at room temperature. The solvent was removed by rotary evaporation and the resulting oil was chased with benzene/dichloromethane (3 times) to give a waxy solid. The salt was dissolved in anhydrous methanol (20 mL) and stirred with Amberlite IRA-400(OH), resin (10 g) for 2 hrs. The resin was removed by vacuum filtration and thoroughly washed with dry methanol. The filtrate was concentrated by rotary evaporation to give the title compound (0.415 g, 88%). MS (DCI/NH3) M/z 187/189 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 3.73 (s, 2H), 8.02 (t, J=2.02 Hz, 1H), 8.50 (d, J=1.47 Hz, 1H), 8.53 (d, J=2.21 Hz, 1H).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8].[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(N(C(C)C)CC)(C)C>C1COCC1>[N+:11]([C:5]1[CH:4]=[CH:3][C:2]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:10][C:6]=1[C:7]([NH2:9])=[O:8])([O-:13])=[O:12]
Reactant: NC(=O)c1cc(F)ccc1[N+](=O)[O-]
Reactant: C1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1cc(N2CCCCC2)ccc1[N+](=O)[O-]
Yield: 93.4 %

Procedure:
To 5-Fluoro-2-nitro-benzamide (850 mg, 4.07 mmol) in THF (100 mL), was added piperidine (381 mg, 4.47 mmol) and diisopropyl ethyl amine (780 mL, 4.07 mmol) and the solution was heated to 70 C in a sealed tube for 12 h. The resulting yellow precipitate was collected to give 2-Nitro-5-piperidin-1-yl-benzamide 948 mg (100% yield) HPLC tr=3.58 min (100%), FIA m/e 250.2 (M+H) 248.8 (M-H); HNMR (500 MHz, dmso): δ 7.95 (1H, d), 7.85 91H, bs), 7.50 (1H, bs), 6.97 (1H, d), 6.80 (1H, s), 3.50 (4H, m), 1.70-1.50 (6H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH3:11][NH:12][C@@H:13]([CH2:22][CH2:23][CH3:24])[CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([OH:21])[CH2:17][CH2:16]1>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:12]([C@@H:13]([CH2:22][CH2:23][CH3:24])[CH2:14][N:15]2[CH2:16][CH2:17][CH:18]([OH:21])[CH2:19][CH2:20]2)[CH3:11])=[O:7])=[CH:4][CH:3]=1
Reactant: CCC[C@@H](CN1CCC(O)CC1)NC
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: ClCCl
Product: CCC[C@@H](CN1CCC(O)CC1)N(C)C(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 70.4 %

Procedure:
4-Chlorobenzoyl chloride (1.683 mL, 13.12 mmol) was added to a solution of (S)-1-(2-(methylamino)pentyl)piperidin-4-ol (Compound J6) (2.629 g, 13.12 mmol) and TEA (3.66 mL, 26.25 mmol) in DCM (25 mL) at 0° C. A white slurry was formed. The reaction was stirred for 45 min at 0° C. and was then allowed to attain rt. The reaction was stirred overnight and was then quenched by addition of NaHCO3 (8% aq., 25 mL). The aqueous phase was extracted with DCM. The organic phases were pooled, dried (MgSO4), filtered and evaporated under reduced pressure. The crude product was chromatographed to give the title product (3.13 g, 70.3%) as a colourless glue. 1H NMR (400 MHz, CD3OD) 0.87, 0.99, 1.17-1.33, 1.35-1.63, 1.71-1.90, 1.95-2.15, 2.15-2.36, 2.43-2.51, 2.52-2.68, 2.71-2.80, 2.89, 2.99-3.08, 3.51-3.64, 3.68-3.77, 4.87-4.97, 7.08-7.24, 7.37-7.51. HRMS (M+H)+: calculated 339.1839. found 339.1827.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]#[N:9].[CH3:10][NH:11][NH2:12]>C(O)C>[CH3:10][N:11]1[C:8]([NH2:9])=[C:3]2[C:2]([CH2:7][CH2:6][CH2:5][CH2:4]2)=[N:12]1
Reactant: N#CC1CCCCC1=O
Reactant: CNN
Solvent: CCO
Product: Cn1nc2c(c1N)CCCC2

Procedure:
A solution of 2-oxocyclohexanecarbonitrile 16 (10 g, 81.2 mmol) and methyl hydrazine 15 (3 equiv, 11.2 g) in 150 mL of absolute ethanol was refluxed for 20 hrs and was concentrated on rotavapor to dryness. The crude product was recrystallized from methanol to afford the desired product 17. (Reference for the preparation of compound 17: J. Am. Chem. Soc. 1959, 81, 2448-2452)
Reaction SMILES: [I-].[K+].Br[CH:4]([C:6]1[CH:7]=[C:8]([C:23]([O:25][CH3:26])=[O:24])[CH:9]=[C:10]2[C:15]=1[O:14][C:13]([N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)=[CH:12][C:11]2=[O:22])[CH3:5].[F:27][C:28]1[CH:29]=[C:30]([CH:33]=[C:34]([F:36])[CH:35]=1)[NH:31][CH3:32]>C(Cl)(Cl)Cl.CO>[F:27][C:28]1[CH:29]=[C:30]([N:31]([CH3:32])[CH:4]([C:6]2[CH:7]=[C:8]([C:23]([O:25][CH3:26])=[O:24])[CH:9]=[C:10]3[C:15]=2[O:14][C:13]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[CH:12][C:11]3=[O:22])[CH3:5])[CH:33]=[C:34]([F:36])[CH:35]=1
Reactant: COC(=O)c1cc(C(C)Br)c2oc(N3CCOCC3)cc(=O)c2c1
Reactant: CNc1cc(F)cc(F)c1
Agent: [I-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)c1cc(C(C)N(C)c2cc(F)cc(F)c2)c2oc(N3CCOCC3)cc(=O)c2c1
Temperature: 25 °C
Yield: 81.2 %

Procedure:
Potassium iodide (1.521 g, 9.16 mmol) was added to a suspension of methyl 8-(1-bromoethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxylate (3.3 g, 8.33 mmol, as described in Example 2.00) and 3,5-difluoro-N-methylaniline (3.58 g, 24.99 mmol) in CHCl3 (16 mL) and MeOH (4 mL). The mixture was stirred at RT over the weekend. The reaction mixture was concentrated to dryness and the resulting dark oil was triturated with diethyl ether to give a solid which was collected by filtration. This solid was suspended in water and pH was adjusted to 6-7 with 2N NaOH. The crude product was filtered and washed with ether, dried and purified by flash chromatography on silica gel eluting with 0 to 10% MeOH in DCM. The solvent was evaporated to dryness to afford methyl 8-(1-((3,5-difluorophenyl)(methyl)amino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxylate (3.1 g, 81%) as a white solid. Mass Spectrum: M+H+ 459.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([S:13][C:14](=O)[CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].FC1C=[C:26]2[C:31](=[CH:32][C:33]=1[Cl:34])[CH:30]=[N:29][CH:28]=[CH:27]2.C1CCN2C(=NCCC2)CC1>CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([S:13][C:14]2[CH:15]=[C:26]3[C:31](=[CH:32][C:33]=2[Cl:34])[CH:30]=[N:29][CH:28]=[CH:27]3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1cc2ccncc2cc1Cl
Reactant: CC(=O)S[C@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@H](Sc2cc3ccncc3cc2Cl)C1
Yield: 86.8 %

Procedure:
3.5 g (14.2 mmol) (S)-3-Acetylsulfanyl-pyrrolidine-1-carboxylic acid tert-butyl ester (266) were dissolved in 95 ml MeOH and treated with 2.34 g (16.9 mmol) potassium carbonate and stirred over night. After evaporation of all volatiles the residue was taken up in 60 ml of degassed DMF, 1.27 g (15 mmol) 6-Fluoro-7-chloroisoquinoline and 2.25 ml (15 mmol) DBU were added. After 3 h at RRT the mixture was concentrated, taken up in ethyl acetate and washed with brine. The organic phases were dried over Sodium sulfate and evaporated. Purification over silica gel (10% to 40% ethyl acetate in heptane) gave 4.5 g of the expected compound.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[N:4]=[CH:5][C:6]2[CH2:12][NH:11][CH2:10][CH2:9][C:7]=2[N:8]=1.[CH3:15][S:16]([C:19]1[CH:20]=[C:21]([C:31](O)=[O:32])[C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:23][CH:24]=1)(=[O:18])=[O:17]>>[CH3:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:21]([C:31]([N:11]2[CH2:10][CH2:9][C:7]3[N:8]=[C:3]([C:2]([F:1])([F:13])[F:14])[N:4]=[CH:5][C:6]=3[CH2:12]2)=[O:32])[CH:20]=1)(=[O:17])=[O:18]
Reactant: CS(=O)(=O)c1ccc(-c2ccccc2)c(C(=O)O)c1
Reactant: FC(F)(F)c1ncc2c(n1)CCNC2
Product: CS(=O)(=O)c1ccc(-c2ccccc2)c(C(=O)N2CCc3nc(C(F)(F)F)ncc3C2)c1

Procedure:
Prepared in analogy to example 1.1 from 2-trifluoromethyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine (CA [74737-17-7]; WO2004069162) and 4-methanesulfonyl-biphenyl-2-carboxylic acid (example 2.5). MS (m/e): 462.0 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6](Cl)=[O:7].[Cl:16][C:17]1[C:18]([OH:24])=[CH:19][C:20](=[O:23])[NH:21][CH:22]=1>N1C=CC=CC=1>[Cl:16][C:17]1[C:18]([O:24][C:6](=[O:7])[C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=2)=[CH:19][C:20](=[O:23])[NH:21][CH:22]=1
Reactant: O=c1cc(O)c(Cl)c[nH]1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Solvent: c1ccncc1
Product: COc1cc(C(=O)Oc2cc(=O)[nH]cc2Cl)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 34 %

Procedure:
A 3.80 g quantity of 3,4,5-trimethoxybenzoyl chloride was added to a suspension of 2.00 g of 5-chloro-4-hydroxy-2-pyridone in 100 ml of pyridine, and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was concentrated and the concentrate was washed with ethyl acetate and water, thereby producing 1.60 g of the title compound in a yield of 34%.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[N:10][C:11]([C:17]2([C:20]#[N:21])[CH2:19][CH2:18]2)=[N:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.N.[Ni]>[NH2:21][CH2:20][C:17]1([C:11]2[N:10]=[C:9]([NH:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[C:8]3[C:13](=[CH:14][CH:15]=[CH:16][C:7]=3[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:12]=2)[CH2:18][CH2:19]1
Reactant: N#CC1(c2nc(NCc3ccccn3)c3c(-c4ccccc4)cccc3n2)CC1
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCC1(c2nc(NCc3ccccn3)c3c(-c4ccccc4)cccc3n2)CC1
Reaction time: 16 h
Yield: 49.8 %

Procedure:
To a solution of 1-(5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl)cyclopropanecarbonitrile (Example 207, 0.6 g, 2 mmol) in 7 M ammonia methanol (10 mL) was added Ra—Ni (200 mg). The resulting slurry was stirred under hydrogen atmosphere for 16 h. After this time, the reaction mixture was filtered and filtrate was concentrated under reduced pressure to yield 2-(1-(aminomethyl)cyclopropyl)-5-phenyl-N-(pyridin-2-ylmethyl)quinazolin-4-amine (380 mg, 63% yield), which was used without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][N:2]=1.Cl.[NH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(N(CC)CC)C.[O-]S([O-])(=O)=O.[Mg+2]>C(Cl)(Cl)Cl>[N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[N:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:3][N:2]=1
Reactant: O=Cc1ccnnc1
Reactant: CCOC(=O)CCCN
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CCCN=Cc1ccnnc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
In a 25 ml, three-necked flask fitted with a magnetic stirrer under inert atmosphere, pyridazine-4-carbaldehyde x66 (0.93 g, 8.6 mmol) and ethyl 4-aminobutanoate hydrochloride x67 (1.58 g, 9.5 mmol) are dissolved in CHCl3 (15 ml). Triethylamine (1.3 ml, 9.5 mmol) and MgSO4 (2 g) are added and the mixture is stirred at room temperature for 4 h. The mixture is filtered, washed with water, dried over MgSO4 and concentrated to give 1.92 g (100%) of crude ethyl 4-[(pyridazin-4-ylmethylene)amino]butanoate x68, which is used in the next step without further purification.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([CH2:16]O)[CH:10]=[CH:9]2.CO>N1C=CC=CC=1.C(Cl)(Cl)Cl>[Cl:3][CH2:16][C:11]1[CH:10]=[CH:9][C:8]2[C:13](=[CH:14][CH:15]=[C:6]([Cl:5])[CH:7]=2)[CH:12]=1
Reactant: OCc1ccc2cc(Cl)ccc2c1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: c1ccncc1
Product: ClCc1ccc2cc(Cl)ccc2c1
Temperature: 20 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
Thionyl chloride (99.4 g.) is added dropwise at 0° C. during 1 hour to a stirred suspension of the 6-chloro-2-hydroxymethylnaphthalene (96.3 g.) in a mixture of pyridine (50.0 g.) and chloroform (2 l.). The mixture is stirred for 1 hour at 20° C., then treated dropwise with methanol (60 ml.) and stored for 18 hours. The solution is washed with water, 3N-hydrochloric acid, and water again, dried with magnesium sulphate and evaporated. The residue is crystallised from light petroleum (b.p. 80°-100° C.) to give 2-chloromethyl-6-chloronaphthalene (101 g.) m.p. 107°-110° C. raised to 110°-111° C. by further crystallisation.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:25])[CH2:12][CH2:13]OS(C2C=CC(F)=CC=2)(=O)=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH2:12][CH2:13][N:37]2[CH2:36][CH2:35][N:34]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[O:27][CH3:26])[CH2:39][CH2:38]2)[CH3:25])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CN(CCOS(=O)(=O)c1ccc(F)cc1)S(=O)(=O)c1ccc(F)cc1
Reactant: COc1ccccc1N1CCNCC1
Product: COc1ccccc1N1CCN(CCN(C)S(=O)(=O)c2ccc(F)cc2)CC1

Procedure:
The title compound was prepared using the procedure described in Example 1 using 4-fluorobenzenesulfonic acid 2-((4-fluorobenzenesulfonyl)-methyl-amino)-ethyl ester (D2) and 4-(2-methoxyphenyl)-piperazine. MH+ 408.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.[O:26]1[CH2:31][CH2:30][N:29]([CH2:32][C:33]2[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=2)[CH2:28][CH2:27]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>CCO>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:37]([C:36]3[CH:35]=[CH:34][C:33]([CH2:32][N:29]4[CH2:30][CH2:31][O:26][CH2:27][CH2:28]4)=[CH:40][CH:39]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=Cc1ccc(CN2CCOCC2)cc1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3ccc(F)cc3)CC2)c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: Fc1ccc(CN2CCN(c3c(Br)cnc4[nH]c(-c5ccc(CN6CCOCC6)cc5)nc34)CC2)cc1
Temperature: 85 °C

Procedure:
To a mixture of 5-bromo-4-(4-(4-fluorobenzyl)piperazin-1-yl)-3-nitropyridin-2-amine (0.12 g, 0.30 mmol) and EtOH (5 mL), 4-(morpholinomethyl)benzaldehyde (0.068, 0.33 mmol) in EtOH (1.8 mL) was added followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.9 mL, 0.9 mmol). The reaction mixture was heated at 85° C. for 24 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was absorbed on silica gel and purified by column chromatography on a Biotage SP1 system eluting with methanol (2-10%) in dichloromethane. The title compound was isolated as a pale yellow solid after trituration with diethyl ether (0.013 g, 7.6%); 1H-NMR (500 Mz, DMSO-d6): δ 2.38 (m, 4H), 2.60 (m, 4H), 3.54 (s, 2H, NCH2), 3.56 (s, 2H, NCH2), 3.59 (t, J=4.5 Hz, 4H), 3.66 (m, 4H), 7.17 (d, J=8.5 Hz, 2H, ArH, C6H4—F), 7.40 (br dd, J=8.5, 6.0 Hz, 2H, ArH, C6H4—F), 7.47 (d, J=8.0 Hz, 2H, ArH), 8.14 (d, J=8.0 Hz, 2H, ArH), 8.23 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.47 (br s, 1H, imidazo[4,5-b]pyridine N—H); LC (Method B)-MS (ESI, m/z) 2.33 min—565/567 [(M+H)+, Br isotopic pattern]. ESI-HRMS: Found: 565.1725, calculated for C28H31BrFN6O (M+H)+: 565.1727.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH2:14][CH2:15][CH:16]=[C:17]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:18]([F:21])([F:20])[F:19])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)C.[Ni]>[O:1]([C:8]1[CH:9]=[C:10]([CH2:14][CH2:15][CH2:16][CH:17]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:18]([F:19])([F:20])[F:21])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: FC(F)(F)C(=CCCc1cccc(Oc2ccccc2)c1)c1ccccc1
Agent: [Ni]
Solvent: CCO
Product: FC(F)(F)C(CCCc1cccc(Oc2ccccc2)c1)c1ccccc1

Procedure:
4-(3-Phenoxyphenyl)-1-phenyl-1-trifluoromethyl-1-butene (3.18 g; 8.6 mmol) was hydrogenated in ethanol (40 ml) with hydrogen with the addition of Raney nickel (0.4 g) at room temperature and under atmospheric pressures. After the calculated amount of hydrogen had been taken up, the catalyst was filtered off and the solvent removed under reduced pressure. After chromatography on silica gel with hexane/toluene, there remained 2.49 g of product (=78% of theory).