Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[NH2:3][CH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1.[C:14]1([S:24](Cl)(=[O:26])=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CC(C)=O.CCOCC.C1(C)C=CC=CC=1>[C:14]1([S:24]([NH:3][CH2:4][C:5]2[CH:6]=[CH:7][C:8]([C:9]([OH:11])=[O:10])=[CH:12][CH:13]=2)(=[O:26])=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: NCc1ccc(C(=O)O)cc1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: CC(C)=O
Product: O=C(O)c1ccc(CNS(=O)(=O)c2cccc3ccccc23)cc1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
4 N NaOH solution (30 ml) is added to a suspension of 4-(aminomethyl)benzoic acid (5.01 g, 31.82 mmol) in acetone (100 ml). Toluene (100 ml) is added and the reaction is heated at 40° C. to obtain dissolution. The solution is cooled to 0° C. and treated with 1-naphthalene sulfonyl chloride (12 g, 51.35 mmol) in acetone (100 ml) and the resulting reaction mixture is stirred for 3 hours. The reaction is acidified using citric acid and concentrated in vacuo. The residue is taken up in EtOAc and washed with water. The aqueous layer is back extracted with EtOAc and the combined organic layers are washed with water, brine, dried (Na2SO4) and the solvent removed in vacuo to yield a light brown solid. Trituration with Et2O yields the title compound.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.[C:11]1([CH2:17][C:18]([OH:20])=O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(Cl)CCl.Cl.[NH2:26][CH:27]([CH:43]([CH3:45])[CH3:44])[C:28]([N:30]1[CH2:35][CH2:34][CH:33]([C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=2)[CH2:32][CH2:31]1)=[O:29]>CN(C=O)C.CCN(C(C)C)C(C)C.CO>[Cl:42][C:39]1[CH:40]=[CH:41][C:36]([CH:33]2[CH2:32][CH2:31][N:30]([C:28](=[O:29])[CH:27]([NH:26][C:18](=[O:20])[CH2:17][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:43]([CH3:45])[CH3:44])[CH2:35][CH2:34]2)=[CH:37][CH:38]=1
Reactant: CC(C)C(N)C(=O)N1CCC(c2ccc(Cl)cc2)CC1
Reactant: O=C(O)Cc1ccccc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C(NC(=O)Cc1ccccc1)C(=O)N1CCC(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A reaction tube was charged with HOBt (10 mg), phenylacetic acid (12 mg) and EDC (14 mg) in DMF (0.7 mL). The resulting mixture was agitated at rt. for 15 min, and then a solution of 2-amino-1-(4-(4-chlorophenyl)piperidin-1-yl)-3-methylbutan-1-one hydrochloride (20 mg) in DIEA (50 μL) and DMF (250 μL) was added and the resulting mixture was shaken overnight at rt. At the conclusion of this period, the resulting solution was diluted with MeOH and purified by preparative LC-MS to provide Example 9. MS found: (M+H)+=414.
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].Br[C:16]1[CH:20]=[CH:19][S:18][CH:17]=1.[Cl-].[NH4+]>C(OCC)C>[CH2:1]([C:16]1[CH:20]=[CH:19][S:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: Brc1ccsc1
Reactant: CCCCCCCCCCCC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCCCCCCCCCCCc1ccsc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a freshly prepared dodecylmagnesium bromide (from 45 mmoles of dodecyl bromide and 45 mmoles of magnesium) in anhydrous diethyl ether (100 ml) was added 3-bromothiophene (45 mmoles) in diethyl ether (25 ml) at ambient temperature under argon and then bis-(1,2-diphenylphosphino)ethane nickel (II) chloride (0.25 g) was added. The reaction mixture was stirred overnight at ambient temperature and then hydrolyzed with ice and saturated aqueous ammonium chloride. The aqueous layer was extracted with diethyl ether (3×25 ml) and the organic phases were combined, washed with water (3×25 ml), dried over anhydrous magnesium sulfate and concentrated in vacuo. The crude product was purified by distillation in vacuo and then flash chromatography to afford the desired product.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[C:14]1[CH:19]=[CH:18][C:17]([I:20])=[CH:16][N:15]=1>C(#N)C>[I:20][C:17]1[CH:18]=[CH:19][C:14]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[N:15][CH:16]=1
Reactant: Clc1ccc(I)cn1
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Ic1ccc(N2CCNCC2)nc1
Yield: 59.5 %

Procedure:
To a solution of piperazine (215 mg, 2.5 mmol) and potassium carbonate (890 mg, 6.45 mmol) in acetonitrile (5 mL) was added 2-chloro-5-iodopyridine (300 mg, 1.25 mmol) (prepared in Example 2(a)). The mixture was heated at reflux for 26 h and allowed to cool. It was then filtered and the solvents removed under reduced pressure. Column chromatograpgy of the residue on silica gel (dichloromethane:methanol:ammonia solution 100:5:1) gave 1-(5-iodopyridin-2-yl)-piperazine as a yellow solid (215 mg, 60%). δH (300 MHz DMSO-d6) 2.76 (4H, m, piperazinyl ), 3.40 (4H, m, piperazinyl ), 6.72 (1H, d, J=9.0), 7.77 (1H, dd, J=2.4 and 9.0), 8.25 (1H, d, J=2.4), ESMS 290 (MH+)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:26]=[C:25]([CH2:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[CH2:35][C:36]([O-:38])=O)[C:24]([C:39]([F:42])([F:41])[F:40])=[CH:23][N:22]=3)=[C:16]([O:43][CH3:44])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].C[N:47](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl-].[NH4+].CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:47][C:36](=[O:38])[CH2:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[CH2:28][CH2:27][C:25]1[C:24]([C:39]([F:40])([F:42])[F:41])=[CH:23][N:22]=[C:21]([NH:20][C:17]2[CH:18]=[CH:19][C:14]([CH:11]3[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:13][CH2:12]3)=[CH:15][C:16]=2[O:43][CH3:44])[N:26]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc(C(F)(F)F)c(CCc2ccccc2CC(=O)[O-])n1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc(C(F)(F)F)c(CCc2ccccc2CC(N)=O)n1

Procedure:
A solution of lithium 2-(2-(2-(2-((4-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-methoxyphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetate (I22) (210 mg, 0.338 mmol), HATU (257 mg, 0.676 mmol), ammonium chloride (362 mg, 6.76 mmol) and DIPEA (115 μL) in dry DMF (4 mL) was stirred at room temperature overnight. The volatiles were evaporated under reduced pressure and the residue diluted with ethyl acetate. The resulting solution was washed with 10% NaHCO3 then the organic layer dried (MgSO4). The volatiles were removed under reduced pressure and the residue chromatographed (SiO2, 0-100% ethyl acetate/petroleum benzine 40-60° C.) to give the title compound (I23) (185 mg, 89%) as a colourless solid; 1H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H), 8.26 (d, J=8.3 Hz, 1H), 7.88 (s, 1H), 7.25 (dd, J=4.4, 2.4 Hz, 2H), 6.86 (dd, J=8.3, 1.7 Hz, 111), 6.76 (d, J=1.7 Hz, 1H), 5.49 (d, J=39.2 Hz, 2H), 4.24 (s, 2H), 3.92 (s, 3H), 3.70 (s, 2H), 3.20-3.02 (m, 4H), 2.80 (m, 2H), 2.64 (s, 2H), 1.84 (d, J=12.8 Hz, 2H), 1.62 (dd, J=12.3, 3.5 Hz, 2H), 1.49 (s, 9H). LCMS Method C: rt 6.64 min; m/z 636.2 [M+Na]+, 614.1 [M+1]+, 612.2 [M−1]−, 558.2 [M-t-Bu+2]+.
Reaction SMILES: Br[CH:2]([CH3:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[NH2:12][C:13]([NH2:15])=[S:14]>CCO>[CH3:11][C:2]1[S:14][C:13]([NH2:15])=[N:12][C:3]=1[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: NC(N)=S
Reactant: CC(Br)C(=O)c1ccccc1
Solvent: CCO
Product: Cc1sc(N)nc1-c1ccccc1
Yield: 109.7 %

Procedure:
A mixture of 2-bromo-1-phenylpropan-1-one (3.00 g, 19.5 mmol) and thiourea (1.56 g, 20.5 mmol) in 95% EtOH (30 mL) was heated at reflux for 60 min. The solution was concentrated and mixed with water (100 mL) and saturated aqueous Na2CO3 (5.0 mL). The resultant precipitate was filtered and recrystallized in toluene. The solids were filtered and dried under vacuum to give 5-methyl-4-phenylthiazol-2-amine (4.07 g) as yellow solids in 77% yield: 1H NMR (500 MHz, DMSO-d6) δ 8.85 (s, 2 H), 7.54-7.49 (m, 5 H), 2.28 (s, 3 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[CH:5]=[CH:4][C:3]=1[NH:15][C:16]([CH:18]1[CH2:22][CH:21]([CH2:23][NH:24][C:25]([C:27]2[S:28][C:29]([Cl:32])=[CH:30][CH:31]=2)=[O:26])[CH:20]([NH:33][CH3:34])[CH2:19]1)=[O:17].[CH3:35][S:36](Cl)(=[O:38])=[O:37]>>[F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[CH:5]=[CH:4][C:3]=1[NH:15][C:16]([CH:18]1[CH2:22][CH:21]([CH2:23][NH:24][C:25]([C:27]2[S:28][C:29]([Cl:32])=[CH:30][CH:31]=2)=[O:26])[CH:20]([N:33]([S:36]([CH3:35])(=[O:38])=[O:37])[CH3:34])[CH2:19]1)=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: CNC1CC(C(=O)Nc2ccc(-n3ccccc3=O)cc2F)CC1CNC(=O)c1ccc(Cl)s1
Product: CN(C1CC(C(=O)Nc2ccc(-n3ccccc3=O)cc2F)CC1CNC(=O)c1ccc(Cl)s1)S(C)(=O)=O

Procedure:
In analogy to example 26 5-chloro-thiophene-2-carboxylic acid {4-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-2-methylamino-cyclopentylmethyl}-amide (example 33) was reacted with methane sulfonylchloride to give 5-chloro-thiophene-2-carboxylic acid [4-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-2-(methanesulfonyl-methyl-amino)-cyclopentylmethyl]-amide. Light yellow solid. 581.2 ([M+H]+).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:9][C@H:8]([S:10][C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][C@H:6]1[CH2:30][OH:31])(=[O:4])=[O:3].[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[H-].[Na+].C(Br)C1C=CC=CC=1.[H-].[Na+]>CN(C=O)C>[CH2:32]([O:31][CH2:30][C@@H:6]1[CH2:7][C@@H:8]([S:10][C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:9][N:5]1[S:2]([CH3:1])(=[O:3])=[O:4])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CS(=O)(=O)N1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CO
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)N1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1COCc1ccccc1
Temperature: 0 °C
Yield: 59.1 %

Procedure:
9.07 g (20 mmol) of (2S,4R)-(1-methanesulfonyl-4-tritylsulfanyl-pyrrolidin-2-yl)-methanol and 9.5 ml (80 mmol) of benzylbromide were dissolved in 660 ml DMF, cooled to 0° C. and treated with 1.4 g (32 mmol) of 55% NaH over 15 min in 4 portions. The reaction was warmed up over night and treated with 4.75 ml (40 mmol) benzylbromide/700 mg (16 mmol) 55% NaH and 6 h later again with the same amount of benzylbromide/NaH. After further 16 h at room temperature the reaction was quenched with saturated NH4Cl solution/EtOAc (3×). The organic phase was washed with aqueous 10% NaCl soution, dried over Na2SO4 and evaporated to give 25 g crude product. Flash-chromatography on silica gel (Hexane/EtOAc 4:1 to 1:4) gave 6.43 g (59%) of (2S,4R)-2-benzyloxymethyl-1-methanesulfonyl-4-tritylsulfanyl-pyrrolidine, MS: 544 (MH+). 6.4 g (11.77 mmol) (2S,4R)-2-benzyloxymethyl-1-methanesulfonyl-4-tritylsulfanyl-pyrrolidine were dissolved in 170 ml TFA and treated at 0° C. with 18.75 ml (117.7 mmol) of triethylsilane. After 18 h at 0° C., the mixture was evaporated and purified by flash-chromatography on silica gel (Hexane/EtOAc 4:1 to 1:4) to give 2.66 g (72%) of (3R,5S)-5-benzyloxymethyl-1-methanesulfonyl-pyrrolidine-3-thiol, MS: 302 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:15][C:16]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:17]=1[CH2:18][OH:19].C(O)(=O)C.[BH3-]C#N.[Na+]>C1(C)C=CC=CC=1.C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:15][C:16]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:17]=2[CH2:18][OH:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Nc1ccc(Cl)cc1CO
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(Cl)cc2CO)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 1-(tert-butyloxycarbonyl)-4-piperidinone (20 g, 0.10 mol), 2-amino-5-chlorobenzyl alcohol (17.34 g, 0.11 mol) and acetic acid (14 mL, 0.22 mol) in dry toluene (500 mL) was heated at reflux temperature, with water elimination by means of azeotrope distillation with a Dean-Stark device, for 6 hours. The mixture was then cooled and vacuum concentrated up to half volume. NaBH3CN (20 g, 0.32 mol) and dry THF (300 mL) were added to the resulting solution. Acetic acid (10 mL, 0.17 mol) was then dripped for one hour. The reaction was stirred at room temperature for 24 hours. The mixture was vacuum concentrated and the residue was dissolved in ethyl acetate (750 mL), washed with a NaHCO3-saturated solution (4×250 mL) and a NaCl-saturated solution (250 mL), dried and evaporated to dryness. The residue was purified by means of flash chromatography eluting with a mixture of ethyl acetate:petroleum ether (1:3). The desired product was thus obtained as an oil (32.7 g, 96%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([Cl:29])[CH:22]=2)[C:11]2[C:16]([CH3:17])=[C:15]([CH3:18])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([Cl:29])[CH:22]=3)[C:11]3[C:16]([CH3:17])=[C:15]([CH3:18])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc(C)c(C)c23)cc1Cl
Reactant: Cc1ncc[nH]1
Product: COc1ccc(CNc2nc(-n3ccnc3C)nc3sc(C)c(C)c23)cc1Cl

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-5,6-dimethyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-5,6-dimethyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:20]4[CH:24]=[CH:23][O:22][CH:21]=4)=[O:19])[CH:16]=3)[NH:11][C:10](=[O:25])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].I[CH3:29].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:20]4[CH:24]=[CH:23][O:22][CH:21]=4)=[O:19])[CH:16]=3)[N:11]([CH3:29])[C:10](=[O:25])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: O=C(c1ccoc1)c1ccc2[nH]c(=O)cc(-c3cccc(Cl)c3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=O)cc(-c2cccc(Cl)c2)c2cc(C(=O)c3ccoc3)ccc21
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 9.6 %

Procedure:
A mixture of (intermediate 26) (0.04 mol) in DMF (200 ml) was cooled to 5° C. under N2 flow. NaH 80% in oil (0.048 mol) was added portionwise. The mixture was stirred at 5° C. for 30 min. Then iodomethane (0.048 mol) was added dropwise. The mixture was stirred at 5° C. for 30 min, hydrolized and poured out into water. The precipitate was filtered off, washed with water and taken up in CH2Cl2. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated till dryness. The residue (15.5 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/EtOAc 85/15; 15–40 μm). The pure fractions were collected and the solvent was evaporated. The residue (13.3 g, 91.7%) was crystallized from CH3CN and DIPE. The precipitate was filtered off and dried, yielding 1.5 g (9.6%) of 4-(3-chlorophenyl)-6-(3-furanylcarbonyl)-1-methyl-2(1H)-quinolinone (intermediate 27), melting point 192° C.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH:8]=O)=[C:6]([OH:10])[CH:5]=[CH:4][CH:3]=1.Cl[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[C:7]2[CH:8]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1c(O)cccc1Br
Reactant: CCOC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(Br)cccc2o1
Temperature: 120 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
A mixture of 6-bromo-2-hydroxybenzaldehyde (4.48 g), ethyl chloroacetate (3.55 g) and powdered potassium carbonate (6.16 g) in N,N-dimethylformamide (56 ml) was stirred at 120° C. for one hour. Insoluble materials were filtered off and the solvent was removed under reduced pressure. Ethyl acetate and water were added to the residue, and the mixture was acidified by hydrochloric acid solution. The layers were separated and the organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with a mixture of hexane and toluene (1:1) to afford 4-bromo-2-ethoxycarbonylbenzofuran (4.20 g).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[NH3:27].C(OCC)C>O1CCOCC1>[CH3:10][C:8]1[N:9]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[S:6][C:7]=1[C:11]1[CH:16]=[CH:15][C:14]([S:17](=[O:19])(=[O:18])[NH2:27])=[CH:13][CH:12]=1
Reactant: N
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)Cl)cc2)s1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(=O)Nc1nc(C)c(-c2ccc(S(N)(=O)=O)cc2)s1

Procedure:
4-(2-Acetylamino-4-methyl-thiazol-5-yl)-benzenesulfonyl chloride (3a) (3.8 g, 11.5 mmol) is dissolved in dioxane (50 ml) with stirring. Sodium carbonate (2.45 g, 23 mmol) is added followed by a solution of ammonia in dioxane (50 ml, 0.75 M). After stirring for 2 hours at room temperature diethyl ether (120 ml) is added and the solid precipitate is removed by filtration. The solid is stirred in tetrahydrofuran (200 ml) and the mixture is then filtered through Celite™ filter material to remove inorganic material. Removal of the solvent affords N-[4-methyl-5-(4-sulfamoyl-phenyl)-thiazol-2-yl]-acetamide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1[CH:8]=[N:9][C:10]([Cl:12])=[CH:11][C:6]=1[C:5]2([CH:18]=[CH2:19])O.[CH3:20][OH:21].S(=O)(=O)(O)O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1[CH:8]=[N:9][C:10]([Cl:12])=[CH:11][C:6]=1[C:5]2=[CH:18][CH2:19][O:21][CH3:20]
Reactant: C=CC1(O)c2cc(Br)ccc2Oc2cnc(Cl)cc21
Reactant: CO
Agent: O=S(=O)(O)O
Product: COCC=C1c2cc(Br)ccc2Oc2cnc(Cl)cc21
Temperature: 50 °C
Yield: 92.3 %

Procedure:
To a sealed vessel was added 7-bromo-3-chloro-5-vinyl-5H-chromeno[2,3-c]pyridin-5-ol (2.50 g, 7.38 mmol), methanol (59.8 mL, 1477 mmol) and sulfuric acid (0.2M in water) (3.70 mL, 0.74 mmol). The clear solution was heated to 50° C. over the weekend. The reaction mixture became light yellow heterogenous. The solvent was removed by rotovap and the residue was diluted with 125 mL of EtOAc. The organic solution was washed with saturated aqueous NaHCO3 and brine, dried over MgSO4, filtered and concentrated in vacuo to give the crude material 7-bromo-3-chloro-5-(2-methoxyethylidene)-5H-chromeno[2,3-c]pyridine (2.40 g, 6.81 mmol, 92% yield) as a yellow solid.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[C:19]([O:23][C:24](=[O:46])[N:25]([CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([C:37](C)(C)[O:38][SiH2]C(C)(C)C)[CH:31]=1)[CH2:26][CH3:27])([CH3:22])([CH3:21])[CH3:20].CCOC(C)=O>C1COCC1>[C:19]([O:23][C:24](=[O:46])[N:25]([CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([CH2:37][OH:38])[CH:31]=1)[CH2:26][CH3:27])([CH3:20])([CH3:21])[CH3:22]
Reactant: CCN(CCc1ccc(Cl)c(C(C)(C)O[SiH2]C(C)(C)C)c1)C(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCN(CCc1ccc(Cl)c(CO)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.4 %

Procedure:
TBAF (1M in THF, 1.39 mL, 1.39 mmol) was added to a sol. of {2-[3-(tert-butyl-dimethyl-silanyloxymethyl)-4-chloro-phenyl]-ethyl}-ethyl-carbamic acid tert-butyl ester (298 mg, 0.696 mmol) in THF (6.82 mL) at 0° C. The mixture was stirred for 1 h while warming up to rt. EtOAc was added, and the mixture was washed with aq. sat. NH4Cl and brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (CH2Cl2/MeOH 19:1) yielded the title compound (110 mg, 50%). LC-MS: tR=0.97 min; ES+: 314.11.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([O:9][C:10](=[O:11])[C:5]=12)=[O:8])([O-:3])=[O:2].[NH4+:15]>>[C:7]([C:6]1[CH:12]=[CH:13][CH:14]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]=1[C:10]([NH2:15])=[O:11])([OH:9])=[O:8]
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Reactant: [NH4+]
Product: NC(=O)c1c(C(=O)O)cccc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 0.75 h

Procedure:
30 g (0.155 mol) of 3-nitrophthalic anhydride are introduced in portions into 180 ml of conc. ammonium solution and the resulting solution is heated at 100° C. with stirring for 45 min. The mixture is evaporated in a rotary evaporator and co-distilled twice with toluene, and the residue is dried in a high vacuum. It is stirred with EA, and the beige precipitate is filtered off with suction and dried in vacuo over P2O5. 31.8 g of the title compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].N1C(C)=CC=CC=1C.[I-].[K+].Br[CH2:27][CH2:28][CH:29]=[C:30]1[C:36]2[CH:37]=[CH:38][CH:39]=[N:40][C:35]=2[CH2:34][O:33][C:32]2[CH:41]=[CH:42][C:43]([C:45]([OH:48])([CH3:47])[CH3:46])=[CH:44][C:31]1=2>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:11][CH2:12][N:13]([CH2:27][CH2:28][CH:29]=[C:30]3[C:36]4[CH:37]=[CH:38][CH:39]=[N:40][C:35]=4[CH2:34][O:33][C:32]4[CH:41]=[CH:42][C:43]([C:45]([OH:48])([CH3:47])[CH3:46])=[CH:44][C:31]3=4)[CH2:14][CH2:15]2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: N#Cc1cc(Cl)ccc1N1CCNCC1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Agent: [I-]
Agent: [K+]
Solvent: CC(C)O
Solvent: Cc1cccc(C)n1
Product: CC(C)(O)c1ccc2c(c1)C(=CCCN1CCN(c3ccc(Cl)cc3C#N)CC1)c1cccnc1CO2
Temperature: 80 °C
Reaction time: 18 h
Yield: 31.9 %

Procedure:
To a solution of 5-chloro-2-piperazin-1-yl-benzonitrile (0.22 g, 1 mmol) in isopropanol (8 mL) was added 2,6-lutidine (0.16 mL, 1.33 mmol) and catalytic potassium iodide. This mixture was heated to 80° C. and treated with 2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.26 g, 0.67 mmol) in portions over 2 h. The solution was then stirred at 80° C. for an additional 18 h. The reaction mixture was concentrated in vacuo, then purified by flash chromatography on silica gel (gradient elution from 95% ethyl acetate/5% methanol to 90% ethyl acetate/10% methanol) to yield the title compound (0.11 g, 54%). 1H-NMR (MeOD) δ: 1.40 (6H, s), 2.30-2.58 (8H, m), 3.00-3.15 (4H, m), 5.20 (1H, br s), 6.18 (1H, t), 6.70 (1H, dd), 7.18-7.84 (7H, m), 8.50 (1H, dd). ESI-MS m/z: 515 (M+1), UV retention time: 1.75 min.
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[CH:14][C:13]([C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])=[C:12]3[NH:24][C@H:25]2[CH2:30][CH2:29][C@H:28]([NH:31]C(=O)OC(C)(C)C)[CH2:27][CH2:26]2)=[CH:5][CH:4]=1)#[N:2].Cl>>[NH2:31][C@H:28]1[CH2:29][CH2:30][C@H:25]([NH:24][C:12]2[C:11]3[C:16](=[CH:17][CH:18]=[C:9]([C:6]4[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[N:8][CH:7]=4)[CH:10]=3)[N:15]=[CH:14][C:13]=2[C:19](=[O:23])[CH:20]([CH3:21])[CH3:22])[CH2:26][CH2:27]1
Reactant: CC(C)C(=O)c1cnc2ccc(-c3ccc(C#N)nc3)cc2c1N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Agent: Cl
Product: CC(C)C(=O)c1cnc2ccc(-c3ccc(C#N)nc3)cc2c1N[C@H]1CC[C@H](N)CC1

Procedure:
Following general procedure A-1, tert-butyl trans-4-[6-(6-cyanopyridin-3-yl)-3-isobutyrylquinolin-4-ylamino]cyclohexylcarbamate (47.7 mg, 0.093 mmol) was reacted with 6 N hydrochloric acid (3 mL) to afford the desired product (20.8 mg, 54%) as a light yellow solid: 1H NMR (500 MHz, CD3OD) δ 9.13-9.11 (m, 1H), 9.06 (s, 1H), 8.55 (d, J=1.8 Hz, 1H), 8.39 (dd, J=8.1, 2.3 Hz, 1H), 8.19 (dd, J=8.7, 1.9 Hz, 1H), 8.04 (d, J=3.8 Hz, 1H), 8.02 (d, J=4.4 Hz, 1H), 4.35-4.27 (m, 1H), 3.82-3.73 (m, 1H), 3.29-3.22 (m, 1H), 2.40 (d, J=12.7 Hz, 2H), 2.19 (d, J=12.1 Hz, 2H), 1.78-1.68 (m, 2H), 1.67-1.56 (m, 2H), 1.25 (d, J=6.8 Hz, 6H); ESI MS m/z 414 [C25H27N5O+H]+; HPLC 98.3% (AUC), tR=7.96 min.