Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[CH2:9][CH:10]=O>CO.N>[N:1]1[CH:9]=[CH:10][N:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=12
Reactant: Nc1ccccn1
Reactant: O=CCCl
Agent: N
Solvent: CO
Product: c1ccn2ccnc2c1
Yield: 88.9 %

Procedure:
A mixture of 9.4 g (0.1 mole) of 2-aminopyridine and 19.2 g (0.11 mole) of 45% aqueous chloroacetaldehyde was stirred, during which spontaneous heating occurred. When the exothermic reaction subsided, the mixture was dissolved in methanol containing 15 ml of concentrated aqueous ammonia and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to an oil. Distillation at 80-83° and 0.2 mm Hg pressure yielded 10.5 g of imidazo[1,2-a]pyridine as an oil. A solution of 9.5 g (80.5 mmole) of imidazo[1,2-a]pyridine in 60 ml of dimethylformamide was heated to 90°. Phosphorus oxychloride (9.27 ml, ca. 100 mmole) was added dropwise over a twenty minute period, and the mixture was stirred at 90° for two hours and at room temperature for an additional twenty hours. The mixture was diluted with 60 ml of water and made basic with 30% aqueous sodium hydroxide. The resultant solid was collected by filtration, washed with water, and air dried to yield 1.8 g of 3-imidazo[1,2-a]pyridinecarboxaldehyde as the analytically pure p hydrate. [Calcd. for C8H6N2O.H2O: C, 58.53; H, 3.68; N, 17.06. Found: C, 58.77; H, 3.68; N, 17.48.]To a solution of 1.6 g (10 mmole) of 3-imidazo[1,2-a]-pyridinecarboxaldehyde in 15 ml of methanol was added 204 mg (5.4 mmole) of sodium borohydride. After one hour the mixture was acidified with concentrated hydrochloric acid and then concentrated in vacuo. Recrystallization of the residue from ethanol yielded 707 mg of 3-hydroxymethylimidazo[1,2-a]pyridine as the hydrochloride salt. A 500 mg (2.7 mmole) portion of the hydroxymethyl compound was dissolved in 3.0 ml of concentrated hydrochloric acid and heated at 80° for one hour. The mixture was concentrated in vacuo and the residue was recrystallized from isopropyl alcohol to yield 465 mg of 3-chloromethylimidazo[1,2-a]pyridine as the hydrochloride salt. A mixture of 390 mg (1.92 mmole) of the chloromethyl compound and 288 mg (1.92 mmole) of 2-mercaptobenzimidazole in 7 ml of isopropyl alcohol was stirred for one hour. The precipitate that formed was collected and partitioned between 5% aqueous sodium hydroxide and dichloromethane. The organic layer was washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo. Trituration of the residue with diethyl ether yielded the title compound as an analytically pure solid. Structure assignment was supported by the nmr spectrum and by elemental analysis.
Reaction SMILES: Cl[CH2:2][CH2:3][C@@H:4]([N:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]([CH2:20][CH3:21])[C:12]1=[O:22])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[I-].[K+].[CH3:25][NH2:26]>CO>[CH2:20]([N:13]1[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:11]([C@@H:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:3][CH2:2][NH:26][CH3:25])[C:12]1=[O:22])[CH3:21]
Reactant: CN
Reactant: CCn1c(=O)n([C@H](CCCl)c2ccccc2)c2ccccc21
Agent: [I-]
Agent: [K+]
Solvent: CO
Product: CCn1c(=O)n([C@H](CCNC)c2ccccc2)c2ccccc21
Temperature: 80 °C

Procedure:
To a mixture of 1-[(1R)-3-chloro-1-phenylpropyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one (0.13 g, 0.4 mmol) and potassium iodide (0.2 g, 1.2 mmol) in methanol (5 mL) was added a solution of 33% methylamine in methanol (10 mL). The reaction solution was heated to 80° C. in a sealed tube for 3 hours and cooled to room temperature. The solvent was removed in vacuo and residue purified on a silica gel column (10-50% methanol in methylene chloride) to afford 1-ethyl-3-[(1R)-3-(methylamino)-1-phenylpropyl]-1,3-dihydro-2H-benzimidazol-2-one as an oil. The free base was dissolved in a minimum amount of ethanol and treated with a 2N ethereal solution of hydrochloric acid and stirred for 1 hour. The solvent was removed in vacuo and the residue was triturated with ether/dichloromethane to give 1-ethyl-3-[(1R)-3-(methylamino)-1-phenylpropyl]-1,3-dihydro-2H-benzimidazol-2-one HCl salt as a yellowish amorphous solid (30 mg, 22%). MS (ES) m/z 309.8.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:23])=[C:8]2[CH:14]=[CH:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:9]2=[CH:10][N:11]=1)=[O:5])C.[NH2:24][CH2:25][C:26]([OH:28])=[O:27].C[O-].[Na+].CO>>[F:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:15][N:12]1[C:9]2=[CH:10][N:11]=[C:6]([C:4]([NH:24][CH2:25][C:26]([OH:28])=[O:27])=[O:5])[C:7]([OH:23])=[C:8]2[CH:14]=[CH:13]1
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1ncc2c(ccn2Cc2ccccc2F)c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CNC(=O)c1ncc2c(ccn2Cc2ccccc2F)c1O

Procedure:
Prepared in analogy to that of Example 1(e) from 1-(2-fluoro-benzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 344 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:35](=[O:41])OC(Cl)(Cl)Cl)Cl.[CH3:43][C:44]1[N:45]=[C:46]([CH:50]([NH2:52])[CH3:51])[S:47][C:48]=1[CH3:49]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:35]([NH:52][CH:50]([C:46]2[S:47][C:48]([CH3:49])=[C:44]([CH3:43])[N:45]=2)[CH3:51])=[O:41])=[C:18]([CH3:23])[CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3)c2cc1OC
Reactant: Cc1nc(C(C)N)sc1C
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc2nccc(Oc3ccc(NC(=O)NC(C)c4nc(C)c(C)s4)c(C)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.8 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-methylaniline (30 mg) was dissolved in chloroform (1 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (35 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. Next, a solution of 1-(4,5-dimethyl-1,3-thiazol-2-yl)-1-ethylamine (35 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (18 mg, yield 39%).
Reaction SMILES: [C:1]([C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].O.NN.C(O)COCCO.[OH-].[K+]>O>[CH2:1]([C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCC(=O)c1cccs1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: CCCCCCc1cccs1
Temperature: 110 °C
Yield: 82.8 %

Procedure:
In a 10 liter-five-necked flask, 300 g (1.65 mol) of 2-hexanoylthiophene, 582.1 ml of 60% hydrazine hydrate and 5 liter of diethyleneglycol were placed and reacted for 2 hours at 180° C. with distilling-off of excessive water and hydrazine hydrate. The mixture was cooled to 110° C. and 313.7 g of KOH was added thereto, followed by heating again for 2 hours of reaction at 180° C. After the reaction, the reaction mixture was poured into 10 liter of water, extracted two times with 2 liter of isopropyl ether and washed four times with 2 liter of water, followed by drying with CaCl2 and distilling-off of the solvent to obtain 285 g of a crude product. The crude product was subjected to reduced-pressure distillation in an atmosphere of nitrogen to obtain 230 g of a pure product (yield: 83%).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:7][CH2:6][CH:5]([C:8]2[S:19][C:11]3[N:12]=[C:13]([CH3:18])[N:14]=[C:15]([C:16]#N)[C:10]=3[CH:9]=2)[CH2:4][CH2:3]1.Cl.[O:22]1CCO[CH2:24][CH2:23]1.CC[OH:30]>>[CH3:1][C:2]1([CH3:20])[CH2:3][CH2:4][CH:5]([C:8]2[S:19][C:11]3[N:12]=[C:13]([CH3:18])[N:14]=[C:15]([C:16]([O:22][CH2:23][CH3:24])=[O:30])[C:10]=3[CH:9]=2)[CH2:6][CH2:7]1
Reactant: CCO
Reactant: Cc1nc(C#N)c2cc(C3CCC(C)(C)CC3)sc2n1
Reactant: C1COCCO1
Agent: Cl
Product: CCOC(=O)c1nc(C)nc2sc(C3CCC(C)(C)CC3)cc12
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a mixture of 6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidine-4-carbonitrile (27.4 g) and EtOH (200 mL) was added 4 M HCl/dioxane (200 mL), followed by stirring at 80° C. overnight. The reaction mixture was left to be cooled to room temperature and then concentrated under reduced pressure. To the residue were added EtOH (200 mL) and water (200 mL), followed by stirring. The precipitate was collected by filtration. To the obtained precipitate was added chloroform, followed by dissolving therein, and MgSO4, activated carbon (10 g), and basic silica gel (100 mL) were added thereto, followed by stirring. The mixture was filtered through Celite and then concentrated under reduced pressure to obtain ethyl 6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidine-4-carboxylate (23.3 g).
Reaction SMILES: [CH:1]1[C:6]2[C:7]3[NH:8][C:9]4[C:14]([C:15]=3[CH2:16][S:17][C:5]=2[CH:4]=[C:3](O)[CH:2]=1)=[CH:13][C:12](O)=[CH:11][CH:10]=4.[Li][CH2:21]CCC.Cl[C:26]([O:28][CH3:29])=[O:27]>C1COCC1>[CH3:29][O:28][C:26]([C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:21])[C:7]1[C:6]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[S:17][CH2:16][C:15]2=1)=[O:27]
Reactant: COC(=O)Cl
Reactant: Oc1ccc2c(c1)SCc1c-2[nH]c2ccc(O)cc12
Reactant: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)c1c(n2C)-c2ccccc2SC1
Temperature: 25 °C

Procedure:
6,11-dihydro-5-thia-11-aza-benzo[a]fluorene-3,8-diol (1 mmol, 330 mg), as prepared in Example 31, in THF (15 ml) was treated with n-BuLi (2.0 M, 0.6 ml, 1.2 mmol) at −78° C. for 30 minutes, then methyl chloroformate (1 equivalent) was added drop by drop to the reaction mixture at −78° C. After slowly warming up to room temperature, the reaction mixture was quenched by saturated ammonium chloride, extracted by ethyl acetate and purified by chromatography (Hexane:ethyl acetate=5:1) to yield the title compound as a white solid.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22](=[O:29])[NH:21][N:20]=2)=[CH:14][C:10]=1[C:11](O)=[O:12].Cl.[CH:31]1([O:36][CH:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH2:35][CH2:34][CH2:33][CH2:32]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CC(N(C)C)=O>[CH:31]1([O:36][CH:37]2[CH2:42][CH2:41][N:40]([C:11]([C:10]3[CH:14]=[C:15]([CH:16]=[CH:17][C:9]=3[F:8])[CH2:18][C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:22](=[O:29])[NH:21][N:20]=3)=[O:12])[CH2:39][CH2:38]2)[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: C1CCC(OC2CCNCC2)C1
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCC(OC2CCCC2)CC1
Temperature: 20 °C
Reaction time: 72 h
Yield: 37.2 %

Procedure:
Triethylamine (0.280 ml, 2.01 mmol) was added in one portion to 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (1) (200 mg, 0.67 mmol), 4-(cyclopentyloxy)piperidine hydrochloride (113 mg, 0.67 mmol) and O-benzotriazol-1-yl-N,N,N′,N′-tetra-methyluronium hexafluorophosphate (331 mg, 0.87 mmol) in DMA (2 ml) at 20° C. under air. The resulting mixture was stirred at 20° C. for 3 days. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired material as a white solid (112 mg, 37.2% yield); 1H NMR (400.132 MHz, DMSO) δ 1.23-1.72 (11H, m), 1.81-1.87 (1H, m), 3.00-3.06 (1H, m), 3.22-3.27 (2H, m), 3.52-3.59 (1H, m), 3.96-4.04 (2H, m), 4.33 (2H, s), 7.18-7.23 (1H, m), 7.34 (1H, d), 7.38-7.42 (1H, m), 7.81-7.91 (2H, m), 7.97 (1H, d), 8.26 (1H, d), 12.56 (1H, s); m/z (LC-MS, ESI+), RT=2.30 (M+H 450.1).
Reaction SMILES: [Sn:1]([Br:3])[Br:2].[C:4]([CH2:7][C:8](=[O:10])[CH3:9])(=O)[CH3:5].C([Cl:14])(=O)C>C(OCC)C>[CH3:5][C:4]([Sn:1]([Br:3])([Br:2])[Cl:14])=[CH:7][C:8](=[O:10])[CH3:9]
Reactant: Br[Sn]Br
Reactant: CC(=O)Cl
Reactant: CC(=O)CC(C)=O
Solvent: CCOCC
Product: CC(=O)C=C(C)[Sn](Cl)(Br)Br
Yield: 95.5 %

Procedure:
The procedure was analogous to Example 6. 26.6 g (0.096 mol) of tin(II) bromide and 9.6 g (0.096 mol) of acetylacetone were reacted with 7.6 g (0.096 mol) of acetyl chloride in 200 ml of diethyl ether and the reaction solution was concentrated to give 36.4 g (96% of theory) of 1-methylbut-1-en-3-onyltin dibromide chloride (Br2 ClSn--C(CH3)=CH--CO--CH3) melting at 112°-115° C.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[N:8]2[C:9]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]=[C:11]([NH2:19])[C:10]=3[N:20]=[C:7]2[CH2:6][O:5][CH2:4]1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30].O>C(Cl)Cl>[NH2:19][C:11]1[C:10]2[N:20]=[C:7]3[CH2:6][O:5][CH2:4][C@H:3]([CH2:2][NH:1][S:29]([CH3:28])(=[O:31])=[O:30])[N:8]3[C:9]=2[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1
Reactant: NC[C@H]1COCc2nc3c(N)nc4ccccc4c3n21
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)NC[C@H]1COCc2nc3c(N)nc4ccccc4c3n21
Temperature: 0 °C
Reaction time: 1.25 h
Yield: 48.5 %

Procedure:
(11S)-11-(Aminomethyl)-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-6-amine (778 mg, 2.89 mmol) was dissolved in 60 mL of CH2Cl2 and treated with triethylamine (804 μL, 5.78 mmol). The solution was cooled to 0° C. under N2. Methanesulfonyl chloride (224 μL, 2.89 mmol) was then added dropwise. After 75 minutes, the reaction was treated with H2O and extracted repeatedly with 10% methanol/CHCl3. The combined organic layers were washed successively with H2O and brine. The organic portion was dried over Na2SO4, filtered and concentrated under reduced pressure. Chromatography (SiO2, 10-15% methanol/CHCl3) gave an off-white solid. Crystallization from methanol gave N-{[(11S)-6-amino-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-11-yl]methyl}methanesulfonamide (487 mg) as white, powdery crystals, mp 285-288° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N:15]([CH3:25])[S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)(=[O:18])=[O:17])[CH:14]=1)[NH:11][C:10]([C:26]([OH:28])=O)=[CH:9]2.[CH2:29]([S:36][C:37]1([CH2:43][NH2:44])[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CCCCCC.C(OCC)(=O)C.CN(C)C=O>[CH2:29]([S:36][C:37]1([CH2:43][NH:44][C:26]([C:10]2[NH:11][C:12]3[C:8]([CH:9]=2)=[CH:7][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:14][C:13]=3[N:15]([CH3:25])[S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)(=[O:17])=[O:18])=[O:28])[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C(=O)O)cc2c1
Reactant: NCC1(SCc2ccccc2)CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C(=O)NCC3(SCc4ccccc4)CCOCC3)cc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.8 %

Procedure:
A mixture of 5-(2-methoxyethoxy)-7-[methyl(pyridin-2-ylsulfonyl)amino]-1H-indole-2-carboxylic acid (1.0 g), 1-[4-(benzylthio)tetrahydro-2H-pyran-4-yl]methanamine (0.65 g), 1H-1,2,3-benzotriazol-1-ol (0.44 g), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.62 g) and N,N-dimethylformamide (15 mL) was stirred at room temperature for 18 hr. The reaction solution was concentrated under reduced pressure, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water, aqueous citric acid solution, saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over magnesium sulfate, and filtrated, and the filtrate was concentrated under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (ethyl acetate:hexane=20:80-80:20) to give the title compound (1.4 g, yield 90%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([OH:18])[CH2:10][CH2:11][CH:12]2[NH:16][C:15](=[O:17])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>>[C:22]([Si:19]([CH3:21])([CH3:20])[O:18][CH:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH2:10][CH2:11][CH:12]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13]1)([CH3:25])([CH3:24])[CH3:23]
Reactant: O=C1CCC(CCC(O)Cc2ccc(F)cc2)N1
Reactant: CC(C)(C)[Si](C)(C)Cl
Product: CC(C)(C)[Si](C)(C)OC(CCC1CCC(=O)N1)Cc1ccc(F)cc1

Procedure:
Analogous to the procedure described for Example 1A, Step C, 5-[4-(4-fluoro-phenyl)-3-hydroxy-butyl]-pyrrolidin-2-one (1.95 g, 7.79 mmol) was reacted with tert-butyldimethylsilyl chloride (1.47 g, 9.76 mmol). Purification by medium pressure chromatography (1% MeOH in CH2Cl2) provided 5-[3-(tert-butyl-dimethyl-silanyloxy)-4-(4-fluoro-phenyl)-butyl]-pyrrolidin-2-one. 1H NMR (CDCl3) δ7.12 (m, 2H), 6.97 (m, 2H), 5.75 (m, 1H), 3.83 (m, 1H), 3.60 (m, 1H), 2.71 (m, 2H), 2.36-2.24 (m, 3H), 1.70-1.38 (m, 5H), 0.84 (s, 9H), −0.05 (d, 3H), −0.2 (d, 3H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:25])[CH:23]=[CH2:24]>C1COCC1>[C:22]([O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:25])[CH:23]=[CH2:24]
Reactant: OCCOCCOCc1ccccc1
Reactant: C=CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CC(=O)OCCOCCOCc1ccccc1
Temperature: 0 °C
Yield: 84 %

Procedure:
To a 1 L three-neck round bottom flask equipped with mechanical stirrer were charged diethylene glycol monobenzyl ether (98.0 g, 0.5 mol), anhydrous triethylamine (120 mL, 0.85 mol), and anhydrous THF (300 mL). The solution was cooled in an ice/salt bath under dry air blanket for 15 minutes. Acryloyl chloride (55 mL, 0.68 mol) was added into the vigorously stirred cold solution through an addition funnel over 90 minutes and the addition rate was adjusted to keep the temperature of the reaction mixture below 10° C. After the addition, the reaction mixture was stirred in the ice/salt bath for additional two hours followed by quenching with the addition of 2M HCl (400 mL). The mixture was extracted with ethyl acetate (300 mL×3) and the combined organic layer was washed with DI water (200 mL×3), aqueous sodium bicarbonate (200 mL×2), and dried over MgSO4. Filtration and removal of solvents under reduced pressure gave the crude product as light brown oil which was purified on silica gel using Hexanes/Ethyl acetate (4/1, v/v) as eluent to give the final product as a colorless oil (105.0 g, 0.42 mol, yield: 84%).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[S:10][C:6]=2[CH:5]=[CH:4][C:3]=1[NH2:12].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21](Cl)=[O:22])=[CH:16][CH:15]=1.C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[S:10][C:6]=2[CH:5]=[CH:4][C:3]=1[NH:12][C:21](=[O:22])[CH2:20][C:17]1[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: Cc1nc2c(Cl)c(N)ccc2s1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1nc2c(Cl)c(NC(=O)Cc3ccc(Cl)cc3)ccc2s1
Yield: 76 %

Procedure:
Reaction of 4-chloro-2-methyl-benzothiazol-5-ylamine (50 mg, 0.25 mmol) in THF (1.5 mL) with 4-chlorophenylacetyl chloride (65 mg, 0.30 mmol) in presence of triethylamine (42 μL, 0.30 mmol) according to method A gave N-(4-chloro-2-methyl-benzothiazol-5-yl)-2-(4-chloro-phenyl)-acetamide (65 mg, 0.19 mmol, 80% yield) as a white powder after crystallisation in hexane/DCM.
Reaction SMILES: [CH3:1][N:2]1[C:14]2[CH2:13][CH2:12][CH2:11][C:10](=[O:15])[C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[C:6]([C:16]([NH2:18])=[O:17])[CH:7]=2.[CH2:19]=O.Cl.[CH3:22][NH:23][CH3:24].N>C(O)(=O)C>[CH3:22][N:23]([CH2:19][CH:11]1[C:10](=[O:15])[C:9]2[C:8]3[C:3](=[CH:4][CH:5]=[C:6]([C:16]([NH2:18])=[O:17])[CH:7]=3)[N:2]([CH3:1])[C:14]=2[CH2:13][CH2:12]1)[CH3:24]
Reactant: C=O
Reactant: CNC
Reactant: Cn1c2c(c3cc(C(N)=O)ccc31)C(=O)CCC2
Agent: Cl
Agent: N
Solvent: CC(=O)O
Product: CN(C)CC1CCc2c(c3cc(C(N)=O)ccc3n2C)C1=O

Procedure:
A mixture of the product of Stage (ii) (1.8 g), paraformaldehyde (0.3 g) and dimethylamine hydrochloride (0.75 g) in acetic acid (14 ml) was heated at 80°-100° under nitrogen for 2 h. The reaction mixture was cooled (20°), evaporated in vacuo and purified by flash chromatography (L) to give a foam. A sample (0.2 g) was stirred in 0.88 ammonia 10 ml) for 3 days to precipitate to title compound (100 mg) as a solid. m.p. 171°-173° (foams).
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]4[S:24][C:25]([C:28](=[O:30])[CH3:29])=[CH:26][CH:27]=4)=[O:22])=[CH:16][CH:15]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:31].[CH3:32][N:33]1[CH2:38][CH2:37][N:36]([C:39]2[CH:44]=[CH:43][C:42]([NH2:45])=[CH:41][CH:40]=2)[CH2:35][CH2:34]1>C1COCC1>[CH3:32][N:33]1[CH2:34][CH2:35][N:36]([C:39]2[CH:44]=[CH:43][C:42]([NH:45][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]6[S:24][C:25]([C:28](=[O:30])[CH3:29])=[CH:26][CH:27]=6)=[O:22])=[CH:16][CH:15]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:31])=[CH:41][CH:40]=2)[CH2:37][CH2:38]1
Reactant: CC(=O)c1ccc(C(=O)Nc2ccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)cc2)s1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: C1CCOC1
Product: CC(=O)c1ccc(C(=O)Nc2ccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(N4CCN(C)CC4)cc3)cc2)s1
Temperature: 65 °C
Reaction time: 24 h
Yield: 57 %

Procedure:
A small screw cap test tube was charged with 5-Acetyl-thiophene-2-carboxylic acid [4-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 34, 40 mg, 0.093 mmol) and THF (2 mL). To the resulting solution was added 4-(4-methyl-piperazin-1-yl)-phenylamine (22 mg, 0.1150 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The solid residue was recrystallized with 2 mL of i-prOH affording the title compound in 57% yield (0.032 g, 0.0528 mmol).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]=[O:5].[CH3:11][Si:12]([C:15]#[CH:16])([CH3:14])[CH3:13].C(N(CC)CC)C>CN(C)C=O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]([C:16]#[C:15][Si:12]([CH3:14])([CH3:13])[CH3:11])[C:3]=1[CH:4]=[O:5]
Reactant: C#C[Si](C)(C)C
Reactant: O=Cc1c(F)cccc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1cccc(F)c1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.6 %

Procedure:
To a solution of 2-bromo-6-fluorobenzaldehyde (Description 39; 10.0 g, 49.3 mmol) and (trimethylsilyl) acetylene (13.94 ml, 98.6 mmol) in anhydrous N,N-dimethylformamide (250 ml) under an atmosphere of nitrogen was added triethylamine (10.25 ml, 73.95 mmol), copper (I) iodide (0.94 g, 4.93 mmol) and Pd(PPh3)2Cl2 (1.73 g, 2.47 mmol). The mixture was degassed and stirred at room temperature overnight. The mixture was poured into water (600 ml) and extracted with ethyl acetate (3×200 ml). The combined organic layers were washed with water (3×300 ml), brine (200 ml) then dried over Na2SO4 and evaporated. The residue was purified by column chromatography on silica gel eluting with 5% Et2O in iso-hexanes to give the title compound (10.38 g, 95%).