Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[C:15]([O:17][CH3:18])=[O:16])[CH:8]=[CH:7]1.[Cl-].O[NH3+].O.[CH3:23][N:24](C)C=O>>[C:23]([C:8]1[C:9]2[C:14](=[C:13]([C:15]([O:17][CH3:18])=[O:16])[CH:12]=[CH:11][CH:10]=2)[NH:6][CH:7]=1)#[N:24]
Reactant: CN(C)C=O
Reactant: COC(=O)c1cccc2cc[nH]c12
Agent: [Cl-]
Agent: [NH3+]O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: COC(=O)c1cccc2c(C#N)c[nH]c12
Temperature: 120 °C
Reaction time: 1 h

Procedure:
9.1 g of phosphoryl chloride are added to 30 ml of dimethylformamide with ice cooling at a reaction temperature of 20-30°. A solution of 8 g of methyl indole-7-carboxylate in dimethylformamide is added dropwise, during which the temperature rises to 40°. After one hour at 125°, the solution is added dropwise while still hot to a solution of 6.3 g of hydroxylammonium chloride in 40 ml of dimethylformamide, and the mixture is stirred at 120° C. for a further 15 minutes. The mixture is poured into water, extracted with ethyl acetate, filtered through neutral aluminium oxide and evaporated, giving 4.5 g of methyl 3-cyanoindole-7-carboxylate having a melting range of 212-213.5° (48.9% of theory).
Reaction SMILES: C([Li])CCC.I[C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH:16]([CH3:18])[CH3:17])=[C:9]([O:19][CH3:20])[CH:8]=1.[B:21](OC(C)C)([O:26]C(C)C)[O:22]C(C)C.O.Cl>O1CCCC1.CCCCCC>[CH:16]([O:15][C:10]1[C:11]([O:13][CH3:14])=[CH:12][C:7]([B:21]([OH:26])[OH:22])=[CH:8][C:9]=1[O:19][CH3:20])([CH3:18])[CH3:17]
Reactant: COc1cc(I)cc(OC)c1OC(C)C
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cc(B(O)O)cc(OC)c1OC(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.4 %

Procedure:
Under nitrogen, 10 mL (159 mmol) of a 1.59 mol/L hexane solution of n-butyl lithium and a solution of 23.0 g (71.4 mmol) of 1-iodo-4-isopropoxy-3,5-dimethoxybenzene in anhydrous tetrahydrofuran (100 ml) were added dropwise to anhydrous tetrahydrofuran cooled in a dry ice-methanol bath, and the mixture was stirred for 30 minutes. After addition of 20 mL (87 mmol) of triisopropyl borate, the reaction mixture was stirred for 15 minutes and the dry ice-methanol bath was removed. With stirring, the reaction mixture was allowed to warm to room temperature over about 1.5 hours. After addition of water (4 mL, 200 mmol), the mixture was concentrated under reduced pressure and the residue was dissolved in a 1 mol/L aqueous sodium hydroxide solution (200 mL). After washing with heptane (20 mL) and chloroform (3×15 mL), the resulting solution was stirred in an ice bath, followed by dropwise addition of 35 mL (420 mmol) of concentrated hydrochloric acid. The mixture was stirred with ice cooling for 2.5 hours. The precipitates were collected by filtration, washed with 0.1 mol/L hydrochloric acid and water and air-dried overnight, whereby 16 g of crude crystals were obtained. A solution of crude crystals in tetrahydrofuran (50 mL) was dried over magnesium sulfate and then concentrated under reduced pressure to about 25 mL. The residue heated to about 80° C. was stirred, and heptane (15 mL) was added. After stirring at room temperature and then, in an ice bath, precipitates were collected by filtration and washed with tetrahydrofuran-heptane (1:10:3×7.5 mL), whereby 12.75 g of 4-isopropoxy-3,5-dimethoxyphenylboronic acid was obtained as a colorless crystalline powder (mp: 211.5° C. (decomposed), yield: 71%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:14]2[O:13][C:12]([CH3:16])([CH3:15])[O:11][C:10]=2[C:9]([C:17]([C:37]2[C:47]3[O:48][C:49]([CH3:52])([CH3:51])[O:50][C:46]=3[C:45]([CH2:53][OH:54])=[C:39]3[O:40][C:41]([CH3:44])([CH3:43])[O:42][C:38]=23)([C:19]2[C:29]3[O:30][C:31]([CH3:34])([CH3:33])[O:32][C:28]=3[C:27]([CH2:35][OH:36])=[C:21]3[O:22][C:23]([CH3:26])([CH3:25])[O:24][C:20]=23)[OH:18])=[C:8]2[C:4]=1[O:5][C:6]([CH3:56])([CH3:55])[O:7]2>N1C=CC=CC=1>[CH3:3][C:2]([O:54][CH2:53][C:45]1[C:39]2[O:40][C:41]([CH3:43])([CH3:44])[O:42][C:38]=2[C:37]([C:17]([C:9]2[C:8]3[O:7][C:6]([CH3:56])([CH3:55])[O:5][C:4]=3[C:3]([CH2:2][O:1][C:6]([CH3:55])=[O:7])=[C:14]3[O:13][C:12]([CH3:16])([CH3:15])[O:11][C:10]=23)([C:19]2[C:29]3[O:30][C:31]([CH3:33])([CH3:34])[O:32][C:28]=3[C:27]([CH2:35][O:36][C:4]([CH3:8])=[O:5])=[C:21]3[O:22][C:23]([CH3:25])([CH3:26])[O:24][C:20]=23)[OH:18])=[C:47]2[C:46]=1[O:50][C:49]([CH3:52])([CH3:51])[O:48]2)=[O:1]
Reactant: CC1(C)Oc2c(CO)c3c(c(C(O)(c4c5c(c(CO)c6c4OC(C)(C)O6)OC(C)(C)O5)c4c5c(c(CO)c6c4OC(C)(C)O6)OC(C)(C)O5)c2O1)OC(C)(C)O3
Solvent: c1ccncc1
Product: CC(=O)OCc1c2c(c(C(O)(c3c4c(c(COC(C)=O)c5c3OC(C)(C)O5)OC(C)(C)O4)c3c4c(c(COC(C)=O)c5c3OC(C)(C)O5)OC(C)(C)O4)c3c1OC(C)(C)O3)OC(C)(C)O2
Temperature: 25 °C

Procedure:
Acetic anhydride (AcO)2O (30 mL) was added to pyridine (35 mL). Tris(8-hydroxymethyl-2,2,6,6-tetramethylbenzo[1,2-d:4,5-d']-bis(1,3)dioxole-4-yl)methanol (0.400 g, 0.51 mmol (Example 33) was added under stirring, which was maintained at room temperature for two days. Pyridine and excess anhydride were evaporated (oil-pump) at 40°-50° C. to a syrup, which was taken up in 70 mL of CH2Cl2. The organic phase was washed with water (30 mL), 0.5M HCl (40 mL), water (50 mL) and NaHCO3 (saturated, 30 mL). The organic phase was separated, dried and the solvent was evaporated, leaving a syrup, which crystallized after standing for ca 1 h and the product tris(8-methylcarbonyloxymethyl-2,2,6,6-tetramethyl-benzo[1,2-d:4,5-d']-bis(1,3)dioxole-4-yl)methanol was isolated (0.460 g, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([N+:17]([O-:19])=[O:18])([CH2:15][OH:16])[CH2:13][OH:14])[CH:6]=[CH:5]2.C(Cl)Cl.CO[C:25](OC)([CH3:27])[CH3:26].B(F)(F)F>CCOC(C)=O.CCCCCC>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]1([N+:17]([O-:19])=[O:18])[CH2:15][O:16][C:25]([CH3:27])([CH3:26])[O:14][CH2:13]1)[CH:6]=[CH:5]2
Reactant: O=[N+]([O-])C(CO)(CO)c1ccc2cc(Br)ccc2c1
Reactant: COC(C)(C)OC
Agent: FB(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCC
Product: CC1(C)OCC(c2ccc3cc(Br)ccc3c2)([N+](=O)[O-])CO1
Reaction time: 0.25 h
Yield: 82 %

Procedure:
2-(6-Bromo-naphthalen-2-yl)-2-nitro-propane-1,3-diol (32.6 g, 0.100 mol) was dissolved in methylene chloride (150 mL, 2.3 mol; Acros, anhydrous) and 2,2-dimethoxypropane (180 mL, 1.5 mol; Aldrich), cooled with an ice bath. Boron trifluoride is etherate (10.1 mL, 0.0800 mol; Aldrich) was added slowly. The mixture was stirred for 15 min and large amount of solid precipitated. The cooling bath was removed and the mixture was stirred at r.t. for 4 hours. The mixture was quenched with aqueous saturated NaHCO3 (˜600 mL) to pH˜8, extracted with EtOAc (600 mL, 300 mL, 2×100 mL). The EtOAc layer was washed with water, brine, dried over Na2SO4, filtered. The solvent was evaporated to 100 mL. The resulted solid product was collected by filtration and the mother liquid was concentrated further to afford the second crop of product. Rf of product=0.4 (EtOAc/hexane=1/4). Total product weighed 30.0 g (yield 82%).
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][C:10]23[CH2:17][CH2:16][C:13]([C:18]([O:20]C)=[O:19])([CH2:14][CH2:15]2)[CH2:12][CH2:11]3)[O:6][CH2:5][CH2:4][O:3]1.CO.[OH-].[K+].Cl>O>[CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][C:10]23[CH2:11][CH2:12][C:13]([C:18]([OH:20])=[O:19])([CH2:16][CH2:17]2)[CH2:14][CH2:15]3)[O:6][CH2:5][CH2:4][O:3]1
Reactant: COC(=O)C12CCC(CCCC3(C)OCCO3)(CC1)CC2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1(CCCC23CCC(C(=O)O)(CC2)CC3)OCCO1

Procedure:
Methyl 4-[3-(2-methyl-1,3-dioxolan-2-yl)propyl]bicyclo[2.2.2]octane-1-carboxylate (4-C) (1.0 g, 3.38 mmol) was stirred in a solution of 90% methanol and 10% water (50 mL). Excess potassium hydroxide (2.0 g) was added. The mixture was refluxed overnight. The cooled mixture was acidified with 1N hydrochloric acid (100 mL) and then washed twice with ethyl acetate (100 mL). The combined organic layers were dried (MgSO4). Ethyl acetate was removed in vacuo yielding pure 4-[3-(2-methyl-1,3-dioxolan-2-yl)propyl]bicyclo[2.2.2]octane-1-carboxylic acid (4-D).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[CH:7]=[CH:6][C:5]=1[NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])([O-])=O>C(O)C.CO.[Pd]>[NH2:1][C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[CH:7]=[CH:6][C:5]=1[NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1N
Reaction time: 12 h
Yield: 69.4 %

Procedure:
To a solution of tert-butyl (2-nitro-4-(thiophen-2-yl)phenyl)carbamate (2 g, 6.2 mmol, 1.0 eq.) in ethanol (20 mL) and methanol (20 mL) was added 10% Pd/C (0.66 g, 0.1 eq.). The reaction mixture was stirred 12 h under a hydrogen atmosphere. The reaction was filtered and the filtrate was concentrated under reduced pressure to give tert-butyl (2-amino-4-(thiophen-2-yl)phenyl)carbamate (1.25 g, 69% yield) as an off-white solid.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:9]([CH3:10])=[C:8]([S:11][CH2:12][C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[CH:7]=[CH:6][N:5]=1.[SH:18][C:19]1[NH:23][C:22]2[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=2[N:20]=1.[OH-].[Na+]>C(O)C>[CH3:10][C:9]1[C:4]([CH2:3][S:18][C:19]2[NH:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[N:20]=2)=[N:5][CH:6]=[CH:7][C:8]=1[S:11][CH2:12][C:13]1[CH:17]=[CH:16][S:15][CH:14]=1
Reactant: Sc1nc2ccccc2[nH]1
Reactant: Cc1c(SCc2ccsc2)ccnc1CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(SCc2ccsc2)ccnc1CSc1nc2ccccc2[nH]1
Yield: 62 %

Procedure:
2-Chloromethyl-3-methyl-4-(3-thienylmethylthio)pyridine hydrochloride, 2-mercapto-1H-benzimidazole and sodium hydroxide are reacted in ethanol at 25° C. for 20 h. After crystallization from toluene/methanol, the title compound is isolated. Yield: 62%, m.p. 161°-164° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:14][OH:15])[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[CH3:28][O:29][C:30](=[O:39])[C:31]1[CH:36]=[CH:35][C:34]([CH2:37]Cl)=[N:33][CH:32]=1>>[CH3:28][O:29][C:30](=[O:39])[C:31]1[CH:36]=[CH:35][C:34]([CH2:37][O:15][CH2:14][CH:13]([N:12]2[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[N:33][CH:32]=1
Reactant: COC(=O)c1ccc(CCl)nc1
Reactant: OCC(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Product: COC(=O)c1ccc(COCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)nc1

Procedure:
The title compound was prepared in analogy to Example 26, from 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Ex. 1, int. c) and 6-chloromethyl-nicotinic acid methyl ester (commercially available) to give the title compound after purification by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane and ethyl acetate (100:0 to 60:40) as a light yellow solid (10%). MS (Turbo Spray): m/z=540.4 [M+H].
Reaction SMILES: [Br:1][C:2]1[C:3]([N:18]2[CH2:21][C:20]([CH3:23])([CH3:22])[CH2:19]2)=[C:4]([C@H:10]([OH:17])[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8]>C(Cl)Cl>[Br:1][C:2]1[C:3]([N:18]2[CH2:21][C:20]([CH3:23])([CH3:22])[CH2:19]2)=[C:4]([C@H:10]([O:17][C:4]([CH3:10])([CH3:5])[CH3:3])[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8]
Reactant: Cc1nc(C)c([C@H](O)C(=O)OC(C)C)c(N2CC(C)(C)C2)c1Br
Solvent: ClCCl
Product: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)OC(C)C)c(N2CC(C)(C)C2)c1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 104.8 %

Procedure:
The isobutylene gas was bubbled into a nitrogen purged, cooled (0° C.) solution of (S)-isopropyl 2-(5-bromo-4-(3,3-dimethylazetidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-hydroxyacetate (970 mg, 2.5 mmol) and 0.5 mL of 70% HClO4 in DCM (20 mL) for 20 min. The reaction mixture was allowed to warm to rt and stirred for 18 h in a pressure sealed vessel, diluted with DCM, washed with 1M Na2CO3 solution, and dried over MgSO4. The crude product was charged (DCM) to a 40 g ISCO silica gel cartridge and gradient elution (5-35% EtOAc/hexanes) using an Isolera chromatography station gave (S)-isopropyl 2-(5-bromo-4-(3,3-dimethylazetidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate 578 mg (52%). 1H NMR (500 MHz, DMSO) δ 5.30 (s, 1H), 5.0-4.95 (m, 1H), 4.12 (d, J=7.2 Hz, 2H), 4.02 (br. s, 2H), 2.44 (s, 3H), 2.25 (br. s, 3H), 1.26 (s, 6H), 1.20 (d, J=6.3 Hz, 3H), 1.17 (d, J=6.3 Hz, 3H), 1.07 (s, 9H). UPLC (M+H)=443.3.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][Si:5](OCC)(OCC)OCC.[CH3:15][O:16][C:17]1[CH:33]=[CH:32][C:20]([C:21]([C:23]23[O:30][C:29](=[O:31])[CH:28]2[CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:22])=[CH:19][CH:18]=1>C(Cl)Cl>[SiH3:5][CH2:4][CH2:3][CH2:2][NH:1][C:29]([CH:28]1[CH2:27][CH2:26][CH2:25][CH2:24][C:23]1([OH:30])[C:21](=[O:22])[C:20]1[CH:19]=[CH:18][C:17]([O:16][CH3:15])=[CH:33][CH:32]=1)=[O:31]
Reactant: COc1ccc(C(=O)C23CCCCC2C(=O)O3)cc1
Reactant: CCO[Si](CCCN)(OCC)OCC
Solvent: ClCCl
Product: COc1ccc(C(=O)C2(O)CCCCC2C(=O)NCCC[SiH3])cc1

Procedure:
3-Aminopropyltriethoxysilane (22.14 g, 0.100 mol) is added to a solution of 26.03 g (0.100 mol) of 6-(4-methoxy-benzoyl)-7-oxa-bicyclo[4.2.0]octan-8-one in methylene chloride. The reaction mixture is heated at reflux for several hours and monitored by thin layer chromatography. Upon completion of the reaction, solvent is evaporated to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])[C:10]2=[O:26])[N:4]=1.C(Cl)Cl>C(O)(C(F)(F)F)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([CH2:18][C:19]([OH:21])=[O:20])[C:10]2=[O:26])[N:4]=1
Reactant: COc1ccnc(-n2c(=O)n(CC(=O)OC(C)(C)C)c3ccccc32)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccnc(-n2c(=O)n(CC(=O)O)c3ccccc32)n1

Procedure:
tert-Butyl[3-(4-methoxypyrimidin-2-yl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]acetate from Step A (110 mg, 0.309 mmol) was dissolved in TFA (2 mL) and CH2Cl2 (2 mL) and the mixture was stirred at ambient temperature for 48 h, then concentrated in vacuo to give the title compound. MS: m/z=301 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]1[NH:16][C:15]([CH3:17])=[N:14][CH:13]=1.C1C(=O)N([Cl:25])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Cl:25][C:13]1[NH:14][C:15]([CH3:17])=[N:16][C:12]=1[C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[CH3:1])[C:6]([O:8][CH3:9])=[O:7]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1ccc(C)c(-c2cnc(C)[nH]2)c1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(C)c(-c2nc(C)[nH]c2Cl)c1
Temperature: 50 °C
Reaction time: 16 h
Yield: 82.1 %

Procedure:
To a solution of methyl 4-methyl-3-(2-methyl-1H-imidazol-5-yl)benzoate (compound 7.1, 317 mg, 1.38 mmol) in carbon tetrachloride (30 mL) was added NCS (184 mg, 1.38 mmol). The mixture was stirred at 50° C. for 16 hours, then cooled to room temperature and washed with brine, dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-50% EtOAc in hexanes) to yield the title compound as a solid (300 mg, 82%). m/z (ES+) 265 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 9.55 (br s, 1H), 8.01-7.87 (m, 2H), 7.37 (d, J=7.8 Hz, 1H), 3.91 (s, 3H), 2.42 (s, 3H), 2.40 (s, 3H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]12[CH2:17][CH2:16][CH2:15][C:13]3[C:14]1=[C:9]([CH:10]=[CH:11][CH:12]=3)[NH:8][C:7]2=[O:18].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2([OH:32])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2([OH:32])[CH2:27][CH2:28][N:29]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]34[CH2:17][CH2:16][CH2:15][C:13]5[C:14]3=[C:9]([CH:10]=[CH:11][CH:12]=5)[NH:8][C:7]4=[O:18])[CH2:30][CH2:31]2)=[CH:22][CH:21]=1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Reactant: O=C1Nc2cccc3c2C1(CCCCBr)CCC3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1Nc2cccc3c2C1(CCCCN1CCC(O)(c2ccc(Cl)cc2)CC1)CCC3
Yield: 84.6 %

Procedure:
2a-(4-bromobutyl)-2a,3,4,5-tetrahydrobenz[cd]indole-2(1H)-one (390 mg, 1.3 mmol), 4-(4-chlorophenyl) -4-hydroxypiperidine (290 mg, 1.4 mmol) and potassium carbonate (260 mg, 1.9 mmol) were stirred in anhydrous N,N-dimethylformamide (10 ml) at 60° C. for 3 hours. The solvent was evaporated under a reduced pressure, and the thus obtained residue was mixed with ethyl acetate and water. The reaction product was extracted with ethyl acetate, washed with saturated brine and dried with anhydrous sodium sulfate. Then the compound obtained by the evaporation of the solvent under a reduced pressure was separated and purified by a silica gel column chromatography to obtain 490 mg of the title compound (1.1 mmol, 90% in yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C:16]1[CH:17]=[N:18][N:19]([CH:21]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22]2)[CH:20]=1.[Cl:27][C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[C:30]([Cl:43])[C:29]=1[OH:44].C([O-])([O-])=O.[Cs+].[Cs+].[ClH:51]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[ClH:27].[ClH:51].[Cl:27][C:28]1[CH:33]=[C:32]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C:16]2[CH:17]=[N:18][N:19]([CH:21]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22]3)[CH:20]=2)[CH:31]=[C:30]([Cl:43])[C:29]=1[OH:44]
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Nc1cnn(C2CCN(C)C2)c1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1Nc1cnn(C2CCN(C)C2)c1
Temperature: 80 °C
Yield: 83.1 %

Procedure:
To a suspension of 1-(6-bromo-4-((1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)quinolin-3-yl)ethanone (80 mg, 0.19 mmol), 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (80 mg, 0.28 mmol) and Pd(dppf)Cl2 (11 mg, 0.015 mmol) in dioxane (4 mL) was added Cs2CO3 (1.0 M in H2O, 0.4 mL, 0.4 mmol). N2 gas was bubbled through the reaction mixture and the mixture was then heated at 80° C. for 2 h. The solution was allowed to cool to room temperature, diluted with a saturated NaHCO3 solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. Purification by column chromatography (silica, 0-20% methanol/dichloromethane) afforded a residue that was further purified by preparative HPLC (C18 silica, 10-90% acetonitrile/water with 0.05% TFA). The resultant residue was dissolved in methanol (8 mL) and HCl (6 M in water, 1.0 mL, 6 mmol) was added. The resultant solution was concentrated to give the desired product (66.2 mg, 60%) as a yellow solid. 1H NMR (500 MHz, MeOD) δ 9.27 (br s, 1H), 8.26-8.17 (m, 2H), 8.11 (s, 1H), 8.02 (d, J=8.8 Hz, 1H), 7.79 (s, 1H), 7.37 (s, 2H), 5.41 (br s, 1H), 4.25-3.93 (m, 2H), 3.84-3.32 (m, 2H), 3.21-3.03 (m, 3H), 2.82-2.78 (br s, 1H), 2.80 (3, 3H), 2.39 (br s, 1H). ESI MS m/z 496 [C25H23Cl2N5O2+H]+; HPLC>99% (AUC), tR=9.56 min.
Reaction SMILES: CCCCCC.[H-].[Na+].[C:9]([O:17]C)(=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:19]([C:22]1[N:23]([CH3:27])[CH:24]=[CH:25][CH:26]=1)(=[O:21])[CH3:20]>C(OCC)C.C(O)C.O>[CH3:27][N:23]1[CH:24]=[CH:25][CH:26]=[C:22]1[C:19](=[O:21])[CH2:20][C:9]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:17]
Reactant: CC(=O)c1cccn1C
Reactant: COC(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCCCCC
Solvent: O
Product: Cn1cccc1C(=O)CC(=O)c1ccccc1
Temperature: 5 °C
Reaction time: 12 h
Yield: 17.6 %

Procedure:
To a stirred, cooled (5° C.) slurry of 0.96 g (0.04 mol) of hexane-washed sodium hydride in 2.72 g (0.02 mol) of methyl benzoate under nitrogen was added a solution of 5.0 g (0.04 mol) of 2-acetyl-1-methylpyrrole in 30 mL of ethyl ether. A few drops of ethanol were added. The reaction mixture was allowed to stir at 5° C. for 12 h. The mixture was poured into water and extracted with ethyl ether. The combined organic layers were washed with brine, dried over magnesium sulfate, and filtered. Removal of solvents gave a waxy solid which was purified by flash-chromatography (silica gel, ethyl acetate/hexane as eluent) to give 0.8 g of 1-(1-methylpyrrol-2-yl)-3-phenyl-1,3-propanedione.
Reaction SMILES: [CH2:1]([C:5]1([CH2:19][CH2:20][CH2:21][CH3:22])[C:11](=[O:12])[NH:10][C:9]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:8]=2[S:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].[N+:23]([C:26]1[CH:31]=[CH:30][C:29](Br)=[CH:28][CH:27]=1)([O-:25])=[O:24].C([O-])([O-])=O.[K+].[K+]>[Cu]I>[CH2:1]([C:5]1([CH2:19][CH2:20][CH2:21][CH3:22])[C:11](=[O:12])[N:10]([C:29]2[CH:30]=[CH:31][C:26]([N+:23]([O-:25])=[O:24])=[CH:27][CH:28]=2)[C:9]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:8]=2[S:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1(CCCC)CSc2cc(OC)ccc2NC1=O
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCC1(CCCC)CSc2cc(OC)ccc2N(c2ccc([N+](=O)[O-])cc2)C1=O
Temperature: 200 °C
Yield: 64 %

Procedure:
To 3,3-dibutyl-4-oxo-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (synthesised by the procedure of WO9616051 for the corresponding 3-butyl-3-ethyl analogue; 2.9 g, 9.0 mmol) was added p-nitrophenylbromide (24 g, 119 mmol), K2CO3 (1.6 g, 12 mmol) and CuI (180 mg, 0.95 mmol). The reaction mixture was heated to 200° C. overnight. Then it was allowed to cool down to room temperature and the resulting solid was purified by chromatography using DCM as eluent. The fractions containing the product were concentrated under reduced pressure and EtOH (95%) was added and the insoluble p-nitrophenylbromide was then filtered off. The residue was purified again by flash chromatography using DCM as eluent. The product was still not pure so the residue was then purified by flash chromatography using EtOAc:heptane, 1:9 as eluent to give the title compound 2.57 g (64%). NMR (600 MHz) 0.77–0.87 (m, 6H), 1.12–1.31 (m, 8H), 1.4–1.6 (m, 4H), 3.09 (brs, 2H), 3.79 (s, 3H), 6.72–6.83 (m, 2H), 7.18–7.27 (m, 3H), 8.3 (d, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:16](=[O:24])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=2)[N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8][C:7]=12)#[N:2].Cl.Cl[CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([C:3]1[CH:4]=[C:5]([C:16](=[O:24])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[CH:18]=2)[N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8][C:7]=12)#[N:2]
Reactant: N#Cc1cc(C(=O)c2cccc(O)c2)n2c1ccc1ccccc12
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1cc(C(=O)c2cccc(OCCN3CCOCC3)c2)n2c1ccc1ccccc12
Yield: 37.6 %

Procedure:
A mixture of 3-cyano-1-(3-hydroxy-benzoyl)-pyrrolo[1,2-a]quinoline (31.2 mg, 0.1 mmol), 4-(2-chloroethyl)morpholine hydrochloride (37.2 mg, 0.2 mmol), potassium carbonate (165 mg, 1 mmol) in acetone (5 mL) was refluxed for 4 h. It was evaporated to dryness and the residue was purified by column chromatography (EtOAc) to give 16 mg (37%) of the title compound. 1H NMR (CDCl3): 8.06 (d, J=8.7 Hz, 1H), 7.86–7.83 (m, 1H), 7.75–7.43 (m, 8H), 7.26–7.20 (m, 1H), 4.20 (t, J=5.60 Hz, 2H), 3.74 (t, J=4.80 Hz, 4H), 2.85 (t, J=5.40 Hz, 2H), 2.60 (t, (t, J=4.50 Hz, 4H).