Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:6]=[CH:5]2.[CH:18]1([NH:21][C:22]([C:24]2[CH:25]=[C:26]([F:34])[C:27]([CH3:33])=[C:28](B(O)O)[CH:29]=2)=[O:23])[CH2:20][CH2:19]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:18]1([NH:21][C:22]([C:24]2[CH:25]=[C:26]([F:34])[C:27]([CH3:33])=[C:28]([C:2]3[CH:3]=[C:4]4[C:8](=[CH:9][CH:10]=3)[N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:6]=[CH:5]4)[CH:29]=2)=[O:23])[CH2:20][CH2:19]1
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Br)ccc21
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(cnn2C(=O)OC(C)(C)C)c1
Yield: 211.1 %

Procedure:
A mixture of tert-butyl 5-bromo-1H-indazole-1-carboxylate (Intermediate 3) (1.07 g) {5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}boronic acid (Intermediate 64) (0.85 g) sodium carbonate (1.9 g) and tetrakis(triphenylphosphine)palladium(0) (0.42 g) in 1,2-dimethoxyethane (70 ml) was stirred at reflux under nitrogen for 20 h. the solvent was removed and the residue was partitioned between water (50 ml) and ethyl acetate (50 ml). The aqueous layer was re-extracted with ethyl acetate (3×30 ml) and the combined organic extracts were dried using a hydrophobic filter tube and concentrated under vacuum. The residue was purified by column chromatography on silica eluting with cyclohexane:ethyl acetate (75:25 to 60:40) to give the title compound (3.1 g).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([O-])([O-])=O.[K+].[K+].CS(C)=O.F[C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1>O>[N:1]1([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: N#Cc1ccc(F)cc1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1ccc(-n2ccnc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.9 %

Procedure:
To a mixture of imidazole (5.13 g, 75.35 mmol) , K2CO3 (11.45 g) and DMSO (50 ml) at room temperature was added to 4-fluorobenzonitrile (10.04 g) in one portion. The reaction mixture was stirred at room temperature for 1 hour, and then was warmed on a steam for 2 hours. The reaction mixture was cooled to room temperature, and poured into cold water. A precipitate formed which was collected by filtration and washed with water and recrystallized from CHCl3 /hexane to afford 4.07 g of 4-(1-imidazolyl)benzonitrile, m.p. 146°-148° C.
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH:22]1[CH2:27][CH2:26][CH2:25][C:24](=[O:28])[CH2:23]1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([N:22]1[CH2:27][CH2:26][CH2:25][C:24](=[O:28])[CH2:23]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCNC1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 32.9 %

Procedure:
Trityl chloride (13.1 g, 47.0 mmol) was added to a stirred suspension of 3-piperidone hydrochloride (5.79 g, 42.7 mmol) and triethylamine (14.9 ml, 107 mmol) in CH2Cl2 (100 ml) and the reaction was stirred for 16 h under N2 at room temperature. The resulting mixture was filtered and the filtrate washed sequentially with H2O and 5% aqueous citric acid, dried over MgSO4 and evaporated under reduced pressure. Trituration with pentane afforded the subtitle compound as a colourless solid (4.8 g, 33%). Rf 0.23 (CH2Cl2/pentane 2/3, v/v). 1H NMR (CDCl3) δ: 2.05 (2H, m), 2.35 (2H, m), 2.45 (2H, m), 2.85 (2H, s), 7.06-7.55 (15H, m).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]2[CH:12]=[C:13]([NH:18][C:19]3[C:28]4[CH2:27][CH2:26][NH:25][CH2:24][C:23]=4[CH:22]=[CH:21][N:20]=3)[CH:14]=[CH:15][C:16]=2[CH3:17])[N:2]=1.CCN(C(C)C)C(C)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C1COCC1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]2[CH:12]=[C:13]([NH:18][C:19]3[C:28]4[CH2:27][CH2:26][N:25]([S:39]([CH3:38])(=[O:41])=[O:40])[CH2:24][C:23]=4[CH:22]=[CH:21][N:20]=3)[CH:14]=[CH:15][C:16]=2[CH3:17])[N:2]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(Nc2nccc3c2CCNC3)cc1-c1cc2ccccc2cn1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(Nc2nccc3c2CCN(S(C)(=O)=O)C3)cc1-c1cc2ccccc2cn1
Reaction time: 8 h

Procedure:
To a solution of N-(3-(isoquinolin-3-yl)-4-methylphenyl)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-amine (37 mg, 0.1 mmol) in THF (2 mL) is added DIEA (26 mg, 0.2 mmol) and methylsulfonyl chloride (14 mg, 0.12 mmol) subsequently. The reaction mixture is stirred overnight. After removing solvent by rotary evaporation, the residue is purified by HPLC to afford N-(3-(isoquinolin-3-yl)-4-methylphenyl)-6-(methylsulfonyl)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-amine as a white solid. MS m/z 445.2 (M+1); 1H NMR 400 MHz (DMSO-d6) δ 9.34 (s, 1H), 8.11 (d, 1H, J=8.0 Hz), 7.97 (d, 1H, J=7.6 Hz), 7.88-7.85 (m, 3H), 7.76-7.71 (m, 2H), 7.66-7.63 (m, 2H), 7.16 (d, 1H, J=8.4 Hz), 6.57 (d, 1H, J=5.2 Hz), 4.24 (s, 2H), 3.45 (t, 2H, J=6.0 Hz), 2.91 (s, 3H), 2.75 (t, 2H, J=6.0 Hz), 2.26 (s, 3H).
Reaction SMILES: [Na].Cl[CH:3]=[C:4]1[CH2:9][C:8]([CH3:11])([CH3:10])[CH2:7][CH2:6][C:5]1=O.[Li+].[OH-].C([O:17][C:18](=[O:21])[CH2:19][SH:20])C>CCO.C1COCC1>[CH3:10][C:8]1([CH3:11])[CH2:7][CH2:6][C:5]2=[C:19]([C:18]([OH:21])=[O:17])[S:20][CH:3]=[C:4]2[CH2:9]1
Reactant: CC1(C)CCC(=O)C(=CCl)C1
Reactant: CCOC(=O)CS
Agent: [Li+]
Agent: [Na]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC1(C)CCc2c(csc2C(=O)O)C1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To a part (300 mL) of a freshly prepared solution of sodium (21 g, 875 mmol) in EtOH (500 mL), mercaptoacetic acid ethyl ester (50 mL) is added. The resulting solution is added over a period of 10 min to a solution of 2-chloromethylene-4,4-dimethyl-cyclohexanone (50 g, 290 mmol) in THF (170 mL). The mixture becomes warm (50° C.). Upon complete addition, the remaining part of the freshly prepared solution of sodium in EtOH (200 mL) is added to the reaction mixture. The mixture is stirred at rt for 15 min before 1 N aq. LiOH solution (300 mL) is added. The solution is refluxed for 3 h, then stirred at rt for 16 h. The THF and EtOH are removed under reduced pressure and the remaining dark solution is extracted with heptane/EA 3:1 (2×200 mL). The aqueous phase is acidified by adding citric acid (30 g) and 2 N aq. HCl (200 mL) and then extracted three times with EA. The combined organic extracts are washed three times with sat. aq. NaHCO3 solution, dried over Na2SO4 and evaporated. The resulting dark brown oil is dissolved in acetonitrile at 60° C. and crystallised at 5° C. The crystals are collected, washed with acetonitrile and dried to give 5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid (31 g) as a slightly grey powder; LC-MS: tR=0.95 min, [M+1+CH3CN]+=252.18; 1H NMR (CDCl3): δ 7.15 (s, 1H), 3.05 (t, J=7.0 Hz, 2H), 2.47 (s, 2H), 1.58 (t, J=7.0 Hz, 2H), 0.97 (s, 6H).
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[OH:26][CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][NH:30][CH2:29]1.CC(=O)CC>O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([N:30]3[CH2:31][CH2:32][CH2:33][CH:28]([CH2:27][OH:26])[CH2:29]3)[O:3][C:4]=2[CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[CH:8][CH:9]=1
Reactant: OCC1CCCNC1
Reactant: COc1ccccc1OCCCc1oc(Cl)nc1-c1ccc(Cl)cc1
Solvent: O
Solvent: CCC(C)=O
Product: COc1ccccc1OCCCc1oc(N2CCCC(CO)C2)nc1-c1ccc(Cl)cc1

Procedure:
A mixture of 2-chloro-4-(4-chlorophenyl)-5-[3-(2-methoxyphenoxy)propyl]oxazole (378 mg), 3-hydroxymethylpiperidine (1.29 g) and 2-butanone (10 ml) was stirred with heating under reflux for 12 hours. The reaction mixture was poured into 100 ml of water and extracted with ethyl acetate (100 ml×2). The organic layer was washed with 100 ml of water, dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography, and 4-(4-chlorophenyl)-2-(3-hydroxymethyl-1-piperidinyl)-5-[3-(2-methoxyphenoxy)propyl]oxazole was obtained as an oil (102 mg, 27%) from an ethyl acetate-hexane (1:1, v/v)-eluted fraction.
Reaction SMILES: [CH3:1][C:2]([CH:4]1[CH2:6][CH2:5]1)=[O:3].[H-].[Na+].[CH3:9][S:10][C:11]1[CH:21]=[CH:20][C:14]([C:15](OCC)=[O:16])=[CH:13][CH:12]=1.Cl>O1CCOCC1>[CH:4]1([C:2](=[O:3])[CH2:1][C:15]([C:14]2[CH:20]=[CH:21][C:11]([S:10][CH3:9])=[CH:12][CH:13]=2)=[O:16])[CH2:6][CH2:5]1
Reactant: CCOC(=O)c1ccc(SC)cc1
Reactant: CC(=O)C1CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CSc1ccc(C(=O)CC(=O)C2CC2)cc1
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 49.4 %

Procedure:
Cyclopropyl methyl ketone (0.84 g) was added to a suspension of sodium hydride (80%, 0.3 g) in dioxane. The mixture was stirred for 20 minutes and ethyl 4(methylsulphenyl)benzoate (1.0 g) was added. The mixture was stirred and heated at 45° C. for 1.5 hours and at 60° C. for 2 hours. It was left to stand at room temperature overnight. Hydrochloric acid (2M) was added and the mixture was extracted with ethyl acetate, washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography eluted with a mixture of ethyl acetate and hexane to give 3-cyclopropyl-1-[4-(methylsulphenyl)-phenyl]-propan-1,3-dione (0.59 g) as an orange solid, NMR (CDCl3) 1.0(m,2H), 1.2(m,2H), 1.8(m, 1H), 2.5(s,3H), 6.25(s, 1H), 7.25(d,2H), 7.8(d,2H), 16.35(bs, 1H).
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([S:14](Cl)(=O)=O)[CH:11]=2)[CH2:6]1)(=[O:3])[CH3:2].O.[CH3:19]I.C[O-].[Na+]>C(O)(=O)C.Cl>[C:1]([NH:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([S:14][CH3:19])[CH:11]=2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CI
Reactant: CC(=O)NC1Cc2ccc(S(=O)(=O)Cl)cc2C1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CSc1ccc2c(c1)CC(NC(C)=O)C2
Temperature: 75 °C
Reaction time: 1 h

Procedure:
5.6 g. of N-acetyl-5-chlorosulfonyl-2-indanamine (0.02 mole) (as prepared in Example 3) is dissolved in acetic acid (50 ml.), warmed to 75° C., and 19 g. of stannous chloride (0.1 mole) in concentrated hydrochloric acid (20 ml.) is added. An exotherm occurs. When the reduction is complete the mixture is cooled to 25° C. and poured into water. The N-acetyl-5-mercapto-2-indanamine is filtered and suspended in methanol (50 ml.) under a nitrogen atmosphere. 5.7 g. of methyl iodide (0.04 mole) and 1.1 g. of sodium methoxide (0.02 mole) are added and the mixture is stirred for one hour. The mixture is filtered, evaporated and the residue purified by chromatography to give N-acetyl-5-methylthio-2-indanamine which is hydrolyzed following the procedure of Example 3 to give 5-methylthio-2-indanamine.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10].[CH2:12]1[CH2:23][O:22][C:21]2[CH:20]=[CH:19][C:16](C#N)=[CH:15][C:14]=2[O:13]1>>[CH2:12]1[CH2:23][O:22][C:21]2[CH:20]=[CH:19][C:16]([C:1]3[NH:2][C:3](=[O:11])[C:4]4[C:5]([CH:10]=3)=[CH:6][CH:7]=[CH:8][CH:9]=4)=[CH:15][C:14]=2[O:13]1
Reactant: CNC(=O)c1ccccc1C
Reactant: N#Cc1ccc2c(c1)OCCO2
Product: O=c1[nH]c(-c2ccc3c(c2)OCCO3)cc2ccccc12
Yield: 32.2 %

Procedure:
According to the method of Example 10-1, N-methyl-2-methylbenzamide (5.97 g) and 3,4-ethylenedioxybenzonitrile (6.41 g) were reacted, to give 3-(3,4-ethylenedioxyphenyl)isoquinolin-1-one (3.58 g).
Reaction SMILES: [C:1]1([C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](O)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:23][CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][CH:30]([C:33]2[CH:34]=[C:35]([NH:39][C:40](=[O:42])[CH3:41])[CH:36]=[CH:37][CH:38]=2)[CH2:29][CH2:28]1>>[C:40]([NH:39][C:35]1[CH:34]=[C:33]([CH:30]2[CH2:31][CH2:32][N:27]([CH2:26][CH2:25][CH2:24][NH:23][C:8](=[O:9])[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:28][CH2:29]2)[CH:38]=[CH:37][CH:36]=1)(=[O:42])[CH3:41]
Reactant: O=C(O)C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: CC(=O)Nc1cccc(C2CCN(CCCNC(=O)C(c3ccccc3)(c3ccccc3)c3ccccc3)CC2)c1

Procedure:
Example 105 was prepared from triphenylacetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}acetamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.34–7.22 (m, 19H), 6.91 (d, 1H, J=7.6 Hz), 6.30 (t, 1H, J=5.6 Hz), 3.43 (dd, 2H, J=6.4, 12.0 Hz), 2.87 (d, 2H, J=12.0 Hz), 2.42 (m, 1H), 2.30 (t, 2H, J=6.8 Hz), 2.17 (s, 3H), 1.93 (t, 2H, J=11.6 Hz), 1.74–1.66 (m, 4H), 1.60–1.50 (m, 2H); ESMS m/e: 546.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12](=[O:16])[CH:13](Cl)[CH3:14])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[CH2:7]2.[OH:17][C:18]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C(N(CC)CC)C.[Li+].[Cl-]>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([C:12](=[O:16])[CH:13]([N:21]2[CH2:22][CH2:23][C:18]([OH:17])([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:19][CH2:20]2)[CH3:14])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[CH2:7]2
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: CC(Cl)C(=O)c1cc(F)c2c(c1)CC(=O)N2
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C(=O)c1cc(F)c2c(c1)CC(=O)N2)N1CCC(O)(c2ccccc2)CC1
Yield: 36.6 %

Procedure:
A mixture of 7-fluoro-5-(2-chloropropionyl)-2(1H,3H)-indolone (1.0 g, 4.14 mmol), 4-hydroxy-4-phenylpiperidine (0.74 g, 4.17 mmol) and triethylamine (1.2 ml, 8.6 mmol) in anhydrous dimethylformamide was heated to between 70 and 90° C. for 3 hours. The mixture was poured into 1N aqueous LiCl and extracted with two portions of ethyl acetate. The combined organic phase was washed with 1N HCI, water and brine. The organic phase was dried over magnesium sulfate, filtered and concentrated to 1.6 g of a reddish solid. The crude product was purified by flash chromatography on silica gel (2×4 inches {50×100 mm}, 50% ethyl acetate/hexane eluent) to yield 0.58 g of the desired product. This product was further purified by recrystallization from acetonitrile/ether to give 0.2 g of light yellow solid; m.p. 197°-199.5° C. NMR (DMSO-d6) 11.25 (s, 1H), 7.90 (d, J=11.6 Hz, 1H), 7.82 (s, 1H), 7.42 (d, J=7.2 Hz, 2H), 7.28 (t, J=7.4 Hz, 2H), 7.17 (t, J=7.2 Hz, 1H), 4.76 (s, 1H), 4.25 (q, J=6.6 Hz, 1H), 3.66 (s, 2H), 2.88-2.63 (m, 2H), 2.60-2.55 (m, 1h), 2.49-2.38 (m, 1H), 1.88 (dt, J=12.2, 4.3 Hz, 1H), 1.77-1.49 (m, 3H), 1.16 (d, J=6.6 Hz, 3H). The mother liquors were rechromatographed to afford another 0.15 g of product for a total yield of 0.35 g (22%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:14]([F:17])([F:16])[F:15])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Br:18][C:19]1[CH:24]=[C:23](F)[CH:22]=[CH:21][C:20]=1[N+:26]([O-:28])=[O:27].C(=O)([O-])[O-].[K+].[K+].O>CN1CCCC1=O>[Br:18][C:19]1[CH:24]=[C:23]([N:11]2[CH2:12][CH2:13][C:9]([C:4]3[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=3)([C:14]([F:17])([F:16])[F:15])[CH2:10]2)[CH:22]=[CH:21][C:20]=1[N+:26]([O-:28])=[O:27]
Reactant: O=[N+]([O-])c1ccc(F)cc1Br
Reactant: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1ccc(N2CCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Br
Temperature: 100 °C
Reaction time: 3 h
Yield: 70.9 %

Procedure:
To the solution of 3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidine (1.3 g) and 2-bromo-4-fluoro-1-nitrobenzene (1.0 g) in 1-methyl-2-pyrrolidinone was added potassium carbonate (1.3 g), and the mixture was heated with stirring at 100° C. for 3 hours. The mixture was cooled to room temperature and then poured into water, which was extracted twice with ethyl acetate. The organic layer was combined, which was then washed with water and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the solvent was distilled away under the reduced pressure, and the residue was then purified by silica gel chromatography to yield 1-(3-bromo-4-nitrophenyl)-3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidine (1.56 g). 1H-NMR (CDCl3) δ: 2.53-2.66 (1H, m), 2.89-2.97 (1H, m), 3.51-3.71 (2H, m), 3.83 (1H, d), 4.16 (1H, d), 6.53 (1H, dd), 6.84 (1H, d), 7.27 (2H, br s), 7.42 (1H, t), 8.07 (1H, d).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1.C([N-]C(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:25]1([CH2:31][CH2:32][S:33][CH:34]([C:38](O)=[O:39])[C:35](O)=[O:36])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[O:11][C:35](=[O:36])[C:34]([S:33][CH2:32][CH2:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[C:38]([OH:39])[CH:10]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: O=C(O)C(SCCc1ccccc1)C(=O)O
Reactant: CC(=O)c1cc(C)cc(C)c1
Agent: CC(C)[N-]C(C)C
Agent: C[Si](C)(C)Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(C)cc(-c2cc(O)c(SCCc3ccccc3)c(=O)o2)c1

Procedure:
The title compound was prepared by Method A using 3',5'-dimethyl acetophenone (1.75 g, 11.82 mmol), lithium diisopropylamide (1.89 g, 17.73 mmol), chlorotrimethylsilane (2.25 mL, 17.73 mmol), THF (120 mL), and diethyl ester of [(2-phenylethyl)thio]-propanedioic acid (1.00 g, 3.37 mmol). m.p. 155°-157° C.; 1H NMR (400 MHz, DMSO-d6) δ 2.34 (s, 6 H), 2.77 (t, 2 H), 2.99 (t, 2 H), 6.72 (s, 1 H), 7.21 (m, 6 H), 7.41 (s, 2 H), 8.74 (d, 2 H).
Reaction SMILES: [Cl:1][CH:2]([Cl:7])[C:3](OC)=[O:4].C(N(CC)CC)C.[NH2:15][C@H:16]([CH2:30][F:31])[C@@H:17]([C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH2:28][F:29])(=[O:27])=[O:26])=[CH:21][CH:20]=1)[OH:18]>CO>[F:31][CH2:30][C@@H:16]([NH:15][C:3](=[O:4])[CH:2]([Cl:1])[Cl:7])[C@@H:17]([C:19]1[CH:20]=[CH:21][C:22]([S:25]([CH2:28][F:29])(=[O:27])=[O:26])=[CH:23][CH:24]=1)[OH:18]
Reactant: N[C@H](CF)[C@H](O)c1ccc(S(=O)(=O)CF)cc1
Reactant: COC(=O)C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(N[C@H](CF)[C@H](O)c1ccc(S(=O)(=O)CF)cc1)C(Cl)Cl
Reaction time: 8 h
Yield: 95.5 %

Procedure:
Methyl dichloroacetate (23.2 g, 5 eq ) and triethylamine (33.0 g, 10 eq) was added to a solution of 17 (8.64 g) in 50 ml of MeOH at room temperature. The reaction mixture was stirred overnight. Methanol was removed in vacuo. The residue was dissolved in 250 ml of ethyl acetate and washed with 1N HCl. The organic layer was washed with a 10% solution of sodium bicarbonate and brine and dried over sodium sulfate and concentrated to dryness. After purification via a column, 11.7 g of the desired product was obtained as a white solid.
Reaction SMILES: Br[C:2]1[C:3]2[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=2[S:5][C:6]=1[CH:7]=[O:8].[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1B(O)O.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:14]1([CH3:13])[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:2]1[C:3]2[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=2[S:5][C:6]=1[CH:7]=[O:8]
Reactant: O=Cc1sc2ccccc2c1Br
Reactant: Cc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccccc1-c1c(C=O)sc2ccccc12
Temperature: 130 °C

Procedure:
A mixture of 3-bromobenzo[b]thiophene-2-carbaldehyde (500 mg, 2.07 mmol), 2-methylphenylboronic acid (394 mg, 2.90 mmol), Pd(PPh3)4 (243 mg, 0.21 mmol), Cs2CO3 (2.02 g, 6.21 mmol) in dioxane (12 mL) and water (4 mL) was degassed with a stream of nitrogen and then was heated at 130° C. in a sealed tube using microwave irradiation for 45 min. The reaction mixture was extracted with EtOAc, then the organic layer was washed with water, followed by brine, dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-70% DCM in cyclohexane) affording the title compound (quantitative yield). LCMS: RT 4.16 min.
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[CH2:6]([S:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30](Cl)=[O:31])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>CN(C)C(=O)C>[CH2:6]([S:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([NH2:5])=[O:31])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: [NH4+]
Reactant: CCCCCCCCCCCCCCCCCCSCCCCCC(=O)Cl
Agent: CC(=O)[O-]
Solvent: CC(=O)N(C)C
Product: CCCCCCCCCCCCCCCCCCSCCCCCC(N)=O
Temperature: 25 °C

Procedure:
19.3 Grams of ammonium acetate and 100 ml of N,N-dimethylacetamide were charged in a flask equipped with a stirrer, a condenser and a calcium chloride drying tube and stirred at room temperature. Thereto was slowly added dropwise 21.0 g of 6-(octadecylthio) hexanoic acid chloride, followed by continuing the stirring for 20 hours and, then, stirring with heating at 60° C. by a water bath for 2 hours. The reaction mixture was cooled to room temperature and the precipitated crystal was filtered off under reduced pressure and washed with acetone. The precipitated crystal was filtered off under reduced pressure and washed with distilled water. The crystal was recrystallized from 2-propanol to obtain 16.0 g of the desired product as a white crystal. m.p. 105° C.
Reaction SMILES: C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C.[F:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][CH:25]=[C:24]2[CH:30]1[CH2:35][CH2:34][CH:33]([C:36]([OH:38])=O)[CH2:32][CH2:31]1.[CH3:39][O:40][C:41]1[CH:47]=[CH:46][C:44]([NH2:45])=[CH:43][C:42]=1[N:48]1[CH2:53][CH2:52][N:51]([CH3:54])[CH2:50][CH2:49]1>ClCCl>[CH3:39][O:40][C:41]1[CH:47]=[CH:46][C:44]([NH:45][C:36]([CH:33]2[CH2:32][CH2:31][CH:30]([C:24]3[C:23]4[C:27](=[CH:28][CH:29]=[C:21]([F:20])[CH:22]=4)[NH:26][CH:25]=3)[CH2:35][CH2:34]2)=[O:38])=[CH:43][C:42]=1[N:48]1[CH2:49][CH2:50][N:51]([CH3:54])[CH2:52][CH2:53]1
Reactant: COc1ccc(N)cc1N1CCN(C)CC1
Reactant: O=C(O)C1CCC(c2c[nH]c3ccc(F)cc23)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(NC(=O)C2CCC(c3c[nH]c4ccc(F)cc34)CC2)cc1N1CCN(C)CC1
Reaction time: 1 h

Procedure:
173 μl (1.2 mmol) of triethylamine and 230 mg (1.2 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride are added to a mixture of 314 mg (1.2 mmol) of 4-(5-fluoro-1H-indol-3-yl)cyclo-hexanecarboxylic acid and 265 mg (1.2 mmol) of 4-methoxy-3-(4-methylpiperazin-1-yl)aniline in 40 ml of dichloromethane. This mixture is initially stirred at 0° for one hour, then at room temperature for 12 h. The reaction mixture is concentrated, the residue is taken up in ethyl acetate, and the mixture is washed with water, 5% citric acid and sat. sodium bicarbonate solution, dried and evaporated. After column chromatographic separation, 4-(5-fluoro-1H-indol-3-yl)-cyclohexanoic acid [4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]amide is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8](SC)=[N:7][C:6]=2[CH:18]=1.C(OC(N[N:27]1[CH2:32][CH:31]2[CH2:33][CH:28]1[CH2:29][NH:30]2)=O)(C)(C)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]([N:27]3[CH2:32][CH:31]4[CH2:33][CH:28]3[CH2:29][NH:30]4)=[N:7][C:6]=2[CH:18]=1
Reactant: CSC1=Nc2cc(Cl)ccc2Nc2ccccc21
Reactant: CC(C)(C)OC(=O)NN1CC2CC1CN2
Product: Clc1ccc2c(c1)N=C(N1CC3CC1CN3)c1ccccc1N2
Yield: 42 %

Procedure:
8-Chloro-11-methylsulfanyl-5H-dibenzo[b,e][1,4]diazepine (166JO50) (50 mg, 0.11 mmol) and N-(tert-butoxycarbonylamino)-2,5-diazabicyclo[2.2.1]heptane (34 mg, 0.2 mmol) were reacted according to GP8 to give 15 mg of the title compound (166JO39-2). MS (ESI) 324 (MH+). Purity for MH+ (UV/MS) 93/100.