Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH:20](O)[CH3:21])=[CH:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].S(Cl)([Cl:25])=O>C(Cl)Cl>[C:1]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH:20]([Cl:25])[CH3:21])=[CH:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: O=S(Cl)Cl
Reactant: CC(O)c1cn(C(=O)OCc2ccccc2)c2ccccc12
Solvent: ClCCl
Product: CC(Cl)c1cn(C(=O)OCc2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 1-(N-carbobenzoxy indol-3-yl)ethanol (1.02 g, 3.45 mmol) in CH2Cl2 (20 ml) at -78° C. under nitrogen was added thionyl chloride (0.63 ml, 8.62 mmol). After warming to room temperature and stirring for 2 hrs, the mixture was evaporated to a brown oil. This was dissolved in CHCl3, treated with activated carbon and filtered through a pad of Super Cel; the filtrate was evaporated to give 1.03 g (95%) of light brown oil: NMR (CDCl3) δ 1.90 (3, d, CH3), 5.26 (1, q, CHCl), 5.33 (2, s, PhCH2), 7.20-7.85 (9, m, aromatic H's) 8.04 ppm (1, m, H-7). This material was relatively unstable, and therefore was used immediately without further purification (e.g., as in Example 13).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[O:11])O[C:8](=[O:12])[NH:7][C:6]=2[CH:13]=1.[C:14]([CH2:16]C(OCC)=O)#[N:15].C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[CH:13]=[C:6]2[C:5]([C:10]([OH:11])=[C:16]([C:14]#[N:15])[C:8](=[O:12])[NH:7]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC#N
Reactant: O=c1[nH]c2cc(F)ccc2c(=O)o1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#Cc1c(O)c2ccc(F)cc2[nH]c1=O

Procedure:
A mixture of 7-fluoro-1H-benzo[d][1,3]oxazine-2,4-dione (515 mg, 2.8 mmol) (commercially available through AstaTech™, Inc.), ethyl 2-cyanoacetate (303 μL, 2.8 mmol), and triethylamine (793 μL, 5.7 mmol) in DMF (1.4 mL) was stirred at 120° C. for 6 h. The reaction mixture was then concentrated. Upon addition of 1M HCl a precipitate formed, which was isolated by filtration and dried under vacuum, affording 7-fluoro-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbonitrile. Mass Spectrum (ESI) m/e=205 (M+1).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[C:12]1([C@@H:18]([NH2:20])[CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[C:12]1([C@@H:18]([NH:20][CH:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)[CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: C[C@H](N)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: C[C@H](NC1CCC2(CC1)OCCO2)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
1,4-Dioxaspiro[4.5]decan-8-one (10 g, 64.03 mmol) was dissolved in dry dichloroethane (300 mL) under an atmosphere of nitrogen. (1S)-1-phenylethylamine (8.96 mL, 70.43 mmol) was added neat at room temperature followed by sodium triacetoxyborohydride (20.36 g, 96.04 mmol) neat in small portions. The reaction was stirred at room temperature overnight. The reaction was quenched by the addition of distilled water (200 mL). The phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over sodium sulfate. The filtrate was concentrated under reduced pressure. A yellow oil was obtained of satisfactory purity based on (11.2 g, 67% yield). M+1: 262.
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[C:7]1([C:13]2[C:24]([CH2:25]O)=[C:16]3[C:17]4[CH2:23][CH2:22][O:21][C:18]=4[CH:19]=[CH:20][N:15]3[N:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>ClCCl.C(=O)([O-])O.[Na+]>[C:7]1([C:13]2[C:24]([CH2:25][C:5]#[N:6])=[C:16]3[C:17]4[CH2:23][CH2:22][O:21][C:18]=4[CH:19]=[CH:20][N:15]3[N:14]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: OCc1c(-c2ccccc2)nn2ccc3c(c12)CCO3
Reactant: C[Si](C)(C)C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: N#CCc1c(-c2ccccc2)nn2ccc3c(c12)CCO3
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.1 %

Procedure:
To a solution of boron trifluoride diethyl ether complex (186 μL, 1.47 mmol) and trimethylsilyl cyanide (260 μL, 1.95 mmol) in dichloromethane (5 mL) was added a solution of (2-phenyl-8,9-dihydrofuro[3,2-c]pyrazolo[1,5-a]pyridin-1-yl)methanol (130 mg, 0.488 mmol) in dichloromethane (10 mL) under ice-cooling and an argon atmosphere, and the mixture was stirred at room temperature for 1 hr. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90→40/60) to give the title compound (117 mg, yield 87%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]2[CH:14]=[C:15]([C:18]([O:20]CC)=[O:19])[C:16]([OH:17])=[C:10]2[C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C(O)(C(F)(F)F)=O>C(O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]2[CH:14]=[C:15]([C:18]([OH:20])=[O:19])[C:16]([OH:17])=[C:10]2[C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cn2c(c1O)C(=O)N(Cc1ccccc1)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cn2c(c1O)C(=O)N(Cc1ccccc1)CC2
Temperature: 100 °C

Procedure:
A mixture of ethyl 2-benzyl-8-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolo-[1,2-α]pyrazine-7-carboxylate (0.30 g; see Example 1) and aqueous sodium hydroxide (1 M, 2 mL) in ethanol (20 mL) was heated in a sealed tube at 100° C. overnight. The product mixture was acidified with addition of TFA and concentrated under vacuum. The residue was subjected to HPLC purification on C-18 stationary phase eluted with water/acetonitrile/TFA mobile phase. Collection and lyophilization of appropriate fractions provided the title compound.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:12]([CH3:45])=[N:13][C:14]2[N:15]([N:29]=[C:30]([C:32]3[CH:33]=[C:34]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=4[CH3:44])[CH:35]=[CH:36][CH:37]=3)[CH:31]=2)[C:16]=1[C:17]1[C:18]([CH3:28])=[C:19]2[C:24](=[C:25]([F:27])[CH:26]=1)[O:23][CH2:22][CH2:21][CH2:20]2)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].C(O)(=O)C>O1CCOCC1.O>[C:1]([O:5][C@@H:6]([C:11]1[C:12]([CH3:45])=[N:13][C:14]2[N:15]([N:29]=[C:30]([C:32]3[CH:33]=[C:34]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=4[CH3:44])[CH:35]=[CH:36][CH:37]=3)[CH:31]=2)[C:16]=1[C:17]1[C:18]([CH3:28])=[C:19]2[C:24](=[C:25]([F:27])[CH:26]=1)[O:23][CH2:22][CH2:21][CH2:20]2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(-c3cccc(-c4ccccc4C)c3)nn2c1-c1cc(F)c2c(c1C)CCCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccccc1-c1cccc(-c2cc3nc(C)c([C@H](OC(C)(C)C)C(=O)O)c(-c4cc(F)c5c(c4C)CCCO5)n3n2)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 67.4 %

Procedure:
To a solution of (2S)-methyl 2-(tert-butoxy)-2-(7-(8-fluoro-5-methylchroman-6-yl)-5-methyl-2-(2′-methyl-[1,1′-biphenyl]-3-yl)pyrazolo[1,5-a]pyrimidin-6-yl)acetate (1.28 g, 2.1 mmol) in dioxane (12 mL) was added 1 N NaOH aqueous solution (9 mL, 9 mmol). The reaction mixture was stirred at 50° C. for 2 h. The reaction mixture was diluted with water (50 ml) and neutralized with acetic acid. The resulted mixture was extracted with ethyl acetate (3×100 ml). The organic phase was combined and dried by sodium sulfate. The solvents were evaporated and the crude product was purified by preparative HPLC to afford (840 mg, 66%) of the title compound. Preparative HPLC condition: Waters Sunfire OBD C18 30×100 mm 5 u, 15 to 60% B over 18 minute gradient, 2 minute hold time, A=5% acetonitrile 95% water 10 mM Ammonium Acetate, B=95% acetonitrile 5% water 10 mM Ammonium Acetate. Flow rate: 40 ml/min. 1H NMR (400 MHz, DMSO-d6) δ 7.86-7.75 (m, 2H), 7.50 (t, J=7.7 Hz, 1H), 7.40-7.22 (m, 5H), 7.18 (s, 1H), 7.09 (d, J=11.0 Hz, 1H), 4.83 (s, 1H), 4.34-4.22 (m, 2H), 2.82-2.66 (m, 5H), 2.24 (s, 3H), 2.13-2.02 (m, 2H), 1.83 (s, 3H), 1.09 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[OH-].[K+].Br[CH2:19][C:20]1([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[O:24][CH2:23][CH2:22][O:21]1.O>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:19][C:20]3([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=4)[O:21][CH2:22][CH2:23][O:24]3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Reactant: Clc1ccc(C2(CBr)OCCO2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: CN1CCc2c(c3cc(Cl)ccc3n2CC2(c3ccc(Cl)cc3)OCCO2)C1
Temperature: 100 °C
Reaction time: 0.08 h

Procedure:
8-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1 g, 4.4 mmol) was dissolved in 10 mL of NMP. KOH (1.77 g, 31.78 mmol) was added at RT under nitrogen atmosphere and the reaction mixture was stirred for 5 min. 2-Bromomethyl-2-(4-chlorophenyl)-1,3-dioxolane (1.68 mg, 6.81 mmol) was added and the reaction mixture was heated at 100° C. for 3 h. Water was added and the product was extracted with EtOAc. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-2% MeOH:DCM.
Reaction SMILES: [S:1]([Cl:5])(Cl)(=[O:3])=[O:2].[C:6]([N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)(=[O:8])[CH3:7].C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:6]([N:9]1[CH2:14][CH2:13][N:12]([S:1]([Cl:5])(=[O:3])=[O:2])[CH2:11][CH2:10]1)(=[O:8])[CH3:7]
Reactant: O=S(=O)(Cl)Cl
Reactant: CC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)N1CCN(S(=O)(=O)Cl)CC1
Reaction time: 6 h

Procedure:
A solution of sulfuryl chloride (3.55 ml) in chloroform (45 ml) was added a solution of 1-acetylpiperazine (5.66 mg) and triethylamine (6.16 ml) in chloroform (15 ml) dropwise under cooling on an ice-water bath. After stirring for 6 hours, a precipitate was collected by filtration. After drying over sodium hydroxide, 1-acetylpiperazine-4-sulfonyl chloride (2.43 g) was obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[CH:5][CH:4]=1)#[N:2].CCN=C=NCCCN(C)C.C1C=C2N=NN(O)C2=CC=1.O.CCN(C(C)C)C(C)C.[CH3:55][O:56][CH2:57][CH2:58][CH2:59][NH2:60].Cl>CN(C=O)C.O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:60][CH2:59][CH2:58][CH2:57][O:56][CH3:55])=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[CH:5][CH:4]=1)#[N:2]
Reactant: COCCCN
Reactant: N#Cc1ccc(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COCCCNC(=O)c1ccc(-n2ncc(-c3ccc(C#N)cc3)c2O)nc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 86.2 %

Procedure:
Combined 6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid (4.00 g, 13.06 mmol), EDCI (3.76 g, 19.59 mmol), and HOBT hydrate (3.00 g, 19.59 mmol) in DMF (39.6 mL) and treated with Hunig's base (6.82 mL, 39.2 mmol). Then 3-methoxypropan-1-amine (2.005 mL, 19.59 mmol) was added and the reaction mixture was stirred at ambient temperature for 24 h. The reaction mixture was then diluted with water (200 mL) and acidified with HCl (aq., 1N) until pH=5 and stirred to give a fine suspension. The solid was collected by filtration, suspended in MeOH (150 mL), and heated to reflux for 8 hours, the slowly cooled to ambient temperature. The solid was collected by filtration and dried in vacuum to give the title compound (4.25 g, 11.26 mmol, 86% yield) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.78 (quin, J=6.63 Hz, 2H) 3.30-3.37 (m, 2H) 3.40 (t, J=6.32 Hz, 2H) 7.79 (d, J=8.34 Hz, 2H) 8.14 (d, J=6.57 Hz, 2H) 8.31-8.69 (m, 3H) 8.71 (t, J=5.31 Hz, 1H) 8.91 (s, 1H) 13.54 (br. s., 1H). MS [M+H]378.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH2:3][CH:4]([CH2:7][C:8]([F:11])([F:10])[F:9])[CH:5]=O.[C:14]1(C)[C:15]([S@@:20]([NH2:22])=[O:21])=[CH:16][CH:17]=[CH:18][CH:19]=1.O.[CH3:25]COCC>[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[CH3:25][C:18]1[CH:19]=[CH:14][C:15]([S:20](/[N:22]=[CH:5]\[CH:4]([CH2:7][C:8]([F:11])([F:10])[F:9])[CH2:3][C:2]([F:13])([F:12])[F:1])=[O:21])=[CH:16][CH:17]=1
Reactant: O=CC(CC(F)(F)F)CC(F)(F)F
Reactant: CCOCC
Reactant: Cc1ccccc1[S@@](N)=O
Agent: [Ti+4]
Agent: CC[O-]
Solvent: O
Product: Cc1ccc(S(=O)/N=C\C(CC(F)(F)F)CC(F)(F)F)cc1
Temperature: 0 °C
Yield: 41.2 %

Procedure:
To the crude organic extract of 4,4,4-trifluoro-2-(2,2,2-trifluoroethyl)butyraldehyde (prepared as in Example 26, part F, 0.6 g, 2.88 mmol) in ether (5 mL) was added titanium (IV) ethoxide (2.63 g, 11.54 mmol) followed by (S)-(+)-toluene sulfinamide (0.537 g, 3.46 mmol) and the solution was heated to reflux for 5 h. The mixture was then cooled to 0° C. and water (35 mL) was added to precipitate titanium salts. The suspension was filtered through a pad of the Celite® reagent and the filter cake washed with CH2Cl2. The layers of the filtrate were separated and the aqueous layer was extracted with CH2Cl2. The combined organic extracts were dried over MgSO4, filtered, and concentrated to obtain a crude yellow oil (1.05 g). The crude product was purified by the Biotage Flash™ 40 chromatography system, eluent: 1:9 EtOAc-hexanes, to afford 4-methyl-N-[(1Z)-4,4,4-trifluoro-2-(2,2,2-trifluoroethyl)butylidene]benzenesulfinamide as a yellow oil (0.41 g, 41.2%). Mass Spectrum (−ESI): 344 (M−H)−.
Reaction SMILES: O[CH:2]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)[CH2:3][CH3:4].P(Br)(Br)[Br:21]>C(Cl)(Cl)Cl.O>[Br:21][CH:2]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)[CH2:3][CH3:4]
Reactant: BrP(Br)Br
Reactant: CCC(O)c1ccc(-c2ccc(C(N)=O)cc2)cn1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCC(Br)c1ccc(-c2ccc(C(N)=O)cc2)cn1
Temperature: 25 °C
Yield: 96.4 %

Procedure:
To a solution of 4-(6-(1-hydroxypropyl)pyridin-3-yl)benzamide (0.1 g, 0.39 mmol) in chloroform (15 mL) was added PBr3 (0.316 g, 1.17 mmol) at 0-5° C. The solution was maintained at the same temperature for 1 h, was slowly warmed to rt and maintained at rt for another 2 h. The contents were diluted with water (75 mL) and chloroform (100 mL), the layers separated, the organic layer was washed with bicarbonate solution (2×30 mL), and the organic layer was dried over sodium sulphate and distilled off to get the crude product. The non-polar impurity was removed by pentane washings (2×7 mL) to provide 4-(6-(1-bromopropyl)pyridin-3-yl)benzamide (0.12 g, crude). LC-MS m/z calcd for [M+H]+ 321.03. found 321.0.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[C:5]([NH:7][C:8]1[CH:25]=[CH:24][C:11]([C:12]([N:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)=[O:13])=[CH:10][CH:9]=1)=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH2:35](I)[CH3:36]>CC(C)=O>[CH2:35]([O:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[C:5]([NH:7][C:8]1[CH:25]=[CH:24][C:11]([C:12]([N:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)=[O:13])=[CH:10][CH:9]=1)=[O:6])[CH3:36]
Reactant: CCI
Reactant: O=C(Nc1ccc(C(=O)N2CCCc3ccccc32)cc1)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1cccc(C(=O)Nc2ccc(C(=O)N3CCCc4ccccc43)cc2)c1
Yield: 83.7 %

Procedure:
To a solution of 1-[4-(3-hydroxybenzoylamino)benzoyl]-1,2,3,4-tetrahydroquinoline (0.4 g) in acetone (5 ml) are added potassium carbonate (0.22 g) and ethyl iodide (0.34 g), and the mixture is refluxed for 5 hours. Then, acetone is distilled off under reduced pressure and water is added to the residue. The precipitated crystal is collected by filtration, and recrystallized from methanol to give 1-[4-(3-ethoxybenzoylamino)benzoyl]-1,2,3,4-tetrahydroquinoline (0.36 g) as white powder, m.p. 170.5-171.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4](=O)[CH2:5]Br.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([NH:26][C:27]([NH2:29])=[S:28])[CH:17]=[CH:18][C:19]=1[N:20]1[CH:24]=[C:23]([CH3:25])[N:22]=[CH:21]1>C(Cl)Cl.C(OCC)C.C(O)C>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]1[N:29]=[C:27]([NH:26][C:16]2[CH:17]=[CH:18][C:19]([N:20]3[CH:24]=[C:23]([CH3:25])[N:22]=[CH:21]3)=[C:14]([O:13][CH3:12])[CH:15]=2)[S:28][CH:5]=1
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Reactant: O=C(CBr)c1ccccc1Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCO
Product: COc1cc(Nc2nc(-c3ccccc3Cl)cs2)ccc1-n1cnc(C)c1
Yield: 99.1 %

Procedure:
The title compound was prepared in analogy to example 1 step e) from 77 mg (0.33 mmol) 2-chlorophenacylbromide and 79 mg (0.3 mmol) [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea. The solvent was evaporated under reduced pressure and the crude reaction was stirred with methylene chloride/diethyl ether/ethanol for 15 minutes at room temperature. The product was filtered off and dried to yield 118 mg (100%) [4-(2-chloro-phenyl)-thiazol-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine as a light yellow solid. MS ISP (m/e): 397.1/399.2 (100/44) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=10.71 (s, 1H), 9.27 (s, 1H), 7.98 (s, 1H), 7.93 (d, 1H), 7.67 (s, 1H), 7.56 (d, 1H), 7.51-7.38 (m, 4H), 7.27 (d, 1H), 3.88 (s, 3H), 2.34 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20]Br)=[CH:13][C:10]=3[S:11][CH:12]=2)=[CH:4][CH:3]=1.[NH:22]([CH2:26][CH2:27][OH:28])[CH2:23][CH2:24][OH:25]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][N:22]([CH2:26][CH2:27][OH:28])[CH2:23][CH2:24][OH:25])=[CH:13][C:10]=3[S:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: BrCCCOc1ccc2c(-c3ccc(Br)cc3)csc2c1
Reactant: OCCNCCO
Product: OCCN(CCO)CCCOc1ccc2c(-c3ccc(Br)cc3)csc2c1

Procedure:
In analogy to example 3.1, 3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[b]thiophene and diethanolamine were converted to yield 2-[{3-[3-(4-Bromo-phenyl)-benzo[b]thiophen-6-yloxy]-propyl}-(2-hydroxy-ethyl)-amino]-ethanol as light yellow oil, MS: 450 (MH+, 1Br).
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.[Cl:16][C:17]1[CH:18]=[C:19]([CH2:23][N:24]2[CH:28]=[CH:27][N:26]=[C:25]2[CH3:29])[N:20]=[N:21][CH:22]=1>>[ClH:16].[C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:17]2[CH:18]=[C:19]([CH2:23][N:24]3[CH:28]=[CH:27][N:26]=[C:25]3[CH3:29])[N:20]=[N:21][CH:22]=2)[CH:2]=1
Reactant: Cc1nccn1Cc1cc(Cl)cnn1
Reactant: OB(O)c1cccc(-c2ccccc2)c1
Product: Cc1nccn1Cc1cc(-c2cccc(-c3ccccc3)c2)cnn1
Product: Cl

Procedure:
The title compound, MS: m/e=327.3 (M+H+), was prepared from 3-biphenylboronic acid and 5-chloro-3-(2-methyl-imidazol-1-ylmethyl)-pyridazine.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][CH:10]=[CH:9]2>S(=O)(=O)(O)O>[Cl:5][C:6]1[C:7]([N+:1]([O-:4])=[O:2])=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][CH:10]=[CH:9]2
Reactant: O=[N+]([O-])O
Reactant: Clc1ccc2ncccc2c1
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1c(Cl)ccc2ncccc12
Temperature: 0 °C
Reaction time: 8 h

Procedure:
HNO3 (90%, 7 mL) was added to 6-chloro-quinoline (4.45 g) in concentrated sulfuric acid (21 mL) at 0° C. The mixture was stirred at 0° C. for 1 h and at room temperature overnight. The reaction mixture was poured into ice, and the solid product (24.1) was collected by filtration, washed with water and dried. MS ESI (pos.) m/z: 209.0 (M+H).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB(/[CH:20]=[CH:21]/[CH2:22][O:23][CH3:24])O1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.O>[CH3:24][O:23][CH2:22]/[CH:21]=[CH:20]/[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: COC/C=C/B1OC(C)(C)C(C)(C)O1
Reactant: O=C1CCc2ccc(Br)cc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC/C=C/c1ccc2c(c1)C(=O)CC2
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 6-bromoindan-1-one (1 eq.) and 4,4,5,5-tetramethyl-2-[(1E)-3-(methyloxy)-1-propen-1-yl]-1,3,2-dioxaborolane (1.3 eq.) in DMF (0.1 M) was added trans-bis(triphenylphosphine) palladium(II) bromide (0.05 eq.). The vessel was repeatedly evacuated and back-filled with nitrogen. Finally, 2 M aq. Na2CO3 (3 eq.) was added and the resulting mixture was stirred at 100° C. for 1 h. The now black suspension was cooled to RT, diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product by way of flash chromatography (SiO2, Hex→1:1 (v/v) Hex:EtOAc) afforded the title compound as a beige solid.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][N:4]=1.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[C:22]1[NH:23][C:24]2[CH:30]=[C:29]([C:31]([NH:33][NH2:34])=O)[CH:28]=[CH:27][C:25]=2[N:26]=1.CCOP(O)N(C(C)C)C(C)C.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1.CCOC(C)=O>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[C:22]1[NH:23][C:24]2[CH:30]=[C:29]([C:31]3[O:8][C:7]([C:6]4[CH:5]=[N:4][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:11][CH:10]=4)=[N:34][N:33]=3)[CH:28]=[CH:27][C:25]=2[N:26]=1
Reactant: NNC(=O)c1ccc2nc(-c3c(Cl)cccc3Cl)[nH]c2c1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)nc1
Agent: CCOP(O)N(C(C)C)C(C)C
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: FC(F)(F)c1ccc(-c2nnc(-c3ccc4nc(-c5c(Cl)cccc5Cl)[nH]c4c3)o2)cn1
Temperature: 150 °C
Reaction time: 17 h
Yield: 57.8 %

Procedure:
6-Trifluoromethyl-nicotinoyl chloride (119 uL, 0.817 mmol) was added to a solution of 2-(2,6-dichloro-phenyl)-3H-benzoimidazole-5-carboxylic acid hydrazide (250 mg, 0.778 mmol) in THF (10 mL) and EDIPA (149 uL, 0.856 mmol). The reaction was stirred for 17 hr. The reaction was diluted with EtOAc (75 mL) and extracted with water (20 mL). The organic phase was dried over Na2SO4 and concentrated. The concentrate was taken up in DMF (3 mL) and transferred to a microwave vial charged with Burgess reagent (555 mg, 2.33 mmol). The reaction was heated to 150° C. for 15 min by microwave irradiation. The reaction was diluted with EtOAc (75 mL) and extracted with water (15 mL). The organic phase was dried over Na2SO4 and concentrated. The concentrate was purified by silica gel column chromatography (15-40% ACN/DCM) and the resulting colorless film triturated with MeOH/DCM to afford the title compound (214 mg): 1H NMR (400 MHz, DMSO-d6) ppm 7.64-7.68 (m, 1 H) 7.71 (s, 1 H) 7.73 (d, J=2.02 Hz, 1 H) 7.83 (tautomer, d, J=8.46 Hz, 1 H) 7.97 (tautomer, d, J=8.59 Hz, 1 H) 8.12 (dd, J=14.15, 8.72 Hz, 1 H) 8.21 (d, J=8.34 Hz, 1 H) 8.41 (tautomer, s, 1 H) 8.60 (tautomer, s, 1 H) 8.85 (d, J=8.34 Hz, 1 H) 9.54 (s, 1 H) 13.41 (d, J=14.15 Hz, 1H); LCMS tR=1.53 min, MS (m/z) 476.7.