Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:8]1[CH:12]=[CH:11][C:10]([CH:13]=O)=[CH:9]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[O:8]1[CH:12]=[CH:11][C:10]([CH2:13][NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:9]1
Reactant: O=Cc1ccoc1
Reactant: Nc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: c1ccc(NCc2ccoc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
A mixture of aniline (1.89 g, 19.6 mmol) and 3-furaldehyde (2.50 g, 26.8 mmol) in 1,2-dichloroethane (100 mL) under argon at 5° was treated with sodium triacetoxyborohydride (5.65 g, 26.8 mmol) and acetic acid (1.5 mL). The reaction mixture was stirred at room temperature overnight, concentrated in vacuo and the residue was diluted with ethyl acetate. The combined extracts were washed with satuirated sodium bicarbonate, dried over MgSO4 and concentrated. The product was purified by flash chromatography on silical gel (Hexane/EtOAc (20:1) to yield the title compound (3.31 g, 98%). Analysis calculated for C11H11NO: C, 76.28; H, 6.40; N, 8.09. Found: C, 76.58; H, 6.46; N, 8.33.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[C:40]([F:48])[CH:39]=2)[C:35](O)=[O:36])[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][N:51]=1>C(Cl)Cl>[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([C:44]([F:46])([F:45])[F:47])=[C:40]([F:48])[CH:39]=2)[C:35]([NH:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][N:51]=2)=[O:36])[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(C(F)(F)F)c(F)c1
Reactant: Nc1ccccn1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(Nc1ccccn1)C(CC1CCCC1)c1ccc(C(F)(F)F)c(F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45.4 %

Procedure:
A solution of triphenylphosphine (312 mg, 1.19 mmol) in methylene chloride (5 mL) was cooled to 0° C. and then slowly treated with N-bromosuccinimide (212 mg, 1.19 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with 3-cyclopentyl-2-(3-fluoro-4-trifluoromethyl-phenyl)-propionic acid (prepared as in Example 70, 300 mg, 0.99 mmol). The resulting reaction mixture was stirred at 0° C. for 15 min and then allowed to warm to 25° C. where it was stirred for 30 min. The reaction mixture was then treated with 2-aminopyridine (205 mg, 2.18 mmol). The resulting reaction mixture was stirred at 25° C. for 3 d. The crude reaction mixture was then directly purified by flash chromatography (Merck Silica gel 60, 230–400 mesh, 2/1 hexanes/ethyl acetate) to afford 3-cyclopentyl-2-(3-fluoro-4-trifluoromethyl-phenyl)-N-pyridin-2-yl-propionamide (171 mg, 45%) as a pale yellow foam: mp 40–44° C. (foam to gel); EI-HRMS m/e calcd for C20H20F4N2O (M+) 380.1512, found 380.1519.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[O:9]1[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1.C(O)(=O)C.C([BH3-])#N.[Na+].[OH-].[Na+]>CO>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH:12]2[CH2:13][CH2:14][O:9][CH2:10][CH2:11]2)=[CH:4][CH:3]=1
Reactant: O=C1CCOCC1
Reactant: Nc1ccc(F)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: Fc1ccc(NC2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 739.9 %

Procedure:
A mixture of 4-fluoroaniline (1 g; 0.9 mmol) and tetrahydro-4H-pyran-4-one (0.98 g; 1.1 equiv.) in methanol (20 ml) was treated with acetic acid (0.67 ml; 1.3 equiv.) and sodium cyanoborohydride (0.73 g; 1.3 equiv.) then stirred at room temperature overnight. The reaction was cooled to 0° C., basified with 2M sodium hydroxide solution and the resultant solid collected by filtration, washed with water and dried under vacuum to give 1.3 g of the title compound. 1H NMR (DMSO-d6) 6.80 (2H, t), 6.48 (2H, dd), 5.25 (1H, d), 3.75 (2H, dt), 3.33-3.23 (3H, m), 1.78-1.71 (2H, m), 1.28-1.18 (2H, m).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][O:13][CH:14]2[C:20]3[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=3[N:18]([C:26](=[O:45])[C:27]3[CH:32]=[CH:31][C:30]([NH:33][C:34](=[O:42])[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=4[CH3:41])=[CH:29][C:28]=3[O:43][CH3:44])[CH2:17][CH2:16][CH2:15]2)(=O)=O)=CC=1.[CH3:47][N:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1.[I-].[Na+]>CN(C)C=O>[CH3:47][N:48]1[CH2:53][CH2:52][N:51]([CH2:11][CH2:12][O:13][CH:14]2[C:20]3[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=3[N:18]([C:26](=[O:45])[C:27]3[CH:32]=[CH:31][C:30]([NH:33][C:34](=[O:42])[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=4[CH3:41])=[CH:29][C:28]=3[O:43][CH3:44])[CH2:17][CH2:16][CH2:15]2)[CH2:50][CH2:49]1
Reactant: CN1CCNCC1
Reactant: COc1cc(NC(=O)c2ccccc2C)ccc1C(=O)N1CCCC(OCCOS(=O)(=O)c2ccc(C)cc2)c2cc(F)ccc21
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(NC(=O)c2ccccc2C)ccc1C(=O)N1CCCC(OCCN2CCN(C)CC2)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
In 10 ml of dimethylformamide were dispersed 0.4 g of 5-[2-(p-toluenesulfonyloxy)ethoxy]-7-fluoro-1-[2-methoxy-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine, 0.38 ml of N-methylpiperazine and 0.3 g of sodium iodide. The dispersion was stirred at room temperature for 3 days. The reaction mixture was concentrated. The residue was mixed with water and the mixture was subjected to extraction with ethyl acetate. The extract was dried over sodium carbonate and purified by silica gel column chromatography (elutant: dichloromethane/-methanol=10/1) to obtain 1.15 g of 5-[2-(4-methyl-1-piperazinyl)ethoxy]-7-fluoro-1-[2-methoxy-4-(2-methyl-benzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][C:10]=2[NH2:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>N1C=CC=CC=1>[C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][C:10]=2[NH:18][S:20]([CH3:19])(=[O:22])=[O:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)c1ccc(OCc2ccccc2)c(N)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)c1ccc(OCc2ccccc2)c(NS(C)(=O)=O)c1
Reaction time: 0.65 h
Yield: 77.6 %

Procedure:
To a mechanically stirred 16° C. pyridine (270 mL) solution of 1-[4-phenylmethoxy-3-aminophenyl]ethanone (57.4 g, 238 mmol) under N2, was added methanesulfonyl chloride (18.6 mL, 240 mmol). After 39 minutes, the completed reaction was quenched with 1.8 L H2O and the resulting suspension stirred for ~2 hours before filtration. The collected solids were washed with H2O (2×250 mL=500 mL) and partially air dried. These solids were dissolved in CHCl3 (450 mL), the aqueous phase removed and heptane (475 mL) added with stirring. The resulting fine suspension was filtered after ~15 minutes, washed with hexane and dried in vacuo at 55° C. to give 59 g (78%) of the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[O:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][N:8]=1.[CH2:17]([O:19][P:20]([O:24]CC)[O:21][CH2:22][CH3:23])[CH3:18].O>C(OCC)(=O)C>[CH3:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][C:5]2[CH:4]=[C:3]([CH:16]=[CH:15][CH:14]=2)[CH2:2][P:20](=[O:24])([O:21][CH2:22][CH3:23])[O:19][CH2:17][CH3:18])=[N:8][CH:9]=1
Reactant: CCOP(OCC)OCC
Reactant: Cc1ccc(Oc2cccc(CCl)c2)nc1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOP(=O)(Cc1cccc(Oc2ccc(C)cn2)c1)OCC
Temperature: 150 °C
Reaction time: 16 h
Yield: 59.3 %

Procedure:
2-(3-(Chloromethyl)phenoxy)-5-methylpyridine (2.0 g, 8.8 mmol) was treated neat with triethylphosphite (1.89 mL, 11 mmol) and heated to 150° C. After 16 h, the reaction mixture was cooled to room temperature and partioned between water and ethyl acetate. The organic layer was separated and the aqueous was extracted again with ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered and concentrated to give a residue. The residue was purified by silica gel chromatography (10-75%, EtOAc:CH2Cl2) to afford the title compound (1.75 g, 59% yield) as a thick oil.
Reaction SMILES: [CH3:1][P:2](Cl)([CH3:4])=[O:3].[CH2:6]([OH:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>ClCCl>[CH3:1][P:2]([CH3:4])(=[O:3])[O:13][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CP(C)(=O)Cl
Reactant: OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CP(C)(=O)OCc1ccccc1

Procedure:
To a cooled (0°) solution of dimethylphosphinyl chloride (3.4 g., 0.03 moles) in dichloromethane (50 ml.) is added dropwise (over a period of 20 minutes), with stirring, a solution of benzyl alcohol (3.2 g., 0.03 moles) and triethylamine (3.4 g., 0.03 moles) in dichloromethane (30 ml.). After stirring at 0° for one hour, and at ambient temperature overnight, the mixture is filtered and the filtrate is concentrated in vacuo. The residue (5 g., 90%) becomes semi-solid at room temperature. It is recrystallized from pentane (450 ml.) with a recovery of dimethylphosphinic acid, phenylmethyl ester, yield 3.6 g. (65%) m.p. 41°-45°. A second recrystallization of 0.5 g. from pentane (75 ml.) gives a recovery of 0.26 g. of product, m.p. 46°-47°.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:13]=[CH:12][C:11]([Mg]Br)=[CH:10][CH:9]=1.[O:16]1[CH:20]=[CH:19][N:18]=[C:17]1[CH:21]=[O:22]>C1COCC1>[O:16]1[CH:20]=[CH:19][N:18]=[C:17]1[CH:21]([C:11]1[CH:12]=[CH:13][C:8]([O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)=[CH:9][CH:10]=1)[OH:22]
Reactant: O=Cc1ncco1
Reactant: Br[Mg]c1ccc(OC2CCCCO2)cc1
Solvent: C1CCOC1
Product: OC(c1ccc(OC2CCCCO2)cc1)c1ncco1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
4-(2-Tetrahydro-3-H-pyranoxy)phenylmagnesium bromide (6.7 mmol) in THF (0.5 M) was added dropwise to a solution of oxazole-2-carbaldehyde (5.15 mmol) in THF (8 mL). After it was stirred at room temperature for 2.5 hours, the reaction was quenched with water and extracted with EtOAc (200 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was column chromatographed (silica gel, 1:2 EtOAc/hexane). Compound M11.1 was obtained. MS ESI (pos.) m/e:276 (M+H). 1H NMR (400 MHz) (DMSO-d6) δ 8.02 (s, 1H); 7.31 (d, J=8.7 Hz, 2H); 7.14 (s, 1H); 6.97-7.01 (m, 2H); 6.27 (d, J=5 Hz, 1H); 5.74 (d, J=5 Hz, 1H); 5.44 (s, 1H); 3.74 (m, 1H); 3.52 (M, 1H); 1.72-1.81 (m, 3H); 1.52-1.60(m, 4H).
Reaction SMILES: Br[C:2]1[C:3]([F:8])=[N:4][CH:5]=[CH:6][CH:7]=1.CC1(C)C(C)(C)OB([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.O.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:8][C:3]1[C:2]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: Fc1ncccc1Br
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: Fc1ncccc1-c1ccncc1

Procedure:
To a 50 mL round-bottomed flask was added 3-bromo-2-fluoropyridine (1.0135 g, 5.759 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.4577 g, 7.141 mmol), and trans-dichlorobis(triphenylphosphine)palladium(ii) (0.2138 g, 0.2879 mmol) in 1,2-dimethoxyethane. An aqueous solution of cesium carbonate (1.567 mL, 15.55 mmol) was added and the temperature was brought to 80° C. The reaction was monitored by LCMS to completion. The reaction mixture was diluted with water (10 mL) and extracted with DCM (3×10 mL). The organic extract was washed with water (1×10 mL), satd sodium chloride solution (1×10 mL), dried with magnesium sulfate, filtered, and concentrated. The solid was washed with ether and filtered to give 2-fluoro-3-(pyridin-4-yl)pyridine.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]2[N:13]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)(=[O:16])=[O:15])[CH:12]=[C:11]([CH2:24][N:25](C)[C:26](=O)OC(C)(C)C)[C:10]=2[F:34])=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].C(OCC)(=O)C.[ClH:41]>C(OCC)(=O)C.CC(O)C>[ClH:41].[F:34][C:10]1[C:11]([CH2:24][NH:25][CH3:26])=[CH:12][N:13]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)(=[O:16])=[O:15])[C:9]=1[C:8]1[C:3]([C:1]#[N:2])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(Cc1cn(S(=O)(=O)c2cccc(F)c2)c(-c2cccnc2C#N)c1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CNCc1cn(S(=O)(=O)c2cccc(F)c2)c(-c2cccnc2C#N)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 73 %

Procedure:
To a solution of tert-butyl ({5-(2-cyanopyridin-3-yl)-4-fluoro-1-[(3-fluorophenyl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (445 mg) in ethyl acetate (3 mL) and 2-propanol (2 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (6 mL), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from a mixed solvent of ethanol and water to give the title compound as a white solid (yield 281 mg, 73%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:12][C:13]3[CH:17]=[CH:16][NH:15][N:14]=3)[N:3]=2)=[CH:21][CH:20]=1
Reactant: Oc1ccc(F)cc1
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Product: Fc1ccc(Oc2nc(Nc3cc[nH]n3)cc3ccccc23)cc1

Procedure:
Similar procedure as described in example 10 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 4-fluoro-phenol to give [1-(4-fluoro-phenoxy)-isoquinolin-3-yl]-(1H-pyrazol-3-yl)-amine. LC-MS m/e 321 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11]([NH2:14])=[N:10][CH:9]=2)=[CH:4][C:3]=1[F:15].Cl[CH:17]([CH2:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[N:34]=[CH:33][CH:32]=[CH:31]2)[CH:18](N1C(=O)CCC1=O)O>C(O)(C)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]3[N:12]([C:17]([CH2:27][C:28]4[CH:29]=[C:30]5[C:35](=[CH:36][CH:37]=4)[N:34]=[CH:33][CH:32]=[CH:31]5)=[CH:18][N:14]=3)[N:13]=2)=[CH:4][C:3]=1[F:15]
Reactant: O=C1CCC(=O)N1C(O)C(Cl)Cc1ccc2ncccc2c1
Reactant: Nc1ncc(-c2ccc(Br)c(F)c2)nn1
Solvent: CC(C)O
Solvent: O
Product: Fc1cc(-c2cnc3ncc(Cc4ccc5ncccc5c4)n3n2)ccc1Br
Temperature: 105 °C
Yield: 55.8 %

Procedure:
A mixture of 6-(4-bromo-3-fluorophenyl)-1,2,4-triazin-3-amine (Step 5, 200 mg, 0.743 mmol) and 1-(2-chloro-1-hydroxy-3-quinolin-6-ylpropyl)pyrrolidine-2,5-dione (Step 7, 284 mg, 0.892 mmol) in isopropyl alcohol (7.4 mL) and water (0.11 mL) in a sealed tube was heated at 105° C. for 5 d. After the reaction mixture was cooled to ambient temperature, the precipitate was collected by filtration, washed with isopropanyl alcohol, and dried in vacuum to give the desired product (180 mg, 55%) LCMS (M+H)+: m/z=433.9/436.0.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[Br:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1>>[Br:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][N:12]2[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]2[CH:2]2[CH:3]3[CH2:4][CH:5]4[CH2:6][CH:7]([CH2:8][CH:1]2[CH2:10]4)[CH2:9]3)=[CH:21][CH:20]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1Cc1ccc(Br)cc1

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 4-bromobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a white crystalline powder.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[N:7]=[C:8]([NH:11][C:12](=[O:14])[CH3:13])[S:9][CH:10]=1)(=[O:3])[CH3:2].[Br:15]Br.C(OCC1N=C(NC(=O)C)SC=1)(=O)C.CC(O)=O>CC(O)=O>[C:1]([O:4][CH2:5][C:6]1[N:7]=[C:8]([NH:11][C:12](=[O:14])[CH3:13])[S:9][C:10]=1[Br:15])(=[O:3])[CH3:2]
Reactant: BrBr
Reactant: CC(=O)Nc1nc(COC(C)=O)cs1
Solvent: CC(=O)O
Product: CC(=O)Nc1nc(COC(C)=O)c(Br)s1
Reaction time: 0.17 h
Yield: 81.2 %

Procedure:
(2-Acetamidothiazol-4-yl)methyl acetate (9.00 g, 42 mmol) was dissolved in 30 mL AcOH. A mixture of Br2 (9.0 g, 56.7 mmol) in 20 mL AcOH was added dropwise to the (2-acetamidothiazol-4-yl)methyl acetate/AcOH mixture. The reaction was complete in 10 minutes. After 200 mL distilled water was added to the reaction mixture, the mixture was extracted with EtOAc. The organic layer was washed a few times with water and saturated sodium bicarbonate. The organic layer was then washed with brine solution and dried over sodium sulfate. Evaporation of the solvent provided the product as a yellow solid (10 g, yield=80%). LCMS (API-ES) m/z (%) 293.2 (100%, M++H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH3:9])[C:5]([NH2:10])=[CH:4][CH:3]=1.[CH2:11]([O:13][CH:14]([O:23][CH2:24][CH3:25])[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[CH:21]=O)[CH3:12]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]=[C:21]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][C:15]=3[CH:14]([O:23][CH2:24][CH3:25])[O:13][CH2:11][CH3:12])[N:8]([CH3:9])[C:6]=2[CH:7]=1
Reactant: CNc1cc(Cl)ccc1N
Reactant: CCOC(OCC)c1ccncc1C=O
Solvent: C1COCCO1
Product: CCOC(OCC)c1ccncc1-c1nc2ccc(Cl)cc2n1C
Temperature: 25 °C

Procedure:
A solution of 5-chloro-N1-methylbenzene-1,2-diamine (383 mg, 2.446 mmol) and 4-diethoxymethyl-pyridine-3-carbaldehyde (512 mg, 2.446 mmol) in 1,4-dioxane (20 mL) was heated to 75° C. overnight. The mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by silica gel flash chromatography employing heptane-ethyl acetate (1:1) to give of 6-chloro-2-(4-diethoxymethyl-pyridin-3-yl)-1-methyl-1H-benzoimidazole.
Reaction SMILES: ClC(N(C)C)=C(C)C.[S:9]1[CH:13]=[C:12]([CH2:14][C:15]([N:17]2[CH2:20][CH2:19][C:18]2([CH3:24])[C:21]([OH:23])=O)=[O:16])[C:11]2[CH:25]=[CH:26][CH:27]=[CH:28][C:10]1=2.[CH2:29]([O:31][C:32](=[O:47])[CH2:33][CH2:34][CH2:35][NH:36][CH2:37][C:38]1[CH:46]=[CH:45][C:41]2[CH:42]=[CH:43][O:44][C:40]=2[CH:39]=1)[CH3:30]>C(Cl)Cl>[CH2:29]([O:31][C:32](=[O:47])[CH2:33][CH2:34][CH2:35][N:36]([C:21]([C:18]1([CH3:24])[CH2:19][CH2:20][N:17]1[C:15](=[O:16])[CH2:14][C:12]1[C:11]2[CH:25]=[CH:26][CH:27]=[CH:28][C:10]=2[S:9][CH:13]=1)=[O:23])[CH2:37][C:38]1[CH:46]=[CH:45][C:41]2[CH:42]=[CH:43][O:44][C:40]=2[CH:39]=1)[CH3:30]
Reactant: CC1(C(=O)O)CCN1C(=O)Cc1csc2ccccc12
Reactant: CCOC(=O)CCCNCc1ccc2ccoc2c1
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Product: CCOC(=O)CCCN(Cc1ccc2ccoc2c1)C(=O)C1(C)CCN1C(=O)Cc1csc2ccccc12
Temperature: 20 °C
Reaction time: 1 h

Procedure:
To a solution of 1-chloro-N,N,2-trimethylpropenylamine (2 eq.) in DCM under nitrogen was added 1-(2-benzo[b]thiophen-3-yl-acetyl)-2-methyl-azetidine-2-carboxylic acid, Intermediate 121 (1 eq.). The solution was stirred at 20° C. for 1 h, then added to a solution of 4-[(Benzofuran-6-ylmethyl)-amino]-butyric acid ethyl ester, Intermediate 82 (1.2 eq.) in DCM at 0° C. TEA (2 eq.) was then added and the mixture was stirred at 0° C. for 3 h. The crude was diluted with DCM, washed twice with a saturated aqueous solution of NaHCO3, twice with aqueous HCl (0.5N), twice with water, dried over MgSO4, filtered, concentrated under reduced pressure and purified by chromatography on silica gel (elution with heptane/EtOAc 25/75 to 10/90) to afford 4-{[1-(2-benzo[b]thiophen-3-yl-acetyl)-2-methyl-azetidine-2-carbonyl]-benzofuran-6-ylmethyl-amino}-butyric acid ethyl ester.
Reaction SMILES: Cl[C:2]1[C:15]2[C:14](=[O:16])[CH:13]=[C:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[O:11][C:10]=2[C:9]([CH2:22][CH2:23][CH3:24])=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][CH2:7]2.[F-:25].[K+].O>CN(C=O)C>[F:25][C:2]1[C:15]2[C:14](=[O:16])[CH:13]=[C:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[O:11][C:10]=2[C:9]([CH2:22][CH2:23][CH3:24])=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][CH2:7]2
Reactant: CCCc1c2c(c(Cl)c3c(=O)cc(C(=O)OCC)oc13)CCCC2
Reactant: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1c2c(c(F)c3c(=O)cc(C(=O)OCC)oc13)CCCC2

Procedure:
A solution of ethyl 5-chloro-6,7,8,9-tetrahydro-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carboxylate (9 g) and desiccated potassium fluoride (2.32 g) in DMF (50 ml) was heated at 160° for 3.5 hours. After cooling, the reaction mixture was poured into water (250 ml) and the precipitate filtered off, washed with water and dried. Recrystallisation from cyclohexane gave the title compound as a pale-yellow solid, mp 126°-9°.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[C:7]([O:11][C:12]([NH:14][C@H:15]([C:28]([OH:30])=[O:29])[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]([CH:26]=[O:27])[CH:18]=1)=[O:13])([CH3:10])([CH3:9])[CH3:8].IC>CN(C=O)C>[C:7]([O:11][C:12]([NH:14][C@H:15]([C:28]([O:30][CH3:1])=[O:29])[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]([CH:26]=[O:27])[CH:18]=1)=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cn(C=O)c2ccccc12)C(=O)O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1cn(C=O)c2ccccc12)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.4 %

Procedure:
To DMF (50 mL) suspension of potassium carbonate (6.2 g) was added dropwise DMF (70 mL) solution of Nα-tert-butoxycarbonyl-1-formyl-L-tryptophan (10.0 g) at 0° C., and the mixture was stirred for 1 hour at room temperature. Next, DMF (25 mL) solution of iodomethane (2.8 mL) was added dropwise at 0° C., and the mixture was stirred for 20 hours at room temperature. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and thereafter the residue obtained by distilling off the solvent under a reduced pressure was purified with silica gel column chromatography (BZ-127ZH, n-hexane:ethyl acetate=7:3), to give the captioned compound (9.0 g, 86%) as crystals.
Reaction SMILES: [CH2:1]([S:8]([C:11]1[CH:16]=[C:15]([N+:17]([O-])=O)[CH:14]=[C:13]([NH2:20])[C:12]=1[CH2:21][CH2:22][NH2:23])(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)C.O.[Ni]>[CH2:1]([S:8]([C:11]1[CH:16]=[C:15]([NH2:17])[CH:14]=[C:13]([NH2:20])[C:12]=1[CH2:21][CH2:22][NH2:23])(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCc1c(N)cc([N+](=O)[O-])cc1S(=O)(=O)Cc1ccccc1
Reactant: [H][H]
Agent: [Ni]
Solvent: O
Solvent: CCO
Product: NCCc1c(N)cc(N)cc1S(=O)(=O)Cc1ccccc1

Procedure:
20.0 g of 2-(2-aminoethyl)-amino-5-nitrophenyl benzyl sulphone are suspended in 100 ml of ethanol and 100 ml of water. In an autoclave 1 g of Raney nickel is added, 40 bar of hydrogen are injected, and the temperature is raised to 60° C. until after a further injection of hydrogen there is no further consumption. After the reduction has ended the resultant solution is clarified hot from Raney nickel, the nickel residue is washed with 40 ml of hot water, and the resulting solution is reacted as per Example 16.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[N:9]1([CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=2)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>O.C(O)(=O)C>[N:9]1([CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:2]3[CH:3]=[C:4]([NH2:8])[N:5]=[CH:6][N:7]=3)=[CH:20][CH:19]=2)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: Nc1cc(Cl)ncn1
Reactant: Nc1ccc(OCCN2CCOCC2)cc1
Solvent: CC(=O)O
Solvent: O
Product: Nc1cc(Nc2ccc(OCCN3CCOCC3)cc2)ncn1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A mixture of 6-chloro-pyrimidin-4-ylamine (194 mg, 1.5 mmol, 1.3 equiv), 4-(2-morpholin-4-yl-ethoxy)-phenylamine (256 mg, 1.15 mmol) in H2O (1 mL) and glacial acetic acid (5 mL) is stirred for 16 h at 100° C. After solvent evaporation, the residue is taken up in DCM and diluted with a saturated aqueous solution of NaHCO3. The aqueous layer is separated and extracted with DCM. The organic phase is washed with brine, dried (Na2SO4), filtered and concentrated. The residue is triturated in EtOAc to provide the title compound as a grey solid: ESI-MS: 316.2 [MH]+; tR=1.00 min (purity: 95%, system 1); TLC: Rf=0.22 (DCM/MeOH+1% NH3aq, 93:7).