Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][CH2:5][CH2:6][C:7](=O)[CH2:8]Br.[C:12]([NH:19][C:20]([NH2:22])=[NH:21])([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].N[C@H](C(O)=O)CC1C=C2C(C=CC=C2)=CC=1>CN(C=O)C>[C:15]([O:14][C:12]([N:19]1[CH:8]=[C:7]([CH2:6][CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:11])[N:21]=[C:20]1[NH2:22])=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: COC(=O)CCCC(=O)CBr
Reactant: CC(C)(C)OC(=O)NC(=N)N
Agent: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Solvent: CN(C)C=O
Product: COC(=O)CCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Temperature: 25 °C
Yield: 64.8 %

Procedure:
6-bromo-5-oxo-hexanoic acid methyl ester (2.30 g, 10.3 mmol), Boc-guanidine (4.92 g, 30.9 mmol),32 and Nal (3.07 g, 20.6 mmol) were dissolved in DMF (30 mL) and allowed to stir at room temperature. After 24 h the DMF was removed under reduced pressure and the residue was taken up in ethyl acetate (100 mL) and washed with water (3×50 mL) and brine (50 mL) before being dried (Na2SO4), filtered and evaporated to dryness. The resulting oil was purified by flash column chromatography (50-100% EtOAc/Hexanes) to obtain a yellow oil. Trituration of the viscous oil with cold hexanes (20 mL) produced a precipitate, which upon filtration yielded 18 (1.89 g, 65%) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 6.53 (s, 1H), 5.6 (br s, 2H), 2.41 (t, 2H, J=7.2 Hz), 2.37 (t, 2H, J=7.2 Hz), 1.93 (quint., 2H, J=7.2 Hz), 1.58 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 174.09, 150.11, 149.61, 138.39, 107.15, 84.81, 51.56, 33.65, 28.18, 27.68, 23.82; HRMS (ESI) calcd for C13H22N3O4 (MH)+284.1604, found 284.1606.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17]([C:19]3[C:20](=[O:32])[N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:22]([CH3:25])[C:23]=3[CH3:24])=[O:18])=[N:14][CH:15]=2)[CH:5]=[CH:4][N:3]=1.CCN(CC)CC.[C:40](Cl)(=[O:42])[CH3:41].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.C1COCC1>[C:40]([NH:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17]([C:19]3[C:20](=[O:32])[N:21]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:22]([CH3:25])[C:23]=3[CH3:24])=[O:18])=[N:14][CH:15]=2)[CH:5]=[CH:4][N:3]=1)(=[O:42])[CH3:41]
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc(N)c3Cl)cn2)c(=O)n(-c2ccccc2)n1C
Reactant: CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nccc(Oc2ccc(NC(=O)c3c(C)n(C)n(-c4ccccc4)c3=O)nc2)c1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 23.4 %

Procedure:
To a solution of N-(5-((2-amino-3-chloropyridin-4-yl)oxy)pyridin-2-yl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (60 mg, 0.13 mmol), and Et3N (26.3 mg, 0.26 mmol) in CH2Cl2 (1 mL) and THF (2 mL) was added acetyl chloride (20 mg, 0.26 mmol). The reaction was stirred at rt for 3 hours, then treated with saturated Na2CO3 aqueous solution (2 mL). The resulted mixture was continued to stir at rt for 5 minutes, then concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/CH3OH (v/v)=50/1) to give the title compound as a light beige solid (15 mg, 22.7%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][N:10]3[C:16](=[O:18])[CH:17]=2)=[N:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br:29]N1C(=O)CCC1=O>O1CCCC1.[Cl-].[NH4+].C(OCC)(=O)C>[Br:29][CH:15]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]2[C:16](=[O:18])[CH:17]=[C:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][N:3]=3)[N:8]=[C:9]12
Reactant: O=C1CCC(=O)N1Br
Reactant: O=c1cc(-c2ccncn2)nc2n1CCCCC2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=c1cc(-c2ccncn2)nc2n1CCCCC2Br
Temperature: -50 °C
Reaction time: 0.17 h
Yield: 30.9 %

Procedure:
To a solution of 1.00 g (4.13 mmol) of 2-pyrimidin-4-yl-7,8,9,10-tetrahydro-6H-pyrimido[1,2-α]azepin-4-one (step 4.1 of example 4) in 35 mL of dry tetrahydrofuran at −50° C., was added 8.25 mL (8.25 mmol) of lithium bis(trimethylsilyl)amide (1M in tetrahydrofuran). The resulting mixture was stirred at −50° C. for 10 min. 0.808 g (4.54 mmol) of N-bromo-succinimide dissolved in 5 mL of tetrahydrofuran was added at −50° C. the resulting mixture was stirred for 1 hours. The mixture was dissolved in a saturated solution of ammonium chloride and ethyl acetate. The organic phases were washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate and evaporated to dryness. The residue was purified by flash chromatography (cyclohexane/ethyl acetate in proportions of 90/10) to afford 0.410 g (31%) of a white solid.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([O:12][CH3:13])=[O:11])[C:4]=2[CH:3]=[CH:2]1.Cl[CH2:15][C:16]([N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[O:17].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(Cl)Cl>[CH3:13][O:12][C:10]([C:5]1[C:4]2[CH:3]=[CH:2][N:1]([CH2:15][C:16](=[O:17])[N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])[C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:11]
Reactant: CCN(CC)C(=O)CCl
Reactant: COC(=O)c1cccc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)Cn1ccc2c(C(=O)OC)cccc21

Procedure:
Methyl indole-4-carboxylate (50 mg, 2.85 mmol) and 2-chloro-N,N-diethylacetamide (854 mg, 5.71 mmol) are dissolved in DMF (10 ml) and to the solution is added potassium carbonate (986 mg, 7.14 mmol). The reaction is heated using microwave radiation at 100° C. for 2 hours, then diluted with DCM (60 ml) and washed with water (5×10 ml). Drying over MgSO4, concentration in vacuo, and trituration with Et2O affords 1-Diethylcarbamoylmethyl-1H-indole-4-carboxylic acid methyl ester; [M+H]+ 289.
Reaction SMILES: [Br:1]N1C(=O)NC(=O)N(Br)C1=O.[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]([O:28][CH3:29])=[O:27])=[C:22]([O:30][CH:31]([CH3:33])[CH3:32])[CH:21]=1.CN(C=O)C>O>[Br:1][C:25]1[CH:24]=[C:23]([C:26]([O:28][CH3:29])=[O:27])[C:22]([O:30][CH:31]([CH3:33])[CH3:32])=[CH:21][C:20]=1[C:14]1[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=1[F:12]
Reactant: O=c1[nH]c(=O)n(Br)c(=O)n1Br
Reactant: COC(=O)c1ccc(-c2ccc(F)cc2F)cc1OC(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)c(-c2ccc(F)cc2F)cc1OC(C)C
Yield: 166.6 %

Procedure:
Dibromoisocyanuric acid (2.19 g) was added to a mixture of methyl 2′,4′-difluoro-3-isopropoxybiphenyl-4-carboxylate (3.90 g) and DMF (40 mL), and the resultant mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The obtained organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (4.90 g).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30]Br)(=[O:25])[CH3:24].[C:32]([OH:39])(=[O:38])/[CH:33]=[CH:34]/[C:35]([OH:37])=[O:36]>C(#N)C.C(O)C>[C:32]([OH:39])(=[O:38])/[CH:33]=[CH:34]/[C:35]([OH:37])=[O:36].[C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][N:12]1[CH2:11][CH2:10][CH:9]([C:6]2[C:5]3[CH:15]=[CH:16][C:2]([F:1])=[CH:3][C:4]=3[O:8][N:7]=2)[CH2:14][CH2:13]1)(=[O:25])[CH3:24]
Reactant: CC(=O)OCCCCBr
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCO
Product: CC(=O)OCCCCN1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (9.5 g, 41 mmol), K2CO3 (7.2 g, 51 mmol), and 4-bromobutyl acetate (10 g, 51 mmol) in acetonitrile (200 ml) was heated at reflux for 3.5 hours. At the end of the reaction, the solution was cooled and filtered. The inorganic salt was washed with DCM (50 ml). The organic solvent was removed. The residue was purified on a flash chromatography column (packed with Sorbsil C30 silica gel, 100 g, eluted with DCM, 1 liter, increasing methanol from 2 to 4%, 2.51). The material thus purified weighed 12.92 g (89%). A small sample (1.67 g) was dissolved in ethanol and treated with 1 equivalent of fumaric acid (580 mg) in ethanol to yield white crystals: 1.8 g,
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:18]1[O:19][CH:20]=[CH:21][N:22]=1)CCC.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(OCC)(=O)C>[CH3:9][O:8][C:6]1[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=[C:2]([C:18]2[O:19][CH:20]=[CH:21][N:22]=2)[N:7]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncco1
Reactant: COc1nc(Cl)ccc1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1nc(-c2ncco2)ccc1[N+](=O)[O-]
Temperature: 110 °C
Yield: 66.1 %

Procedure:
An oven-dried resealable Schlenk tube was charged with 6-chloro-2-methoxy-3-nitropyridine (0.50 g, 2.6 mmol), 2-tributylstannanyloxazole (1.20 g, 3.4 mmol) and 1,4-dioxane (10 mL) and then subjected to several cycles of evacuation-backfilling with argon. Tetrakis(triphenylphosphine)palladium (0.18 g, 0.16 mmol) was then added and, after three new cycles of evacuation-backfilling with argon, the Schlenk tube was sealed and the mixture was stirred and heated in an oil bath to 110° C. After stirring overnight, water and ethyl acetate were added and the organic layer was washed with water, dried (MgSO4) and evaporated. The residue was purified by flash chromatography (2:1 hexanes/ethyl acetate) to give the title compound (0.38 g, 67%) as a yellow solid.
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]=[CH:9][N:8]([CH2:11][CH3:12])[C:4]=2[N:5]=[N:6][CH:7]=1.[CH2:13]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:25]([OH:39])=[CH:26][CH:27]=[C:28](B3OC(C)(C)C(C)(C)O3)[CH:29]=2)=[C:20]([O:40][CH3:41])[CH:19]=1)(=[O:17])=[O:16])[CH3:14].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:11]([N:8]1[C:4]2[N:5]=[N:6][CH:7]=[C:2]([C:28]3[CH:29]=[C:24]([C:21]4[CH:22]=[CH:23][C:18]([S:15]([CH2:13][CH3:14])(=[O:16])=[O:17])=[CH:19][C:20]=4[O:40][CH3:41])[C:25]([OH:39])=[CH:26][CH:27]=3)[C:3]=2[N:10]=[CH:9]1)[CH3:12]
Reactant: CCS(=O)(=O)c1ccc(-c2cc(B3OC(C)(C)C(C)(C)O3)ccc2O)c(OC)c1
Reactant: CCn1cnc2c(Cl)cnnc21
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCn1cnc2c(-c3ccc(O)c(-c4ccc(S(=O)(=O)CC)cc4OC)c3)cnnc21
Temperature: 100 °C
Yield: 9.8 %

Procedure:
To a stirred solution 4-chloro-7-ethyl-7H-imidazo[4,5-c]pyridazine (Preparation 8, 80 mg, 0.44 mmol) and 4′-(ethylsulfonyl)-2′-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-2-ol (Preparation 89, 167 mg, 0.44 mmol) in dioxane (15 mL) and water (5 mL) was added sodium carbonate (106 mg, 1.0 mmol) and the reaction mixture was degassed before adding tetrakis(triphenylphosphine) palladium(0) (46 mg, 0.04 mmol). The reaction was heated to 100° C. for 18 hours. After this time the reaction was allowed to cool to room temperature, filtered through celite and the filtrate evaporated under reduced pressure. The crude was purified by silica gel column chromatography eluting with CH2Cl2:MeOH from 95:5 to 9:1 and then further purified by preparative HPLC to afford the title compound as colourless solid 11%, 19 mg.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[C:17]1([C:23]#[CH:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.C(N(CC)CC)C>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]([C:5]2[CH:15]=[CH:16][C:2]([C:24]#[C:23][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:3][CH:4]=2)=[O:7])=[CH:9][CH:10]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(Br)cc1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd]Cl
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(c1ccc(F)cc1)c1ccc(C#Cc2ccccc2)cc1
Temperature: 23 °C
Reaction time: 16 h

Procedure:
4-Fluoro-4'-phenylethynylbenzophenone was synthesized by the cuprous iodide catalyzed coupling of 4-bromo-4'-fluorobenzophenone. More specifically, 4-bromo-4'-fluorobenzophenone (30 grams, 0.11 mol), phenylacetylene (11 grams, 0.11 mol), triphenylphosphine (0.2 gram), cuprous iodide (0.1 gram), bis(triphenylphosphine) palladium dichloride (0.1 gram) and 450 milliliters of triethylamine were charged to a 500 milliliter flask equipped with a mechanical stirrer, N2 inlet, and reflux condenser. The mixture was heated to reflux for 4 hours, cooled to 23° C., and stirred for an additional 16 hours. The mixture was then poured into water acidified with HCl and the precipitate was collected by filtration. Recrystallization from acetone gave 23 grams (75 percent yield) of the desired product.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[C:34]([NH:42][C:43](=[O:57])[C@@H:44]2[CH2:48][C@@H:47]([OH:49])[CH2:46][N:45]2[C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH:33]=1.[OH-].[Na+]>O1CCCC1.O.C(O)=O>[N:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[C:34]([NH:42][C:43](=[O:57])[C@@H:44]2[CH2:48][C@H:47]([OH:49])[CH2:46][N:45]2[C:50]([O:52][C:53]([CH3:55])([CH3:54])[CH3:56])=[O:51])[CH:33]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)Nc1cnc2ccccc2c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O=CO
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@@H](O)C[C@H]1C(=O)Nc1cnc2ccccc2c1
Reaction time: 0.5 h

Procedure:
Diethyl azodicarboxylate (40% solution in toluene, 1.4 mL) was added to a solution of triphenylphosphine (808 mg) in tetrahydrofuran (5 mL) at ñ15° C. After stirring at −15° C. to 0° C. for 30 min, trans-4-hydroxy-N-tert-butoxycarbonyl-L-proline 3-quinolylamide (A, 729 mg), and formic acid (100 mL) were added. After stirring at room temperature for 3.5 hr, formic acid (100 mL) was added, and stirring was continued for 2 hr. Then additional Mitsunobu reagent which was prepared from triphenylphosphine (803 mg) and diethyl azodicarboxylate (40% solution in toluene, 1.4 mL) was added. After the resulting solution was stirred for 3 hr, 1 N sodium hydroxide (20 mL) was added at 0° C. and stirred at room temperature for 1.5 hr. Then water (100 mL) was added to the reaction mixture and the solvents were evaporated in vacuo. The residue was extracted with ethyl acetate and the extract was washed with brine, dried over anhydrous sodium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform then chloroform:methanol=30:1, v/v) to afford the title compound (576 mg) as a pale yellow sticky oil: 1H NMR (400 MHz, CD3OD) δ 1.3-1.6 (m, 9H), 1.9-2.2 (m, 1H), 2.3-2.6 (m, 1H), 3.4-3.7 (m, 3H), 4.24.5 (m, 1H), 7.60 (m, 1H), 7.70 (m, 1H), 7.90 (m, 1H), 7.98 (m, 1H), 8.72 (m, 1H), and 8.92 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4](I)[CH:3]=1.[C:10]([C@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])#[CH:11]>>[NH2:6][C:5]1[CH:7]=[CH:8][C:2]([Br:1])=[CH:3][C:4]=1[C:11]#[C:10][C@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]
Reactant: Nc1ccc(Br)cc1I
Reactant: C#C[C@H]1CCCN1C(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1C#Cc1cc(Br)ccc1N
Yield: 89 %

Procedure:
(R)-tert-butyl 2-((2-amino-5-bromophenyl)ethynyl)pyrrolidine-1-carboxylate (4.32 g) was prepared via Sonogashira coupling according to the general procedure described in Example 156, Step 1, from 4-bromo-2-iodoaniline (3.96 g, 13.29 mmol) and (R)-tert-butyl 2-ethynylpyrrolidine-1-carboxylate (3.25 g, 16.64 mmol) in 89% yield.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[F:17][C:18]([F:27])([F:26])[C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22].C(=O)(O)[O-].[Na+]>C(O)C>[N+:12]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:15]#[N:16])=[C:2]2[NH:22][C:21]1[CH:23]=[CH:24][CH:25]=[C:19]([C:18]([F:17])([F:26])[F:27])[CH:20]=1)([O-:14])=[O:13]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Nc1cccc(C(F)(F)F)c1
Yield: 66.6 %

Procedure:
A mixture of 10.6 g (45.7 mmol) of 4-chloro-6-nitro-3-quinolinecarbonitrile and 8.82 g (54.8 mmol) of 3-(trifluoromethyl)aniline in 270 mL of ethanol was refluxed under N2 for 5 h. The reaction was diluted with ethanol, neutralized with said sodium bicarbonate and evaporated. The residue was slurried with hexane, collected, washed with hexane and water and dried in vacuo(60° C.) to give 10.9 g of yellow solid. A 2.00 g sample was recrystallized from ethanol to give 1.20 g of bright yellow solid; mp 260-261° C.
Reaction SMILES: [C:1]1([C:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3C(=O)C4=CC=CC=C4C3=O)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.NN>C(O)C>[NH2:17][CH2:16][CH2:15][CH2:14][N:11]1[CH2:12][CH2:13][C:8](=[C:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:9][CH2:10]1
Reactant: O=C1c2ccccc2C(=O)N1CCCN1CCC(=C(c2ccccc2)c2ccccc2)CC1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCCN1CCC(=C(c2ccccc2)c2ccccc2)CC1
Yield: 72.9 %

Procedure:
A mixture of 900 mg (2.06 mmole) of 4-(diphenylmethylene)-1-(3-phthalimidopropyl)piperidine (prepared as described in Preparation 10'), 350 mg (7 mmole) of hydrazine hydrate and 20 ml of ethanol was heated under reflux for 2 hours. At the end of this time, the crystals which precipitated were filtered off and the solvent was removed from the filtrate by distillation under reduced pressure, to afford 460 mg (yield 73%) of the title compound as an oil.
Reaction SMILES: [F-].[K+].C[Si](C)(C)[C:5]([F:8])([F:7])[F:6].[Cl:11][C:12]1[N:19]=[C:18]([Cl:20])[C:17](I)=[CH:16][C:13]=1[C:14]#[N:15].N>CN(C=O)C.[Cu]I.C1COCC1>[Cl:11][C:12]1[N:19]=[C:18]([Cl:20])[C:17]([C:5]([F:8])([F:7])[F:6])=[CH:16][C:13]=1[C:14]#[N:15]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: N#Cc1cc(I)c(Cl)nc1Cl
Agent: [Cu]I
Agent: N
Agent: [F-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: N#Cc1cc(C(F)(F)F)c(Cl)nc1Cl
Temperature: 25 °C
Yield: 37.5 %

Procedure:
KF (1.95 g, 33.5 mmol) and CuI (6.40 g, 33.5 mmol) were weighed in a flask, and the mixture was heated with a gas burner while gently shaking under high vacuum until the content becomes a pale-yellow green. After cooling to room temperature, anhydrous DMF (50 ml), anhydrous THF (20 ml) and trimethyl (trifluoromethyl)silane (4.80 g, 33.5 mmol) were added. The mixture was heated to 50° C., and stirred for 21 hrs. A mixed solution of Compound 2,6-dichloro-5-iodonicotinonitrile (5.00 g, 16.7 mmol) in anhydrous DMF (10 ml) anhydrous THF (20 ml) was added dropwise to the above mentioned reaction mixture at 50° C. and stirred for 30 hrs. The reaction mixture was cooled to room temperature, poured into 12% aqueous ammonia, and the mixture was extracted EtOAc. The combined organic layer was concentrated in vacuo and the residue was purified by flash chromatography on silica to afford Compound 2,6-dichloro-5-(trifluoromethyl)nicotinonitrile. (1.5 g, yield: 37.5%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm) 9.12 (s, 1H).
Reaction SMILES: [CH:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)([CH2:3][CH3:4])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:20][C:21]1[O:25][N:24]=[C:23]([CH:26]2[CH2:28][CH2:27]2)[N:22]=1.O>CN(C)C=O>[CH:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:20][C:21]2[O:25][N:24]=[C:23]([CH:26]3[CH2:28][CH2:27]3)[N:22]=2)=[CH:10][CH:11]=1)([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)Oc1ccc(O)cc1
Reactant: ClCc1nc(C2CC2)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(C)Oc1ccc(OCc2nc(C3CC3)no2)cc1
Temperature: 20 °C
Reaction time: 8 h
Yield: 77.2 %

Procedure:
5 g of 4-(sec-butyloxy)-phenol and 6.2 g of potassium carbonate are stirred in 50 ml of anhydrous dimethylformamide for 1 hour at 80° C. Subsequently, 4.8 g of 5-chloromethyl-3-cyclopropyl-1,2,4-oxadiazole in 20 ml anhydrous dimethylformamide is dripped in and the mixture stirred for 8 hours at 80° C. and overnight at room temperature (about 20° C.). The mixture is then poured into 100 ml of water and extracted three times with ethyl acetate, and the organic phases are dried over magnesium sulfate. The solvent is evaporated off and the crude product is purified by chromatography on silica gel using n-hexane/ethyl acetate (4:1) as eluant. There is obtained 6.7 g of 5-[4-(sec-butyloxy)-phenoxymethyl]-3-cyclopropyl-1,2,4-oxadiazole as a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([CH2:14][CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[S:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].C(N(CC)CC)C.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1.CCOCC>[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([S:37]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([CH2:14][CH2:15][CH2:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[S:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])(=[O:39])=[O:38])=[CH:33][CH:32]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)CSC(CCCCN)CCCc1cccnc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)CSC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCc1cccnc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 0.219 g ethyl 8-amino-4-[3-(3-pyridyl)propyl]-3-thiaoctanoate in 1.5 ml methylene chloride is added a few crystals of 4-dimethylaminopyridine followed by 60 mcl triethylamine and 0.068 g p-chlorophenylsulfonyl chloride. The mixture is stirred at room temperature for 18 h, diluted with ether and washed with saturated aqueous sodium bicarbonate. The ether layer is dried, filtered and evaporated to leave an amber oil which is chromatographed using 3:2 ethyl acetate/hexane to give ethyl 8-(p-chlorophenylsulfonamido)-4-[3-(3-pyridyl)propyl]-3-thia-octanoate as an oil; NMR (CDCl3): delta 8.0 (d,2H), 7.55 (d,2H), 3.15 (s,2H); such being the compound of formula X wherein X represents sulfur, Ar represents p-chlorophenyl, Het represents 3-pyridyl and R1 represents ethoxy.
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]([OH:17])=O)=[CH:14][C:9]=2[N:8]=[C:7]1[CH2:18][C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)[CH2:4][CH3:5])[CH3:2].C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[N:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[CH:49]([NH2:53])[CH2:50][CH2:51][CH3:52].Cl>CN(C=O)C.O.C(Cl)CCl>[N:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[CH:49]([NH:53][C:15]([C:13]1[CH:12]=[CH:11][C:10]2[N:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[C:7]([CH2:18][C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)=[N:8][C:9]=2[CH:14]=1)=[O:17])[CH2:50][CH2:51][CH3:52]
Reactant: CCC(CC)n1c(Cc2cccs2)nc2cc(C(=O)O)ccc21
Reactant: CCCC(N)c1ccccn1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCCC(NC(=O)c1ccc2c(c1)nc(Cc1cccs1)n2C(CC)CC)c1ccccn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.8 %

Procedure:
To a solution of 50 mg of 1-(1-ethyl-propyl)-2-thiophen-2-ylmethyl-1H-benzoimidazole-5-carboxylic acid in 2 ml of dry DMF 10 mg of HOAT, 35 mg of EDC and 0.1 ml of DIPEA were added at 0° C. After 15 min 25 mg of 1-pyridin-2-ylbutylamine were added and the reaction was stirred at rt for 16 h. The reaction was then poured into water and the pH was adjusted to 4 by the addition of 2 M aqueous hydrochloric acid. The reaction was extracted with ethyl acetate three times. The combined organic phases were dried over magnesium sulphate and concentrated. 70 mg (100%) of 1-(1-ethyl-propyl)-2-thiophen-2-ylmethyl-1H-benzoimidazole-5-carboxylic acid (1-pyridin-2-yl-butyl)-amide were obtained.