Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([Cl:14])=[CH:9][C:8]=2[Cl:15])[N:5]=[C:4]([CH3:16])[CH:3]=1.[I:17]N1C(=O)CCC1=O>C(#N)C>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([Cl:14])=[CH:9][C:8]=2[Cl:15])[N:5]=[C:4]([CH3:16])[C:3]=1[I:17]
Reactant: Cc1cc(N)n(-c2c(Cl)cc(Cl)cc2Cl)n1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: Cc1nn(-c2c(Cl)cc(Cl)cc2Cl)c(N)c1I

Procedure:
A stirred solution of 5-amino-3-methyl-1-(2,4,6-trichlorophenyl)pyrazole (WO-A-94/13643; 35 g) and N-iodosuccinimide (29 g) in acetonitrile (450 ml) was heated under reflux for 1.5 hours, then the reaction mixture allowed to cool and evaporated under reduced pressure. The residue was dissolved in dichloromethane and the solution washed successively with aqueous sodium thiosulphate solution, water and brine, then dried (Na2SO4) and evaporated under reduced pressure. The resulting dark coloured solid was triturated with hexane to yield the title compound as a pale orange solid, m.p. 135-137° C. δ(CDCl3): 2.25 (s,3H), 3.67 (br.s,2H), 7.49 (s,2H). MS (thermospray): M/Z [M+H] 401.4; C10H7Cl3 lN3 +H requires 401.88.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH2:7])[NH:4][N:3]=1.O.[N+:9]([CH:12]([CH:15]=O)[CH:13]=O)([O-:11])=[O:10].[Na].CC(O)=O>O>[CH3:1][C:2]1[C:6]2[C:5](=[N:7][CH:13]=[C:12]([N+:9]([O-:11])=[O:10])[CH:15]=2)[NH:4][N:3]=1
Reactant: Cc1cc(N)[nH]n1
Reactant: O=CC(C=O)[N+](=O)[O-]
Agent: [Na]
Solvent: CC(=O)O
Solvent: O
Product: Cc1n[nH]c2ncc([N+](=O)[O-])cc12
Temperature: 90 °C
Yield: 52.1 %

Procedure:
A 5 mL reaction vessel was charged with 3-methyl-1H-pyrazol-5-amine (68 mg, 0.70 mmol), sodium nitromalonaldehyde monohydrate (121 mg, 0.77 mmol) and AcOH (2 mL). The flask was heated to 90° C. under a nitrogen atmosphere overnight. The following day the mixture was poured into water (10 mL), and the precipitate was filtered and rinsed with water (3×5 mL). The precipitate was triturated with minimal Et2O to provide 3-methyl-5-nitro-1H-pyrazolo[3,4-b]pyridine as a solid (65 mg, 52% yield).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.C([Sn](CCCC)(CCCC)[C:33]1[S:37][CH:36]=[N:35][CH:34]=1)CCC>CC(N(C)C)=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>[O:25]1[CH2:26][CH2:27][N:22]([C:4]2[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=[C:2]([C:33]3[S:37][CH:36]=[N:35][CH:34]=3)[N:3]=2)[CH2:23][CH2:24]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncs1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)N(C)C
Product: CS(=O)(=O)N1CCN(Cc2cc3nc(-c4cncs4)nc(N4CCOCC4)c3s2)CC1
Temperature: 150 °C
Yield: 50 %

Procedure:
A suspension of 2-chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine, prepared via General Procedure B-3, (144 mg, 0.33 mmol), 5-tributylstannanyl-thiazole (187 mg, 0.5 mmol), and Pd(PPh3)4 (19 mg, 0.017 mmol) in anhydrous DMA was heated in a microwave at 150° C. for 10 mins. The crude reaction was loaded onto a preconditioned SCX cartridge, washing the cartridge with methanol and dichloromethane before eluting with 7N ammonia in methanol to give crude material. This was purified by on silica using 5% methanol in ethyl acetate as the eluent to give 152 as an off-white solid (80 mg, 50%). NMR (CDCl3, 400 MHz), 2.68-2.72 (4H, m), 2.83 (3H, s), 3.32-3.36 (4H, m), 3.88-3.93 (6H, m), 4.03-4.06 (4H, m), 7.32 (1H, s), 8.67 (1H, m), 8.84 (1H, s). MS: (ESI+): MH+=481
Reaction SMILES: [N:1]1[N:2]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH:3]=[C:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[CH:5]2.[I-].[Na+].[H-].[Na+].Cl[CH2:22][CH2:23][CH2:24][N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>CN(C)C=O>[N:25]1([CH2:24][CH2:23][CH2:22][O:16][C:13]2[CH:14]=[CH:15][C:10]([N:2]3[CH:3]=[C:4]4[C:9]([CH:8]=[CH:7][CH:6]=[CH:5]4)=[N:1]3)=[CH:11][CH:12]=2)[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: Oc1ccc(-n2cc3ccccc3n2)cc1
Reactant: ClCCCN1CCCC1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc2nn(-c3ccc(OCCCN4CCCC4)cc3)cc2c1
Temperature: 85 °C
Yield: 12 %

Procedure:
To a solution of 4-Indazol-2-ylphenol (28 mg, 0.13 mmol) and sodium iodide (6 mg, 0.04 mmol) in N,N-dimethylformamide (3 mL) was added sodium hydride (8.0 mg, 60% in mineral oil, 0.2 mmol) followed by 1-(3-chloropropyl)pyrrolidine (30 mg, 0.20 mmol). After the reaction was heated at 85° C. overnight and allowed to cool, it was partitioned between water and methylene chloride. The organic layer was dried (MgSO4), concentrated and purified by semi-prep LC-MS to give 5.0 mg of the desired indazole. LC-MS (C20H23N3O calc'd 321) m/z 322 (M+H); 1H NMR (300 MHz, CDCl3) δ 8.33 (s, 1H), 7.81-7.77 (m, 3H), 7.71 (d, J=8.7 Hz, 1H), 7.34-7.29 (m, 1H), 7.14-7.09 (m, 1H), 7.05-7.02 (m, 2H), 4.10 (t, J=6.6 Hz, 2H), 2.72 (t, J=7.2 Hz, 2H), 2.63 (m, 4H), 2.08 (quint, J=6.3 Hz, 2H), 1.86-1.81 (m, 4H).
Reaction SMILES: CC1[N:3]([C:8]2[CH:9]=[C:10]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=2)C(C)=CC=1.[OH-].[K+].Cl.NO>CCO.O>[CH3:24][N:21]1[CH2:20][CH2:19][N:18]([C:10]2[CH:9]=[C:8]([CH:13]=[C:12]([C:14]([F:17])([F:15])[F:16])[CH:11]=2)[NH2:3])[CH2:23][CH2:22]1
Reactant: Cc1ccc(C)n1-c1cc(N2CCN(C)CC2)cc(C(F)(F)F)c1
Agent: Cl
Agent: NO
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CN1CCN(c2cc(N)cc(C(F)(F)F)c2)CC1
Yield: 73.3 %

Procedure:
To a mixture of 1-[3-(2,5-dimethyl-1H-pyrrol-1-yl)-5-(trifluoromethyl)phenyl]-4-methylpiperazine (440 mg, 1.3 mmol) and potassium hydroxide (1.46 g, 26. mmol) in EtOH (10 mL) and water (3 mL) was added hydroxylamine hydrochloride (2.72 g, 39 mmol. The reaction mixture was heated at reflux overnight. The reaction mixture was then concentrated and the residue was dissolved in water and EtOAc. The reaction mixture was extracted with EtOAc. The organic solutions were combined, washed with brine, dried over Na2SO4 filtered and concentrated. The residue was purified by column chromatography to give 3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)aniline (247 mg, 73%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ: 6.55 (d, 1H), 6.40 (d, 1H), 6.33 (d, 1H), 3.24 (t, 4H), 2.61 (t, 4H), and 2.38 (s, 3H). LCMS: (FA) ES+ 260.2.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:12][F:13])[N:3]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][CH3:23])=[CH:18][CH:17]=1.Cl.C([O-])(O)=O.[Na+]>C(O)(C)C>[F:13][CH2:12][C:4]1[N:3]=[C:2]([N:22]([C:19]2[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[CH:17][CH:18]=2)[CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: FCc1nc(Cl)c2ccccc2n1
Reactant: CNc1ccc(OC)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: COc1ccc(N(C)c2nc(CF)nc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.5 %

Procedure:
(2-Fluoromethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine: A suspension of 2-fluoromethyl-quinazolin-4(3H)-one (70 mg, 0.39 mmol) in phosphoryl chloride (2 ml) and N,N-dimethylaniline (0.035 ml, 0.27 mmol) was heated under reflux for 12 hours. The reaction mixture was poured onto ice and the precipitate was collected by filtration, then washed and dried to give 4-chloro-2-fluoromethyl-quinazoline, which was used directly for the next reaction. To a solution of 4-chloro-2-fluoromethyl-quinazoline with (4-methoxy-phenyl)-methylamine (160 mg, 1.2 mmol) in isopropyl alcohol (5 ml) was added concentrated HCl (0.05 ml) and the solution was stirred at room temperature overnight. The solution was neutralized with saturated aqueous NaHCO3, and was extracted by ethyl acetate. The extracts were evaporated, and the residue was purified by column chromatography on silica gel with ethyl acetate and hexane (1:1) as eluent, yielding 11 mg (9.5%) of the title compound. 1H NMR (CDCl3): 7.87-7.84 (m, 1H), 7.60-7.54 (m, 1H), 7.14-7.10 (m, 2H), 7.04-7.01 (m, 2H), 6.95-6.91 (m, 2H), 5.60 (s, 1H), 5.44 (s, 1H), 3.85 (s, 3H), 3.60 (s, 3H).
Reaction SMILES: CC([O-])(C)C.[K+].[CH3:7][O:8][C:9]1[CH:31]=[CH:30][C:12]([CH2:13][N:14]2[C:20](=[O:21])[CH2:19][C:18]3[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=3[C:16]3[CH:26]=[CH:27][CH:28]=[CH:29][C:15]2=3)=[CH:11][CH:10]=1.C([O:37][N:38]=O)CC(C)C.[Na+].[Cl-]>C1COCC1.ClCCl>[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][N:14]2[C:20](=[O:21])[C:19](=[N:38][OH:37])[C:18]3[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=3[C:16]3[CH:26]=[CH:27][CH:28]=[CH:29][C:15]2=3)=[CH:30][CH:31]=1
Reactant: CC(C)CCON=O
Reactant: COc1ccc(CN2C(=O)Cc3ccccc3-c3ccccc32)cc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc(Cn2c(=O)c(=NO)c3ccccc3c3ccccc32)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 115.8 %

Procedure:
Potassium tert-butylate (7.6 g) was added slowly to a solution of 5-(4-methoxy-benzyl)-5H,7H-dibenzo[b,d]azepin-6-one (14.6 g) in THF (146 mL) cooled to 0° C. After 10 minutes of stirring at 0° C., isopentylnitrite (10.6 g) was slowly added and the reaction mixture was further stirred for 105 minutes at 0° C. The reaction mixture was poured onto half-saturated aqueous NaCl (1200 mL), cooled to 0° C. and dichloromethane (500 mL) was added. The phases were separated, the organic phase was washed with half-saturated aqueous NaCl (1200 mL) and the aqueous layers were extracted with dichloromethane (250 mL) twice. The combined organic layers were dried (MgSO4), concentrated under reduced pressure and dried under high vacuum affording 5-(4-methoxy-benzyl)-5H-dibenzo[b,d]azepine-6,7-dione 7-oxime (18.4 g, quant.) as a yellow foam, which was used in the next step without further purification.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[C:10]([N+:21]([O-])=O)=[C:11]([NH:15][C:16](=O)OCC)[CH:12]=[CH:13][CH:14]=1>O1CCCC1>[NH2:21][C:10]1[C:9]([O:8][CH3:7])=[CH:14][CH:13]=[CH:12][C:11]=1[NH:15][CH3:16]
Reactant: CCOC(=O)Nc1cccc(OC)c1[N+](=O)[O-]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNc1cccc(OC)c1N
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 15.1 %

Procedure:
To a suspension of lithium aluminum hydride (2.27 g) in tetrahydrofuran (50 ml) was added a suspension of ethyl N-(3-methoxy-2-nitrophenyl)carbamate (7.17 g) in tetrahydrofuran (15 ml) under ice-cooling, and the mixture was stirred for 1.5 hours at ambient temperature. Insoluble material was filtered off, and the filtrate was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1, v/v) to give 2-amino-3-methoxy-N-methylaniline (687 mg).
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[C:7]([F:13])([F:12])[C:8]([F:11])([F:10])[F:9].[H-].[Na+].Cl[C:17]1[C:22]([Cl:23])=[CH:21][C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=1.O>CN(C)C=O>[Cl:23][C:22]1[C:17]([N:6]2[C:2]([CH3:1])=[C:3]([C:7]([F:13])([F:12])[C:8]([F:10])([F:9])[F:11])[N:4]=[CH:5]2)=[N:18][CH:19]=[C:20]([C:24]([F:26])([F:25])[F:27])[CH:21]=1
Reactant: Cc1[nH]cnc1C(F)(F)C(F)(F)F
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C(F)(F)C(F)(F)F)ncn1-c1ncc(C(F)(F)F)cc1Cl
Reaction time: 0.17 h
Yield: 43.9 %

Procedure:
To a solution of 0.6 g (3 m mol) of 5-methyl-4-pentafluoroethylimidazole in 5 ml of N,N-dimethyl formamide was added slowly 120 mg (3 m mol) of an oily sodium hydride (60%) while cooling with ice, followed by stirring at the same temperature for 10 minutes. After the reaction was completed, to the reaction mixture was added dropwise 0.65 g (3 m mol) of 2,3-dichloro-5-trifluoromethylpyridine, followed by stirring at room temperature for 9 hours. After the reaction was completed, the reaction mixture was poured into water, and extracted with ethyl acetate. Further, then the residue was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to give 0.5 g of 1-(3-chloro-5-trifluoromethylpyridin-2-yl)-5-methyl-4-pentafluoroethylimidazole.
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][CH2:6][C@H:5]([CH2:9][N:10]3[C:14]4[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:13]=4[N:12]=[CH:11]3)[CH2:4]2)[CH2:2]1.[NH2:21][CH2:22][C:23]([CH3:29])([CH3:28])[C:24]([O:26][CH3:27])=[O:25]>C(O)(C)C>[C:19]([C:16]1[CH:17]=[CH:18][C:13]2[N:12]=[CH:11][N:10]([CH2:9][CH:5]3[CH2:6][CH2:7][CH2:8][C:3]([CH2:2][NH:21][CH2:22][C:23]([CH3:29])([CH3:28])[C:24]([O:26][CH3:27])=[O:25])([OH:1])[CH2:4]3)[C:14]=2[CH:15]=1)#[N:20]
Reactant: N#Cc1ccc2ncn(C[C@H]3CCCC4(CO4)C3)c2c1
Reactant: COC(=O)C(C)(C)CN
Solvent: CC(C)O
Product: COC(=O)C(C)(C)CNCC1(O)CCCC(Cn2cnc3ccc(C#N)cc32)C1
Yield: 66.2 %

Procedure:
A solution of 1-[(55)-1-oxaspiro[2.5]oct-5-ylmethyl]-1H-benzimidazole-6-carbonitrile (1.064 g, 3.98 mmol) and methyl 3-amino-2,2-dimethylpropanoate (0.679 g, 5.17 mmol) in isopropanol (13.27 mL) was stirred at 100° C. for 1 day. Reaction was concentrated and purified via silica gel chromatography (ISCO, 120 g silica gel column. Solvent A was DCM and solvent B was 0.1M NH3 in MeOH; 0-10% B over 15 min; 10% B over 6 min) to give methyl 3-[({3-[(6-cyano-1H-benzimidazol-1-yl)methyl]-1-hydroxycyclohexaneyl}methyl)amino]-2,2-dimethylpropanoate as a sticky solid (1.05 g, 66.1% yield). MS (m/z) 399.2 (M+H+).
Reaction SMILES: O.C(O)C.[CH:5]12[CH2:10][CH:9]1[CH2:8][N:7]([C:11]1[N:16]=[C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([F:27])[CH:20]=3)[C:14]([C:28]([O:30]CC)=[O:29])=[CH:13][N:12]=1)[CH2:6]2.[OH-].[Na+]>C1COCC1>[CH:5]12[CH2:10][CH:9]1[CH2:8][N:7]([C:11]1[N:16]=[C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([F:27])[CH:20]=3)[C:14]([C:28]([OH:30])=[O:29])=[CH:13][N:12]=1)[CH2:6]2
Reactant: CCOC(=O)c1cnc(N2CC3CC3C2)nc1NCc1ccc(OC)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(CNc2nc(N3CC4CC4C3)ncc2C(=O)O)cc1F
Reaction time: 5 h
Yield: 41.5 %

Procedure:
In the mixture of water (5 mL), ethanol (5 mL) and THF (15 mL) were dissolved ethyl 2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-((3-fluoro-4-methoxybenzyl)amino)pyrimidine-5-carboxylate (1.5 g, 3.9 mmol) and sodium hydroxide (260 mg, 6.5 mmol). The reaction was conducted at ambient temperature for 5 h. The solvent was removed by evaporation, followed by addition of water and washing with DCM. The aqueous phase was adjusted to a pH of 2 with dilute hydrochloric acid, and extracted with DCM. The organic phase was dried over sodium sulfate and concentrated to give 2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-((3-fluoro-4-methoxybenzyl)amino)pyrimidine-5-carboxylic acid as a faint yellow solid (580 mg, 41.5% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][C:6]=2[CH:14]=1.[C:15]1([S:21]([N:24]([CH2:28][CH2:29]Cl)[CH2:25][CH2:26]Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CCCC)CCCC)CCC>CO>[C:15]1([S:21]([N:24]2[CH2:28][CH2:29][N:1]([C:2]3[CH:3]=[CH:4][C:5]4[O:9][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][C:6]=4[CH:14]=3)[CH2:26][CH2:25]2)(=[O:23])=[O:22])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=S(=O)(c1ccccc1)N(CCCl)CCCl
Reactant: COC(=O)c1cc2cc(N)ccc2o1
Solvent: CO
Solvent: CCCCN(CCCC)CCCC
Product: COC(=O)c1cc2cc(N3CCN(S(=O)(=O)c4ccccc4)CC3)ccc2o1
Temperature: 27.5 °C
Yield: 53.6 %

Procedure:
Methyl 5-aminobenzofuran-2-carboxylate (200 g) and N-benzenesulfonyl-N,N-bis(2-chloroethyl)amine (289 g) were added to tributyl amine (1012 ml) under stirring at 25-30° C. The resulting mixture was heated to 73-77° C., followed by stirring for 43 hours at the same temperature. The reaction mass was cooled to 25-30° C., followed by the addition of methanol (506 ml) and then stirring for 30 minutes at 25-30° C. The resulting mass was filtered, washed with chilled methanol (200 ml) and then dried to produce 220 g of methyl 5-[4-(benzenesulfonyl)-1-piperazinyl]benzofuran-2-carboxylate as a fine powder (Purity by HPLC: 99.5%).
Reaction SMILES: C1(OC)C=CC=CC=1.C(OC([N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([CH2:25][C@@H:26]2[CH2:31][N:30]3[CH2:32][C:33]([C:36]4[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=4)=[CH:34][CH2:35][C@@H:29]3[CH2:28][N:27]2[C:42](=[O:57])[C:43]2[CH:48]=[C:47]([C:49]([F:52])([F:51])[F:50])[CH:46]=[C:45]([C:53]([F:56])([F:55])[F:54])[CH:44]=2)=[CH:17]1)=O)(C)(C)C.C(OC(N1C2C(=CC=CC=2)C(C[C@@H]2CN3C=C(C4C=CN=CC=4)CC[C@@H]3CN2C(=O)C2C=C(C(F)(F)F)C=C(C(F)(F)F)C=2)=C1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:56][C:53]([F:54])([F:55])[C:45]1[CH:44]=[C:43]([C:42]([N:27]2[C@H:26]([CH2:25][C:18]3[C:19]4[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=4)[NH:16][CH:17]=3)[CH2:31][N:30]3[CH:32]=[C:33]([C:36]4[CH:37]=[CH:38][N:39]=[CH:40][CH:41]=4)[CH2:34][CH2:35][C@@H:29]3[CH2:28]2)=[O:57])[CH:48]=[C:47]([C:49]([F:50])([F:51])[F:52])[CH:46]=1
Reactant: CC(C)(C)OC(=O)n1cc(C[C@@H]2CN3CC(c4ccncc4)=CC[C@@H]3CN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccccc21
Agent: CC(C)(C)OC(=O)n1cc(C[C@@H]2CN3C=C(c4ccncc4)CC[C@@H]3CN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccccc21
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1C[C@H]2CCC(c3ccncc3)=CN2C[C@H]1Cc1c[nH]c2ccccc12
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To mixture of anisole (35 mg), (3R,9aR)-3-[2-(3,5-bis(trifluoromethyl)-benzoyl)-7-pyridin-4-yl-1,3,4,6,9,9a-hexahydro-2H-pyrido[1,2-a]pyrazin-3-ylmethyl]-indole-1-carboxylic acid tert-butyl ester and (3R,9aR)-3-[2-(3,5-bis(trifluoromethyl)-benzoyl)-7-pyridin-4-yl-1,3,4,8,9,9a-hexahydro-2H-pyrido[1,2-a]pyrazin-3-ylmethyl]-indole-1-carboxylic acid tert-butyl ester (0.20 g) in dichloromethane (2 ml) was added trifluoroacetic acid, at 0° C. After 1.5 h at room temperature the mixture was diluted with dichloromethane, quenched with ice, and carefully basified with ammonium hydroxide. The layers were separated, the organic layer dried filtered and concentrated in vacuo. The residue was dissolved in methanol and heated at 50° C. for 1 h, then cooled to room temperature and concentrated in vacuo. The residual solid was stirred with hexanes overnight and then collected by filtration to afford (3R,9aR)-(3,5-bis(trifluoromethyl)phenyl)-[3-(1H-indol-3-ylmethyl)-7-pyridin-4-yl-1,3,4,8,9,9a-hexahydro-pyrido[1,2-a]pyrazin-2-yl]-methanone (compound 1) (70 mg). Rf 0.51 (SiO2, CH2Cl2/MeOH/NH4OH 93:7:0.5).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: Nc1ccccc1
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(S(=O)(=O)Nc2ccccc2)ccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.8 %

Procedure:
4-Chloro-3-nitrobenzenesulfonyl chloride (460 mg, 1.8 mmol) was added to a colorless solution of aniline (250 mg, 2.7 mmol) in CH2Cl2 (10 mL) followed by pyridine (0.80 mL, 10.0 mmol). The resulting orange solution was stirred at room temperature for 30 minutes, after which time the mixture was concentrated under vacuum. Acidification with 2M aq. HCl followed by extraction using EtOAc and drying with Na2SO4 followed by filtration through a plug of silica, gave 500 mg (62%) of 4-chloro-3-nitro-N-phenylbenzenesulfonamide 1H NMR (CDCl3) δ 8.30 (d, 1H), 7.80 (dd, 2H), 7.55 (d, 1H), 7.20 (m, 5H). MS(negESI) m/z=311(M−H+). 1-Methylhomopiperazine (258 mg, 2.3 mmol) was added to a solution of 4-chloro-3-nitro-N-phenylbenzenesulfonamide obtained as above (500 mg, 1.6 mmol) in CH2Cl2 (20 mL) followed by addition of K2CO3 (310 mg, 2.3 mmol The reaction mixture was heated to reflux. After 2.5 h, the solution was concentrated under vacuum. After adjusting to pH=6, the product was extracted using EtOAc to give, after drying with Na2SO4 and concentration, 450 mg (72%) of 4-(4-methyl-1,4-diazepan-1-yl)-3-nitro-N-phenylbenzenesulfonamide as an orange oil. 1H NMR (CDCl3) δ 8.15 (d, 1H), 7.60 (dd, 1H), 7.15 (m), 6.95 (d, 1H), 3.45 (m, 2H), 3.30 (m, 2H), 2.75 (m, 2H), 2.60 (m, 2H), 2.35 (s, 3H), 1.95 (m, 2H). MS (posESI) m/z=391(M+H+). To a solution of 4-(4-methyl-1,4-diazepan-1-yl)-3-nitro-N-phenylbenzenesulfonamide (225 mg, 0.58 mmol) in EtOH/THF (4/1, 25 mL) activated Raney-Ni (slurry in EtOH) and hydrazine monohydrate (142 μL, 2.9 mmol) were added. After stirring for 30 minutes at room temperature, the mixture was filtered and the yellow solution concentrated to give yellow oil. The oil was dissolved in a mixture diethyl ether/EtOAc followed by addition of excess of HCl/ether. The resulting precipitate was filtered and washed with ether to give, after drying under vacuum at 40° C., 88 mg (38%) of 3-amino4-(4-methyl-1,4-diazepan-1-yl)-N-phenylbenzenesulfonamide as a beige solid. Mp 84-85° C. MS (posESI) m/z=361 (M+H+). 1H NMR (MeOH-d3) δ 7.85 (d, 2H), 7.60 (d, 1H), 7.15 (m, 5H), 3.50 (m, 7H), 3.15 (m, 2H), 3.00 (s, 3H), 2.30 (m, 1H), 2.20 (m, 1H). Anal. (C18H24N4SO2.2HCl) C,H,N,S.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([O:28][CH2:29][CH3:30])[CH:25]=[C:24](Br)[CH:23]=2)[C:10]=1[CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH3:2].[N:40]1[CH:45]=[C:44](B(O)O)[CH:43]=[N:42][CH:41]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([O:3][C:4](=[O:39])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:44]3[CH:45]=[N:40][CH:41]=[N:42][CH:43]=3)[CH:25]=[C:26]([O:28][CH2:29][CH3:30])[CH:27]=2)[C:10]=1[CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH3:2]
Reactant: OB(O)c1cncnc1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(OCC)c2)c1CCC(=O)OCC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(OCC)cc(-c3cncnc3)c2)c1CCC(=O)OCC
Yield: 31 %

Procedure:
A similar procedure as described in Example 44, step 3 was used, starting from 4-[3-[6-(3-bromo-5-ethoxy-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (305 mg, 0.5 mmol), pyrimidin-5-ylboronic acid (124 mg, 1.0 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (55 mg, 0.075 mmol), and cesium carbonate (331 mg, 1.0 mmol) to obtain 4-[2-(2-ethoxycarbonyl-ethyl)-3-[6-(3-ethoxy-5-pyrimidin-5-yl-phenoxy)-hexyl]-phenoxy]-butyric acid ethyl ester (94 mg, 31%) as a light brown oil: ES(+)-HRMS m/e calcd for C35H46N2O7 (M+H)+ 607.3378. found 607.3379.