Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2](=[CH:4][CH3:5])[CH3:3].[N+:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])([O-:8])=[O:7]>>[CH:3]([O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[N+:6]([O-:8])=[O:7])=[CH:2][CH2:4][CH3:5]
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: CC=C(C)Br
Product: CCC=COc1ccccc1[N+](=O)[O-]

Procedure:
2-Bromo-but-2-ene was reacted with o-nitrophenol to yield 2-but-1-en-oxynitrobenzene; which was reduced to the corresponding aniline; then reacted with N-chloromethyl-2-pyrrolidone to form the corresponding N-methylene-2-pyrrolidonyl derivative.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[Cl:9].C([Li])CCC.C[O:16][C:17]1[CH2:21][CH2:20][C:19](=O)[CH:18]=1>C1COCC1>[Cl:9][C:3]1[CH:4]=[C:5]([C:19]2[CH2:20][CH2:21][C:17](=[O:16])[CH:18]=2)[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: COC1=CC(=O)CC1
Reactant: Clc1ccc(I)cc1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C1C=C(c2ccc(Cl)c(Cl)c2)CC1
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 36 %

Procedure:
A solution of 1,2-dichloro-4-iodobenzene (1.0 g, 3.66 mmol) in THF (50 mL) at −78° C. was treated with a solution of n-butyllithium (2.5 M in hexanes; 1.5 mL, 3.8 mmol) such that the reaction temperature remained ≦−78° C. After 15 min, a solution of 3-methoxy-2-cyclopenten-1-one (0.452 g, 3.96 mmol) in THF (20 mL) was added such that the reaction temperature remained ≦−78° C. The reaction mixture was warmed to −20° C. over 2 h, quenched with a solution of 1N HCl and concentrated in vacuo to remove THF. A solution of 1N HCl (5 mL) was added, the solution was stirred for 30 min and extracted with EtOAc (2×). The combined organic extracts were washed with saturated aqueous NaHCO3, brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography using EtOAc/Heptanes as the eluting solvent to afford 0.3 g of target compound as a white powder (Yield 36%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.58-2.62 (m, 2 H) 2.97-3.03 (m, 2 H) 6.56 (t, 1 H) 7.45-7.55 (m, 2 H) 7.71 (d, 1 H).
Reaction SMILES: [CH3:1][CH:2]([CH3:23])[CH2:3][N:4]1[C:16]2[C:15]3[N:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N+:9]([O-])=[CH:8][C:7]=2[N:6]=[C:5]1[NH:18][C:19](=[O:22])[O:20][CH3:21].[OH-].[NH4+:25].C1(S(Cl)(=O)=O)C=CC=CC=1>CO>[NH2:25][C:8]1[C:7]2[N:6]=[C:5]([NH:18][C:19](=[O:22])[O:20][CH3:21])[N:4]([CH2:3][CH:2]([CH3:23])[CH3:1])[C:16]=2[C:15]2[N:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: [NH4+]
Reactant: COC(=O)Nc1nc2c[n+]([O-])c3cccnc3c2n1CC(C)C
Agent: O=S(=O)(Cl)c1ccccc1
Agent: [OH-]
Solvent: CO
Product: COC(=O)Nc1nc2c(N)nc3cccnc3c2n1CC(C)C
Temperature: 50 °C
Yield: 29.7 %

Procedure:
A suspension of methyl [1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridin-2-yl]carbamate (0.9 g, 3 mmol) in methanol (25 mL) was stirred vigorously and heated to 50° C. Concentrated ammonium hydroxide (0.95 mL, 14 mmol) was added followed by benzenesulfonyl chloride (1.06 g, 5.99 mmol), which was added dropwise. The mixture was stirred for two hours at 50° C. An analysis by LC/MS indicated the reaction was incomplete. Additional benzenesulfonyl chloride (1.06 g) and concentrated ammonium hydroxide (0.95 mL) were added, and the reaction mixture was stirred overnight at 45° C. The solvent was removed under reduced pressure, and the residue dissolved in chloroform (100 mL). The solution was washed sequentially with aqueous sodium carbonate (2×100 mL of 4% w/w) and water (100 mL) and then purified by automated flash chromatography (40+M silica cartridge, eluting with 5% to 25% CMA in chloroform) followed by recrystallization from ethyl acetate to provide 0.28 g of methyl [4-amino-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-2-yl]carbamate as a yellow solid.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:13]=[CH:12]3)O1.I[C:27]1[C:35]2[C:30](=[N:31][CH:32]=[N:33][C:34]=2[NH2:36])[N:29]([CH:37]([CH3:39])[CH3:38])[N:28]=1.C([O-])([O-])=O.[Na+].[Na+].[CH3:46][CH2:47]O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:36][C:34]1[N:33]=[CH:32][N:31]=[C:30]2[N:29]([CH:37]3[CH2:39][CH2:47][CH2:46][CH2:38]3)[N:28]=[C:27]([C:9]3[CH:10]=[C:11]4[C:15](=[CH:16][CH:17]=3)[N:14]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH:13]=[CH:12]4)[C:35]=12
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Reactant: CCO
Reactant: CC(C)(C)OC(=O)n1ccc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)n1ccc2cc(-c3nn(C4CCCC4)c4ncnc(N)c34)ccc21
Temperature: 80 °C

Procedure:
A solution of tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate (130 mg, 0.38 mmol) in EtOH (3.3 ml) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (50 mg, 0.15 mmol) in DME (12 ml). Pd(PPh3)4 (30 mg, 0.03 mmol) and saturated Na2CO3 (1.9 ml) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O) to yield BA88. ESI-MS (M+H)+ m/z calcd 419.2, found 419.1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15]CN)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[N:19]1([C:24]2[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=2)[CH:23]=[CH:22][N:21]=[CH:20]1.C([N:34](CC)CC)C>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:34][CH2:28][C:27]2[CH:30]=[CH:31][C:24]([N:19]3[CH:23]=[CH:22][N:21]=[CH:20]3)=[CH:25][CH:26]=2)[CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)COc1cccc(CCN)c1
Reactant: O=Cc1ccc(-n2ccnc2)cc1
Product: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-n3ccnc3)cc2)c1

Procedure:
The title compound of Step A was prepared from (3-aminoethyl-phenoxy)-acetic acid tert-butyl ester, of Preparation 20, and 4-imidazol-1-yl-benzaldehyde, of Preparation 43, using the method described in Example 3, Step A, except no triethylamine was used. 1H NMR (400 MHz, CDCl3) δ 7.78 (s, 1H), 7.40 (d, 2H), 7.28 (d, 2H), 7.22 (m, 2H), 7.13 (m, 1H), 6.89 (m, 2H), 6.73 (m, 1H); 4.47 (s, 2H), 3.78 (s, 2H), 3.74 (s, 2H), 1.43 (s, 9H; MS 394 (M+1).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C:7](=[N:14][NH:15][C:16](=[O:25])[C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[CH3:24])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[N+:2]=[N-:3].[C:26](Cl)(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28].O>N1C=CC=CC=1>[N:1]([CH2:4][CH2:5][CH2:6][C:7]1([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:14]([C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[N:15]=[C:16]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[CH3:24])[O:25]1)=[N+:2]=[N-:3]
Reactant: Cc1ccc(Cl)cc1C(=O)NN=C(CCCN=[N+]=[N-])c1ccccc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(Cl)cc1C1=NN(C(=O)C(C)(C)C)C(CCCN=[N+]=[N-])(c2ccccc2)O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.3 %

Procedure:
To a solution of N′-(4-azido-1-phenylbutylidene)-5-chloro-2-methyl benzohydrazide (100 mg, 0.28 mmol) in pyridine (1 mL) was added pivaloyl chloride (70 μL, 0.56 mmol). After stirring at room temperature for 16 hours the heterogeneous mixture was treated with water (10 mL) and extracted with EtOAc (3×10 mL). The combined organic phases were washed successively with 10% NaHSO4 (2×10 mL), NaHCO3 (10 mL) and brine (10 mL) then dried over Na2SO4 and concentrated. The residue was purified by preparative TLC (9:1 hexanes/EtOAc) to afford the product (62 mg, 50%) as a colorless oil.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C=O)C.[F:25][C:26]1[CH:27]=[C:28]([S:33](Cl)(=O)=O)[CH:29]=[CH:30][C:31]=1[F:32].Cl>C(Cl)Cl>[F:25][C:26]1[CH:27]=[C:28]([SH:33])[CH:29]=[CH:30][C:31]=1[F:32]
Reactant: O=S(=O)(Cl)c1ccc(F)c(F)c1
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Fc1ccc(S)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of triphenylphosphine (37.0 g) and DMF (2 ml) in DCM (100 ml) was maintained at 20° C. with an ice bath during addition of 3,4-difluorobenzenesulphonyl chloride (10 g). The mixture was stirred at room temperature for 2 hours then aqueous hydrochloric acid (50 ml of a 1M solution) was added. The mixture was stirred for a further 1 hour. The organic layer was separated, dried and the solvent removed by evaporation to give the title compound as an oil which was used without purification.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH:6]=[C:7]([Si:14]([CH3:17])([CH3:16])[CH3:15])[C:8]([OH:13])=[CH:9]2)=[CH:4][CH:3]=1.Br[CH2:19][CH3:20].C(=O)([O-])[O-].[K+].[K+]>CC(CC)=O>[CH2:19]([O:13][C:8]1[C:7]([Si:14]([CH3:17])([CH3:16])[CH3:15])=[CH:6][C:5]2[C:10]([CH:9]=1)=[C:11]([F:12])[C:2]([F:1])=[CH:3][CH:4]=2)[CH3:20]
Reactant: CCBr
Reactant: C[Si](C)(C)c1cc2ccc(F)c(F)c2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOc1cc2c(F)c(F)ccc2cc1[Si](C)(C)C

Procedure:
54.7 g (about 0.12 mol) of 7,8-difluoro-3-trimethylsilanylnaphthalen-2-ol are stirred at 80° C. for 19 h together with 19.5 ml (0.26 mol) of bromoethane and 34.5 g (0.25 mol) of potassium carbonate in 400 ml of ethyl methyl ketone. The batch is filtered, and the residue is washed with ethyl methyl ketone. The filtrate is concentrated, and the residue is taken up in MTBE. The solution is washed with water and sat. sodium chloride soln. and dried using sodium sulfate. The residue remaining after removal of the solvent is purified by column chromatography (SiO2, toluene:ethyl acetate=9:1), giving (3-ethoxy-5,6-difluoronaphthalen-2-yl)trimethylsilane as a dark-brown solid.
Reaction SMILES: Cl.[NH2:2][N:3]1[C:12]2[N:11]=[C:10]([N:13]3[CH:17]=[CH:16][N:15]=[C:14]3[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]=[CH:8][C:7]=2[N:6]([CH3:24])[C:5](=[O:25])[CH:4]1[CH2:26][CH3:27].Br[CH2:29][CH2:30][CH2:31][CH2:32]Br.C(=O)([O-])[O-].[K+].[K+]>CC#N>[CH2:26]([CH:4]1[N:3]([N:2]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[C:12]2[N:11]=[C:10]([N:13]3[CH:17]=[CH:16][N:15]=[C:14]3[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]=[CH:8][C:7]=2[N:6]([CH3:24])[C:5]1=[O:25])[CH3:27]
Reactant: BrCCCCBr
Reactant: CCC1C(=O)N(C)c2cnc(-n3ccnc3-c3ccccc3)nc2N1N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCC1C(=O)N(C)c2cnc(-n3ccnc3-c3ccccc3)nc2N1N1CCCC1
Temperature: 80 °C

Procedure:
8-amino-7-ethyl-5-methyl-2-(2-phenyl-1H-imidazol-1-yl)-7,8-dihydropteridin-6(5H)-one hydrochloride salt (Example 278, 28 mg, 0.073 mmol) was combined with 1,4-dibromobutane (0.05 mL, 0.42 mmol) and potassium carbonate (38 mg, 0.27 mmol) in 0.2 mL of CH3CN. This mixture was heated to 80° C. for 19 h, then filtered, washed with EtOAc, and the filtrate concentrated under reduced pressure. The residue was purified by HPLC to give the title compound. 1H NMR (CD3OD) δ: 8.01 (s, 2H), 7.73 (d, J=1.8 Hz, 1H), 7.70-7.50 (m, 5H), 4.43 (t, J=4.1 Hz, 1H), 3.36 (s, 3H), 2.98-2.83 (m, 2H), 2.83-2.70 (m, 2H), 2.12-1.95 (m, 2H), 1.60-1.40 (m, 4H), 0.79 (t, J=7.5 Hz, 3H); LCMS [M+H]: 404.1 m/z (M+H)+; ret. Time: 6.82 min (Analytical Method C).
Reaction SMILES: [C:1]1([NH:7][C:8]([NH:10][C:11]2[CH:12]=[C:13]([C:17]([NH:19][CH2:20][C:21]([NH:23][CH:24]([C:31]3[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=3)[CH2:25][C:26]([O:28]CC)=[O:27])=[O:22])=[O:18])[CH:14]=[CH:15][CH:16]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Li+].[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42]>O.C(#N)C>[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42].[C:1]1([NH:7][C:8]([NH:10][C:11]2[CH:12]=[C:13]([C:17]([NH:19][CH2:20][C:21]([NH:23][CH:24]([C:31]3[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=3)[CH2:25][C:26]([OH:28])=[O:27])=[O:22])=[O:18])[CH:14]=[CH:15][CH:16]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CC(NC(=O)CNC(=O)c1cccc(NC(=O)Nc2ccccc2)c1)c1cccnc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: O=C(O)CC(NC(=O)CNC(=O)c1cccc(NC(=O)Nc2ccccc2)c1)c1cccnc1
Temperature: 25 °C

Procedure:
The compound of Example 107 (500 mg, 0.095 mmol) was dissolved in water/acetonitrile (1:1), followed by the addition of lithium hydroxide (100 mg, 0.4 mmol). The reaction mixture was stirred at 25° C., and monitored by HPLC. After complete hydrolysis (1-2 hours) trifluoroacetic acid was added until pH=2. The product was purified by reverse phase chromatography (water/acetonitrile) to result in a white solid (350 mg). MS and 1H-NMR were consistent with proposed structure.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[C:31]([F:34])([F:33])[F:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[NH2:78][CH:79]1[CH2:84][CH2:83][N:82]([CH3:85])[CH2:81][CH2:80]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:78][CH:79]5[CH2:84][CH2:83][N:82]([CH3:85])[CH2:81][CH2:80]5)=[O:27])=[CH:24][C:23]=4[C:31]([F:33])([F:34])[F:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3C(F)(F)F)ncc21
Reactant: CN1CCC(N)CC1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCC3)CC(F)(F)C(=O)N4C)c(C(F)(F)F)c2)CC1
Reaction time: 0.17 h
Yield: 43.5 %

Procedure:
To a mixture of 0.075 g (0.155 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-trifluoromethyl-benzoic acid (I-204) and 8 mL of dimethylformamide was added 0.0313 g (0.232 mmole) of 1-hydroxybenzotriazole, 0.0880 g (0.232 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 0.080 g (0.617 mmole) of diisopropylethylamine. The mixture was stirred for 10 minutes, then 0.027 g (0.236 mmole) of 4-amino-1-methylpiperidine was added. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of ethyl acetate and washed three times with 10 mL of 1M sodium hydroxide, twice with 15 mL of brine, dried, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-80:20) gave 0.0392 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-methyl-piperidin-4-yl)-3-trifluoromethyl-benzamide (I-205) as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])(C)(C)C.[CH3:26][C:27]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[C:28]=1[CH:29]=[O:30]>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([CH:29]([C:28]3[C:31]([CH3:35])=[CH:32][CH:33]=[CH:34][C:27]=3[CH3:26])[OH:30])=[CH:16][CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc(C2CN(Cc3ccccc3)CCO2)cc1
Reactant: Cc1cccc(C)c1C=O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: Cc1cccc(C)c1C(O)c1ccc(C2CN(Cc3ccccc3)CCO2)cc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 65.5 %

Procedure:
To a solution of 4-benzyl-2-(4-bromo-phenyl)-morpholine (2.1 g, 6.3 mmol) in THF (30 mL), at −78° C., was added dropwise t-butyl lithium (7.9 mL; 1.6 mol/l in heptanes; 12.6 mmol). The mixture was stirred for 20 min. at −78° C., and subsequently 2,6-dimethylbenzaldehyde (1 g, 7.6 mmol) was added. The mixture was allowed to warm to RT and stirred overnight. The resulting mixture was partitioned between water and EtOAc. The layers were separated. The organic layer was washed with water, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (EtOAc:heptanes 1:1) to afford [4-(4-benzyl-morpholin-2-yl)-phenyl]-(2,6-dimethyl-phenyl)-methanol (1.6 g), which was used as such in the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([N:14]3[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][NH2:22])[CH2:16][CH2:15]3)=[N:10][CH:11]=[CH:12][N:13]=2)=[CH:4][CH:3]=1.N1CCOCC1.[C:29]1([S:35]([Cl:38])(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>ClCCl>[ClH:38].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([N:14]3[CH2:15][CH2:16][N:17]([CH2:20][CH2:21][NH:22][S:35]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)(=[O:37])=[O:36])[CH2:18][CH2:19]3)=[N:10][CH:11]=[CH:12][N:13]=2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: NCCN1CCN(c2nccnc2-c2ccc(F)cc2)CC1
Solvent: C1COCCN1
Solvent: ClCCl
Product: Cl
Product: O=S(=O)(NCCN1CCN(c2nccnc2-c2ccc(F)cc2)CC1)c1ccccc1
Yield: 69.3 %

Procedure:
Dissolve 2-[3′-(4-fluorophenyl)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-yl]-ethylamine (0.099 g, 0.329 mmol) in dichloromethane (3 mL). Add resin-bound morpholine (0.145 g, 0.362 mmol) and shake at ambient temperature for 10 min. Add benzenesulfonyl chloride (0.064 g, 0.362 mmol)) and shake reaction at room temperature for 18 hr. Filter, concentrate and purify (SCX chromatography, followed by silica gel chromatography, eluting with 0:100 to 10:90 methanol:dichloromethane), to give free base of the title compound (109 mg, 75%). Dissolve the free base of the title compound (0.105 g, 0.238 mmol) in methanol and add a solution of ammonium chloride (0.013 g, 0.238 mmol) in a minimal volume of MeOH. Shake for 18 hr. at ambient temperature and concentrate to give the title compound (114 mg, 100%). MS (ES): m/z=442 [M+H]+.
Reaction SMILES: ClC(OCC)=O.[CH:7]1([C:13]([OH:15])=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[N:16]1([CH2:22][C:23]2[CH:28]=[CH:27][N:26]=[C:25]([O:29][CH2:30]/[CH:31]=[CH:32]\[CH2:33][NH:34][C:35](=[O:41])[CH2:36][S:37][CH2:38][CH2:39]O)[CH:24]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>C(OCC)(=O)C>[N:16]1([CH2:22][C:23]2[CH:28]=[CH:27][N:26]=[C:25]([O:29][CH2:30]/[CH:31]=[CH:32]\[CH2:33][NH:34][C:35](=[O:41])[CH2:36][S:37][CH2:38][CH2:39][O:14][C:13]([CH:7]3[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]3)=[O:15])[CH:24]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=C(CSCCO)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Reactant: O=C(O)C1CCCCC1
Agent: CCOC(=O)Cl
Solvent: CCOC(C)=O
Product: O=C(CSCCOC(=O)C1CCCCC1)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
0.10 ml of ethyl chloroformate was added, whilst ice-cooling, to a solution of 0.13 ml of cyclohexanecarboxylic acid in 18 ml of ethyl acetate, and the resulting mixture was stirred at room temperature for 1 hour. At the end of this time, a solution of 0.40 g of N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-2-(2-hydroxyethylthio)acetamide (prepared as described in Example 1) in 4 ml of ethyl acetate was added to the reaction mixture, whilst ice-cooling. The reaction mixture was then stirred at room temperature for 1 hour, after which it was heated under reflux for 16 hours. At the end of this time, it was concentrated by evaporation under reduced pressure. The concentrate was purified by column chromatography through silica gel, using a 1:9 by volume mixture of methanol and ethyl acetate as the eluent, to give 0.18 g of the title compound in a 35% yield.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][OH:5].[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([SH:15])=[CH:11][CH:10]=1)([O-:8])=[O:7].[OH-].[Na+]>O>[OH:5][CH2:4][CH2:3][CH2:2][S:15][C:12]1[CH:13]=[CH:14][C:9]([N+:6]([O-:8])=[O:7])=[CH:10][CH:11]=1
Reactant: OCCCCl
Reactant: O=[N+]([O-])c1ccc(S)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=[N+]([O-])c1ccc(SCCCO)cc1
Temperature: 80 °C
Yield: 98.4 %

Procedure:
3-Chloropropanol (6.0 g, 63.5 mmol) was added dropwise to a solution of 4-nitrothiophenol (8.2 g, 52.9 mmol) and sodium hydroxide (3.2 g) in water (120 ml) stirred and heated at 80° C. under nitrogen and the mixture heated at 80° C. for 205 minutes. The mixture was allowed to cool and then extracted with EtOAc (2×100 ml). The extracts were combined, washed with water (50 ml) and brine (50 ml), dried and evaporated to give the title compound (11.1 g, 98%). NMR (CDCl3) 1.99 (m, 2H), 3.18 (t, 2H), 3.81 (m, 2H), 7.35 (d, 2H), 8.13 (d, 2H).
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]([CH3:28])[C:14](=[O:27])[C:15]3[CH:20]=[CH:19][C:18]([CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:17][CH:16]=3)=[CH:9][CH:8]=2)[C:3]1=[O:29].[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[CH:21]1([C:18]2[CH:19]=[CH:20][C:15]([C:14]([N:13]([CH3:28])[C:10]3[CH:11]=[CH:12][C:7]([N:4]4[CH2:5][CH2:6][CH:2]([N:30]5[CH2:35][CH2:34][O:33][CH2:32][CH2:31]5)[C:3]4=[O:29])=[CH:8][CH:9]=3)=[O:27])=[CH:16][CH:17]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: C1COCCN1
Reactant: CN(C(=O)c1ccc(C2CCCCC2)cc1)c1ccc(N2CCC(Br)C2=O)cc1
Product: CN(C(=O)c1ccc(C2CCCCC2)cc1)c1ccc(N2CCC(N3CCOCC3)C2=O)cc1

Procedure:
N-[4-(3-Bromo-2-oxo-pyrrolidin-1-yl)phenyl]-4-cyclohexyl-N-methylbenzamide was reacted with morpholine by method L. This resulted in the product with the molecular weight 461.61 (C28H35N3O3); MS (ESI): 462 (M+H+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[N:24]3[C:19]([CH:20]=[CH:21][CH:22]=[CH:23]3)=[C:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:17]=2[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:33]=2[CH3:39])=[O:15])[CH2:10][C@@H:9]1[CH2:40][C:41](=[O:50])[NH:42][CH2:43][CH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1)=O)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[F:38][C:34]1[C:33]([CH3:39])=[C:32]([CH:37]=[CH:36][CH:35]=1)[CH2:31][C:17]1[C:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:19]2[N:24]([C:16]=1[C:14]([N:11]1[CH2:12][CH2:13][NH:8][C@@H:9]([CH2:40][C:41]([NH:42][CH2:43][CH:44]3[CH2:45][CH2:46][O:47][CH2:48][CH2:49]3)=[O:50])[CH2:10]1)=[O:15])[CH:23]=[CH:22][CH:21]=[CH:20]2
Reactant: Cc1c(F)cccc1Cc1c(-c2ccccc2)c2ccccn2c1C(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](CC(=O)NCC2CCOCC2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1c(F)cccc1Cc1c(-c2ccccc2)c2ccccn2c1C(=O)N1CCN[C@@H](CC(=O)NCC2CCOCC2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.7 %

Procedure:
To a solution of the compound of step 3 (0.113 g, 0.17 mmol) in 1.65 ml of DCM cooled to 0° C. was added a 4 N solution of hydrogen chloride in dioxane (0.41 ml, 1.65 mmol). The mixture was stirred for 3 h at room temperature and then evaporated to dryness. The solid was triturated several times with diethyl ether and dried in vacuo at 40° C. to give 0.071 g of the title compound in the form of 2-{(S)-4-[2-(3-fluoro-2-methyl-benzyl)-1-phenyl-indolizine-3-carbonyl]-piperazin-2-yl}-N-(tetrahydropyran-4-ylmethyl)-acetamide hydrochloride with the following characteristics: