Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]Br.[Br-].[Br-].[Br-].[CH2:6]([N+:9]([CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30])([CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])[CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH3:16])[CH2:7][CH3:8].[CH2:31]([N+:34]([CH2:49][CH2:50][O:51][CH2:52][CH2:53][O:54][CH3:55])([CH2:42][CH2:43][O:44][CH2:45][CH2:46][O:47][CH3:48])[CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH3:41])[CH2:32][CH3:33].[CH2:56]([N+:59]([CH2:74][CH2:75][O:76][CH2:77][CH2:78][O:79][CH3:80])([CH2:67][CH2:68][O:69][CH2:70][CH2:71][O:72][CH3:73])[CH2:60][CH2:61][O:62][CH2:63][CH2:64][O:65][CH3:66])[CH2:57][CH3:58]>>[Br-:1].[Br-:1].[Br-:1].[CH:6]([N+:9]([CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH3:16])([CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30])[CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])=[CH:7][CH3:8].[CH:31]([N+:34]([CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH3:41])([CH2:49][CH2:50][O:51][CH2:52][CH2:53][O:54][CH3:55])[CH2:42][CH2:43][O:44][CH2:45][CH2:46][O:47][CH3:48])=[CH:32][CH3:33].[CH:56]([N+:59]([CH2:60][CH2:61][O:62][CH2:63][CH2:64][O:65][CH3:66])([CH2:74][CH2:75][O:76][CH2:77][CH2:78][O:79][CH3:80])[CH2:67][CH2:68][O:69][CH2:70][CH2:71][O:72][CH3:73])=[CH:57][CH3:58]
Reactant: BrBr
Reactant: CCC[N+](CCOCCOC)(CCOCCOC)CCOCCOC
Agent: [Br-]
Product: CC=C[N+](CCOCCOC)(CCOCCOC)CCOCCOC

Procedure:
The crude quaternary ammonium salt (5.36 g, 12 mmoles) was placed in a round bottom flask and bromine (0.61 ml, 1.92 g, 12 mmoles) added dropwise from a buret with vigorous stirring. The product, N-propyl-N,N,N-tris(3,6-dioxaheptyl)ammonium tribromide, was a dark red oil (yield 7.27 g, 100%). %Brtot =39.18 (exp), 39.54 (calc); %Brox =20.38 (exp), 26.36 (calc).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15](=[O:23])[C:16]3[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=3)=[CH:11][CH:12]=2)[C:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([CH3:24])[CH2:6][C:5]1([CH3:32])[CH3:31])(=[O:3])[CH3:2].[Cl:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1.[F-].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(COC)OC.C(O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15](=[O:23])[C:16]3[CH:21]=[CH:20][C:19]([C:37]4[CH:38]=[CH:39][C:34]([Cl:33])=[CH:35][CH:36]=4)=[CH:18][CH:17]=3)=[CH:11][CH:12]=2)[C:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([CH3:24])[CH2:6][C:5]1([CH3:32])[CH3:31])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(NC(=O)c3ccc(I)cc3)cc2C(C)(c2ccccc2)CC1(C)C
Reactant: OB(O)c1ccc(Cl)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Cs+]
Solvent: COCCOC
Solvent: CCO
Product: CC(=O)N1c2ccc(NC(=O)c3ccc(-c4ccc(Cl)cc4)cc3)cc2C(C)(c2ccccc2)CC1(C)C

Procedure:
A mixture of 1-acetyl-6-(4-iodobenzoyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (25 mg), 4-chlorobenzeneboronic acid (22 mg), cesium fluoride (14 mg), triphenylphosphine (5.0 mg) and tris(dibenzylideneacetone)dipalladium(0). (4.3 mg) in dimethoxyethane/ethanol 4:1 (5 ml) was stirred for 15 min. as nitrogen was bubbled through the solution. After 3 h. at 80° C. the reaction mixture was concentrated in vacuo, the residue was dissolved in ethyl acetate and washed with 0.5 M HCl, water, 5% aq. NaHCO3, water and brine. The organic layer was dried (MgSO4) and concentrated in vacuo. The residue was chromatographed on silicagel in heptane/ethyl acetate=1/0=>0/1 (v/v) as eluent.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](Cl)=[O:14])=[CH:10][CH:11]=2)[C:6]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:5]1)(=O)C.[CH3:23][N:24]1[C:28]([CH2:29][CH2:30][NH2:31])=[CH:27][N:26]=[CH:25]1>>[F:22][C:19]1[CH:18]=[CH:17][C:16]([C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[C:9]([C:13]([NH:31][CH2:30][CH2:29][C:28]4[N:24]([CH3:23])[CH:25]=[N:26][CH:27]=4)=[O:14])[CH:8]=3)[NH:4][N:5]=2)=[CH:21][CH:20]=1
Reactant: CC(=O)n1nc(-c2ccc(F)cc2)c2cc(C(=O)Cl)ccc21
Reactant: Cn1cncc1CCN
Product: Cn1cncc1CCNC(=O)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Yield: 31.8 %

Procedure:
The product was synthesized as described in Example 109 using 1-acetyl-3-(4-fluorophenyl)-1H-indazole-5-carbonyl chloride (142.5 mg, 0.45 mmol) and 3-methylhistamine 100 mg, 0.5 mmol). The product was purified by semipreparative HPLC (20–80% acetonitrile gradient over 30 minutes at 20 mL/min) to yield the title compound (52 mg, 32% yield). 1H NMR (DMSO-d6) δ 8.85 (s, 1H), 8.5 (s, 1H), 8.05 (m, 2H), 7.9 (d, 1H), 7.7 (d, 1H), 7.4 (m, 3H), 3.9 (s, 3H), 3.6 (m, 2H), 3.0 (m, 2H). ES-MS m/z 364 [M+1]+.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:24](O)=[O:25]>>[OH:9][C:4]1[CH:5]=[CH:6][C:7]([CH:24]=[O:25])=[CH:8][C:3]=1[C:2]([F:10])([F:11])[F:1]
Reactant: O=C(O)C(F)(F)F
Reactant: Oc1ccccc1C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Product: O=Cc1ccc(O)c(C(F)(F)F)c1
Yield: 36 %

Procedure:
A solution of 2-trifluoromethyl phenol (5.0 g, 30.86 mmol) and hexamethylenetetramine (8.64 g, 61.72 mmol) in trifluoracetic acid (50 mL) was heated at 65° C. for 18 h. At the end of this time the solution was concentrated and diluted with a 2N aqueious solution of hydrochloric acid. The acid phase was extracted twice with ethyl acetate and the combined organic extract dried over magnesium sulfate and concentrated. The residue was subjected to chromatography via Biotage (FLASH 40 M, silica, 20% ethyl acetate/hexane) to yield 2.1 g (36%) of 4-hydroxy-3(trifluoromethyl)benzaldehyde. MS (ES) m/z 188.9; HRMS: calcd for C8H5F3O2, 190.0242; found (ESI, [M+H]+), 191.0324.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:17])[CH2:10][CH2:11][CH2:12][C:13](=O)[CH2:14]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]([NH:25][C:26]([NH2:28])=[NH:27])([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>CN(C=O)C>[C:21]([O:20][C:18]([N:25]1[CH:14]=[C:13]([CH2:12][CH2:11][CH2:10][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:17])[N:27]=[C:26]1[NH2:28])=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)NC(=N)N
Reactant: O=C(CBr)CCCC(=O)OCc1ccccc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1cc(CCCC(=O)OCc2ccccc2)nc1N
Temperature: 25 °C
Yield: 64.7 %

Procedure:
6-bromo-5-oxo-hexanoic acid benzyl ester (3.42 g, 11.99 mmol) and Boc-guanidine (5.73 g, 35.97 mmol) were dissolved in DMF (35 mL) and allowed to stir at room temperature. After 48 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 (30-100% EtOAc/Hexanes) to obtain the title compound (2.79 g, 66%) as a colorless oil which solidified upon prolonged standing. 1H NMR (400 MHz, CDCl3) δ 7.35 (m, 5H), 6.51 (s, 1H), 5.91 (s, 2H), 5.12 (s, 2H), 2.41 (m, 4H), 1.94 (quint., 2H, J=7.2 Hz), 1.57 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 173.45, 150.31, 149.59, 138.27, 136.36, 128.67, 128.29, 128.27, 107.05, 84.73, 66.23, 33.82, 28.16, 27.62, 23.79; HRMS (ESI) calcd for C19H26N3O4 (MH)+ 360.1917. found 360.1919.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:19]=[C:18]([CH3:20])[C:17]([O:21][CH2:22][C@@H:23]4[CH2:25][O:24]4)=[C:16]([CH2:26][CH3:27])[CH:15]=3)[N:10]=2)[CH:6]=[C:5]([CH3:28])[N:4]=1)[CH3:2].[NH3:29]>CO>[NH2:29][CH2:25][C@@H:23]([OH:24])[CH2:22][O:21][C:17]1[C:18]([CH3:20])=[CH:19][C:14]([C:11]2[N:10]=[C:9]([C:7]3[CH:6]=[C:5]([CH3:28])[N:4]=[C:3]([CH2:1][CH3:2])[CH:8]=3)[O:13][N:12]=2)=[CH:15][C:16]=1[CH2:26][CH3:27]
Reactant: N
Reactant: CCc1cc(-c2nc(-c3cc(C)c(OC[C@@H]4CO4)c(CC)c3)no2)cc(C)n1
Solvent: CO
Product: CCc1cc(-c2nc(-c3cc(C)c(OC[C@H](O)CN)c(CC)c3)no2)cc(C)n1

Procedure:
(S)-2-ethyl-4-[3-(3-ethyl-5-methyl-4-oxiranylmethoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-6-methyl-pyridine is treated with ammonia in MeOH as described in Example 46 step b) to give (R)-1-amino-3-{2-ethyl-4-[5-(2-ethyl-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenoxy}-propan-2-ol.
Reaction SMILES: Br[C:2]1[S:6][C:5]([N+:7]([O-:9])=[O:8])=[C:4]([C:10]([NH2:12])=[O:11])[CH:3]=1.CC1(C)C(C)(C)OB([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.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>[CH3:30][S:27]([C:24]1[CH:25]=[CH:26][C:21]([C:2]2[S:6][C:5]([N+:7]([O-:9])=[O:8])=[C:4]([C:10]([NH2:12])=[O:11])[CH:3]=2)=[CH:22][CH:23]=1)(=[O:29])=[O:28]
Reactant: CC1(C)OB(c2ccc(S(C)(=O)=O)cc2)OC1(C)C
Reactant: NC(=O)c1cc(Br)sc1[N+](=O)[O-]
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: C1CCOC1
Product: CS(=O)(=O)c1ccc(-c2cc(C(N)=O)c([N+](=O)[O-])s2)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
5-Bromo-2-nitrothiophene-3-carboxamide (1 g, 3.98 mmol), 4,4,5,5-tetramethyl-2-[4-(methylsulfonyl)phenyl]-1,3,2-dioxaborolane (1.236 g, 4.38 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.230 g, 0.199 mmol) were taken up in THF (14 mL)/2 N Na2CO3 (6 mL) The reaction was stirred at 80° C. overnight. Room temperature was attained and the resulting precipitate was collected by filtration, washed with water and triturated in EtOH to give the title compound as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.Cl.[F:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1>C(N(CC)CC)C>[F:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]2[CH2:26][CH2:25][N:24]([CH2:8][C:7]3[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[CH2:23][CH2:22]2)=[CH:19][CH:20]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(CN2CCN(c3ccc(F)cc3)CC2)cc1

Procedure:
In the manner given in Example 1A, p-nitrobenzyl chloride is reacted with 1-(p-fluorophenyl)piperazine dihydrochloride in the presence of triethylamine to give 1-(p-fluorophenyl)-4-(p-nitrobenzyl)piperazine
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:6][CH:5]([C:7]2[C:8]([O:28][CH3:29])=[C:9]([CH:15]([N:17]3[C:21]4=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]4[C:19]([CH3:27])=[N:18]3)[CH3:16])[CH:10]=[C:11]([Cl:14])[C:12]=2[CH3:13])[CH2:4]1.FC(F)(F)S(O[CH2:36][C:37]([F:40])([F:39])[F:38])(=O)=O.C(N(CC)CC)C>C(Cl)Cl>[Cl:14][C:11]1[C:12]([CH3:13])=[C:7]([CH:5]2[CH2:4][N:3]([CH2:36][C:37]([F:40])([F:39])[F:38])[CH2:6]2)[C:8]([O:28][CH3:29])=[C:9]([CH:15]([N:17]2[C:21]3=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]3[C:19]([CH3:27])=[N:18]2)[CH3:16])[CH:10]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CN(CC(F)(F)F)C1
Temperature: 25 °C
Yield: 40 %

Procedure:
A mixture of 1-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride (15 mg, 0.024 mmol, chiral intermediate from first peak of Example 1, step 7), 2,2,2-trifluoroethyl trifluoromethanesulfonate (6.8 mg, 0.029 mmol) and triethylamine (12 μL, 0.085 mmol) in methylene chloride (0.3 mL) was stirred over a weekend at room temperature. The solvents were evaporated and the crude purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give 4.5 mg (39%) of the desired product. The product was isolated as a single enantiomer. LCMS calculated for C21H25ClF3N6O (M+H)+: m/z=469.2; Found: 469.1.
Reaction SMILES: [ClH:1].[C:2]1([C@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[NH2:13])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH:15]1([C@@H:21]2CCC[C@H:22]2[NH2:26])[CH2:20][CH2:19][CH2:18]CC1>>[ClH:1].[CH:2]1([C@@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[N:13]=[C:22]2[CH2:21][CH2:15][CH2:20][CH2:19][CH2:18][NH:26]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: N[C@@H]1CCC[C@H]1C1CCCCC1
Reactant: N[C@@H]1CCC[C@@H]1c1ccccc1
Agent: Cl
Product: C1CCNC(=N[C@@H]2CCC[C@H]2C2CCCCC2)CC1

Procedure:
By the procedure described in Example 3(A) only substituting for cis-2-phenylcyclopentylamine hydrochloride an appropriate amount of trans-2-phenylcyclopentylamine hydrochloride, M.P. 142°-143° C., the hydrochloride salt of trans-2-cyclohexylcyclopentylamine was obtained, M.P. 199°-200° C. Following the procedure of Example 1 only substituting for cis-2-phenylcyclopentylamine hydrochloride an appropriate amount of trans-2-cyclohexylcyclopentylamine hydrochloride and employing a reaction time of 38 days, the desired product was obtained, M.P. 208°-210° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].C([O-])([O-])=O.[K+].[K+].Br[CH2:18][CH:19]1[CH2:21][CH2:20]1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:18][CH:19]1[CH2:21][CH2:20]1)[CH:5]=[O:6]
Reactant: O=Cc1ccc(O)c(Br)c1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCC2CC2)c(Br)c1
Temperature: 60 °C
Yield: 84.6 %

Procedure:
A well stirred mixture of commercially available 3-bromo-4-hydroxy-benzaldehyde (40.2 g; 220 mmol), anhydrous K2CO3 (30.4 g; 220 mmol) and commercially available bromomethyl-cyclopropane (32.4 g; 240 mmol) in dry DMF (200 mL) is heated to 60° C. over night. The reaction mixture is filtered, concentrated under reduced pressure, diluted with water and extracted with tert. BuOMe. The combined organic extracts are washed with brine, dried over Mg2SO4 and concentrated under reduced pressure. The residue is chromatographed on silica gel (cyclohexane/AcOEt 100:0 to 85:15) to yield 47.5 g of the title compound as pale yellow oil.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[CH2:9][CH:10]([C:12]1[CH:13]=[C:14]2[C:18](=[C:19]([C:21]([NH2:23])=[O:22])[CH:20]=1)[NH:17][CH:16]=[CH:15]2)[OH:11])C1C=CC=CC=1>CO.[Pd]>[NH2:8][CH2:9][CH:10]([C:12]1[CH:13]=[C:14]2[C:18](=[C:19]([C:21]([NH2:23])=[O:22])[CH:20]=1)[NH:17][CH:16]=[CH:15]2)[OH:11]
Reactant: NC(=O)c1cc(C(O)CN(Cc2ccccc2)Cc2ccccc2)cc2cc[nH]c12
Agent: [Pd]
Solvent: CO
Product: NCC(O)c1cc(C(N)=O)c2[nH]ccc2c1

Procedure:
A solution of 5-[2-(dibenzylamino)-1-hydroxyethyl]-indole-7-carboxamide (119.7 mg, 0.3 mmol, described above) was hydrogenated for 28 hours at atmospheric pressure and room temperature in dry methanol (12.0 mL) containing 10% palladium on carbon. The mixture was filtered and the filtrate was evaporated. Crystallization from an ethyl acetate-diethyl ether mixture gave 5-(2-amino-1-hydroxyethyl)indole-7-carboxamide: mp 88°-90° C.; and NMR (DMSO-d6) δ 2.70 (d, 2H), 2.80-3.60 (br s, 5H), 4.50 (t, 1H), 6.40 (m, 1H), 7.00-7.70 (m, 3H) and 10.75 (br s, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].CCOCC>O>[CH3:20][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1
Reactant: CN(C)CCCCCC(=O)N1CCCc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CN(C)CCCCCCN1CCCc2ccccc21

Procedure:
The 1-(6-dimethylaminohexanoyl)-1,2,3,4-tetrahydroquinoline (4.0 g) was added to a mixture of lithium aluminium hydride (1.4 g) and ether (200 ml). The mixture was refluxed for 5 hours, then cooled. Water was added cautiously, and the organic solution was separated, dried and evaporated to give the title compound as an oil which is then converted to the dihydrochloride, mp 116°-119°.
Reaction SMILES: O=[C:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.[CH3:13][NH:14][CH:15]1[CH2:18][CH2:17][CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(OCC)(=O)C>[CH:15]1([N:14]([CH3:13])[CH:2]2[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]2)[CH2:18][CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: CNC1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN(C1CCC1)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 20 °C
Reaction time: 3 h
Yield: 48.7 %

Procedure:
Combined a solution of tert-butyl 3-oxoazetidine-1-carboxylate (500 mg, 2.92 mmol) and N-methylcyclobutanamine (0.373 mL, 3.50 mmol) in methylene chloride (15 mL) and added sodium triacetoxyborohydride (929 mg, 4.38 mmol) and the solution stirred at 20° C. for 3 h. The solution was concentrated in vacuo to give a white solid. The solid was taken up in ethyl acetate (50 mL), washed with saturated sodium bicarbonate (50 mL) and brine, dried with magnesium sulfate, and concentrated in vacuo to give a residue which was purified on a 40 g silica gel column eluted with 0 to 70% ethyl acetate in hexanes to give the title compound (342 mg, 1.423 mmol, 48.7%) as a clear, colorless oil. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.43 (s, 9 H) 1.60-1.75 (m, 2 H) 1.85-2.04 (m, 4 H) 2.07 (s, 3 H) 2.81-2.94 (m, 1 H) 3.27-3.30 (m, 1 H) 3.81-3.88 (m, 2 H) 3.88-3.97 (m, 2 H); MS: 241 (M+H).
Reaction SMILES: [C:1]1(=[CH:5][C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1>C1(C)C=CC=CC=1>[F:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]2[C:10]=1[C:1]1([CH2:4][CH2:3][CH2:2]1)[CH2:5][C:6](=[O:7])[NH:8]2
Reactant: O=C(C=C1CCC1)Nc1cccc(F)c1
Solvent: Cc1ccccc1
Product: O=C1CC2(CCC2)c2c(F)cccc2N1
Yield: 13.8 %

Procedure:
A solution of 400 mg (1.94 mmol) of 2-cyclobutylidene-N-(3-fluorophenyl)-acetamide obtained in step 31.1 was dissolved in 19.5 ml of toluene and irradiated with a Hg middle pressure lamp in a suitable device till completion of the reaction indicated by liquid chromatography. The crude solution was concentrated in vacuo and the residue was purified by column chromatography on silica (eluent: 10-30% ethyl acetate in heptane) to yield 55 mg (14%) of the title compound as a beige solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:12]2[CH2:25][CH2:24][C:15]3([O:20][CH2:19][C:18](=[O:21])[N:17]([CH2:22][CH3:23])[CH2:16]3)[CH2:14][CH2:13]2)[C:9]([NH2:11])=[O:10])=[C:4]([F:26])[CH:3]=1.CC1(C)C(C)(C)OB(B2OC(C)(C)C(C)(C)O2)O1.C([O-])(=O)C.[K+].Br[C:51]1[CH:60]=[C:59]2[C:54]([CH:55]=[C:56]([CH3:61])[CH:57]=[N:58]2)=[CH:53][CH:52]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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].C(Cl)Cl>[CH2:22]([N:17]1[CH2:16][C:15]2([CH2:24][CH2:25][N:12]([CH:8]([C:5]3[CH:6]=[CH:7][C:2]([C:51]4[CH:60]=[C:59]5[C:54]([CH:55]=[C:56]([CH3:61])[CH:57]=[N:58]5)=[CH:53][CH:52]=4)=[CH:3][C:4]=3[F:26])[C:9]([NH2:11])=[O:10])[CH2:13][CH2:14]2)[O:20][CH2:19][C:18]1=[O:21])[CH3:23]
Reactant: CCN1CC2(CCN(C(C(N)=O)c3ccc(Br)cc3F)CC2)OCC1=O
Reactant: Cc1cnc2cc(Br)ccc2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCN1CC2(CCN(C(C(N)=O)c3ccc(-c4ccc5cc(C)cnc5c4)cc3F)CC2)OCC1=O
Temperature: 120 °C
Reaction time: 1 h
Yield: 53.4 %

Procedure:
To a solution of 2-(4-bromo-2-fluorophenyl)-2-(4-ethyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)acetamide (212 mg, 0.5 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (126 mg, 0.5 mmol), and potassium acetate (97 mg, 0.99 mmol) in 1,4-dioxane (2.5 mL) was added PdCl2(dppf)-CH2Cl2 adduct (40 mg, 0.05 mmol). The reaction mixture was purged with nitrogen and heated at 120° C. for 4 h. The reaction mixture was cooled and 7-bromo-3-methylquinoline (110 mg, 0.5 mmol) and 2M aq K2CO3 (0.55 mL, 1.09 mmol) were added. The reaction mixture was purged with nitrogen and was heated with stirring at 100° C. for 1 h. The reaction mixture was diluted with dichloromethane (60 mL) and any salts were filtered away. The organic mixture was filtered through a plug of celite and sodium sulfate. The filtrate was treated with a small amount of Silicycle Si-thiol resin for 30 min. The mixture was filtered and concentrated in vacuo. Purification of the residue by reverse phase HPLC (10-70% acetonitrile:water with 0.1% NH4OH) provided the title product (131 mg, 51% yield). MS(ES)+ m/e 491 [M+H]+; 1H NMR (400 MHz, CD2Cl2) δ ppm 1.12 (t, J=7.20 Hz, 3 H) 1.63-1.86 (m, 3 H) 1.86-2.05 (m, 2 H) 2.29-2.41 (m, 1 H) 2.53-2.59 (m, 3 H) 2.59-2.74 (m, 2 H) 2.79 (d, J=11.62 Hz, 1 H) 3.41 (q, J=7.33 Hz, 2 H) 3.95-4.10 (m, 2 H) 4.52 (s, 1 H) 5.87 (d, J=4.04 Hz, 1 H) 7.28 (d, J=3.54 Hz, 1 H) 7.41-7.50 (m, 1 H) 7.55 (dd, J=11.37, 1.77 Hz, 1 H) 7.62 (dd, J=7.96, 1.89 Hz, 1 H) 7.82 (dd, J=8.46, 1.89 Hz, 1 H) 7.90 (d, J=8.59 Hz, 1 H) 7.97-8.05 (m, 1 H) 8.27-8.36 (m, 1 H) 8.83 (d, J=2.27 Hz, 1 H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].Cl[C:13]1[C:14]2[C:27]([Cl:28])=[C:26]([CH3:29])[S:25][C:15]=2[N:16]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[N:18]=1>>[N:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:17]1[N:18]=[C:13]([NH:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:14]2[C:27]([Cl:28])=[C:26]([CH3:29])[S:25][C:15]=2[N:16]=1
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: Cc1sc2nc(-c3ccccn3)nc(Cl)c2c1Cl
Product: Cc1sc2nc(-c3ccccn3)nc(NCc3cccc([N+](=O)[O-])c3)c2c1Cl

Procedure:
With the procedure of Example 1, the reaction of 3-nitrobenzylamine with 4-chloro-2-(pyridin-2-yl)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-(3-nitrobenzylamino)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]([OH:8])[C:5]2[CH:9]=[CH:10][O:11][C:4]=2[CH2:3]1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16](F)=[CH:15][C:14]=1[N+:20]([O-:22])=[O:21]>>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([O:8][CH:6]2[CH2:7][N:2]([CH3:1])[CH2:3][C:4]3[O:11][CH:10]=[CH:9][C:5]2=3)=[CH:15][C:14]=1[N+:20]([O-:22])=[O:21]
Reactant: CN1Cc2occc2C(O)C1
Reactant: O=[N+]([O-])c1cc(F)ccc1Cl
Product: CN1Cc2occc2C(Oc2ccc(Cl)c([N+](=O)[O-])c2)C1

Procedure:
The same method as in Example 1 was conducted using 6-methyl-4,5,6,7-tetrahydrofuro[2,3-c]pyridin-4-ol (Reference Example 1) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 2-chloro-5-fluoronitrobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[NH:10][NH2:11].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=O)[CH:20]([S:28][CH3:29])[C:21](=O)[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:15][CH:14]=1>C(O)C>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:10]([C:4]3[CH:5]=[CH:6][C:7]([Cl:9])=[CH:8][C:3]=3[Cl:2])[N:11]=[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:20]=2[S:28][CH3:29])=[CH:15][CH:14]=1
Reactant: NNc1ccc(Cl)cc1Cl
Reactant: CCOC(=O)C(=O)C(SC)C(=O)c1ccc(Cl)cc1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1nn(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)c1SC
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.4 %

Procedure:
To a solution of 15.6 g of 2,4-dichlorophenylhydrazine hydrochloride (5) in mL of ethanol was added 22 g of ethyl 4-(4-chlorophenyl)-3-(methylthio)-2,4-dioxobutanoate (4) in 120 mL of ethanol at room temperature. After 2 hours, the mixture was refluxed for 15 hours and then cooled to the room temperature. The mixture was filtered off and the filtrate was evaporated off under the reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: hexane/EtOAc mixture (80/20; v/v) to obtain 25 g of the title compound as pale orange color solid.