Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:7]2[C:12]([OH:13])=[C:11]([C:14]([NH:16][CH2:17][C:18]([O:20]CC)=[O:19])=[O:15])[C:10](=[O:23])[NH:9][C:8]2=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[Cl:31][C:32]1[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[C:33]=1[CH2:34]Br.Cl>CC(N(C)C)=O>[CH:1]1([N:7]2[C:12]([OH:13])=[C:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[C:10](=[O:23])[N:9]([CH2:34][C:33]3[C:32]([Cl:31])=[CH:39][CH:38]=[CH:37][C:36]=3[Cl:40])[C:8]2=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Clc1cccc(Cl)c1CBr
Reactant: CCOC(=O)CNC(=O)c1c(O)n(C2CCCCC2)c(=O)[nH]c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=C(O)CNC(=O)c1c(O)n(C2CCCCC2)c(=O)n(Cc2c(Cl)cccc2Cl)c1=O
Reaction time: 8 h
Yield: 31.9 %

Procedure:
A mixture of ethyl N-[(1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate (340 mg, 1.0 mmoles), pulv. potassium carbonate (750 mg, 5.35 mmoles) and 2,6-dichlorobenzyl bromide (440 mg, 2.0 mmoles) in dimethylacetamide (6 mL) was vigorously stirred at 100° C. for 3 hours. The mixture was poured into 1 molar hydrochloric acid and extracted with ethyl acetate (×2). The combined organic solutions were washed with 1 molar hydrochloric acid and evaporated. The residue was purified by flash chromatography (10-50% ethyl acetate in hexane), the required fractions evaporated, dissolved in ethanol (5 mL) and 1 molar sodium hydroxide solution (3.0 mL) added. The mixture was stirred overnight, acidified and extracted with ethyl acetate (×2), the combined extracts washed with 1 molar hydrochloric acid, dried and evaporated. Recrystallization from ethanol-water gave the title compound (150 mg, 32%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.07 (br. s., 1 H), 9.98 (br. s., 1 H), 7.43 (dd, 2 H), 7.30 (dd, 1 H), 5.26 (s, 2 H), 4.60 (t, J=12.00 Hz, 1 H), 2.14-2.31 (m, 2 H), 1.77 (d, J=12.88 Hz, 2H), 1.47-1.66 (m, 3 H), 1.27 (q, 2 H), 1.10 (q, 1 H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][CH2:15][C@H:14]([OH:18])[CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O.O.NN>CO>[NH2:9][C:8]1[CH:7]=[CH:6][C:5]([N:12]2[CH2:17][CH2:16][CH2:15][C@H:14]([OH:18])[CH2:13]2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(N2CCC[C@H](O)C2)ccc1[N+](=O)[O-]
Agent: NN
Solvent: CO
Solvent: O
Product: COc1cc(N2CCC[C@H](O)C2)ccc1N
Yield: 74.4 %

Procedure:
A solution of (3S)-1-[3-(methyloxy)-4-nitrophenyl]-3-piperidinol (3.90 g, 15.5 mmol), FeCl3 (0.630 g, 3.9 mmol), activated carbon (4.0 g), and hydrazine hydrate (3.9 mL, 124 mmol) was heated in methanol (100 mL) for 3 hours. Once the starting material was judged consumed by thin layer chromatography (10% MeOH/CH2CL2) the mixture was filtered over celite and concentrated to afford (3S)-1-[4-amino-3-(methyloxy)phenyl]-3-piperidinol as a dark purple solid (2.56 g, 11.53 mmol, 74% yield). 1H NMR (400 MHz, CDCl3) δ ppm 1.62-1.72 (m, 2 H), 1.75 (d, J=3.30 Hz, 1H), 1.93 (td, J=8.07, 4.40 Hz, 1 H), 2.44 (s, 2 H), 2.88 (s, 1 H), 2.93 (d, J=9.53 Hz, 1H), 2.99 (dd, J=10.81, 6.05 Hz, 2 H), 3.12 (d, J=10.63 Hz, 1 H), 3.84 (s, 3 H), 3.95 (s, 1 H), 6.44 (d, J=8.07 Hz, 1 H), 6.53 (s, 1 H), 6.64 (d, J=8.07 Hz, 1 H).
Reaction SMILES: [Br-].[CH3:2][C:3]1([CH3:33])[S:7][C:6]2[CH:8]=[CH:9][C:10]([CH:12]([P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH3:13])=[CH:11][C:5]=2[S:4]1.[CH:34](=O)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH3:33][C:3]1([CH3:2])[S:7][C:6]2[CH:8]=[CH:9][C:10](/[C:12](/[CH3:13])=[CH:34]/[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:11][C:5]=2[S:4]1
Reactant: O=Cc1ccccc1
Reactant: CC(c1ccc2c(c1)SC(C)(C)S2)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: C/C(=C\c1ccccc1)c1ccc2c(c1)SC(C)(C)S2

Procedure:
In analogy to Example 45, by reacting [1-(2,2-dimethyl-1,3-benzodithiol-5-yl)ethyl]triphenylphosphonium bromide with benzaldehyde, there was obtained 2,2-dimethyl-5-[(E)-α-methylstyryl]-1,3-benzodithiol, melting point 57°-58° C.
Reaction SMILES: [C:1]1([C:7]2[CH:23]=[CH:22][C:10]3[N:11]=[C:12]([CH2:14][C:15]4[O:19][C:18]([CH2:20][NH2:21])=[N:17][N:16]=4)[S:13][C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:24]([O:28][C:29]([N-:31][S:32](N1C=CC(=[N+](C)C)C=C1)(=[O:34])=[O:33])=[O:30])([CH3:27])([CH3:26])[CH3:25]>C(Cl)Cl>[C:1]1([C:7]2[CH:23]=[CH:22][C:10]3[N:11]=[C:12]([CH2:14][C:15]4[O:19][C:18]([CH2:20][NH:21][S:32]([NH:31][C:29](=[O:30])[O:28][C:24]([CH3:26])([CH3:25])[CH3:27])(=[O:33])=[O:34])=[N:17][N:16]=4)[S:13][C:9]=3[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NCc1nnc(Cc2nc3ccc(-c4ccccc4)cc3s2)o1
Reactant: C[N+](C)=c1ccn(S(=O)(=O)[N-]C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NS(=O)(=O)NCc1nnc(Cc2nc3ccc(-c4ccccc4)cc3s2)o1
Temperature: 25 °C
Reaction time: 72 h
Yield: 94.8 %

Procedure:
To a solution of (5-((6-phenylbenzo[d]thiazol-2-yl)methyl)-1,3,4-oxadiazol-2-yl)methanamine (788 mg, 2.44 mmol) (described in WO 2011/074560) in DCM (10 mL) was added N-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin-1-ylsulfonyl]azanide (737 mg, 2.44 mmol) (Winum, J.-Y. et al., Org. Lett., 3(14):2241-2243 (2001)) and the reaction mixture stirred at rt for 3 days. The mixture was diluted with satd. NH4Cl and extracted with EtOAc (3×). The combined extracts were washed with brine, dried (Na2SO4) filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 10-100% EtOAc/DCM to give Compound 46a (1.16 g, 95% yield) as a brown oil. LCMS=0.99 min using analytical method (M), 502.0 (M+H). 1H NMR (400 MHz, CDCl3) δ 8.07 (d, J=8.5 Hz, 1H), 8.06 (s, 1H), 7.74 (dd, J=8.4, 1.9 Hz, 1H), 7.68-7.61 (m, 2H), 7.49 (t, J=7.4 Hz, 2H), 7.44-7.36 (m, 1H), 6.96 (br. s., 1H), 5.26 (br. s., 2H), 4.79 (s, 2H), 4.63 (s, 2H), 1.37 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[N:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:20][N:19]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:29](NCC)[CH3:30].C(Br)C>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[N:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:20][N:19]=2)[CH2:29][CH3:30])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCNCCCOc2noc(-c3ccccc3)n2)cc1OC
Reactant: CCNCC
Solvent: CN(C)C=O
Solvent: CCBr
Product: CCN(CCCOc1noc(-c2ccccc2)n1)CCc1ccc(OC)c(OC)c1
Temperature: 50 °C

Procedure:
2 g of 3-{3-[2-(3,4-dimethoxyphenyl)-ethylamino]-propyloxy}-5-phenyl-1,2,4-oxadiazole (for preparation, see Example 69) were dissolved in 20 ml dimethylformamide. 0.9 ml of diethylamine and 0.6 g ethyl bromide were added to the solution and the reaction mixture was heated at 50° C. for 3.5 hours. For workup, the reaction mixture was then concentrated to dryness and the residue dissolved in dichloromethane. A sufficient quantity of water was added to the solution for a clear phase separation to occur. The mixture was shaken and the organic phase separated out, dried with sodium sulfate, filtered, and concentrated. The crude oily title compound obtained was refined by medium-pressure chromatography on fine-grained silica gel using ethyl acetate/methanol/concentrated aqueous ammonia solution, ratio 9:1:0.05, as the eluent. 1.3 g of the title compound were obtained as a yellow oil.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[S:5]([Cl:8])(Cl)=[O:6].[CH:9]12[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]3)[CH2:10]1)[CH2:16]2>>[C:9]12([S:5]([Cl:8])=[O:6])[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]3)[CH2:10]1)[CH2:16]2
Reactant: C1C2CC3CC1CC(C2)C3
Reactant: O=S(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=S(Cl)C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Aluminum trichloride (40 g, 3 mol) was added slowly to thionyl chloride (200 ml, 2.7 mol), and the mixture was cooled to -20°. Adamantane was added in portions over 21/2 hrs, and the resulting mixture was stirred 1 hr and allowed to warm to room temperature. After the thionyl chloride was removed under vacuum, the residue was diluted with CCl4 ; and the aluminum trichloride was decomposed with ice and water. The layers were separated; and the organic layer was washed (brine), dried (Na2SO4), filtered, and concentrated under vacuum. The residue was distilled under vacuum (1 torr, 133.3 Pascals) with a vigreaux column to give the product (28.8 g; bp 118°-128°) as a waxy solid; TLC, Rf =0.6-0.4, EtOAc:hexanes (15:85).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][C@@H:9]([CH3:15])[CH2:10][CH2:11][C:12]([OH:14])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[CH3:30][C@@H:31]1[C@H:35]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[O:34][C:33](=[O:42])[NH:32]1.[Cl-].[Li+]>C1COCC1>[CH:1]1([CH2:7][CH2:8][C@@H:9]([CH3:15])[CH2:10][CH2:11][C:12]([N:32]2[C@H:31]([CH3:30])[C@H:35]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[O:34][C:33]2=[O:42])=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C[C@H]1NC(=O)O[C@H]1c1ccccc1
Reactant: C[C@@H](CCC(=O)O)CCC1CCCCC1
Agent: CC(C)(C)C(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@@H](CCC(=O)N1C(=O)O[C@@H](c2ccccc2)[C@H]1C)CCC1CCCCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A flask was charged with 4.17 g (19.6 mmol) of (R)-6-cyclohexyl-4-methyl-hexanoic acid, 40 mL of THF, and 8.56 mL (61.4 mmol) of triethylamine. The mixture was cooled in a 0° C. bath, and 2.41 mL (19.6 mmol) of pivaloyl chloride was added. The mixture was stirred for 1 h at 0° C. Then 2.79 g (16.4 mmol) of (4R,5S)-4-methyl-5-phenyl-2-oxazolidinone and 0.823 g (19.6 mmol) of lithium chloride were added as solids. The mixture was allowed to warm to room temperature and stirred overnight. The resulting solids were filtered off. The solvent was stripped under reduce pressure, and the residue was purified by column chromatography (eluent: 4:1 hexanes/ethyl acetate) to give 6.09 g (quant.) of a clear oil: 1H NMR (400 MHz, CDCl3) δ ppm 0.89 (m, 8H) 1.16 (m, 6H) 1.68 (m, 9H) 2.87 (m, 1H) 2.99 (m, 1H) 4.76 (qd, J=6.83, 6.59 Hz, 1H) 5.66 (d, J=7.32 Hz, 1H) 7.30 (m, 2H) 7.40 (m, 3H). MS (APCI) m+1/z=372.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:17][C@H:16]3[N:12]([CH2:13][CH2:14][CH2:15]3)[C:11]([CH3:19])([CH3:18])[CH2:10]2)[C:5]([F:20])=[CH:4][N:3]=1.[O:21]1[CH2:24][CH:23]([N:25]2[CH2:30][CH2:29][CH:28]([O:31][C:32]3[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][C:33]=3[C:39]([F:42])([F:41])[F:40])[CH2:27][CH2:26]2)[CH2:22]1.CC1C=CC(S(O)(=O)=O)=CC=1>CC(O)C.CCOC(C)=O>[CH3:18][C:11]1([CH3:19])[CH2:10][C@H:9]([NH:8][C:6]2[C:5]([F:20])=[CH:4][N:3]=[C:2]([NH:36][C:35]3[CH:37]=[CH:38][C:32]([O:31][CH:28]4[CH2:27][CH2:26][N:25]([CH:23]5[CH2:24][O:21][CH2:22]5)[CH2:30][CH2:29]4)=[C:33]([C:39]([F:42])([F:41])[F:40])[CH:34]=3)[N:7]=2)[CH2:17][C@H:16]2[N:12]1[CH2:13][CH2:14][CH2:15]2
Reactant: Nc1ccc(OC2CCN(C3COC3)CC2)c(C(F)(F)F)c1
Reactant: CC1(C)C[C@H](Nc2nc(Cl)ncc2F)C[C@@H]2CCCN21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CC1(C)C[C@H](Nc2nc(Nc3ccc(OC4CCN(C5COC5)CC4)c(C(F)(F)F)c3)ncc2F)C[C@@H]2CCCN21
Temperature: 100 °C
Yield: 70 %

Procedure:
A mixture of (7R,8aS)-N-(2-chloro-5-fluoropyrimidin-4-yl)-5,5-dimethyloctahydroindolizin-7-amine (0.25 g, 1.0 eq, 0.8 mmol), 4-((1-(oxetan-3-yl)piperidin-4-yl)oxy)-3-(trifluoromethyl)aniline (0.3 g, 1.2 eq, 1.0 mmol), PTSA (0.14 g, 0.9 eq, 0.8 mmol) was taken in iPrOH (20 mL) and heated at 100° C. overnight. The volatiles were removed under vacuum to leave a crude solid. The crude mixture was dissolved in EtOAc (50 mL) and partitioned with 1N aqueous NaOH solution (25 mL). Organic layers were separated and the aqueous layer was washed with EtOAc (2×20 mL). The combined organic layers were dried over Na2SO4 and concentrated under vacuum to leave a crude solid. The solid was purified by column chromatography on silica gel (ISCO System) using 2M NH3 in MeOH/CH2Cl2 (gradient system from 0:1 to 2:8) as eluent to give the product in 70% yield.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][CH2:12][CH2:13][NH2:14])[C:5]=2[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH:22]1([C:26](Cl)=[O:27])[CH2:25][CH2:24][CH2:23]1>ClCCl>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][CH2:12][CH2:13][NH:14][C:26]([CH:22]3[CH2:25][CH2:24][CH2:23]3)=[O:27])[C:5]=2[CH2:4][CH2:3]1
Reactant: NCCCc1cccc2c1CCO2
Reactant: O=C(Cl)C1CCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCCc1cccc2c1CCO2)C1CCC1
Reaction time: 3 h

Procedure:
3-(2,3-Dihydro-benzofuran-4-yl)-propylamine hydrochloride (100 mg) was suspended in dichloromethane (3 ml) containing triethylamine (0.33 ml) and cooled in ice. A solution of cyclobutanecarbonyl chloride (0.054 ml) in dichloromethane (1 ml) was added and the mixture stirred in ice for 3 h. The mixture was purified by elution through a solid phase extraction cartridge to give the title compound as a white solid (110 mg).
Reaction SMILES: C([O:3][C:4](=O)[C:5]([NH:7][CH2:8][CH3:9])=[O:6])C.[CH3:11][O:12][CH:13]([O:16][CH3:17])[CH2:14][NH2:15]>CC(O)C>[CH3:11][O:12][CH:13]([O:16][CH3:17])[CH2:14][NH:15][C:4](=[O:3])[C:5]([NH:7][CH2:8][CH3:9])=[O:6]
Reactant: COC(CN)OC
Reactant: CCNC(=O)C(=O)OCC
Solvent: CC(C)O
Product: CCNC(=O)C(=O)NCC(OC)OC
Yield: 80.5 %

Procedure:
59.9 g (412.6 mM) of ethyl(ethylamino)(oxo)acetate and 45 ml (412.6 mM) of (2,2-dimethoxyethyl)amine in 480 ml of 2-propanol were stirred at room temperature for 16 h. A white precipitate was filtered, washed with 2-propanol and dried under vacuum, to give 67.8 g of N-(2,2-dimethoxyethyl)-N′-ethylethanediamide. Yield: 80.5%.
Reaction SMILES: [CH:1]1([CH:6]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[CH2:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][C:27]=4[F:30])[C:22]3=[O:31])=[CH:16][CH:15]=2)[C:7]([O:9]C(C)(C)C)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([CH:6]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[CH2:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][C:27]=4[F:30])[C:22]3=[O:31])=[CH:16][CH:15]=2)[C:7]([OH:9])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)C(c1ccc(CN2Cc3c(F)cccc3C2=O)cc1)C1CCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C(c1ccc(CN2Cc3c(F)cccc3C2=O)cc1)C1CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
150.0 mg (0.35 mmol) of tert-butyl(+/−)-cyclopentyl{4-[(4-fluoro-1-oxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}acetate were initially charged in 300 μl of dichloromethane, and 515 μl of trifluoroacetic acid were added. The mixture was stirred at RT for 1 h. The reaction mixture was then concentrated on a rotary evaporator, and the residue was dried under high vacuum. Acetonitrile was added to the product, and the precipitated solid was triturated and then filtered off with suction. This gave 112.0 mg (86.1% of theory) of the target compound.
Reaction SMILES: ClC(Cl)(Cl)[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[N:8]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:6].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.CO>[CH3:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:17])[CH3:18])=[O:14])[N:8]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:6]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1C(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 80.7 %

Procedure:
To a solution of (S)-tetrahydro-pyridazine-1,2,3-tricarboxylic acid 1,2-di-tert-butyl ester 3-(2,2,2-trichloro-ethyl) ester (5.0 g, 10.8 mmol) in tetrahydrofuran/methanol (50 mL, 1:1) containing 3 Å molecular sieves at 0° C. was added tetra n-butylammonium fluoride (22 mL, 22 mmol, 1 M in tetrahydrofuran). After stirring at room temperature for 24 h, the mixture was filtered through a pad of Celite and the filtrate was evaporated. The residue was partitioned between diethyl ether and saturated sodium hydrogen carbonate solution. The aqueous layer was extracted with diethyl ether. The organic extracts were combined and the solution was filtered through a hydrophobic frit and the solvent was evaporated. The residue was purified by silica gel chromatography eluting with iso-hexanes/ethyl acetate 20:1 to 3:2 to afford (S)-tetrahydro-pyridazine-1,2,3-tricarboxylic acid 1,2-di-tert-butyl ester 3-methyl ester (3.0 g, 82%) as a colorless oil and as a mixture of rotamers. LCMS (m/z) 345.1 [M+H], Tr=2.78 min. A solution of (S)-tetrahydro-pyridazine-1,2,3-tricarboxylic acid 1,2-di-tert-butyl ester 3-methyl ester (3.0 g, 8.72 mmol) in tetrahydrofuran (20 mL) at −78° C. was treated with lithium bis(trimethylsilyl)amide (13 mL, 13.0 mmol, 1 M in tetrahydrofuran). After stirring at −78° C. for 1 h, the mixture was treated with iodomethane (1.4 mL, 22.5 mmol). The reaction mixture was stirred at −78° C. for 1 h, then at 0° C. for 1 h and at room temperature for 1 h. The reaction mixture was re-cooled to 0° C. and quenched with water. The aqueous phase was extracted with dichloromethane (2×) and the organic solution was passed through a hydrophobic frit and the solvent was evaporated. The residue was purified by silica gel chromatography eluting with a gradient of iso-hexanes/ethyl acetate 4:1 to 0:1 to afford the title compound (1.62 g, 52%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 1.41-1.52 (m, 18H), 1.53-1.67 (m, 4H), 1.71-1.99 (m, 3H), 3.17-3.51 (m, 1H), 3.70-3.81 (m, 3H), 3.90-4.21 (m, 1H). LCMS (m/z) 359.0 [M+H], Tr=2.90 min.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[NH:14][C:13]([NH2:15])=[N:12][C:11]2[C:7]=1[N:8]=[CH:9][N:10]=2.[CH:16]1([CH2:22][CH2:23]O)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>CN(C=O)C.C1COCC1>[CH:16]1([CH2:22][CH2:23][N:10]2[CH:9]=[N:8][C:7]3[C:11]2=[N:12][C:13]([NH2:15])=[N:14][C:6]=3[C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: OCCC1CCCCC1
Reactant: Nc1nc2ncnc-2c(-c2ccco2)[nH]1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Nc1nc(-c2ccco2)c2ncn(CCC3CCCCC3)c2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 58.9 %

Procedure:
A solution of 6-(2-furyl)-1H-purine-2-amine (25 mg, 0.12 mmol) in anhydrous DMF (0.5 mL) and anhydrous THF (2 mL) was treated with triphenylphosphine polystyrene (65 mg, 0.25 mmol) and 2-cyclohexylethanol (35 mg, 0.25 mmol), shaken at room temperature for 10 min, treated with di-tert-butyl azodicarboxylate (0.058 g, 0.25 mmol), shaken at room temperature for 16 h, filtered and concentrated in vacuo. The resulting oil was dissolved in CH2Cl2 (2 mL) and TFA (1 mL), shaken for 2 h and concentrated in vacuo. The resulting oil was dissolved in CH2Cl2 (3 mL), shaken with 1-M aq HCl (1 mL) for 15 min and the organic phase concentrated in vacuo and purified by chromatography (SiO2; EtOAc) to give the title compound (22 mg, 57%) as a yellow solid.
Reaction SMILES: [CH2:1]([CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11]1=O)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=O.[NH2:17][C:18]1[CH:26]=[C:22]([C:23]([OH:25])=[O:24])[C:21]([OH:27])=[C:20]([Cl:28])[CH:19]=1>C(O)(=O)C>[C:23]([C:22]1[CH:26]=[C:18]([N:17]2[C:11]3[CH2:12][CH2:13][CH2:14][CH2:15][C:10]=3[CH:1]=[C:2]2[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:19]=[C:20]([Cl:28])[C:21]=1[OH:27])([OH:25])=[O:24]
Reactant: O=C(CC1CCCCC1=O)c1ccccc1
Reactant: Nc1cc(Cl)c(O)c(C(=O)O)c1
Solvent: CC(=O)O
Product: O=C(O)c1cc(-n2c(-c3ccccc3)cc3c2CCCC3)cc(Cl)c1O

Procedure:
a mixture of 10.3 g. (0.047 mole) of 2-phenacylcyclohexanone, 8.8 g. (0.047 mole) of 5-amino-3-chlorosalicylic acid, and 45 ml. of glacial acetic acid was heated under reflux for 1 hour, cooled and filtered. The collected solid was recrystallized from acetonitrile to provide 13.3 g. (77%) of crystals, m.p. 223°-225°.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[NH:11][C:12]([S:18][C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=2)=[C:13]([CH:15]([CH3:17])[CH3:16])[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)Cl.[N:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[C:32]([CH2:40]Br)[CH:31]=1.[OH-].[Na+]>O1CCCC1>[CH2:1]([O:8][CH2:9][C:10]1[N:14]([CH2:40][C:32]2[CH:31]=[N:30][C:39]3[C:34]([CH:33]=2)=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:13]([CH:15]([CH3:17])[CH3:16])=[C:12]([S:18][C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=2)[N:11]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCc1cnc2ccccc2c1
Reactant: CC(C)c1nc(COCc2ccccc2)[nH]c1Sc1cc(Cl)cc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)c1c(Sc2cc(Cl)cc(Cl)c2)nc(COCc2ccccc2)n1Cc1cnc2ccccc2c1
Reaction time: 8 h
Yield: 2.6 %

Procedure:
In tetrahydrofuran (10 ml) was dissolved 245 mg (2 mmol) of 2-benzyloxymethyl-5-(3,5-dichlorophenylthio)-4-isopropyl-1H-imidazole (101a). To this solution, a methylene chloride solution of quinolin-3-ylmethylbromide was added at room temperature with stirring, followed by addition of 200 mg (5 mmol) of sodium hydroxide and 39 mg (0.12 mmol) of n-tetrabutylammonium bromide. After stirring for 2 hours, the mixture was left overnight and worked up. The reaction mixture was distilled off under reduced pressure. The residue was extracted with methylene chloride, and the extract was washed with water and dried. The solvent was distilled off, and the residual oil was purified by silica gel column chromatography (methylene chloride-ethyl acetate). As the first eluate, 26 g (2.6%) of 2-benzyloxymethyl-4-(3,5-dichlorophenylthio)-5-isopropyl-1-(quinolin-3-ylmethyl)-1H-imidazole (100a) was obtained. From the subsequent eluate, 730 mg of 2-benzyloxymethyl-5-(3,5-dichlorophenylthio)-4-isopropyl-1-(quinolin-3-ylmethyl)-1H-imidazole (100b) suited to the next step of the reaction was obtained (yield 73%).
Reaction SMILES: Br[CH:2]([CH3:17])[C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:16])[CH:11]=2)[CH:6]=1)=[O:4].[CH2:18]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[BH4-].[Na+].NO>>[CH2:18]([N:25]1[CH2:30][CH2:29][N:28]([CH:2]([CH3:17])[C:3]([C:5]2[CH:14]=[CH:13][C:12]3[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:16])[CH:11]=3)[CH:6]=2)=[O:4])[CH2:27][CH2:26]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COc1ccc2cc(C(=O)C(C)Br)ccc2c1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: NO
Agent: [BH4-]
Agent: [Na+]
Product: COc1ccc2cc(C(=O)C(C)N3CCN(Cc4ccccc4)CC3)ccc2c1
Yield: 54 %

Procedure:
From 2-bromo-1-(6-methoxy-2-naphtyl)-1-propanone and 1-benzylpiperazine, the compound 2-(4-benzyl-1-piperazinyl)-1-(6-methoxy-2-naphtyl)-1-propanone is prepared (MG 14256; m.p. 89°-91° C., which is reduced with NaBH4 to the corresponding amino alcohol as a mixture of the two stereoisomeric forms which are separated by flash chromatography.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:6]2[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17][C:5]1=2.[C:25]1([N:31]=[C:32]=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1>[NH:31]([C:32]([NH:1][CH2:2][CH2:3][N:4]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:6]2[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17][C:5]1=2)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C=Nc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(CCN)c3ccccc23)CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2c(n(CCNC(=O)Nc3ccccc3)c3ccccc23)CC1
Reaction time: 2.5 h
Yield: 71.9 %

Procedure:
tert-Butyl 6-(2-aminoethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.0399 g, 0.121 mmol) was dissolved in THF (2 mL) at rt under N2. Phenyl isocyanate (0.016 g mL, 0.0173 g, 0.145 mmol, 1.20 equiv.) was added, then the reaction mixture was stirred for 2.5 h. The reaction mixture was concentrated and the crude product (0.0598 g) was chromatographed (SiO2 25 g, eluted with 3:2 hexane:EtOAc) to give tert-butyl 6-{2-[(anilinocarbonyl)amino]ethyl}-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.0390 g) in 72% yield. 1H NMR (300 MHz, CDCl3) δ 1.36, 1.44, 2.96-3.08, 3.42-3.51, 3.65-3.72, 4.17, 4.23, 5.14, 5.23, 6.94-7.30, 7.43-7.49; MS (ESI+) for C26H32N4O3 m/z 449.1 (M+H)+.