Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)C.O.O1CCOCC1.[CH3:11][C:12]1[N:17]=[C:16]([C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[N:23]([CH3:27])[CH:22]=[CH:21]3)[C:15]([C:28]([O:30]CC)=[O:29])=[CH:14][N:13]=1.O.[OH-].[Li+]>C(OCC)(=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH3:11][C:12]1[N:17]=[C:16]([C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[N:23]([CH3:27])[CH:22]=[CH:21]3)[C:15]([C:28]([OH:30])=[O:29])=[CH:14][N:13]=1
Reactant: CCOC(=O)c1cnc(C)nc1-c1ccc2c(ccn2C)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1ncc(C(=O)O)c(-c2ccc3c(ccn3C)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.3 %

Procedure:
In a mix of ethanol:water:dioxane (1:1:1, 9 mL) was placed ethyl 2-methyl-4-(1-methyl-1 H-indol-5-yl)pyrimidine-5-carboxylate (391 mg, 1.324 mmol) and lithium hydroxide hydrate (222 mg, 5.30 mmol). The mix stirred at RT overnight. The mix was diluted with ethyl acetate (25 mL) and 5% citric acid (20 mL). The organic phase was separated, washed with brine (20 mL) and dried over sodium sulfate. The solvent was evaporated at reduced pressure to give 2-methyl-4-(1-methyl-1 H-indol-5-yl)pyrimidine-5-carboxylic acid as a tan solid (132 mg, 37% yield). MS (ESI) m/z: 268.0 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:21]=[C:14]3[CH2:15][N:16]([CH2:19][CH3:20])[CH2:17][CH2:18][N:13]3[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:22]([O:25][CH2:26][C:27]1[C:32]([N:33]2[CH2:44][CH2:43][N:42]3[C:35](=[CH:36][C:37]4[CH2:38][C:39]([CH3:46])([CH3:45])[CH2:40][C:41]=43)[C:34]2=[O:47])=[CH:31][C:30]([F:48])=[CH:29][C:28]=1B1OC(C)(C)C(C)(C)O1)(=[O:24])[CH3:23].COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>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.CO.C(OCC)C.O.C(OCC)(=O)C>[CH2:19]([N:16]1[CH2:17][CH2:18][N:13]2[N:12]=[C:11]([NH:10][C:4]3[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=[C:2]([C:28]4[C:27]([CH2:26][O:25][C:22](=[O:24])[CH3:23])=[C:32]([N:33]5[CH2:44][CH2:43][N:42]6[C:35](=[CH:36][C:37]7[CH2:38][C:39]([CH3:45])([CH3:46])[CH2:40][C:41]=76)[C:34]5=[O:47])[CH:31]=[C:30]([F:48])[CH:29]=4)[CH:3]=3)[CH:21]=[C:14]2[CH2:15]1)[CH3:20]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Reactant: CCN1CCn2nc(Nc3cc(Br)cn(C)c3=O)cc2C1
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: CCOCC
Solvent: CO
Solvent: CCOC(C)=O
Product: CCN1CCn2nc(Nc3cc(-c4cc(F)cc(N5CCn6c(cc7c6CC(C)(C)C7)C5=O)c4COC(C)=O)cn(C)c3=O)cc2C1
Temperature: 130 °C
Yield: 37.4 %

Procedure:
A microwave tube equipped with a magnetic stirrer was charged with 285c (190 mg, 0.5 mmol), 230a (350 mg, 0.7 mmol), 1,2-dimethoxyethane (6.4 mL) and 1M aqueous sodium carbonate (1.6 mL). After bubbling N2 for 15 min, Pd(PPh3)4 (31 mg, 0.03 mmol) was added. The mixture was heated in microwave to 130° C. for 15 min. After this time, ethyl acetate (5 mL) and water (5 mL) were added. The separated aqueous layer was extracted with ethyl acetate (2×5 mL). The combined organics were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography eluting with a gradient of methylene chloride-60:35:5 methylene chloride:diethyl ether:methanol to afford a 35% yield (120 mg) of 285d.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C:7](=[CH2:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9]>>[Cl:3][CH2:6][C:7](=[CH2:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: O=S(Cl)Cl
Reactant: C=C(CO)C(=O)OCC
Product: C=C(CCl)C(=O)OCC
Reaction time: 0.5 h
Yield: 103.4 %

Procedure:
Thionyl chloride (10.6 g, 89.1 mmol) was dropwise added to ethyl α-hydroxymethylacrylate (10 g, 76.8 mmol) with ice-cooling; stirring was conducted for 30 minutes; then, a reaction was allowed to take place at 90° C. for 2 hours. After the completion of the reaction, low-boiling compounds were removed under reduced pressure to obtain unpurified ethyl α-chloromethylacrylate (11.8 g). Then, L-arabinoaminooxazoline (11.8 g, 64.0 mmol) was suspended in dimethylacetamide (80 ml). Thereto was dropwise added the ethyl α-chloromethylacrylate (11.8 g) with ice-cooling. A reaction was allowed to take place at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. To the residue was added isopropanol (100 ml), and the resulting mixture was stirred at room temperature for 1 hour. The resulting crystals were collected by filtration, washed with isopropanol (10 ml), and dried under reduced pressure to obtain a title compound (12.5 g g, 60.5%).
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[K+].[Br:11][C:12]1[CH:13]=[CH:14][C:15](F)=[N:16][CH:17]=1.[CH:19]1([C:22]#[N:23])[CH2:21][CH2:20]1.[NH4+].[Cl-]>C1(C)C=CC=CC=1>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([C:19]2([C:22]#[N:23])[CH2:21][CH2:20]2)=[N:16][CH:17]=1
Reactant: Fc1ccc(Br)cn1
Reactant: N#CC1CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: N#CC1(c2ccc(Br)cn2)CC1

Procedure:
Potassium hexamethyldisilazide (0.5 mol/L in toluene, 34 mL) was added over a period of 5 min to a solution of 5-bromo-2-fluoro-pyridine (1.50 g) and cyclopropanecarbonitrile (0.63 mL) in toluene (2 mL) chilled in an ice bath. Aqueous NH4Cl solution was then added and the resulting mixture was extracted with ethyl acetate. The combined extracts were dried (Na2SO4) and the solvent was evaporated. The residue was chromatographed on silica gel (cyclohexane/ethyl acetate 1:0→8:2) to give the title compound as a colorless solid. Yield: 0.19 g (10% of theory); LC (method 2): tR=3.34 min; Mass spectrum (ESI+): m/z=223/225 (Br) [M+H]+.
Reaction SMILES: [C:1]1(=O)O[C:5](=[O:6])[C:4]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:3]2[CH2:2]1.[C:13]([C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1CBr)#[N:14].C(N(CC)CC)C>C(#N)C>[O:6]=[C:5]1[C:4]2[C:3](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:2]2[CH2:1][C:16]3[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=3[C:13]=2[NH:14]1
Reactant: N#Cc1ccccc1CBr
Reactant: O=C1Cc2ccccc2C(=O)O1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=c1[nH]c2c(c3ccccc13)Cc1ccccc1-2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of homophthalic anhydride (324 mg, 2.0 mmol) in acetonitrile (15 mL) was added 2-cyanobenzyl bromide (431 mg, 2.0 mmol, 1.0 eq) and triethylamine (5 mL). The reaction was stirred under inert atmosphere at room temperature for 30 minutes, after which time a yellow precipitate appeared. The reaction mixture was then heated at reflux for 18 h and the resulting white precipitate was filtered, washed using acetonitrile (3×8 mL) and dried under vacuum to provide Compound 13a as a white crystalline solid. Yield=150 mg (32%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=O)[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)=[CH:5][CH:4]=1.S(Cl)([Cl:23])=O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]([Cl:23])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(NC(=O)c2cccc([N+](=O)[O-])c2)cc1
Product: COc1ccc(N=C(Cl)c2cccc([N+](=O)[O-])c2)cc1

Procedure:
Using the procedure of Step A of Example 1, 13 g of N-(4-methoxyphenyl)-3-nitrobenzamide prepared as in Step A of Example 1 and melting at 170° C. and 40 ml of thionyl chloride were reacted at reflux for 12 hours to obtain 14.5 g of N-(4-methoxyphenyl)-3-nitrobenzene-carboximidoyl chloride melting at 108° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[C:16](Br)[CH:17]=[N:18][CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([Mg]Cl)[CH2:22][CH3:23]>C1COCC1.C(OCC)C>[CH2:21]([C:16]1[CH:15]=[C:14]([O:13][CH2:12][C@@H:9]2[CH2:10][CH2:11][N:8]2[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:19]=[N:18][CH:17]=1)[CH2:22][CH3:23]
Reactant: CCC[Mg]Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(Br)c1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCc1cncc(OC[C@@H]2CCN2C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Yield: 22 %

Procedure:
To a solution of 5-(N-t-butyloxycarbonyl-(2S)-azetidinylmethoxy)-3-bromopyridine (1.50 g, 4.37 mmol, Example 12a above) in THF (30 mL) at 0° C. was added [1,3-bis(diphenylphosphino)-propane]nickel(II) (14.0 mg) followed by propylmagnesium chloride (5.50 mL of a 2 M solution in diethyl ether, Aldrich). The reaction mixture was refluxed for 3 h, cooled to ambient temperature and then quenched with saturated aqueous ammonia chloride. The desired product was extracted with CH2Cl2. The organic phase was dried over MgSO4, filtered and concentrated. The residue was chromatographed (silica gel; hexane/EtOAc, 10:1 to 1:1) to afford 5-propyl-3-(N-t-butyloxycarbonyl-(2S)-azetidinylmethoxy)pyridine as an oil (292 mg, 22%): MS (CI/NH3) mn/z: 307 (M+H)+ ; 1H NMR (CDCl3, 300 MHz) δ 0.95 (t, J=8.3 Hz, 3H), 1.42 (s, 4.5H), 1.46 (s, 4.5H), 1.60-1.70 (m, 2H), 2.22-2.40 (m, 2H), 2.56 (t, J=8.3 Hz, 2H), 3.70-3.80 (m, 2H), 3.90(m, 1H), 4.13 (m, 1H), 4.51 (m, 1H), 7.04 (s, 1H), 8.06 (s, 1H), 8.18 (d, J=3.3 Hz, 1H). To a 0° C. solution of 5-propyl-3-(N-t-butyloxycarbonyl-(2S)-azetidinylmethoxy)pyridine (290 mg, 0.950 mmol) in CH2Cl2 (3 mL) was added TFA (3 mL). After stirring for 30 min the reaction mixture was basified with 15% aqueous NaOH and extracted with CH2Cl2 (3×). The combined organic extracts were dried over MgSO4, filtered and concentrated. Purification by chromatography (silica gel; CH2Cl2 /MeOH, 10:0.5) afforded the free base of the title compound as an oil (103 mg, 53%): MS (CI/NH3) m/z: 207 (M+H)+ ; 1H NMR (CDCl3, 300 MHz) δ 0.94 (t, J=8.3 Hz, 3H), 1.58-1.70 (m, 2H), 2.30-2.48 (m, 2H), 2.55 (t, J=8.3 Hz, 2H), 3.57 (m, 1H), 3.76 (q, J=8.3 Hz, 1H), 4.04-4.10 (m, 2H), 4.39 (m, 1H), 7.03 (t, J=3.0 Hz, 1H), 8.04 (s, 1H), 8.14 (d, J=3.3 Hz, 1H). The free base was dissolved in Et2O and a saturated solution of HCl in Et2O was added dropwise carefully. The solvent was removed, and the resultant solid was recrystallized from MeOH/Et2O to afford the title compound as a yellow hygroscopic solid: mp 79-80° C.; MS (CI/NH3) m/z: 207 (M+H)+ ; 1H NMR (D2O, 300 MHz) δ 1.01 (t, J=3.05 Hz, 3H), 1.68-1.80 (m, 2H), 2.62-2.78 (m, 2H), 2.80 (t, J=7.1 Hz, 2H), 4.04-4.21 (m, 3H), 4.44-4.60 (m, 2H), 7.40 (s, 1H), 8.04 (s, 1H), 8.14 (s, 1H). Anal. Calcd for C12H18N2O.2 HCl.H2O: C, 48.49; H, 7.46; N, 9.43. Found: C, 48.35; H, 7.23; N, 9.48.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:6]=1[S:12]([NH2:15])(=[O:14])=[O:13])=[O:4].S(Cl)(Cl)=O.N1C=CC=CC=1.[C:26](Cl)(Cl)=[O:27]>ClCCCl>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:6]=1[S:12]([N:15]=[C:26]=[O:27])(=[O:14])=[O:13])=[O:4]
Reactant: O=C(Cl)Cl
Reactant: COC(=O)c1ccc(I)cc1S(N)(=O)=O
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: ClCCCl
Product: COC(=O)c1ccc(I)cc1S(=O)(=O)N=C=O

Procedure:
50 g of the sulfonamide obtained in Example 6 are suspended in 150 ml of 1,2-dichloroethane and the suspension is treated with 27.7 ml of thionyl chloride. The mixture is heated at the boil for 4 hours, cooled to 50°-55° C. and treated with 0.5 ml of pyridine, and phosgene is passed for 31/2 hours into the solution which has now been brought to the boil. The mixture is concentrated under reduced pressure with the exclusion of moisture. The crude sulfonyl isocyanate which remains (52.6 g) crystallises upon standing.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[OH-].[Na+].Br[CH2:14][CH2:15][CH2:16][Cl:17]>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C>[Cl:17][CH2:16][CH2:15][CH2:14][N:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[CH3:1]
Reactant: ClCCCBr
Reactant: Cc1nc2ccccc2[nH]1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Product: Cc1nc2ccccc2n1CCCCl
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
To a stirred mixture of 13.2 parts of 2-methyl-1H-benzimidazole, 2 parts of N,N,N-triethylbenzenemethanaminium chloride and 150 parts of a sodium hydroxide solution 60% are added 30 parts of 1-bromo-3-chloropropane. To start the reaction, the whole is heated to about 40° C., whereupon the temperature rises to 50° C. (exothermic reaction). Stirring at about 50° C. is continued for 30 minutes. The reaction mixture is poured onto water and the product is extracted with methylbenzene. The extract is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10) as eluent. The pure fractions are collected and the eluent is evaporated, yielding 1-(3-chloropropyl)-2-methyl-1H-benzimidazole as a residue.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([CH2:32][N:33]5[CH2:38][C@@H:37]6[CH2:39][C@H:34]5[CH2:35][NH:36]6)=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[C:40](Cl)(=[O:42])[CH3:41].C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[C:40]([N:36]1[CH2:35][C@@H:34]2[CH2:39][C@H:37]1[CH2:38][N:33]2[CH2:32][C:29]1[CH:30]=[N:31][C:26]([C:24]2[NH:25][C:21]([CH:13]([C:10]3[CH:9]=[CH:8][C:7]([S:4]([CH:1]4[CH2:2][CH2:3]4)(=[O:5])=[O:6])=[CH:12][CH:11]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:22][CH:23]=2)=[CH:27][CH:28]=1)(=[O:42])[CH3:41]
Reactant: O=S(=O)(c1ccc(C(CC2CCOCC2)c2ccc(-c3ccc(CN4C[C@@H]5C[C@H]4CN5)cn3)[nH]2)cc1)C1CC1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)N1C[C@@H]2C[C@H]1CN2Cc1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32 %

Procedure:
To a solution of (1S,4S)-2-{[6-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridin-3-yl]methyl}-2,5-diazabicyclo[2.2.1]heptane (29.0 mg) in dichloromethane (5 mL) were added acetyl chloride (6 μL) and triethylamine (23 μL) under ice-cooling, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to preparative HPLC to give the title compound (10.0 mg, yield 32%) as a colorless amorphous solid. MS: 589 (MH+).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1)C=C.C(N(CC)CC)C.O>C(O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[OH:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1
Reactant: C=CCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc3ccccc3c2)cc1
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
A mixture of 400 mg (0.8 mmol) of tert-butyl (3RS,4RS)-4-(4-allyloxy-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate, 0.2 ml of triethylamine, 0.5 ml of water and 78 mg of tris-(triphenylphosphine)rhodium(I) chloride in 10 ml of ethanol was stirred at reflux for 1 hour. The tert-butyl (3RS,4RS)-4-(4-hydroxy-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate formed in part (30% of theory), MS: 434 (M+H)+, was separated by chromatography and was used in the following step.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.C(N(CC)CC)C.[NH:21]1[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>C(O)C>[N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[CH:13][C:4]=1[CH2:3][N:21]1[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1
Reactant: ClCc1ccc2ccccc2n1
Reactant: C1CNCCNC1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: c1ccc2nc(CN3CCCNCC3)ccc2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 39.3 %

Procedure:
After a mixture consisting of 2-chloromethyl-quinoline hydrochloride (63.16 g, 295 mmol), triethyl-amine (29.85 g, 295 mmol), homopiperazine (50.08 g, 591 mmol) and ethanol (600 ml) was stirred at room temperature for 2 days, the solvent was distilled off under reduced pressure. Water was added to the residue. After the resulting mixture was washed three times with ethyl ether, sodium chloride was added to the water layer, followed by extraction four times with chloroform-methanol (2:1). The extract was washed with an aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, whereby 28.00 g of the title compound were obtained as a yellow oil (yield: 39.3%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[C:9]#[C:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]([N+:17]([O-:19])=[O:18])[CH:3]=1.[N+:20](=[CH:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:24])=[N-:21]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:9]2[C:22]([C:23](=[O:24])[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[N:20][NH:21][C:10]=2[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:16])=[C:4]([N+:17]([O-:19])=[O:18])[CH:3]=1
Reactant: [N-]=[N+]=CC(=O)c1ccccc1
Reactant: CCOC(=O)C#CC(=O)c1ccc(Cl)cc1[N+](=O)[O-]
Solvent: C1CCOC1
Product: CCOC(=O)c1[nH]nc(C(=O)c2ccccc2)c1C(=O)c1ccc(Cl)cc1[N+](=O)[O-]
Yield: 74.3 %

Procedure:
A solution of ethyl 4-(4-chloro-2-nitrophenyl)-4-oxo-2-butynoate (prepared as described in Example 48(a)) (1.2 g, 4.11 mmol) and diazoacetophenone (1.2 g 8.22 mmol, prepared as described in Org. Syn. Coll. Vol. VI. pp. 386-388) in tetrahydrofiuran (THF) (21.6 mL) was stirred at room temperature for 16 hours. The reaction was concentrated by rotary evaporation and purified by flash chromatography eluting with hexanes:ethyl acetate (90:10, 80:20, 70:30) to give the title compound (1.3 g, 74.3%); Rf 0.38 (1:1 ethyl acetate:hexanes).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH2:22][O:23][CH3:24])=[CH:18][CH:19]=2)[O:14][CH2:13][CH:12]1[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][O:33][CH3:34])=[CH:27][CH:26]=1.C(N(CC)CC)C.[CH3:42][S:43](Cl)(=[O:45])=[O:44].O>C(Cl)Cl>[CH3:42][S:43]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH2:22][O:23][CH3:24])=[CH:18][CH:19]=2)[O:14][CH2:13][CH:12]1[C:25]1[CH:26]=[CH:27][C:28]([O:31][CH2:32][O:33][CH3:34])=[CH:29][CH:30]=1)(=[O:45])=[O:44]
Reactant: COCOc1ccc(C2COc3cc(OCOC)ccc3C2CCCCCCCCCO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COCOc1ccc(C2COc3cc(OCOC)ccc3C2CCCCCCCCCOS(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 98.5 %

Procedure:
To a solution of (3RS,4RS)-4-(9-hydroxynonyl)-7-methoxymethoxy-3-(4-methoxymethoxyphenyl)chroman (222 mg, 0.470 mmol) and triethylamine (0.135 ml, 0.961 mmol) in CH2Cl2 (5 ml) at 0° C. under nitrogen was added methanesulfonyl chloride (0.055 ml, 0.71 mmol). The resulting solution was stirred at 0° C. for 45 min, and then poured into H2O. The mixture was extracted with CH2Cl2. The organic layer was washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated to afford (3RS,4RS)-4-(9-methanesulfonyloxynonyl)-7-methoxymethoxy-3-(4-methoxymethoxyphenyl)chroman (255 mg, 99%).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([C:10]3[CH:15]=[C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[NH:13][C:12](=[O:22])[CH:11]=3)=[CH:4][C:3]=2[O:2]1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH:28]([CH3:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30]>C(=O)([O-])[O-].[Ag+2].CN(C)C=O>[CH3:34][CH:28]([CH2:27][CH2:26][CH2:25][CH2:24][O:22][C:12]1[CH:11]=[C:10]([C:5]2[CH:6]=[CH:7][C:8]3[O:9][CH2:1][O:2][C:3]=3[CH:4]=2)[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:13]=1)[C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: CCOC(=O)C(C)CCCCBr
Reactant: O=c1cc(-c2ccc3c(c2)OCO3)cc(-c2ccccc2)[nH]1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)CCCCOc1cc(-c2ccc3c(c2)OCO3)cc(-c2ccccc2)n1
Temperature: 100 °C

Procedure:
The procedure in Example 5 is followed but using 4-(3,4-methylenedioxyphenyl)-6-phenyl-2-pyridinone (2.5 g), ethyl 6-bromo-2-methylhexanoate (4 g), silver carbonate (1.2 g) and dimethylformamide (100 cc). The reaction mixture is heated at 100° C. for 72 hours. The product is purified by chromatography under pressure on silica gel (30-60 mm; eluent: n-hexane-ethyl acetate 9-1). (yellowish oil)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])=[CH:11][CH:10]=2)[CH:5]=[N:4][CH:3]=1.[NH2:21][C:22]1[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(OCC)(=O)C.O>[CH3:27][C:25]1[CH:26]=[C:22]([NH:21][C:2]2[N:7]=[C:6]([S:8][C:9]3[CH:14]=[CH:13][C:12]([NH:15][C:16]([CH:18]4[CH2:20][CH2:19]4)=[O:17])=[CH:11][CH:10]=3)[CH:5]=[N:4][CH:3]=2)[NH:23][N:24]=1
Reactant: O=C(Nc1ccc(Sc2cncc(Cl)n2)cc1)C1CC1
Reactant: Cc1cc(N)n[nH]1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(Nc2cncc(Sc3ccc(NC(=O)C4CC4)cc3)n2)[nH]n1
Temperature: 120 °C
Yield: 5.9 %

Procedure:
To a solution of N-(4-(6-chloropyrazin-2-ylthio)phenyl)cyclopropanecarboxamide (0.49 mmol) and 3-amino-5-methylpyrazole (0.52 mmol) in 1,4-dioxan (3 mL), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.03 mmol), tris(dibenzylideneacetone) dipalladium (0.02 mmol) and sodium carbonate (0.69 mmol) were added. The resulting solution was heated at 120° C. in the microwave (175 W, 25 psi) for 30 min. Water (10 mL) and ethyl acetate (10 mL) were added and the layers separated. The aqueous layer was extracted further with ethyl acetate (2×10 mL), the combined organic layers dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography (EtOAc/Petroleum ether, 0-100% gradient EtOAc) and then purified further using mass directed HPLC purification (sunfire C18 column, trifluoroacetic acid/MeCN/MeOH as eluent) to give the title compound (10.6 mg, 6%) as a light yellow solid; 1H NMR (400 MHz, DMSO-d6) δ 0.81 (4H, m), 1.83 (1H, m), 2.05 (3H, s), 5.55 (1H, s), 7.54 (2H, m), 7.59 (1H, s), 7.74 (2H, m), 8.02 (1H, s), 9.77 (1H, s), 10.47 (1H, s); MS (ES+): m/e=367.41 (100%).
Reaction SMILES: [OH:1][CH:2]([CH3:9])[C:3](=[CH2:8])[C:4]([O:6][CH3:7])=[O:5].Br[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]#[N:19])=[CH:13][CH:12]=1.C(N(CC)CC)C.C(O)(=O)C>C(#N)C.C1(C)C=CC=CC=1>[C:18]([CH2:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:8][CH:3]([C:2](=[O:1])[CH3:9])[C:4]([O:6][CH3:7])=[O:5])=[CH:12][CH:13]=1)#[N:19]
Reactant: N#CCc1ccc(Br)cc1
Reactant: C=C(C(=O)OC)C(C)O
Solvent: CC#N
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COC(=O)C(Cc1ccc(CC#N)cc1)C(C)=O
Temperature: 70 °C
Reaction time: 0.17 h

Procedure:
A stirred mixture of methyl 3-hydroxy-2-methylenebutanoate (30.0 g, 0.23 mol), 2-(4-bromophenyl)acetonitrile (54.2 g, 0.28 mol), PdCl2[P(o-tol)3]2 (1.8 g, 2 mmol) and triethylamine (46.7 g, 0.46 mol) in acetonitrile (90 g) was heated at 70° C. for 6 hours under a N2 atmosphere. The mixture was cooled to 25° C., diluted with toluene (300 g) and 10% aq. acetic acid (360 g), and stirred for 10 minutes. The organic layer was separated, washed with water (360 g), and concentrated under reduced pressure to give the subtitle compound as a red oil, 67.3 g. This product was used in the next step without further purification.