Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.C(OC([NH:20][CH2:21][CH2:22][CH2:23]Br)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[CH2:12][CH2:11][N:10]([CH2:23][CH2:22][CH2:21][NH2:20])[CH2:9][CH2:8]1
Reactant: c1ccc(C2CCNCC2)nc1
Reactant: CC(C)(C)OC(=O)NCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: NCCCN1CCC(c2ccccn2)CC1
Temperature: 25 °C
Yield: 74.4 %

Procedure:
To 1-benzyl-4-(2-pyridyl)-piperidine (3.26 g, 12.9 mmol) in dry methanol (25 mL), 10% palladium hydroxide (1.9 g) was added and the solution was hydrogenated at 200 psi for 24 hours. The solution was filtered over celite, concentrated to give 2.1 g (99%) of 4-(2-pyridyl)-piperidine which was used as such for the subsequent step. A mixture of 3-bromopropylamine hydrobromide (20 g, 91.3 mmol), potassium carbonate (37.85 g, 273.9 mmol) and di-tert-butyldicarbonate (21.90 g, 100 mmol) in methanol was stirred at room temperature for 24 hours. The reaction mixture was concentrated and partitioned between 250 mL EtOAc and 50 mL water, dried over sodium sulfate, filtered and concentrated. Purification of the crude product by column chromatography (hexane: EtOAc, 4. 5:0.5) gave 17.5 g (80%) of the product as a pale yellow oil. To a stirred solution of the 4-(2-pyridyl)-piperidine (1.86 g, 11.4 mmol) in dioxane (20 mL), N-(tert-butoxycarbonyl)-3-bromopropylamine (2.82 g, 11.4 mmol) and potassium carbonate (3.16 g, 22.9 mmol) were added and the solution was refluxed for 24 hours. The reaction mixture was cooled to room temperature, concentrated and partitioned between 40 mL chloroform and 5 mL water. The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (ethyl acetate:methanol, 4:1) to yield 1.86 g (49%) of the required product as a colorless oil; 1H-NMR (CDCl3): δ 1.45 (s, 9 H), 1.54-1.69 (m, 8 H), 2.21-2.68 (m, 2 H), 2.74-2.80 (m, 1 H), 3.02-3.22 (m, 4 H), 5.41 ( s, 1 H), 7.13-7.17 (m, 1 H), 7.33 (d, J=7.93 Hz, 1 H), 7.63 (t, J=7.6 Hz, 1 H), 8.54 (d, J=4.6 Hz, 1 H). To N-(tert-butoxycarbonyl)-3-[4-(2-pyridyl)-piperidin-1-yl]propylamine (0.15 g, 0.45 mmol) in 5 mL of dichloromethane, 1 mL of trifluoroacetic acid was added and the solution was stirred at room temperature for 1 hour. The solution was concentrated, neutralized with 10% KOH solution and extracted into 25 mL of dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated to give 0.098 g (100%) of 3-[4-2-pyridyl)-piperidin-1-yl]propylamine which was used as such for the subsequent step.
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][O:5][C:6]1[C:7]([Br:24])=[CH:8][C:9]2[O:13][C:12]([C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:11][C:10]=2[C:22]=1[Br:23].[K+].[Br-]>>[C:14]([C:12]1[O:13][C:9]2[CH:8]=[C:7]([Br:24])[C:6]([O:5][CH2:4][C:3]([OH:25])=[O:2])=[C:22]([Br:23])[C:10]=2[CH:11]=1)(=[O:21])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)COc1c(Br)cc2oc(C(=O)c3ccccc3)cc2c1Br
Agent: [Br-]
Agent: [K+]
Product: O=C(O)COc1c(Br)cc2oc(C(=O)c3ccccc3)cc2c1Br

Procedure:
The title compound was prepared as an off white solid (0.060 g, 88%) from (2-benzoyl-4,6-dibromobenzofuran-5-yloxy)acetic acid methyl ester using a procedure similar to step 2 of Example 36, mp 179-181° C.; 1H NMR (DMSO-d6) δ 4.54 (s, 2H), 7.58 (d, J=0.88 Hz, 1H), 7.60-7.65 (m, 2H), 7.74 (tt, J=1.3, 6.8 Hz, 1H), 7.99-8.03 (m, 2H), 8.31 (d, J=0.88 Hz, 1H), 12.98-13.32 (bs, 1H); IR (KBr) 3420, 3080, 2910, 2580, 1740, 1645, 1610, 1540, 1440, 1410, 1330, 1290, 1250, 1175, 1125, 1070, 1000, 970, 915, 860, 800, 715, and 675 cm−1; mass spectrum [(−) ESI], m/z 451 (M−H)−; Anal. Calcd. for C17H10Br2O5: C, 44.97; H, 2.22; N, 0.00, Found: C, 44.71; H, 2.13; N, 0.04.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:14]=[C:13]([C:15]2[S:16][CH:17]=[CH:18][N:19]=2)[NH:12][C:11]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH:23]([C:27]([OH:29])=O)[CH2:22]2)=[C:10]1[C:30]([O:32][CH2:33][CH3:34])=[O:31].[NH2:35][CH2:36][CH2:37][OH:38]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:10]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:11]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH:23]([C:27](=[O:29])[NH:35][CH2:36][CH2:37][OH:38])[CH2:22]2)[NH:12][C:13]([C:15]2[S:16][CH:17]=[CH:18][N:19]=2)=[N:14]1
Reactant: CCOC(=O)C1=C(CN2CCOC(C(=O)O)C2)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Reactant: NCCO
Product: CCOC(=O)C1=C(CN2CCOC(C(=O)NCCO)C2)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Yield: 59.6 %

Procedure:
4-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholine-2-carboxylic acid (0.5 g, 0.9 mmol) was reacted with 2-aminoethanol (72 mg, 1.2 mmol) according to the procedure as described in Example 53 to give the title compound as a yellow solid (0.32 g, 60%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][CH2:6][C:7](Cl)=[O:8].[C:10]1([CH:17]=[CH:16][CH:15]=[C:13]([OH:14])[CH:12]=1)[OH:11].Cl>[N+](C1C=CC=CC=1)([O-])=O.O.C(Cl)(Cl)Cl>[Cl:5][CH2:6][C:7]([C:15]1[CH:16]=[CH:17][C:10]([OH:11])=[CH:12][C:13]=1[OH:14])=[O:8]
Reactant: O=C(Cl)CCl
Reactant: Oc1cccc(O)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C(CCl)c1ccc(O)cc1O
Temperature: 0 °C
Reaction time: 16 h
Yield: 64 %

Procedure:
A mixture of 4.91 g (51.84 mmol) of chloroacetic acid, 4 mL (54.84 mmol) of thionyl chloride and one drop of DMF was stirred at 90° C. for 3 hours. The resulting solution was cooled and evaporated to remove excess thionyl chloride, hydrogen chloride and sulfur dioxide to yield crude chloroacetyl chloride as a colorless oil, pure enough to use in the next step without further purification. To a stirred suspension of 8.01 g (60.07 mmol) of anhydrous aluminum chloride in 10 mL of nitrobenzene were added 2 mL of chloroacetyl chloride and 2.37 g (21.52 mmol) of resorcinol at 0° C. The mixture was stirred at 0° C. for 10 minutes and at room temperature for 16 hours, poured into ice (ca. 20 mL), hydrolyzed by conc. HCl (10 mL), diluted with water (20 mL) and chloroform (50 mL) and separated. The organic layer was dried over MgSO4, evaporated and purified by column chromatography (75 g of SiO2, 20% ethyl acetate-hexane) to yield 2.57 g (13.77 mmol, 64.0% yield) of 4-(2-chloroacetyl)resorcinol. A mixture of 167.2 mg (0.896 mmol) of 4-(2-chloroacetyl)resorcinol and 109.0 mg (0.990 mmol) of resorcinol in methanesulfonic acid (0.5 mL) was stirred at 85° C. for 1 hour. To the resulting deep red solution, ice (ca. 10 mL) was added to precipitate a product as a black gummy material which eventually became reddish brown fine powder after scratching with a spatula. The precipitate was collected by filtration, washed with water and dried over P2O5 under vacuum to yield 196.6 mg (0.754 mmol, 84% yield) of 9-chloromethylxanthene as a reddish brown solid. 1H NMR (D2O+K2CO3) δ 7.66 (1H, d, J=9 Hz). 6.60 (1H, dd, J=9 & 2 Hz), 6.30 (1H, d, J=2 Hz), 4.82 (2H, s); MS (ES, positive) 261.4, 263.4; UV (KMOPS, pH 7.2) λmax (ε) 515 nm (41,200 M−1cm−1).
Reaction SMILES: [N:1]1([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][CH:28]=2)=[C:23]([C:35]([F:38])([F:37])[F:36])[CH:22]=1>C(Cl)Cl.CO>[N:1]1([C:10]2[CH:11]=[CH:12][C:13]([CH2:16][C:17]([NH:20][C:21]3[CH:22]=[C:23]([C:35]([F:36])([F:37])[F:38])[C:24]([C:27]4[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][CH:28]=4)=[CH:25][CH:26]=3)=[O:19])=[CH:14][CH:15]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)Cc1ccc(-n2cnc3ccccc32)cc1
Reactant: N#Cc1ccc(-c2ccc(N)cc2C(F)(F)F)cc1
Solvent: CO
Solvent: ClCCl
Product: N#Cc1ccc(-c2ccc(NC(=O)Cc3ccc(-n4cnc5ccccc54)cc3)cc2C(F)(F)F)cc1

Procedure:
The title compound is prepared as described in Example 1 but using (4-benzoimidazol-1-yl-phenyl)-acetic acid (Step 20.1) and 4′-amino-2′-trifluoromethyl-biphenyl-4-carbonitrile. Title compound: ES-MS: 496.9 [M+H]+; single peak at tR=4.37 min (System 1); Rf=0.12 (CH2Cl2/MeOH, 96:4).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23](B(O)O)[CH:24]=2)[CH:19]=[CH:18]1>>[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:2]3[N:3]=[C:4]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)[C:5]4[S:10][CH:9]=[CH:8][C:6]=4[N:7]=3)[CH:24]=2)[CH:19]=[CH:18]1
Reactant: Clc1nc(N2CCOCC2)c2sccc2n1
Reactant: OB(O)c1ccc2cc[nH]c2c1
Product: c1cc2ccc(-c3nc(N4CCOCC4)c4sccc4n3)cc2[nH]1

Procedure:
2-Chloro-4-moropholinothieno[3.2-d]pyrimidine 4 was reacted with 6-indole boronic acid in General Procedure A on a 23.5 mmol scale to give 30 mg. of 272 after RP-HPLC purification. MS (Q1) 337.1 (M)+.
Reaction SMILES: Cl[CH2:2][C:3]1[N+:12]([O-:13])=[C:11]([C:14]2[CH:19]=[CH:18][C:17]3[O:20][CH2:21][O:22][C:16]=3[CH:15]=2)[C:10]2[C:5](=[CH:6][C:7]3[O:25][CH2:24][O:23][C:8]=3[CH:9]=2)[N:4]=1.[CH3:26][NH:27][CH3:28]>C1COCC1>[CH3:26][N:27]([CH2:2][C:3]1[N+:12]([O-:13])=[C:11]([C:14]2[CH:19]=[CH:18][C:17]3[O:20][CH2:21][O:22][C:16]=3[CH:15]=2)[C:10]2[C:5](=[CH:6][C:7]3[O:25][CH2:24][O:23][C:8]=3[CH:9]=2)[N:4]=1)[CH3:28]
Reactant: [O-][n+]1c(CCl)nc2cc3c(cc2c1-c1ccc2c(c1)OCO2)OCO3
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)Cc1nc2cc3c(cc2c(-c2ccc4c(c2)OCO4)[n+]1[O-])OCO3
Temperature: 65 °C
Reaction time: 2 h

Procedure:
To a suspension of 2-chloromethyl-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazoline-3-oxide (200 mg, 0.55 mmol), in THF (6 mL), was added dimethylamine (2M in THF, 2 mL, 4 mmol). The mixture %-as stirred at 65° C. for 2 h. After cooling, the solvent was evaporated and the residue was purified by column chromatography on silica gel (hexane:acetone 4:1); mp 205-210° C. 1H NMR (CDCl3) 7.41 (s, 1H), 6.90-7.06 (m, 4H), 6.78 (s 1H), 6.11 (s, 2H), 6.08 (s, 2H), 4.05 (s, 2H), 2.52 (s, 6H).
Reaction SMILES: C([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12](C)=[CH:11][CH:10]=1)#N.NN.N([O-])=O.[Na+].Cl>C(O)C>[C:4]1([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=[CH:8][CH:3]=1
Reactant: Cc1ccc(-c2ccccc2C#N)cc1
Agent: Cl
Agent: NN
Agent: O=N[O-]
Solvent: CCO
Product: c1ccc(-c2ccccc2)cc1
Reaction time: 48 h

Procedure:
First, 26.9 mmol of 2-cyano-4′-methyl-1,1′-biphenyl was dissolved in 150 ml of ethanol, and 270 mmol of hydrazine and 77.7 nmuol of 28% methylate were added thereto, followed by keeping at 50° C. for 48 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in 100 ml of ethanol, and 55 mmol of sodium nitrite and 110 mmol of concentrated hydrochloric acid were added to the solution at 0° C. After keeping at 0-5° C. for 2 hours, the reaction mixture was concentrated to give 2-(tetrazol-5-yl)-4′-methyl-1, I′-biphenyl. Yield, 46%
Reaction SMILES: C([O:5][C:6](=[O:36])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH2:31][CH2:30][C@@H:29]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:28][CH:27]=3)=[CH:22][CH:21]=2)[C:15]([O:17]CC)=[O:16])=[CH:9][CH:8]=1)(C)(C)C.[OH-].[Li+].OP([O-])(O)=O.[K+]>C1COCC1.CO.O>[C:32]([C@@H:29]1[CH2:30][CH2:31][C:26]([C:23]2[CH:24]=[CH:25][C:20]([CH:14]([C:15]([OH:17])=[O:16])[CH2:13][C:10]3[CH:9]=[CH:8][C:7]([C:6]([OH:36])=[O:5])=[CH:12][CH:11]=3)=[CH:21][CH:22]=2)=[CH:27][CH2:28]1)([CH3:35])([CH3:33])[CH3:34]
Reactant: CCOC(=O)C(Cc1ccc(C(=O)OC(C)(C)C)cc1)c1ccc(C2=CC[C@H](C(C)(C)C)CC2)cc1
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C)[C@H]1CC=C(c2ccc(C(Cc3ccc(C(=O)O)cc3)C(=O)O)cc2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To 4-{2-[4-(4-(R)-tert-Butylcyclohex-1-enyl)-phenyl]-2-ethoxylcarbonyl-ethyl}-benzoic acid tert-butyl ester (63 mg, 0.13 mmol) dissolved in a solution of THF (3 mL), MeOH (1 mL) and water (1 mL) was added lithium hydroxide (27 mg, 0.64 mmol). The solution was stirred at rt for 5 hrs then neutralized with 3M KH2PO4 and extracted with ethyl acetate. The organic portion was washed with brine, dried over Na2SO4 and concentrated under vacuum to afford crude material which was used without further purification.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[N:17]=[C:16]4[C:12]([N:13]=[C:14]([CH:19]=O)[N:15]4[CH3:18])=[C:11]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:10]=3)[C:7]3[CH:27]=[CH:28][CH:29]=[CH:30][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[O:31]1[CH2:36][CH2:35][CH:34]([CH:37]2[CH2:40][NH:39][CH2:38]2)[CH2:33][CH2:32]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH:1]1([C:4]2[N:8]([C:9]3[N:17]=[C:16]4[C:12]([N:13]=[C:14]([CH2:19][N:39]5[CH2:40][CH:37]([CH:34]6[CH2:35][CH2:36][O:31][CH2:32][CH2:33]6)[CH2:38]5)[N:15]4[CH3:18])=[C:11]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:10]=3)[C:7]3[CH:27]=[CH:28][CH:29]=[CH:30][C:6]=3[N:5]=2)[CH2:2][CH2:3]1
Reactant: C1CC(C2CNC2)CCO1
Reactant: Cn1c(C=O)nc2c(N3CCOCC3)nc(-n3c(C4CC4)nc4ccccc43)nc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cn1c(CN2CC(C3CCOCC3)C2)nc2c(N3CCOCC3)nc(-n3c(C4CC4)nc4ccccc43)nc21
Reaction time: 16 h

Procedure:
A mixture of 2-(2-cyclopropylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (100 mg, 0.25 mmol), 3-(tetrahydropyran-4-yl)azetidine (37 mg, 0.26 mmol) and 4 Å powdered molecular sieves (250 mg) in DCE (5 mL) was stirred at room temperature for 5 h before the addition of sodium triacetoxyborohydride (233 mg, 0.92 mmol). The reaction mixture was stirred for 16 h then filtered through celite, washing with DCM. The organic phase was washed with brine (×1) and concentrated in vacuo. The organic phase was dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 0-10%). The resulting oil was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH affording 499 as an orange solid (76 mg, 57%). LCMS (Method I): RT 2.72 min [M+H]+ 529.3. 1H NMR (CDCl3, 400 MHz): δ 7.93 (d, J=7.6 Hz, 1 H); 7.67 (d, J=7.4 Hz, 1 H); 7.27-7.18 (m, 2 H); 4.36 (m, 4 H); 4.00-3.93 (m, 2 H); 3.88-3.83 (m, 9 H); 3.55 (m, 2 H); 3.37 (m, 2 H); 3.06 (m, 2 H); 2.89-2.81 (m, 1 H); 2.34 (m, 1 H); 1.71 (m, 1 H); 1.54 (m, 2 H); 1.38-1.32 (m, 2 H); 1.22 (m, 2 H) and 1.06 (m, 2 H)
Reaction SMILES: [C:1]([OH:12])(=[O:11])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]>S(Cl)(Cl)=O.O>[CH2:1]([O:11][C:1](=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCC/C=C/C(=O)O
Solvent: O=S(Cl)Cl
Solvent: O
Product: CCCCCCC/C=C/COC(=O)/C=C/CCCCCCC

Procedure:
Trans-2-decenoic acid was dissolved in thionyl chloride (10 ml) and treated in water bath for 3 hours to distill off excess thionyl chloride. Trans-2-decen-1-ol (30 ml) was added to chloride of trans-2-decenoic acid and refluxed in water bath for 2 hours. After cooling, the reaction mixture was added to 1N HCl (80 ml) to be acidic and distributed with EtOAc. The distributed liquid was purified with column chromatography (developing solvent: C6H14-EtOAc (3:1)) after concentration, and trans-2-decenoic acid-trans-2-decenyl ester shown in the following was isolated.
Reaction SMILES: COC([C:5]1([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[CH2:9][CH2:8][C:7]([CH2:11][O:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])([CH3:10])[C:6]1=[O:23])=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[Cl:31][C:28]1[CH:27]=[CH:26][C:25]([CH2:24][CH:5]2[CH2:9][CH2:8][C:7]([CH2:11][O:12][S:13]([C:16]3[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=3)(=[O:14])=[O:15])([CH3:10])[C:6]2=[O:23])=[CH:30][CH:29]=1
Reactant: COC(=O)C1(Cc2ccc(Cl)cc2)CCC(C)(COS(=O)(=O)c2ccc(C)cc2)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCC2(C)CCC(Cc3ccc(Cl)cc3)C2=O)cc1
Temperature: 80 °C
Reaction time: 38.5 h
Yield: 79.2 %

Procedure:
To 521 mg of Compound 3-1-2 synthesized in Production Example 3, 256 mg of 4-toluenesulfonic acid monohydrate and 32.3 μl of water were added, and the resulting mixture was stirred at 80° C. for 38.5 hours. After the reaction, water was added to the reaction solution thus obtained, and extraction with ethyl acetate was then carried out. The extract was washed with an aqueous solution of sodium hydrogen carbonate and saturated brine. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled away. The residue was purified by silica gel column chromatography to obtain 361.1 mg of Compound 4-1-2.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][C:4]=2[S:5][C:6]=1[CH2:7][CH:8]1[CH2:12][CH2:11][N:10]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:9]1=[O:19].Cl.Br[CH2:27][CH2:28][CH2:29][N:30]([CH3:32])[CH3:31].[I-].[Na+].C(=O)([O-])[O-].[Cs+].[Cs+]>>[ClH:1].[Cl:1][C:2]1[C:3]2[CH:23]=[CH:22][C:21]([O:24][CH2:27][CH2:28][CH2:29][N:30]([CH3:32])[CH3:31])=[CH:20][C:4]=2[S:5][C:6]=1[CH2:7][CH:8]1[CH2:12][CH2:11][N:10]([CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]2)[C:9]1=[O:19]
Reactant: O=C1C(Cc2sc3cc(O)ccc3c2Cl)CCN1C1CCCCC1
Reactant: CN(C)CCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CN(C)CCCOc1ccc2c(Cl)c(CC3CCN(C4CCCCC4)C3=O)sc2c1

Procedure:
Using the procedure to synthesize Example 12 and using reagents 3-(3-chloro-6-hydroxy-benzo[b]thiophen-2-ylmethyl)-1-cyclohexyl-pyrrolidin-2-one (150 mg, 0.412 mmol), (3-bromo-propyl)-dimethyl-amine hydrochloride (167 mg, 0.824 mmol), sodium iodide (62 mg, 0.412 mmol), and cesium carbonate (1.07 g, 3.30 mmol) afford the freebase of the title compound. Dissolve freebase in dichloromethane (5 mL) and add HCl in ether (2M, 0.4 mL), concentrate to give title compound (105 mg, 52%) as a yellow solid: Mass spectrum (apci) m/z=449.3 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:32]2[CH2:31][CH2:30][N:29]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[O:22][CH3:21])[CH2:34][CH2:33]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1
Reactant: CCOC(=O)Nc1nc2cc(OC)ccc2nc1OC
Reactant: COc1ccccc1N1CCNCC1
Product: COc1ccc2nc(OC)c(NC(=O)N3CCN(c4ccccc4OC)CC3)nc2c1
Yield: 84 %

Procedure:
Ethyl N-(2,6-dimethoxyquinoxalin-3-yl)carbamate and 1-(2-methoxyphenyl) piperazine were reacted by the same way with the example 64 to obtain the titled compound (yield, 84%). 1H NMR (300 MHz, CDCl3): δ 3.15 (s, 4H), 3.83-3.89 (m, 9H), 4.12-4.17 (m, 4H), 6.88-6.95 (m, 3H), 7.02-7.05 (m, 1H), 7.14 (d, J=8.7 Hz, 1H), 7.31 (s, 1H), 7.51 (d, J=8.7 Hz, 1H), 7.63 (d, J=9.0 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([OH:16])=O)=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.C(O)(=O)/C=C/C(O)=O.[NH2:29][CH2:30][CH2:31][C:32]#[N:33]>>[C:30]([CH2:31][CH2:32][NH:33][C:14]([C:9]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:16])#[N:29]
Reactant: N#CCCN
Reactant: Cc1ccc(-c2ccccc2C(=O)O)cc1
Agent: O=C(O)/C=C/C(=O)O
Solvent: O=S(Cl)Cl
Product: Cc1ccc(-c2ccccc2C(=O)NCCC#N)cc1
Yield: 84335.3 %

Procedure:
4'-Methylbiphenyl-2-carboxylic acid (50.0 g, 0.24 mmol) was converted into the corresponding acid chloride as described in Example 89, Part B using thionyl chloride. This acid chloride was subsequently reacted with 3-aminopropionitrile fumarate (30.25 g, 0.24 mmol) under Schotten-Baumann reaction conditions described in Example 209, Part B to yield 53.50 g of white powder after recrystallization from methylcyclohexane/butylchloride; m.p. 102.0°-103.5° C.; NMR (200 MHz, CDCl3): δ7.68 (d, 1H, J=7 Hz); 7.56-7.19 (m, 7H); 5.65 (bm, 1H); 3.43 (d of t, 2H, J=7,7 Hz); 2.39 (t, 2H, J=7 Hz). Anal. calcd. for C17H16N2O: C, 77.25; H, 6.10; N, 10.60. Found: C, 77.42; H, 6.40; N, 10.68.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[F:19][C:20]([F:33])([F:32])[O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](O)=[O:30])=[CH:24][CH:23]=1>>[N:12]1([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:18])[N:2]([NH:1][C:29](=[O:30])[CH2:28][C:25]3[CH:26]=[CH:27][C:22]([O:21][C:20]([F:32])([F:19])[F:33])=[CH:23][CH:24]=3)[N:11]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: O=C(O)Cc1ccc(OC(F)(F)F)cc1
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Product: O=C(Cc1ccc(OC(F)(F)F)cc1)Nn1nc(N2CCOCC2)c2ccccc2c1=O

Procedure:
The product of Example 1B and 2-[4-(trifluoromethoxy)phenyl]acetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.31 (dd, J=7.9, 1.3 Hz, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.97-8.01 (m, 1H), 7.89-7.93 (m, 1H), 7.50-7.52 (m, 2H), 7.34-7.37 (m, 2H), 3.80-3.84 (m, 4H), 3.75 (s, 2H), 3.07-3.11 (m, 2H); MS (ESI+) M/Z 449 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([C:12]3[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=3[CH3:20])[N:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:21])[C:3]=1[CH2:22][CH2:23]Cl>NC(CC)CC>[CH2:7]([CH:6]([N:5]1[C:2]2[C:11]3[CH:10]=[CH:9][N:8]=[C:7]([C:12]4[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=4[CH3:20])[C:6]=3[N:5]=[C:4]([CH3:21])[C:3]=2[CH2:22][CH2:23]1)[CH2:11][CH3:10])[CH3:12]
Reactant: Cc1cc(C)c(-c2nccc3c(Cl)c(CCCl)c(C)nc23)c(C)c1
Agent: CCC(N)CC
Product: CCC(CC)N1CCc2c(C)nc3c(-c4c(C)cc(C)cc4C)nccc3c21
Yield: 198.9 %

Procedure:
A solution of 4-chloro-3-(2-chloroethyl)-8-mesityl-2-methyl[1,7]naphthyridine (100 mg, 0.28 mmol) in 3-aminopentane (5.0 mL) was stirred at 200° C. for six hours in a sealed tube. After evaporating, the residue was purified by silica gel column chromatography (30-50% ethyl acetate/hexane), to give the title compound (104 mg) as pale brown crystals.