Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:11](I)=[CH:10][N:9]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1.[CH2:24]([OH:29])[CH2:25][CH2:26][C:27]#[CH:28]>>[NH2:8][C:6]1[N:7]=[C:2]([Cl:1])[C:3]2[C:11]([C:28]#[C:27][CH2:26][CH2:25][CH2:24][OH:29])=[CH:10][N:9]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)[C:4]=2[N:5]=1
Reactant: COc1c(C)cnc(Cn2cc(I)c3c(Cl)nc(N)nc32)c1C
Reactant: C#CCCCO
Product: COc1c(C)cnc(Cn2cc(C#CCCCO)c3c(Cl)nc(N)nc32)c1C

Procedure:
The title compound was prepared by Sonogashira coupling of 4-chloro-5-iodo-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine (see Example 1) with 4-pentyn-1-ol according to the General Procedure A. tR: 4.71 min. 1H-NMR (DMSO-d6) δ 8.04 (s, 1H), 7.22 (s, 1H), 6.69 (br. s, 2H), 5.25 (s, 2H), 4.48 (d, 1H), 3.71 (s, 3H), 3.50 (q, 2H), 2.42 (t, 2H), 2.23 (s, 3H), 2.14 (s, 3H), 1.65 (5, 2H).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:17][C:18]([CH3:23])=[CH:19][C:20]([OH:22])=[O:21]>C(=S)=S>[CH3:17][C:18]([C:4]1[CH:5]=[CH:6][C:1]([C:7]2[CH:8]=[CH:9][C:10]([C:18]([CH3:23])([CH3:17])[CH2:19][C:20]([OH:22])=[O:21])=[CH:11][CH:12]=2)=[CH:2][CH:3]=1)([CH3:23])[CH2:19][C:20]([OH:22])=[O:21]
Reactant: CC(C)=CC(=O)O
Reactant: c1ccc(-c2ccccc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(C)(CC(=O)O)c1ccc(-c2ccc(C(C)(C)CC(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a 1 liter flask equipped with a magnetic stirrer, a reflux condenser capped with a nitrogen bubbler, and an addition funnel was put 250 g of carbon disulfide, 23.1 g of biphenyl and 80 g of anhydrous aluminum chloride. To this stirred mixture, a solution of 30.0 g of β,β-dimethyl acrylic acid dissolved in 165 ml of carbon disulfide was added from the addition funnel in about 1/4 hour. The resulting mixture was stirred at room temperature for 2 hours and then heated to gentle reflux for 1 hour. After being cooled to room temperature, the mixture was poured into 1 kilogram of chopped ice with vigorous stirring, and stirred for about 16 hours.
Reaction SMILES: [F:1][C:2]1[C:3](B(O)O)=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.Br[C:14]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:15]=1[C:16]#[N:17]>>[Cl:22][C:20]1[CH:21]=[CH:14][C:15]([C:16]#[N:17])=[C:18]([C:3]2[C:2]([F:1])=[CH:7][N:6]=[C:5]([O:8][CH3:9])[CH:4]=2)[CH:19]=1
Reactant: N#Cc1ccc(Cl)cc1Br
Reactant: COc1cc(B(O)O)c(F)cn1
Product: COc1cc(-c2cc(Cl)ccc2C#N)c(F)cn1

Procedure:
256 mg (1.5 mmol) of 5-fluoro-2-methoxypyridin-4-ylboronic acid and 295 mg (1.34 mmol) of 2-bromo-4-chlorobenzonitrile were reacted according to General Method 2A. The product was precipitated with water. Yield: 146 mg (37% of theory)
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C:8]2[C:13]([C:14]#[N:15])=[CH:12][N:11]=[CH:10][CH:9]=2)[CH:7]=1.N([O-])=O.[Na+].[BrH:21]>O.[Cu]Br>[Br:21][C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C:8]2[C:13]([C:14]#[N:15])=[CH:12][N:11]=[CH:10][CH:9]=2)[CH:7]=1
Reactant: Br
Reactant: N#Cc1cnccc1-c1cc(N)ccc1F
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: N#Cc1cnccc1-c1cc(Br)ccc1F
Temperature: 3 °C
Reaction time: 2 h

Procedure:
4-(5-Amino-2-fluorophenyl)nicotinonitrile (0.65 g, 3.05 mmol) was treated with 48% hydrobromic acid (25 ml) and the resulting suspension stirred and cooled to 3° C. (internal temperature). A solution of sodium nitrite (0.24 g, 3.5 mmol) in water (1 ml) was then added dropwise over 20 min keeping the internal temperature <5° C. Stirring at <5° C. was continued for 2 h before pouring the reaction into a cooled (5° C.) solution of freshly purified copper(I) bromide (1.53 g, 10.7 mmol) in 48% hydrobromic acid (10 ml). The resulting purple reaction mixture was stirred at 5° C. for 10 min then warmed to 50° C. for 20 min. The reaction was diluted with ice-cold water (50 ml) and extracted with ethyl acetate (2×25 ml). The organic extracts were combined, washed with 5% aqueous sodium sulfite and saturated aqueous ammonium chloride, dried over anhydrous magnesium sulfate, filtered and pre-adsorbed onto silica. Purification by chromatography (silica gel, CH2Cl2) afforded 4-(5-bromo-2-fluorophenyl)-nicotinonitrile as a white solid: 1H NMR (400 MHz, CDCl3) δ 7.17 (1H, t, J 9 Hz), 7.44-7.46 (1H, m), 7.57 (1H, dd, J 6, 2 Hz), 7.61-7.66 (1H, m), 8.87 (1H, d, J 5), 9.00 (1H, d, J 1 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12](C)[NH:11][C:10]([CH2:19][O:20][CH2:21][CH2:22][N:23]2[C:27]([CH3:28])=[C:26]([CH3:29])[N:25]=[C:24]2[CH3:30])=[C:9]1[C:31]([O:33][CH2:34][CH3:35])=[O:32].N1C=CC=CC=1.C1C=C[NH+]=CC=1.Br[Br-]Br>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:9]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:10]([CH2:19][O:20][CH2:21][CH2:22][N:23]2[C:27]([CH3:28])=[C:26]([CH3:29])[N:25]=[C:24]2[CH3:30])[NH:11][C:12]2[CH2:17][O:16][C:14](=[O:15])[C:13]1=2
Reactant: CCOC(=O)C1=C(COCCn2c(C)nc(C)c2C)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCOC(=O)C1=C(COCCn2c(C)nc(C)c2C)NC2=C(C(=O)OC2)C1c1ccccc1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2-[2-(2,4,5-trimethylimidazol-1-yl)ethoxymethyl)-1,4-dihydropyridine (3.0 g) in chloroform (50 cm3) stirred at 0° C. under N2 was treated with pyridine (790 mg) followed by pyridinium bromide perbromide (2.1 g) in portions over five minutes and the mixture stirred at 0° C. for one hour and then heated at reflux temperature for three hours. The solution was cooled, washed with 2N hydrochloric acid (2×50 cm3) and brine (50 cm3), dried over MgSO4 filtered and evaporated to dryness. The residue was purified by silica-gel column chromatography eluting with diethylamine/ethyl acetate (1:9). The appropriate fractions were evaporated to dryness and taken up in ethyl acetate (25 cm3) from which the title compound crystallised as a colourless solid (440 mg). M.p. 215°-217° C.
Reaction SMILES: Cl.[NH2:2][C:3]([CH3:11])([CH3:10])[C:4]#[C:5][CH:6]([O:8][CH3:9])[CH3:7].[Cl:12][C:13]1[CH:14]=[C:15]([O:19][CH:20]([CH2:24][CH3:25])[C:21](O)=[O:22])[CH:16]=[N:17][CH:18]=1>>[Cl:12][C:13]1[CH:14]=[C:15]([O:19][CH:20]([CH2:24][CH3:25])[C:21]([NH:2][C:3]([CH3:11])([CH3:10])[C:4]#[C:5][CH:6]([O:8][CH3:9])[CH3:7])=[O:22])[CH:16]=[N:17][CH:18]=1
Reactant: CCC(Oc1cncc(Cl)c1)C(=O)O
Reactant: COC(C)C#CC(C)(C)N
Agent: Cl
Product: CCC(Oc1cncc(Cl)c1)C(=O)NC(C)(C)C#CC(C)OC

Procedure:
5-Amino-2-methoxy-5-methylhex-3-yne hydrochloride was reacted with 2-(5-chloro-3-pyridyloxy)butyric acid in a similar procedure to Example 1, Stage 3 to give 2-(5-chloro-3-pyridyloxy)-N-(2-methoxy-5-methylhex-3-yn-5-yl)butyramide as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](Cl)(=[O:14])=[O:13])[CH:7]=1.[CH2:17]([NH2:27])[C:18]1[CH:26]=[CH:25][C:24]2[O:23][CH2:22][O:21][C:20]=2[CH:19]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.O>[CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](=[O:14])(=[O:13])[NH:27][CH2:17][C:18]2[CH:26]=[CH:25][C:24]3[O:23][CH2:22][O:21][C:20]=3[CH:19]=2)[CH:7]=1
Reactant: NCc1ccc2c(c1)OCO2
Reactant: COC(=O)C=Cc1cccc(S(=O)(=O)Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)C=Cc1cccc(S(=O)(=O)NCc2ccc3c(c2)OCO3)c1
Yield: 82.4 %

Procedure:
A solution of 3-(3-chlorosulfonylphenyl)acrylic acid methyl ester (0.4 g, 1.53 mmol) in dioxane (5 ml) was added to a mixture of piperonylamine (0.23 g, 1.52 mmol) in dioxane (1 ml) and NaHCO3 (0.25 g, 3.06 mmol) in water (3 ml), and the resultant solution was stirred at room temperature until the completion of the reaction (control by TLC). The reaction mixture was evaporated and the residue was partitioned between ethyl acetate and 2N HCl. The organic layer was washed successively with water, saturated NaCl, and dried (Na2SO4). The solvent was removed and the residue was chromatographed on silica gel with petroleum ether-ethyl acetate (2:1, v/v) as eluent. The obtained product was washed with diethyl ether to give the title compound (0.47 g, 81%) as a white solid, 1H NMR (DMSO-d6, HMDSO), δ: 3.72 (3H, s); 3.96 (2H, d, J=6.4 Hz); 5.94 (2H, s); 6.66-6.85 (3H, m); 6.71 (1H, d, J=16.4 Hz); 7.49-8.07 (5H, m); 8.14 (1H, br t, J=6.4 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11].[CH:12](O)(C)[CH3:13].[OH-].[Na+].C(Br)C>C1OCCOCCOCCOCCOCCOC1.O>[CH2:12]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11])[CH3:13]
Reactant: COc1cc(C=O)ccc1O
Reactant: CC(C)O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: CCBr
Solvent: O
Product: CCOc1ccc(C=O)cc1OC
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 91 %

Procedure:
A 1-liter four-necked flask fitted with thermometer, mechanical stirrer, and reflux condenser was charged with 62 g 4-hydroxy-3-methoxybenzaldehyde (0.41 mol) and 400 ml isopropyl alcohol. The mixture was stirred for 20 min, and then a 120 ml water solution containing 5 g 18-crown-6 ether and 106.3 g sodium hydroxide (2.66 mol) was gradually dropped thereto using a constant pressure funnel. After dropping, the mixture was stirred for 30 min, and then heated to 60° C. At this temperature, 67.3 g ethyl bromide (0.62 mol) was introduced within 5-6 hours and the reaction was monitored with TLC. After the reaction finished, the mixture was cooled to 15° C., and 400 ml water was then added to quench the reaction. The resulting mixture was extracted three times with ether (300 ml×3). The organic layer was washed with water to pH=7, and dried with anhydrous magnesium sulfate. Part of the ether was removed by flash distillation and then large amount of petroleum ether was added to precipitate crude product. The crude product was recrystallized from diethyl ether/petroleum ether to give 67 g 4-ethoxy-3-methoxybenzaldehyde in a yield of 91%. 1H-NMR (ppm) δ: 9.87 (1H, s; —CHO); 7.31 (1H, m; 2-ArH); 7.26 (1H, m; 6-ArH); 6.86 (1H, m; 5-ArH); 3.98 (2H, q; —CH2); 3.73 (3H, s; —OCH3); 1.42 (3H, t; —CH3). MS (m/Z): 180 (M+).
Reaction SMILES: [H-].[Na+].Br[CH2:4][CH2:5][O:6][CH2:7][CH2:8]Br.[F:10][C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:18][C:19]#[N:20]>CN1C(=O)CCC1.CCOCC>[F:10][C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=1[C:18]1([C:19]#[N:20])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: N#CCc1cccc(F)c1F
Reactant: BrCCOCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOCC
Product: N#CC1(c2cccc(F)c2F)CCOCC1
Temperature: 0 °C
Yield: 73.4 %

Procedure:
A mixture of sodium hydride (2 mL, 88 mmol) in 120 mL NMP was stirred at 0° C. and treated with a mixture of bis(2-bromoethyl)ether (9 mL, 40 mmol) and 2-(2,3-difluorophenyl)acetonitrile (6.12 g, 40 mmol) in 20 mL ether. The reaction was stirred at room temperature for 4 hours, carefully quenched with 20 mL H2O, and neutralized to pH=5 with concentrated HCl. The mixture was further diluted with 200 mL water, and the precipitate was collected by filtration. The solid was redissolved in 200 mL ether, washed with 20 mL saturated NaCl, dried over anhydrous Na2SO4, and concentrated to give 6.55 g of the title compound as a white solid. MS m/e: (M+H)+ 224.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[S:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:9]=2[CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:18]([O:20]CC)=[O:19])[NH:6]2>CO.O>[CH3:1][C:2]1[C:10]2[S:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:9]=2[CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:18]([OH:20])=[O:19])[NH:6]2
Reactant: CCOC(=O)c1cc2c(C)c3sc4ccccc4c3cc2[nH]1
Solvent: CO
Solvent: O
Product: Cc1c2cc(C(=O)O)[nH]c2cc2c1sc1ccccc12
Temperature: 25 °C

Procedure:
Ethyl 4-methyl-1H-[1]benzothieno[2,3-f]indole-2-carboxylate (1.0 g, 3.2 mmol) was suspended in a mixture of methanol (110 ml) and water (30 ml). Casium carbonate (10 g) was added and the mixture was heated at reflux under nitrogen for 2 h. The solution was allowed to cool to room temperature, and the methanol was removed in vacuo. The solution was acidified with 0.1 Molar Hydrochloric acid and the resulting yellow precipitate was collected by fitration and washed with water. The wet precipitate was dissolved in acetone and the solvent removed in vacuo to give the product as a yellow solid with m.p. 271°-272° C.; δH [2H6 ]-DMSO 11.88 (1H, s, 1-NH), 8.29 (1H, dd, J 6, 3, 9H), 8.18 (1H, s, 10-H), 7.89-7.99 (1H, m, 6-H), 7.44-7.54 (2H, m, 7-H, 8-H), 7.35 (1H, d, J 2, 3-H), 2.72 (3H, s, 4-CH3); m/z (%) 281 (90, M+), 263 (100), 235 (69).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([CH3:7])([SH:6])[CH3:5].C(N(CC)CC)C.[C:15]1(=[O:22])[O:21][C:19](=[O:20])[CH2:18][CH2:17][CH2:16]1>ClCCl>[CH3:5][C:4]([SH:6])([CH3:7])[CH2:3][NH:2][C:15]([CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[O:22]
Reactant: CC(C)(S)CN
Reactant: O=C1CCCC(=O)O1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(S)CNC(=O)CCCC(=O)O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 71.6 %

Procedure:
To a suspension of 1-Amino-2-methylpropane-2-thiol hydrochloride (1.41 g, 10 mmol) in anhydrous dichloromethane (10 mL) was added triethylamine (1.5 mL) at 0° C. The mixture was stirred at 0° C. for 10 minutes and glutaric anhydride (1.14 g, 10 mmol) in anhydrous dichloromethane (20 mL) was added at 0° C. under argon atmosphere. The reaction mixture was stirred at 0° C. for 10 minutes and then at room temperature for 2 hours. The solvent was evaporated at reduced pressure and the residue was extracted with ethyl acetate and water. The combined ethyl acetate extracts were washed with 1 N HCl, dried over sodium sulfate and solvent was evaporated at reduced pressure to give colorless oil, which upon trituration with ethyl ether/hexane gave 1.57 g of the title compound as a colorless powder in 72% yield, mp 101-104° C.; 1H NMR (CDCl3): δ1.31 (s, 6H), 1.94 (m, 2H), 2.22-2.38 (m, 4H), 3.33 (d, J=6.1 Hz, 2H), 6.28 (s, 1H), 9.2 (br s, 1H; LRMS (APIMS) (m/z) 220 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[C:14]([C:15]([OH:17])=O)=[CH:13][O:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.[Cl:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=1[C:57]1([OH:62])[CH2:61][CH2:60][NH:59][CH2:58]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[C:14]([C:15]([N:59]3[CH2:60][CH2:61][C:57]([C:52]4[CH:53]=[CH:54][CH:55]=[CH:56][C:51]=4[Cl:50])([OH:62])[CH2:58]3)=[O:17])=[CH:13][O:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: OC1(c2ccccc2Cl)CCNC1
Reactant: COc1ccc(-c2nocc2C(=O)O)cc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2nocc2C(=O)N2CCC(O)(c3ccccc3Cl)C2)cc1Cl
Yield: 34.6 %

Procedure:
A solution of 3-(3-chloro-4-methoxyphenyl)isoxazole-4-carboxylic acid (10 mg, 0.04 mmol), N-ethyl-N-isopropylpropan-2-amine (14 μL, 0.08 mmol, 2 equ.) and TBTU (15 mg, 0.046 mmol, 1.2 equ.) in DMF (0.3 mL) was added to 3-(2-chlorophenyl)pyrrolidin-3-ol hydrochloride (9 mg, 0.04 mmol). After 1 h at rt the crude product was purified by RP-HPLC, evaporated and dried in vacuum to yield the title compound (6 mg). MS (ESI, pos. ion) m/z: calcd for C21H18Cl2N2O4: 432.0644, found 432.0645.
Reaction SMILES: Cl[C:2]1[C:13]2=[C:14]3[N:9]([CH:10]([CH3:15])[CH2:11][CH2:12]2)[CH:8]=[C:7]([C:16]([OH:18])=[O:17])[C:6](=[O:19])[C:5]3=[CH:4][C:3]=1[Cl:20].[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>CN(C)P(=O)(N(C)C)N(C)C>[Cl:20][C:3]1[CH:4]=[C:5]2[C:14]3[N:9]([CH:8]=[C:7]([C:16]([OH:18])=[O:17])[C:6]2=[O:19])[CH:10]([CH3:15])[CH2:11][CH2:12][C:13]=3[C:2]=1[N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CC1CCc2c(Cl)c(Cl)cc3c(=O)c(C(=O)O)cn1c23
Reactant: C1CCNCC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC1CCc2c(N3CCCCC3)c(Cl)cc3c(=O)c(C(=O)O)cn1c23
Yield: 24.4 %

Procedure:
In a 200 ml autoclave were placed 4.6 g of 8,9-dichloro-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, 5 g of piperidine and 50 ml of hexamethylphosphoric triamide and the mixture was reacted at 160° C. on an oil bath for 5 hours. After completion of reaction hexamethylphosphoric triamide and piperidine were distilled off under reduced pressure and to the residue was added ethyl acetate and crystallized. Recrystallization from dimethylformamide-water give 1.3 g of 9-chloro-8-(1-piperidyl)-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid. m.p. 246° to 248° C.
Reaction SMILES: [CH:1]1([S:4]([NH:7][C:8]([C:10]2([NH:15][C:16]([CH:18]3[CH2:22][CH:21]([OH:23])[CH2:20][CH:19]3[C:24]([N:26]([CH2:28][CH2:29][CH2:30][CH2:31][CH:32]=[CH2:33])[CH3:27])=[O:25])=[O:17])[CH2:12][CH:11]2[CH:13]=[CH2:14])=[O:9])(=[O:6])=[O:5])[CH2:3][CH2:2]1.[H-].[Na+].[Cl:36][C:37]1[N:42]=[C:41](Cl)[CH:40]=[CH:39][N:38]=1>CN(C=O)C>[CH:1]1([S:4]([NH:7][C:8]([C:10]2([NH:15][C:16]([CH:18]3[CH2:22][CH:21]([O:23][C:39]4[CH:40]=[CH:41][N:42]=[C:37]([Cl:36])[N:38]=4)[CH2:20][CH:19]3[C:24]([N:26]([CH2:28][CH2:29][CH2:30][CH2:31][CH:32]=[CH2:33])[CH3:27])=[O:25])=[O:17])[CH2:12][CH:11]2[CH:13]=[CH2:14])=[O:9])(=[O:6])=[O:5])[CH2:2][CH2:3]1
Reactant: Clc1ccnc(Cl)n1
Reactant: C=CCCCCN(C)C(=O)C1CC(O)CC1C(=O)NC1(C(=O)NS(=O)(=O)C2CC2)CC1C=C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCCCCN(C)C(=O)C1CC(Oc2ccnc(Cl)n2)CC1C(=O)NC1(C(=O)NS(=O)(=O)C2CC2)CC1C=C
Temperature: 0 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
Compound 10e (43 mg, 89.3 mmol) was dissolved in DMF (2 ml) and the solution was cooled to 0° C. and NaH (11 mg, 0.27 mmol) was added. After 0.5 h 2,4-dichloro-pyrimidine was added. The reaction was stirred at 0° C. for 2 h and then quenched by addition of citric acid. The reaction mixture was extracted with DCM (3×10 ml) and the combined organic phases were washed with citric acid, water and brine. The organic phase was dried over MgSO4 and filtered. The solvent was removed in vacuo to yield the crude target compound (43 mg, 81%); LC/MS m/z (ESI+)=595 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([CH2:14][CH:15]=[CH2:16])[CH:8]=1)[CH3:2].Br[CH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:27][CH:26]=1>>[CH2:1]([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:21][CH2:22][CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:27][CH:26]=2)=[C:9]([CH2:14][CH:15]=[CH2:16])[CH:8]=1)[CH3:2]
Reactant: C=CCc1cc(C[C@H](OC)C(=O)OCC)ccc1O
Reactant: BrCCCOc1ccc(Oc2ccccc2)cc1
Product: C=CCc1cc(C[C@H](OC)C(=O)OCC)ccc1OCCCOc1ccc(Oc2ccccc2)cc1

Procedure:
(2S)-3-(3-Allyl-4-hydroxy-phenyl)-2-methoxy-propionic acid ethyl ester from Step A was allowed to react with 4-(3-bromopropoxy)-1-phenoxybenzene under the Standard Procedure I to give the title compound.
Reaction SMILES: [CH2:1]([N:8]([CH2:14][CH:15]([OH:17])[CH3:16])[CH2:9][CH:10](O)[CH2:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+]>S(=O)(=O)(O)O>[CH2:1]([N:8]1[CH2:14][CH:15]([CH3:16])[O:17][CH:10]([CH2:11][CH3:12])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(O)CN(Cc1ccccc1)CC(C)O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCC1CN(Cc2ccccc2)CC(C)O1
Temperature: 150 °C

Procedure:
A mixture of 1-[Benzyl-(2-hydroxy-propyl)-amino]-butan-2-ol (Intermediate 486, 10.5 g, 44.30 mmol) and sulfuric acid (70% w/w, 10 mL) was heated at 150° C. for 36 hour. The reaction mixture was cooled to 0° C., basified with 10% NaHCO3 to pH˜10 and extracted with diethyl ether (3×50 mL). The organic layer was washed with brine (2×25 mL), water (2×25 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography using n-heptane in diethyl ether to give product as a light yellow oil. Yield: 2.0 g (20%)
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.COP([CH2:19][C:20]1[S:21][C:22]2[N:23]=[C:24]([N:35]3[C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=4[N:37]=[C:36]3[CH2:44][CH3:45])[N:25]=[C:26]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[C:27]=2[N:28]=1)(=O)OC.[C:46]([O:50][C:51]([N:53]1[CH2:56][C:55](=O)[CH2:54]1)=[O:52])([CH3:49])([CH3:48])[CH3:47]>C1COCC1>[C:46]([O:50][C:51]([N:53]1[CH2:56][C:55](=[CH:19][C:20]2[S:21][C:22]3[N:23]=[C:24]([N:35]4[C:39]5[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=5[N:37]=[C:36]4[CH2:44][CH3:45])[N:25]=[C:26]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)[C:27]=3[N:28]=2)[CH2:54]1)=[O:52])([CH3:49])([CH3:47])[CH3:48]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CP(=O)(OC)OC)sc2n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=C3CN(C(=O)OC(C)(C)C)C3)sc2n1
Reaction time: 0.33 h

Procedure:
To a solution of diisopropylamine (200 μL, 1.42 mmol) in THF (0.5 mL) at −78° C. was added n-BuLi (556 μL, 1.42 mmol, 2.5 M in hexanes) and the resulting mixture stirred for 20 min. The resulting solution was added to a suspension of [5-(2-ethylbenzoimidazol-1-yl)-7-morpholin-4-ylthiazolo[5,4-d]pyrimidin-2-ylmethyl]phosphonic acid dimethyl ester (620 mg, 1.27 mmol) in THF (11 mL) at −78° C. The resulting mixture was warmed to r.t. before a solution of 3-oxo-azetidine-1-carboxylic acid tert-butyl ester (250 mg, 1.46 mmol) in THF (1.5 mL) was added. The resulting mixture was stirred at r.t. for 5 h then quenched with H2O. The mixture was concentrated in vacuo and the residue was partitioned between DCM and brine. The organic phase was dried (MgSO4) and concentrated in vacuo. The resulting residue was filtered through a pad of silica affording the title compound (493 mg, 73%). LCMS (method H): RT 3.72 min, [M+H]+ 534.3
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:13]([CH2:14][CH2:15][CH3:16])[CH2:12][N:11]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:10][CH:9]2[OH:24])=[CH:4][CH:3]=1.Cl[CH2:26][C:27]1[N:31]([CH2:32][CH3:33])[C:30]2[CH:34]=[CH:35][CH:36]=[CH:37][C:29]=2[N:28]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH:13]([CH2:14][CH2:15][CH3:16])[CH2:12][N:11]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:10][CH:9]2[O:24][CH2:26][C:27]2[N:31]([CH2:32][CH3:33])[C:30]3[CH:34]=[CH:35][CH:36]=[CH:37][C:29]=3[N:28]=2)=[CH:6][CH:7]=1
Reactant: CCCC1CN(C(=O)OC(C)(C)C)CC(O)C1c1ccc(Cl)cc1
Reactant: CCn1c(CCl)nc2ccccc21
Product: CCCC1CN(C(=O)OC(C)(C)C)CC(OCc2nc3ccccc3n2CC)C1c1ccc(Cl)cc1

Procedure:
In an analogous manner to that described in Example 62(h), by alkylating tert-butyl (3RS,4RS,5SR)-4-(4-chloro-phenyl)-3-hydroxy-5-propyl-piperidine-1-carboxylate with 2-chloromethyl-1-ethyl-1H-benzoimidazole [Acta Pol. Pharm. 1977, 34(4), 359-369] there was obtained tert-butyl (3RS,4RS,5SR)-4-(4-chloro-phenyl)-3-(1-ethyl-1H-benzimidazol-2-ylmethoxy)-5-propyl-piperidine-1-carboxylate as a colourless oil, MS: 495 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:11]([NH:12][C:13](=[S:21])OC2C=CC=CC=2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:22][C:23]1[CH:24]=[C:25]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:26]=[C:27]([CH3:29])[CH:28]=1>>[CH3:1][C:2]1[C:11]([NH:12][C:13]([N:33]2[CH2:34][CH2:35][N:30]([C:25]3[CH:26]=[C:27]([CH3:29])[CH:28]=[C:23]([CH3:22])[CH:24]=3)[CH2:31][CH2:32]2)=[S:21])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1nc2ccccc2cc1NC(=S)Oc1ccccc1
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Product: Cc1cc(C)cc(N2CCN(C(=S)Nc3cc4ccccc4nc3C)CC2)c1
Yield: 81 %

Procedure:
Phenyl N-(2-methylquinolin-3-yl)thiocarbamate and 1-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 125 to obtain the titled compound.