Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][C:4]([N:7]2[N:11]=[C:10]([OH:12])[CH:9]=[N:8]2)=[CH:3][CH:2]=1.[OH-].[Na+].S(OC)(O[CH3:20])(=O)=O.C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Na+]>C(Cl)Cl.O>[C:1]1([CH3:13])[CH:2]=[CH:3][C:4]([N:7]2[N:11]=[C:10]([O:12][CH3:20])[CH:9]=[N:8]2)=[CH:5][CH:6]=1
Reactant: Cc1ccc(-n2ncc(O)n2)cc1
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1cnn(-c2ccc(C)cc2)n1
Yield: 64.7 %

Procedure:
With efficient stirring, 71.5 g of 2-p-tolyl-4-hydroxy-2H-1,2,3-triazole (m.p. 178°-180° C., prepared in accordance with Synthesis 1974 (March), pp. 198-199) are added at room temperature to a mixture of 350 ml of water and 25 g of sodium hydroxide. After half an hour, 64 g of dimethyl sulphate are added dropwise to the reaction mixture over a period of half an hour, in the course of which time the reaction temperature rises to approx. 40° C. and a slighly brownish coloured emulsion forms. After the exothermic reaction has subsided, the mixture is heated for 1 hour to 50°-55° C., then 10 g of calcined sodium carbonate are added and the methylation product is expelled with steam. To the distillate is added 10% sodium chloride and the oily product is taken up in methylene chloride, dried over magnesium sulphate and the solvent is distilled off after filtration. Distillation in vacuo yields 50 g of 2-p-tolyl-4-methoxy- 2H-1,2,3-triazole (b.p. 145°-149° C.) as a slightly yellowish liquid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])/[C:5](/[O:29][CH2:30][CH3:31])=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][C:8]=1[CH3:28])[CH3:2]>CO.C1COCC1.CC(O)=O.[Pd]>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([O:29][CH2:30][CH3:31])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][C:8]=1[CH3:28])[CH3:2]
Reactant: CCOC(=O)/C(=C/c1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1C)OCC
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)C(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1C)OCC
Yield: 94.6 %

Procedure:
A suspension of 400 mg of 2Z-ethoxy-3-{2-methyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-acrylic acid ethyl ester and 98 mg of Pd/C (10%) in 8 ml of MeOH, 2 ml of THF and 0.5 ml of AcOH was hydrogenated at 22° C./1 bar overnight. The suspension was filtered, the filtrate evaporated and dried to give 380 mg (95%) of the title compound as colourless oil.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][CH2:10][O:11]C2CCCCO2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:18][N:19]([CH3:25])[C:20]([CH3:24])([CH3:23])[CH2:21][OH:22].CC(C)([O-])C.[K+].C(O)(C)(C)C>C1(C)C=CC=CC=1>[CH3:18][N:19]([CH3:25])[C:20]([CH3:24])([CH3:23])[CH2:21][O:22][C:2]1[C:7]([O:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Clc1ncccc1OCCOC1CCCCO1
Reactant: CN(C)C(C)(C)CO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1
Product: CN(C)C(C)(C)COc1ncccc1OCCO
Temperature: 50 °C
Reaction time: 48 h
Yield: 79.5 %

Procedure:
A solution of 2-chloro-3-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]pyridine (from Example 4; 100 mg, 0.39 mmol), 2-(dimethylamino)-2-methyl-1-propanol (68 μl, 0.58 mmol) and 1.0 M potassium tert-butoxide in tert-butanol (0.8 mL, 0.80 mmol) in 4 mL of toluene was heated at 100° C. for 1 day. The organic phase was washed with 3×2 mL of water and 2 mL of brine. The organic phase was shaken at 50° C. with 4 mL of 2.0 M acetic acid for 2 days. The aqueous phase was washed with 3×3 mL of ethyl acetate, made basic by addition of potassium hydroxide, saturated with sodium chloride and extracted with 3×2 mL of ethyl acetate. The organic phase was dried (MgSO4) and concentrated under reduced pressure to give 79 mg (0.31 mmol, 80%) of the title compound as a colorless oil. LC-UV purity 95%. MS m/z 255 (M+1)+, calc. 255 (M+1)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=[C:5]2[NH:4][C:3]1=O.P(Cl)(Cl)([Cl:18])=O.C(=O)(O)[O-].[Na+]>CN(C)C=O>[Cl:18][C:3]1[N:2]([CH3:1])[C:6]2=[N:7][CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=[C:5]2[N:4]=1
Reactant: Cn1c(=O)[nH]c2cc(C(F)(F)F)cnc21
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(Cl)nc2cc(C(F)(F)F)cnc21
Temperature: 100 °C
Reaction time: 3 h
Yield: 51.6 %

Procedure:
A mixture of 1.09 g of 3-methyl-6-trifluoromethyl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one, one drop of dimethylformamide and 10 g of phosphorus oxychloride was stirred at 100° C. for 3 hours. The cooled reaction mixture was poured to a saturated aqueous sodium bicarbonate solution, and the mixture was extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 0.61 g of 2-chloro-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[F:17][C:18]([F:29])([F:28])[C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:26]([NH:25][C:22]2[CH:21]=[CH:20][C:19]([C:18]([F:17])([F:28])[F:29])=[CH:24][CH:23]=2)=[O:27])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(C(F)(F)F)cc2)cc1-c1c(Br)cnn1C
Yield: 85 %

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.035 g, 0.12 mmol) was treated with α,α,α-trifluoro-p-tolyl isocyanate (0.024 g, 19.0 μL, 0.13 mmol, 1.05 equiv.) in CH2Cl2 (1 mL), in a similar manner as described in Example 1.2 to afford Compound 12 (0.048 g, 0.102 mmol, 83%) as a white solid. LCMS m/z (%)=469 (M+H79Br, 92), 471 (M+H81Br, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.51 (s, 1H), 8.27 (s, 1H), 7.76 (d, J=8.3 Hz, 2H), 7.71 (dd, J=2.3, 9.0 Hz, 1H), 7.62 (d, J=8.4 Hz, 2H), 7.52 (s, 1H), 7.46 (d, J=2.3 Hz, 1H), 7.16 (d, J=8.9 Hz, 1H), 3.84 (s, 3H), 3.70 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=2)=[O:7])=[CH:4][N:3]=1.[NH2:20][NH2:21].O>C(O)(C)C>[C:16]([C:13]1[CH:14]=[CH:15][C:10]([CH2:9][NH:8][C:6](=[O:7])[C:5]2[CH:18]=[CH:19][C:2]([NH:20][NH2:21])=[N:3][CH:4]=2)=[CH:11][CH:12]=1)#[N:17]
Reactant: N#Cc1ccc(CNC(=O)c2ccc(Cl)nc2)cc1
Reactant: NN
Solvent: CC(C)O
Solvent: O
Product: N#Cc1ccc(CNC(=O)c2ccc(NN)nc2)cc1
Yield: 20.5 %

Procedure:
Combined 6-chloro-N-(4-cyanobenzyl)nicotinamide (500 mg, 1.840 mmol) and hydrazine (0.578 mL, 18.40 mmol) in isopropanol (5 mL) and heated at 90° C. for 5 h. The supernatant was decanted and concentrated in vacuo to give a white solid which was stirred vigorously with water (ca. 10 mL) for 2 hours, then was filtered and the solid dried to give the title compound (batch 1, 101 mg) as a pink solid. The fine solids from the reaction (after supernatant was removed) was stirred vigorously with water (ca. 10 mL) for 2 hours, then filtered and dried in the lyophilizer to give the title compound (batch 2, 179 mg) as a tan solid. Large solids from the reaction (after supernatant was removed) were crushed and stirred vigorously with water (10 mL) for 1 hour, then filtered and dried in the lyophilizer to give the title (batch 3, 135 mg) as a beige solid. The combined yield was 415 mg (84% yield). MS m/z 268 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([C:9](=O)[CH:10]=[C:11]([NH:14][C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([F:25])[CH:16]=2)SC)[CH:5]=[CH:4][N:3]=1.[NH:27]([CH2:29][CH2:30][C:31]([N:33]([CH3:35])[CH3:34])=[O:32])[NH2:28]>CC(O)(C)C>[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[N:27]([CH2:29][CH2:30][C:31]([N:33]([CH3:35])[CH3:34])=[O:32])[N:28]=[C:11]([NH:14][C:15]3[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([F:25])[CH:16]=3)[CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CSC(=CC(=O)c1ccnc(Cl)c1C)Nc1cc(F)cc(C(F)(F)F)c1
Reactant: CN(C)C(=O)CCNN
Solvent: CC(C)(C)O
Product: Cc1c(-c2cc(Nc3cc(F)cc(C(F)(F)F)c3)nn2CCC(=O)N(C)C)ccnc1Cl
Temperature: 150 °C
Reaction time: 16 h
Yield: 34.3 %

Procedure:
D6 (prepared according to Description 6) (1.0 g; 2.48 mmol) was added to a mixture of 3-hydrazinyl-N,N-dimethylpropanamide (0.65 g; 4.95 mmol) in t-BuOH (20 ml) and the reaction mixture stirred at 150° C. for 16 h. The solvent was then evaporated in vacuo and the residue purified by flash chromatography over silica gel (Biotage flash purification system: gradient acetone/heptane from 20/80 to 50/50). The solvent was then evaporated in vacuo and two fractions were collected. The desired fraction yielded 0.40 g of E1 (34.3%).
Reaction SMILES: [OH-].[Na+].[SH:3][CH2:4][C:5]1([CH2:8][C:9]([O-:11])=[O:10])[CH2:7][CH2:6]1.CO.Cl>O.CC(=O)OCC>[SH:3][CH2:4][C:5]1([CH2:8][C:9]([OH:11])=[O:10])[CH2:7][CH2:6]1
Reactant: O=C([O-])CC1(CS)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: O=C(O)CC1(CS)CC1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
A 5 L 4-neck round bottle flask was equipped with mechanical stirrer, a thermometer, a condenser, a nitrogen inlet and an additional funnel. Prepare 47% of sodium hydroxide solution from 855 g of sodium hydroxide was dissolved in 972 mL of water. Charge 1800 g of [1-(mercaptomethyl)cyclopropyl]acetate, 1540 mL of methanol to the reaction flask. 1540 g of 47% sodium hydroxide aqueous solution was slowly added to the reaction mixture. After the addition, the reaction mixture was heated to 70˜80° C. and was aged for a period of about 2 hours until completion of reaction as check by TLC (mobile phase: EA/hx=1/2(V/V)). When the reaction was complete, the temperature was lowered below 40° C. The resulting resolution was acidified to pH=3.0˜4.0 with about 1800 mL of 32% HCl aqueous solution. After the reaction mixture was filtered, 2700 g of ethylacetate was added to the filtrate with vigorous stirring over 30 min. The layers were separated; cake and 1000 g of water were added to the aqueous layer and back extracted with 2700 g of ethylacetate. Combined the organic layers and concentrated by rotatory evaporator. Temperature was controlled at 3018 40° C. and pressure was controlled below 100 torr. Distillation was continued to collect about 4000˜5000 mL of distillate. 2000 mL of heptanes was added and the distillation was continued to collect about 1000˜2000 mL at 30˜40° C./<100 torr. After the addition of 2100 g of heptanes, the reaction mixture was cooled to at 10° C. for about 4˜5 hours. A large amount of white solid was obtained by filtration. Cake was washed with 1000 g of heptanes. 1468 g of pure [1-(mercaptomethyl)cyclopropyl]acetic acid was obtained by vacuum dried. (purity by GC: >99%, m.p.=42˜45° C.), H1-NMR(CDCl3): 0.55 ppm (CH2, t), 0.58 ppm (CH2,t), 1.34 ppm (SH, t), 2.50 ppm (CH2, s), 2.60 ppm (CH2, d)
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:17][CH2:18][O:19][CH2:20][C:21]#[C:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH2:15])[C:8]=2[N:16]=1)[CH3:2].[ClH:29]>C(OCC)C>[ClH:29].[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:17][CH2:18][O:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH2:15])[C:8]=2[N:16]=1)[CH3:2]
Reactant: CCOCc1nc2c(N)nc(C)c(C)c2n1CCOCC#Cc1ccccc1
Agent: Cl
Solvent: CCOCC
Product: CCOCc1nc2c(N)nc(C)c(C)c2n1CCOCCCc1ccccc1
Reaction time: 18 h

Procedure:
The general method described in Example 112 was used to hydrogenate 2-ethoxymethyl-6,7-dimethyl-1-{2-[(3-phenylprop-2-ynyl)oxy]ethyl}-1H-imidazo[4,5-c]pyridin-4-amine (1.17 g, 3.09 mmol), prepared as described in Example 122. The reaction was complete after 18 hours. The crude product, isolated as an oil, was dissolved with diethyl ether (20 mL) and treated with a 1 M solution of hydrochloric acid in diethyl ether. The resulting salt was isolated by filtration, dried under reduced pressure, and recrystallized from ethyl acetate. The crystals, obtained in two crops, were dried for three hours under high vacuum at 60° C. to provide 0.777 g of 2-ethoxymethyl-6,7-dimethyl-1-[2-(3-phenylpropoxy)ethyl]-1H-imidazo[4,5-c]pyridin-4-amine hydrochloride as a white powder, mp 128-130° C.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:20]([OH:22])=[O:21])[C:6]([C:9]2[C:10](=[CH:14][C:15]([O:18]C)=[CH:16][CH:17]=2)[C:11]([OH:13])=[O:12])=[CH:7][CH:8]=1.Br>C(O)(=O)C>[OH:2][C:3]1[CH:4]=[C:5]([C:20]([OH:22])=[O:21])[C:6]([C:9]2[C:10](=[CH:14][C:15]([OH:18])=[CH:16][CH:17]=2)[C:11]([OH:13])=[O:12])=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2ccc(OC)cc2C(=O)O)c(C(=O)O)c1
Agent: Br
Solvent: CC(=O)O
Product: O=C(O)c1cc(O)ccc1-c1ccc(O)cc1C(=O)O
Yield: 91.2 %

Procedure:
The following reactants, 9.06 g of 4,4'-dimethoxydiphenic acid, 100 ml of glacial acetic acid and 50 g of 48% HBr were heated at reflux for 12 hours. After most of the solvent had been distilled off, water was added and the solution heated to dissolve the solid residue. The solution was decolorized twice using active charcoal and cooled to yield 7.5 g of white 4,4'-dihydroxydiphenic acid.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]3[C:14]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]4[C:24](=[O:25])[CH2:23][S:22][C:21]4=[O:26])=[CH:13][CH:12]=[CH:11][N:10]3[CH:27]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:28](=O)[CH2:29][CH2:30][CH3:31].N1CCCCC1>C(O)C>[CH:28](=[C:23]1[S:22][C:21](=[O:26])[N:20]([CH2:19][CH2:18][CH2:17][CH2:16][O:15][C:14]2[C:9]3[N:10]([CH:27]=[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=3)[CH:11]=[CH:12][CH:13]=2)[C:24]1=[O:25])[CH2:29][CH2:30][CH3:31]
Reactant: O=C1CSC(=O)N1CCCCOc1cccn2cc(-c3ccccc3)nc12
Reactant: CCCC=O
Solvent: C1CCNCC1
Solvent: CCO
Product: CCCC=C1SC(=O)N(CCCCOc2cccn3cc(-c4ccccc4)nc23)C1=O

Procedure:
To a solution of 1.91 g (5.0 mmol) of 3-[4-(2-phenylimidazo[1,2-a]pyridin-8-yloxy)butyl]thiazolidine-2,4-dione and 0.45 ml (5.0 mmol) of n-butyraldehyde in 20 ml of ethanol, 0.05 ml (0.5 mmol) of piperidine was added, followed by refluxing for 2 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=2/1) to yield 1.70 g (78.0%, yellow foamy substance) of the desired product.
Reaction SMILES: [CH3:1][C:2]([CH3:12])=[CH:3][C:4]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:5].[N+:13]([CH3:16])([O-:15])=[O:14].C1CCN2C(=NCCC2)CC1.Cl>CCOCC>[CH3:1][C:2]([CH3:12])([CH2:16][N+:13]([O-:15])=[O:14])[CH2:3][C:4]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:5]
Reactant: C[N+](=O)[O-]
Reactant: CC(C)=CC(=O)c1cccnc1
Agent: Cl
Solvent: CCOCC
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(CC(=O)c1cccnc1)C[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 56 %

Procedure:
To a mixture of 3-methyl-1-pyridin-3-yl-but-2-en-1-one (440 mg, 2.73 mmol) and nitromethane (0.74 mL, 13.65 mmol) that is cooled with a water bath, add DBU (0.41 mL, 2.73 mmol) dropwise. After 30 min, add ether (15 mL) and 1N hydrochloric acid (15 mL). Neutralize with 1M NaOH and extract with ether. Dry over magnesium sulfate and evaporate to obtain 340 mg (61%) of the title compound as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C@H:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:21]([O:23][C:24](=[O:30])[CH2:25][CH2:26][CH2:27][CH2:28]Br)[CH3:22].CCN(C(C)C)C(C)C>CC#N>[CH2:21]([O:23][C:24](=[O:30])[CH2:25][CH2:26][CH2:27][CH2:28][N:9]1[C@H:8]([C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[CH2:13][CH2:12][CH2:11][C@@H:10]1[C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=1)[CH3:22]
Reactant: Cc1cccnc1[C@@H]1CCC[C@H](c2ncccc2C)N1
Reactant: CCOC(=O)CCCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)CCCCN1[C@@H](c2ncccc2C)CCC[C@H]1c1ncccc1C
Reaction time: 23 h
Yield: 94.1 %

Procedure:
A solution of (2′R,6′S)-3,3″-dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine (306 mg, 1.12 mmol), 5-bromo-pentanoic acid ethyl ester (263 mg, 1.12 mmol), DIPEA (260 μL, 1.49 mmol) and KI (10 mg, 0.060 mmol) in CH3CN (12 mL) was warmed to 60° C. and stirred for 23 h according to General Procedure A. Purification by flash chromatography on silica gel using CH2Cl2/MeOH/NH4OH (94:5:1) afforded 5-((2′R,6′S)-3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-yl)-pentanoic acid ethyl ester (417 mg, 90%) as a yellow oil. 1H NMR (CDCl3) δ 0.75-0.94 (m, 3H), 1.17 (t, 3H, J=7.1 Hz), 1.55-2.01 (m 8H), 2.20-2.35 (m, 6H), 2.47 (s, 6H), 3.99 (q, 2H, J=7.2 Hz), 7.05-7.09 (m, 2H), 7.43 (d, 2H, J=7.6 Hz), 8.46 (bs, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].CN(C=O)C.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24]>O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24]
Reactant: Sc1ccccc1Br
Reactant: CC(C)=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)=CCSc1ccccc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
19.30 g (102.0 mmol) of 2-bromothiophenol, 160 ml of DMF and 15.50 g (112.0 mmol) of potassium carbonate are introduced into a three-necked flask. 13 ml (112.0 mmol) of 1-bromo-3-methyl-2-butene are added dropwise and the mixture is stirred at room temperature for two hours. The reaction medium is poured into water and extracted with ethyl acetate, and the organic phase is separated out after settling has taken place, washed with water, dried over magnesium sulphate and evaporated. 26.00 g (99%) of the expected compound are collected in the form of an orange-coloured oil.
Reaction SMILES: C1(C)C=CC=CC=1.[CH:8]12[CH2:22][CH:13]([C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=31)[CH2:12][NH:11][CH2:10][CH2:9]2.[C:23]1([CH2:29][C:30](Cl)=O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(N(CC)CC)C>[CH2:30]([N:11]1[CH2:10][CH2:9][CH:8]2[CH2:22][CH:13]([CH:14]([OH:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=32)[CH2:12]1)[CH2:29][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C1c2ccccc2C2CCNCC1C2
Reactant: O=C(Cl)Cc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: OC1c2ccccc2C2CCN(CCc3ccccc3)CC1C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
20 ml of anhydrous toluene was added to 1 g of 2,3,4,5-tetrahydro-1,6-methano-1H-4-benzazonin-7(6H)-one and 2 g of triethylamine, and 1 g of phenylacetyl chloride was added dropwise to the mixture over a period of 30 minutes under ice cooling and agitation. After completion of the dropwise addition, the mixture was agitated for 1 hour at room temperature. The reaction mixture liquid was washed twice with 50 ml of water and the toluene layer was dried with anhydrous sodium sulfate and filtered. Toluene was removed from the filtrate by distillation under reduced pressure, and the residue was dissolved in 20 ml of anhydrous dioxane and the solution was heated and refluxed for 6 hours together with 0.3 g of lithium aluminum hydride. Then, excess lithium aluminum hydride was decomposed with drops of ethyl acetate, and 50 ml of saturated aqueous solution of Rochelle salt was added and the mixture was shaken. The resulting solution was extracted with ether, and the ether extract was subjected to distillation to remove ether therefrom. The residue was subjected to vacuum distillation to obtain 0.9 g of a fraction of 4-phenethyl-2,3,4,5,6,7-hexahydro-1,6-methano-1H-4-benzazonin-7-ol boiling at 148° to 152° C. (bath temperature) under 1 mmHg. The product was a light-yellow oil.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([C:13]1[NH:14][C:15](=[O:25])[C:16]([OH:24])=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:18]=1)([O:9][CH2:10][CH2:11]O)[CH2:7][Cl:8])(=[O:3])[CH3:2].[CH3:26][S:27](Cl)(=[O:29])=[O:28].CCN(CC)CC>O1CCCC1>[C:1]([O:4][CH2:5][C:6]1([CH2:7][Cl:8])[C:13]2=[N:18][C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:16]([O:24][S:27]([CH3:26])(=[O:29])=[O:28])[C:15](=[O:25])[N:14]2[CH2:11][CH2:10][O:9]1)(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1nc(C(CCl)(COC(C)=O)OCCO)[nH]c(=O)c1O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1nc2n(c(=O)c1OS(C)(=O)=O)CCOC2(CCl)COC(C)=O
Temperature: 60 °C

Procedure:
A solution of ethyl 2-(3-acetoxy-1-chloro-2-(2-hydroxyethoxy)propan-2-yl)-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxylate (2.322 g, 6.13 mmol) in tetrahydrofuran (100 mL) was treated with methane sulfonylchloride (2.11 g, 18.4 mmol) and Et3N (2.25 g, 22 mmol) and then heated (60° C., oil bath) for 3 hrs. Solvent was removed in-vacuo and the crude product was dissolved in ethyl acetate (100 mL), then washed with water (2×50 mL). The organic solution was dried (Na2SO4), filtered and concentrated in-vacuo to give the title compound as a viscous amber oil which was used immediately in the following reaction.
Reaction SMILES: [CH2:1]([NH:8][C@H:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[CH3:22][C:23]1[N:28]=[CH:27][C:26](/[CH:29]=[CH:30]/[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:25][CH:24]=1.[NH4+].[Cl-]>C1COCC1>[CH2:1]([N:8]([C@H:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:10])[C@@H:29]([C:26]1[CH:27]=[N:28][C:23]([CH3:22])=[CH:24][CH:25]=1)[CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(/C=C/C(=O)OC(C)(C)C)cn1
Reactant: C[C@H](NCc1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccc([C@@H](CC(=O)OC(C)(C)C)N(Cc2ccccc2)[C@@H](C)c2ccccc2)cn1
Reaction time: 1 h

Procedure:
To a solution of (S)-N-benzyl-1-phenylethanamine (3.64 g, 17.26 mmol) in THF (40 mL) at −70° C., was added dropwise n-BuLi (1.6 M, 14.7 mmol) over a period of 30 min and stirred further. After 1 h, a solution of (E)-tert-butyl 3-(6-methylpyridin-3-yl)acrylate (2.7 g, 12.3 mmol) in THF was added slowly to the above mixture and stirred further. After 2 h, sat. NH4Cl solution was added to the reaction mixture and extracted with EtOAc (3×). The combined organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo to afford a residue. Purification of the residue by column chromatography (Neutral Al2O3, Et2O/Pet ether 5:95) afforded the title compound. MS: 431.6 [M+H]+;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10](=[O:26])[N:11]([CH2:24][CH3:25])[N:12]=[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:14]=2[CH:15]([OH:17])[CH3:16])[CH:5]=[CH:6][CH:7]=1.[CH3:27]O>O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10](=[O:26])[N:11]([CH2:24][CH3:25])[N:12]=[C:13]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:14]=2[CH:15]([O:17][CH3:27])[CH3:16])[CH:5]=[CH:6][CH:7]=1
Reactant: CO
Reactant: CCn1nc(-c2ccccc2)c(C(C)O)c(Nc2cccc(Cl)c2)c1=O
Solvent: O
Product: CCn1nc(-c2ccccc2)c(C(C)OC)c(Nc2cccc(Cl)c2)c1=O
Temperature: 120 °C
Reaction time: 10 h
Yield: 96 %

Procedure:
To a solution of the title product of example 1 (111 mg, 0.3 mmol mmol) in methanol (5 mL), PPA (600 mg) was added and the mixture was stirred in a sealed tube at 120° C. for 10 h. Then it was let to cool down and was diluted with water. The final product was isolated by filtration (96% yield).