Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NN1CCCC1.Cl[C:8]1[N:13]=[C:12]2[CH:14]=[CH:15][S:16][C:11]2=[C:10]([N:17]2[CH2:22][CH2:21][CH:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH2:19][CH2:18]2)[CH:9]=1.Cl.[NH2:28][C@H:29]1[CH2:33][CH2:32][N:31]([C:34](=[O:47])[CH2:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][C:43]([F:46])([F:45])[F:44])=[CH:38][CH:37]=2)[CH2:30]1.CC(C)([O-])C.[Na+]>C(OCC)(=O)C.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH3:26][S:23]([CH:20]1[CH2:21][CH2:22][N:17]([C:10]2[CH:9]=[C:8]([NH:28][C@H:29]3[CH2:33][CH2:32][N:31]([C:34](=[O:47])[CH2:35][C:36]4[CH:37]=[CH:38][C:39]([O:42][C:43]([F:44])([F:45])[F:46])=[CH:40][CH:41]=4)[CH2:30]3)[N:13]=[C:12]3[CH:14]=[CH:15][S:16][C:11]=23)[CH2:18][CH2:19]1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)C1CCN(c2cc(Cl)nc3ccsc23)CC1
Reactant: N[C@H]1CCN(C(=O)Cc2ccc(OC(F)(F)F)cc2)C1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)C1CCN(c2cc(N[C@H]3CCN(C(=O)Cc4ccc(OC(F)(F)F)cc4)C3)nc3ccsc23)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 38.2 %

Procedure:
A mixture of 5,7-dichlorothieno[3,2-b]pyridine (0.52 g), triethylamine (0.90 mL), 4-(methylsulfonyl)piperidine mono hydrochloride (0.62 g), and ethylene glycol (1.1 mL) was stirred at 120° C. for 6 h. Ethylene glycol (4.0 mL) and 1,4-dioxane (4.0 mL) were added, and the mixture was further stirred at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried with anhydrous magnesium sulfate, and then silica gel was added to the organic layer. Silica gel and the desiccant were removed by filtration, the filtrate was concentrated under reduced pressure, and the resulting solids were washed with a mixture solution of ethyl acetate and diisopropyl ether. The resulting solids were purified by silica gel column chromatography (ethyl acetate/hexane=1:1-1:0) to obtain 5-chloro-7-(4-(methylsulfonyl)piperidin-1-yl)thieno[3,2-b]pyridine (0.11 g). (2) To a mixture of 5-chloro-7-(4-(methylsulfonyl)piperidin-1-yl)thieno[3,2-b]pyridine (0.11 g), Pd2(dba)3 (0.016 g), (±)-BINAP (0.032 g), 1-((S)-3-aminopyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone mono hydrochloride (0.13 g), and 1,4-dioxane (2.2 mL) was added sodium t-butoxide (0.099 g) under nitrogen atmosphere, and the mixture was stirred at room temperature for 20 h. The mixture was further stirred at 70° C. for 2 h and 30 min. The reaction mixture was diluted with ethyl acetate and water, and then the organic layer was washed with water. The organic layer was dried with anhydrous magnesium sulfate, then the desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH silica gel, ethyl acetate/hexane=2:1−ethyl acetate/methanol=10:1, and silica gel, chloroform/methanol=50:1-10:1) to obtain colorless amorphous (S)-1-(3-(7-(4-methylsulfonylpiperidin-1-yl)thieno[3,2-b]pyridin-5-ylamino)pyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone (0.074 g).
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][C@H:10]2[CH3:16])[N:5]=[C:4]([CH3:17])[N:3]=1.O.[NH2:19][NH2:20]>O1CCOCC1>[CH3:16][C@@H:10]1[CH2:11][N:12]([CH3:15])[CH2:13][CH2:14][N:9]1[C:6]1[C:7]([F:8])=[C:2]([NH:19][NH2:20])[N:3]=[C:4]([CH3:17])[N:5]=1
Reactant: NN
Reactant: Cc1nc(Cl)c(F)c(N2CCN(C)C[C@H]2C)n1
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc(NN)c(F)c(N2CCN(C)C[C@H]2C)n1
Temperature: 85 °C
Reaction time: 24 h
Yield: 100.7 %

Procedure:
To a solution of 4-chloro-6-[(2R)-2,4-dimethyl-1-piperazinyl]-5-fluoro-2-methylpyrimidine (9.6 g, assumed 31.4 mmol) in 1,4-dioxane (126 mL) was added hydrazine monohydrate (8.5 mL, 175 mmol). The mixture was heated at 85° C. and stirred for 24 h. The mixture was cooled to room temperature and then concentrated in vacuo. The residue was partitioned between DCM (200 mL) and sat. aq. NaHCO3 (100 mL). The aqueous phase was extracted with a fresh portion of DCM (50 mL), and the combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give crude 4-[(2R)-2,4-dimethyl-1-piperazinyl]-5-fluoro-6-hydrazino-2-methylpyrimidine (8.04 g, >100% crude yield) as a dark orange oil. LCMS: (M+H)+: 254.9.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:12])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Cl)=[CH:17][CH:16]=1.[Cl-].[NH4+]>CN(C=O)C>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][O:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][OH:12])=[CH:17][CH:16]=1
Reactant: COc1ccc(CCl)cc1
Reactant: OCCCCCCCCO
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COc1ccc(COCCCCCCCCO)cc1

Procedure:
The oil attached to 63 wt % sodium hydride (1.14 g, 30.1 mmol, 1.00 eq.) was washed three times with hexane and removed. Subsequently, thereto were added dry DMF (30.0 mL) and 1,8-octanediol (4.40 g, 30.1 mmol, 1.00 eq.) at 0 degrees. The mixture was allowed to react for 5 minutes with ice-cooling, and then thereto was dropwise added a solution of PMBCl (4.08 mL, 30.1 mmol, 1.00 eq.) in dry DMF (20.0 mL) over 1 hour. The reaction mixture was allowed to react for further 1.5 hours and then poured into an aqueous ammonium chloride solution with ice-cooling, and the organic phase was extracted with ethyl acetate. The resulting organic phase was washed with 1 M hydrochloric acid, saturated sodium bicarbonate, and a saturated salt solution. The washed organic phase was dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=75:25) to obtain 8-((4-methoxybenzyl)oxy)octa-1-nol as shown below (4.66 g, 17.5 mmol, 58%).
Reaction SMILES: C([O:3][C:4]([C:6]1([S:22]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][CH2:7]1)=[O:5])C>C1COCC1.CO.[OH-].[Na+]>[CH2:32]([O:31][C:28]1[CH:27]=[CH:26][C:25]([S:22]([C:6]2([C:4]([OH:5])=[O:3])[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][O:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:8][CH2:7]2)(=[O:24])=[O:23])=[CH:30][CH:29]=1)[CH2:33][CH2:34][CH3:35]
Reactant: CCCCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(CCCOc3ccccc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(CCCOc3ccccc3)CC2)cc1

Procedure:
4-(4-n-Butoxy-benzenesulfonyl)-1-(3-phenoxy-propyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-n-Butoxy-benzenesulfonyl)-1-(3-phenoxy-propyl)-piperidine-4-carboxylic acid ethyl ester(4.0 g, 7.9 mmol) dissolved in THF:Methanol 3:1 and 10 N NaOH (40 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 3.0 g (79%); off white powder; mp 191° C.; MS: 476.5 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:11]([N:12]([CH3:19])[CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:10][C:9]([CH:20]2[CH2:23][N:22]([CH3:24])[CH2:21]2)=[CH:8][C:3]=1[C:4](OC)=[O:5].[OH-].[Na+].Cl.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:61][CH2:62][C:63]1[C:64](=[O:71])[NH:65][C:66]([CH3:70])=[CH:67][C:68]=1[CH3:69]>C1COCC1.CO>[CH3:69][C:68]1[CH:67]=[C:66]([CH3:70])[NH:65][C:64](=[O:71])[C:63]=1[CH2:62][NH:61][C:4](=[O:5])[C:3]1[CH:8]=[C:9]([CH:20]2[CH2:21][N:22]([CH3:24])[CH2:23]2)[CH:10]=[C:11]([N:12]([CH3:19])[CH:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)[C:2]=1[CH3:1]
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: COC(=O)c1cc(C2CN(C)C2)cc(N(C)C2CCOCC2)c1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: Cc1cc(C)c(CNC(=O)c2cc(C3CN(C)C3)cc(N(C)C3CCOCC3)c2C)c(=O)[nH]1
Temperature: 25 °C
Yield: 12.7 %

Procedure:
To a stirred solution of methyl 2-methyl-3-[methyl(oxan-4-yl)amino]-5-(1-methylazetidin-3-yl)benzoate (296 mg, 0.89 mmol) in THF (10 ml) and MeOH (1 ml) was added 2M NaOH solution (4.5 ml, 8.9 mmol) and the reaction was stirred at 50° C. for 16 h after which time 4M NaOH solution (1 ml, 4.5 mmol) was added and the reaction was heated for a further 24 h. The reaction was cooled to room temperature and the product was neutralised with 1M HCl and evaporated to dryness followed by azeotrope with toluene to remove residual water. The crude acid was taken through to the next stage without any purification. The crude residue of 2-methyl-3-[methyl(oxan-4-yl)amino]-5-(1-methylazetidin-3-yl)benzoic acid was suspended in DMF (10 ml) and the solution was cooled using an ice bath followed by the addition of DIPEA (433 μl, 2.49 mmol) and HATU (567 mg, 1.49 mmol). The reaction was stirred at 0° C. for 5 min after which time 3-(aminomethyl)-4,6-dimethyl-1,2-dihydropyridin-2-one (89%, 221 mg, 1.29 mmol) was added and the reaction was warmed room temperature for 16 h. The reaction mixture was then poured onto distilled water (50 ml) and the aqueous phase was extracted with DCM (3×50 ml), washed with brine (50 ml) dried (Na2SO4), filtered and evaporated to give an oil. The product was then purified using preparative HPLC method (and evaporated to dryness followed by trituration with ether and filtration to afford the title compound as an off-white solid (51 mg, 10%). LC-MS 91%, m/z=453.2, 1H NMR (500 MHz, MeOD) δ 7.14 (d, J=1.7 Hz, 1H), 7.09 (d, J=1.7 Hz, 1H), 6.12 (s, 1H), 4.46 (s, 2H), 4.41 (t, J=9.2 Hz, 2H), 4.22 (t, J=9.3 Hz, 2H), 4.14 (dd, J=17.4, 8.5 Hz, 1H), 3.98-3.89 (m, 2H), 3.36 (td, J=11.3, 3.4 Hz, 2H), 3.06 (ddd, J=14.6, 9.8, 4.9 Hz, 1H), 2.97 (s, 3H), 2.64 (s, 3H), 2.39 (s, 3H), 2.26 (s, 3H), 2.24 (s, 3H), 1.73-1.62 (m, 4H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([Br:14])[C:8]2[O:12][CH:11]=[CH:10][C:9]=2[CH:13]=1)=O.[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[OH:2][CH2:3][C:5]1[CH:6]=[C:7]([Br:14])[C:8]2[O:12][CH:11]=[CH:10][C:9]=2[CH:13]=1
Reactant: COC(=O)c1cc(Br)c2occc2c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: OCc1cc(Br)c2occc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.4 %

Procedure:
A solution of 0.63 gm (2.46 mmol) 5-methoxycarbonyl-7-bromobenzofuran in 10 mL toluene was cooled to −78° C. When material precipitated, 5 mL dichloromethane were added to effect solution. To this solution were then slowly added 1.5 mL (8.6 mmol) diisobutylaluminum hydride and the reaction mixture was allowed to warm gradually to room temperature. After 10 minutes the reaction was quenched by the addition of methanol followed by 1.5 gm sodium fluoride and 50 mL water and then Rochelle's salt solution. The mixture was diluted with additional dichloromethane and was stirred vigorously for about 1 hour. The phases were separated and the aqueous phase extracted well with ethyl acetate. The organic phases were combined and concentrated under reduced pressure. The residue was crystallized from hexane and dichloromethane to provide 0.46 gm (82%) of the title compound as a white crystalline solid.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:17][C:18]([F:24])([F:23])[CH2:19][CH2:20][CH2:21][NH2:22]>>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([NH:22][CH2:21][CH2:20][CH2:19][C:18]([F:24])([F:23])[F:17])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCCC(F)(F)F
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Product: O=C(NCCCC(F)(F)F)C(c1ccccc1)c1ccccc1

Procedure:
The title compound, white solid, m.p. 166° C. and MS: m/e=321 (M+) was prepared in accordance with the general method of example 1 from diphenylacetyl chloride and 4,4,4-trifluoro-butylamine.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:18]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)=[N:17][C:9]2[C@H:10]3[N:14]([C:15](=[O:16])[C:8]=2[C:7]=1[C:31]1[CH:39]=[CH:38][C:34]([C:35]([OH:37])=O)=[CH:33][CH:32]=1)[CH2:13][CH2:12][CH2:11]3)=[O:5])[CH3:2].[N:40]1[CH:45]=[CH:44][C:43]([C@H:46]([NH2:48])[CH3:47])=[CH:42][CH:41]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl.CCOC(C)=O.CO>[O:16]=[C:15]1[N:14]2[C@@H:10]([CH2:11][CH2:12][CH2:13]2)[C:9]2[N:17]=[C:18]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:7]([C:31]3[CH:39]=[CH:38][C:34]([C:35]([NH:48][C@@H:46]([C:43]4[CH:44]=[CH:45][N:40]=[CH:41][CH:42]=4)[CH3:47])=[O:37])=[CH:33][CH:32]=3)[C:8]1=2
Reactant: C[C@@H](N)c1ccncc1
Reactant: CCOC(=O)c1c(CCc2ccc(C(F)(F)F)cc2)nc2c(c1-c1ccc(C(=O)O)cc1)C(=O)N1CCC[C@@H]21
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)c1c(CCc2ccc(C(F)(F)F)cc2)nc2c(c1-c1ccc(C(=O)N[C@H](C)c3ccncc3)cc1)C(=O)N1CCC[C@@H]21
Reaction time: 3 h
Yield: 36.3 %

Procedure:
4-((9aS)-3-(Ethoxycarbonyl)-5-oxo-2-{2-[4-(trifluoromethyl)phenyl]ethyl}-7,8,9,9a-tetrahydro-5H-pyrido[2,3-α]pyrrolizin-4-yl)benzoic acid (0.178 g, 0.331 mmol) was dissolved in 4 mL DCM. (1R)-1-(4-Pyridinyl)ethylamine (0.081 g, 0.661 mmol) was added followed by HOBT (0.054 g, 0.397 mmol) and EDC (0.076 mg, 0.397 mmol). After 3 h, the reaction mixture was washed with pH 4.0 phosphate buffer (2×), 5% NaHCO3, and brine and dried over MgSO4. Purification on SiO2 (EtOAc 100% to EtOAc:MeOH:NH4OH 95:5:0.3) then by TLC (SiO2; EtOAc:MeOH 95:5) provided the title compound as a tan solid (0.077 g, 0.12 mmol, 36%): 1H NMR (400 MHz, CDCl3) δ 8.52 (d, J=6.0 Hz, 2H), 7.80 (d, J=8.0 Hz, 2H), 7.51 (d, J=8.0 Hz, 2H), 7.42 (d, J=8.4 Hz, 2H), 7.30 (d, J=8.4 Hz, 2H), 7.27 (d, J=4.4 Hz, 2H), 6.51 (d, J=7.2 Hz, 1H), 5.27 (m, 1H), 4.69 (dd, J=10.4, 6.4 Hz, 1H), 3.99 (m, 2H), 3.66 (m, 1H), 3.35 (m, 1H), 3.18 (m, 2H), 3.14 (m, 1H), 2.45 (m, 1H), 2.33 (m, 2H), 1.7 (bs, 1NH, 2H2O), 1.56 (d, J=6.8 Hz, 3H), 1.35 (m, 1H), 0.91 (t, J=6.8 Hz, 3H) ppm. ESMS m/z (pos. ion) 643 (M+H)+, (neg. ion) 641 (M−H)+.
Reaction SMILES: [OH-].[Li+].C[O:4][C:5](=[O:23])[C:6]1[CH:11]=[C:10]([C:12]#[C:13][C:14]2[CH:15]=[N:16][CH:17]=[C:18]([C:20]#[N:21])[CH:19]=2)[CH:9]=[CH:8][C:7]=1[F:22].O1CCCC1>C(OCC)C.O>[C:20]([C:18]1[CH:19]=[C:14]([C:13]#[C:12][C:10]2[CH:9]=[CH:8][C:7]([F:22])=[C:6]([CH:11]=2)[C:5]([OH:23])=[O:4])[CH:15]=[N:16][CH:17]=1)#[N:21]
Reactant: COC(=O)c1cc(C#Cc2cncc(C#N)c2)ccc1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: N#Cc1cncc(C#Cc2ccc(F)c(C(=O)O)c2)c1
Yield: 77.7 %

Procedure:
Add lithium hydroxide to a solution of 5-(5-cyanopyridin-3-ylethynyl)-2-fluorobenzoic acid methyl ester, (prepared as described in EXAMPLE 121), (890 mg, 3.18 mmol) in 3:1 tetrahydrofuran:water (50 mL) and stir for 1 h. Dilute the reaction mixture with diethyl ether and water and separate the layers. Adjust the pH of the aqueous layer to approximately pH=2 by dropwise addition of concentrated hydrochloric acid and then extract it three times with diethyl ether and three times with ethyl acetate. Extract the combined organic layers with an aqueous saturated solution of sodium chloride, dry (sodium sulfate), filter and concentrate. Recrystallize the resulting residue using ethyl acetate and methanol, to give the title compound as a white solid (658 mg, 78%).
Reaction SMILES: ClC(OC1C=CC([N+]([O-])=O)=CC=1)=O.C(N(CC)CC)C.C(O[C:29](=[O:61])[NH:30][C:31]1[N:60]=[C:34]2[N:35]([C:50]3[CH:55]=[CH:54][CH:53]=[C:52]([C:56]([F:59])([F:58])[F:57])[CH:51]=3)[C:36]([CH3:49])=[C:37]([C:47]#[N:48])[C@@H:38]([C:39]3[CH:44]=[CH:43][C:42]([C:45]#[N:46])=[CH:41][CH:40]=3)[N:33]2[N:32]=1)C1C=CC=CC=1.[NH2:62][CH2:63][CH2:64][OH:65]>CN(C1C=CN=CC=1)C.ClCCl>[C:47]([C:37]1[C@@H:38]([C:39]2[CH:44]=[CH:43][C:42]([C:45]#[N:46])=[CH:41][CH:40]=2)[N:33]2[N:32]=[C:31]([NH:30][C:29]([NH:62][CH2:63][CH2:64][OH:65])=[O:61])[N:60]=[C:34]2[N:35]([C:50]2[CH:55]=[CH:54][CH:53]=[C:52]([C:56]([F:57])([F:59])[F:58])[CH:51]=2)[C:36]=1[CH3:49])#[N:48]
Reactant: NCCO
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NC(=O)OCc3ccccc3)nc2N1c1cccc(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NC(=O)NCCO)nc2N1c1cccc(C(F)(F)F)c1
Temperature: 4 °C
Reaction time: 12 h

Procedure:
Under an atmosphere of argon protective gas and at 0° C., 4-nitrophenyl chloroformate (7.3 mg, 36 μmol, 2 eq.), triethylamine (3.1 mg, 40 μmol, 2.2 eq.) and DMAP (0.2 mg, 1.8 μmol, 0.1 eq.) were added to a solution of benzyl{(7R)-6-cyano-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}carbamate (10 mg, 18 μmol) in dry dichloromethane (1 ml), and the mixture was stirred at 4° C. for 12 h. At 0° C., 2-aminoethanol (8.5 mg, 139 μmol, 10 eq.) was then added, and the mixture was once more stirred at 4° C. for 12 h. The reaction mixture was then concentrated under reduced pressure and purified by preparative HPLC (Gromsil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (1.9 mg, 27% of theory).
Reaction SMILES: [C:1]([OH:14])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH2:15]([OH:18])CO>>[C:1]([OH:14])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH3:1][O:18][CH3:15]
Reactant: OCCO
Agent: CCCCCCCCCCCC(=O)O
Product: COC
Temperature: 65 °C

Procedure:
Lauric acid (9.0 g; 44.9 mmol; 1.0 equiv) was combined with poly (ethylene glycol) methyl ether (25.8 g; 44.9 mmol; 1.0 equiv) having an average molecular weight of 574 (available from Sigma Aldrich) in a 100-mL 3 neck round bottom flask equipped with a magnetic stir bar. Immobilized lipase Novozym®435 was added to the flask in an amount of 1.00 grams (2.9 wt % based on the total weight of starting materials). The mixture was stirred and heated to 65° C. and purged with a subsurface stream of nitrogen at a rate of 200 mL/min. After 24 hours a final sample was removed and analyzed by HPLC to determine conversion of poly(ethylene glycol) methyl ether and lauric acid to PEG-12 methyl ether dilaurate. Conversion was 100%.
Reaction SMILES: [C:1]([C:3]1[CH:23]=[CH:22][C:6]([CH2:7][NH:8][C:9](=[O:21])[CH:10]([C:13]2[C:18]([OH:19])=[CH:17][CH:16]=[CH:15][C:14]=2[F:20])[O:11][CH3:12])=[CH:5][CH:4]=1)#[N:2].I[CH2:25][C:26]([NH2:28])=[O:27].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:26]([CH2:25][O:19][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]([F:20])[C:13]=1[CH:10]([O:11][CH3:12])[C:9]([NH:8][CH2:7][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:23][CH:22]=1)=[O:21])(=[O:27])[NH2:28]
Reactant: NC(=O)CI
Reactant: COC(C(=O)NCc1ccc(C#N)cc1)c1c(O)cccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1c(F)cccc1OCC(N)=O

Procedure:
In analogy to example 16.4 (RS)-N-(4-cyano-benzyl)-2-(2-fluoro-6-hydroxy-phenyl)-2-methoxy-acetamide (example 80.4) was reacted with iodo acetamide in the presence of potassium carbonate in DMF to give 2-(2-carbamoylmethoxy-6-fluoro-phenyl)-N-(4-cyano-benzyl)-2-methoxy-acetamide. Solid. MS 372.2 ([M+H]+)
Reaction SMILES: C([O:3][C:4](=[O:32])[CH:5]([CH:29](C)[CH3:30])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:13]=[C:12]1[CH3:28])C.[OH-].[Na+]>CO>[CH2:29]([CH:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[C:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:13]=[C:12]1[CH3:28])[C:4]([OH:32])=[O:3])[CH3:30]
Reactant: CCOC(=O)C(CCCCCn1c(C)nc(-c2ccccc2)c1-c1ccccc1)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC(CCCCCn1c(C)nc(-c2ccccc2)c1-c1ccccc1)C(=O)O
Yield: 65.4 %

Procedure:
(Scheme 3 (P)) This compound was obtained using the procedures as described above. The following scales and reagents were used: 2-Isopropyl-7-(2-methyl-4,5-diphenyl-imidazol-1-yl)-heptanoic acid ethyl ester (80 mg, 0.18 mmole), Sodium hydroxide (2N, 0.5 mL, 1.0 mmole), Methanol (5 mL). Product was obtained as white solid (46 mg, 64%). Mass Spec: 405.37 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=NC2N(O)N=NC=2C=1.Cl.[CH:28]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][C@@H:32]1[CH3:37])([CH3:30])[CH3:29].C(N(CC)C(C)C)(C)C>CN(C=O)C.O.C(Cl)CCl>[CH:28]([N:31]1[CH2:36][CH2:35][N:34]([C:14]([CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)=[O:16])[CH2:33][C@@H:32]1[CH3:37])([CH3:30])[CH3:29]
Reactant: CC(C)N1CCNC[C@@H]1C
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCN(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)C[C@@H]1C
Reaction time: 8 h
Yield: 96 %

Procedure:
1-(tert-Butoxycarbonyl)-piperidine4-carboxylic acid (3.2 g) in dry DMF (30 ml) was treated first with EDC (5.4 g) and catalytic HOAt followed by (S)-1-isopropyl-2-methyl piperazine hydrochloride (D27)(2 g) and N,N-diisopropylethylamine (5 ml). After the reaction mixture was stirred overnight, water (50 ml) was added and the cloudy precipitate was extracted into EtOAc (2×25 ml), dried (MgSO4) and filtered. The filtrate was absorbed on silica and purified by column chromatography [silica gel, step gradient 0-10% MeOH (containing 10% 0.88 ammonia solution) in DCM]. The fractions containing the required product were evaporated to give the title compound (D28) as an oil (3.8 g). LCMS electrospray (+ve) 354 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5]C(O)=O.O1C2C(=CC=CC=2)C=CC1=O.[Li+].[OH-].N1C=CN=C1>CS(C)=O>[OH:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH2:5]
Reactant: O=C(O)C=Cc1ccccc1O
Agent: O=c1ccc2ccccc2o1
Agent: [Li+]
Agent: [OH-]
Solvent: CS(C)=O
Product: C=Cc1ccccc1O
Yield: 58 %

Procedure:
A mixture of 2-hydroxycinnamic acid or coumarin (2H-1-Benzopyran-2-one) (0.0083 mol), LiOH (10%, 4 mL), imidazole (1 mL) and dimethylsulphoxide were taken in a 100 ml round bottom flask fitted with reflux condenser. The flask was placed inside the microwave oven and irradiated (200 W, 180° C.) for 5-8 minutes. After completion of reaction, it was worked up and purified as in example V and provided viscous liquid. 58% yield; 1H NMR (CDCl3) δ 7.40 (1H, d, J=7.67 Hz), 7.14 (1H, m), 6.95 (2H, m), 6.80 (1H, d, J=8.07 Hz), 5.78 (1H, d, J=17.10 Hz), 5.37 (1H, d, J=11.20 Hz), 5.01 (1H, s); 13C NMR (CDCl3) δ 153.1, 132.2, 129.8, 128.4, 125.6, 121.8, 116.7 and 116.4.
Reaction SMILES: [CH3:1][CH:2]1[C:10]2[C:5](=[C:6]([CH3:11])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:12]([OH:14])=[O:13]>C(O)C.O.[Pd]>[CH3:1][C@@H:2]1[C:10]2[C:5](=[C:6]([CH3:11])[CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@H:3]1[C:12]([OH:14])=[O:13]
Reactant: Cc1cccc2c1C=C(C(=O)O)C2C
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: Cc1cccc2c1C[C@H](C(=O)O)[C@@H]2C

Procedure:
1,4-Dimethyl-indene-2-carboxylic acid (35.5 g) is hydrogenated in ethanol-water (700 ml-70 ml) over 10% palladium on carbon at ambient temperature. After filtration ethanol is evaporated. Water is added and the precipitated cis-2,3-dihydro-1,4-dimethyl-1H-indene-2-carboxylic acid is filrated. Yield 33.3 g, 93% M.p. 132°-135° C.