Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[CH:8]=[C:7]3[O:14][CH2:15][O:16][C:6]3=[CH:5][C:4]=2[N:3]=1.[CH3:17][NH2:18]>O1CCOCC1>[CH3:17][NH:18][C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[CH:8]=[C:7]3[O:14][CH2:15][O:16][C:6]3=[CH:5][C:4]=2[N:3]=1
Reactant: O=Cc1cc2cc3c(cc2nc1Cl)OCO3
Reactant: CN
Solvent: C1COCCO1
Product: CNc1nc2cc3c(cc2cc1C=O)OCO3
Temperature: 160 °C
Reaction time: 0.42 h
Yield: 99 %

Procedure:
To a stirred solution of 6-chloro[1,3]dioxolo[4,5-g]quinoline-7-carboxaldehyde (1.14 g, 4.84 mmol) in 1,4-dioxane (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added methylamine (40 wt. %, 4.0 mL, 46.2 mmol) and the reaction mixture was stirred for 25 min at 160° C. under microwave irradiation. After cooling to RT, the volatiles were removed at 40° C. under vacuum and the resulting yellow oil was taken up in a mixture of THF:2 N aq. HCl=1:1 (10 mL) and stirred for 20 min at RT. The volatiles were then removed at 40° C. under vacuum and the residue was then neutralised with a 10 N aqueous NaOH solution before extraction with CH2Cl2 (100 mL). The organic phase was washed with brine (20 mL), dried over MgSO4, filtered, and concentrated under vacuum to give 6-(methylamino)-[1,3]dioxolo[4,5-g]quinoline-7-carbaldehyde CCH 34158-1 as a yellow solid (1.10 g, 99% yield).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][C:3]=1[OH:9].[CH3:10][C:11]([CH3:16])=[CH:12][C:13](O)=[O:14]>>[Br:1][C:2]1[CH:8]=[C:7]2[C:5](=[CH:4][C:3]=1[OH:9])[O:6][C:11]([CH3:16])([CH3:10])[CH2:12][C:13]2=[O:14]
Reactant: Oc1ccc(Br)c(O)c1
Reactant: CC(C)=CC(=O)O
Product: CC1(C)CC(=O)c2cc(Br)c(O)cc2O1
Temperature: 90 °C
Reaction time: 0.25 h

Procedure:
A mixture of 4-bromoresorcinol (5.00 g, 26.5 mmol) and 3,3-dimethylacrylic acid (2.64 g, 26.5 mmol) were ground in a mortar. The mixture was then added portion-wise into polyphosphoric acid (8 g) at 90° C. After stirred at 90° C. for 15 min, the reaction mixture was cooled to room temperature and quenched with water. The mixture was then extracted with diethyl ether. The organic layer was separated, washed with water, brine, dried (MgSO4) and concentrated at reduced pressure to give a yellow residue. Purification by recrystallization (methanol and water) afforded the title compound as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][C:12]([C:16]([OH:18])=O)=[CH:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C.Cl.[CH3:35][NH:36][O:37][CH3:38]>ClCCl.CN(C=O)C>[CH3:38][O:37][N:36]([CH3:35])[C:16]([C:12]1[CH2:11][CH:10]2[CH:14]([CH2:15][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]2)[CH:13]=1)=[O:18]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N1CC2C=C(C(=O)O)CC2C1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)C1=CC2CN(C(=O)OC(C)(C)C)CC2C1
Reaction time: 1 h
Yield: 82.2 %

Procedure:
To a solution of 3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]-oct-6-ene-7-carboxylic acid (0.080 g, 0.32 mmol) in dichloromethane (3.0 mL) was added oxalyl chloride (0.20 g, 1.6 mmol), followed by a drop of DMF. After stirring for 1 h, the the reaction mixture was concentrated in vacuo, and the residual acid chloride was dissolved in acetonitrile (3.0 mL). DIPEA (0.17 mL, 0.96 mmol) and N,O-dimethylhydroxylamine hydrochloride (0.042 g, 0.43 mmol) were added, and the reaction was stirred at ambient temperature for 1 h. The solvent was evaporated, and the residue was purified by silica gel column chromatography, eluting with 80-90% ethyl acetate in hexanes, to obtain 0.078 g (82% yield) of N-methoxy-N-methyl-3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]oct-6-ene-7-carboxamide, as an oil. This was dissolved in dichloromethane (3.0 mL), treated with TFA (2.0 mL) and stirred at ambient temperature for 1 h. The volatiles were evaporated, and the residue was vacuum dried to obtain 0.07 g of N-methoxy-N-methyl-3-azabicyclo[3.3.0]oct-6-ene-7-carboxamide trifluoroacetate, as an oil (1H NMR (CD3OD, 300 MHz): δ 6.29 (bs, 1H), 3.80-3.89 (m, 1H), 3.88 (s, 3H), 3.54-3.41 (m, 2H), 3.38-3.30 (m, 1H), 3.26 (s, 3H), 3.22-3.03 (m, 3H), 2.66-2.59 (m, 1H); MS (m/z): 197 (M+1)).
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]=O)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[N+:21]([CH3:24])([O-:23])=[O:22]>C(O)(=O)C>[F:1][C:2]1[C:7](/[CH:8]=[CH:24]/[N+:21]([O-:23])=[O:22])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1cccc(NC(=O)OCc2ccccc2)c1F
Solvent: CC(=O)O
Product: O=C(Nc1cccc(/C=C/[N+](=O)[O-])c1F)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.4 %

Procedure:
A solution of benzyl 2-fluoro-3-formylphenylcarbamate (4.0253 g, 14.73 mmol), nitromethane (1.98 mL, 36.8 mmol) and nitromethane (1.979 mL, 36.8 mmol) in acetic acid (49.1 mL) under nitrogen was heated at 90° C. After 2 hr, the reaction was cooled to room temperature and concentrated in vacuo. The residue was dissolved in CH2Cl2 (75 mL) and water (75 mL), and Na2CO3 (s) was added until pH basic by litmus paper. After separation of layers, the aqueous layer was extracted with CH2Cl2 (3×75 mL). The organic layers were combined and washed with brine (50 mL), dried over MgSO4, and concentrated in vacuo to give the desired product (4.251 g, 10.08 mmol, 68.4% yield) as a burgundy oil.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([C:12]1[CH:33]=[CH:32][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[N:24]=[CH:25][C:18]=23)=[CH:14][CH:13]=1)(=[O:11])=[O:10].[S:34]1[CH:38]=[CH:37][CH:36]=[C:35]1[C:39](Cl)=[O:40].C(N(C(C)C)CC)(C)C>ClCCl>[CH3:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:27][CH2:28][N:29]([C:39]([C:35]5[S:34][CH:38]=[CH:37][CH:36]=5)=[O:40])[CH2:30][CH2:31]4)[N:24]=[CH:25][C:18]=23)=[CH:32][CH:33]=1)(=[O:11])=[O:10]
Reactant: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCNCC2)cc1
Reactant: O=C(Cl)c1cccs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCN(C(=O)c3cccs3)CC2)cc1
Temperature: 25 °C
Yield: 82.7 %

Procedure:
A mixture of 4-(4-methanesulfonyl-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoroacetate salt (Intermediate 27; 63 mg, 0.13 mmol), thiophene-2-carbonyl chloride (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA; 25 mg, 0.17 mmol), and diisopropylethylamine (0.14 mL, 0.8 mmol) in dry dichloromethane (4 mL) was stirred at room temperature over the weekend. The solution was diluted with dichloromethane (˜6 mL) and washed with 1 M aqueous hydrochloric acid (5 mL), water (5 mL), saturated aqueous sodium bicarbonate (5 mL) and brine (5 mL). The organic layer was evaporated and the crude product was purified by HPLC to give {4-[4-(4-methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidin-1-yl}-thiophen-2-yl-methanone (52 mg, 83%) as a white solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH3:13]C(C)([O-])C.[K+].IC>C1COCC1>[CH3:13][C:3]1([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:5][CH2:6][CH2:7][C:2]1=[O:1]
Reactant: CCOC(=O)C1CCCCC1=O
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)C1(C)CCCCC1=O
Reaction time: 0.08 h

Procedure:
For the synthesis of the protected acid side-chain 1-methyl-2-(tetrahydropyran-2′-yloxy)-cyclohexane carboxylic acid, ethyl 2-oxocyclohexane carboxylate (8.5 g, 50 mmol) was dissolved in dry THF at ambient temperature under N2. Potassium tert-butoxide (75 mmol) was added slowly and the reaction was stirred for 5 minutes. Iodomethane (100 mmol) was then added and the reaction was stirred at ambient temperature for 1 hour. The reaction solvent was removed under reduced pressure and the residue was partitioned between water and hexane. The organic layer was dried over sodium sulfate and reduced under reduced pressure to give racemic ethyl 1-methyl-2-oxo-cyclohexanecarboxylate as a colourless oil (8.11 g 88%); δH (400 MHz, CDCl3) 4.25-4.12 (2H, m, OCH2CH3), 2.55-2.40 (3H, m, CH2CO and one other cyclohexane peak), 2.05-1.95 (1H, m, cyclohexane), 1.77-1.57 (3H, m, cyclohexane), 1.50-1.40 (1H, m, cyclohexane), 1.28 (3H, s, CCH3) and 1.25 (1H, t, J 7, CH2CH3). Ethyl 1-methyl-2-oxo-cyclohexanecarboxylate (5.52 g, 30 mmol) was dissolved in ethanol (100 ml) at ambient temperature and sodium borohydride (1.14 g, 30 mmol) was added slowly. After 1 hour the reaction solvent was removed in vacuo and the residue was partitioned between water and dichloromethane. The organic extracts were dried over sodium sulphate and reduced to give ethyl 2-hydroxy-1-methylcyclohexanecarboxylate as a mixture of diastereoisomers (5.37 g 96%). This material was then protected and the ester hydrolysed as follows: Ethyl 2-hydroxy-1-methylcyclohexanecarboxylate (16.7 mmol) was dissolved in dichloromethane along with 3,4-dihydro-2H-pyran (17 mmol) and para-toluene-sulphonic acid (5 mg), and the reaction was stirred at ambient temperature for 16 hours. The solvent was removed under reduced pressure to give a residue to which was added ethanol (40 ml), water (10 ml) and potassium hydroxide (20 mmol). The mixture was heated at reflux overnight and allowed to cool. The reaction solvent was removed under reduced pressure and the residue was partioned between water and diethyl ether. The aqueous layer was acidified to pH 2 and then extracted with diethyl ether. This ether layer was dried over sodium sulphate and reduced in vacuo to give crude 1-methyl-2-(tetrahydropyran-2′-yloxy)-cyclohexane carboxylic acid (2.52 g) as a mixture of diastereoisomers. This material was used in the synthesis of (S)-3-(2′-hydroxy-1′-methylcyclohexanecarbonyl)amino-caprolactam above
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]([CH3:15])[CH2:9][CH2:10][N:11]([CH3:14])[C:12](=[O:13])[C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([NH:28][CH3:29])=[O:27])[C:20]([Cl:34])=[CH:19][N:18]=1.Cl>C(O)(C)C.O1CCOCC1.C(Cl)Cl>[Cl:34][C:20]1[C:21]([NH:23][C:24]2[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([NH:28][CH3:29])=[O:27])=[N:22][C:17]([NH:1][C:2]2[C:7]3[N:8]([CH3:15])[CH2:9][CH2:10][N:11]([CH3:14])[C:12](=[O:13])[C:6]=3[CH:5]=[CH:4][CH:3]=2)=[N:18][CH:19]=1
Reactant: CN1CCN(C)c2c(N)cccc2C1=O
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CNC(=O)c1ccccc1Nc1nc(Nc2cccc3c2N(C)CCN(C)C3=O)ncc1Cl
Temperature: 110 °C
Yield: 42 %

Procedure:
9-Amino-1,4-dimethyl-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one (#) (50 mg, 0.24 mmol) and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (#) (79 mg, 0.27 mmol) were combined in isopropanol (1 mL). 4 N HCl in dioxane (67 μL) was added, and the resulting mixture was heated to 110° C. in the microwave for 20 min. The resulting solution was diluted with CH2Cl2 (50 ml) washed with saturated aqueous NaHCO3 (2×50 ml), dried over MgSO4, filtered, and concentrated. The resulting residue was purified with silica gel chromatography (0-100% EtOAc in hexanes) to obtain 2-[5-Chloro-2-(1,4-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-9-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide as an off-white solid (47 mg, 41%). mp 243-244° C.; LCMS: m/z=466.16 (M+H+); 1H NMR (400 MHz, CDCl3) δ 11.00 (s, 1H), 8.54 (m, 3H), 8.12 (s, 1H), 7.51 (m, 2H), 7.26 (m, 1H), 7.19 (dd, J=7.8 Hz, 1H), 7.09 (dd, J=7.8 Hz, 1H), 6.42 (d, J=4.5 Hz, 1H), 3.36 (m, 4H), 3.21 (s, 3H), 3.03 (d, J=4.8 Hz, 3H), 2.82 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:19]=[C:18]([C:20](OC)=[O:21])[O:17][N:16]=1.[H-].C([Al+]CC(C)C)C(C)C.O.O.O.O.O.O.O.O.O.O.[O-]S([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:19]=[C:18]([CH2:20][OH:21])[O:17][N:16]=1
Reactant: COC(=O)c1cc(OCc2nc(-c3ccccc3)sc2C)no1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1sc(-c2ccccc2)nc1COc1cc(CO)on1
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.4 %

Procedure:
To a solution of methyl 3-(5-methyl-2-phenyl-4-thiazolylmethoxy)-5-isoxazolecarboxylate (5.27 g) in tetrahydrofuran (100 ml) was slowly added diisobutylaluminum hydride (0.95 M hexane solution, 60 ml) at 0° C. and the mixture was stirred at 0° C. for 1 hr. Sodium sulfate 10 hydrate (17.01 g) was added to the reaction mixture and the mixture was further stirred at room temperature for 30 min. The insoluble materials were removed by filtration, and the filtrate was concentrated to give [3-(5-methyl-2-phenyl-4-thiazolylmethoxy)-5-isoxazolyl]methanol (3.88 g, 80%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane. melting point: 84-85° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[OH-].[K+].Br[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:23][CH:22]=1>CN1CCCC1=O.O>[C:28]([O:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][CH2:19][CH:3]2[C:4]3[C:12]4[CH:11]=[C:10]([CH3:13])[CH:9]=[CH:8][C:7]=4[NH:6][C:5]=3[CH2:14][CH2:15][N:2]2[CH3:1])=[CH:26][CH:25]=1)([CH3:30])([CH3:29])[CH3:31]
Reactant: CC(C)(C)Oc1ccc(CCBr)cc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1ccc2[nH]c3c(c2c1)C(CCc1ccc(OC(C)(C)C)cc1)N(C)CC3
Temperature: 100 °C
Reaction time: 2 h
Yield: 6.4 %

Procedure:
2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.2 g, 0.001 mol) was dissolved in N-methyl 2-pyrolidone (2.0 mL). Powdered potassium hydroxide (0.5 g, 0.0089 mol) was added and heated at 100° C. for 3 h. Reaction mass was cooled to RT and 1-(2-Bromo-ethyl)-4-tert-butoxy-benzene (0.245 g, 0.001 mol) was added at the same temperature and stir for 2 h at RT (TLC showed incomplete reaction). Reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2×100 mL). Organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure using rotary evaporator. The crude was purified through column chromatography (0.5% MeOH:DCM in neutral alumina, Diameter of column—2.5 cm, Height of alumina—approx. 5 inch) then further purified by preparative TLC to provide the desired compound as light yellow oil (0.024 g, 6% yield). 5-[2-(4-tert-Butoxy-phenyl)-ethyl]-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.024 g, 0.000063 mol) was dissolved in THF (1.0 mL), A solution of oxalic acid dihydrate (0.008 g, 0.000063 mol) in THF (1.0 mL) was added and stirred for 30 min at RT. The precipitate was filtered and dried to give oxalate salt as off white solid (0.020 g, 67% yield).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=1)[CH:11]=[CH:12][C:13](O)=[O:14]>C1COCC1>[Cl:7][C:8]1[CH:9]=[C:10]([CH2:11][CH2:12][CH2:13][OH:14])[CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O)C=Cc1cccc(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCCc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 110.6 %

Procedure:
A slurry of lithium aluminum hydride (2.08 g, 54.7 mmol) in THF (100 mL) was cooled to −78° C. A solution of 3-chlorocinnamic acid (5.00 g, 27.4 mmol) in THF (25 mL) was added dropwise. The cold bath was removed and the mixture was warmed to room temperature. After 6 h, the reaction was quenched by addition of sodium sulfate decahydrate and the mixture was stirred overnight. The solids were removed by filtration with the aid of EtOAc and the organic solution was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to yield 3-(3-chloro-phenyl)-propan-1-ol (5.17 g) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.30-7.07 (m, 4H), 5.06 (bs, 1H), 3.67 (m, 2H), 2.69 (m, 2H), 1.89 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][CH2:6][CH2:5]2>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][CH:6]=[CH:5]2
Reactant: Fc1cc2c(c(F)c1Br)CCN2
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: Fc1cc2[nH]ccc2c(F)c1Br
Temperature: 25 °C
Yield: 100.8 %

Procedure:
To a solution of 5-bromo-4,6-difluoroindoline (3.6 g, 15.4 mmol) in chloroform (150 mL) was added manganese dioxide (5.3 g, 61 mmol) at room temperature/. The mixture was heated to reflux temperature for 2 hours then cooled to room temperature. The reaction was filtered and the filtrate was concentrated in vacuo. Flash column chromatography was then used to provide the title compound (3.6 g, yield 100%) as brown solid. MS (ES+): 232.0 (M+H). 1H NMR (CDCl3, 400 MHz): δ 8.27 (br. s, 1 H), 7.19 (m, 1 H), 7.02 (d, 1 H), 6.61 (m, 1 H).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=4)=[O:22])[CH2:17]3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)#[N:2].[N-:37]=[N+:38]=[N-:39].[Na+].N(CC)(CC)CC.Cl>O1CCOCC1>[N:2]1[NH:37][N:38]=[N:39][C:1]=1[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:34])([F:35])[F:33])[CH:27]=4)=[O:22])[CH2:17]3)[CH2:12][CH2:11]2)=[CH:8][CH:9]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCc1ccc(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cc1
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(c3ccc(Cc4nn[nH]n4)cc3)CC2)C1

Procedure:
A solution of N-({1-[4-(4-cyanomethyl-phenyl)-cyclohexyl]-azetidin-3-ylcarbamoyl}-methyl)-3-trifluoromethyl-benzamide (as prepared in Example 21, 250 mg, 0.50 mmol), sodium azide (Aldrich, 160 mg, 2.50 mmol), and Et3N HCl salt (350 mg, 2.50 mmol) in dioxane (5 mL) was heated in a sealed tube to 120° C. overnight. The solvent was removed in vacuo and the residue was purified on a silica gel column using a CombiFlash® system using ethyl acetate and 7N NH3 in MeOH as eluent (from pure ethyl acetate to 5% 7N NH3 in MeOH in ethyl acetate) to afford the title compound as a white solid.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([C@:9]23[CH2:14][C@H:13]2[CH2:12][N:11]([CH:15]([CH3:19])[CH2:16][CH2:17]O)[CH2:10]3)=[CH:5][CH:4]=1.S(Cl)([Cl:24])=O.[OH-].[Na+].ClCCl>C(Cl)(Cl)Cl>[Cl:24][CH2:17][CH2:16][CH:15]([N:11]1[CH2:12][C@H:13]2[C@:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:21])([F:20])[F:1])=[CH:4][CH:5]=3)([CH2:14]2)[CH2:10]1)[CH3:19]
Reactant: CC(CCO)N1C[C@@H]2C[C@]2(c2ccc(C(F)(F)F)cc2)C1
Reactant: O=S(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(CCCl)N1C[C@@H]2C[C@]2(c2ccc(C(F)(F)F)cc2)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 76.8 %

Procedure:
To a solution of 3-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}-1-butanol (Preparation 19, 130 mg) in chloroform (4 mL), thionyl chloride (0.87 mmol) was added and the mixture was stirred at room temperature for 6 h. After addition of NaOH (1 M), dichloromethane was added and the organic layer was washed with Brine and dried over Na2SO4. The solution was concentrated in vacuo and the crude product purified by flash chromatography (ethyl acetate: cyclohexane=5:95) to give 106 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C@@H:7]([CH2:13][N:14]([CH3:34])[CH2:15][CH2:16][CH2:17][N:18]1[C:24](=[O:25])[CH2:23][C:22]3[CH:26]=[C:27]([O:32][CH3:33])[C:28]([O:30][CH3:31])=[CH:29][C:21]=3[CH:20]=[CH:19]1)[CH2:6]2.C(O)C>[OH-].[OH-].[Pd+2].C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C@@H:7]([CH2:13][N:14]([CH3:34])[CH2:15][CH2:16][CH2:17][N:18]1[C:24](=[O:25])[CH2:23][C:22]3[CH:26]=[C:27]([O:32][CH3:33])[C:28]([O:30][CH3:31])=[CH:29][C:21]=3[CH2:20][CH2:19]1)[CH2:6]2
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)C[C@H]1Cc3cc(OC)c(OC)cc31)C=C2
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)C[C@H]1Cc3cc(OC)c(OC)cc31)CC2
Reaction time: 5 h

Procedure:
In a 250-ml autoclave, 4 g of the product obtained in Example 1 and 2 g of Pd(OH)2 (20%, 50% moist) are added to a solution of ethanol (90 mL) and acetic acid (10 mL). After remaining in contact for 5 hours at ambient temperature under a hydrogen pressure of 5 bar, the reaction mixture is filtered over Celite®. The residue obtained after concentrating under reduced pressure is taken up in dichloromethane (100 mL) and then washed with saturated aqueous sodium bicarbonate solution. The oil obtained after drying the organic phase over MgSO4 and then concentrating under reduced pressure is purified by chromatography over silica (dichloromethane/ethanol/NH4OH 28%: 95/5/0.5), and 2.6 g of the title product are obtained in the form of an oil.
Reaction SMILES: O[Li].O.[CH2:4]([N:11]1[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][C:13]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[C:12]1[C:27]([N:29]([CH2:31][C:32]([CH3:38])([CH3:37])[C:33]([O:35]C)=[O:34])[CH3:30])=[O:28])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.OS([O-])(=O)=O.[K+]>O.C1COCC1>[CH2:4]([N:11]1[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][C:13]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[C:12]1[C:27]([N:29]([CH2:31][C:32]([CH3:38])([CH3:37])[C:33]([OH:35])=[O:34])[CH3:30])=[O:28])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: COC(=O)C(C)(C)CN(C)C(=O)c1c(-c2ccc(Cl)cc2)cc(C(F)(F)F)n1Cc1ccccc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CN(CC(C)(C)C(=O)O)C(=O)c1c(-c2ccc(Cl)cc2)cc(C(F)(F)F)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.5 %

Procedure:
A solution of LiOH H2O (214 mg, 5.11 mmol) in H2O (3 mL) was added to a stirred solution of methyl 3-(1-benzyl-3-(4-chlorophenyl)-N-methyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxamido)-2,2-dimethylpropanoate (259 mg, 0.511 mmol) in THF (3 mL). The reaction mixture was stirred at room temperature overnight. An extra portion of LiOH H2O (107 mg, 2.55 mmol) was added, followed by the addition of H2O (11 mL) and THF (11 mL). The reaction mixture was stirred at room temperature for 2 d and then acidified with aqueous 0.5 M KHSO4 (10 mL). The product was extracted with DCM (3×20 mL). The organic layers were combined and washed with brine (3×10 mL). The combined organic layers were dried on Na2SO4 and filtered. Solvents were removed in vacuo to give the desired product (233 mg, 93%) as a white foam.
Reaction SMILES: C(OC(=O)C[CH:8]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:9]([OH:11])=[O:10])(C)(C)C.[CH3:17]O>C1COCC1>[CH:13]([CH:12]1[CH2:17][O:11][C:9](=[O:10])[CH2:8]1)([CH3:14])[CH3:15]
Reactant: CO
Reactant: CC(C)CC(CC(=O)OC(C)(C)C)C(=O)O
Solvent: C1CCOC1
Product: CC(C)C1COC(=O)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 89 %

Procedure:
A solution of 2-isobutyl-succinic acid-4-t-butyl ester (8.0 g, 34.7 mmol) in 100 mL of THF is cooled to 0° C. under Ar and borane dimethyl sulphide complex (2.6 g, 34.7 mmol) is added. The reaction mixture is stirred at 0° C. for 10 minutes, and at room temperature overnight. The solution is cooled to 0° C. and 100 mL of MeOH is added. The solvents are evaporated, and the remaining oil is dried under hi-vacuum for 2 hours. The oil remaining is taken up in 100 mL of THF, and a catalytic amount of p-toluene sulfonic acid is added. The solution is warmed to reflux overnight. After being cooled to room temperature, the solvent is evaporated, and the oil is taken up in Et2O (100 mL). The Et2O solution is extracted with 2.0N Na2CO3 (2×50 mL) followed by 100 mL of brine and dried over MgSO4. Evaporation of Et2O followed by medium pressure chromatography (MPLC) of the remaining oil in 20% EtOAc/Hexanes gives 4.4 g (89% yield) of 4-isopropyldihydro-furan-2-one as an oil. NMR (H1, 400 MHz, CDCl3) δ 0.9 (6H, m); δ 1.3 (2H, dd); δ 1.5 (1H, m); δ 2.1 (1H, m); δ 2.6 (2H, m); δ 3.6 (1H, m); δ 4.4(1 H, m).