Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:11][C:12]([CH3:28])([CH3:27])[CH:13]=[C:14]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:15](OC)=[O:16])=O)C1C=CC=CC=1>CO.[Pd]>[CH3:27][C:12]1([CH3:28])[NH:11][C:15](=[O:16])[CH:14]([NH:19][C:20](=[O:21])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:13]1
Reactant: COC(=O)C(=CC(C)(C)NC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC1(C)CC(NC(=O)OC(C)(C)C)C(=O)N1
Yield: 89.9 %

Procedure:
A solution of methyl 4-(benzyloxycarbonylamino)-2-(tert-butoxycarbonylamino)-4-methyl-pent-2-enoate (which may be prepared as described in Description 27) (2499 mg, 6.37 mmol) in methanol (125 mL) was passed over a 10% Pd/C cartridge on an H-Cube under full hydrogen flow at 25° C. The methanol solution evaporated to give tert-butyl N-(5,5-dimethyl-2-oxo-pyrrolidin-3-yl)carbamate (D28) (1307 mg, 5.7252 mmol, 89.9% yield);
Reaction SMILES: [C:1](=[N:6][CH:7]([CH3:9])[CH3:8])=[N:2][CH:3]([CH3:5])[CH3:4].[CH3:10][C:11]([OH:14])([CH3:13])[CH3:12]>[Cu]Cl>[CH:3]([NH:2]/[C:1](=[N:6]\[CH:7]([CH3:9])[CH3:8])/[O:14][C:11]([CH3:13])([CH3:12])[CH3:10])([CH3:5])[CH3:4]
Reactant: CC(C)N=C=NC(C)C
Reactant: CC(C)(C)O
Agent: Cl[Cu]
Product: CC(C)/N=C(\NC(C)C)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 70.3 %

Procedure:
To a solution of N,N′-methanediylidenebis(propan-2-amine) (307 ml, 1981 mmol) in t-BuOH (227 ml, 2377 mmol) at r.t. was added copper(I) chloride (1.961 g, 19.81 mmol). The reaction was stirred at room temperature for 24 h and the resulting mixture was distilled under reduced pressure to afford (E)-tert-butyl N,N′-diisopropylcarbamimidate (279 g, 1393 mmol, 70.3% yield) as a colorless liquid. 1H NMR (400 MHz, CHLOROFORM-d4) δ ppm 1.04 (d, J=−6.06 Hz, 6 H) 1.08 (d, J=6.57 Hz, 6 H) 1.46 (s, 9 H) 2.98-3.19 (m, 1 H) 3.25 (m, 1 H) 3.64 (s, 1 H)
Reaction SMILES: Cl.[CH3:2][C@H:3]1[CH2:8][C@H:7]([CH3:9])[CH2:6][NH:5][CH2:4]1.Cl[CH2:11][CH2:12][CH2:13][OH:14].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[OH:14][CH2:13][CH2:12][CH2:11][N:5]1[CH2:6][C@@H:7]([CH3:9])[CH2:8][C@H:3]([CH3:2])[CH2:4]1
Reactant: OCCCCl
Reactant: C[C@@H]1CNC[C@@H](C)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(C)=O
Product: C[C@H]1C[C@H](C)CN(CCCO)C1

Procedure:
A mixture of (3S,5S)-3,5-dimethylpiperidine, hydrochloride (2.58 g), 3-chloropropanol (1.44 mL), potassium carbonate (3.58 g) and a catalytic amount of potassium iodide in acetone (10 mL) is stirred under reflux for 24 h. Precipitate is filtrated and rinsed with acetone. Filtrate is concentrated under reduced pressure and purified by chromatography over silica gel with a gradient dichloromethane/methanol/triethylamine from 80/20/1 to 50/50/1 to give 1.9 g of (3S,5S)-1-(3-hydroxypropyl)-3,5-dimethylpiperidine as a yellow oil.
Reaction SMILES: [CH2:1]1[C@@H:5]2[CH:6]3[C:11](=[O:12])[O:10][C:8](=[O:9])[CH:7]3[C@H:2]1[CH:3]=[CH:4]2.C1(C)C=CC=CC=1.COC1C=CC2N=CC=C([C@@H](O)[C@H]3N4C[C@H](C=C)[C@@H](CC4)C3)C=2C=1.[CH3:44][OH:45]>C(Cl)(Cl)(Cl)Cl>[CH3:44][O:45][C:11]([C@@H:6]1[C@H:5]2[CH2:1][C@H:2]([CH:3]=[CH:4]2)[C@@H:7]1[C:8]([OH:10])=[O:9])=[O:12]
Reactant: CO
Reactant: O=C1OC(=O)C2C1[C@@H]1C=C[C@H]2C1
Agent: C=C[C@H]1CN2CC[C@H]1C[C@H]2[C@H](O)c1ccnc2ccc(OC)cc12
Solvent: ClC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)[C@H]1[C@@H](C(=O)O)[C@H]2C=C[C@@H]1C2
Temperature: -55 °C
Reaction time: 20 h
Yield: 98 %

Procedure:
The starting material (a) was prepared as described in J. Org. Chem. 2000, 65, 6984-6991. cis-5-Norbornene-endo-2,3-dicarboxylic anhydride (4.104 g, 25 mmol) was suspended in a 1:1 mixture of toluene and carbon tetrachloride (500 mL). The mixture was stirred for 20 min Quinine (8.92 g, 27.5 mmol) was added and the flask was degassed and backfilled with nitrogen. The solution was cooled to −55° C. While stifling, methanol (3.04 mL, 75 mmol) was added. The mixture was stirred at −55° C. for 20 h. Upon warming to 25° C., the mixture was concentrated in vacuo to a thick oil. The oil was dissolved in ethyl acetate (400 mL), washed with 1.0 M aqueous hydrochloric acid solution (2×400 mL), saturated aqueous brine solution (100 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the desired product, (1R,2S,3R,4S)-3-(methoxycarbonyl)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid (4.8 g, 24.5 mmol, 98%), as a clear waxy solid. 1H NMR (400 MHz, DMSO-d6) δ: 1.26 (1H, d, J=8.5 Hz), 1.33 (1H, d, J=8.8 Hz), 3.00 (1H, s), 3.03 (1H, s), 3.21-3.30 (2H, m), 3.45 (3H, s), 6.02-6.04 (1H, m), 6.14-6.16 (1H, m), 11.86 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]2[C:8]([CH3:20])=[C:9]([CH3:19])[C:10]([CH:17]=C)=[C:11]([CH:16]=2)[C:12]([O:14][CH3:15])=[O:13])=[CH:4][CH:3]=1.CC(C)=[O:25].C(#N)C.I([O-])(=O)(=O)=O.[Na+]>[Os]=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[C:8]([CH3:20])=[C:9]([CH3:19])[C:10]([CH:17]=[O:25])=[C:11]([CH:16]=2)[C:12]([O:14][CH3:15])=[O:13])=[CH:21][CH:22]=1
Reactant: C=Cc1c(C(=O)OC)cc(Cc2ccc(Cl)cc2)c(C)c1C
Reactant: CC(C)=O
Agent: O=[Os]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1cc(Cc2ccc(Cl)cc2)c(C)c(C)c1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 5-(4-chlorobenzyl)-3,4-dimethyl-2-vinylbenzoate (0.17 g) in a mixed solvent of acetone (4.00 mL)-acetonitrile (4.00 mL)-water (4.00 mL) were added osmium oxide (fixed catalyst I) (0.07 g) and sodium periodate (0.58 g), and the mixture was stirred overnight at room temperature under argon atmosphere. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.02 g).
Reaction SMILES: NC(=O)[C@@H](N[C:6]([C@@H:8]1[C:10]2([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:9]1)=[O:7])C.[OH:17]S(O)(=O)=O>O1CCOCC1>[C@@H:8]1([C:6]([OH:7])=[O:17])[C:10]2([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:9]1
Reactant: C[C@H](NC(=O)[C@H]1CC12CCCCC2)C(N)=O
Reactant: O=S(=O)(O)O
Solvent: C1COCCO1
Product: O=C(O)[C@H]1CC12CCCCC2

Procedure:
The product from Example 4 (25.0 0.112 mol, 97% diastereomeric excess), 1,4-dioxane (50 mL), and 4M H2SO4 (100 mL) were refluxed for 8 hours. The resulting solution was extracted with heptane (3×150 mL). The combined organic extracts were concentrated to afford the title compound (97% enantiomeric excess). The enantiomeric excess of the carboxylic acid was determined by chiral gas chromatography (GC) performed on a Hewlett-Packard 5890 Series gas chromatograph with a flame ionization detector (250° C.), and split mode capillary injection system (ratio 30:1), using a Chiraldex GTA column (30 m×0.25 mm, lot 06847 Serial # G0112-15); 1.0 μL injection volume, 250° C. injection temperature, helium carrier gas at 20 psi, oven temperature 160° C. isothermal, retention time of 9.02 minutes.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8]Br)[N:3]=1.Cl.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH:12]1[C:17]([NH2:19])=[O:18].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:1][C:2]1[N:3]=[C:4]([CH2:8][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH:12]2[C:17]([NH2:19])=[O:18])[CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)C1COCCN1
Reactant: BrCc1cccc(Br)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)C1COCCN1Cc1cccc(Br)n1
Temperature: 25 °C

Procedure:
2-Bromo-6-(bromomethyl)pyridine (Example 190, Step 1) (150 mg, 0.60 mmol), morpholine-3-carboxamide hydrochloride (100 mg, 0.560 mmol) and potassium carbonate (207 mg, 1.50 mmol) were taken up in DMF (3 mL) and the reaction was maintained at room temperature overnight. Water was then added and the mixture was extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give the title compound as an orange oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]3[N:15]=[C:14]([O:16][C:17]4[C:23]([CH3:24])=[CH:22][C:20]([NH2:21])=[C:19]([CH3:25])[CH:18]=4)[S:13][N:12]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CO.CO[CH:30](OC)[N:31]([CH2:33][CH3:34])[CH3:32]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]3[N:15]=[C:14]([O:16][C:17]4[C:23]([CH3:24])=[CH:22][C:20]([N:21]=[CH:30][N:31]([CH2:33][CH3:34])[CH3:32])=[C:19]([CH3:25])[CH:18]=4)[S:13][N:12]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CCN(C)C(OC)OC
Reactant: Cc1cc(Oc2nc(C3(c4ccc(Cl)cc4)CC3)ns2)c(C)cc1N
Solvent: CO
Solvent: Cc1ccccc1
Product: CCN(C)C=Nc1cc(C)c(Oc2nc(C3(c4ccc(Cl)cc4)CC3)ns2)cc1C
Yield: 61.6 %

Procedure:
0.30 g (0.81 mmol) of 4-({3-[1-(4-chlorophenyl)cyclopropyl]-1,2,4-thiadiazol-5-yl}oxy)-2,5-dimethylaniline is dissolved in 3 ml of toluene and 0.75 ml of methanol and treated with 0.32 g (2.42 mmol) of N-ethyl-N-methylformamide dimethylacetal. The reaction mixture is refluxed for 18 h, subsequently cooled, freed from the solvent under vacuum and purified by column chromatography. 0.22 g of product is obtained (99.3% purity, 61.7% yield; log P (pH2.3)=2.28).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1O.C(N(CC)CC)C.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH3:46][O:47][C:48](=[O:60])[N:49]([CH2:51][C:52]1[CH:57]=[CH:56][C:55]([C:58]#[CH:59])=[CH:54][CH:53]=1)[CH3:50]>C(#N)C>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1[C:59]#[C:58][C:55]1[CH:56]=[CH:57][C:52]([CH2:51][N:49]([C:48]([O:47][CH3:46])=[O:60])[CH3:50])=[CH:53][CH:54]=1
Reactant: COC(=O)c1cc(F)cc([N+](=O)[O-])c1O
Reactant: C#Cc1ccc(CN(C)C(=O)OC)cc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)c1cc(F)cc([N+](=O)[O-])c1C#Cc1ccc(CN(C)C(=O)OC)cc1
Temperature: -8 °C
Reaction time: 2 h
Yield: 156.8 %

Procedure:
The nitro compound 8 (47.87 g, 0.223 mol) was dissolved in acetonitrile (240 ml) and cooled to −8° C. Triethylamine (33.8 g, 0.334 mol) was added. A clear dark solution was formed. Triflic anhydride (69.17 g, 0.245 mol) was added slowly and the reaction temperature was maintained at −10° C. 10 minutes after addition was complete, TLC analysis indicate the completion of triflate formation. Cooling bath was removed. Alkyne 5 (47.46 g, 0.234 mol) was added. The solution was degassed 3 times by evacuating the flask and backfilling it with nitrogen. The solution was then transferred into an addition funnel. Into a separate reaction flask was added acetonitrile (240 ml) and triethylamine (22.5 g, 0.223 mol). The solution was degassed 3 times by exposing the reaction flask to vacuum and nitrogen alternatively. Dichlorobis(triphenylphosphine) palladium (II) (3.13 g, 0.0045 mol) was added to the solution and the solution was degassed again 3 times. This solution was heated to 65° C. under protection of nitrogen. Once the temperature reached 65° C., one quarter of the solution of alkyne 5 and triflate in addition funnel was quickly added to the reaction flask. The remaining solution in addition funnel was added over 30 minutes at 65° C. After the addition was complete, the reaction solution was stirred at 65° C. for 2 hours. HPLC analysis indicated the reaction was complete. Reaction mixture was cooled to room temperature. Solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (500 ml) and washed with water (300 ml). The aqueous phase was separated and back extracted with ethyl acetate (200 ml). The combined organic solution was washed with water (200 ml). It was then concentrated to dryness to provide a dark oil residue (140 g). This crude product was used in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 2.87 (d, br, 3H), 3.755 (s, 3H), 4.011 (s, 3H), 4.50 (s, br, 2H), 7.21 (s, br, 2H), 7.55 (d, 2H, J=9 Hz), 7.80 (dd, 1H, J=2.7 Hz and J=7.2 Hz), 7.86 (dd, 1H, J=2.7 Hz and J=8.1 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([O:19][CH3:20])[CH:13]=[C:12]([O:21][CH3:22])[C:11]=2[C@@H:23]1[CH2:28][CH2:27][NH:26][CH2:25][C@H:24]1[OH:29].[CH3:30][CH2:31][CH2:32]Br.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([O:19][CH3:20])[CH:13]=[C:12]([O:21][CH3:22])[C:11]=2[C@@H:23]1[CH2:28][CH2:27][N:26]([CH2:30][CH2:31][CH3:32])[CH2:25][C@H:24]1[OH:29]
Reactant: COc1cc(OC)c2c(=O)cc(-c3ccccc3Cl)oc2c1[C@@H]1CCNC[C@H]1O
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCN1CC[C@@H](c2c(OC)cc(OC)c3c(=O)cc(-c4ccccc4Cl)oc23)[C@H](O)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of compound of example 128 (0.871 g, 2.09 mmol), n-propyl bromide (0.335 g, 2.72 mmol) and anhydrous K2CO3 (1.15 g, 8.33 mmol) in dry DMF (20 mL) was stirred at 25° C. for 2 h. The reaction mixture was treated with water and extracted with EtOAc (2×100 mL). The organic extract was washed with water, dried (anhydrous Na2SO4) and concentrated. The crude obtained was purified on a silica gel column using a mixture of 1% MeOH+1% liquor NH3 in CHCl3 as eluant to get the title compound.
Reaction SMILES: [NH2:1][C:2]1([CH3:19])[C:14]2[N:13]3[CH:15]=[CH:16][N:17]=[C:12]3[C:11](=[O:18])[NH:10][C:9]=2[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.CO[CH:22]1[CH2:26][CH2:25][CH:24](OC)O1>C(O)(=O)C.O>[CH3:19][C:2]1([N:1]2[CH:22]=[CH:26][CH:25]=[CH:24]2)[C:14]2[N:13]3[CH:15]=[CH:16][N:17]=[C:12]3[C:11](=[O:18])[NH:10][C:9]=2[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2
Reactant: COC1CCC(OC)O1
Reactant: CC1(N)c2ccccc2-c2[nH]c(=O)c3nccn3c21
Solvent: O
Solvent: CC(=O)O
Product: CC1(n2cccc2)c2ccccc2-c2[nH]c(=O)c3nccn3c21
Temperature: 20 °C
Reaction time: 1 h
Yield: 54.3 %

Procedure:
To a solution of 1.3 g of 10-amino-10-methyl-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one in 25 ml of acetic acid is added 0.66 g of 2,5-dimethoxytetrahydrofuran. The mixture is stirred at boiling for 1 hour, cooled to 20° C. and concentrated to dryness under reduced pressure (15 mmHg; 2 kPa) at 60° C. The product obtained is suspended in 100 ml of distilled water and the insoluble product formed is isolated by filtration, washed successively 4 times with 40 ml in total of distilled water, 3 times with 30 ml in total of methanol and 3 times with 30 ml in total of acetone, and then dried under reduced pressure (1 mmHg; 0.13 kPa) at 100° C. 0.82 g of 10-methyl-10-(1-pyrrolyl)-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one is thus obtained, melting at 320° C. (decomposition) (Analysis, % calculated C: 71.51, H: 4.67, N: 18.53, O: 5.29, % found C: 71.7, H: 4.5, N: 18.3).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C@@H:14]([F:15])[CH2:13][O:12][CH2:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[O:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1>>[F:15][C@H:14]1[CH2:13][O:12][CH2:11][C:10]([NH2:16])=[N:9][C@@:8]1([C:6]1[CH:7]=[C:2]([NH:1][CH:22]2[CH2:23][CH2:24][O:19][CH2:20][CH2:21]2)[CH:3]=[CH:4][C:5]=1[F:18])[CH3:17]
Reactant: O=C1CCOCC1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)COC[C@@H]1F
Product: C[C@]1(c2cc(NC3CCOCC3)ccc2F)N=C(N)COC[C@@H]1F
Yield: 38.3 %

Procedure:
In an analogous manner as described for example 1 the reductive amination of (5R,6R)-5-(5-amino-2-fluoro-phenyl)-6-fluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-3-ylamine (intermediate A10B) (20 mg, 78.4 μmol) and dihydro-2H-pyran-4(3H)-one (CAS [29943-42-8]) (8.63 mg, 7.96 μl, 86.2 μmol) yielded the title compound (10.2 mg, 38.4%) as a colorless oil. MS (ISP): m/z=340.2 [M+H]+.
Reaction SMILES: [O:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[O:3][CH:2]1[C:10](OC)=[O:11].[H-].[H-].[H-].[H-].[Li+].[Al+3].[NH4+].[Cl-]>C1COCC1.O.C(OCC)(=O)C>[O:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[O:3][CH:2]1[CH2:10][OH:11]
Reactant: COC(=O)C1Oc2cccnc2O1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: OCC1Oc2cccnc2O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.2 %

Procedure:
Reaction under a nitrogen atmosphere. A solution of intermediate (4) (0.042 mol) in THF (48 ml) was added dropwise to LiAlH4 (1 Min THF) (0.0466 mol) and cooled with an ice-water bath. The resulting reaction mixture was stirred for one hour at room temperature. The reaction mixture was treated carefully with a 10% NH4Cl solution and it was diluted with water and ethyl acetate. The reaction mixture was filtered over Celite and the filtrate was extracted. The separated organic layer was dried, filtered and the solvent was evaporated. The residue was washed with DCM, filtered off and dried, yielding 2.78 g of (±)-1,3-dioxolo[4,5-b]pyridine-2-methanol (intermediate 5).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=O)[CH2:12][CH2:11]3)=[C:4]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:21][CH:20]=2)[CH:3]=1.[Cl-].[OH:35][NH3+:36].N1C=CC=CC=1.O>C(O)C.O1CCCC1>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[N:36][OH:35])[CH2:12][CH2:11]3)=[C:4]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]3[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]3)=[CH:21][CH:20]=2)[CH:3]=1
Reactant: O=C1CCc2cc(-c3ccc(O)cc3Nc3ccc(OCCN4CCCCC4)cc3)ccc21
Reactant: [NH3+]O
Agent: [Cl-]
Solvent: CCO
Solvent: O
Solvent: c1ccncc1
Product: ON=C1CCc2cc(-c3ccc(O)cc3Nc3ccc(OCCN4CCCCC4)cc3)ccc21
Temperature: 60 °C
Reaction time: 8 h
Yield: 20.7 %

Procedure:
To a solution of 5-{4-hydroxy-2-[4-(2-piperidin-1-ylethoxy)phenylamino]phenyl}indan-1-one (28 mg) in ethanol (1 ml) and tetrahydrofuran (0.2 ml) were sequentially added hydroxylammonium chloride (43 mg) and pyridine (0.2 ml), and the solution was stirred overnight at 60° C. Water was added thereto followed by stirring, the solution was extracted with ethyl acetate, then sequentially washed with water and brine, and the solvent was evaporated in vacuo. The residue was purified by NH silica gel column chromatography (ethyl acetate-methanol system) to provide the title compound (6 mg).
Reaction SMILES: [CH:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH3:17])[C:14]([OH:16])=[O:15])=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C[O-].[Na+:20]>CO>[CH:1]1([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([CH:13]([CH3:17])[C:14]([O-:16])=[O:15])=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1.[Na+:20]
Reactant: CC(C(=O)O)c1ccc(CC2CCCC2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C(=O)[O-])c1ccc(CC2CCCC2)cc1

Procedure:
50 mg. of 2-(4-cyclopentylmethylphenyl)propionic acid is dissolved in 2 ml. of methanol, titrated with a 3% methanolic sodium methylate solution, concentrated under vacuum, and 50 mg. of sodium 2-(4-cyclopentylmethylphenyl)propionate, m.p. 206° is obtained in this way.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17](=[O:23])[N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:12][CH2:11]2)=[O:9])[N:6]=1.[Br:24][C:25]1[S:29][C:28]([C:30](O)=[O:31])=[CH:27][CH:26]=1>>[O:9]=[C:8]([N:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17](=[O:23])[N:18]2[CH2:19][CH2:20][CH2:21][CH2:22]2)[CH2:12][CH2:11]1)[CH2:7][C:5]1[N:6]=[C:2]([NH:1][C:30]([C:28]2[S:29][C:25]([Br:24])=[CH:26][CH:27]=2)=[O:31])[S:3][CH:4]=1
Reactant: O=C(O)c1ccc(Br)s1
Reactant: Nc1nc(CC(=O)N2CCN(CC(=O)N3CCCC3)CC2)cs1
Product: O=C(Nc1nc(CC(=O)N2CCN(CC(=O)N3CCCC3)CC2)cs1)c1ccc(Br)s1

Procedure:
In analogy to example 37.5, 2-(2-amino-thiazol-4-yl)-1-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethanone (example 37.4) was coupled with 5-bromothiophene-2-carboxylic acid, using general method D, to give 5-bromo-thiophene-2-carboxylic acid (4-{2-oxo-2-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethyl}-thiazol-2-yl)-amide. Light yellow solid. MS 528.1 ([M+H]+)
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:23])=[CH:4][C:5]([Cl:22])=[C:6]([CH:21]=1)[O:7][C:8]1[CH:20]=[CH:19][CH:18]=[CH:17][C:9]=1[O:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].Cl[C:25](OC(Cl)(Cl)Cl)=[O:26]>C1(C)C=CC=CC=1>[Cl:22][C:5]1[C:6]([O:7][C:8]2[CH:20]=[CH:19][CH:18]=[CH:17][C:9]=2[O:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:21][C:2]([N:1]=[C:25]=[O:26])=[C:3]([F:23])[CH:4]=1
Reactant: CCOC(=O)COc1ccccc1Oc1cc(N)c(F)cc1Cl
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)COc1ccccc1Oc1cc(N=C=O)c(F)cc1Cl

Procedure:
Into a mixture of ethyl [2-(5-amino-2-chloro-4-fluorophenoxy)phenoxy]acetate [Intermediate compound A3-23], trichloromethyl chloroformate and toluene is added dropwise activated carbon, and the mixture is heated under reflux. The reaction solution is filtrated and the solvent is distilled off to obtain 4-chloro-2-fluoro-5-{2-(ethoxycarbonylmethoxy)phenoxy}phenyl isocyanate [Intermediate compound A12-23].
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:8]=2)[C:3]=1[C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1.[CH2:28](Br)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>CCOCC>[F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:8]=2)[C:3]=1[C:21]1[CH:22]=[CH:23][C:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:25][CH:26]=1
Reactant: CCCCCCCCBr
Reactant: CCCCCCCCc1ccc2c(-c3ccc(O)cc3)c(F)c(F)cc2c1
Solvent: CCOCC
Product: CCCCCCCCOc1ccc(-c2c(F)c(F)cc3cc(CCCCCCCC)ccc23)cc1

Procedure:
From 4-(2,3-difluoro-6-octylnaphthalen-1-yl)phenol and 1-octyl bromide by means of the Williamson ether synthesis.
Reaction SMILES: C=O.[C:3]([BH3-])#N.[Na+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH2:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[N:15]=[CH:14][N:13]([CH2:27][O:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[C:12]2=[O:35]>C1COCC1.CO>[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH2:20][CH:21]1[CH2:22][CH2:23][N:24]([CH3:3])[CH2:25][CH2:26]1)[N:15]=[CH:14][N:13]([CH2:27][O:28][C:29](=[O:34])[C:30]([CH3:31])([CH3:32])[CH3:33])[C:12]2=[O:35]
Reactant: [BH3-]C#N
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCC1CCNCC1
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCC1CCN(C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.4 %

Procedure:
A 37% aqueous solution of formaldehyde (501 μl, 6 mmol) followed by sodium cyanoborohydride (228 mg, 3.6 mmol) were added in portions to a solution of 6-methoxy-7-(piperidin-4-ylmethoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (1.21 g, 3 mmol) in a mixture of THF/methanol (10 ml/10 ml). After stirring for 30 minutes at ambient temperature, the organic solvents were removed under vacuum and the residue was partitioned between methylene chloride and water. The organic layer was separated, washed with water and brine, dried (MgSO4) and the volatiles were removed by evaporation. The residue was triturated with ether and the resulting solid was collected by filtration, washed with ether and dried under vacuum to give 6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (1.02 g, 82%).
Reaction SMILES: C1(C([N:6]2[C:10]3=[CH:11][N:12]=[C:13]([C:15]4[CH:16]=[N:17][C:18]([CH3:21])=[CH:19][CH:20]=4)[CH:14]=[C:9]3[C:8]([NH:22][C:23]([CH:25]3[CH2:27][CH2:26]3)=[O:24])=[N:7]2)=O)CC1>N1CCCCC1>[CH3:21][C:18]1[N:17]=[CH:16][C:15]([C:13]2[CH:14]=[C:9]3[C:8]([NH:22][C:23]([CH:25]4[CH2:27][CH2:26]4)=[O:24])=[N:7][NH:6][C:10]3=[CH:11][N:12]=2)=[CH:20][CH:19]=1
Reactant: Cc1ccc(-c2cc3c(NC(=O)C4CC4)nn(C(=O)C4CC4)c3cn2)cn1
Solvent: C1CCNCC1
Product: Cc1ccc(-c2cc3c(NC(=O)C4CC4)n[nH]c3cn2)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Cyclopropanecarboxylic acid [1-(1-cyclopropylmethanoyl)-5-(6-methylpyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl]amide (Description 4; 196 mg, 0.542 mmol), was dissolved in piperidine (2 mL) and stirred at room temperature for 16 hours. The piperidine was removed in vacuo, and the resulting oily residue was triturated with water to give the title compound as a solid.