Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:8][NH2:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:10](N1C=CN=C1)(N1C=CN=C1)=[O:11]>C1COCC1.O.CCOC(C)=O>[Br:1][C:2]1[C:3]2[N:4]([C:10](=[O:11])[NH:9][N:8]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NNc1ncccc1Br
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=c1[nH]nc2c(Br)cccn12
Reaction time: 2 h
Yield: 35.1 %

Procedure:
To a solution of 1-4 (5.0 g, 26.6 mmol) in THF (50 mL) was added carbonyldiimidazole (5.61 g, 34.6 mmol), and the heterogeneous mixture was stirred for 2 h. The reaction was diluted with water (150 mL) and EtOAc (150 mL), causing a precipitate to form. The mixture was filtered through a sintered glass filter, yielding 2.0 g (35%) of 1-5 as a tan solid. 1H NMR (300 MHz, DMSO-d6) δ12.73 (s, 1H), 7.88 (dd, J=7.2, 0.9 Hz, 1H), 7.58 (dd, J=7.2, 0.9 Hz, 1H), 6.51 (app t, J=7.2 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:8])=[C:6]([N+:9]([O-:11])=[O:10])[C:5](=[O:12])[NH:4][C:3]1=[O:13].Br[CH2:15][CH2:16][CH2:17][O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CC(=O)OCC.O>[CH3:1][N:2]1[C:7]([CH3:8])=[C:6]([N+:9]([O-:11])=[O:10])[C:5](=[O:12])[N:4]([CH2:15][CH2:16][CH2:17][O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[C:3]1=[O:13]
Reactant: Cc1c([N+](=O)[O-])c(=O)[nH]c(=O)n1C
Reactant: BrCCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1c([N+](=O)[O-])c(=O)n(CCCOC2CCCCO2)c(=O)n1C
Temperature: 65 °C
Yield: 47.7 %

Procedure:
To a solution of 1,6-dimethyl-5-nitropyrimidine-2,4(1H,3H)-dione (6 g, 0.032 mol) in DMF (20 mL) was added 2-(3-bromopropoxy)tetrahydro-2H-pyran (10.85 g, 0.049 mol) and K2CO3 (13.44 g, 0.097 mol). The reaction was heated at 65° C. for 2 h, cooled to RT then diluted with EA (20 mL) and water (20 mL). The organic layer was washed with aq. 1N LiCl (3×30 mL), dried over Na2SO4 and concentrated to a residue which was purified by chromatography eluted with PE/EA (5:1 to 1:1) to give 1,6-dimethyl-5-nitro-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl) pyrimidine-2,4(1H,3H)-dione (5 g, 47.1% yield) as a yellow oil. LCMS: [MH+-THP] 244 and TR=1.180 min. Used without further purification.
Reaction SMILES: [CH3:1][O:2][C@@H:3]([C@@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1C(OC(C)(C)C)=O)[C@@H:4]([CH3:16])[C:5](=[O:15])[NH:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[ClH:29]>O1CCOCC1.CO>[ClH:29].[CH3:1][O:2][C@@H:3]([C@@H:17]1[CH2:21][CH2:20][CH2:19][NH:18]1)[C@@H:4]([CH3:16])[C:5]([NH:6][CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:15]
Reactant: CO[C@H]([C@@H](C)C(=O)NCCc1ccccc1)[C@@H]1CCCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CO[C@@H]([C@@H]1CCCN1)[C@@H](C)C(=O)NCCc1ccccc1
Reaction time: 18 h

Procedure:
To #20 (7.00 g, 17.9 mmol, 1 eq.) in dioxane (50 mL, 0.36 M) and methanol (2 mL) was added a 4 M solution of hydrochloric acid in dioxane (20 mL, 80 mmol, 4.4 eq.). After stirring for 18 hours, the mixture was concentrated to afford #24 (5.86 g, quantitative) as a gum, which was used without further purification; LC-MS: 292.2 [M+H+], retention time=0.47 minutes.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:4][CH2:3]1.[Cl:19][C:20]1[N:21]=[C:22]([C:27](O)=[O:28])[NH:23][C:24]=1[CH2:25][CH3:26].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>CN(C)C(=O)C.ClCCl.O.C(O)(C(F)(F)F)=O.C(OCC)(=O)C>[Cl:19][C:20]1[N:21]=[C:22]([C:27]([NH:1][C@@H:2]2[CH2:7][CH2:6][C@H:5]([C:8]3[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=3)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:4][CH2:3]2)=[O:28])[NH:23][C:24]=1[CH2:25][CH3:26]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: CCOC(=O)c1cccc([C@H]2CC[C@@H](N)CC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cccc([C@H]2CC[C@@H](NC(=O)c3nc(Cl)c(CC)[nH]3)CC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl cis-3-(4-aminocyclohexyl)benzoate obtained in Example (194a) (57 mg, 0.23 mmol) was dissolved in a mixed solution of N,N-dimethylacetamide/dichloromethane=1/1 (10 mL). 4-Chloro-5-ethyl-1H-imidazole-2-carboxylic acid (described in Example 1d, 60 mg, 0.345 mmol), 1-hydroxybenzotriazole (64 mg, 0.472 mmol), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (90 mg, 0.472 mmol) and triethylamine (66 μL, 0.472 mmol) were added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with brine, and then dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=1/1) to obtain 50 mg of the title compound as a white solid (53%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][S:10][C:11]2[NH:12][C:13]([CH3:30])=[C:14]([C:26]([O:28][CH3:29])=[O:27])[CH:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=3)[N:16]=2)=[CH:5][CH:4]=1.[CH2:31]([N:33]=[C:34]=[O:35])[CH3:32].C(=O)([O-])[O-].[K+].[K+].ClCCl.CO>CC(C)=O>[CH2:31]([NH:33][C:34]([N:16]1[CH:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)[C:14]([C:26]([O:28][CH3:29])=[O:27])=[C:13]([CH3:30])[N:12]=[C:11]1[S:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:35])[CH3:32]
Reactant: CCN=C=O
Reactant: COC(=O)C1=C(C)NC(SCc2ccc(OC)cc2)=NC1c1cccc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Solvent: CC(C)=O
Product: CCNC(=O)N1C(SCc2ccc(OC)cc2)=NC(C)=C(C(=O)OC)C1c1cccc([N+](=O)[O-])c1
Yield: 91.7 %

Procedure:
A solution of 1,4-dihydro-2-[[(4-methoxyphenyl)methyl]thio]-6-methyl-4-(3-nitrophenyl)-5-pyrimidinecarboxylic acid, methyl ester (1.5 g, 3.5 mmole) in acetone under argon at room temperature was treated with ethyl isocyanate (0.5 ml, 0.45 g, 6.3 mmole) and powdered potassium carbonate (50 mg, 0.36 mmole). Examination of the reaction mixture using thin layer chromatography (tlc) (dichloromethane/methanol, 95:5) showed a new spot at higher Rf which did not increase after 1 to 2 hours. Volatiles were evaporated in vacuo and the residue was partitioned between ethyl acetate and water. The organic fraction was washed with water, 1N hydrochloric acid, water and saturated brine. The aqueous fractions were back-extracted with fresh ethyl acetate. The combined organic fractions were dried (magnesium sulfate) and concentrated in vacuo to give 1.6 g of crude product.
Reaction SMILES: C(Cl)CCl.[C:5]([O:9][C:10]([NH:12][CH:13]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1)[C:14]([OH:16])=O)=[O:11])([CH3:8])([CH3:7])[CH3:6].C1C=CC2N(O)N=NC=2C=1.Cl.[NH2:38][CH2:39][CH2:40][C:41]([NH2:43])=[O:42].CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[C:5]([O:9][C:10](=[O:11])[NH:12][CH:13]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:25])([F:26])[F:24])[CH:18]=1)[C:14]([NH:38][CH2:39][CH2:40][C:41]([NH2:43])=[O:42])=[O:16])([CH3:7])([CH3:6])[CH3:8]
Reactant: NCCC(N)=O
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1cccc(C(F)(F)F)c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC(C(=O)NCCC(N)=O)c1cccc(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
360 mg (1.88 mmol) of EDC were added to a mixture of 400 mg (1.25 mmol) of [(tert-butoxycarbonyl)amino][3-(trifluoromethyl)phenyl]acetic acid and 254 mg (1.88 mmol) of HOBt in 12 ml of DMF, and the mixture was stirred at RT for 30 min 234 mg (1.88 mmol) of beta-alaninamide hydrochloride and 436 μl (2.50 mmol) of N,N′-diisopropylethylamine were added, and the mixture was stirred for another 1 h. The mixture was diluted with ethyl acetate and washed four times with water. The organic phase was dried over sodium sulphate and freed from the solvent on a rotary evaporator. The residue was dried under high vacuum. This gave 446 mg (91% of theory) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2C=N[CH:14]=[CH:13][N:12]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].ClC1N=C(C)[CH:21]=[CH:20][N:19]=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2[N:12]=[C:13]([CH3:14])[CH:21]=[CH:20][N:19]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: Cc1ccc(-c2cnccn2)c(C(=O)O)c1
Reactant: Cc1ccnc(Cl)n1
Product: Cc1ccc(-c2nccc(C)n2)c(C(=O)O)c1

Procedure:
The title compound was prepared following the same general protocol as described for 5-methyl-2-(pyrazin-2-yl)benzoic acid in Example A19, starting from 2-chloro-4-methylpyrimidine. ESI-MS (m/z): 229 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:28])[CH:9]([CH2:15][C:16]2[O:20][N:19]=[C:18]([O:21][C:22]([F:27])([F:26])[CH:23]([F:25])[F:24])[CH:17]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.Cl>C(OCC)C.[BH4-].[Zn+2].[BH4-]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:28])[CH:9]([CH2:15][C:16]2[O:20][N:19]=[C:18]([O:21][C:22]([F:26])([F:27])[CH:23]([F:25])[F:24])[CH:17]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Cc1cc(OC(F)(F)C(F)F)no1)C(=O)c1ccc(F)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Zn+2]
Solvent: CCOCC
Product: CCOC(=O)C(Cc1cc(OC(F)(F)C(F)F)no1)C(O)c1ccc(F)cc1

Procedure:
While stirring zinc chloride (6.35 g, 46.6 mmol) in diethyl ether (100 ml), sodium borohydride (3.53 g, 93.2 mmol) was added at room temperature, and the mixture was stirred as it was for 2 hrs. The insoluble material of the mixture was removed by filtration and washed with diethyl ether to give a solution of zinc borohydride in diethyl ether. A solution of ethyl 3-(4-fluorophenyl)-3-oxo-2-[[3-(1,1,2,2-tetrafluoroethoxy)isoxazol-5-yl]methyl]propionate (2.372 g, 5.824 mmol) in diethyl ether (30 ml) was added to the obtained solution under ice-cooling, and the mixture was heated under reflux for 4 hrs. To the reaction solution was added dilute hydrochloric acid by small portions to decompose excess zinc borohydride, and the mixture was extracted twice with ethyl acetate. The recovered organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane/ethyl acetate=6/1−3/1) to give the objective substance.
Reaction SMILES: C[C:2]1([C:14]([O-:16])=O)[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[NH2:17][NH2:18]>C(O)C>[NH:17]([C:14]([CH:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1)=[O:16])[NH2:18]
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C(=O)[O-])C1
Reactant: NN
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NN)C1
Temperature: 25 °C

Procedure:
A solution of 1-tert-butyl 3-methylpyrrolidine-1,3-dicarboxylate (1.00 equiv.) and hydrazine (excess of 50% aq. solution) in ethanol (0.2 M final conc.) is heated to reflux. After the reaction is deemed complete, the reaction mixture is cooled to rt and partially concentrated. The resulting mixture is diluted with EtOAc, and the resulting organics are washed with water and brine, dried (sodium sulfate) and concentrated in vacuo to afford the title compound i-13a.
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH:17]1[CH2:22][CH2:21][CH:20]([C:23]2[NH:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[N:24]=2)[CH2:19][CH2:18]1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([S:7]([N:17]2[CH2:18][CH2:19][CH:20]([C:23]3[NH:24][C:25]4[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=4[N:27]=3)[CH2:21][CH2:22]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: c1ccc2[nH]c(C3CCNCC3)nc2c1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1ccc(-c2ccccc2)cc1)N1CCC(c2nc3ccccc3[nH]2)CC1
Yield: 20.1 %

Procedure:
To a stirred mixture of 4-biphenylsulfonyl chloride (63 mg, 0.25 mmol) and 2-(piperidin-4-yl)-1H-benzimidazole (50 mg, 0.25 mmol) in DCM (10 mL) is added N,N-diisopropylethylamine (62 μL, 0.37 mmol). After 18 h the reaction mixture is washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Trituration with heptane gives 21 mg of 2-[1-(biphenyl-4-ylsulfonyl)piperidin-4-yl]-1H-benzimidazole.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][C:11]1[CH:15]=[C:14]([N:16]2[C:24]3[CH:23]=[CH:22][N:21]=[CH:20][C:19]=3[N:18]=[CH:17]2)[S:13][C:12]=1[C:25]([O:27]C)=O)[CH3:9].[NH3:29]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][C:11]1[CH:15]=[C:14]([N:16]2[C:24]3[CH:23]=[CH:22][N:21]=[CH:20][C:19]=3[N:18]=[CH:17]2)[S:13][C:12]=1[C:25]([NH2:29])=[O:27])[CH3:9]
Reactant: COC(=O)c1sc(-n2cnc3cnccc32)cc1OC(C)c1ccccc1Cl
Reactant: N
Solvent: CO
Product: CC(Oc1cc(-n2cnc3cnccc32)sc1C(N)=O)c1ccccc1Cl
Temperature: 125 °C
Reaction time: 4 h

Procedure:
A mixture of 87 mg of the above-synthesized methyl 3-[1-(2-chlorophenyl)ethoxy]-5-(1H-imidazo[4,5-c]pyridin-1-yl)thiophene-2-carboxylate and 10 ml of a saturated solution of ammonia in methanol was stirred in a microwave vial at 125° C. for 4 h in the microwave cavity. The reaction mixture was allowed to cool down to room temperature, then another 10 ml of a saturated solution of ammonia in methanol were added and the procedure was repeated as described above. The solvent was removed under vacuum and the residue was purified by flash chromatography to yield the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[C:6]([CH2:8][OH:9])[CH:7]=1.Cl[C:18]1[C:27]2[C:22](=[CH:23][C:24]([Cl:28])=[CH:25][CH:26]=2)[N:21]=[CH:20][CH:19]=1>C(O)CCCC>[Cl:28][C:24]1[CH:23]=[C:22]2[C:27]([C:18]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([N:10]4[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]4)=[C:6]([CH2:8][OH:9])[CH:7]=3)=[CH:19][CH:20]=[N:21]2)=[CH:26][CH:25]=1
Reactant: CN1CCN(c2ccc(N)cc2CO)CC1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Solvent: CCCCCO
Product: CN1CCN(c2ccc(Nc3ccnc4cc(Cl)ccc34)cc2CO)CC1
Yield: 83 %

Procedure:
[5-amino-2-(4-methylpiperazin-1-yl)phenyl]methanol (100 mg, 0.45 mmol) and 4,7-dichloroquinoline (94 mg, 1.1 eq) were refluxed in 1 mL of n-pentanol overnight. The reaction mixture was then evaporated and purified by flash chromatography (DCM/MeOH/NH4OH//8/2/0.1) to yield expected compound as a pale brown solid (143 mg, 83% yield). m/z (ESI) 383.1 [M+H]+;
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:13][CH2:12][N:11](C(OCC[Si](C)(C)C)=O)[CH2:10][CH:9]2[O:23]C(OCC[Si](C)(C)C)=O)[CH:5]=[CH:6][CH:7]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH:9]2[OH:23])[CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCOC(=O)OC1CN(C(=O)OCC[Si](C)(C)C)CCC1c1cccc(Br)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OC1CNCCC1c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 81.4 %

Procedure:
A solution of 470 mg (0.863 mmol) of 2-trimethylsilylethyl (3RS,4RS)-4-(3-bromophenyl)-3-(2-trimethylsilyl-ethoxy-carbonyloxy)-piperidine-1-carboxylate in 3 ml of absolute tetrahydrofuran was treated with 2.65 ml (2.91 mmol) of tetrabutylammonium fluoride solution (1.1 M in THF) and stirred at room temperature for 2.5 hours. Subsequently, the mixture was partitioned between methylene chloride and saturated sodium carbonate solution, the organic phase was dried over magnesium sulphate and finally the solvent was removed under reduced pressure. The crude product (440 mg) was purified by chromatography on silica gel with a 6.5:1:0.1 mixture of methylene chloride, MeOH and 25% ammonia as the eluent. There were obtained 180 mg (81% of theory) of (3RS,4RS)-4-(3-bromophenyl)-piperidin-3-ol as a light yellow oil. MS: 255, 257 (M)+.
Reaction SMILES: [Br:1][C:2]1[C:11]2[O:10][CH2:9][C@H:8]([NH:12][CH:13]([CH3:15])[CH3:14])[CH2:7][C:6]=2[C:5]([O:16][CH3:17])=[CH:4][CH:3]=1.[CH:18](=O)[CH2:19][CH3:20].C([BH3-])#N.[Na+].C(Cl)(Cl)Cl>CO>[Br:1][C:2]1[C:11]2[O:10][CH2:9][C@H:8]([N:12]([CH:13]([CH3:14])[CH3:15])[CH2:18][CH2:19][CH3:20])[CH2:7][C:6]=2[C:5]([O:16][CH3:17])=[CH:4][CH:3]=1
Reactant: CCC=O
Reactant: COc1ccc(Br)c2c1C[C@@H](NC(C)C)CO2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCN(C(C)C)[C@H]1COc2c(Br)ccc(OC)c2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
(R)-8-Bromo-3-(N-isopropylamino)-5-methoxy-3,4-dihydro-2H-1-benzopyran (3.8 g, 11.3 mmol) was dissolved in anhydrous methanol (80 mL) and to this was propanal (8.1 mL, 0.113 mol) added. The reaction was cooled (ice-bath) then sodium cyanoborohydride (1.3 g, 20.3 mmol) was added, the pH was adjusted to 5, and the reaction was allowed to stir at room temperature overnight. The solvent was removed in vacuo, the remains were twice with diethyl ether. The combined ether portions were treated with brine, dried (Na2SO4) filtered, and taken into a 1M solution of Na2CO3 and then extracted the solvent removed in vacuo to give the crude residue. Chromatography on silica (eluent: 7% ethyl acetate/hexane) gave 3.75 g (97% yield) of the title compound as a clear oil [α]21D =-82.5° (C=0.1 CHCl3). GC-MS (70 eV) M=343 (29%). The hydrochloride salt was made by dissolving the base in diethyl ether and dropping an excess of an ethereal HCl solution. The salt was recrystallized from ethanol/diethyl ether to give a white solid. Mp: 177°-9° C.
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[C:8]([CH:11]=[CH2:12])[CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)(Cl)Cl>[CH3:20][S:21]([O:1][N:2]1[C:6]2[CH:7]=[C:8]([CH:11]=[CH2:12])[CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1)(=[O:23])=[O:22]
Reactant: C=Cc1ccc2nnn(O)c2c1
Reactant: CS(=O)(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: C=Cc1ccc2nnn(OS(C)(=O)=O)c2c1
Yield: 76.6 %

Procedure:
In chloroform (80 ml) are dissolved 1-hydroxy-6-vinyl-1,2,3-benzotriazole (8.0 g) and triethylamine (5.1 g) under stirring, and thereto is added dropwise a solution of methanesulfonyl chloride (5.73 g) in chloroform (20 ml) at a temperature of less than 10° C. The mixture is stirred at room temperature for 1.5 hours. The reaction mixture is washed with water, an aqueous sodium hydrogen carbonate and water in order, dried over anhydrous magnesium sulfate, treated with charcoal and then concentrated till about 40 ml. After dissolving the precipitated crystals by heating, the mixture is allowed to stand. The precipitated crystals are separated by filtration to give 1-methanesulfonyloxy-6-vinyl-1,2,3-benzotriazole (9.1 g), melting point: 129°-129.5° C. The filtrate is concentrated, and the resulting residue is recrystallized from benzene to give additionally the desired product (2.3 g).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([NH2:16])=[O:15])=[CH:12][CH:11]=2)=[N:7][CH:8]=1)=O.[C:19]1([CH:25]2[CH2:29][CH2:28][NH:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>C(Cl)Cl>[C:19]1([CH:25]2[CH2:29][CH2:28][N:27]([CH2:1][C:3]3[CH:4]=[CH:5][C:6]([O:9][C:10]4[CH:18]=[CH:17][C:13]([C:14]([NH2:16])=[O:15])=[CH:12][CH:11]=4)=[N:7][CH:8]=3)[CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cn2)cc1
Reactant: c1ccc(C2CCNC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: NC(=O)c1ccc(Oc2ccc(CN3CCC(c4ccccc4)C3)cn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.2 %

Procedure:
Combine 4-(5-formyl-pyridin-2-yloxy)-benzamide (100 mg, 0.413 mmol), (±)-3-phenyl-pyrrolidine (78 mg, 0.318 mmol), sodium triacetoxy-borohydride (101 mg, 0.477 mmol), AcOH (0.018 mL, 0.318 mmol) in CH2Cl2 (5 mL). Stir at rt overnight. Pour the reaction mixture onto an SCX column, eluting with ammonia (2M in methanol) followed by chromatography [CH2Cl2:ammonia (2.0 M in methanol) 20:1] to provide the title compound (43 mg, 36%). Mass spectrum (ion spray): m/z=373.9 (M+1); 1H NMR (DMSO-d6): 8.09 (d, J=1.9 Hz, 1H), 7.93 (bs, 1H), 7.89 (d, J=8.6 Hz, 2H), 7.82 (dd, J=2.2 Hz, 8.6 Hz, 1H), 7.30 (bs, 1H), 7.27-7.24 (m, 4H), 7.17-7.12 (m, 3H), 7.03 (d, J=8.3 Hz, 1H), 3.61 (dd, J=13.1 Hz, 19.5 Hz, 2H), 3.33-3.24 (m, 1H), 2.88 (t, J=8.3 Hz, 1H), 2.66 (t, J=7.0 Hz, 2H), 2.42 (t, J=8.3 Hz, 1H), 2.28-2.18 (m, 1H), 1.79-1.70 (m, 1H).
Reaction SMILES: C[O:2][C:3](=[O:34])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:30](=[CH:31][CH:32]=1)[O:29][C:11]1([CH2:17][CH2:16][CH2:15][N:14]([CH2:18][C:19]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]([CH3:28])[CH:20]=3)[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:33].[OH-].[Na+]>>[CH3:28][N:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19]([CH2:18][N:14]2[CH2:15][CH2:16][CH2:17][C:11]3([CH2:10][C:9](=[O:33])[C:8]4[C:30](=[CH:31][CH:32]=[C:6](/[CH:5]=[CH:4]/[C:3]([OH:34])=[O:2])[CH:7]=4)[O:29]3)[CH2:12][CH2:13]2)=[CH:20]1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(Cc3cn(C)c4ccccc34)CC1)O2
Agent: [Na+]
Agent: [OH-]
Product: Cn1cc(CN2CCCC3(CC2)CC(=O)c2cc(/C=C/C(=O)O)ccc2O3)c2ccccc21

Procedure:
(±)-(E)-3-[1′-(1-Methyl-1H-indol-3-ylmethyl)-4-oxo-spiro(chromane-2,4′-azepane)-6-yl]-acrylic acid methyl ester (350 mg, 0.76 mmol) was hydrolyzed with 1 M NaOH (0.99 ml) following the procedure described in Example 30, Step A, giving ((±)-(E)-3-[1′-(1-methyl-1H-indol-3-ylmethyl)-4-oxo-spiro(chromane-2,4′-azepane)-6-yl]-acrylic acid as a white solid [LC-MS: (ES+) MH+: 445]. The obtained acid was suspended in DCM (15 ml), treated with TEA (0.16 ml, 1.14 mmol) and then with EDC (218 mg, 1.14 mmol), HOBt (154 mg, 1.14 mmol) and NH2OTHP (106 mg, 0.905 mmol) following the procedure described in Example 30, Step B, giving (±)-(E)-3-[1′(1-methyl-1H-indol-3-ylmethyl)-4-oxo-spiro(chromane-2,4′-azepane)-6-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (280 mg) as a light yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]1([C:17]#[N:18])[C:11]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[NH2:20][OH:21]>C(O)C>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]1([C:17](=[NH:18])[NH:20][OH:21])[C:11]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:10]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC1(C#N)CC12CCCCC2
Reactant: NO
Solvent: CCO
Product: CC(C)(C)OC(=O)NCC1(C(=N)NO)CC12CCCCC2
Temperature: 25 °C
Yield: 54.3 %

Procedure:
To a solution of (1-cyano-spiro[2.5]oct-1-ylmethyl)-carbamic acid tert-butyl ester (10.0 g, 37.8 mmol) in ethanol (150 mL) was added 50% aqueous hydroxylamine (12 mL, 189 mmol). The solution was heated to reflux for 14 hours, cooled to room temperature and the solvent removed under reduced vacuum. The residue was partitioned between water (200 mL) and ether (300 mL). An emulsion formed in the ether layer, which was separable. The aqueous layer was extracted with ether (2×300 mL). The combined organic layers were filtered to remove emulsified material. The organic layer was washed with brine (200 mL), dried over sodium sulfate, filtered and evaporated to give 6.1 g (54%) of [1-(N-hydroxycarbamimidoyl)-spiro[2.5]oct-1-ylmethyl]-carbamic acid tert-butyl ester as a white solid: 1H NMR (300 MHz, CDCl3) δ 0.52 (d, J=4.8 Hz, 1H), 0.90 (d, J=4.8 Hz, 1H), 1.4 (m, 1H), 1.43 (s, 9H), 1.3-1.7 (m, 9H), 3.11 (s, 1H), 3.23 (dd, J=5.2, 13.9 Hz, 1H), 3.47 (dd, J=5.2, 13.9 Hz, 1H), 4.68 (s, 2H), 5.12 (s, 1H); MS (APCI) m/z 298 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[N:3]=1.[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>ClCCCl>[Br:14][CH2:13][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([CH3:1])[NH:11][C:10]2=[O:12]
Reactant: Cc1ccc2nc(C)[nH]c(=O)c2c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCCl
Product: Cc1nc2ccc(CBr)cc2c(=O)[nH]1
Yield: 65.4 %

Procedure:
According to example 4, 1.00 g of 3,4-dihydro-2,6dimethyl-4-oxoquinazoline (Sen, A. B.; Gupta, J. K. J. Indian Chem. Soc., 1962, 31, 369) was subjected to bromination using 1.05 g of N-bromosuccinimide (Aldrich) and 0.17 g of benzoyl peroxide in 50 mL of 1,2-dichloro-ethane for 30 min to afford 0.95 g (64%) of 6-bromomethyl-3,4-dihydro-2-methyl4-oxoquinazoline as a tan solid.