Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]2[C:6]([CH3:13])([CH3:12])[NH:7][C:8](=[O:11])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([NH:28][CH3:29])=[O:27])[C:20]([Cl:35])=[CH:19][N:18]=1>Cl.O1CCOCC1.CC(O)C>[NH2:7][C:8](=[O:11])[CH2:9][CH2:10][C:4]1[CH:3]=[C:2]([NH:1][C:17]2[N:22]=[C:21]([NH:23][C:24]3[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:25]=3[C:26]([NH:28][CH3:29])=[O:27])[C:20]([Cl:35])=[CH:19][N:18]=2)[CH:15]=[CH:14][C:5]=1[C:6]([CH3:13])=[CH2:12]
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: CC1(C)NC(=O)CCc2cc(N)ccc21
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: C=C(C)c1ccc(Nc2ncc(Cl)c(Nc3c(F)cccc3C(=O)NC)n2)cc1CCC(N)=O
Temperature: 120 °C

Procedure:
A mixture of 7-amino-1,1-dimethyl-1,2,4,5-tetrahydrobenzo[c]azepin-3-one (40 mg), 2-(2,5-dichloropyrimidin-4-ylamino)-3-fluoro-N-methylbenzamide (50 mg), and 2 drops of 4 N HCl/dioxane in IPA (3 mL) were microwave-heated at 120° C. for 1.5 hours. The mixture was concentrated to afford crude 2-(2-(3-(3-amino-3-oxopropyl)-4-(prop-1-en-2-yl)phenylamino)-5-chloropyrimidin-4-ylamino)-3-fluoro-N-methylbenzamide. The crude mixture was stirred for 4 hours in TFA and concentrated. Purification by semi-preparative HPLC provided 2-(5-chloro-2-(1,1-dimethyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-ylamino)pyrimidin-4-ylamino)-3-fluoro-N-methylbenzamide (45.7 mg) as a TFA salt: 1H NMR (300 MHz, CD3OD) δ 8.3 (s, 1H), 7.7-7.5 (m, 3H), 7.65 (s, 1H, slowly exchanging NH), 7.4 (d, 1H), 7.32 (d, 1H), 7.28 (dd, 1H), 3.0 (m, 2H), 3.0 (s, 3H), 2.7 (m, 2H), 1.8 (s, 6H).
Reaction SMILES: [BH4-].[Na+].[CH3:3][CH:4]([CH3:16])[C:5](=[O:15])[CH2:6][CH2:7][NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CO>[CH3:3][CH:4]([CH3:16])[CH:5]([OH:15])[CH2:6][CH2:7][NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)C(=O)CCNc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)C(O)CCNc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 27.2 %

Procedure:
At −10° C., NaBH4 (56.7 g, 1.5 mol) was gradually added to a mixture of the crude 4-methyl-1-(phenylamino)-pentan-3-one (about 80 g) in MeOH (500 mL). After addition, the reaction mixture was allowed to warm to room temperature and stirred for 20 min. The solvent was removed and the residue was repartitioned between water and CH2Cl2. The organic phase was separated, washed with brine, dried over Na2SO4, filtered and concentrated. The resulting gum was triturated with ether to give 4-methyl-1-(phenylamino)-pentan-3-ol as a white solid (22 g, 23%).
Reaction SMILES: [NH:1]1[CH:5]=[C:4](/[CH:6]=[CH:7]/[C:8]([OH:10])=[O:9])[N:3]=[CH:2]1.[ClH:11].[CH3:12]O>>[ClH:11].[CH3:12][O:9][C:8](=[O:10])/[CH:7]=[CH:6]/[C:4]1[N:3]=[CH:2][NH:1][CH:5]=1
Reactant: CO
Reactant: O=C(O)/C=C/c1c[nH]cn1
Agent: Cl
Product: COC(=O)/C=C/c1c[nH]cn1
Temperature: 25 °C

Procedure:
A solution of trans-4-imidazoleacrylic acid (20.0 g 145 mmol) in methanol (300 ml) was saturated with anhydrous HCl and the resulting solution was then refluxed for 90 min. After cooling to room temperature the solvent was removed in vacu to to give the title compound as a white solid: 1H NMR (CD3OD) d 3.80 (s, 3 H), 6.61 (d, J=16 Hz, 1 H), 7.60 (d, J=16 Hz, 1 H), 7.92, (s, 1 H), 9.05, (s, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4](C2CCCCO2)[C:5]2[C:10]([N:11]=1)=[C:9]([NH2:12])[N:8]=[C:7]([O:13][CH2:14][CH2:15][O:16][CH3:17])[N:6]=2.[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27]>CO>[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27].[CH3:1][O:2][C:3]1[NH:4][C:5]2[C:10]([N:11]=1)=[C:9]([NH2:12])[N:8]=[C:7]([O:13][CH2:14][CH2:15][O:16][CH3:17])[N:6]=2
Reactant: COCCOc1nc(N)c2nc(OC)n(C3CCCCO3)c2n1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COCCOc1nc(N)c2nc(OC)[nH]c2n1
Reaction time: 48 h

Procedure:
8-(Methoxy)-2-{[2-(methyloxy)ethyl]oxy}-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (1.2032 g) was dissolved in methanol (10 mL) which was treated with neat trifluoroacetic acid (1 mL) and then stirred for 2 days. The reaction mixture was evaporated under reduced pressure and the resultant solid suspended in ethyl acetate (25 mL) before being filtered to give the title compound (1.1310 g) as a white solid.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:20])[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:21][C:22]1[CH:26]=[CH:25][N:24]([CH2:27][CH2:28][CH2:29][OH:30])[N:23]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:20])[C:8]([NH:21][C:22]2[CH:26]=[CH:25][N:24]([CH2:27][CH2:28][CH2:29][OH:30])[N:23]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)[C@H](CC1CCCC1)N1Cc2ccccc2C1=O
Reactant: Nc1ccn(CCCO)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccn(CCCO)n1)[C@H](CC1CCCC1)N1Cc2ccccc2C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 24.4 %

Procedure:
To a solution of (S)-3-cyclopentyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid (prepared as in Example 9, 80 mg, 0.29 mmol) and 3-(3-amino-pyrazol-1-yl)-propan-1-ol (prepared as in US 20080021032, Example 23, 49 mg, 0.35 mmol) and benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (Chemimpex, 0.15 g, 0.35 mmol) in methylene chloride (8 mL) was added N,N-diisopropylethylamine (0.15 mL, 0.88 mmol) dropwise and the resulting solution stirred at room temperature for 4 h. The solution was diluted with methylene chloride, washed with a 1 N hydrochloric acid solution (25 mL), a saturated sodium bicarbonate solution (25 mL) dried over magnesium sulfate. The mixture was filtered and evaporated and the resulting material purified via automated flash chromatography (Analogix, SF4-12 g column, 50-70% ethyl acetate/hexanes) to afford (S)-3-cyclopentyl-N-[1-(3-hydroxy-propyl)-1H-pyrazol-3-yl]-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide (28 mg, 24%) as an off white solid: HR-ES(+) m/e calcd for C22H28N4O3 [M+H]+ 397.2234, observed 397.2233; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.94-2.34 (m, 7H), 4.04 (t, J=6.79 Hz, 3H), 4.37-5.28 (m, 6H), 6.39 (s, 2H), 7.31-7.90 (m, 8H), 10.86 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8](O)=[O:9])=[CH:4][CH:3]=1.C1COCC1>>[Br:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]([CH3:11])([CH3:12])[CH2:8][OH:9])=[CH:4][CH:3]=1
Reactant: CC(C)(Oc1ccc(Br)cc1)C(=O)O
Solvent: C1CCOC1
Product: CC(C)(CO)Oc1ccc(Br)cc1
Yield: 84.8 %

Procedure:
The sub-title compound was prepared by reduction of 2-(4-bromophenoxy)-2-methylpropanoic acid (2 g, 7.7 mmol) with BH3×THF (1M, 27.0 mmol, 27.0 mL) in accordance with the procedure described in Example 29(b). Distillation under reduced pressure gave the sub-title compound (1.60 g, 85%).
Reaction SMILES: [CH3:1][CH:2]([CH2:8][CH3:9])[CH:3]([OH:7])[CH:4]=[CH:5][CH3:6].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].S(=O)(=O)(O)O>>[CH3:1][CH:2]([CH2:8][CH3:9])[C:3](=[O:7])[CH:4]=[CH:5][CH3:6]
Reactant: CC=CC(O)C(C)CC
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC=CC(=O)C(C)CC
Yield: 33.6 %

Procedure:
2-Butylmagnesium bromide is prepared from 24.32 g of magnesium filings and 137 g of 2-bromobutane in 100 ml of ether. 56 g of crotonaldehyde dissolved in 60 ml of ether are added dropwise to the solution at 0° to 10° C. The mixture is then boiled for 2 hours under reflux temperature. Thereafter it is cooled, the batch decomposed with ice water/hydrochloric acid and the product extracted, neutralized and distilled. 56 g of 5-methyl-hept-2-en-4-ol of boiling point 70° C./18 mb are obtained. To 52 g of this alcohol there is slowly added a mixture of 40.34 g of sodium dichromate and 54.1 g of sulphuric acid, while cooling with ice. After a further hour's reaction at room temperature, the batch is extracted with ether, the organic phase is washed until neutral, the solvent stripped off and the crude product distilled. Redistillation using a slotted tube column gives 17.2 g of 5-methyl-hept-2-en-4-one of boiling point 72° C./20 mb.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[N:10]([C:16]1[CH:17]=[N:18][CH:19]=[C:20]([CH2:22]O)[CH:21]=1)[C:9]2([CH3:25])[CH3:24]>C(Cl)Cl>[Cl:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[N:10]([C:16]1[CH:17]=[N:18][CH:19]=[C:20]([CH2:22][Cl:3])[CH:21]=1)[C:9]2([CH3:25])[CH3:24]
Reactant: CC1(C)c2cc(Cl)ccc2C(=O)N1c1cncc(CO)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CC1(C)c2cc(Cl)ccc2C(=O)N1c1cncc(CCl)c1
Temperature: 3.5 °C
Reaction time: 2 h
Yield: 116.3 %

Procedure:
Thionyl chloride (1.4 mL, 19.0 mmol) was added slowly at 0° C. to a solution of 5-chloro-2-(5-hydroxymethyl-pyridin-3-yl)-3,3-dimethyl-2,3-dihydro-isoindol-1-one (1.14 g, 3.8 mmol) in DCM (50 mL). After the addition, the reaction mixture was stirred at 2-5° C. for 2 hours before it was poured into satd. aq. NaHCO3 solution (50 mL) and extracted with EtOAc (2×150 mL). The organic layer was washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product (1.42 g, 92%) as a light yellowish solid. MS: 322.1 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][NH:15][C:16]2[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][N:19]=[C:18](Cl)[N:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[N:34]1([C:40]2[CH:41]=[C:42]([CH:45]=[CH:46][CH:47]=2)[CH2:43][NH2:44])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.CCO>C(Cl)Cl.CC(N(C)C)=O>[C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][N:19]=[C:18]([NH:44][CH2:43][C:42]3[CH:45]=[CH:46][CH:47]=[C:40]([N:34]4[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]4)[CH:41]=3)[N:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCc1cccc(N2CCCCC2)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CNc2nc(Cl)ncc2[N+](=O)[O-])CC1
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CCC(CNc2nc(NCc3cccc(N4CCCCC4)c3)ncc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.7 %

Procedure:
{trans-4-[(2-Chloro-5-nitro-pyrimidin-4-ylamino)-methyl]-cyclohexyl}-carbamic acid tert-butyl ester (200 mg, 0.52 mmol) was dissolved in CH2Cl2 (10 mL) and Et3N (0.289 mL, 2.07 mmol) was added. 3-Piperidin-1-yl-benzylamine (197 mg, 1.04 mmol) was dissolved in DMA:EtOH (2 mL, 1:1) and added to the reaction solution. The reaction was stirred at room temperature for 18 h. The volatiles were removed in vacuo and the crude was purified via flash chromatography (SiO2, 25-50% EtOAc:Hexanes then 5% MeOH:CH2Cl2) to afford 176 mg (63%) of (4-{[5-nitro-2-(3-piperidin-1-yl-benzylamino)-pyrimidin-4-ylamino]-methyl}-cyclohexyl)-carbamic acid tert-butyl ester
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[NH2:11])([O-:3])=[O:2].[N:12]([O-])=O.[Na+]>CC(O)=O>[N+:1]([C:4]1[C:5]2[N:11]=[N:12][NH:10][C:6]=2[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=N[O-]
Reactant: Nc1cccc([N+](=O)[O-])c1N
Agent: [Na+]
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cccc2[nH]nnc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83.7 %

Procedure:
To a mixture of 3-nitrobenzene-1,2-diamine (15.0 g) in AcOH (100 mL) was added NaNO2 (7.0 g). The reaction mixture was stirred for 15 min at RT, then heated at 60° C. for about 2 h, over which time the reaction mixture turned red. The mixture was cooled to RT, diluted with ice water, and the resulting precipitate filtered off and washed with ice water, then dried under vacuum to yield 4-nitro-1H-benzotriazole (13.45 g, 83.6% yield) as a light brown solid. The product was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][N:9]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH:11]([NH:18][CH:19]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:10]1=[O:33])=[O:7])(C)(C)[CH3:2].Cl>C(O)C>[CH2:1]([O:5][C:6]([CH2:8][N:9]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH:11]([NH:18][CH:19]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:10]1=[O:33])=[O:7])[CH3:2]
Reactant: CCOC(=O)C(CCc1ccccc1)NC1CCCCCCN(CC(=O)OC(C)(C)C)C1=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CN1CCCCCCC(NC(CCc2ccccc2)C(=O)OCC)C1=O

Procedure:
1-t-Butoxycarbonylmethyl-3-(1-ethoxycarbonyl-3-phenylpropyl)aminoperhydroazonin-2-one (Example 1) is treated with hydrogen chloride in ethanol followed by concentration and partitioning of the residue between aqueous potassium carbonate and ethyl acetate. Drying and concentration of the organic phase affords the title product.
Reaction SMILES: [NH2:1][C:2]12[CH2:9][CH2:8][C:5]([CH2:10][NH:11][C:12]3[N:17]=[C:16]([N:18]4[C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[N:20]=[C:19]4[CH:27]([F:29])[F:28])[CH:15]=[C:14]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[N:13]=3)([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.C(N(CC)C(C)C)(C)C.[CH3:45][C:46]1([CH3:49])[CH2:48][O:47]1>C(O)C>[F:29][CH:27]([F:28])[C:19]1[N:18]([C:16]2[CH:15]=[C:14]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[N:13]=[C:12]([NH:11][CH2:10][C:5]34[CH2:6][CH2:7][C:2]([NH:1][CH2:45][C:46]([CH3:49])([OH:47])[CH3:48])([CH2:9][CH2:8]3)[CH2:3][CH2:4]4)[N:17]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=1
Reactant: CC1(C)CO1
Reactant: NC12CCC(CNc3nc(N4CCOCC4)cc(-n4c(C(F)F)nc5ccccc54)n3)(CC1)CC2
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(O)CNC12CCC(CNc3nc(N4CCOCC4)cc(-n4c(C(F)F)nc5ccccc54)n3)(CC1)CC2
Temperature: 140 °C
Reaction time: 1 h

Procedure:
N-[(4-Aminobicyclo[2.2.2]oct-1-yl)methyl]-4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(morpholin-4-yl)pyrimidin-2-amine (150 mg) was dissolved in ethanol (3 mL), and N,N-diisopropyl ethylamine (81 μL) and 2,2-dimethyloxirane (36 μL) were added thereto, followed by stirring at 120° C. for 1 hour and at 140° C. for 1 hour using a microwave reactor. The reaction solution was concentrated and the residue was purified by amino silica gel column chromatography (hexane:ethyl acetate=20:80, and subsequently chloroform:methanol=98:2) to obtain 1-({4-[({4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(morpholin-4-yl)pyrimidin-2-yl}amino)methyl]bicyclo[2.2.2]oct-1-yl}amino)-2-methylpropan-2-ol (148 mg) as a white amorphous substance.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([CH3:14])[C:12]=1[CH3:13])[N:9]([C:15](=[O:17])C)[CH2:8][C:7]1([CH2:20][CH2:19][CH2:18]1)[CH2:6]2.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([CH3:14])[C:12]=1[CH3:13])[N:9]([CH:15]=[O:17])[CH2:8][C:7]1([CH2:20][CH2:19][CH2:18]1)[CH2:6]2
Reactant: COc1cc2c(c(C)c1C)N(C(C)=O)CC1(CCC1)C2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1c(O)cc2c(c1C)N(C=O)CC1(CCC1)C2
Reaction time: 1.5 h
Yield: 78 %

Procedure:
1-(6′-methoxy-7′,8′-dimethyl-2′,4′-dihydro-1′H-spiro[cyclobutane-1,3′-quinoline]-1′-yl)ethanone (100 mg) was dissolved in dichloromethane (2 mL), to which solution was added BBr3 (19.3 mL) at 10° C. After 1.5 h, it was quenched with water, extracted with dichloromethane, and the organic layers were washed with brine, dried and evaporated to give an oil. Elution on a column (dichloromethane:methanol=10:0.2) gave 6′-hydroxy-7′,8′-dimethyl-2′,4′-dihydro-1′H-spiro[cyclobutane-1,3′-quinoline]-1′-carbaldehyde (70 mg) as a white solid.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([O:27][CH3:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:3]1.[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>>[CH3:34][O:35][CH2:36][C:37]([N:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([O:27][CH3:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:3]1)=[O:38]
Reactant: COCC(=O)Cl
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CCCNC4)c[nH]c23)cc1F
Agent: Cl
Product: COCC(=O)N1CCC[C@@H](NC(=O)c2c[nH]c3c(-c4cc(F)c(OC)cc4OCC4CC4)ncnc23)C1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-fluoro-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (R)-piperidin-3-ylamide hydrochloride (example A167) and methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])[C:18]([C:27]4[N:32]=[C:31]([C:33]5[N:34](C(OC(C)(C)C)=O)[C:35]6[C:40]([C:41]=5[CH3:42])=[CH:39][CH:38]=[CH:37][CH:36]=6)[C:30]([CH2:50][CH2:51][OH:52])=[CH:29][CH:28]=4)=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])[C:18]([C:27]4[CH:28]=[CH:29][C:30]([CH2:50][CH2:51][OH:52])=[C:31]([C:33]5[NH:34][C:35]6[C:40]([C:41]=5[CH3:42])=[CH:39][CH:38]=[CH:37][CH:36]=6)[N:32]=4)=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:6][CH:7]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(CCO)c(-c4c(C)c5ccccc5n4C(=O)OC(C)(C)C)n3)cc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(CCO)c(-c4[nH]c5ccccc5c4C)n3)cc12

Procedure:
To a solution of tert-butyl 2-(6-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)-3-(2-hydroxyethyl)pyridin-2-yl)-3-methyl-1H-indole-1-carboxylate (50 mg, 0.069 mmol) in CH2Cl2 (1.5 mL) was added TFA (1.5 mL). The resultant mixture was stirred at ambient temperature for 1.5 h then was concentrated in vacuo, diluted with EtOAc and washed successively with saturated NaHCO3 (aq) solution (1×) and brine (1×). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to give the title compound, which was used without further purification. MS (M+H): 627.
Reaction SMILES: [C:1](=[O:16])([O:9]C1C=CC=CC=1)[O:2]C1C=CC=CC=1.[OH:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)([CH3:26])[CH3:25])=[CH:20][CH:19]=1>>[CH3:26][C:24]([C:21]1[CH:22]=[CH:23][C:18]([OH:17])=[CH:19][CH:20]=1)([C:27]1[CH:28]=[CH:29][C:30]([OH:33])=[CH:31][CH:32]=1)[CH3:25].[C:1]([OH:16])([OH:9])=[O:2]
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Product: O=C(O)O
Temperature: 180 °C
Reaction time: 0.12 h

Procedure:
A 1-l glass melt polymerization reactor was passivated by acid washing, rinsing with deionized water and overnight drying at 70° C. it was charged with 130.4 g (608.6 mmol) of diphenyl carbonate and 120 g (525.6 mmol) of bisphenol A. A solid nickel stirrer was suspended in the mixture and the reactor was purged with nitrogen and heated to 180° C., whereupon the reaction mixture melted. Upon complete melting, it was allowed to equilibrate for 5-10 minutes, with stirring. There were then added, with stirring, 600 μl of a 0.221 M aqueous tetramethylammonium maleate solution and 500 μl of a 0.01 M aqueous sodium hydroxide solution. Heating at 180° C. and stirring were continued for 5 minutes, after which the temperature was raised to 210° C. and the pressure decreased to 180 torr, whereupon phenol began to distill. After 10 minutes, a bisphenol A polycarbonate oligomer had been produced.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][CH2:12][CH2:13][CH2:14][OH:15])[CH:6]=1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>N1C=CC=CC=1.O>[CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][CH2:12][CH2:13][CH2:14][O:15][S:23]([C:20]2[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=2)(=[O:25])=[O:24])[CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)Cc1cccc(CCCCO)c1
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)Cc1cccc(CCCCOS(=O)(=O)c2ccc(C)cc2)c1
Yield: 63.4 %

Procedure:
A solution of {3-[4-hydroxybutyl]phenyl)acetic acid methyl ester (300 mg, 1.35 mmol) and p-toluenesulfonyl chloride (513 mg, 2.7 mmol) in pyridine (5 ml) was stirred at RT for 18 hr. The reaction was diluted with water (50 ml) and extracted with diethyl ether. The organic extracts were washed with water and cold 1N HCl, dried, and the solvent evaporated to give the title compound as an oil (322 mg, 63%). MS (ESI) 377.3 (M+H)+.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]2[O:10][CH:11]=[C:12]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]O)=[CH:18][CH:17]=3)[N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:28]1[CH:32]=[N:31][CH:30]=[N:29]1>>[C:1]1(/[CH:7]=[CH:8]/[C:9]2[O:10][CH:11]=[C:12]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N:28]4[CH:32]=[N:31][CH:30]=[N:29]4)=[CH:18][CH:17]=3)[N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCCCc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Reactant: c1nc[nH]n1
Product: C(=C/c1nc(COc2ccc(CCCCCn3cncn3)cc2)co1)\c1ccccc1
Yield: 60 %

Procedure:
In substantially the same manner as in Working Example 1, 5-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]pentanol was allowed to react with 1,2,4-triazole to give 1-[5-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]pentyl]-1,2,4-triazole. The yield was 60%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 103-104° C.
Reaction SMILES: [OH:1][CH:2]([C:17]1[N:18]=[CH:19][N:20](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:21]=1[CH3:22])[CH:3]1[C:15](=[O:16])[N:7]2[C:8]3[C:13]([CH:14]=[C:6]2[CH2:5][CH2:4]1)=[CH:12][CH:11]=[CH:10][CH:9]=3.[ClH:42]>C(O)(=O)C.O.C(OCC)(=O)C.CCOCC>[ClH:42].[OH:1][CH:2]([C:17]1[N:18]=[CH:19][NH:20][C:21]=1[CH3:22])[CH:3]1[C:15](=[O:16])[N:7]2[C:8]3[C:13]([CH:14]=[C:6]2[CH2:5][CH2:4]1)=[CH:12][CH:11]=[CH:10][CH:9]=3
Reactant: Cc1c(C(O)C2CCc3cc4ccccc4n3C2=O)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: O
Solvent: CCOCC
Solvent: CC(=O)O
Product: Cc1[nH]cnc1C(O)C1CCc2cc3ccccc3n2C1=O

Procedure:
A solution of 8,9-dihydro-7-[(hydroxy)(5-methyl-1-trityl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one (1.1 g) in acetic acid-water (3:1, 48 ml) was stirred at 65° C. for 90 minutes. After evaporation of the solvent, the residue was diluted with water, neutralized with an aqueous solution of sodium hydrogencarbonate, and extracted with chloroform. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The obtained amorphous powder contained two products which showed close Rf values (0.3 and 0.4 respectively) by TLC (20% methanol-chloroform). Separation with silica gel column chromatography (10% methanol-chloroform) gave two fractions. The residue obtained from the first eluted fraction was dissolved in ethyl acetate and treated with hydrogen chloride in ether to give one isomer with an upper Rf value of 8,9-dihydro-7-[(hydroxy)(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one hydrochloride (86.1 mg), which was designated as the isomer A.