Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[N:7]([C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[NH2:17])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[O:19]=[C:20]1[NH:24][C:23](=[O:25])[CH:22]([CH2:26][C:27]2[CH:37]=[CH:36][C:30]([O:31][CH2:32][C:33](O)=[O:34])=[CH:29][CH:28]=2)[S:21]1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C(Cl)Cl.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:18])[N:7]([C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[NH:17][C:33](=[O:34])[CH2:32][O:31][C:30]1[CH:29]=[CH:28][C:27]([CH2:26][CH:22]2[S:21][C:20](=[O:19])[NH:24][C:23]2=[O:25])=[CH:37][CH:36]=1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(N)c(N(C)C(=O)OC(C)(C)C)c1
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(NC(=O)COc2ccc(CC3SC(=O)NC3=O)cc2)c(N(C)C(=O)OC(C)(C)C)c1
Reaction time: 2 h
Yield: 85.1 %

Procedure:
To a suspension at 0° C. of N-(2-amino-5-methoxyphenyl)-N-methylcarbamic acid t-butyl ester (4.2 g) and 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid (5.2 g) in methylene chloride (30 ml) was added triethylamine (5.1 ml) and 50% propylphosphonic acid cyclic anhydride in ethyl acetate (12.7 g) and the mixture was stirred at the same temperature for 2 hours. At the end of this time to the reaction mixture was added 5% aqueous sodium hydrogencarbonate solution and the mixture was extracted with methylene chloride. The extract was washed with water and diluted hydrochloric acid and concentrated in vacuo. To the residue was added methanol (40 ml) and the precipitated crystals were filtered to give the title compound (7.3 g, yield 85%).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]5[CH2:26][N:25](CC(N)=O)[CH2:24]5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].Br[C:32]([CH3:38])([CH3:37])[C:33]([O:35][CH3:36])=[O:34].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:36][O:35][C:33](=[O:34])[C:32]([N:25]1[CH2:26][CH:23]([C:21]2[CH:20]=[CH:19][C:16]3[C:17]4[N:18]=[C:9]([C:8]5[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[CH:6][N:7]=5)[S:10][C:11]=4[CH2:12][CH2:13][O:14][C:15]=3[CH:22]=2)[CH2:24]1)([CH3:38])[CH3:37]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(CC(N)=O)C3)ccc1-2
Reactant: COC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)N1CC(c2ccc3c(c2)OCCc2sc(-c4ncnn4C(C)C)nc2-3)C1

Procedure:
The title compound was prepared by a similar procedure to 2-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-acetamide using methyl 2-bromoisobutyrate, cesium carbonate instead of potassium carbonate and DMF. The reaction was performed at 80° C. to give 2-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-2-methyl-propionic acid methyl ester isolated as a white solid (147 mg, 60%). LCMS: RT=3.16 min, [M+H]+=468
Reaction SMILES: B(Br)(Br)Br.FC(F)(F)C(O)=O.[CH2:12]([N:14]([CH2:41][CH3:42])[C:15]([C:17]1[CH:18]=[CH:19][C:20]2[C:21](=[C:33]3[CH2:39][CH:38]4[NH:40][CH:35]([CH2:36][CH2:37]4)[CH2:34]3)[C:22]3[C:27]([O:28][C:29]=2[CH:30]=1)=[CH:26][C:25]([O:31]C)=[CH:24][CH:23]=3)=[O:16])[CH3:13].[OH-].[NH4+]>ClCCl>[CH2:41]([N:14]([CH2:12][CH3:13])[C:15]([C:17]1[CH:18]=[CH:19][C:20]2[C:21](=[C:33]3[CH2:39][CH:38]4[NH:40][CH:35]([CH2:36][CH2:37]4)[CH2:34]3)[C:22]3[C:27]([O:28][C:29]=2[CH:30]=1)=[CH:26][C:25]([OH:31])=[CH:24][CH:23]=3)=[O:16])[CH3:42]
Reactant: CCN(CC)C(=O)c1ccc2c(c1)Oc1cc(OC)ccc1C2=C1CC2CCC(C1)N2
Agent: BrB(Br)Br
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC)C(=O)c1ccc2c(c1)Oc1cc(O)ccc1C2=C1CC2CCC(C1)N2
Temperature: 0 °C

Procedure:
A 1.0 M solution of boron tribromide in dichloromethane (2.14 mL, 2.14 mmol) was added to a solution of the trifluoroacetic acid salt of 9-(8-aza-bicyclo[3.2.1]oct-3-ylidene)-6-methoxy-9H-xanthene-3-carboxylic acid diethylamide (0.285 g, 0.535 mmol) in dichloromethane (10 mL) at 0° C. The resultant mixture was stirred at room temperature for 2 h. The mixture was cooled to 0° C., and treated with 10% aqueous ammonium hydroxide (˜20 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine and dried over sodium sulfate. The solvent was evaporated in vacuo, and the residues was dissolved in DMSO and applied to reverse phase C18 column for purification via HPLC, using a gradient of acetonitrile (10% to 90%) in water with trifluoroacetic acid (0.1%) as the eluant. Fractions containing the title compound were combined and further purified via reverse phase HPLC to give the purified title compound (0.035 g). MS: m/z 405.1 (MH+). 1H NMR (DMSO-d6): δ 1.0-1.2 (br m, 6H), 1.29 (d, 12H, J=8.1 Hz), 1.7-1.8 (br m, 2H), 2.8-3.0 (br m, 4H), 3.1-3.5 (br m, 4H), 3.99 (br s, 2H), 6.63-6.65 (m, 2H), 7.13 (d, 1H, J=7.9 Hz), 7.18-7.21 (m, 3H), 7.41 (d, 1H, J=7.9 Hz), 8.70 (br s, 1H), 9.01 br d, 1H) and 9.93 (br s 1H).
Reaction SMILES: [Cl-:1].[Cl-].[Cl-].[Cl-].[Zr+4:5].[CH2:6]1[CH2:10]O[CH2:8][CH2:7]1.[CH3:11][Si:12]1([CH:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17]2)[CH2:15][CH2:14][CH2:13]1.[Li]>ClCCl>[Cl-:1].[Cl-:1].[CH3:11][Si:12]1([C:7]2[CH:8]([Zr+2:5][CH:24]3[C:19]4[C:18](=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:17]=[C:16]3[Si:12]3([CH3:11])[CH2:13][CH2:14][CH2:15]3)[C:18]3[C:10]([CH:6]=2)=[CH:23][CH:24]=[CH:16][CH:17]=3)[CH2:15][CH2:14][CH2:13]1
Reactant: C1CCOC1
Reactant: [Zr+4]
Reactant: C[Si]1(C2C=Cc3ccccc32)CCC1
Agent: [Cl-]
Agent: [Li]
Solvent: ClCCl
Product: C[Si]1(C2=Cc3ccccc3C2[Zr+2]C2C([Si]3(C)CCC3)=Cc3ccccc32)CCC1
Reaction time: 0.5 h
Yield: 86.6 %

Procedure:
Under nitrogen atmosphere, 4.46 g (21.65 mmol) of lithium 1-(1-methyl-1-silacyclobutyl)indene and 4.08 g (10.81 mmol) of ZrCl4(THF)2, which was obtained by reacting ZrCl4 with THF, was placed in each flask respectively. 50 mL of dichloromethane was added to each flask with stirring for about 30 minutes to form suspension. The suspension of ZrCl4(THF)2 in the second flask was slowly added into the suspension of lithium 1-(1-methyl-1-silacyclobutyl)indene in the first flask, and then the remained solid in the second flask was washed with 10 mL of dichloromethane and added into the first flask. With repeating the washing and addition process for three times, the reaction mixture was stirred overnight. After completion of reaction, LiCl was filtered and removed from yellowish solution with 11G4 filter. The solvent was then evaporated from the filtrate under vacuum until solid powder is formed in the filtrate. The condensed filtrate was placed at −20° C. for about 24 hours for crystallization. The yellowish powder formed by crystallization was filtered, washed several times with hexane, and dried under vacuum overnight to obtain 5.25 g (yield: 86.6%) of pure bis((1-methyl-1-silacyclobutyl)indenyl)zirconium dichloride having the following 1H NMR (CDCl3, ppm) data: δ7.9-7.27 (m, 8H, Ar), 6.59 (d, 2H, 2-lndH), 6.35 (d, 2H, 3-lndH), 2.36-2.11 (m, 4H), 1.50-1.22 (m, 4H), 0.68 (s, 6H, 2CH3).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH2:6][O:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([O:24]CC2C=CC=CC=2)=[CH:20][CH:19]=1)[CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:3].C(O)(=O)C.C(O)C>[Pd].[H][H]>[CH3:1][N:2]([CH2:4][CH2:5][CH2:6][O:7][CH:8]([C:18]1[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=1)[CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH3:3]
Reactant: CN(C)CCCOC(CCCc1ccccc1)c1ccc(OCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CN(C)CCCOC(CCCc1ccccc1)c1ccc(O)cc1

Procedure:
A mixture of 1.5 g of 1-[3-(N,N-dimethylamino)propoxy]-1-(p-benzyloxyphenyl)-4-phenylbutane obtained in Example 6, 0.5 g of 10% palladium on charcoal (50% wet reagent), 1 g of acetic acid and 50 ml of ethanol was vigorously stirred in hydrogen atmosphere at room temperature until the theoretical amount of hydrogen was consumed. The reaction mixture was poured into water, made alkaline with aqueous ammonium hydroxide and extracted. After the catalyst was filtered off, the organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 1-[3-(N,N-dimethylamino)propoxy]-1-(p-hydroxyphenyl)-4-phenylbutane. M.P., 91.5°-94.5° C. (oxalate).
Reaction SMILES: C([O:5][C:6](=[O:30])[CH2:7][N:8]1[C:12]2[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=2[N:10]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C:9]1=[O:29])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]2[N:10]([S:18]([C:21]3[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=3)(=[O:20])=[O:19])[C:9](=[O:29])[N:8]([CH2:7][C:6]([OH:30])=[O:5])[C:12]=2[CH:13]=1
Reactant: COc1ccc(S(=O)(=O)n2c(=O)n(CC(=O)OC(C)(C)C)c3cc(Cl)ccc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)n2c(=O)n(CC(=O)O)c3cc(Cl)ccc32)cc1
Temperature: 25 °C

Procedure:
1.10 g (2.43 mmol) of tert-butyl[6-chloro-3-(4-methoxybenzenesulfonyl)-2-oxo-2,3-dihydrobenzimidazol-1-yl]acetate (XIIg) were dissolved in dichloromethane (40 ml) and, while stirring at room temperature, trifluoroacetic acid (20 ml) was added. The reaction solution was stirred for 2 h and then the solvent and excess trifluoroacetic acid were removed in vacuo. The residue was taken up again in toluene, concentrated in vacuo and then dried in vacuo. Yield: 0.82 g (95%) of white solid
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)[CH:5]=[CH:6][CH:7]=1.C([Li])(C)(C)C.[Br:18][CH2:19][CH2:20][CH2:21][CH2:22]Br>>[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][C:2]1[CH:3]=[C:4]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: BrCCCCBr
Reactant: Brc1cccc(C2OCCO2)c1
Agent: [Li]C(C)(C)C
Product: BrCCCCc1cccc(C2OCCO2)c1
Temperature: -20 °C
Reaction time: 0.75 h

Procedure:
To a clean and dry 2000 ml round bottom flask equipped with a 500 ml addition funnel, low temperature thermometer and magnetic stir bar was transferred anhydrous tetrahydrofuran (800.0 ml) under nitrogen. 2-(3-bromophenyl)-1,3-dioxolane (33.0 ml, 0.2183 mol) was added to this flask by syringe. The reaction vessel was placed into a dry ice/acetone bath until a temperature of <−65° was achieved. The reaction mixture was then allowed to stir for 45 minutes at a stirring speed of 550 rpm in order to verify the integrity of the stirring apparatus at this temperature. Tert-butyllithium solution (257.0 ml, 0.4690 mol) was transferred to the addition funnel by cannula, then added drop wise to the reaction never allowing the temperature to rise above −65° C. Following addition, the reaction was allowed to stir for a period of 30 minutes. The vessel was then removed from the dry ice/acetone bath and allowed to warm to a temperature of −20° C. The vessel was then again placed into the dry ice/acetone bath until a temperature of <−65° was achieved. 1,4-dibromobutane (103.5 ml, 0.8740 mol) was added to the reaction dropwise via syringe, maintaining the current temperature. The reaction was allowed to stir for 30 minutes at this temperature following addition. The reaction was slowly warmed to room temperature over the following 12 hours. After warming, the reaction was quenched by the addition of isopropanol (20.0 ml) via syringe.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][O:15][C:16]1[C:21]([C:22]2[CH:31]=[CH:30][CH:29]=[C:28]3[C:23]=2[CH2:24][CH2:25][NH:26][CH:27]3[CH3:32])=[CH:20][CH:19]=[C:18]([O:33][CH3:34])[N:17]=1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:26]3[CH2:25][CH2:24][C:23]4[C:28](=[CH:29][CH:30]=[CH:31][C:22]=4[C:21]4[C:16]([O:15][CH3:14])=[N:17][C:18]([O:33][CH3:34])=[CH:19][CH:20]=4)[CH:27]3[CH3:32])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: COc1ccc(-c2cccc3c2CCNC3C)c(OC)n1
Product: COc1ccc(-c2cccc3c2CCN(C(=O)c2cc4ncc(Cl)cn4n2)C3C)c(OC)n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-(2,6-Dimethoxy-pyridin-3-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[O:11][CH3:12].[CH3:13][N:14]([CH:16]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C:18]1=[O:23])[CH3:15].[Cl-:30]>O1CCCC1>[ClH:30].[CH3:12][O:11][C:4]1[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=1[C:18]1([OH:23])[CH2:19][CH2:20][CH2:21][CH2:22][CH:17]1[CH:16]([N:14]([CH3:13])[CH3:15])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COc1ccc(OC)c(Br)c1
Reactant: CN(C)C(c1ccccc1)C1CCCCC1=O
Reactant: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1ccc(OC)c(C2(O)CCCCC2C(c2ccccc2)N(C)C)c1
Product: Cl
Temperature: 65 °C
Reaction time: 1.5 h
Yield: 84.2 %

Procedure:
0.38 g (15.6 mmole) of magnesium turnings was stirred in 15 ml of tetrahydrofuran of analysis purity. 3.39 g (15.6 mmole) of 1-bromo-2,5-dimethoxybenzene dissolved in 15 ml of tetrahydrofuran were added dropwise so that the reaction mixture boiled gently. After completion of the addition the reaction mixture was stirred for a further 1.5 hours at 65° C. 3.0 g (13.0 mmole) of the 2-(dimethylaminophenylmethyl) cyclohexanone prepared according to Example 1 were dissolved in 15 ml of tetrahydro-furan, added dropwise to the Grignard reagent while cooling in an ice bath, and stirred for 15 hours at RT. The reaction solution was worked up by adding 30 ml of saturated anmonium chloride solution while cooling in an ice bath, and was extracted three times at RT with in each case 60 ml of ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 5.17 g of crude base (108% of theory) were obtained. 4.43 g of 1-(2,5-dimethoxy-phenyl)-2-(dimethylaminophenylmethyl)cyclohexanol, hydrochloride (84.2% of theory) with a melting point above 240° C. were obtained from the crude base according to the procedure described in Example 1 (3rd stage) with chlorotri-methylsilane/water in 2-butanone.
Reaction SMILES: [Mg].C(O[CH2:5][CH3:6])C.[CH:7]1[CH:12]=[CH:11][C:10]([N:13]([C:20]2[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:9][CH:8]=1.[CH2:27]([Si:31](Cl)(Cl)Cl)[CH2:28][CH2:29][CH3:30]>O>[C:14]1([N:13]([C:6]2[CH:5]=[CH:25][CH:20]=[CH:21][CH:22]=2)[C:10]2[CH:9]=[CH:8][C:7]([C:30]([C:17]3[CH:18]=[CH:19][C:14]([N:13]([C:10]4[CH:9]=[CH:8][CH:7]=[CH:12][CH:11]=4)[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:15][CH:16]=3)([C:23]3[CH:24]=[CH:25][C:20]([N:13]([C:10]4[CH:11]=[CH:12][CH:7]=[CH:8][CH:9]=4)[C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)=[CH:21][CH:22]=3)[CH2:29][CH2:28][CH2:27][SiH3:31])=[CH:12][CH:11]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOCC
Reactant: Brc1ccc(N(c2ccccc2)c2ccccc2)cc1
Reactant: CCCC[Si](Cl)(Cl)Cl
Agent: [Mg]
Solvent: O
Product: [SiH3]CCCC(c1ccc(N(c2ccccc2)c2ccccc2)cc1)(c1ccc(N(c2ccccc2)c2ccccc2)cc1)c1ccc(N(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Yield: 68 %

Procedure:
0.6 g (24.9 mmol) of metallic magnesium was placed in a 200-ml four-necked flask equipped with a mechanical stirrer, a condenser, a nitrogen-inlet tube and a dropping funnel, and the inside atmosphere was replaced with nitrogen. 100 ml of diethyl ether was added and stirring was initiated. To this solution, 20 ml of a diethyl ether solution of 6.5 g (20 mmol) of 4-bromotriphenylamine was gradually added dropwise. When about 5 ml was added, mild reflux began. Under reflux conditions, the remainder of the diethyl ether solution was added. After completion of the addition, reflux was continued for 1 more hour. The Gringnard solution thus obtained was cooled to room temperature, and then 20 ml of a diethyl ether solution of 1.3 g (6.6 mmol) of n-butyltrichlorosilane was gradually added dropwise under reflux conditions. After completion of the addition, the reaction mixture was stirred under reflux conditions for 2 hours. Then, the mixture was cooled on ice water bath, and ice cooling conditions, 50 ml of water was added for hydrolysis. The ether layer was extracted and washed with a saturated aqueous solution of sodium hydrogen carbonate and then with two portions of water, followed by drying with anhydrous sodium sulfate. After drying, the diethyl ether was distilled off to yield a white solid, which was then recrystallized with n-hexane/toluene (1/1) to yield 3.7 g of the desired product (yield 68%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][C:7]=1[CH2:14][N:15]([CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:16]1[S:17][CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:20]=1)[CH:2]([CH3:4])[CH3:3].CO.O1CCCC1.[BH4-].[Na+]>C(OCC)(=O)C>[CH2:1]([O:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][OH:11])=[CH:8][C:7]=1[CH2:14][N:15]([CH2:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:16]1[S:17][CH:18]=[C:19]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:20]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)COc1ccc(C=O)cc1CN(CCc1ccccc1)c1nc(-c2ccccc2)cs1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)COc1ccc(CO)cc1CN(CCc1ccccc1)c1nc(-c2ccccc2)cs1
Temperature: 0 °C
Yield: 89.1 %

Procedure:
To a mixture of 4-isobutoxy-3-{[(2-phenylethyl)(4-phenyl-1,3-thiazol-2-yl)amino]methyl}benzaldehyde (1.43 g, 3.04 mmol), methanol (5 mL) and tetrahydrofuran (10 mL) was added sodium borohydride (58 mg, 1.52 mmol) under stirring at 0° C., and the mixture was stirred at the same temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-1/1) to give the title compound (1.28 g, yield 88%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH3:11][NH:12][CH3:13].N1C=CC=CC=1.Cl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:12]([CH3:13])[CH3:11])=[O:7])=[CH:4][CH:3]=1
Reactant: CNC
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CN(C)C(=O)c1ccc(Cl)cc1

Procedure:
The procedure of Example 13 is followed, but the endcapper is 4-chloro-N,N-dimethylbenzamide (0.20 g, 1.09 mmol) to yield the amido-functionalized macromonomer. 4-Chloro-N,N-dimethylbenzamide is prepared by reacting 4-chlorobenzoyl chloride with dimethylamine in toluene with some pyridine (1 mol equivalent per acid chloride) to trap the HCl that is evolved. After aqueous extraction of the pyridinium salt and any excess starting materials, the product is crystallized from the toluene solution.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([C:12]([NH2:14])=[O:13])[CH2:11][CH2:10]1)#[CH:2].[Cl:15][C:16]1[N:21]=[C:20](Cl)[C:19]([Cl:23])=[CH:18][N:17]=1.CCN(CC)CC>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:15][C:16]1[N:21]=[C:20]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:9]2([C:12]([NH2:14])=[O:13])[CH2:11][CH2:10]2)[C:19]([Cl:23])=[CH:18][N:17]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: C#Cc1ccccc1C1(C(N)=O)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: NC(=O)C1(c2ccccc2C#Cc2nc(Cl)ncc2Cl)CC1
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
PdCl2(PPh3)2 (16 mg, 0.023 mmol) was added to a stirred solution of 1-(2-ethynylphenyl)cyclopropanecarboxamide (K6) (0.420 g, 2.26 mmol), 2,4,5-trichloropyrimidine (0.338 mL, 2.94 mmol), Et3N (1.26 mL, 9.07 mmol) and copper(I) iodide (8.6 mg, 0.045 mmol) in 1,4-dioxane (4.5 mL). The resulting mixture was stirred at 60° C. for 2.5 hours under a nitrogen atmosphere before being diluted with petroleum benzine 40-60° C. (25 mL). The resultant precipitate was filtered, dried, washed with water (50 mL) and dried to give the title compound A13 as light coloured tan solid (0.570 g, 75%); 1H NMR (300 MHz, d6-DMSO) δ 9.01 (s, 1H), 7.72 (d, J=7.1 Hz, 1H), 7.41-7.57 (m, 3H), 6.97 (brs, 1H), 6.20 (brs, 1H), 1.53 (dq, J=4.0 Hz, 2H) 1.06 (dq, J=3.7 Hz, 2H). LCMS-B: rt 6.593 min; m/z 332 [M+H]+.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:23]=[CH:22][C:7]2[CH:8]=[C:9]([C:11]([NH:13][C@@H:14]3[CH:19]4[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]4)[CH2:15]3)=[O:12])[S:10][C:6]=2[CH:5]=1.C(N(CC)CC)C.[N:31]([CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[C:32]=[O:33]>C1COCC1>[ClH:1].[N:16]12[CH2:21][CH2:20][CH:19]([CH2:18][CH2:17]1)[C@@H:14]([NH:13][C:11]([C:9]1[S:10][C:6]3[CH:5]=[C:4]([NH:3][C:32]([NH:31][CH2:34][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[O:33])[CH:23]=[CH:22][C:7]=3[CH:8]=1)=[O:12])[CH2:15]2
Reactant: O=C=NCCc1ccccc1
Reactant: Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NCCc1ccccc1)Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Reaction time: 18 h

Procedure:
A solution of 40 mg (0.11 mmol) of 6-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide dihydrochloride in 2 ml of THF is mixed with 29.8 μl (0.21 mmol) of triethylamine and 31.5 mg (0.21 mmol) of (2-isocyanatoethyl)benzene. After 18 h at room temperature, the product is purified by preparative HPLC. The concentrated product fraction is dissolved in a mixture of acetonitrile and 1 N hydrochloric acid (5:1), again concentrated and dried under high vacuum. 32 mg (61.8% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[NH:4][N:3]=1.Br[C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:16]=1[C:17]([OH:19])=[O:18]>>[C:17]([C:16]1[C:20]([O:24][CH3:25])=[CH:21][CH:22]=[CH:23][C:15]=1[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=2)[C:2]([CH3:1])=[N:3]1)([OH:19])=[O:18]
Reactant: Cc1n[nH]c2cc([N+](=O)[O-])ccc12
Reactant: COc1cccc(Br)c1C(=O)O
Product: COc1cccc(-n2nc(C)c3ccc([N+](=O)[O-])cc32)c1C(=O)O
Yield: 75.9 %

Procedure:
3-Methyl-6-nitroindazole (5.31 g) and 6.93 g of 2-bromo-6-methoxybenzoic acid were subjected to reaction in the same manner as in Example 11 to obtain 1-(2-carboxy-3-methoxyphenyl)-3-methyl-6-nitroindazole (yield: 75.9%). The nitro group of the compound was reduced to give 6-amino-(2-carboxy-3-methoxyphenyl)-3-methylindazole (yield: 100%), which was then cyclized to obtain 1.83 g (28.9%) of 5-amino-7-methoxy-2-methyl-6H-pyrazolo[4,5,1-d,e]acridin-6-one.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH2:14].[CH2:15]([N:19]=[C:20]=[O:21])[CH2:16][CH2:17][CH3:18]>CCOCC>[CH2:15]([NH:19][C:20]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])=[O:21])[CH2:16][CH2:17][CH3:18]
Reactant: NCCCCCCCCCCCCN
Reactant: CCCCN=C=O
Solvent: CCOCC
Product: CCCCNC(=O)NCCCCCCCCCCCCN

Procedure:
22 grams (.110 mole) of 1,12-diaminododecane in 300 cc ether was reacted with 5.0 g (0.0505 mole) Butyl isocyanate, as in Example 2. The precipitate is filtered, washed, and recrystallized from 250 cc alcohol containing 50 cc water. Recovered 7.8 grams. Chilled mother liquor, thereby recovering a second batch of crystals which combined with the first precipitate to give a total of 12.1 grams having a melting point of 97°C.