Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[C:13](=[O:21])[N:12]([CH2:22][C:23]([O:25]CC)=[O:24])[C:11]2=[O:28])=[C:5]([F:29])[CH:4]=1.S(=O)(=O)(O)O>C(O)(=O)C>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[C:13](=[O:21])[N:12]([CH2:22][C:23]([OH:25])=[O:24])[C:11]2=[O:28])=[C:5]([F:29])[CH:4]=1
Reactant: CCOC(=O)Cn1c(=O)c2cc(Cl)ccc2n(Cc2ccc(Br)cc2F)c1=O
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: O=C(O)Cn1c(=O)c2cc(Cl)ccc2n(Cc2ccc(Br)cc2F)c1=O
Temperature: 0 °C
Yield: 88.6 %

Procedure:
Into 280 ml of concentrated hydrochloric acid and 140 ml of acetic acid were suspended 18.0 g of ethyl 1-(4-bromo-2-fluorophenyl)methyl-6-chloro-1,4-dihydro-2,4-dioxo-3(2H)quinazolineacetate, and, after added 1 ml of concentrated sulfuric acid, the mixture was refluxed for 3 hours. After cooling, the reaction liquor was poured into 600 ml of ice water and the deposits were collected by filtration. They were recrystallized from ethanol to obtain 15.0 g of title compound. m.p. 189° C.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](O)=[O:16].C(Cl)(=O)C(Cl)=O.C(N(CC)C(C)C)(C)C.[CH3:37][CH2:38][O:39][C:40]([N:42]1[C:46]([NH2:47])=[C:45]2[CH2:48][N:49]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[C:50]([CH3:52])([CH3:51])[C:44]2=[N:43]1)=[O:41]>ClCCl.O1CCCC1.CN(C)C=O>[CH3:37][CH2:38][O:39][C:40]([N:42]1[C:46]([NH:47][C:15](=[O:16])[C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[CH2:12][N:3]2[C:2](=[O:1])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]2=[O:11])=[C:45]2[CH2:48][N:49]([C:53]([O:55][C:56]([CH3:58])([CH3:57])[CH3:59])=[O:54])[C:50]([CH3:51])([CH3:52])[C:44]2=[N:43]1)=[O:41]
Reactant: O=C(O)c1ccccc1CN1C(=O)c2ccccc2C1=O
Reactant: CCOC(=O)n1nc2c(c1N)CN(C(=O)OC(C)(C)C)C2(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)n1nc2c(c1NC(=O)c1ccccc1CN1C(=O)c3ccccc3C1=O)CN(C(=O)OC(C)(C)C)C2(C)C
Temperature: 0 °C
Yield: 63.8 %

Procedure:
To a suspension of 2-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-benzoic acid (1.35 g, 4.8 mmol) in dry dichloromethane (30 mL), at 0° C., under stirring, was added oxalyl chloride (2.1 mL, 24 mmol) and dry N,N-dimethylformamide (35 microL). The mixture was allowed to warm to room temperature, stirred for 1.5 hours then evaporated to dryness. The residue was diluted with dry toluene and evaporated again. The crude acyl chloride thus obtained (yellow solid) was dissolved in dry tetrahydrofuran (20 mL) and treated with N,N-diisopropylethylamine (2.5 mL, 15 mmol) and with a solution of 3-amino-6,6-dimethyl-4H,6H-pyrrolo[3,4-c]pyrazole-2,5-dicarboxylic acid 5-tert-butyl ester 2-ethyl ester (1.3 g, 4 mmol) in 15 mL of dry tetrahydrofuran. The mixture was stirred at room temperature for 2 days then evaporated to dryness. The residue was dissolved in dichloromethane, washed with 1N HCl, water, saturated solution of NaHCO3, brine, dried over sodium sulfate and evaporated to dryness. The crude was purified by flash chromatography on silica gel using dichloromethane/methanol 98.5:1.5 as the eluant affording the title compound as white solid (1.5 g).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([C:8](=[O:23])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18]COCC)=[CH:14][CH:13]=2)=[O:11])[S:4][N:3]=1>C(O)(C)C.O1CCCC1>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([C:8](=[O:23])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[O:11])[S:4][N:3]=1
Reactant: CCOCOc1ccc(C(=O)CC(=O)c2snc(Cl)c2Cl)cc1
Solvent: C1CCOC1
Solvent: CC(C)O
Product: O=C(CC(=O)c1snc(Cl)c1Cl)c1ccc(O)cc1
Reaction time: 12 h
Yield: 88.8 %

Procedure:
To a solution of 1-(3,4-dichloro-5-isothiazolyl)-3-(4-ethoxymethoxyphenyl)-1,3-propanedione (1.20 g) in a mixture of isopropanol (20 ml) and tetrahydrofuran (20 ml) concentrated hydrochloric acid (3.40 g) was added at room temperature and the mixture was stirred for 12 hours. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent hexane:ethyl acetate=50:50) to obtain 1-(3,4-dichloro-5-isothiazolyl)-3-(4-hydroxyphenyl)-1,3-propanedione (0.90 g). mp 224-227° C.
Reaction SMILES: [OH:1][C@H: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.[H-].[Na+].Cl[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([F:27])[CH:25]=2)[CH:20]=[C:19]([Cl:28])[N:18]=1>C1COCC1.CCOC(C)=O>[Cl:28][C:19]1[N:18]=[C:17]([O:1][C@H:2]2[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]2)[C:26]2[C:21]([CH:20]=1)=[CH:22][CH:23]=[C:24]([F:27])[CH:25]=2
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Reactant: Fc1ccc2cc(Cl)nc(Cl)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2nc(Cl)cc3ccc(F)cc23)C1
Temperature: 25 °C
Reaction time: 10 h
Yield: 71.9 %

Procedure:
To a solution of (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (1.56 g, 8.3 mmol) in THF (20 mL) was added NaH (0.33 g, 8.3 mmol) under nitrogen at 0° C. The mixture was warmed to RT over a 30 minute period and 1,3-dichloro-7-fluoroisoquinoline (0.9 g, 4.17 mmol) was added. The resulting mixture was stirred for 10 hours at RT. The mixture was subsequently diluted with EtOAc (100 mL), quenched with saturated aqueous NH4Cl (100 mL), and extracted with EtOAc (3×100 mL). The combined organic layers were dried over Na2SO4 and concentrated. The crude product was purified by column chromatography eluting with petroleum ether and ethyl acetate (PE/EtOAc=50:1-10:1 gradient) to give the title compound (1.1 g, 72%). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.00-7.98 (m, 1H), 7.82-7.80 (m, 2H), 7.62 (s, 1H), 5.67-5.63 (d, J=16 Hz, 1H), 3.69-3.66 (m, 1H), 3.53-3.487 (m, 3H), 2.30-2.22 (m, 2H), 1.41-1.39 (d, J=10.8 Hz, 2H).
Reaction SMILES: [O:1]=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[S:5][C:4]2[CH:13]=[C:14]([C:17]([OH:19])=[O:18])[CH:15]=[CH:16][C:3]1=2.[BH4-].[Na+]>C(=O)(O)[O-].[Na+]>[OH:1][CH:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[S:5][C:4]2[CH:13]=[C:14]([C:17]([OH:19])=[O:18])[CH:15]=[CH:16][C:3]1=2
Reactant: O=C(O)c1ccc2c(c1)Sc1ccccc1CC2=O
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Product: O=C(O)c1ccc2c(c1)Sc1ccccc1CC2O
Reaction time: 0.5 h
Yield: 96.2 %

Procedure:
16.3 G. 10,11-dihydro-11-oxodibenzo-[b,f]thiepin-3-carboxylic acid is stirred in aqueous sodium bicarbonate solution and 5 g. sodium borohydride is added in portions. The foaming mixture is stirred for an additional half hour. The solution is extracted with ether and the aqueous layer acidified with hydrochloric acid and the solid filtered and dried to yield 15.8 g. of the desired yellow solid (96.2% yield), m.p. 202°-204° C.
Reaction SMILES: [S:1]([OH:5])(O)(=O)=[O:2].[C:6]1([C:13]2[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=2)[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1>S(=O)(=O)(O)O>[NH2:10][C:9]1[CH:8]=[CH:7][C:6]2[C:13]3[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][C:14]=3[S:1](=[O:5])(=[O:2])[C:12]=2[CH:11]=1
Reactant: O=S(=O)(O)O
Reactant: Nc1ccc(-c2ccc(N)cc2)cc1
Product: Nc1ccc2c(c1)S(=O)(=O)c1cc(N)ccc1-2
Temperature: 70 °C
Yield: 86.6 %

Procedure:
The title compound was prepared as described in U.S. Pat. Nos. 2,590,632 and 2,620,343. At 10° C., 30 g of benzidine sulfate was added, in portions, to 100 ml of fuming sulfuric acid. After the addition, the reaction was maintained at 70° C. for 18 hours, cooled and poured into 250 g of cracked ice. The beige solid was collected, washed with water and saturated sodium bicarbonate yielding a yellow solid. The yellow solid was stirred with bicarbonate solution 2×, collected, washed with large volumes of water, and dried in vacuo to give 22.66 g (87%) of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:21][CH2:22]CS([O-])(=O)=O)([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([CH3:20])[CH:14]=2)[CH2:9]1)=[O:7].O1CCCC1.Cl.[C:41]1([C:47]2([C:53]([NH2:55])=[O:54])[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(=O)([O-])[O-].[K+].[K+]>CO.ClCCl.C(OCC)(=O)C.O>[CH3:20][C:15]1[CH:14]=[C:13]([C:10]2([CH2:21][CH2:22][N:50]3[CH2:49][CH2:48][C:47]([C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)([C:53]([NH2:55])=[O:54])[CH2:52][CH2:51]3)[CH2:11][CH2:12][N:8]([C:6](=[O:7])[C:5]3[CH:28]=[C:29]([O:33][CH3:34])[C:30]([O:31][CH3:32])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:9]2)[CH:18]=[CH:17][C:16]=1[CH3:19]
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(C)c(C)c3)C2)cc(OC)c1OC
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3ccc(C)c(C)c3)C2)cc(OC)c1OC
Reaction time: 80 h

Procedure:
Combine 2-[1-(3,4,5-trimethoxy-benzoyl)-3-(3,4-dimethyl-phenyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (3.0 g, 6.1 mmol) and tetrahydrofuran (45 mL)/water (15 mL). Add 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride (2.2 g, 9.14 mmol) and potassium carbonate (2.6 g, 18.8 mmol). Heat to reflux. After 80 hours, evaporate the reaction mixture in vacuo to remove most of the tetrahydrofuran and then extract with dichloromethane. Separate the organic layer and extract with water. Dry the organic layer over MgSO4, filter, and concentrate in vacuo to give a residue. Chromatograph the residue on silica gel eluting sequentially with ethyl acetate, 3% methanol/dichloromethane, 6% methanol/dichloromethane, and then 10% methanol/dichloromethane to give the title compound: Rf =0.44 (silica gel, 10% methanol/dichloromethane).
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[OH-].[K+].[CH3:11][CH:12]([CH3:16])[CH2:13][CH2:14]Br>C(O)C>[CH3:11][CH:12]([CH3:16])[CH2:13][CH2:14][O:2][C:1]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[O:4][CH2:14][CH2:13][CH:12]([CH3:16])[CH3:11]
Reactant: CC(C)CCBr
Reactant: Oc1ccccc1O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)CCOc1ccccc1OCCC(C)C
Reaction time: 1 h
Yield: 61 %

Procedure:
A solution of catechol (27.53 g, 0.25 mol) in 100 ml of ethanol was slowly added to a stirred solution of KOH (35.07 g, 0.63 mol) in 350 ml of ethanol at room temperature. The reaction mixture was stirred for 1 h. A solution of 3-methylbutyl bromide (113.25 g, 0.75 mol) in 50 ml of ethanol was added dropwise. The reaction mixture was refluxed overnight. Ethanol was removed by rotary evaporation and the reaction mixture was partitioned between ethyl acetate and sodium carbonate solution. After drying over sodium sulfate, the product was obtained by reduced pressure distillation to get 38.2 g 1,2-bis(3′-methylbutoxy)benzene (61%). NMR (ppm) (400 MHz, CDCl3): δ 6.914 (s, 4H), 4.059-4.025 (t, 4H), 1.895-1.861 (m, 2H), 1.757-1.707 (m, 4H), 0.993-0.976 (m, 12H).
Reaction SMILES: Br[CH:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[F:17][C:18]1[CH:19]=[CH:20][C:21]([OH:24])=[N:22][CH:23]=1>C(OCC)(=O)C>[F:17][C:18]1[CH:19]=[CH:20][C:21](=[O:24])[N:22]([CH:2]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3](=[O:4])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:23]=1
Reactant: O=C(c1ccccc1)C(Br)c1ccccc1
Reactant: Oc1ccc(F)cn1
Solvent: CCOC(C)=O
Product: O=C(c1ccccc1)C(c1ccccc1)n1cc(F)ccc1=O
Temperature: 120 °C

Procedure:
1.2 g (4.36 mmol) of 2-bromo-1,2-diphenylethanone and 740 mg (6.54 mmol) of 5-fluoro-2-hydroxypyridine were intimately ground in a mortar, and the mixture was subsequently heated at 120° C. for 2 hours. The still hot, oily mass was dissolved in ethyl acetate. Cooling resulted in the 5-fluoro-1-(2-oxo-1,2-diphenylethyl)-1H-pyridin-2-one in crystalline form, 1.01 g (75%), which was immediately dissolved in 15 ml of methanol. After addition of 340 mg (9.03 mmol) of sodium borohydride, the mixture was left at room temperature for one hour and then diluted with water. The resulting mass of crystals was filtered off with suction. The product contains the diastereoisomeric pyrid-2-one alcohols in the ratio of about 1:2 and was not fractionated further.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]#[N:19])[CH:16]=2)[NH:11][N:10]=1.[N:20]([Sn](CCCC)(CCCC)CCCC)=[N+:21]=[N-:22]>C1(C)C=CC=CC=1>[N:19]1[NH:20][N:21]=[N:22][C:18]=1[C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: COc1ccccc1-c1n[nH]c2ccc(C#N)cc12
Solvent: Cc1ccccc1
Product: COc1ccccc1-c1n[nH]c2ccc(-c3nn[nH]n3)cc12
Temperature: 0 °C

Procedure:
To a solution of 3-(2-methoxyphenyl)-1H-indazole-5-carbonitrile in toluene (20 mL) was added azidotributyl tin (0.716 g, 0.591 mL, 2.156 mmol). The reaction mixture was heated to reflux temperature for 18 hours. The solvent was removed under reduced pressure with no heat. The resulting oil was dissolved in tetrahydrofuran (2 mL) and toluene was added (20 mL). Hydrogen chloride was bubbled through the solution for 15 min, which resulted in the precipitation of a white solid. The product was collected by filtration after cooling to 0° C. and was washed with 5 mL portions of toluene. The impure solid was dissolved in 5 mL of aqueous sodium hydroxide (2.0 N) and the aqueous phase was washed with ethyl acetate. The product was precipitated out of the aqueous phase by bubbling hydrogen chloride gas. The solid was collected by filtration and washed with small portions of water. The product was isolated as an off-white solid after drying in a vacuum oven (0.110 g, 0.377 mmol, 20% over 2 steps): 1H NMR (DMSO-d6) δ 13.5 (br s, 1H), 8.4 (s, 1H), 8.0 (d, 1H), 7.7 (d, 1H), 7.5 (d, 1H), 7.4 (t, 1H), 7.2 (d, 1H), 7.1 (t, 1H), 3.8 (s, 3H); ES-MS (m/z) 293 [M+1]+.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[C:12]([CH3:23])=[N:11][C:10]=2[OH:24])[CH:5]=[CH:4][CH:3]=1.[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([O-])([O-])=O.[Na+].[Na+].O>CCO.CCOC(C)=O.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.C(COC)OC>[CH3:20][O:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][C:15]=1[O:21][CH3:22])[C:12]([CH3:23])=[N:11][C:10]([OH:24])=[C:9]2[CH2:8][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:7]=1
Reactant: OB(O)c1ccccc1
Reactant: COc1cc2c(C)nc(O)c(Cc3cccc(Br)n3)c2cc1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COc1cc2c(C)nc(O)c(Cc3cccc(-c4ccccc4)n3)c2cc1OC
Temperature: 25 °C

Procedure:
To a stirred solution of 4-((6-bromopyridin-2-yl)methyl)-6,7-dimethoxy-1-methylisoquinolin-3-ol CCH 34150 (59 mg, 152 μmol) in absolute EtOH (0.9 mL) in a 20 mL microwave vial equipped with a magnetic stirrer were added phenylboronic acid (18 mg, 148 μmol), Pd(PPh3)2Cl2 (10 mg, 14 μmol), a 2 N aq. Na2CO3 solution (0.30 mL, 0.60 mmol), H2O (2.7 mL) and dimethoxyethane (3.5 mL) and the resulting mixture was stirred at 140° C. for 25 min. After cooling to RT, the mixture was diluted with EtOAc (30 mL) and the organic solution was filtered through a celite plug, then washed with brine (10 mL). The organic layer was isolated and the celite plug was then further washed with CH2Cl2 (50 mL) and the resulting organic layer was washed with brine (20 mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 94:6) provided 32 mg of 6,7-dimethoxy-1-methyl-4-((6-phenylpyridin-2-yl)methyl)isoquinolin-3-ol. This free base was dissolved in MeOH (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.49 M HCl solution in MeOH (0.5 mL). The reaction mixture was stirred for 5 min at RT then concentrated at 40° C. under vacuum to afford 6,7-dimethoxy-1-methyl-4-((6-phenylpyridin-2-yl)methyl)isoquinolin-3-ol dihydrochloride 12 as a pale brown solid (38 mg, 56% yield).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11]C(=O)C2C=CC=CC=2)[O:8][C@@H:7]([N:20]2[CH:27]=[C:26]([Br:28])[C:24]([NH2:25])=[N:23][C:21]2=[O:22])[C@H:6]1[F:29])(=O)C>N>[F:29][C@H:6]1[C@H:5]([OH:4])[C@@H:9]([CH2:10][OH:11])[O:8][C@H:7]1[N:20]1[CH:27]=[C:26]([Br:28])[C:24]([NH2:25])=[N:23][C:21]1=[O:22]
Reactant: CC(=O)O[C@H]1[C@H](F)[C@H](n2cc(Br)c(N)nc2=O)O[C@@H]1COC(=O)c1ccccc1
Agent: N
Product: Nc1nc(=O)n([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2F)cc1Br
Reaction time: 24 h
Yield: 81.3 %

Procedure:
1-(3-O-Acetyl-5-O-benzoyl-2-deoxy-2-fluoro-β-D-arabinofuranosyl)-5-bromocytosine (1.0 g) is dissolved in saturated methanolic ammonia (100 ml) and the solution is left standing for 24 hours at room temperature. The solvent is removed in vacuo and the residue was crystallized from ethanol to give 560 mg of 1-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)-5-bromocytosine, m.p. 201°-202°.
Reaction SMILES: Br[C:2]1[C:3](=[O:32])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18])=[CH:8][CH:7]=[C:6]([O:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:24][CH2:23]1)[CH:5]=2.O1CCN(CCOC2C=C3C(C(C4C=CC=CC=4)=C(Br)C3=O)=CC=2)CC1.[N:59]1[C:68]2[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=2)[CH:62]=[C:61](B(O)O)[CH:60]=1>>[F:18][C:12]1[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=1[C:10]1[C:9]2[C:4](=[CH:5][C:6]([O:19][CH2:20][CH2:21][N:22]3[CH2:23][CH2:24][N:25]([S:28]([CH3:31])(=[O:29])=[O:30])[CH2:26][CH2:27]3)=[CH:7][CH:8]=2)[C:3](=[O:32])[C:2]=1[C:61]1[CH:60]=[N:59][C:68]2[C:63]([CH:62]=1)=[CH:64][CH:65]=[CH:66][CH:67]=2
Reactant: OB(O)c1cnc2ccccc2c1
Reactant: CS(=O)(=O)N1CCN(CCOc2ccc3c(c2)C(=O)C(Br)=C3c2ccc(F)cc2F)CC1
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Product: CS(=O)(=O)N1CCN(CCOc2ccc3c(c2)C(=O)C(c2cnc4ccccc4c2)=C3c2ccc(F)cc2F)CC1
Yield: 71 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 2-bromo-3-(2,4-difluorophenyl)-6-{2-[4-(methylsulfonyl)piperazin-1-yl]ethoxy}-1H-inden-1-one obtained in Step 1 of Example 116 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one and 3-quinolinylboronic acid instead of 3-pyridinylboronic acid to obtain the title compound (71%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]=[CH:21][N:20]=[C:19]3[C:15]=2[N:16]([CH2:32][C:33]#[C:34][CH3:35])[C:17](=[O:31])[N:18]3[C:23]2[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[CH2:32]([N:16]1[C:15]2[C:19](=[N:20][CH:21]=[N:22][C:14]=2[N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[N:18]([C:23]2[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[C:17]1=[O:31])[C:33]#[C:34][CH3:35]
Reactant: CC#CCn1c(=O)n(-c2ccc(OC)nc2)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Solvent: O=C(O)C(F)(F)F
Product: CC#CCn1c(=O)n(-c2ccc(OC)nc2)c2ncnc(N3CCNCC3)c21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
4-[7-(2-Butynyl)-9-(6-methoxy-pyridin-3-yl)-8-oxo-8,9-dihydro-7H-purin-6-yl]piperazi ne-1-carboxylic acid t-butyl ester (60 mg) was dissolved in trifluoroacetic acid, and this reaction solution was stirred at room temperature for five minutes, and then concentrated. The residue was purified by reverse phase high performance liquid chromatography to give the title compound (48.25 mg).
Reaction SMILES: [Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:46]=[CH:45][C:8]([CH2:9][NH:10][C:11]2[N:16]=[C:15]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])[N:14]=[C:13]([NH:23][C:24]3[CH:44]=[CH:43][C:27]([C:28]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][NH:35]C(=O)OC(C)(C)C)=[O:29])=[CH:26][CH:25]=3)[N:12]=2)=[CH:7][CH:6]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:35][CH2:34][CH2:33][CH2:32][CH2:31][NH:30][C:28](=[O:29])[C:27]1[CH:43]=[CH:44][C:24]([NH:23][C:13]2[N:12]=[C:11]([NH:10][CH2:9][C:8]3[CH:45]=[CH:46][C:5]([O:4][CH2:3][CH2:2][Br:1])=[CH:6][CH:7]=3)[N:16]=[C:15]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])[N:14]=2)=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)NCCCCNC(=O)c1ccc(Nc2nc(NCc3ccc(OCCBr)cc3)nc(OCC(F)(F)F)n2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCCCNC(=O)c1ccc(Nc2nc(NCc3ccc(OCCBr)cc3)nc(OCC(F)(F)F)n2)cc1

Procedure:
Tert-butyl (4-(4-((4-((4-(2-bromoethoxy)benzyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzamido)butyl)carbamate (3.0 g, 4.21 mmol) was stirred in TFA/DCM (1:1) solution (20 mL) for 1 h. The solution was concentrated under vacuum to give N-(4-aminobutyl)-4-((4-((4-(2-bromoethoxy)benzyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzamide which was carried to the next step without purification.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][C:15]3[NH:19][C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[N:16]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)C=O.[H-].[Na+].Cl[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1>O>[F:39][C:36]1[CH:37]=[CH:38][C:33]([CH2:32][N:19]2[C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=[C:15]2[CH2:14][CH:11]2[CH2:10][CH2:9][N:8]([CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:13][CH2:12]2)=[CH:34][CH:35]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: c1ccc(CN2CCC(Cc3nc4ccccc4[nH]3)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(Cn2c(CC3CCN(Cc4ccccc4)CC3)nc3ccccc32)cc1
Reaction time: 1 h
Yield: 90 %

Procedure:
To a stirred mixture of 55 parts of 2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-benzimidazole and 450 parts of N,N-dimethylformamide were added 10.6 parts of a sodium hydride dispersion 50% and stirring was continued for 1 hour. Then there were added dropwise 26 parts of 1-(chloromethyl)-4-fluorobenzene (slightly exothermic reaction). Upon completion, stirring was continued overnight at room temperature. Water was added and the product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The solid residue was stirred in 1,1'-oxybisethane. The product was filtered off and dried, yielding 67.6 parts (90%) of 1-[(4-fluorophenyl)methyl]-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-benzimidazole; mp. 127.5° C. (34).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[N:7][C:8]#[N:9].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>C(#N)C>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[N:7][C:8]#[N:9])[CH3:22]
Reactant: N#CN=C1CCCCN1
Reactant: CCOC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CN1CCCCC1=NC#N
Temperature: 85 °C
Yield: 98.4 %

Procedure:
Piperidin-2-ylidene-cyanamide (C) (9.67 g, 78.5 mmol) was dissolved in acetonitrile (150 mL) under a low heat. Potassium carbonate (13.0 g, 94.2 mmol, 1.2 eq.) and Ethyl chloroacetate (11.7 mL, 109.9 mmol, 1.4 eq.) were then added thereto and the resulting suspension was heated for 16 hours at 85° C. A further amount of ethyl chloroacetate (1.67 mL, 15.7 mmol, 0.2 eq.) was then added. The reaction mixture was heated under reflux for 6 hours. The cooled suspension was then filtered and the solid residue was washed with DCM. The filtrate was reduced under vacuum and, after column chromatographic purification (SiO2, heptane/EtOAc 2:3), 16.16 g (98%) of the desired product (2-cyanoimino-piperidin-1-yl)-acetic acid ethyl ester (D) was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([CH3:11])[CH:10]=2)[CH:7]=1.[C:12]1([C:18]#[CH:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:11][C:9]1[CH:10]=[C:5]2[N:4]=[CH:3][C:2]([C:19]#[C:18][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:7][N:6]2[N:8]=1
Reactant: Cc1cc2ncc(Br)cn2n1
Reactant: C#Cc1ccccc1
Product: Cc1cc2ncc(C#Cc3ccccc3)cn2n1

Procedure:
The title compound, white solid, MS: m/e=234.1 (M+H+), can be prepared in accordance with the general method of example 1 from 6-bromo-2-methylpyrazolo[1,5-a]pyrimidine and phenylacetylene.