Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1([C:16]2[O:17][C:18]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:20]=2)[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1.S([O-])(O)(=O)=O.[K+]>C1(C)C=CC=CC=1>[C:21]1([C:19]2[N:20]=[C:16]([C:2]3[CH:3]([CH2:7][C:8]4[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=4)[CH2:4][CH2:5][CH:6]=3)[O:17][C:18]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COc1cccc(CC2CCCC2(O)c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1cccc(CC2CCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reaction time: 1 h
Yield: 104.4 %

Procedure:
To a solution of 1-hydroxy-1-(4,5-diphenyloxazol-2-yl)-2-(3-methoxybenzyl)cyclopentane (8.0 g) in toluene (160 ml) was added potassium hydrogensulfate (2.6 g), and the solution was stirred for 1 hour under reflux. After being cooled, the solution was washed with water, saturated sodium bicarbonate aqueous solution and brine and evaporated in vacuo. The oily residue was chromatographed on silica gel to afford a mixture (8.0 g) of 1-(4,5-diphenyloxazol-2-yl)-5-(3-methoxybenzyl)-cyclopentene and 1-(4,5-diphenyloxazol-2-yl)-2-(3-methoxybenzyl)cyclopentene.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:22])[C:5]2[N:6]=[CH:7][N:8]([C:20]=2[N:21]=1)[C@@H:9]1[O:18][C@H:15]([CH2:16][OH:17])[C@@H:12]([O:13][CH3:14])[C@@:10]1([CH3:19])[OH:11].[CH3:23]I>>[CH3:1][C:2]1[N:3]=[C:4]([NH:22][CH3:23])[C:5]2[N:6]=[CH:7][N:8]([C:20]=2[N:21]=1)[C@@H:9]1[O:18][C@H:15]([CH2:16][OH:17])[C@@H:12]([O:13][CH3:14])[C@@:10]1([CH3:19])[OH:11]
Reactant: CO[C@@H]1[C@@H](CO)O[C@@H](n2cnc3c(N)nc(C)nc32)[C@]1(C)O
Reactant: CI
Product: CNc1nc(C)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](OC)[C@@]1(C)O

Procedure:
Compound 63 was methylated by methyl iodide and then rearranged to give 2,N6,2',3'-O-tetramethyladenosine (Compound 64).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:26]([O:28]C)=O)=[N:4][C:5]([C:8]2[CH:9]=[C:10]3[N:16]=[C:15]([CH3:17])[N:14]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:11]3=[N:12][CH:13]=2)=[CH:6][CH:7]=1.[CH:30]([NH2:32])=O>>[CH3:17][C:15]1[N:14]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:24])([CH3:23])[CH3:25])[C:11]2=[N:12][CH:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]4[N:1]=[CH:30][NH:32][C:26](=[O:28])[C:3]=4[N:4]=3)[CH:9]=[C:10]2[N:16]=1
Reactant: COC(=O)c1nc(-c2cnc3c(c2)nc(C)n3COCC[Si](C)(C)C)ccc1N
Reactant: NC=O
Product: Cc1nc2cc(-c3ccc4nc[nH]c(=O)c4n3)cnc2n1COCC[Si](C)(C)C
Yield: 36 %

Procedure:
1.00 g of methyl 3-amino-6-[2-methyl-3-(2-trimethylsilanylethoxymethyl)-3H-imidazo[4,5-b]pyridin-6-yl]pyridine-2-carboxylate in 16 ml of formamide are heated at 130° C. under nitrogen in a flask until the reaction is complete (HPLC check, about 48 hours). The excess formamide is distilled off (120° C., 1 mbar). The residue is dissolved in dichloromethane, washed with water, dried and purified by means of column chromatography (gradient EA: methanol 0-50% in 15 min), giving 0.40 g of 6-[2-methyl-3-(2-trimethylsilanylethoxymethyl)-3H-imidazo[4,5-b]pyridin-6-yl]-3H-pyrido[3,2-d]pyrimidin-4-one as reddish solid (yield 36%, content 95%); MS-FAB (M+H+)=409.1; Rf (polar method): 2.01 min.
Reaction SMILES: [NH:1]([C:25]([O:27][CH2:28][CH:29]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]2[C:30]1=[CH:31][CH:32]=[CH:33][CH:34]=2)=[O:26])[C@H:2]([C:10]([NH:12][C@H:13]([C:18]([O:20]C(C)(C)C)=[O:19])[C@H:14]([CH2:16][CH3:17])[CH3:15])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8]>FC(F)(F)C(O)=O>[NH:1]([C:25]([O:27][CH2:28][CH:29]1[C:30]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:36]2[C:41]1=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:26])[C@H:2]([C:10]([NH:12][C@H:13]([C:18]([OH:20])=[O:19])[C@H:14]([CH2:16][CH3:17])[CH3:15])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9]
Reactant: CC[C@H](C)[C@H](NC(=O)[C@H](CCCNC(=N)N)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)[C@H](NC(=O)[C@H](CCCNC(=N)N)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reaction time: 1 h

Procedure:
15.8 g of Fmoc-Arg-Ile-OtBu are dissolved in 150 ml of 90% strength aqueous trifluoroacetic acid. The solution is left to stand at room temperature for 1 hour, and is concentrated. The residue is triturated twice with diethyl ether, the ether being decanted off each time. Water is added to the residue, and the pH is adjusted to with saturated NaHCO3 solution. The precipitate is filtered off with suction and dried.
Reaction SMILES: [CH:1]1([CH:4]2[CH2:9][NH:8][C:7](=O)[CH2:6][S:5]2)[CH2:3][CH2:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[O-]S([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH:1]1([CH:4]2[S:5][CH2:6][CH2:7][NH:8][CH2:9]2)[CH2:3][CH2:2]1
Reactant: O=C1CSC(C2CC2)CN1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: C1CSC(C2CC2)CN1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.8 %

Procedure:
A solution of 6-cyclopropylthiomorpholin-3-one (4-13, 355 mg, 2.258 mmol) in THF (10 ml) was cooled to 0° C. To this was added 2M LAH (2.3 ml, 4.60 mmol) slowly. After the addition was complete the cooling bath was removed and the mixture allowed to warm to rt. After stirring overnight the mixture was cooled to 0° C. and slowly quenched with 2M NaOH until gas evolution had ceased and a fine white precipitate formed. Anhydrous Na2SO4 was added and the mixture stirred for 15 minutes. The slurry was filtered through a pad of Celite washing with THF and the filtrate concentrated to afford 2-cyclopropylthiomorpholine (4-14, 242 mg, 75%) as a pale yellow oil which was used in subsequent steps as is.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:21][C@@H:22]2[C@H:26]([CH2:27][CH3:28])[CH2:25][C@H:24]([NH:29][S:30]([CH:33]3[CH2:35][CH2:34]3)(=[O:32])=[O:31])[CH2:23]2)=[C:4]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:5]2=[N:6][CH:7]=1.[N:36]#[C:37]Br>CO>[NH2:36][C:37]1[N:21]([C@@H:22]2[C@H:26]([CH2:27][CH3:28])[CH2:25][C@H:24]([NH:29][S:30]([CH:33]3[CH2:35][CH2:34]3)(=[O:31])=[O:32])[CH2:23]2)[C:3]2=[C:4]3[CH:10]=[CH:9][N:8]([S:11]([C:14]4[CH:15]=[CH:16][C:17]([CH3:18])=[CH:19][CH:20]=4)(=[O:12])=[O:13])[C:5]3=[N:6][CH:7]=[C:2]2[N:1]=1
Reactant: CC[C@@H]1C[C@H](NS(=O)(=O)C2CC2)C[C@@H]1Nc1c(N)cnc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Reactant: N#CBr
Solvent: CO
Product: CC[C@@H]1C[C@H](NS(=O)(=O)C2CC2)C[C@@H]1n1c(N)nc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)c21
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.3 %

Procedure:
To a solution of N-((1S,3S,4R)-3-(5-amino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-4-ethylcyclopentyl)cyclopropanesulfonamide (0.200 g, 0.301 mmol, Example #23 Step I) in MeOH (3.0 mL) was added cyanogen bromide (5 M in MeCN, 0.482 mL, 2.41 mmol) dropwise. The reaction was stirred at ambient temperature for about 16 h. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography eluting with a gradient of 0-10% MeOH in DCM to give N-((1S,3S,4R)-3-(2-amino-6-tosylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-4-ethylcyclopentyl)cyclopropane-sulfonamide (0.11 g, 67%) as a brown solid: LC/MS (Table 1, Method a) Rt=2.00 min; MS m/z: 543 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH2:3]([CH:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][C:11]([F:20])=[C:12]([O:18][CH3:19])[C:13]=2[Cl:17])[C:8]1=[O:21])[CH2:4][CH2:5][CH3:6].[CH2:22](I)[CH:23]=[CH2:24]>>[CH2:24]([C:7]1([CH2:3][CH2:4][CH2:5][CH3:6])[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][C:11]([F:20])=[C:12]([O:18][CH3:19])[C:13]=2[Cl:17])[C:8]1=[O:21])[CH:23]=[CH2:22]
Reactant: CCCCC1CCc2c(cc(F)c(OC)c2Cl)C1=O
Reactant: C=CCI
Agent: [H-]
Agent: [Na+]
Product: C=CCC1(CCCC)CCc2c(cc(F)c(OC)c2Cl)C1=O
Reaction time: 0.08 h

Procedure:
Sodium hydride (15 mg, 61% dispersion in mineral oil, 0.38 mmol) was placed in a flame dried flask, then washed with hexanes to remove mineral oil, and finally suspended in DMF (0.3 mL) under an atmosphere of N2. A solution of 2-butyl-5-chloro-7-fluoro-6-methoxy-3,4-dihydro-2H-naphthalen-1-one (54 mg in 0.2 mL DMF, 0.19 mmol) was added at room temperature to give a bright yellow reaction mixture. After five minutes, allyl iodide (0.055 mL, 0.6 mmol) was added. The reaction was stirred for 1.5 hours, then partitioned between EtOAc/H2O. The organic phase was washed twice with water, dried over MgSO4, filtered and then evaporated under vacuum. The crude product was purified by preparative layer chromatography on a 0.1×20×20 cm silica gel GF plate (Analtech, Newark, Del.), developing with 10:1 hexane-EtOAc. The product band at Rf 0.45-0.55 was eluted with 5% MeOH in CH2Cl2 and concentrated under vacuum to give 2-allyl-2-butyl-5-chloro-7-fluoro-6-methoxy-3,4-dihydro-2H-naphthalen-1-one as an oil.
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]([CH2:11][CH2:12][CH2:13][Cl:14])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[O:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=1)[NH2:19]>C(O)(C)C>[Cl:14][CH2:13][CH2:12][CH2:11][N:10]1[C:3]2[C:2]([NH:19][C:18]3[CH:20]=[CH:21][C:22]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:32])[F:33])[CH:25]=4)=[C:16]([Cl:15])[CH:17]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:8]=[CH:9]1
Reactant: ClCCCn1ccc2ncnc(Cl)c21
Reactant: Nc1ccc(Oc2cccc(C(F)(F)F)c2)c(Cl)c1
Solvent: CC(C)O
Product: FC(F)(F)c1cccc(Oc2ccc(Nc3ncnc4ccn(CCCCl)c34)cc2Cl)c1
Temperature: 80 °C
Reaction time: 4.5 h
Yield: 88.5 %

Procedure:
A mixture of 4-chloro-5-(3-chloropropyl)-5H-pyrrolo[3,2-d]pyrimidine (789 mg), 3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline (1.09 g) and isopropyl alcohol (5 mL) was stirred at 80° C. for 4.5 hrs. The mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate (30 mL) was added to the residue, and the mixture was extracted with ethyl acetate (40 mL×3). The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent, hexane:ethyl acetate=90:10→20:80) to give the title compound (1.46 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[N+:17]([O-])=O)=[O:5])[CH3:2].[CH:20]([NH2:23])([CH3:22])[CH3:21]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:23][CH:20]([CH3:22])[CH3:21])=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:17])=[O:5])[CH3:2]
Reactant: CC(C)N
Reactant: CCOC(=O)c1cnc2c([N+](=O)[O-])cccc2c1Cl
Product: CCOC(=O)c1cnc2c(N)cccc2c1NC(C)C
Yield: 80 %

Procedure:
The compound prepared in Example 3 was reacted with isopropylamine according to the method as described in Example 4 and the obtained compound was treated as described in Example 14 to prepare the title compound (yield 80%).
Reaction SMILES: [Mg].[CH3:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[CH2:6]Cl.[Cl:12][CH2:13][C:14](=[O:16])[CH3:15].Cl>CCOCC.O1CCCC1>[Cl:12][CH2:13][C:14]([CH2:6][C:5]1[CH:4]=[C:3]([CH3:2])[CH:10]=[C:9]([CH3:11])[CH:8]=1)([OH:16])[CH3:15]
Reactant: Cc1cc(C)cc(CCl)c1
Reactant: CC(=O)CCl
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cc(C)cc(CC(C)(O)CCl)c1
Reaction time: 2 h
Yield: 51.7 %

Procedure:
25 g of magnesium turnings and 155 g of 3,5-dimethylbenzyl chloride were reacted in 300 ml of ether. After dilution with 200 ml of tetrahydrofuran, a mixture of 92.5 g of chloroacetone and 100 ml of tetrahydrofuran was added dropwise with ice cooling in the course of one hour. After reacting for 2 hours at 25° C., the mixture was poured onto a mixture of ice and 2.5 mol hydrochloric acid. The upper layer was separated off and the aqueous layer was extracted with ether. The combined organic layers were washed with water until neutral, dried using Na2SO4, filtered and distilled. 110 g of 1-chloro-2-(3,5-dimethylbenzyl)-propan-2-ol were obtained at 110°-112° C./0.2 mbar. 109 g of this compound were stirred at 30° C. for 2 hours with 20 ml of methyl tert.-butyl ether and a solution of 31 g of NaOH in 750 ml of water. The layers were then separated, and the organic phase was washed with water until neutral, dried using Na2SO4 and distilled. 65 g of 2-(3,5-dimethylbenzyl)-propylene oxide were obtained at a boiling point of 68°-70° C./0.3 mbar. 80 g of this compound were dissolved in 100 ml of cyclohexane and put into a 0.5 l shaking autoclave with 0.8 g of 5% Pd on active carbon. After flushing with inert gas, the autoclave was pressuried with hydrogen (130 bar) and heated at 150° C. for 8 hours. The cooled mixture was depressurized, flushed with inert gas, the catalyst was filtered off and the filtrate was distilled through a 30-cm long column containing steel helices. 18 g of 2-methyl-3-(3,5-dimethylphenyl)-propan-1-ol passed over at 80°-81° C./0.07 mbar.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[O:33][CH3:34])=[CH:23][CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].Cl.Cl.Cl.[N:40]1[CH:45]=[CH:44][CH:43]=[C:42]([CH:46]([N:49]2[CH2:53][CH2:52][CH2:51][CH2:50]2)[CH2:47][NH2:48])[CH:41]=1.C(N(CC)CC)C.CS(C)=O>C(#N)C>[CH3:34][O:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:24]1[CH:25]=[CH:26][C:21]([C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:48][CH2:47][CH:46]([C:42]4[CH:41]=[N:40][CH:45]=[CH:44][CH:43]=4)[N:49]4[CH2:53][CH2:52][CH2:51][CH2:50]4)=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:20])=[CH:22][CH:23]=1
Reactant: NCC(c1cccnc1)N1CCCC1
Reactant: COc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)cc1
Agent: Cl
Solvent: CS(C)=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCC(c4cccnc4)N4CCCC4)n3Cc3ccccc32)cc1

Procedure:
The title compound was prepared according to the procedure Example 6, Step D, from 2,2,2-trichloro-1-{10-[(2′-methoxy-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone (1.21 g, 2.25 mmol), 2-(3-pyridyl)-2-pyrrolidinylethyl amine trihydrochloride (0.450 g, 1.5 mmol), triethylamine (5 equivalents), dimethylsulfoxide (0.540 mL) and acetonitrile (28 mL). The crude material was flash chromatographed over silica gel Merck-60 using a gradient of methanol (1-5%) in dichloromethane containing 0.2% ammonium hydroxide, to provide a brown foam. The material was further purified by preparative HPLC (40:60 acetonitrile:water containing 0.1% formic acid; Primesphere 10 C18, 250×50 mm column; flow 90 mL/min). The solution was brought to pH 8 with concentrated ammonium hydroxide prior to concentration to small volume in vacuo. The residue was redissolved in dichloromethane, dried over anhydrous potassium carbonate and evaporated to dryness to provide an off-white foam (0.560 g). This material was sonicated with hexane (containing a few drops of ethyl acetate). The resulting off-white powder was collected and dried (0.442 g).
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][C:17]#[CH:18])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.C(Cl)Cl.CO>C1COCC1>[CH2:4]([NH2:1])[CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][C:17]#[CH:18]
Reactant: C#CCOCCOCCOCCOCCN=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: C#CCOCCOCCOCCOCCN
Yield: 85.3 %

Procedure:
1-azido-3,6,9,12-tetraoxapentadec-14-yne 6 (2.45 g, 9.53 mmol, 1 equiv.), triphenylphosphine (3.00 g, 11.4 mmol, 1.2 equiv.), and water (172 mL, 9.53 mmol, 1.0 equiv.) were dissolved in THF (30 mL) and stirred for 12 h when TLC (95:5 CH2Cl2/CH3OH) indicated completion. Reaction was concentrated and chromatographed (100% CH2Cl2 to 80:20:1 CH2Cl2/MeOH/Et3N) to yield 7 as a clear oil (1.88 g, 85% yield). IR (thin film, NaCl) 3372 (br), 3251 (s), 2868 (s), 2112 (w), 1652 (m), 1596 (m), 1459 (m), 1350 (m), 1301 (m), 1249 (m), 1100 (s), 946 (m), 681 (m) cm−1. 1H-NMR (500 MHz, CDCl3) δ 4.16 (m, 2H), 3.66-3.57 (m, 12H), 3.49 (t, 2H, J=5.3 Hz), 2.85 (t, 2H, J=5.0 Hz), 2.56 (bs, 2H), 2.41 (m, 1H). 13C NMR (125 MHz, CDCl3) δ 79.52, 74.63, 73.06, 70.45, 70.41, 70.24, 70.11, 68.96, 58.26, 41.50. HRMS (ES+) calc'd for C11H21NO4 (M+H) m/z 232.154335. Found 232.15402.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:28](C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.Cl.COC1CCNC1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][CH:24]([O:25][CH3:28])[CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Agent: COC1CCNC1
Agent: Cl
Product: COC1CCN(c2nc(C(C)(C)C)nc3c2nnn3Cc2ccccc2Cl)C1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-methoxypyrrolidine hydrochloride and isolated as colorless gum (13.2 mg, 70%). MS (m/e): 401.4 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:20][NH:21][C:22]1[C:27]([CH:28]=[O:29])=[C:26]([N:30]2[CH2:35][CH2:34][CH:33]([C:36]3[CH:45]=[CH:44][C:43]4[CH2:42][CH2:41][CH2:40][NH:39][C:38]=4[N:37]=3)[CH2:32][CH2:31]2)[N:25]=[CH:24][N:23]=1)[C:13]([O:15]C(C)(C)C)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:46][C:47]([F:52])([F:51])[C:48]([OH:50])=[O:49].C1(C)C=CC=CC=1>ClCCl>[F:46][C:47]([F:52])([F:51])[C:48]([OH:50])=[O:49].[F:46][C:47]([F:52])([F:51])[C:48]([OH:50])=[O:49].[CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:20][NH:21][C:22]1[C:27]([CH:28]=[O:29])=[C:26]([N:30]2[CH2:35][CH2:34][CH:33]([C:36]3[CH:45]=[CH:44][C:43]4[CH2:42][CH2:41][CH2:40][NH:39][C:38]=4[N:37]=3)[CH2:32][CH2:31]2)[N:25]=[CH:24][N:23]=1)[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)C(CNc1ncnc(N2CCC(c3ccc4c(n3)NCCC4)CC2)c1C=O)NC(=O)OCc1ccccc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=Cc1c(NCC(NC(=O)OCc2ccccc2)C(=O)O)ncnc1N1CCC(c2ccc3c(n2)NCCC3)CC1

Procedure:
120 mg (0.195 mmole) of tert-butyl 2-benzyloxycarbonylamino-3-{5-formyl-6-[4-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-piperidin-1-yl]-pyrimidin-4-ylamino}-propionate in 10 ml of dichloromethane with 1 ml of trifluoroacetic acid is stirred at ambient temperature for 24 hours. Toluene is added and the reaction mixture is evaporated to dryness under reduced pressure (2 kPa). The residue is solubilized in the minimum amount of dichloromethane with a little methanol then poured into diisopropyl ether. The precipitate is filtered. 60 mg of expected product is obtained in the form of a white solid.
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:4]=1[CH2:5][C:6]#[N:7].[CH2:13]([O:15][C:16](=[O:24])[CH2:17][CH2:18][C:19](OCC)=[O:20])[CH3:14]>>[Cl:2][C:3]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:4]=1[CH:5]([C:6]#[N:7])[C:19](=[O:20])[CH2:18][CH2:17][C:16]([O:15][CH2:13][CH3:14])=[O:24]
Reactant: CCOC(=O)CCC(=O)OCC
Reactant: N#CCc1ccc(Cl)cc1Cl
Agent: [Na]
Product: CCOC(=O)CCC(=O)C(C#N)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Yield: 49.8 %

Procedure:
A clean, dry 500 ml 3-neck R.B. flask was equipped with a reflux condenser, mechanical stirrer, addition funnel, and nitrogen inlet. The flask was charged with 600 ml of ethanol (distilled from magnesium turnings and stored over type 3A molecular sieves) followed by 30.0 g (1.30 mol) of sodium, and the reaction mixture stirred and heated until all the sodium had dissolved. The temperature of the reaction mixture was then raised to the reflux point, and a mixture of 186.03 g (1.00 mol) of 2,4-dichlorobenzyl cyanide and 261.3 g (1.50 mol) of diethylsuccinate added at a rapid drop rate through the addition funnel. The reaction mixture was refluxed for 12 hours, then approximately 2/3 of the ethanol was distilled off, the reaction mixture refluxed for two additional hours, cooled to room temperature, and poured into 600 ml of ice water. The basic solution was extracted twice with 300 ml of ether, and then acidified with 6 N HCl. An oil formed, and the aqueous acid solution was extracted twice with 250 ml portions of ether. The ether extract was washed twice with water, dried (MgSO4), and the ether stripped to leave 156.61 g (50% yield) of product as a viscous red oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:4]([C:20]2[O:21][C:22]([CH2:25]Cl)=[N:23][N:24]=2)[CH:3]=1.[I-].[Na+].[NH2:29][CH2:30][CH:31]([OH:39])[CH2:32][N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.CCN(C(C)C)C(C)C>C(#N)C.C(Cl)Cl>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:4]([C:20]2[O:21][C:22]([CH2:25][NH:29][CH2:30][CH:31]([OH:39])[CH2:32][N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)=[N:23][N:24]=2)[CH:3]=1
Reactant: O=S(=O)(c1ccccc1)n1ncc2c(-c3nnc(CCl)o3)cc(Br)cc21
Reactant: NCC(O)CN1CCOCC1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CC#N
Product: O=S(=O)(c1ccccc1)n1ncc2c(-c3nnc(CNCC(O)CN4CCOCC4)o3)cc(Br)cc21
Temperature: 70 °C
Yield: 57.6 %

Procedure:
6-Bromo-4-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-1-(phenylsulfonyl)-1H-indazole (300 mg, 0.661 mmol) and sodium iodide (138 mg, 0.921 mmol) were weighed into a round-bottomed flask and dissolved in acetonitrile (2 ml) before 1-amino-3-morpholin-4-ylpropan-2-ol (212 mg, 1.322 mmol, available from Enamine Ltd) and DIPEA (0.231 ml, 1.322 mmol) were added. The mixture was heated to 70° C. for 2 h, then cooled, diluted with DCM and washed with 2 M aqueous HCl (5 ml). The organic layer was separated with a hydrophobic frit and the aqueous layer was neutralised to pH 7 by addition of 2M NaOH resulting in the formation of a solid precipitate. This was filtered off under vacuum and dried in air for 2 h to give the title compound as a cream solid (220 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[CH:6]=[N:7][NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])#[N:2]>CO.[Pd]>[C:1]([C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[CH2:6][NH:7][NH:8][C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])#[N:2]
Reactant: CC(C)(C)OC(=O)NN=Cc1cccc(C#N)c1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NNCc1cccc(C#N)c1
Reaction time: 6 h
Yield: 95 %

Procedure:
tert-Butyl 2-(3-cyanobenzylidene)-1-hydrazinecarboxylate (60.0 mmol) was dissolved in MeOH (250 mL) and 10% Pd/C (10 w/w %) was added. The mixture was hydrogenated for 6 h. The catalyst was filtered off and the filtrate was evaporated in vacuo to yield oily tert-butyl 2-(3-cyanobenzyl)-1-hydrazinecarboxylate which crystallized overnight.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].COC1C=CC(O)=CC=1.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18](S(O)(=O)=O)=[CH:17][CH:16]=1.C(O)C1C=CC=CC=1>O>[C:1]([O:5][CH2:25][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: COc1ccc(O)cc1
Solvent: O
Solvent: OCc1ccccc1
Product: C=CC(=O)OCc1ccccc1
Reaction time: 5 h

Procedure:
144 g (2 mols) of acrylic acid, which have been inhibited with 1.4 g of hydroquinone monomethyl ether, are dissolved in 139 g of a high-boiling aromatics mixture in a 1 l four-necked flask with stirrer, contact thermometer, water separator and gas inlet tube. 3.2 g of p-toluenesulfonic acid are added thereto, the mixture is heated to 70° C. and, at this temperature, 216 g (2 mols) of benzyl alcohol are allowed to run in over a period of 10 minutes. After the end of the addition, the mixture is heated to reflux. To accelerate the removal of water, air is passed through the solution. The reaction is complete after about 5 hours. The progress of the reaction is monitored via the acid number. After 5 hours, the latter gives a conversion of about 97%.