Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][C@H:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:7][C@H:6]1[CH3:20])=[O:4].[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([OH:33])=[C:26]([CH2:28][S:29]([NH2:32])(=[O:31])=[O:30])[CH:27]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.O>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([O:33][CH2:2][C:3]([N:5]2[CH2:10][C@H:9]([CH3:11])[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[CH2:7][C@H:6]2[CH3:20])=[O:4])=[C:26]([CH2:28][S:29]([NH2:32])(=[O:31])=[O:30])[CH:27]=1
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)CCl
Reactant: NS(=O)(=O)Cc1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1CS(N)(=O)=O
Temperature: 60 °C
Yield: 30.8 %

Procedure:
To a solution of 2-chloro-1-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-ethanone (0.028 g, 0.094 mmol) in dimethylformamide (1 mL) was added (5-chloro-2-hydroxy-phenyl)-methanesulfonamide (0.023 g, 0.10 mmol), potassium carbonate (0.026 g, 0.19 mmol) and potassium iodide (0.016 g, 0.094 mmol). The reaction was heated at 60° C. for 17 hours, cooled, diluted with water and extracted with ethyl acetate (3×). The organic layers were combined, dried over sodium sulfate, filtered and concentrated in vacuo. Chromatography on silica gel gave the title compound (0.014 g).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:10][C:11]([N:13]([CH3:15])[CH3:14])=[O:12].Cl.[CH3:17][N:18]1[C:22]2[N:23]=[C:24]([C:46]#[N:47])[N:25]=[C:26]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][CH:36]4[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]4)=[C:29]([C:42]([F:45])([F:44])[F:43])[CH:28]=3)[C:21]=2[CH:20]=[CH:19]1>C(#N)C.O>[C:46]([C:24]1[N:25]=[C:26]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][CH:36]3[CH2:37][CH2:38][N:39]([CH2:10][C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[CH2:40][CH2:41]3)=[C:29]([C:42]([F:43])([F:44])[F:45])[CH:28]=2)[C:21]2[CH:20]=[CH:19][N:18]([CH3:17])[C:22]=2[N:23]=1)#[N:47]
Reactant: CN(C)C(=O)CCl
Reactant: Cn1ccc2c(-c3ccc(OCCC4CCNCC4)c(C(F)(F)F)c3)nc(C#N)nc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Solvent: O
Product: CN(C)C(=O)CN1CCC(CCOc2ccc(-c3nc(C#N)nc4c3ccn4C)cc2C(F)(F)F)CC1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Potassium carbonate (133 mg), potassium iodide (160 mg), and 2-chloro-N,N-dimethylacetamide (34 μL) were added to a suspension of 7-methyl-4-{4-[2-(piperidin-4-yl)ethoxy]-3-(trifluoromethyl)phenyl}-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile monohydrochloride (150 mg) in acetonitrile (6 mL) at room temperature, and the mixture was stirred at 60° C. for 2 hours. After the reaction mixture was cooled to room temperature, water was added thereto, extraction thereof was performed using EtOAc, and the extract was washed with a saturated aqueous ammonium chloride solution, water, and saturated brine. The organic layer was dried over MgSO4 and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (Hex:EtOAc=1:3). The obtained product was washed with diisopropyl ether, and collected by filtration, whereby 2-(4-{2-[4-(2-cyano-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-(trifluoromethyl)phenoxy]ethyl}piperidin-1-yl)-N,N-dimethylacetamide (118 mg) was obtained as a white solid.
Reaction SMILES: [CH:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CS(O[CH2:18][CH2:19][C@@:20]1([C:42]2[CH:47]=[CH:46][C:45]([Cl:48])=[C:44]([Cl:49])[CH:43]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:41])[CH2:26][C:27]2[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([C:37]([F:40])([F:39])[F:38])[CH:28]=2)[CH2:21]1)(=O)=O.C(#N)C>>[Cl:49][C:44]1[CH:43]=[C:42]([C@@:20]2([CH2:19][CH2:18][N:10]3[CH2:11][CH2:12][N:7]([CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:8][CH2:9]3)[CH2:24][CH2:23][N:22]([C:25](=[O:41])[CH2:26][C:27]3[CH:32]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:30]=[C:29]([C:37]([F:40])([F:38])[F:39])[CH:28]=3)[CH2:21]2)[CH:47]=[CH:46][C:45]=1[Cl:48]
Reactant: C1CCC(N2CCNCC2)CC1
Reactant: CS(=O)(=O)OCC[C@@]1(c2ccc(Cl)c(Cl)c2)CCN(C(=O)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1
Solvent: CC#N
Product: O=C(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@](CCN2CCN(C3CCCCC3)CC2)(c2ccc(Cl)c(Cl)c2)C1

Procedure:
In 30 ml of acetonitrile (R)-3-(2-methanesulfonyloxyethyl)-3-(3,4-dichlorophenyl)-1-[[3,5-bis(trifluoromethyl)phenyl]acetyl]pyrrolidine (3.17 g), prepared as described, supra, is mixed with an equimolar amount of 1-cyclohexylpiperazine. The reaction mixture is then heated to reflux and refluxed for about ten hours. The mixture is then concentrated under vacuum and the residue is taken up in methylene chloride and washed with a 3N solution of hydrochloric acid, followed by a wash with brine. The organic fraction is dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue precipitates from an acetone/diethyl ether mixture to give the desired title product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[C:5]#[N:6].[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[C:5]#[N:6]
Reactant: N#Cc1ccc(F)c(Cl)c1
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1ccc(N2CCNCC2)c(Cl)c1

Procedure:
A solution of 3-chloro-4-fluoro-benzonitrile (236 mg, 1.52 mmoles), piperazine (784 mg, 9.1 mmoles) and potassium carbonate (276 mg, 2 mmoles) in acetonitrile (5 mL) was heated to 100° C. overnight. The mixture was cooled, filtered and the filtrate concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, 0-5% 2N methanolic ammonia in DCM) to provide the title compound. MS (APCI+) m/z 222 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[CH2:12][CH2:11]3)=[CH:4][CH:3]=1.Br[CH2:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[CH:20]1([CH2:19][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:9]=[C:10]4[C:14](=[CH:15][CH:16]=3)[C:13](=[O:17])[CH2:12][CH2:11]4)=[CH:6][CH:7]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C1CCc2cc(-c3ccc(O)cc3)ccc21
Reactant: BrCC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C1CCc2cc(-c3ccc(OCC4CCCCC4)cc3)ccc21
Yield: 393.5 %

Procedure:
A solution of 5-(4-hydroxyphenyl)-1-indanone (0.52 g, 0.23 mmol, from Step A), bromomethylcyclohexane (0.53 g, 0.30 mmol) and potassium carbonate (0.58 g, 0.42 mmol) in acetonitrile (2.5 mL) was stirred at 80° C. for 16 h. The reaction mixture was cooled, diluted with ethyl acetate and washed with water. Silica gel chromatography eluting with 10% ethyl acetate/hexane yielded 0.29 g of product. 1H NMR (500 MHz, CDCl3): δ 7.83 (d, J=7.8 Hz, 1H), 7.67 (s, 1H), 7.60 (d, J=8.3 Hz, 3H), 7.03 (d, J=8.2 Hz, 2H), 3.85 (s, 2H), 3.21 (s, 2H), 2.78 (s, 2H), 2.08 (s, 1H), 1.90–1.98 (m, 2H), 1.80–1.86 (m, 2H), 1.20–1.42 (m, 4H), 1.07–1.18 (m, 2H).
Reaction SMILES: [C:1]12([NH2:11])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(N(CC)CC)C.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[CH2:30][CH2:29][N:28]([CH:31]([CH3:34])[CH2:32]Br)[CH2:27][CH2:26]1.O>CN(C=O)C>[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[CH2:26][CH2:27][N:28]([CH:31]([CH3:34])[CH2:32][NH:11][C:1]23[CH2:8][CH:7]4[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]4)[CH2:2]2)[CH2:10]3)[CH2:29][CH2:30]1
Reactant: NC12CC3CC(CC(C3)C1)C2
Reactant: CC(CBr)N1CCN(c2ccccn2)CC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(CNC12CC3CC(CC(C3)C1)C2)N1CCN(c2ccccn2)CC1
Temperature: 50 °C

Procedure:
A suspension of 1-adamantylamine (12.0 grams; 0.079 moles) in 250 cc of DMF is prepared. Triethylamine (21.9 cc; 0.158 moles), is added and the mixture is warmed to about 50° C. To the warm solution, there is added over a period of 3 hours, 1-(2-pyridyl)-4-(2-bromo-1-methylethyl)piperazine (18.0 grams; 0.063 moles) keeping the temperature about the same. The reaction mixture is poured into 500 cc of water and then extracted with ether. The ethereal phase, washed with water, then washed to neutrality and allowed to evaporate, gives as a residue, a crude oily product, which is purified by column chromatography. (THF-diisopropyl ether-Et3N 50:40:10). Compound (26) is an oil, which solidifies after prolonged standing; m.p. 67°-68° C. from n-hexane); Rf=0.22 (from ethyl acetate Et3N 9:1); IR (nujol) νmax: 1590, 1480, 1430, 1310, 1240, 1160, 775 cm-1 ; νN-H: 3250 cm-1 ; 1H-NMR (CDCl3): 0.93 (d, J=5 Hz; 3H); 1.20-2.23 (m; 16H); 2.23-3.00 (m; 7H); 3.20-3.70 (m; 4H); 6.40-6.73 (m; 2H; 7.23-7.63 (m; 1H); 8.03-8.27 (m; 1H); tripicrate: m.p. 185° C. (from ethanol).
Reaction SMILES: CO[C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7](O)=[CH:6][CH:5]=1.C(Cl)CCCCCC[CH2:19][CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23]>>[CH2:3]([OH:11])[CH2:4][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:19][CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23]
Reactant: CC(C)CCCCCCCCCCCl
Reactant: COC(=O)c1ccc(O)cc1
Product: CC(C)CCCCCCCCCCO

Procedure:
This compound was prepared from 4-hydroxybenzoic acid methylester and isotridecylchloride, initially obtained from isotridecanol (an oxalcohol prepared from tetrapropylene) using known techniques. The product recovered exhibited a refractive index of
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH3:13])([CH3:12])[CH:6]=[CH:5]2.[CH2:14](O)[CH2:15][CH2:16]O.C(P(CCCC)CCCC)CCC>COCCOC.[Ru](Cl)(Cl)Cl>[CH3:12][C:7]1([CH3:13])[O:8][C:9]2=[CH:10][C:11]3[CH:14]=[CH:15][CH:16]=[N:1][C:2]=3[CH:3]=[C:4]2[CH:5]=[CH:6]1
Reactant: CC1(C)C=Cc2cc(N)ccc2O1
Reactant: OCCCO
Agent: Cl[Ru](Cl)Cl
Agent: CCCCP(CCCC)CCCC
Solvent: COCCOC
Product: CC1(C)C=Cc2cc3ncccc3cc2O1
Temperature: 180 °C
Reaction time: 5 h
Yield: 59 %

Procedure:
Under nitrogen atmosphere, to a solution of 6-amino-2,2-dimethylchromene (3.88 g, 22.1 mmol) and ruthenium trichloride (55.0 mg, 0.265 mmol) in dimethylene glycol dimethyl ether (8 mL), 1,3-propanediol (0.639 mL, 8.84 mmol) and tri-n-butyl phosphine (0.132 mL, 0.530 mmol) were addled at room temperature, and the resulting mixture was stirred at 180° C. for 5 hours. Upon the completion of the reaction, ruthenium complex was removed by florisil column, and solvent was distilled off. The residue was purified by medium pressure column chromatography (hexane/ethyl acetate=5/1) and the aimed product was obtained (yield: 59%).
Reaction SMILES: [O:1]([CH2:8][CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:16]=[C:15](O)[NH:14][N:13]=1.CC1C=CC(S(O)(=O)=O)=CC=1>>[O:1]([CH2:8][CH2:9][O:10][C:15]1[CH:16]=[C:12]([NH2:11])[NH:13][N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCOc1ccccc1
Reactant: Nc1cc(O)[nH]n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: Nc1cc(OCCOc2ccccc2)n[nH]1
Temperature: 130 °C
Reaction time: 11 h
Yield: 30.7 %

Procedure:
A mixture of 2-phenoxyethanol (56.1 g, 406 mmol), 3-amino-1H-pyrazol-5-ol (8.0648 g, 81.4 mmol) and TsOH (30.96 g, 162.8 mmol) was stirred at 130° C. under vacuum for 11 h. After cooled down to room temperature, the solid was washed with MeCN (200 mL), then treated with 6% aqueous NaHCO3 solution (500 mL). The suspension was filtered, and the solid collected was dissolved in EtOAc (100 mL), dried over MgSO4, filtered and concentrated, giving the title compound (5.4734 g, 30.7% yield). ESI m/z=220.19 [(M+1)+; calcd for C11H13N3O2+H: 220.11].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[NH:4][C:5]1[CH:21]=[C:20]2[C:8]([C:9]3[N:24]=[C:12]([C@@H:13]([NH2:23])[CH2:14][CH2:15][CH2:16][CH2:17][C:18](=[O:22])[NH:19]2)[NH:11][C:10]=3[F:25])=[CH:7][CH:6]=1.[C:27](=[O:30])([O-])[O-:28].[Na+].[Na+]>CN(C=O)C.CO>[CH3:1][O:2][C:3](=[O:26])[NH:4][C:5]1[CH:21]=[C:20]2[C:8]([C:9]3[N:24]=[C:12]([C@@H:13]([NH:23][C:27]([O:28][C:8]([CH3:20])([CH3:9])[CH3:7])=[O:30])[CH2:14][CH2:15][CH2:16][CH2:17][C:18](=[O:22])[NH:19]2)[NH:11][C:10]=3[F:25])=[CH:7][CH:6]=1.[CH3:1][O:2][C:3](=[O:26])[NH:4][C:5]1[CH:21]=[C:20]2[C:8]([C:9]3[N:24]=[C:12]([C@@H:13]([NH2:23])[CH2:14][CH2:15][CH2:16][CH2:17][C:18](=[O:22])[NH:19]2)[NH:11][C:10]=3[F:25])=[CH:7][CH:6]=1
Reactant: O=C([O-])[O-]
Agent: COC(=O)Nc1ccc2c(c1)NC(=O)CCCC[C@H](N)c1nc-2c(F)[nH]1
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)Nc1ccc2c(c1)NC(=O)CCCC[C@H](NC(=O)OC(C)(C)C)c1nc-2c(F)[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
I-20B. ((S)-14-Amino-17-fluoro-9-oxo-8,16,18-triaza-tricyclo[13.2.1.02,7]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl)-carbamic acid methyl ester: To a solution of I-20A (40 mg, 0.090 mmol) in DMF (3 mL) was added sodium carbonate (12.43 mg, 0.117 mmol) and 1-Fluoro-4-hydroxy-1,4 diazoniabicyclo[2,2,2]octanebis(tetrafluoroborate) (50% in alumina) (62.9 mg, 0.090 mmol) in a portion, respectively and the resulting solution was stirred for 2 h at rt. The reaction mixture was diluted with MeOH and purified by reverse phase chromatography which gave both ((S)-14-tert-Butoxycarbonylamino-17-fluoro-9-oxo-8,16,18-triaza-tricyclo[13.2.1.02,7]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl)-carbamic acid methyl ester and ((S)-14-Amino-17-fluoro-9-oxo-8,16,18-triaza-tricyclo[13.2.1.02,7]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl)-carbamic acid methyl ester. The mixture was dissolved in 4N HCl dioxane (10 mL) and stirred overnight at 50° C. Concentration of the solution provided 11 mg of I-20B (34%).
Reaction SMILES: [C:1]([C:4]1[C:9]2[O:10][C:11]([CH3:14])=[C:12]([CH3:13])[C:8]=2[CH:7]=[CH:6][CH:5]=1)(O)=[O:2].S(Cl)([Cl:17])=O>CN(C)C=O>[Cl:17][C:1]([C:4]1[C:9]2[O:10][C:11]([CH3:14])=[C:12]([CH3:13])[C:8]=2[CH:7]=[CH:6][CH:5]=1)=[O:2]
Reactant: O=S(Cl)Cl
Reactant: Cc1oc2c(C(=O)O)cccc2c1C
Solvent: CN(C)C=O
Product: Cc1oc2c(C(=O)Cl)cccc2c1C

Procedure:
A mixture of 7-carboxy-2,3-dimethylbenzo[b]furan (2 g) and N,N-dimethylformamide (1 drop) in thionyl chloride (10 ml) was refluxed for 2 hours. The reaction mixture was cooled and concentrated in vacuo. The crystalline residue was triturated with n-hexane to give 7-chlorocarbonyl-2,3-dimethylbenzo[b]furan (2.17 g).
Reaction SMILES: [Sn](Cl)Cl.Cl.[Cl:5][C:6]1[CH:7]=[C:8]([CH:22]=[CH:23][CH:24]=1)[O:9][CH2:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[C:12]=1[C:13]#[N:14].[OH-].[K+]>>[NH2:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:11]([CH2:10][O:9][C:8]2[CH:22]=[CH:23][CH:24]=[C:6]([Cl:5])[CH:7]=2)[C:12]=1[C:13]#[N:14]
Reactant: N#Cc1c(COc2cccc(Cl)c2)cccc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [K+]
Product: N#Cc1c(N)cccc1COc1cccc(Cl)c1
Temperature: 15 °C
Reaction time: 3 h
Yield: 42 %

Procedure:
To a cooled (15° C.) and stirred solution of tin (II) chloride (0.4 g, 1.73 mmol) and cone. hydrochloric acid (1.2 mL) was added a solution of 2-(3-chlorophenoxymethyl)-6-nitrobenzonitrile (100.0 mg, 0.35 mmol). The reaction mixture was slowly warmed to room temperature and stirred for 3 hours. The reaction mixture was poured on to crushed-ice and potassium hydroxide solution, stirred, extracted with dichloromethane, filtered and dried. Purification by silica gel chromatography (dichloromethane) yielded 38 mg of 2-amino-6-(3-chlorophenoxymethyl)benzonitrile.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][OH:11])([O-:3])=[O:2].[OH-].[Na+].[CH3:14]OS(OC)(=O)=O>C(Cl)Cl.O.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:14][O:11][CH2:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1CO
Reactant: COS(=O)(=O)OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COCc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 91.4 %

Procedure:
To a solution of (2-nitrophenyl)methanol (5.13 g, 33.50 mmol) in DCM (75 mL) was added 3.35 N NaOH (75 mL, 251.2 mmol) in water at ambient temperature and stirred at ambient temperature for 10 minutes. Me2SO4 (6.38 ml, 67.0 mmol) and tetrabutylammonium hydrogen sulfate (0.57 g, 1.68 mmol) were added and the mixture stirred vigorously for 20 hours at ambient temperature. The reaction mixture was diluted with DCM (100 mL) and organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (5:1 hexane/ethyl acetate) to give 1-(methoxymethyl)-2-nitrobenzene (5.12 g, 91.4%) as an oil.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:15][CH2:14][C@@H:13]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH2:12][NH:11][C:10]1=[O:24])=O)(C)(C)C.C[Si](I)(C)C.O>C(Cl)Cl.CO>[NH2:8][C@H:9]1[CH2:15][CH2:14][C@@H:13]([O:16][Si:17]([C:20]([CH3:22])([CH3:21])[CH3:23])([CH3:18])[CH3:19])[CH2:12][NH:11][C:10]1=[O:24]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](O[Si](C)(C)C(C)(C)C)CNC1=O
Agent: C[Si](C)(C)I
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@H](N)C(=O)NC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 95.9 %

Procedure:
(3S, 6R)-3-(tert-butoxycarbonyl)aminohexahydro-6-tert-butyldimethylsilyloxy-2H-azepin-2-one (8.0 g, 22 mmol) is dissolved in 40 mL of CH2Cl2 and cooled to −78° C. Trimethylsilyl iodide (3.5 mL, 24.5 mmol) is added slowly. The mixture is allowed to react at −78° C. for 30 min. The reaction is warmed to 0° C. and stirred for 15 min. The solution turned yellow. The reaction is quenched with NH4HCO3 (3.43 g, 44 mmol) dissolved in 30 mL of CH3OH, and 15 mL water. The mixture is concentrated and chromatographed with a 95:5 mixture of CH2Cl2 and methanol to yield 5.45 g (96%) of (3S, 6R)-3-aminohexahydro-6-tert-butyldimethylsilyloxy-2H-azepin-2-one as a white solid: 1H NMR (CDCl3) δ5.61 (s, 1H), 3.88 (s, 1H), 3.42 (d, J=8 Hz, 1H), 3.32(dd, J=6 Hz and 16 Hz, 1H), 3.06 (m, 1H), 1.87 (m, 2H), 1.76 (m, 1H), 1.65 (s, 3H), 0.83 (s, 9H), 0.001 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][CH:15]=1)[NH:8][CH2:7][CH2:6]2.[O:28]1[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][CH:15]=1)[N:8]([CH:31]1[CH2:32][CH2:33][O:28][CH2:29][CH2:30]1)[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCNC2Cc1ccc(OCc2ccccc2)cc1
Reactant: O=C1CCOCC1
Product: COc1ccc2c(c1)CCN(C1CCOCC1)C2Cc1ccc(OCc2ccccc2)cc1
Yield: 77.7 %

Procedure:
The title compound was prepared as described in Example 14.C, using 6-methoxy-1-[4-(phenylmethoxy)benzyl]-1,2,3,4-tetrahydroisoquinoline (0.5 g, 1.39 mmol) and tetrahydro-4H-pyran-4-one (1.084 g, 10.8 mmol) to provide the title compound (0.479 g, 78% yield): ES-MS (m/z) 444 [M+H]+.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[C:18]3=[C:19]4[CH:25]=[CH:24][NH:23][C:20]4=[N:21][CH:22]=[C:17]3[NH:16][N:15]=2)[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>[OH-].[OH-].[Pd+2].CCO>[NH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[C:18]3=[C:19]4[CH:25]=[CH:24][NH:23][C:20]4=[N:21][CH:22]=[C:17]3[NH:16][N:15]=2)[CH2:9]1
Reactant: c1ccc(CN2CCCC(c3n[nH]c4cnc5[nH]ccc5c34)C2)cc1
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: c1cc2c(ncc3[nH]nc(C4CCCNC4)c32)[nH]1
Yield: 100.6 %

Procedure:
A mixture of 1-(1-benzylpiperidin-3-yl)-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine (0.18 g, 0.54 mmol), Pearlman's catalyst (0.05 g, 0.36 mmol) and ammonium formate (0.684 g, 10.8 mmol) was heated in EtOH (20 mL) at reflux for about 1 h. The catalyst was removed by filtration through a Celite® pad and the filtrate concentrated in vacuo to yield 1-(piperidin-3-yl)-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine (0.13 g, 0.543 mmol, quantitative) as a yellow amorphous solid that was used directly in the next step without further purification: LC/MS (Table 2, Method a) Rt=1.31 min; MS m/z: 242 (M+H)+.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:19]=[C:18]3[C:13]([CH2:14][CH2:15][C@H:16]([CH2:20][NH2:21])[O:17]3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:23]([C@H:25]([O:27][C:28](=[O:30])[CH3:29])[CH3:26])=[O:24]>C(Cl)Cl>[C:1]1([S:7]([C:10]2[CH:19]=[C:18]3[C:13]([CH2:14][CH2:15][CH:16]([CH2:20][NH:21][C:23]([C@H:25]([O:27][C:28](=[O:30])[CH3:29])[CH3:26])=[O:24])[O:17]3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)O[C@H](C)C(=O)Cl
Reactant: NC[C@H]1CCc2ccc(S(=O)(=O)c3ccccc3)cc2O1
Solvent: ClCCl
Product: CC(=O)O[C@H](C)C(=O)NCC1CCc2ccc(S(=O)(=O)c3ccccc3)cc2O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(R)—C-(7-Benzenesulfonyl-chroman-2-yl)-methylamine (57 mg, 0.19 mmol) triethylamine (0.02 mL) and acetic acid 1-(R)-chlorocarbonyl-ethyl ester were added to 1 mL methylene chloride, and the mixture was stirred for two hours at room temperature. The reaction was quenched by addition of water, and the mixture was extracted with methylene chloride. The combined organic layers were washed with water and brine, dried (Na2SO4), filtered and contrated under reduced pressure. Purification of the residue by flash chromatography gave 7.59 mg of (R)-acetic acid 1-[(7-benzenesulfonyl-chroman-2-ylmethyl)-carbamoyl]-ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:29])[N:6]2[CH2:16][C:17]1[CH:18]=[C:19]([P:23](=[O:28])([OH:27])[O:24]CC)[CH:20]=[CH:21][CH:22]=1.Br[Si](C)(C)C>C(#N)C>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:29])[N:6]2[CH2:16][C:17]1[CH:18]=[C:19]([P:23](=[O:24])([OH:28])[OH:27])[CH:20]=[CH:21][CH:22]=1
Reactant: CCOP(=O)(O)c1cccc(Cn2c(O)nc3c(N)nc(OCCOC)nc32)c1
Agent: C[Si](C)(C)Br
Solvent: CC#N
Product: COCCOc1nc(N)c2nc(O)n(Cc3cccc(P(=O)(O)O)c3)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.1 %

Procedure:
Ethyl hydrogen 3-((6-amino-8-hydroxy-2-(2-methoxyethoxy)-9H-purin-9-yl)methyl)phenylphosphonate (K) (10 mg, 0.0236 mmol) was suspended in anhydrous acetonitrile (3 mL). Bromotrimethylsilane (0.2 mL) was added. After stirring at room temperature overnight, the mixture was concentrated under vacuum and treated with water (2 mL). Acetonitrile (1 mL) was added and the product was purified by preparative reverse phase HPLC, yielding 3-((6-amino-8-hydroxy-2-(2-methoxyethoxy)-9H-purin-9-yl)methyl)phenylphosphonic acid (L) (1.5 mg) as a white solid. 1H-NMR (DMSO) δ: 10.0 (s, 1H), 7.64-7.35 (m, 5H), 6.48 (br, 2H), 4.86 (s, 2H), 4.25 (t, J=4.5 Hz, 2H), 3.57 (t, J=4.5 Hz, 2H), 3.25 (s, 3H). MS: 396 (MH+).
Reaction SMILES: CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[NH2:14][N+:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=1[NH2:22].[CH3:23][O:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](Cl)=O>>[Br:21][C:18]1[CH:19]=[CH:20][N:15]2[N:14]=[C:27]([C:26]3[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=3[O:24][CH3:23])[N:22]=[C:16]2[CH:17]=1
Reactant: COc1ccccc1C(=O)Cl
Reactant: Nc1cc(Br)cc[n+]1N
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Product: COc1ccccc1-c1nc2cc(Br)ccn2n1
Yield: 28.4 %

Procedure:
The product was prepared in the same manner as described in example 1b using 1,2-diamino-4-bromopyridinium 2,4,6-trimethylbenzenesulfonate (2.2 g, 5.67 mmol) and 2-methoxybenzoyl chloride (1.52 ml, 11.3 mmol) as starting materials. The reaction affords 7-bromo-2-(2-methoxyphenyl)-[1,2,4]triazolo[1,5-a]pyridine (490 mg, 28.4%) as a white solid. MS: m/z=306.0 (M+H+).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:16]2[CH2:21][CH2:20][S:19](=[O:22])[CH2:18][CH2:17]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([NH:12][CH2:13][CH2:14][CH3:15])[C:6]=2[N:7]=1.[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[O:22]=[S:19]1[CH2:20][CH2:21][N:16]([C:4]2[C:5]3[N:11]=[CH:10][N:9]=[C:8]([NH:12][CH2:13][CH2:14][CH3:15])[C:6]=3[N:7]=[C:2]([N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[N:3]=2)[CH2:17][CH2:18]1
Reactant: C1CNCCN1
Reactant: CCCNc1ncnc2c(N3CCS(=O)CC3)nc(Cl)nc12
Product: CCCNc1ncnc2c(N3CCS(=O)CC3)nc(N3CCNCC3)nc12

Procedure:
This compound was prepared analagous to Example 123 from 2-chloro-4-(1-oxido-thiomorpholino)-8-propylamino-pyrimido-[5,4-d]-pyrimidine (m.p.: 174°-176° C.) and piperazine.