Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[C:12]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:11][C:10]3[C:6](=[C:7]([C:25]([NH:27][CH3:28])=[O:26])[N:8]([C:18]4[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=4)[N:9]=3)[CH:5]=2)[CH2:3][CH2:2]1.[O:29]1[CH2:32][CH:31]([CH2:33][CH2:34]O)[CH2:30]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.CCOC(C)=O>[CH:1]1([C:4]2[C:12]([N:13]([S:14]([CH3:17])(=[O:15])=[O:16])[CH2:34][CH2:33][CH:31]3[CH2:32][O:29][CH2:30]3)=[CH:11][C:10]3[C:6](=[C:7]([C:25]([NH:27][CH3:28])=[O:26])[N:8]([C:18]4[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=4)[N:9]=3)[CH:5]=2)[CH2:2][CH2:3]1
Reactant: OCCC1COC1
Reactant: CNC(=O)c1c2cc(C3CC3)c(NS(C)(=O)=O)cc2nn1-c1ccc(C)cn1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNC(=O)c1c2cc(C3CC3)c(N(CCC3COC3)S(C)(=O)=O)cc2nn1-c1ccc(C)cn1
Reaction time: 2.5 h
Yield: 53.8 %

Procedure:
To a stirred suspension of Compound 1 (11 mg, 0.03 mmol) and 2-(oxetan-3-yl)ethanol (5.6 mg, 0.06 mmol) in THF (200 μL) was added triphenylphosphine (11 mg, 0.04 mmol) followed by DIAD (8 μL, 0.04 mmol). The suspension dissolved slowly upon stirring. Analysis of the reaction mixture after 2.5 h by LCMS showed the presence of starting material and so further aliquots of triphenylphosphine (5.0 mg, 0.05 mmol) and DIAD (8 μL, 0.04 mmol) were added. After stirring for 2 h, the reaction was diluted with EtOAc (10 mL), the organics washed with water (10 mL), brine (10 mL) and dried (MgSO4). The organics were concentrated in vacuo and the residue purified by automated column chromatography on silica gel (Biotage SP4, 4 g Grace Resolve cartridge) eluting with acetic acid: DCM (10% v/v, 10 CV) to remove the triphenylphosphine oxide followed by MeOH: DCM (gradient elution, 0% to 20%, 20 CV) to give Compound (4) (7.8 mg, 59%). ESI-MS m/z calculated for [M+H]+: 484.2; found: 484.2. 1H NMR (400 MHz, CDCl3) δ 8.47 (brs, 1H), 8.36 (s, 1H), 7.83-7.76 (m, 2H), 7.72 (s, 1H), 7.60 (s, 1H), 4.84-4.71 (m, 2H), 4.34 (q, J=6.0 Hz, 2H), 3.74-3.56 (m, 2H), 3.10-2.99 (m, 7H), 2.47 (s, 3H), 2.30 (ddd, J=13.6, 8.3, 5.4 Hz, 1H), 2.07-1.95 (m, 2H), 1.09-0.94 (m, 3H), 0.65-0.56 (m, 1H).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:6][CH:7]=[C:8]([CH:10]3[CH2:12][CH2:11]3)[CH:9]=2)[CH2:3][CH2:2]1.[I:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>>[CH:1]1([C:4]2[C:5]([N:13]3[CH2:14][CH2:15][N:16]([C:24]([C:23]4[CH:27]=[CH:28][C:20]([I:19])=[CH:21][CH:22]=4)=[O:25])[CH2:17][CH2:18]3)=[N:6][CH:7]=[C:8]([CH:10]3[CH2:12][CH2:11]3)[CH:9]=2)[CH2:2][CH2:3]1
Reactant: c1nc(N2CCNCC2)c(C2CC2)cc1C1CC1
Reactant: O=C(Cl)c1ccc(I)cc1
Product: O=C(c1ccc(I)cc1)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Yield: 90.9 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 65 and using 1-(3,5-dicyclopropylpyridin-2-yl)piperazine (5.52 g) described in Preparation Example 62, 4-iodobenzoyl chloride (6.35 g), the title compound (9.76 g) was obtained.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[N:12]([C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:13]=[C:8]3[C:9]2=[C:4]([CH2:5][CH2:6][N:7]3[CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[N:3]=1.[OH:42][C:43]([CH3:56])([CH3:55])[C@@H:44]([NH:51][C:52]([NH2:54])=[O:53])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.C(Cl)Cl>[OH:42][C:43]([CH3:56])([CH3:55])[C@@H:44]([NH:51][C:52]([NH:54][C:2]1[CH:11]=[C:10]2[N:12]([C:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:13]=[C:8]3[C:9]2=[C:4]([CH2:5][CH2:6][N:7]3[CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[N:3]=1)=[O:53])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: COc1ccc(CN2CCc3nc(Cl)cc4c3c2nn4C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(O)[C@@H](NC(N)=O)c1ccccc1
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Product: COc1ccc(CN2CCc3nc(NC(=O)N[C@@H](c4ccccc4)C(C)(C)O)cc4c3c2nn4C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1

Procedure:
7-chloro-3-(4-methoxybenzyl)-1-trityl-1,3,4,5-tetrahydropyrazolo[3,4,5-de][1,6]naphthyridine (40 mg, 0.072 mmol), (S)-1-(2-hydroxy-2-methyl-1-phenylpropyl)urea (22.4 mg, 0.108 mmol), cesium carbonate (82 mg, 0.25 mmol) and BrettPhos pre-catalyst (6.5 mg, 7.18 μM) were charged in a 1 dram vial, evacuated and backfilled with nitrogen and taken in 1,4-dioxane (0.4 mL) and heated reaction to 100° C. for 30 minutes. The reaction mixture was diluted with DCM, washed with water, brine, dried with sodium sulfate and concentrated. Purification of the residue by flash column (0-75% EtOAc-hexanes) gave (S)-1-(2-hydroxy-2-methyl-1-phenylpropyl)-3-(3-(4-methoxybenzyl)-1-trityl-1,3,4,5-tetrahydropyrazolo[3,4,5-de][1,6]naphthyridin-7-yl)urea. MS ESI calc'd. for C46H44N6O3 [M+H]+ 729. found 729.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14]([C:16]([C:18]2([N:21]3[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]3)[CH2:20][CH2:19]2)=[O:17])[C@H:13]([C:34](=[O:41])[NH:35][C:36]2([C:39]#[N:40])[CH2:38][CH2:37]2)[CH2:12]1)(=[O:10])=[O:9].C(=O)([O-])O.[Na+]>C(O)=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14]([C:16]([C:18]2([N:21]3[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]3)[CH2:19][CH2:20]2)=[O:17])[C@H:13]([C:34]([NH:35][C:36]2([C:39]#[N:40])[CH2:37][CH2:38]2)=[O:41])[CH2:12]1)(=[O:10])=[O:9]
Reactant: CC(C)(C)OC(=O)N1CCN(C2(C(=O)N3C[C@H](S(=O)(=O)c4ccccc4Cl)C[C@H]3C(=O)NC3(C#N)CC3)CC2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Solvent: O
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2C(=O)C2(N3CCNCC3)CC2)CC1
Yield: 73.2 %

Procedure:
A solution of tert-butyl 4-(1-((2S,4R)-4-(2-chlorophenylsulfonyl)-2-(1-cyanocyclopropylcarbamoyl)pyrrolidine-1-carbonyl)cyclopropyl)piperazine-1-carboxylate (367 mg, 605 μmol) in formic acid (6.05 mL) was stirred at room temperature for 5 hours. The reaction was diluted with water under ice cooling and set to pH 7-8 slowly by first adding saturated aqueous sodium hydrogen carbonate solution and then with solid sodium hydrogen carbonate. The reaction was extracted three times with methylenechloride. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure to yield the title compound as a light yellow foam (224 mg, 73%). MS ISP (m/e): 506.1/508.2 (100/45) [(M+H)]+.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:21]([C:23]([C@@H:25]1[CH2:30][CH2:29][CH2:28][CH2:27][N:26]1[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[O:24])[NH2:22].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:22][NH:21][C:23]([C@@H:25]1[CH2:30][CH2:29][CH2:28][CH2:27][N:26]1[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[O:24])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)NN
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
To a solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.25 g, 0.90 mmol) in dry DCM (30 mL) were added tert-butyl (2S)-2-(hydrazinylcarbonyl)piperidine-1-carboxylate 270 (0.33 g, 1.35 mmol), 1-hydroxybenzotriazole (0.19 g, 1.35 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.26 g, 1.35 mmol) and 4-(dimethylamino)pyridine (0.16 g, 1.35 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight and concentrated under vacuum. The residue was purified by column chromatography to give tert-butyl (2S)-2-[(2-{[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]piperidine-1-carboxylate 271 (0.37 g, 82%) as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=3)[C:5]2=[CH:4][N:3]=1.[CH3:19][N:20]([CH3:24])[CH2:21][CH2:22][NH2:23].C(N(CC)CC)C>CC(O)C>[CH3:19][N:20]([CH3:24])[CH2:21][CH2:22][NH:23][C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=3)[C:5]2=[CH:4][N:3]=1
Reactant: CN(C)CCN
Reactant: CSc1nccc(-c2n[nH]c3nc(Cl)ncc23)n1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CSc1nccc(-c2n[nH]c3nc(NCCN(C)C)ncc23)n1
Yield: 75.3 %

Procedure:
To a solution of 6-chloro-3-(2-methylsulfanyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidine (from Example 7 supra) (400 mg, 1.43 mmol) in 2-propanol (40 mL) was added N, N-dimethylethane-1,2-diamine (139 mg, 1.58 mmol) followed by triethylamine (159 mg, 1.57 mmol). The reaction mixture was stirred at reflux for 15 hours and the solvent was then removed under reduced pressure. The residue was extracted with dichloromethane (3×30 mL), washed with water (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford N,N-dimethyl-N′-[3-(2-methylsulfanyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-ethane-1,2-diamine (Yield 356 mg, 75%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[CH:8]=[C:9]([N:11]([C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])[CH3:12])[CH:10]=1)=O.[N:25]1[CH:30]=[CH:29][N:28]=[CH:27][C:26]=1[CH:31]([NH2:33])[CH3:32].C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[N:25]1[CH:30]=[CH:29][N:28]=[CH:27][C:26]=1[CH:31]([NH:33][C:3]([C:5]1[CH:6]=[C:7]([C:18]2[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=2)[CH:8]=[C:9]([N:11]([C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])[CH3:12])[CH:10]=1)=[O:2])[CH3:32]
Reactant: CC(N)c1cnccn1
Reactant: COC(=O)c1cc(-c2ccc(C)cc2)cc(N(C)C(=O)C(C)C)c1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: Cc1ccc(-c2cc(C(=O)NC(C)c3cnccn3)cc(N(C)C(=O)C(C)C)c2)cc1
Temperature: 25 °C
Yield: 34.9 %

Procedure:
5-(Isobutyryl-methyl-amino)-4′-methyl-biphenyl-3-carboxylic acid methyl ester (67 mg, 0.22 mmol) was added to methylene chloride (3 mL) and stirred at room temperature. TEA (0.87 g), 1-pyrazin-2-yl-ethylamine (32 mg, 0.25 mmol), HOBt (29 mg) and ECDI (54 mg) were added, and the reaction mixture was stirred overnight at room temperature. The reaction mixture was placed directly onto a silica column and eluted with 50% ethyl acetate/hexanes to give 32 mg of 5-(isobutyryl-methyl-amino)-4′-methyl-biphenyl-3-carboxylic acid (1-pyrazin-2-yl-ethyl)-amide as a white solid, MS (M+H)=417.
Reaction SMILES: [CH:1]([C:3]1[CH:30]=[CH:29][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:16]=[CH:17][C:18]([O:24][S:25]([CH3:28])(=[O:27])=[O:26])=[C:19]([CH:23]=3)[C:20]([O-:22])=[O:21])[O:12][C:13]=2[CH3:14])=[C:5]([O:31][CH3:32])[CH:4]=1)=[O:2].[CH2:33](O)C.[BH4-].[Na+].Cl>O1CCCC1>[OH:2][CH2:1][C:3]1[CH:30]=[CH:29][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:16]=[CH:17][C:18]([O:24][S:25]([CH3:28])(=[O:27])=[O:26])=[C:19]([CH:23]=3)[C:20]([O:22][CH3:33])=[O:21])[O:12][C:13]=2[CH3:14])=[C:5]([O:31][CH3:32])[CH:4]=1
Reactant: CCO
Reactant: COc1cc(C=O)ccc1OCc1nc(-c2ccc(OS(C)(=O)=O)c(C(=O)[O-])c2)oc1C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1cc(-c2nc(COc3ccc(CO)cc3OC)c(C)o2)ccc1OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
To a solution of methyl (5-{4-[(4-formyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}-2-methanesulfonyloxybenzoate (5.70 g) in tetrahydrofuran (100 mL)-ethanol (10 mL) was gradually added sodium borohydride (0.23 g) at 0° C. After stirring the reaction mixture at room temperature for 2 hrs, dilute hydrochloric acid was added to acidify the solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-hexane (5:1, v/v) to give methyl 5-{4-[(4-hydroxymethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}-2-methanesulfonyloxybenzoate as colorless crystals (4.02 g, yield 70%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 126-127° C.
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[CH:5]=[CH:6][CH:7]=[C:8]3[C:14](=[O:15])[NH:13][CH2:12][CH2:11][C:10]=1[C:9]=23.C([Sn](CCCC)(CCCC)[C:21]#[C:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)CCC.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>CN(C=O)C.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:23]1([C:22]#[C:21][N:3]2[C:4]3[CH:5]=[CH:6][CH:7]=[C:8]4[C:14](=[O:15])[NH:13][CH2:12][CH2:11][C:10]([C:9]=34)=[CH:2]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C1NCCc2c(Br)[nH]c3cccc1c23
Reactant: CCCC[Sn](C#Cc1ccccc1)(CCCC)CCCC
Agent: [Pd]
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C1NCCc2cn(C#Cc3ccccc3)c3cccc1c23
Temperature: 60 °C
Yield: 55.2 %

Procedure:
Tricyclic bromide 11 (58.6 mg, 0.22 mmol) in DMF (1 mL) was degassed and treated with tributyl(phenylethynyl)tin (95.2 mg, 0.24 mmol) and tetrakis(triphenylphosphine) palladium(0) (13 mg, 2 mol %). One crystal of 2,6-di-t-butyl-4-methyl phenol was added, and the solution was heated at 60° C. for 10 h. Starting material was still present, so the solution was heated at 100° C. for an additional 2 h. The reaction mixture was cooled to ambient temperature and diluted with water (2 mL) and extracted with EtOAc (5 mL×3). The organic solution was washed with water and brine, dried (Na2SO4), filtered, and concentrated. The crude product was purified by radial chromatography (2 mm SiO2; 3% MeOH in CH2Cl2) to yield 17 as a white solid (34.8 mg, 55%). mp 255-256° C. (dec); 1H NMR (DMSO-d6) δ 11.86 (s, 1H), 8.17 (m, 1H), 7.75 (d, 1H, J=7.6 Hz), 7.63 (m, 3H), 7.51 (m, 3H), 7.33 (t, 1H, J=7.6 Hz), 3.50 (m, 2H), 3.09 (m, 2H); HRMS (FAB, M+H) Calcd for C19H14N2O+H: 287.1184, Found: 287.1192; Anal. (C19H14N2O.0.6 H2O) C, H, N.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]2[C:11]3[CH2:19][CH2:18][CH2:17][C:12]=3[C:13]([CH3:16])([CH3:15])[O:14][C:9]=2[CH:8]=[C:7]([CH:20]([CH3:28])[CH:21]([CH3:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:6]=1)(=[O:3])[CH3:2].[O:29]1C=CC=CC1.C(OC(=O)C)(=O)C>N1C=CC=CC=1.C(O)(=O)C.C(Cl)(Cl)Cl>[C:1]([O:4][C:5]1[C:10]2[C:11]3[CH2:19][CH2:18][C:17](=[O:29])[C:12]=3[C:13]([CH3:16])([CH3:15])[O:14][C:9]=2[CH:8]=[C:7]([CH:20]([CH3:28])[CH:21]([CH3:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CCCCCC(C)C(C)c1cc(OC(C)=O)c2c(c1)OC(C)(C)C1=C2CCC1
Reactant: C1=CCOC=C1
Solvent: CC(=O)O
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CCCCCC(C)C(C)c1cc(OC(C)=O)c2c(c1)OC(C)(C)C1=C2CCC1=O
Reaction time: 0.5 h

Procedure:
To a stirring mixture of 9-acetoxy-4,4-dimethyl-7-(1,2-dimethylheptyl)-1,2,3,4-tetrahydrocyclopenta[ c][l] benzopyran (7.59 g., 19.7 mmole) in 60 ml. of 50% acetic acid and 10 ml. of chloroform under a nitrogen atmosphere, was added dropwise a solution of ceric ammonium nitrate (43.2 g., 78.8 mmole) in 100 ml. of 50% acetic acid. After the addition was completed, the reaction mixture was stirred over a steam bath for 1/2 hour. It was then extracted with several portions of chloroform and the organic solvents were removed by evaporation under reduced pressure. The residue was taken up in ether, neutralized with 5% NaHCO3, washed with water and dried over Na2SO4. Evaporation of the ether in vacuo left 14.7 g. of crude material. Purification of the crude product involved three chromatograhpies, two column and a final preparative thin-layer chromatography, with each using diethyl ether/petroleum ether solvent mixtures. An nmr spectrum taken at this time, however, showed that the compound had been partially deacetylated as a result of the chromatograhpies. The product was reacetylated in the usual manner by heating the pyran with acetic anhydride in pyridine. Upon workup, 57 mg. of product was obtained which gave a single fluorescent spot on tlc (R f 0.41). The ir and nmr were in agreement with the proposed structure.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH2:5][CH2:4]1.CS(O[CH2:22][CH2:23][CH:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=O)=O.[Na+].[I-]>CC#N>[Cl:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][N:6]2[CH2:7][CH2:8][CH:3]([CH2:2][NH:1][CH2:22][CH2:23][CH:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:4][CH2:5]2)=[CH:15][CH:14]=1
Reactant: NCC1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: CS(=O)(=O)OCCC(c1ccccc1)c1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: Clc1ccc(CN2CCC(CNCCC(c3ccccc3)c3ccccc3)CC2)cc1
Yield: 54 %

Procedure:
4-(Aminomethyl)-1-(4-chlorobenzyl)piperidine (120 mg) was alkylated with 3,3-diphenylpropyl methanesulfonate (1.0 equiv.) in the presence of NaI (2.6 equiv.) in CH3CN at 70° C. for 16 h. General workup and column chromatography (SiO2) afforded 1-(4-chlorobenzyl)-4-{N-(3,3-diphenylpropyl)aminomethyl}piperidine (118 mg, 54%): The purity was determined by RPLC (98%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]([CH3:32])([CH3:31])[CH2:6][S:7][CH2:8][C:9]1[C:14]([CH3:15])=[C:13]([O:16][CH3:17])[CH:12]=[CH:11][N+:10]=1[C:18]1[NH:19][C:20]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:21]=2[N:22]=1.[CH3:33][S:34]([OH:37])(=[O:36])=[O:35]>CO>[CH3:33][S:34]([O-:37])(=[O:36])=[O:35].[OH:1][CH2:2][CH2:3][O:4][C:5]([CH3:32])([CH3:31])[CH2:6][S:7][CH2:8][C:9]1[C:14]([CH3:15])=[C:13]([O:16][CH3:17])[CH:12]=[CH:11][N+:10]=1[C:18]1[NH:19][C:20]2[CH:26]=[C:25]([C:27]([F:28])([F:30])[F:29])[CH:24]=[CH:23][C:21]=2[N:22]=1
Reactant: CS(=O)(=O)O
Agent: COc1cc[n+](-c2nc3ccc(C(F)(F)F)cc3[nH]2)c(CSCC(C)(C)OCCO)c1C
Solvent: CO
Product: CS(=O)(=O)[O-]

Procedure:
370 mg of intramolecularly deprotonized 2-[[[2-(2-hydroxyethoxy)-2-methylpropyl]thio]methyl]-4-methoxy-3-methyl-1-[5-(trifluoromethyl)-2-benzimdazolyl]pyridinium cation were dissolved in methanol, whereupon 100 mg of methanesulfonic acid were added thereto, the solution was concentrated and the residue was crystallized from ether/ethyl acetate. The 2-[[[2-(2-hydroxyethoxy)-2-methylpropyl]thio]methyl]-4-methoxy-3-methyl-1-[5-(trifluoromethyl)-2-benzimidazolyl]pyridinium methanesulfonate obtained exhibited a melting point of 105°-107° (decomposition).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.C1C[O:12][CH2:11][CH2:10]1.[Li+].CC([N-]C(C)C)C.C(=O)C>CCOC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([CH:11]([OH:12])[CH3:10])[C:5]([F:8])=[CH:4][N:3]=1
Reactant: Fc1ccc(Br)nc1
Reactant: C1CCOC1
Agent: CC(C)[N-]C(C)C
Agent: CC=O
Agent: [Li+]
Solvent: CCOC(C)=O
Product: CC(O)c1cc(Br)ncc1F
Temperature: -78 °C
Reaction time: 4 h
Yield: 86 %

Procedure:
To a 1000 mL 3-neck flask was added 2-bromo-5-fluoropyridine (8.80 g, 50 mmol) and THF (200 mL) at −78° C. followed by dropwise addition of LDA (20.0 mL, 50 mmol, 2.5 M). After stirring at −78° C. for 4 h, acetaldehyde (3.1 mL, 55 mmol) was added dropwise via syringe. The contents were removed from the cold bath and stirred at room temperature overnight. The mixture was diluted with H2O (150 mL), and vigorously stirred for 5 min. The contents were extracted with ethyl ether (3×150 mL), the combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to afford a yellow oil. The crude product was passed through a short silica column (eluent: 3:1 PE/EtOAc) to afford 1-(2-bromo-5-fluoropyridin-4-yl)ethanol as a white solid (9.5 g, 86%). ESI MS m/z=220 (M+1)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:10]=[CH:9][NH:8][N:7]=1)=[O:5])[CH3:2].C(N(CC)C(C)C)(C)C.[C:20](Cl)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C=O)C.C(OC(=O)C)C>[CH2:1]([O:3][C:4]([C:6]1[N:10]=[CH:9][N:8]([C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc[nH]n1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 2 h
Yield: 43 %

Procedure:
In 60 ml of DMF was dissolved 7.62 g (54 mmol) of 1H-1,2,4-triazole-3-carboxylic acid ethyl ester. To the solution were added at room temperature 14 g (108 mmol) of N,N-diisopropylethylamine and 15.8 g (56.7 mmol) of tritylchloride. The mixture was stirred for 2 hours. 300 ml of water and 300 ml of ethylacetate were added thereto. The crystal was filtered, dissolved in 150 ml of chloroform, washed with water and dried. The solvent was removed. The residue was crystallized from ether to give 8.91 g of the titled compound. The ethylacetate layer was washed with water, dried and evaporated. The residue was crystallized from ether to give 4.73 g of the titled compound. 13.64 g of 1-trityl-1,2,4-triazole-3-carboxylic acid ethyl ester was totally obtained. Yield: 66%.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[CH:19]=[N:20][CH:21]=[C:22]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:23]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[CH:19]=[N:20][CH:21]=[C:22]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:23]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3cncc(S(C)(=O)=O)c3)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(Nc3cncc(S(C)(=O)=O)c3)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.3 %

Procedure:
To a solution of N-tert-butyl-2-(5-(methylsulfonyl)pyridin-3-ylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (125 mg, 241 mol) in dichloromethane was added trifluoroacetic acid (550 mg, 371 μL, 4.82 mmol) and the mixture stirred at room temperature for 16 h. The mixture was concentrated then re-dissolved in dichloromethane (3.7 mL), methanol (1.6 mL) and ammonium hydroxide (0.5 mL) and the mixture stirred at room temperature for 1 h. The mixture was concentrated in vacuo then triturated with water and filtered. The solid obtained was washed with ether then dried to give N-tert-butyl-2-(5-(methylsulfonyl)pyridin-3-ylamino)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (92 mg, 237 mol, 98%) as a yellow solid. 1H NMR (400 MHz, DMSO-d) δ ppm: 12.38 (s, 1H), 9.90 (s, 1H), 9.40 (d, J=2.5, 1 H), 8.55 (d, J=1.9, 1 H), 8.06 (t, J=2.2, 1H), 8.01 (s, 1H), 7.96 (s, 1H), 7.54 (s, 1H), 3.22 (s, 3H), 1.31 (s, 9H); MS (EI/CI) m/z: 389.1 [M+H].