Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: 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.[CH3:34][C:35]1[N:40]=[C:39]2[N:41]=[C:42]([CH2:44][CH3:45])[NH:43][C:38]2=[C:37]([CH3:46])[CH:36]=1.[Cl:47][C:48]1[CH:65]=[C:64]([CH2:66]O)[CH:63]=[C:62]([CH2:68][CH:69]=[CH2:70])[C:49]=1[O:50][CH:51]([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[C:52]([O:54][CH3:55])=[O:53]>C1COCC1>[C:52]([CH:51]([C:56]1[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1)[O:50][C:49]1[C:62]([CH2:68][CH:69]=[CH2:70])=[CH:63][C:64]([CH2:66][N:41]2[C:39]3=[N:40][C:35]([CH3:34])=[CH:36][C:37]([CH3:46])=[C:38]3[N:43]=[C:42]2[CH2:44][CH3:45])=[CH:65][C:48]=1[Cl:47])([O:54][CH3:55])=[O:53]
Reactant: CCc1nc2nc(C)cc(C)c2[nH]1
Reactant: C=CCc1cc(CO)cc(Cl)c1OC(C(=O)OC)c1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CCc1cc(Cn2c(CC)nc3c(C)cc(C)nc32)cc(Cl)c1OC(C(=O)OC)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.8 %

Procedure:
To a magnetically stirred solution of 0.541 g (2.06 mmol) of triphenylphosphine in 4 mL anhydrous THF was added 406 μL (2.06 mmol) of diisopropylazodicarboxylate at -20° C. The reaction mixture was stirred for 1 hour, followed by addition of a solution of 0.301 g (1.72 mmol) of 5,7-dimethyl-2-ethylimidazo[4,5-b]pyridine and 0.596 g (1.72 mmol) of the product of Step C in 6 mL THF. The reaction mixture was stirred 20 min at -20° C., then warmed to room temperature and stirred an additional 1 hour. The reaction mixture was then evaporated in vacuo and applied to a silica gel flash chromatography column. Elution with 50% EtOAc-hexane, evaporation of the purified fractions and drying in vacuo afforded 0.440 g (51%) of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8]C(N)CN)=[CH:3][CH:2]=1.[CH2:13]([NH2:16])[CH2:14][NH2:15]>>[N:1]1[CH:2]=[CH:3][C:4]([CH2:7][CH2:8][NH:15][CH2:14][CH2:13][NH2:16])=[CH:5][CH:6]=1
Reactant: NCCN
Reactant: NCC(N)CCc1ccncc1
Product: NCCNCCc1ccncc1
Yield: 35 %

Procedure:
This was an adaptation of the procedure reported by R. G. Lacoste and A. E. Martel in Inorganic Chemistry 1964, 3(6), 881, for the preparation of N-[2-(4-pyridyl-ethyl]ethylene diamine. To a 250 ml three neck round bottom flask, fitted with a dropping funnel, a reflux condenser, and magnetic stirring, was added 12.02 g (0.2 mol) ethylene diamine, 24 g distilled water, and 31.50 g (0.3 mol) freshly distilled 4-vinylpyridine. The temperature was maintained at 20°-30° C. while 12.0 g glacial acetic was added through the dropping funnel. After all the acetic acid was added, the reaction mixture was heated on the steam bath for two hours. The product was fractionally distilled to give 11.48 g (35% yield). The product was characterized by IR and NMR.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:20]([CH2:21][N:22]3[C:26](=O)[C:25]4=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]4C3=O)=[N:19][N:18]=[C:17]2[CH2:33][CH2:34][N:35]([CH3:37])[CH3:36])=[C:6]([CH:15]=1)C(C1C=CC=CC=1)=O.O.NN>C(O)C>[CH3:36][N:35]([CH3:37])[CH2:34][CH2:33][C:17]1[N:16]2[C:5]3[CH:6]=[CH:15][C:2]([F:1])=[CH:3][C:4]=3[C:26]([C:25]3[CH:24]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:22][CH2:21][C:20]2=[N:19][N:18]=1
Reactant: CN(C)CCc1nnc(CN2C(=O)c3ccccc3C2=O)n1-c1ccc(F)cc1C(=O)c1ccccc1
Agent: NN
Solvent: CCO
Solvent: O
Product: CN(C)CCc1nnc2n1-c1ccc(F)cc1C(c1ccccc1)=NC2

Procedure:
In the manner given in Example 1C, 5-fluoro-2-[3-[2-(dimethylamino)ethyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone in ethanol is refluxed with hydrazine hydrate to give 1-[2-(dimethylamino)ethyl]-8-fluoro-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine. This compound is converted to its hydrobromide by treating it with hydrogen bromide gas in ether.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11](=O)[CH3:12])[C:8]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:28].[Na+]>CO.C(#N)C>[Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([NH2:28])[CH3:12])[C:8]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2
Reactant: [BH3-]C#N
Reactant: CC(=O)c1cc(Cl)c2cn[nH]c2c1-c1cc(F)cc(F)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: CC(N)c1cc(Cl)c2cn[nH]c2c1-c1cc(F)cc(F)c1
Temperature: 65 °C

Procedure:
A mixture of 1-[4-chloro-7-(3,5-difluorophenyl)-1H-indazol-6-yl]ethanone (0.20 g, 0.65 mmol) and ammonium acetate (0.50 g, 6.5 mmol) and sodium cyanoborohydride (0.082 g, 1.3 mmol) in methanol (2 mL) and acetonitrile (2 mL) was heated at 65° C. overnight in a sealed tube. The mixture was then cooled to room temperature and quenched with sat. sodium bicarbonate and then extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness to give the crude amine which was used directly in the next step. LCMS calculated for C15H10ClF2N2 (M−NH2)+: m/z=291.0; Found: 291.0.
Reaction SMILES: N[C:2]1([NH2:16])[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]1=[N:4][CH:5]=[N:6]2.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:26]>CN(C=O)C>[NH2:16][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]=[CH:5][N:6]2[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:26]
Reactant: COCCOC1=NC(N)(N)C2=NC=NC2=N1
Reactant: O=C(CBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1nc(N)c2ncn(CC(=O)c3ccccc3)c2n1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 6-amino-2-(2-methoxyethoxy)adenine (500 mg, 2.39 mmol) in DMF (5 ml) was added K2CO3 (330 mg, 2.39 mmol). Then 2-bromoacetophenone was added and the reaction mixture was heated to 70° C. with stirring for 30 min. The solvent was removed under vacuum and the residue was washed with brine. The aqueous phase was extracted with DCM and the organic layer was dried over Na2SO4, filtered, concentrated, and purified by silica gel chromatography using linear gradient of MeOH in DCM as eluent. 1H NMR (CDCl3) δ 3.40 (s, 3H), δ 3.72 (t, 2H), δ 4.45 (t, 2H), δ 5.58 (s, 2H), δ 5.67 (bs, 2H), δ 7.53-7.74 (m, 4H), δ 8.03 (s, 1H), δ 8.06 (s, 1H); MS: 328.2 (M+1), 326.0 (M−1).
Reaction SMILES: [Br:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[O:9]([C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>N1C=CC=CC=1.CCOC(C)=O>[Br:1][C:2]1[C:7]([NH:8][S:22]([C:19]2[CH:18]=[CH:17][C:16]([O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:21][CH:20]=2)(=[O:24])=[O:23])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Oc2ccccc2)cc1
Reactant: Nc1cccnc1Br
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=S(=O)(Nc1cccnc1Br)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C

Procedure:
To a solution of 2-bromo-3-aminopyridine (0.69 g, 3.98 mmol) in dry pyridine (15 mL) was added a solution of 4-phenoxy-benzenesulfonyl chloride (1.03 g, 3.98 mmol) in pyridine (3 mL) at 0 C. The resulting mixture was allowed to warm to room temperature and stirred until TCL showed the completion of the reaction. The reaction mixture was diluted with EtOAc and washed with aqueous HCl solution. After the pyridine was neutralized, the organics were washed with water, brine and dried over anhydrous Na2SO4. The filtration (Celite) and concentration under vacuo gave a crude material, which was purified by silica column (30% EtOAc/hexanes). MS: 405, 407 (M+H)+.
Reaction SMILES: [C:1]([O:9]CC)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH2:17]C#N.CC[O-].[Na+].[Na]>O.C(O)C>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:1]([CH2:17][C:16]2[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:14]([O:13][CH3:12])[CH:15]=2)=[O:9])[CH:3]=1
Reactant: CCOC(=O)c1cccnc1
Reactant: COc1ccc(CC#N)cc1OC
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CCO
Product: COc1ccc(CC(=O)c2cccnc2)cc1OC

Procedure:
A mixture of 45.4 g of ethyl nicotinate and 35.4 g of 3,4-dimethoxybenzyl cyanide is added dropwise to a boiling solution of sodium ethylate prepared from 6 g of sodium and 100 ml of ethanol. The mixture is kept at reflux for 5 hours and, after cooling, is poured into 1 liter of water. The excess nicotinic ester is removed with toluene, and the aqueous solution is neutralized with glacial acetic acid, 50.7 g of α-cyano-3,4-dimethoxybenzyl 3-pyridyl ketone separating out as crystals (melting point 149°-152° C.). This cyanoketone (31.0 g) is hydrolyzed in 6N hydrochloric acid at 80°-90° C. The hydrochloride of the 3,4-dimethoxybenzyl 3-pyridyl ketone crystallizes from ethanol with melting point 188°-191° C. and the free base has a melting point of 60°-64° C. The compound is converted into the oxime without further purification.
Reaction SMILES: [CH2:1]([S:4]([N:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[C:33]([NH2:35])[CH:32]=[CH:31][C:30]=4[O:36][C:37]([F:40])([F:39])[F:38])=[CH:25][CH:24]=3)=[O:22])=[CH:16][CH:15]=2)[CH2:9][CH2:8]1)(=[O:6])=[O:5])[CH2:2][CH3:3].C(N(CC)C(C)C)(C)C.[CH:50]1([C:53](Cl)=[O:54])[CH2:52][CH2:51]1>C1COCC1>[CH2:1]([S:4]([N:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[C:33]([NH:35][C:53]([CH:50]5[CH2:52][CH2:51]5)=[O:54])[CH:32]=[CH:31][C:30]=4[O:36][C:37]([F:39])([F:40])[F:38])=[CH:25][CH:24]=3)=[O:22])=[CH:16][CH:15]=2)[CH2:9][CH2:8]1)(=[O:5])=[O:6])[CH2:2][CH3:3]
Reactant: O=C(Cl)C1CC1
Reactant: CCCS(=O)(=O)N1CCN(Cc2ccc(NC(=O)c3ccc(-c4cc(N)ccc4OC(F)(F)F)cc3)cc2)CC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCCS(=O)(=O)N1CCN(Cc2ccc(NC(=O)c3ccc(-c4cc(NC(=O)C5CC5)ccc4OC(F)(F)F)cc3)cc2)CC1
Yield: 32.2 %

Procedure:
A stirred solution of 5′-amino-2′-trifluoromethoxy-biphenyl-4-carboxylic acid {4-[4-(propane-1-sulfonyl)-piperazin-1-ylmethyl]-phenyl}-amide (50 mg) in dry THF (1 ml) was treated with N,N-diisopropylethylamine (60 μl) followed by cyclopropane carbonyl chloride (18 mg). After 16 h the mixture was evaporated and the residue purified by chromatography. Gradient elution with 0%-30% 20DCM:8EtOH:1NH3 in DCM over 35 mins gave the title compound as an off-white solid (18 mg).
Reaction SMILES: [CH3:1][C:2]([CH3:20])=[CH:3][CH2:4][C@H:5]1[O:7][C@@:6]1([C@@H:9]1[C@:14]2([O:16][CH2:15]2)[CH2:13][CH2:12][C@@H:11]([OH:17])[C@H:10]1[O:18][CH3:19])[CH3:8].[Cl:21][CH2:22][C:23]([N:25]=[C:26]=[O:27])=[O:24].CN(C1C=CC=CN=1)C.O>ClCCl>[CH3:1][C:2]([CH3:20])=[CH:3][CH2:4][C@@H:5]1[O:7][C@:6]1([C@@H:9]1[C@:14]2([O:16][CH2:15]2)[CH2:13][CH2:12][C@@H:11]([O:17][C:26]([NH:25][C:23]([CH2:22][Cl:21])=[O:24])=[O:27])[C@H:10]1[O:18][CH3:19])[CH3:8]
Reactant: CO[C@@H]1[C@H](O)CC[C@]2(CO2)[C@H]1[C@@]1(C)O[C@@H]1CC=C(C)C
Reactant: O=C=NC(=O)CCl
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: O
Product: CO[C@@H]1[C@H](OC(=O)NC(=O)CCl)CC[C@]2(CO2)[C@H]1[C@]1(C)O[C@H]1CC=C(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 71.2 %

Procedure:
To a solution of fumagillol (314 mg) in dichloromethane (5 ml) was added dropwise chloroacetyl isocyanate (160 mg) under ice cooling, followed by addition of dimethylaminopyridine (130 mg). The mixture was stirred at 0° C. for 2 hours. To this reaction mixture was added water and the mixture was extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was subjected to silica gel column chromatography. The eluate obtained with a mixture of n-hexane and ethyl acetate (3:1) was concentrated under reduced pressure to give colorless, powdery O-chloroacetylcarbamoylfumagillol (318 mg) (71% yield).
Reaction SMILES: C([O:4][CH2:5][CH2:6][S:7][C:8]([F:26])([F:25])[C:9]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[F:24])([OH:16])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1)(=O)C.O.[OH-].[Li+]>C(O)C>[F:24][C:18]1[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=1[C:9]([OH:16])([CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1)[C:8]([F:26])([F:25])[S:7][CH2:6][CH2:5][OH:4]
Reactant: CC(=O)OCCSC(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: OCCSC(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 27 %

Procedure:
To a solution of 1-(2-acetoxyethyl)thio-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)propan-2-ol (14.3 g, 0.12 mol) in ethanol (200 ml), a 10% aqueous solution (20 ml) of lithium hydroxide monohydrate was added and they were stirred at room temperature for one hour. After the completion of the reaction, the reaction mixture was distilled off under reduced pressure. Water was added to the residue so obtained, followed by extraction with chloroform. The chloroform solution was washed with water, dried over magnesium sulfate and then distilled off under reduced pressure, whereby 2-(2,4-difluorphenyl)-1,1-difluoro-1-(2-hydroxyethyl)thio-3-(1H-1,2,4-triazol-1-yl)propan-2-ol (11.4 g, yield: 89.8%) was obtained as colorless crystals.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[O:3].[C:6]([C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)([CH3:9])([CH3:8])[CH3:7].S(=O)(=O)(O)O>C(O)(=O)C>[C:1]([OH:5])(=[O:4])[CH3:2].[C:6]([C:10]1[CH:11]=[C:12]([CH3:17])[C:13]([CH:2]([OH:3])[C:1]([OH:5])=[O:4])=[C:14]([CH3:16])[CH:15]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: O=CC(=O)O
Reactant: Cc1cc(C)cc(C(C)(C)C)c1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1cc(C(C)(C)C)cc(C)c1C(O)C(=O)O
Temperature: 35 °C
Reaction time: 9 h

Procedure:
A mixture of 89 g of 50% aqueous glyoxylic acid solution [0.6 mol], 400 ml of glacial acetic acid and 81.1 g [0.5 mol] of 1-tert-butyl-3,5-dimethylbenzene is initially charged. Starting at room temperature, 85.8 g of 96% strength sulfuric acid [0.84 mol] are added dropwise over a period of 15 minutes, during which time the temperature of the reaction mixture increases to about 35° C. The mixture is heated to 60° C. and stirred at this temperature for 9 hours. The cooled reaction mixture is then stirred into 750 ml of ice-water. The mixture is extracted three times with in each case 150 ml of methylene chloride, the combined organic phases are washed with 100 ml of saturated aqueous NaCl solution, dried over sodium sulfate and concentrated under reduced pressure. This gives 136.7 g of a yellowish thick oil, which, according to GC/MS(sil.), has the following composition:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21](O)=[O:22])=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[NH2:32][C@H:33]([CH3:36])[CH2:34][OH:35].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[OH:35][CH2:34][C@H:33]([NH:32][C:21]([C:20]1[C:14]2[C:15](=[N:16][CH:17]=[C:12]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:8]([CH3:11])[N:7]=3)[N:13]=2)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:31])[CH3:30])[CH:19]=1)=[O:22])[CH3:36]
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Reactant: C[C@@H](N)CO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](CO)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.7 %

Procedure:
A 25 mL round-bottomed flask was charged with 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (0.15 g, 0.33 mmol), (R)-2-aminopropan-1-ol (49 mg, 0.66 mmol), HBTU (155 mg, 0.41 mmol), and HOBT (58 mg, 0.49 mmol). Then added DMF (1.1 mL) followed by N,N-diisopropylethylamine (0.17 mL, 0.97 mmol). The yellow reaction mixture was stirred at room temperature overnight then quenched with water and extracted with EtOAc (30 mL). The organic layer was washed once with saturated NaHCO3 and water. The combined aqueous layers were back extracted with EtOAc (25 mL). The combined organic layers was dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography over SiO2 with EtOAc/hexanes (gradient: 0-60% EtOAc) to afford 110 mg (65%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-2-hydroxy-1-methyl-ethyl)-amide as an off-white solid. MS: [M+H]+=515.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[O:15][CH:14]([CH2:17]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:13][C:12]=2[CH:11]=[C:10]([O:29][CH3:30])[CH:9]=1.[CH3:31][NH2:32]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[O:15][CH:14]([CH2:17][NH:32][CH3:31])[CH2:13][C:12]=2[CH:11]=[C:10]([O:29][CH3:30])[CH:9]=1
Reactant: COc1cc2c(c(-c3ccccc3C)c1)OC(COS(=O)(=O)c1ccc(C)cc1)C2
Reactant: CN
Product: CNCC1Cc2cc(OC)cc(-c3ccccc3C)c2O1

Procedure:
The title compound was prepared (0.055 g, 54%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-{[7-(2-methylphenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}4-methylbenzenesulfonate (0.135 g, 0.32 mmol) and methylamine (0.099 g, 3.2 mmol). mp 167-169° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[CH:12][CH:11]=[CH:10]3)=[N:5][N:4]=[C:3]1[SH:17].Br[CH2:19][CH2:20][CH2:21][CH:22]1[O:27][CH2:26][C:25]([CH3:29])([CH3:28])[CH2:24][O:23]1.[OH-].[Li+]>CN(C)C=O>[CH3:28][C:25]1([CH3:29])[CH2:24][O:23][CH:22]([CH2:21][CH2:20][CH2:19][S:17][C:3]2[N:2]([CH3:1])[C:6]([C:7]3[CH:8]=[C:9]4[C:14](=[CH:15][CH:16]=3)[N:13]=[CH:12][CH:11]=[CH:10]4)=[N:5][N:4]=2)[O:27][CH2:26]1
Reactant: Cn1c(S)nnc1-c1ccc2ncccc2c1
Reactant: CC1(C)COC(CCCBr)OC1
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cn1c(SCCCC2OCC(C)(C)CO2)nnc1-c1ccc2ncccc2c1
Yield: 64.2 %

Procedure:
4-Methyl-5-quinolin-6-yl-4H-[1,2,4]triazole-3-thiol (0.5 g, 2.07 mmol), 2-(3-Bromo-propyl)-5,5-dimethyl-[1,3]dioxane (0.49 g, 2.07 mmol) and lithium hydroxide (50 mg) were heated in dimethylformamide at 100° C. for 3 h. The mixture was cooled and partitioned between water (80 ml) and ethyl acetate (100 ml). The layers were separated and the aqueous re-extracted with ethyl acetate (100 ml). The combined organic portions were washed with brine (100 ml) and then dried (Na2SO4), filtered and evaporated to give a colourless oil. Purification by silica gel chromatography (eluent EtOAc—10% MeOH:EtOAc) which gave the title compound as a colourless solid (0.53 g, 65%).
Reaction SMILES: Cl[C:2]([O:4][CH:5]([Cl:7])[CH3:6])=[O:3].[CH2:8]([OH:26])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].N1C=CC=CC=1>C(Cl)(Cl)Cl>[C:2](=[O:3])([O:26][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[O:4][CH:5]([Cl:7])[CH3:6]
Reactant: CCCCCCCCCCCCCCCCCCO
Reactant: CC(Cl)OC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCCOC(=O)OC(C)Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1-Chloroethyl chloroformate (7.15 g, 50 mmol) and 1-octadecanol (13.53 g, 50 mmol) were suspended in chloroform (100 ml) at 0° C. Pyridine (3.96 g, 50 mmol) was added dropwise during 20 minutes, maintaining the temperature below 10° C. After stirring at room temperature for 24 hours the reaction mixture was washed four times with 1N hydrochloric acid, once with a saturated sodium bicarbonate solution and finally twice with water. The organic solution was dried with magnesium sulphate and the solvent was removed at reduced pressure. Yield: 19 g.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[C:18]1([CH2:24][CH2:25]Br)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O.O>[C:18]1([CH2:24][CH2:25][C:4]2([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2][NH:1][CH2:11][CH2:10]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCCc1ccccc1
Reactant: CCOC(=O)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1(CCc2ccccc2)CCNCC1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 83.7 %

Procedure:
A mixture of ethyl isonipecotate (64 mmol; 10.0 g), anhydrous potassium carbonate (192 mmol; 26.5 g) and phenylethyl bromide (77 mmol, 14.25 g) in anhydrous N,N-dimethylformamide (100 ml) was stirred at 70° C. for 5 hours 30 minutes. After cooling, the reaction mixture was diluted with water (300 ml) and extracted with ethyl acetate (3×200 ml). The combined organic phases were washed with saturated NaCl solution (3×100 ml), dried over sodium sulfate and evaporated under reduced pressure. A crude product was obtained, which was purified on a column of alumina (eluting with 2/1 n-hexane/ethyl acetate) to give 14.0 g (84%) of pure product as a yellow oil.
Reaction SMILES: [Br:1]Br.[CH:3]1([C:6]([CH:13]2[CH2:15][CH2:14]2)([C:8]2[S:9][CH:10]=[CH:11][N:12]=2)[OH:7])[CH2:5][CH2:4]1.CC([O-])=O.[Na+]>C(O)(=O)C>[Br:1][C:10]1[S:9][C:8]([C:6]([CH:3]2[CH2:5][CH2:4]2)([CH:13]2[CH2:14][CH2:15]2)[OH:7])=[N:12][CH:11]=1
Reactant: OC(c1nccs1)(C1CC1)C1CC1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: OC(c1ncc(Br)s1)(C1CC1)C1CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 57.1 %

Procedure:
Bromine (0.271 mL, 5.26 mmol) was added dropwise to a stirred mixture of the product of Step 1 (411 mg, 2.10 mmol) and NaOAc (863 mg, 10.5 mmol) in acetic acid (9.17 mL) and the mixture was stirred at room temperature for 4 h. The reaction was quenched with brine and the aqueous layer was extracted with ethyl acetate (3×). The combined organics were washed with brine, dried (sodium sulfate), filtered, and concentrated. The residue was purified by chromatography on silica gel (0-100% ethyl acetate in hexanes) to give (5-bromo-1,3-thiazol-2-yl)(dicyclopropyl)methanol (329 mg, 1.20 mmol, 57% yield) as an off-white solid. MS APCI: [M-OH]+ m/z 255.9
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[O:23])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(=O)([O-])O.[Na+]>C(O)C>[C:9]([O:13][C:14]([N:16]1[CH2:17][CH2:18][N:19]([C:22]([CH:24]2[CH2:29][CH2:28][N:27]([C:2]3[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=3)[CH2:26][CH2:25]2)=[O:23])[CH2:20][CH2:21]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)C2CCNCC2)CC1
Reactant: Clc1cc(Cl)ncn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(C(=O)C2CCN(c3cc(Cl)ncn3)CC2)CC1
Yield: 89.5 %

Procedure:
A solution of 4,6-dichloropyrimidine (3.60 g), 1-(tert-butoxycarbonyl)-4-(-4-piperidylcarbonyl)piperazine (6.00 g) and sodium hydrogen carbonate (4.20 g) in ethanol (100 ml) was heated at reflux for 6 hours. Solvent was evaporated and the residue dissolved in ethyl acetate and washed with water, dried (Na2SO4) and evaporated. The residue was recrystallised from ethyl acetate to give, as a solid 1-(tert-butoxycarbonyl)-4-[1-(6-chloro-pyrimidin-4-yl)-piperidin-4-ylcarbonyl]piperazine (7.40 g).
Reaction SMILES: Br[C:2]1[S:27][C:5]2[C:6]3[CH:14]=[N:13][C:12]([N:15]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:11][C:7]=3[O:8][CH2:9][CH2:10][C:4]=2[CH:3]=1.[Cl:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[N:35]=[C:36]=[O:37]>>[C:23]([N:15]([C:12]1[N:13]=[CH:14][C:6]2[C:5]3[S:27][C:2]([C:36](=[O:37])[NH:35][C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[Cl:28])=[CH:3][C:4]=3[CH2:10][CH2:9][O:8][C:7]=2[CH:11]=1)[C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])([CH3:24])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)N(c1cc2c(cn1)-c1sc(Br)cc1CCO2)C(C)(C)C
Reactant: O=C=Nc1ccccc1Cl
Product: CC(C)(C)OC(=O)N(c1cc2c(cn1)-c1sc(C(=O)Nc3ccccc3Cl)cc1CCO2)C(C)(C)C
Yield: 61 %

Procedure:
Following Scheme 4, tert-butyl 2-bromo-4,5-dihydropyrido[4,3-b]thieno[2,3-d]oxepin-8-yl(tert-butyl)carbamate and 2-chlorophenylisocyanate were reacted to give tert-Butyl tert-butyl(2-(2-chlorophenylcarbamoyl)-4,5-dihydropyrido[4,3-b]thieno[2,3-d]oxepin-8-yl)carbamate (61%). MS: (ESI+) 528.2