Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[CH:15]=[C:14]([CH:16]=O)[CH:13]=[C:12]2[C:18]2[CH:23]=[CH:22][C:21]3[O:24][CH2:25][O:26][C:20]=3[CH:19]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[NH2:27][CH2:28][CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[CH:15]=[C:14]([CH2:16][NH:27][CH2:28][CH2:29][CH2:30][N:31]3[CH2:32][CH2:33][N:34]([CH3:37])[CH2:35][CH2:36]3)[CH:13]=[C:12]2[C:18]2[CH:23]=[CH:22][C:21]3[O:24][CH2:25][O:26][C:20]=3[CH:19]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCN(CCCN)CC1
Reactant: O=Cc1cc(-c2ccc3c(c2)OCO3)n(S(=O)(=O)c2cccc(Cl)c2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CN1CCN(CCCNCc2cc(-c3ccc4c(c3)OCO4)n(S(=O)(=O)c3cccc(Cl)c3)c2)CC1

Procedure:
1-(m-Chlorobenzenesulfonyl)2-(3,4methylenedioxyphenyl)-pyrrole-4-carboxaldehyde and 1-(3-aminopropyl)-4-methylpiperazine are condensed and reduced with NaBH(OAc)3 following the procedure of Example 2. HPLC: RT (program 1) 3.26, MS: 531.0.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH3:7])[C:4]([OH:6])=[O:5].C1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=2)(OC)OC)=[CH:24][CH:23]=1>C1(C)C=CC=CC=1>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=3)[O:9][CH2:8][C:3]([CH3:7])([C:4]([OH:6])=[O:5])[CH2:2][O:1]2)=[CH:26][CH:27]=1
Reactant: COC(OC)(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: CC(CO)(CO)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1(C(=O)O)COC(c2ccc(Cl)cc2)(c2ccc(Cl)cc2)OC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a round bottom flask, (0.9 g) 3-hydroxy-2-(hydroxymethyl)-2-methylpropanoic acid and (9.8 mg) p-toluene sulfonic acid and 2 ml toluene was taken. The reaction mixture was stirred at room temperature and subsequently 2 g (1 equiv) bis-(4-chlorophenyl)-dimethoxymethane [IIa4] diluted with 5 ml toluene was added through droping funnel. The reaction mixture was heated at reflux temperature and the water was removed azeotropically under Dean Stark. Continuous removal and addition of toluene was done up to 2 hrs. Then the reaction mixture was cooled at room temperature to obtain off white solid. It was filtered and washed with toluene and then water.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:6][C:5]([C:7]2[O:11][N:10]=[C:9]([C:12]([OH:14])=O)[C:8]=2[CH3:15])=[CH:4][CH2:3]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:41][C:42]1[C:43](=[O:55])[N:44]([CH:49]2[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]2)[N:45]([CH3:48])[C:46]=1[CH3:47].C(N(CC)CC)C>CN1C(=O)CCC1.CS(C)=O>[CH:49]1([N:44]2[C:43](=[O:55])[C:42]([NH:41][C:12]([C:9]3[C:8]([CH3:15])=[C:7]([C:5]4[CH2:6][C:2]([CH3:1])([CH3:16])[CH2:3][CH:4]=4)[O:11][N:10]=3)=[O:14])=[C:46]([CH3:47])[N:45]2[CH3:48])[CH2:50][CH2:51][CH2:52][CH2:53][CH2:54]1
Reactant: Cc1c(C(=O)O)noc1C1=CCC(C)(C)C1
Reactant: Cc1c(N)c(=O)n(C2CCCCC2)n1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1c(C(=O)Nc2c(C)n(C)n(C3CCCCC3)c2=O)noc1C1=CCC(C)(C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 5-(4,4-dimethylcyclopent-1-en-1-yl)-4-methylisoxazole-3-carboxylic acid (105 mg, 0.475 mmol) in dry NMP (3 mL), HATU (198 mg, 0.522 mmol) was added followed by 4-amino-2-cyclohexyl-1,5-dimethyl-1H-pyrazol-3(2H)-one (Intermediate D) (109 mg, 0.522 mmol) and triethylamine (0.146 mL, 1.044 mmol). The mixture was stirred at room temperature overnight. The resulting mixture was partitioned between EtOAc (20 mL) and 1M NaOH (aq) (20 mL) and the organic phase was washed with water (20 mL), brine (20 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was adsorbed onto silica and purification by chromatography eluting with 0-60% EtOAc in iso-hexane afforded crude material. The crude material was dissolved in DMSO and purified using mass-directed automated reverse phase chromatography over a 9.5 minute gradient of 40-80% MeCN in water (0.1% formic acid). The product fraction was added to EtOAc (50 mL) and washed with a saturated aqueous NaHCO3 solution (50 mL). The organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to afford the title compound;
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:11]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:10]=[CH:9][C:5]2=[N+:6]([O-])[CH:7]=1.C[CH2:23][N:24](CC)CC.C[Si](C#N)(C)C>ClCCCl>[Br:1][C:2]1[CH:3]=[C:4]2[N:11]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:10]=[CH:9][C:5]2=[N:6][C:7]=1[C:23]#[N:24]
Reactant: CCN(CC)CC
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2cc(Br)c[n+]3[O-])cc1
Agent: C[Si](C)(C)C#N
Solvent: ClCCCl
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(C#N)c(Br)cc32)cc1
Temperature: 76 °C
Reaction time: 16 h
Yield: 60 %

Procedure:
To a stirred mixture of 6-bromo-1-tosyl-1H-pyrrolo[3,2-b]pyridine 4-oxide (5.66 g, 15.41 mmol), Et3N (21.5 mL, 154 mmol) and DCE (40 mL) was added trimethylsilyl cyanide (10.33 mL, 77 mmol), and the reaction mixture was stirred at 76° C. for 16 hours. The dark reaction mixture was concentrated in vacuo and purified by silica gel chromatography (1% to 2% MeOH/DCM) to give the title compound as a white solid (3.48 g, 60%). 1H NMR (500 MHz, CDCl3) δ ppm 8.56 (d, 1H, J=1.0 Hz), 7.90 (d, 1H, J=4.0 Hz), 7.79 (d, 2H, J=8.0 Hz), 7.33 (d, 2H, J=8.0 Hz), 6.88 (d, 1H, J=4.0 Hz), 2.41 (s, 3H); ESI-MS m/z [M+H]+ calc'd for C15H10BrN3O2S, 376, 378; found 376, 378. Further elution of the silica gel column with 4% MeOH/DCM gave a second major fraction, which was the tosyl-deprotected product, which was collected to give impure 6-bromo-1H-pyrrolo[3,2-b]pyridine 5-carbonitrile as a brown solid (1.25 g, 36%). ESI-MS m/z [M+H]+ calc'd for C8H4BrN3, 222, 224; found 222, 224.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH:8]([CH3:10])[CH3:9])[S:6][CH:7]=1.CCN(C(C)C)C(C)C.[C:20]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>C(Cl)Cl.CCOC(C)=O>[CH:8]([C:5]1[S:6][CH:7]=[C:3]([CH2:2][N:30]2[CH2:29][CH2:28][N:27]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:32][CH2:31]2)[N:4]=1)([CH3:10])[CH3:9]
Reactant: CC(C)c1nc(CCl)cs1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1nc(CN2CCN(C(=O)OC(C)(C)C)CC2)cs1
Temperature: 35 °C
Reaction time: 5 h
Yield: 64.7 %

Procedure:
4-(Chloromethyl)-2-isopropyl-thiazole (0.500 g, 2.85 mmol, 1 eq) was suspended in DCM (4.5 mL). DIPEA (1.24 mL, 7.1 mmol, 2.5 eq) was added dropwise, followed by N-Boc-piperazine (1.170 g, 6.3 mmol, 2.2. eq). The reaction mixture was stirred at 35° C. for 5 h, then diluted with EtOAc, and washed with H2O and brine. The organic layer was separated, dried (MgSO4) and the solvent removed in vacuo. The crude product was purified by column chromatography on a Biotage SP1 system (DCM/EtOAc; v/v 1:1) to give the title compound as a clear oil (0.600 g, 65%); 1H-NMR (500 MHz, CDCl3): δ 1.39 (d, J=7.0 Hz, 6H, iPr—CH3), 1.46 (s, 9H, C(CH3)3), 2.47 (br t, J=5.0 Hz, 4H, piperazine N(CH2)2), 3.34 (m, 1H, iPr—CH), 3.6 (br t, J=5.0 Hz, 4H, piperazine N(CH2)2), 3.66 (s, 2H, NCH2), 6.98 (s, 1H, thiazole 5-H); LC (Method B)-MS (ESI, m/z): Rt=2.80 min—326 [(M+H)+, 100%].
Reaction SMILES: [F-:1].[K+].[CH2:3]1OCCOCCOCCOCCOCCOC1.Br[CH2:22][C:23]([C:25]1[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=1)=[O:24]>C(#N)C.O>[CH3:3][O:31][C:29](=[O:30])[C:28]1[CH:32]=[CH:33][C:25]([C:23](=[O:24])[CH2:22][F:1])=[CH:26][CH:27]=1
Reactant: O=C(O)c1ccc(C(=O)CBr)cc1
Reactant: [F-]
Reactant: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1ccc(C(=O)CF)cc1
Temperature: 90 °C
Yield: 31 %

Procedure:
To a suspension of potassium fluoride (3.11 mmol) in acetonitrile (1 mL) was added 18-crown-6 (0.1 mmol) and the reaction was heated at 90° C. for 30 mins. 4-(2-Bromo-acetyl)-benzoic acid (1.56 mmol) was added and the reaction heated at 90° C. for 16 h. The reaction was diluted with water (10 mL) and extracted with ethyl acetate (3×20 mL). The product was purified on silica eluting with 5-15% ethyl acetate in iso-hexane to yield on concentration in vacuo of the desired fractions, the title product as a white solid (31%). 1H NMR (400 MHz, CDCl3) 3.98 (3H, s), 5.55 (2H, d, J=50 Hz), 7.95 (2H, d, J=8 Hz), 8.18 (2H, d, J=8 Hz).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:12](=[O:13])[C:11]2[CH:14]=[CH:15][S:16][C:10]=2[S:9][CH2:8][CH2:7]1.[Br:17]Br.O>C(O)(=O)C>[Br:17][C:15]1[S:16][C:10]2[S:9][CH2:8][CH2:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])[C:12](=[O:13])[C:11]=2[CH:14]=1
Reactant: BrBr
Reactant: O=C1c2ccsc2SCCN1CCCCCl
Solvent: CC(=O)O
Solvent: O
Product: O=C1c2cc(Br)sc2SCCN1CCCCCl
Temperature: 60 °C

Procedure:
To a solution of 3.0 g of 4-(4-chlorobutyl)-2,3-dihydrothieno[3,2-f]-1,4-thiazepin-5(4H)-one in 60 ml of acetic acid was added 1.5 ml of bromine with stirring at 60° C. and the mixture was stirred for 20 minutes at the same temperature. The mixture was poured into chilled water and extracted with chloroform. The extract was washed with water, dried over magnesium sulfate and the solvent was distilled off. The resulting crystals were recrystallized from ethanol to give 2.0 g of 7-bromo-4-(4-chlorobutyl)-2,3-dihydrothieno[3,2-f]-1,4-thiazepin-5(4H)-one as white crystals, melting at 81°-89° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9][C:10](O)=[S:11].S(Cl)([Cl:15])=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9][C:10]([Cl:15])=[S:11]
Reactant: O=S(Cl)Cl
Reactant: OC(=S)Cc1cc(Cl)ccc1Cl
Solvent: ClCCl
Product: S=C(Cl)Cc1cc(Cl)ccc1Cl
Temperature: 25 °C
Yield: 106.5 %

Procedure:
A solution of 2,5-dichlorophenylthioacetic acid (13.0 g, 54.9 mmol) in methylene chloride (55 mL) and thionyl chloride (10 mL, 137 mmol) was heated at reflux for 3 h. The reaction mixture was allowed to cool to room temperature and was concentrated in vacuo. The residue was evaporated two times from toluene to give 14 g of 2,5-dichlorophenylthioacetyl chloride (100% yield) as a slightly colored product which was used in the next step without purification. 1H NMR (300 MHz, CDCl3) δ4.13 (s, 2H), 7.22 (dd, J=2, 9 Hz, 1H), 7.35 (d, J=9 Hz, 1H), 7.39 (d, J=2 Hz, 1H).
Reaction SMILES: [NH2:1][C@@H:2]([C:14]([NH:16][C@@H:17]([C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[CH2:18][CH2:19][CH2:20][CH3:21])=[O:15])[CH2:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[CH:11]2)=[CH:6][CH:5]=1.[NH:32]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C@H:33]([C:38](O)=[O:39])[CH2:34][CH:35]([CH3:37])[CH3:36].O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>ClCCl.C(OCC)(=O)C.O>[NH:32]([C:41]([O:43][C:44]([CH3:46])([CH3:45])[CH3:47])=[O:42])[C@H:33]([C:38]([NH:1][C@@H:2]([C:14]([NH:16][C@@H:17]([C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23])[CH2:18][CH2:19][CH2:20][CH3:21])=[O:15])[CH2:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[CH:11]2)=[CH:6][CH:5]=1)=[O:39])[CH2:34][CH:35]([CH3:37])[CH3:36]
Reactant: CCCC[C@@H](NC(=O)[C@H](N)Cc1ccc2ccccc2c1)C(=O)OCc1ccccc1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCC[C@@H](NC(=O)[C@@H](Cc1ccc2ccccc2c1)NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 88 %

Procedure:
To a solution of H-DNal-DNle-OBzl (180 mg, prepared in (2)) in dichloromethane (5 ml) were added Boc-Leu-OH.H2O (180 mg), HOBT.H2O (70 mg) and EDCI.HCl (99 mg) successively under ice cooling. After being stirred at room temperature for 14 h, the mixture was diluted with ethyl acetate, washed with sat. aq. NaHCO3, 10% aq. citric acid, water and brine successively, dried over MgSO4 and evaporated in vacuo. The residue was purified by dry column flash chromatography (Merck, Kieselgel 60) with ethyl acetate/hexane=1/2 for elution to give Boc-Leu-DNal-DNle-OBzl (239 mg). A solution of the tripeptide derivative (87 mg) in 95% ethanol (10 ml) was hydrogenated over 10% Pd/C (21 mg) at an atmospheric pressure of hydrogen for 1 h. After removal of the catalyst by filtration, the filtrate was concentrated in vacuo to give Compound 16 (74 mg).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CON(C)[C:39]([C:41]1[N:42]=[CH:43][N:44]([CH3:46])[CH:45]=1)=[O:40]>>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[C:22]([C:39]([C:41]2[N:42]=[CH:43][N:44]([CH3:46])[CH:45]=2)=[O:40])[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2F)C[C@H](C)O1
Reactant: CON(C)C(=O)c1cn(C)cn1
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(=O)c3cn(C)cn3)c(F)c2F)C[C@H](C)O1

Procedure:
Starting materials: (2R,6S)-4-[6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2,3-difluorophenyl]-2,6-dimethylmorpholine (Intermediate 3) and N-methoxy-N,1-dimethyl-1H-imidazole-4-carboxamide
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]=[O:15])=[CH:10][C:9]=1[O:16][CH3:17].[N+:19]([O-])([OH:21])=[O:20].O>C(OC(=O)C)(=O)C>[CH3:1][O:2][C:3](=[O:18])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[C:12]([N+:19]([O-:21])=[O:20])[C:11]([CH:14]=[O:15])=[CH:10][C:9]=1[O:16][CH3:17]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)CCCOc1ccc(C=O)cc1OC
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: COC(=O)CCCOc1cc([N+](=O)[O-])c(C=O)cc1OC
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
A solution of the aldehyde 11 (50 g, 0.197 mol) in acetic anhydride (150 mL) was slowly added to a mixture of 70% nitric acid (900 mL) and acetic anhydride (200 mL) at 0° C. and was then left to stir for 2.5 hours at 0° C. The solution was then poured onto ice in a 5 L flask and the volume adjusted to 5 L with ice and water. The resulting light sensitive pale yellow precipitate was immediately filtered (the ester is slowly hydrolysed at room temperature in those conditions) and washed with cold water. The product 12 was used directly in the next step. TLC analysis (50/50 EtOAc/Pet Et) proved the product pure. 1H NMR (CDCl3) δ 10.4 (2H, s), 7.61 (1H, s), 7.4 (1H, s), 4.21 (2H, t, J=6.2 Hz), 4.00 (3H, s), 3.71 (2H, s), 2.58 (2H, t, J=7.1 Hz), 2.23 (2H, p, J=6.3 Hz); 13C NMR (CDCl3) δ 188.5, 172.8, 152.7, 151.0, 143.5, 124.7, 110.1, 108.2, 68.4, 56.4, 51.3, 29.7, 23.8; MS (ES+) m/z (relative intensity) 298 ([M+H]+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([OH:8])[CH2:7][CH2:6]1)=[O:4].[O:9]1[CH:14]=[CH:13][CH2:12][CH2:11][CH2:10]1.[NH+]1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.C(OCC)C>[CH3:1][O:2][C:3]([C:5]1([O:8][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14][O:9]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: C1=COCCC1
Reactant: COC(=O)C1(O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)C1(OC2CCCCO2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.6 %

Procedure:
Hydroxy-cyclopropanecarboxylic acid methyl ester (5.07 g, 43.71 mmol) was dissolved in methylene chloride (75 mL) and 3,4-dihydro-2H-pyran (3.86 g, 45.90 mmol) was added followed by pyridinium-p-toluene-sulfonic acid (1.10 g, 4.37 mmol). The reaction stirred at 25° C. for 3 h. The reaction was concentrated in vacuo to give a clear oil. The oil was dissolved in diethyl ether (75 mL), washed with saturated aqueous brine solution (25 mL), dried over sodium sulfate and concentrated in vacuo to an oil. The oil was passed through a plug of silica gel (Merck silica gel 60, 40-63 μm; 100% ethyl acetate) to afford 1-(tetrahydro-pyran-2-yloxy)-cyclopropanecarboxylic acid methyl ester (7.49 g, 86%) as a clear oil: H1-NMR (400 MHz, CDCl3) δ 1.14-1.42 (4H, m), 1.88-3.46 (6H, m), 3.46-3.54 (1H, m), 3.70-3.72 (3H, m), 3.82-3.90 (1H, m), 4.81-4.96 (1H, m).
Reaction SMILES: Cl[CH2:2][CH:3]=O.[Cl:5][C:6]1[CH:7]=[C:8]([NH:12][C:13]([NH2:15])=[S:14])[CH:9]=[CH:10][CH:11]=1>C(O)C>[Cl:5][C:6]1[CH:7]=[C:8]([NH:12][C:13]2[S:14][CH:2]=[CH:3][N:15]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: NC(=S)Nc1cccc(Cl)c1
Reactant: O=CCCl
Solvent: CCO
Product: Clc1cccc(Nc2nccs2)c1
Temperature: 60 °C
Reaction time: 16 h
Yield: 81 %

Procedure:
Aqueous chloro acetaldehyde solution (15 mL) was added to a solution of 26A (15.5 g, 80 mmol) in ethanol (150 mL) and stirred at 60° C. for 16 h. The reaction mixture was concentrated in vacuo, and partitioned between ethyl acetate and water. The separated organic layer was washed with saturated NaCl, dried over sodium sulfate and filtered, and the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography using 10% ethyl acetate in hexane to afford the title compound (15 g, 81%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.39 (s, 1H), 7.96 (t, J=2.1 Hz, 1H), 7.45-7.38 (dd, J1=2.0 Hz, J2=8.4 Hz, 1H), 7.37-7.26 (m, 2H), 7.02-6.95 (m, 2H). ESI-MS m/z: 211 (M+H)+.
Reaction SMILES: C[Al](C)C.[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.[Si:13]([O:30][CH2:31][CH2:32][O:33][CH2:34][C@H:35]([O:40][C:41]1[N:46]=[CH:45][N:44]=[C:43]2[N:47]([C:50]3[C:55]([Cl:56])=[CH:54][CH:53]=[CH:52][N:51]=3)[N:48]=[CH:49][C:42]=12)[C:36](OC)=[O:37])([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[Si:13]([O:30][CH2:31][CH2:32][O:33][CH2:34][C@H:35]([O:40][C:41]1[N:46]=[CH:45][N:44]=[C:43]2[N:47]([C:50]3[C:55]([Cl:56])=[CH:54][CH:53]=[CH:52][N:51]=3)[N:48]=[CH:49][C:42]=12)[C:36]([NH:12][C:9]1[CH:8]=[CH:7][C:6]([Cl:5])=[CH:11][N:10]=1)=[O:37])([C:26]([CH3:27])([CH3:28])[CH3:29])([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)[C@H](COCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)Oc1ncnc2c1cnn2-c1ncccc1Cl
Reactant: Nc1ccc(Cl)cn1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](OCCOC[C@H](Oc1ncnc2c1cnn2-c1ncccc1Cl)C(=O)Nc1ccc(Cl)cn1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Trimethylaluminium (2M in hexane) (0.455 mL, 0.91 mmol) was added to 5-chloropyridin-2-amine (112 mg, 0.87 mmol) in toluene (10 mL) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 20 minutes. (2S)-methyl 3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanoate (Intermediate AB2) (500 mg, 0.79 mmol) in toluene (2 mL) was added and the reaction was heated to reflux for 24 hours. The reaction mixture was concentrated in vacuo and neutralised with citric acid (1M, aq) and then diluted with water (10 ml) and DCM (10 mL). The mixture was poured onto a phase separator and the organic layer collected and evaporated. The crude material was used without purification.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][OH:8].C([Li])CCC.CCCCCC.[CH2:20]([O:24][C:25]1[C:29](S(C)(=O)=O)=[N:28][S:27][N:26]=1)[CH2:21][CH2:22][CH3:23]>C1COCC1>[CH2:20]([O:24][C:25]1[C:29]([O:8][CH2:7][C@@H:3]2[CH2:4][CH2:5][CH2:6][N:2]2[CH3:1])=[N:28][S:27][N:26]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCCOc1nsnc1S(C)(=O)=O
Reactant: CN1CCC[C@H]1CO
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCOc1nsnc1OC[C@@H]1CCCN1C

Procedure:
A solution of (S)-1-methyl-2-pyrrolidinemethanol (0.86, 0.0075 mol) in THF (20 mL) was treated with 1.6M n-butyllithium in hexane (4.7 mL, 0.0075 mol). To the solution was added 3-butyloxy-4-methanesulfonyl-1,2,5-thiadiazole (1.2 g, 0.005 mol) and the reaction heated to reflux for 6.5 h. The solvent was evaporated, the residue acidified with cold 1N HCl, and the mixture extracted with ether. The aqueous was made basic and extracted with EtOAc. The extracts were washed with water, dried, and the solvent evaporated to give a liquid. The HCl salt (0.72 g) crystallized from EtOAc, m.p. 115°-116° C. (Compound 31).
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.Cl.[NH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:27][C:26]3[CH:25]=[N:24][N:23]([CH3:28])[C:22]=3[NH:21][C:20]3[CH:29]=[C:30]([Cl:33])[CH:31]=[CH:32][C:19]2=3)=[O:17])=[CH:12][C:11]=1[F:34].C1C(N=NC2C(=O)N(C3C=CC(S([O-])(=O)=O)=CC=3)N=C2C([O-])=O)=CC=C(S([O-])(=O)=O)C=1.[Na+].[Na+].[Na+].CCN(C(C)C)C(C)C>ClCCl>[Cl:33][C:30]1[CH:31]=[CH:32][C:19]2[N:18]([C:16]([C:13]3[CH:14]=[CH:15][C:10]([CH2:9][NH:8][C:4]([CH:1]4[CH2:3][CH2:2]4)=[O:5])=[C:11]([F:34])[CH:12]=3)=[O:17])[CH2:27][C:26]3[CH:25]=[N:24][N:23]([CH3:28])[C:22]=3[NH:21][C:20]=2[CH:29]=1
Reactant: O=C(Cl)C1CC1
Reactant: Cn1ncc2c1Nc1cc(Cl)ccc1N(C(=O)c1ccc(CN)c(F)c1)C2
Agent: Cl
Agent: O=C([O-])C1=NN(c2ccc(S(=O)(=O)[O-])cc2)C(=O)C1N=Nc1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc2c1Nc1cc(Cl)ccc1N(C(=O)c1ccc(CNC(=O)C3CC3)c(F)c1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
Cyclopropanecarbonyl chloride (0.045 ml, 0.5 mmol) was added to a solution of (4-aminomethyl-3-fluoro-phenyl)-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone hydrochloride from Example E102.2 (210 mg, 0.5 mmol) in dichloromethane (40 ml) and DIEA (0.30 ml, 1.7 mmol) at 0° C. The mixture was stirred for 1 h at room temperature then washed with saturated NaHCO3, brine, dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloro-methane) to give a white powder identified as the title compound (134 mg, 59%).
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1.[CH2:13]([O:15][C:16](=[O:24])[CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]1)[CH3:14].C([O-])([O-])=O.[K+].[K+].O>C(#N)C>[CH2:13]([O:15][C:16](=[O:24])[CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][N:20]([CH2:2][CH:3]2[O:8][C:7]3[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=3[O:5][CH2:4]2)[CH2:19]1)[CH3:14]
Reactant: BrCC1COc2ccccc2O1
Reactant: CCOC(=O)CC1CCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)CC1CCCN(CC2COc3ccccc3O2)C1

Procedure:
To a mixture of 2-bromomethyl-2,3-dihydrobenzo[1,4]dioxine (1.34 g, 5.84 mmol), piperidin-3-yl-acetic acid ethyl ester (1.0 g, 5.84 mmol) in acetonitrile (25 ml) was added K2CO3 (0.81 g, 5.84 mmol) and KI (0.97 g, 5.84 mmol). The reaction mixture was irradiated under microwaves at 82° C. for 8 h. Water (100 ml) was then added. The reaction mixture was extracted with DCM (3×50 ml). The combined organic phases were dried (Na2SO4), filtered and the filtrate was evaporated to give the title compound, which was purified by column chromatography (DCM/MeOH, 95:5).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH3:16][CH2:17][SH:18]>CN(C=O)C>[CH2:17]([S:18][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])[CH3:16]
Reactant: O=Cc1ccccc1F
Reactant: CCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCSc1ccccc1C=O
Temperature: 55 °C
Yield: 72.5 %

Procedure:
2-fluoro-benzaldehyde (2.00 g, 16.1 mmol), potassium carbonate (2.45 g, 17.7 mmol) and thioethanol (17.1 mmol) were dissolved in 10.0 mL DMF in a 50 mL round-bottomed flask under dry nitrogen, topped with a reflux condenser. The reaction mixture was heated to 55° C. for 3 days. After cooling, the mixture was added to 50 mL of saturated potassium carbonate solution and extracted with 3×50 mL portions of ether. The extracts were dried with magnesium sulfate and evaporated. The crude product was further purified by chromatography on silica gel using 2:1 dichloromethane/n-hexane as eluent to give a yellow oil (1.94 g, 72%). 1H NMR (200 MHz, CDCl3): δ 1.37 (t, J=7.5, 3H), 2.99 (q, J=7.5, 2H), 7.26-7.56 (m, 3H), 7.84 (dd, J1=8.0, 1H), 10.37 (s, 1H) ppm.