Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[C:12]([C:13]([OH:15])=O)=[CH:11][O:10][N:9]=1.[Cl:16][C:17]1[C:18]([NH2:24])=[N:19][C:20]([NH2:23])=[CH:21][N:22]=1>CN(C)C=O.N1C=CC=CC=1>[NH2:24][C:18]1[N:19]=[C:20]([NH:23][C:13]([C:12]2[C:8]([CH3:7])=[N:9][O:10][CH:11]=2)=[O:15])[CH:21]=[N:22][C:17]=1[Cl:16]
Reactant: Nc1cnc(Cl)c(N)n1
Reactant: Cc1nocc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cc1nocc1C(=O)Nc1cnc(Cl)c(N)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 49.3 %

Procedure:
Oxalyl chloride (0.06 ml, 0.69 mmol) was added to a solution of 3-Methyl-isoxazole-4-carboxylic acid (0.06 g, 0.48 mmol) followed by 1 drop of dimethylformamide. The mixture was stirred at room temperature for 4 hours before concentrating in vacuo and azeotroping with dichloromethane. The residue was taken up in pyridine (1 ml) and added to a solution of 3-chloro-pyrazine-2,6-diamine (Preparation 1) (0.035 g, 0.24 mmol) in anhydrous pyridine (3 ml) and the mixture heated at 50° C. for 3 hours before cooling to room temperature and concentrating to dryness in vacuo. The residue was purified by silica gel column chromatography, eluting with ethyl acetate:heptane 1:1, to afford the product as a white solid (30 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7](C(OC(C)(C)C)=O)[CH:6]=[CH:5]2.C([O-])([O-])=O.[Cs+].[Cs+].[NH:24]1[CH2:31][CH2:30][CH2:29][C@H:25]1C(O)=O.N1CCCC1>[Cu]I.CS(C)=O>[N:24]1([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[CH:5]3)[CH2:31][CH2:30][CH2:29][CH2:25]1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)n1ccc2cc(Br)ccc21
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCNC1
Solvent: CS(C)=O
Product: c1cc2cc(N3CCCC3)ccc2[nH]1
Temperature: 95 °C
Reaction time: 18 h
Yield: 383.5 %

Procedure:
t-Butyl 5-bromo-1H-indole-1-carboxylate (200 mg, 0.68 mmol) was placed in a 10 mL sealed tube. Cs2CO3 (440 g, 1.35 mol) was then added, followed by CuI (13 mg, 0.07 mmol), L-proline (16 mg, 0.14 mmol), DMSO (3 mL), and pyrrolidine (480 g, 6.75 mol). After sparging with nitrogen, the resulting solution was stirred at 95° C. for 18 hours. The mixture was extracted with ethyl acetate (3×40 mL), and the organic layers were combined and washed with brine. The residue was purified by column chromatography using 1:5 and 1:2 ethyl acetate/petroleum ether solvent systems. The collected fractions were combined and concentrated to give 100 mg (80%) of 5-(pyrrolidin-1-yl)-1H-indole as brown oil.
Reaction SMILES: CN(C)[CH:3]=[C:4]([C:10](=O)[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[N+]([O-])(O)=O.[N+]([O-])(O)=O.[F:28][C:29]1[CH:30]=[C:31]([NH:41][C:42]([NH2:44])=[NH:43])[CH:32]=[CH:33][C:34]=1[N:35]1[CH:39]=[C:38]([CH3:40])[N:37]=[CH:36]1>>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]2[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3][N:44]=[C:42]([NH:41][C:31]3[CH:32]=[CH:33][C:34]([N:35]4[CH:39]=[C:38]([CH3:40])[N:37]=[CH:36]4)=[C:29]([F:28])[CH:30]=3)[N:43]=2)=[CH:16][CH:15]=1
Reactant: Cc1cn(-c2ccc(NC(=N)N)cc2F)cn1
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1ccc(Cl)cc1
Solvent: O=[N+]([O-])O
Product: CCOC(=O)c1cnc(Nc2ccc(-n3cnc(C)c3)c(F)c2)nc1-c1ccc(Cl)cc1

Procedure:
The title compound was prepared from crude ethyl 3-dimethylamino-2-(4-chloro-benzoyl)-acrylate (89 mg, 0.3 mmol) and N-[3-fluoro-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (80 mg, 0.22 mmol) using in analogous manner the procedure described in example 28b). Obtained as a pale-yellow solid (28 mg, 28%). Mp 232-234° C.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:41]=[CH:40][C:23]([CH2:24][N:25](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=[CH:22][CH:21]=3)[N:16]=2)[CH:3]=1.FC(F)(F)C(O)=O.O>ClCCl>[CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=2)[N:5]=[C:4]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:21]=[CH:22][C:23]([CH2:24][NH2:25])=[CH:40][CH:41]=3)[N:16]=2)[CH:3]=1
Reactant: Cc1ccc(Cn2nc(-c3nc(-c4ccc(CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc4)no3)cc2C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1ccc(Cn2nc(-c3nc(-c4ccc(CN)cc4)no3)cc2C)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mechanically stirred solution of di-tert-butyl (4-{5-[5-methyl-1-(4-methylbenzyl)-1H-pyrazol-3-yl]-1,2,4-oxadiazol-3-yl}benzyl)imidodicarbonate (Example 98, 2.73 g, 4.88 mmol) in dichloromethane (37 mL) was added trifluoroacetic acid (3.7 mL, 48.8 mmol). After the reaction mixture had been stirred at rt for 3 h, water (50 mL) was added, and it was extracted with dichloromethane (3×30 mL). The aqueous phase was then made alkaline (pH 10) by addition of potassium carbonate. It was extracted with dichloromethane (3×30 mL). The combined organic extracts were dried over anhydrous sodium sulfate. After filtration and evaporation of the solvent, the title compound was obtained (1.28 g, 73%): 1H NMR (400 MHz, DMSO-d6) 8.02 (d, 2H), 7.55 (d, 2H), 7.18 (d, 2H), 7.11 (d, 2H), 6.90 (s, 1H), 5.43 (s, 2H), 3.85 (s, 2H), 2.32 (s, 3H), 2.28 (s, 3H); ES-MS m/z 360, HPLC RT (Method D) 1.56 min.
Reaction SMILES: C([O:3][C:4](=[O:17])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1[C:14](=[O:16])[NH2:15])C.Br[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=O>>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:3])=[O:17])=[C:8]([C:14]2[O:16][CH:19]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:15]=2)[CH:9]=1
Reactant: CCOC(=O)COc1ccc(Br)cc1C(N)=O
Reactant: O=C(CBr)c1ccccc1
Product: O=C(O)COc1ccc(Br)cc1-c1nc(-c2ccccc2)co1

Procedure:
Title compound was prepared from (4-bromo-2-carbamoylphenoxy)acetic acid ethyl ester and 2-bromoacetophenone according to GP7: LC/MS (an 10p8) Rt 2.32 min, m/z 374/376 [M+H]+.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:25]=[C:24](Cl)[C:23]4[C:18](=[C:19]([Br:29])[CH:20]=[C:21]([O:27][CH3:28])[CH:22]=4)[N:17]=3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:30][NH:31][CH3:32]>O1CCCC1>[N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:25]=[C:24]([N:31]([CH3:32])[CH3:30])[C:23]4[C:18](=[C:19]([Br:29])[CH:20]=[C:21]([O:27][CH3:28])[CH:22]=4)[N:17]=3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: COc1cc(Br)c2nc(C(=O)Nc3ccc(N4CCOCC4)cc3)cc(Cl)c2c1
Reactant: CNC
Solvent: C1CCOC1
Product: COc1cc(Br)c2nc(C(=O)Nc3ccc(N4CCOCC4)cc3)cc(N(C)C)c2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92 %

Procedure:
A solution of 8-bromo-4-chloro-6-methoxy-quinoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide (Reference Example 28a) (0.1512 g, 0.317 mmol) in 100 mL 2.0 M dimethyl amine in tetrahydrofuran was heated at 100° C. in a Parr bomb. The initial pressure was 75-80 psi and then remained at approximately 60 psi. After 18 hours, the reaction was cooled to room temperature, concentrated and dried to afford the crude product as a brown solid. Purification on silica gel using a gradient of 100:0 to 95:5 methylene chloride:methanol afforded the clean product (0.142 g, 92%); 1H NMR (300 MHz, DMSO, d6) δ 10.20 (s, 1H, C(O)NH), 7.90 (d, 1H, Jm=2.7 Hz, ArH5), 7.69 (d, 2H, Jo=9.0 Hz, ArH2′ & H6′), 7.60 (s, 1H, ArH3), 7.41 (d, 1H, Jm=2.7 Hz, ArH7), 7.01 (d, 2H, J=9.0 Hz, ArH3′ & H5′), 3.96 (s, 3H, OCH3), 3.75 (t, 4H, J=4.8 Hz, OCH2CH2N), 3.10 (t, 4H, J=4.8 Hz, OCH2CH2N), 3.08 (s, 6H, N(CH3)2); Mass Spec.: calc. for [C21H19BrClN3O3+H]+ Theor. m/z=485, 487; Obs.=485, 487.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:17]=[C:13]([C:14](O)=[O:15])[C:12]([OH:18])=[C:11]([I:19])[CH:10]=1.FC1C(O)=C(F)C(F)=C(F)C=1F.CC([N:35]=C=NC(C)C)C.C(=O)(O)[O-].[NH4+]>C(#N)C.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:17]=[C:13]([C:14]([NH2:35])=[O:15])[C:12]([OH:18])=[C:11]([I:19])[CH:10]=1
Reactant: O=C(O)c1cc(-c2ccc(F)cc2F)cc(I)c1O
Reactant: CC(C)N=C=NC(C)C
Agent: O=C([O-])O
Agent: Oc1c(F)c(F)c(F)c(F)c1F
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: NC(=O)c1cc(-c2ccc(F)cc2F)cc(I)c1O

Procedure:
1 g (2.66 mmol) of 5-(2,4-difluorophenyl)-3-iodo-salicylic acid was mixed with 0.738 g (4.01 mmol) of pentafluorophenol in 20 ml of acetonitrile. 10 ml of N,N-diisopropylcarbodiimide was added at 0° C. and it was stirred continuously. 0.634 g of ammonium bicarbonate was dissolved in water. Consumption of the starting product was confirmed by HPLC and the crude was diluted with water and extracted with dichloromethane. The organic phase was dried over magnesium sulphate and purified on a silica gel column, using chloroform and methanol as eluents, in increasing polarity beginning with a proportion (v/v) of (40:1) up to (10:1).
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[C:8]1([OH:16])[CH:15]=[C:13]([CH3:14])[CH:12]=[C:10]([OH:11])[CH:9]=1>[OH-].[Na+]>[CH3:5][O:11][C:10]1[CH:9]=[C:8]([OH:16])[CH:15]=[C:13]([CH3:14])[CH:12]=1
Reactant: COS(=O)(=O)OC
Reactant: Cc1cc(O)cc(O)c1
Agent: [Na+]
Agent: [OH-]
Product: COc1cc(C)cc(O)c1
Yield: 43 %

Procedure:
Dimethyl sulfate (39 ml; 0.41 mol) was added to a solution of orcinol (64 g; 0.45 mol) in 10% aqueous sodium hydroxide solution (360 ml). The mixture was refluxed for 1½ hours and extracted with ether. The organic phase was evaporated and purified by flash chromatography eluting with dichloromethane/ethanol (98/2) to give 3-methoxy-5-methylphenol. Yield=43%.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7]CC)=O)[CH2:3][CH2:2]1.Br[CH2:13][CH2:14][CH2:15][CH3:16].C(=O)([O-])[O-].[K+].[K+].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>C(O)C.CCOCC.O>[CH2:13]([N:1]1[CH2:2][CH2:3][CH:4]([CH2:5][OH:7])[CH2:10][CH2:11]1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCBr
Reactant: CCOC(=O)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCO
Solvent: CCOCC
Solvent: O
Product: CCCCN1CCC(CO)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.5 %

Procedure:
A mixture of ethyl isonipecotate (102 g, 0.65 mole) and 1-bromobutane (72 ml, 0.67 mole) in ethanol (1.2 L) was treated with anhydrous potassium carbonate (180 g, 1.3 mole) and heated under reflux for 2 h. The mixture was allowed to cool an then filtered through kieselguhr. The filtrate was concentrated in vacuo to leave a yellow oil, which was dissolved in ether (300 ml) and added dropwise over 20 minutes to a stirred suspension of lithium aluminium hydride (50 g, 1.3 mole) in ether (500 ml) at 0° C. under nitrogen. The mixture was stirred at room temperature for 18 h, then cooled to 0° C. and treated with water (50 ml), 10% NaOH solution (50 ml) and water (150 ml). The mixture was filtered through keiselguhr and the filtrate concentrated under vacuum to leave a pale yellow oil, which was distilled to afford the title compound as a colourless oil (88.5 g, 80%) bp 102°-108° C. at 0.1 mm Hg.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][C:5]=12.[F:17][C:18]([F:23])([F:22])[C:19]([OH:21])=[O:20]>ClCCl>[F:17][C:18]([F:23])([F:22])[C:19]([OH:21])=[O:20].[N:1]1[CH:2]=[CH:3][N:4]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=12
Reactant: CC(C)(C)OC(=O)N1CCn2ccnc2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cn2c(n1)CNCC2
Reaction time: 0.75 h

Procedure:
1,1-Dimethylethyl 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-carboxylate (Description 163, 505 mg, 2.26 mmol) in dichloromethane (2.5 mL) was added to stirred, cooled (0° C.) trifluoroacetic acid (5 mL) and the mixture was stirred at 0° C. for 15 minutes, then at room temperature for 45 minutes. The solvent was evaporated under reduced pressure to give the title compound. m/z (ES+) 124 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([O:11][C:12]3[N:20]=[CH:19][CH:18]=[CH:17][C:13]=3[C:14]([OH:16])=O)[CH:9]=[CH:10][C:5]=2[O:4][N:3]=1.[CH3:21][CH:22]([OH:24])[CH3:23]>>[OH:24][C:22]([CH:9]1[CH2:8][CH2:7][CH:6]([CH2:2][NH:3][C:14](=[O:16])[C:13]2[CH:17]=[CH:18][CH:19]=[N:20][C:12]=2[O:11][C:8]2[CH:9]=[CH:10][C:5]3[O:4][N:3]=[C:2]([CH3:1])[C:6]=3[CH:7]=2)[CH2:5][CH2:10]1)([CH3:23])[CH3:21]
Reactant: CC(C)O
Reactant: Cc1noc2ccc(Oc3ncccc3C(=O)O)cc12
Product: Cc1noc2ccc(Oc3ncccc3C(=O)NCC3CCC(C(C)(C)O)CC3)cc12

Procedure:
Prepared from 2-(3-Methyl-benzo-(d)isoxazol-5-yloxy)-nicotinic acid and trans-2-Aminomethyl-cyclohexyl)-propan-2-ol. mp 135-7° C.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C:11]2[C:6](=[C:7]([C:12]3[N:16]=[C:15]([C:17]4[CH:18]=[CH:19][C:20]([O:25][CH:26]([CH3:28])[CH3:27])=[C:21]([CH:24]=4)[C:22]#[N:23])[O:14][N:13]=3)[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.[CH3:29][O:30][C:31](=[O:37])[CH2:32][S:33](Cl)(=[O:35])=[O:34]>C(Cl)Cl>[C:22]([C:21]1[CH:24]=[C:17]([C:15]2[O:14][N:13]=[C:12]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:6]=3[CH2:5][CH2:4][C@@H:3]4[NH:2][S:33]([CH2:32][C:31]([O:30][CH3:29])=[O:37])(=[O:35])=[O:34])[N:16]=2)[CH:18]=[CH:19][C:20]=1[O:25][CH:26]([CH3:28])[CH3:27])#[N:23]
Reactant: COC(=O)CS(=O)(=O)Cl
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@@H]4N)no2)cc1C#N
Agent: Cl
Solvent: ClCCl
Product: COC(=O)CS(=O)(=O)N[C@H]1CCc2c(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)cccc21
Reaction time: 0.5 h
Yield: 70.5 %

Procedure:
Prepared using General Procedure 16: To a stirred solution of (S)-5-(3-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile 50 (0.36 g, 1.0 mmol) in DCM (5 mL) was added methyl-2-(chlorosulfonyl)acetate (112 mg, 0.6 mmol). After 0.5 h, the crude reaction was partitioned between DCM and saturated NaHCO3. The organic layer was dried over MgSO4, concentrated, and purified by column chromatography (EA/hexanes) to give 0.21 g (42%) of (S)-methyl 2-(N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl)acetate 72. LCMS-ESI (m/z) calculated for C24H24N4O6S: 496.1. found 519.1 [M+Na]+, tR=3.71 min. 1H NMR (400 MHz, CDCl3) δ 8.41 (d, J=2.1 Hz, 1H), 8.32 (dd, J=8.9, 2.2 Hz, 1H), 8.13 (d, J=7.7 Hz, 1H), 7.66 (d, J=7.6 Hz, 1H), 7.43 (t, J=7.7 Hz, 1H), 7.11 (d, J=9.0 Hz, 1H), 5.20-5.00 (m, 2H), 4.78 (hept, J=6.2 Hz, 1H), 4.16 (d, J=14.9 Hz, 1H), 4.08 (d, J=14.9 Hz, 1H), 3.82 (s, 3H), 3.51 (ddd, J=17.4, 8.9, 3.5 Hz, 1H), 3.28-3.11 (m, 1H), 2.71 (dtd, J=11.3, 8.1, 3.6 Hz, 1H), 2.16-2.02 (m, 1H), 1.46 (d, J=6.1 Hz, 6H). (R)-methyl 2-(N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl)acetate was synthesized in an analogous fashion from (R)-5-(3-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile 49.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[NH:8][C:6](=[O:7])[C:5]2=[CH:11][C:12]=1[S:13](=[O:16])(=[O:15])[NH2:14].[NH3:17]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([NH2:8])=[O:10])[C:5]([C:6]([NH2:17])=[O:7])=[CH:11][C:12]=1[S:13](=[O:16])(=[O:15])[NH2:14]
Reactant: NS(=O)(=O)c1cc2c(cc1Cl)C(=O)NC2=O
Reactant: N
Product: NC(=O)c1cc(Cl)c(S(N)(=O)=O)cc1C(N)=O

Procedure:
A solution of 4-chloro-5-sulfamoylphthalimide (21.3 g., 0.076 mole) and 250 ml. of liquid ammonia was stirred at room temperature while permitting ammonia to evaporate. Water was added to residual material, the pH adjusted to 7 with hydrochloric acid and precipitated material collected to provide 14.5 g. (63%) of hydrated 4-chloro-5-(sulfamoyl)-1,2-benzenedicarboxamide, m.p. 270°-275° C.
Reaction SMILES: I[C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9].[CH3:10][Si:11]([C:14]#[CH:15])([CH3:13])[CH3:12]>C(N(CC)CC)C>[CH3:8][C:6]1[N:7]=[C:2]2[CH:15]=[C:14]([Si:11]([CH3:13])([CH3:12])[CH3:10])[O:9][C:3]2=[CH:4][CH:5]=1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1ccc(O)c(I)n1
Solvent: CCN(CC)CC
Product: Cc1ccc2oc([Si](C)(C)C)cc2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
To a degassed solution of 6-iodo-2-picolin-5-ol (855 mg; 3.64 mmol; 1.00 eq.) in triethylamine (20.00 mL) were added (trimethylsilyl)acetylene (1 g; 10.19 mmol; 2.80 eq.), cuprous iodide (90.07 mg; 0.47 mmol; 0.13 eq.) and dichlorobis(triphenyl phosphine) palladium(II) (229.82 mg; 0.33 mmol; 0.09 eq.). The solution was heated under reflux. After 3 h, the reaction was complete, and allowed to cool down to rt. The solution was filtered over celite (washed with AcOEt and MeOH). The solvents were removed. AcOEt and water were added and the combined organic layers were dried over magnesium sulfate, filtered and concentrated to give the expected compound. The crude was purified by short flash chromatography using cyclohexane then AcOEt/Cyclohexane 20/80 to afford 603 mg of the desired compound as a solid (Intermediate 5.1). Amount: 603 mg; Yield: 81%; Formula: C11H15NOSi; HPLC Purity: 93.14%; HPLC H2O TFA 0.1%-ACN TFA 0.05%): Rt (min); Area %=2.17 min; 93.14%; 1H NMR (CDCl3) δ 7.65 (d, 1H, J=8.5 Hz), 7.10 (s, 1H), 7.06 (d, 1H, J=8.5 Hz), 2.67 (s, 3H), 0.36 (s, 9H); LC-MS: M/Z ESI: Rt (min) 1.89 min, 206.06 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH2:9][O:10][CH3:11])=[CH:6][C:5]([O:12][CH2:13][O:14][CH3:15])=[CH:4][C:3]=1[CH2:16][OH:17].[H-].[Na+].[CH3:20]I>C1COCC1>[Br:1][C:2]1[C:3]([CH2:16][O:17][CH3:20])=[CH:4][C:5]([O:12][CH2:13][O:14][CH3:15])=[CH:6][C:7]=1[O:8][CH2:9][O:10][CH3:11]
Reactant: COCOc1cc(CO)c(Br)c(OCOC)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCOc1cc(COC)c(Br)c(OCOC)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 96 %

Procedure:
A solution of (2-bromo-3,5-bis-methoxymethoxy-phenyl)-methanol (10.2 g, 33.3 mmol) in THF (60 mL) was treated with NaH (2.67 g, 66.7 mmol) at 0° C. The resulting suspension was stirred at room temperature for 20 min. CH3I was added to the mixture and the reaction was stirred at room temperature for 1 h. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was separated, dried (Na2SO4), and concentrated. The residue was purified by flash column chromatography (silica, hexanes/ethyl acetate=5:1) to afford the title compound (10.5 g, 96%). 1H NMR (300 MHz, CDCl3) δ 6.88 (s, 1H), 6.80 (s, 1H), 5.23 (s, 2H), 5.17 (s, 2H), 4.50 (s, 2H), 3.51 (s, 3H), 3.47 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([CH3:12])([CH3:11])[CH2:9][C:8]([CH3:14])([CH3:13])[CH2:7][C:5]=2[N:6]=1.Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17]>N1C=CC=CC=1>[CH3:13][C:8]1([CH3:14])[CH2:7][C:5]2[N:6]=[C:2]([NH:1][C:16](=[O:17])[O:18][CH2:19][CH3:20])[S:3][C:4]=2[C:10]([CH3:12])([CH3:11])[CH2:9]1
Reactant: CC1(C)Cc2nc(N)sc2C(C)(C)C1
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1nc2c(s1)C(C)(C)CC(C)(C)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Amino-5,5,7,7-tetramethyl-4,5,6,7-tetrahydrobenzothiazole (16 grams; 0.075 mol) dissolved in pyridine (100 ml) was charged into a glass reaction vessel equipped with a mechanical stirrer and addition funnel. Ethyl chloroformate (11 grams; 0.1 mol) was then added dropwise with stirring and cooling of the reaction mixture. After the addition was completed the reaction mixture was allowed to warm to room temperature and stirring was continued for a period of about 1 hour. After this time the reaction mixture was poured into ice water resulting in a white precipitate. The precipitate was recovered by filtration, was dried and recrystallized from methanol to yield the desired product ethyl N-(5,5,7,7-tetramethyl-4,5,6,7-tetrahydrobenzothiazol-2-yl) carbamate having a melt point of 124° to 125° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[C:8]2[N:13]([CH:14]=1)[CH:12]=[CH:11][CH:10]=[CH:9]2.[C:15](Cl)(=[O:19])[C:16]([Cl:18])=[O:17]>C1COCC1>[O:19]=[C:15]([C:14]1[N:13]2[C:8]([CH:9]=[CH:10][CH:11]=[CH:12]2)=[CH:7][C:6]=1[C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[C:16]([Cl:18])=[O:17]
Reactant: O=C(Cl)C(=O)Cl
Reactant: c1csc(-c2cc3ccccn3c2)c1
Solvent: C1CCOC1
Product: O=C(Cl)C(=O)c1c(-c2cccs2)cc2ccccn12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.3 %

Procedure:
To an ice-cold solution of 2-thiophen-2-yl-indolizine (0.5 g, 2.51 mmol) in THF (8 ml) was added oxalyl chloride (0.3 ml, 3.48 mmol). The reaction mixture was stirred at room temperature for 30 min. The solvent was evaporated under vacuum. The crude product was recrystallized from dichloromethane-hexane to give oxo-(2-thiophen-2-yl-indolizin-3-yl)-acetyl chloride (0.3 g, 41%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[N+:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17](Cl)(=[O:19])=[O:18])([O-])=O>>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([S:17]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[NH2:8])(=[O:19])=[O:18])[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Product: CN1CCN(S(=O)(=O)c2ccccc2N)CC1
Yield: 80 %

Procedure:
The title compound (2.1 g, 80%) was obtained as a white solid from N-methylpiperazine and 2-nitrobenzenesulfonyl chloride following the same procedure as described in Preparation 2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]([CH2:12][CH2:13][OH:14])[CH:7]=[C:6]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:5]2=[O:20].C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]([CH2:12][CH2:13][O:14][S:29]([CH3:28])(=[O:31])=[O:30])[CH:7]=[C:6]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:5]2=[O:20]
Reactant: CCOC(=O)c1cn(CCO)c2ncc(Br)cc2c1=O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn(CCOS(C)(=O)=O)c2ncc(Br)cc2c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
A solution of ethyl 6-bromo-1-(2-hydroxyethyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (Intermediate 17, 800 mg, 2.34 mmol) and triethylamine (473 mg, 4.69 mmol) in dichloromethane (50 mL) was cooled to 0° C. and methane sulphonyl chloride (400 mg, 3.50 mmol) was added drop wise. The mixture was allowed to stir at room temperature for 3 h. The reaction mixture was washed with water and the organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 700 mg, (71%) of ethyl 6-bromo-1-{2-[(methylsulfonyl)oxy]ethyl}-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate, which was taken without further purification to next step.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:11])[CH2:9][CH3:10].[Si:13]([O:20][C:21]1[CH:26]=[C:25]([O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH:24]=[CH:23][C:22]=1[CH:35]1[CH2:40][CH2:39][CH:38]([CH2:41][OH:42])[CH2:37][CH2:36]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>CN(C)C1C=CN=CC=1.ClCCl>[C:8]([O:42][CH2:41][CH:38]1[CH2:37][CH2:36][CH:35]([C:22]2[CH:23]=[CH:24][C:25]([O:27][Si:28]([C:31]([CH3:33])([CH3:34])[CH3:32])([CH3:30])[CH3:29])=[CH:26][C:21]=2[O:20][Si:13]([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:15])[CH3:14])[CH2:40][CH2:39]1)(=[O:11])[CH2:9][CH3:10]
Reactant: CCC(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C2CCC(CO)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)OCC1CCC(c2ccc(O[Si](C)(C)C(C)(C)C)cc2O[Si](C)(C)C(C)(C)C)CC1
Reaction time: 16 h

Procedure:
4-Dimethylaminopyridine (catalytic amount), triethylamine (68 μl) and propionyl chloride (42 μl) were added to a stirred solution of [4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl) cyclohexyl]methanol in anhydrous dichloromethane (3 ml) at room temperature under argon. After 16 hr, the reaction mixture was partitioned between water (10 ml) and ethyl acetate (20 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×20 ml). The combined organic extracts were dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate/petrol, 1:19 v/v) to give the title compound as a yellow oil and a mixture of diastereoisomers (114 mg, 92%); δH(CDCl3) −0.04 (6H, s), 0.02 (6H, s), 0.96 (9H, s), 1.00 (9H, s), 1.08-1.18 (3H, m), 1.20-2.10 (9H, m), 2.24-2.40 (2H, m), 2.76-2.92 (1H, m), 3.94 (0.6H, d), 4.18 (0.4H, d), 6.26 (1H, m), 6.40 (1H, dd), 6.94-6.98 (1H, m).