Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[OH-].[K+].[Mn]([O-])(=O)(=O)=[O:16].[K+].C(O)CO>O>[OH:16][C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(C(=O)O)cc1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: CC(C)(O)c1ccc(C(=O)O)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 92.8 %

Procedure:
4-Isopropylbenzoic acid (5.0 g, 30.5 mmol) was dissolved in a solution of potassium hydroxide (4.1 g, 2 mL, 73.1 mmol) in water (125 mL). To the reaction mixture was added a solution of potassium permanganate (9.6 g, 60.9 mmol) in water (125 mL). The combined mixture was allowed to stir at 60° C. for 2 hours. The reaction mixture was cooled to 0° C. and treated with ethylene glycol (100 μL) and cooled to 0° C. The solid were removed by filtration and the filtrate was acidified to pH 1 by addition of 6 N HCl solution. The solid was removed by filtration, and the filtrate was extracted with diethyl ether (3×200 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to provide 4-(1-hydroxy-1-methyl-ethyl)benzoic acid (5.1 g, 93%) as a white solid. ESI-MS m/z calc. 180.1. Found 181.2 (M+1)+; Retention time: 0.6 minutes (3 min run). 1H NMR (400 MHz, MeOD) δ 8.00-7.95 (m, 2H), 7.61-7.56 (m, 2H), 2.64 (s, 1H), 1.54 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][C:14]([NH2:16])=[CH:15][C:10]=2[O:9][CH2:8][CH2:7][CH2:6]1)=[O:4].Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])[C:21]([Cl:36])=[CH:20][N:19]=1>>[CH3:1][O:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][C:14]([NH:16][C:18]3[N:23]=[C:22]([NH:24][C:25]4[C:26]([C:27](=[O:28])[NH:29][CH3:30])=[CH:31][CH:32]=[CH:33][C:34]=4[F:35])[C:21]([Cl:36])=[CH:20][N:19]=3)=[CH:15][C:10]=2[O:9][CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)N1CCCOc2cc(N)ccc21
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)OCCCN3C(=O)OC)ncc1Cl

Procedure:
3-[5-Chloro-4-(2-fluoro-6-methylcarbamoyl-phenylamino)-pyrimidin-2-ylamino]-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid methyl ester was prepared from 3-amino-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid methyl ester and 2-(2,5-dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide in an analogous manner to Example 1410. Product isolated as a white foam (71 mg, 37%). LCMS (m/e) 501 (M+H); 1H-NMR (d6-DMSO, 400 MHz) δ 9.48-9.34 (m, 2H), 8.61-8.52 (m, 1H), 8.20 (s, 1H), 7.55-7.37 (m, 3H), 7.33-7.25 (m, 1H), 7.14-7.07 (m, 1H), 6.99-6.91 (m, 1H), 4.03-3.87 (m, 2H), 3.73-3.44 (m, 5H), 2.74 (d, 3H, J=4.4 Hz), 1.96-1.82 (m, 2H).
Reaction SMILES: [OH:1][C@@H:2]([C@H:6]([OH:23])[C:7](=[O:22])[NH:8][C@H:9]([C:14](=[O:21])[NH:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:10][CH:11]([CH3:13])[CH3:12])[C:3]([OH:5])=[O:4].C(=O)(O)[O-].[Na+].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.O>CN(C)C=O>[OH:1][C@@H:2]([C@H:6]([OH:23])[C:7](=[O:22])[NH:8][C@H:9]([C:14](=[O:21])[NH:15][CH2:16][CH2:17][CH:18]([CH3:19])[CH3:20])[CH2:10][CH:11]([CH3:12])[CH3:13])[C:3]([O:5][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:4]
Reactant: BrCc1ccccc1
Reactant: CC(C)CCNC(=O)[C@H](CC(C)C)NC(=O)[C@@H](O)[C@H](O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)CCNC(=O)[C@H](CC(C)C)NC(=O)[C@@H](O)[C@H](O)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 63.5 %

Procedure:
(2S,3S)-2,3-dihydroxy-3-[(S)-3-methyl-1-(3-methylbutylcarbamoyl)butylcarbamoyl]propionic acid (1.40 g) obtained in Example 9 and sodium bicarbonate (712 mg) were suspended in dimethylformamide (20 ml). A dimethylformamide (20 ml) solution of benzyl bromide (3.56 g) was added to the resultant suspension, and the suspension was stirred at room temperature for 24 hours. Water was added after the reaction, and then was extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated sodium chloride solution. After the resultant layer was dried with magnesium sulfate, the solvent was distilled off under reduced pressure to obtain a crude product. This crude product was purified by silica gel column chromatography (a developing solvent; hexane:ethyl acetate=1:1→1:3) to obtain 1.13 g of a target compound. NMR data of the compound were as follows.
Reaction SMILES: Br[C:2]1[C:3]([C:7]([NH2:9])=[O:8])=[CH:4][S:5][CH:6]=1.C([Sn]([C:23]#[C:24][Si:25]([CH3:28])([CH3:27])[CH3:26])(CCCC)CCCC)CCC>>[CH3:26][Si:25]([C:24]#[C:23][C:2]1[C:3]([C:7]([NH2:9])=[O:8])=[CH:4][S:5][CH:6]=1)([CH3:28])[CH3:27]
Reactant: CCCC[Sn](C#C[Si](C)(C)C)(CCCC)CCCC
Reactant: NC(=O)c1cscc1Br
Product: C[Si](C)(C)C#Cc1cscc1C(N)=O
Yield: 27.7 %

Procedure:
The product from step B (1 g), tributylstannyl(trimethylsilyl)acetylene (2.16 g) and palladium(tetrakis)triphenylphoshine (0.28 g) were placed into degassed toluene (20 ml) and the mixture was heated under reflux for 16 hours under an atmosphere of nitrogen. After cooling, the solvent was removed and the residue was chromatographed on silica gel (hexane:ethylacetate 3:1). After three consecutive crystallisations from hexane, 0.3 g of 4-(trimethylsilyl)ethinyl-3-thiophene formamide was obtained (m.p. 90-94° C.).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[CH:28]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)=[O:29].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:23]1([NH:22][C:4]2[C:5]([CH3:21])=[C:6]([C:7]([NH:9][CH2:10][C:11]3[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=3[CH3:17])=[O:8])[CH:20]=[C:2]([C:33]3[CH:34]=[CH:35][C:30]([CH:28]=[O:29])=[CH:31][CH:32]=3)[CH:3]=2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(NC3CCCC3)c2C)c(=O)[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(C=O)cc3)cc(NC3CCCC3)c2C)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A solution of 5-bromo-3-(cyclopentylamino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide (1 equiv.), (4-formylphenyl)boronic acid (1.2 equiv.) and Pd (PPh3)4 (0.1 equiv.) in 1,4-dioxane (4 mL) was purged with argon for 10 min. Then, 2 M Na2CO3 solution (3.6 equiv.) was added to it and argon was purged again for 10 min. The reaction mixture was stirred at 100° C. for 2 h. After cooling to room temperature water was added to the mixture and then product was extracted with DCM. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography over silica gel (60-120 mesh size) to afford 5-(cyclopentylamino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-4′-formyl-4-methyl-[1,1′-biphenyl]-3-carboxamide.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]2[C:3]=1[C:4]([CH2:14][CH2:15][CH3:16])=[CH:5][C:6](=[O:13])[O:7]2.[N+](C1C=CC=CC=1)([O-])=O.[C:26](OC(=O)C)(=[O:28])[CH3:27].Cl>ClCCCl>[OH:1][C:2]1[CH:11]=[C:10]([OH:12])[C:9]([C:26](=[O:28])[CH3:27])=[C:8]2[C:3]=1[C:4]([CH2:14][CH2:15][CH3:16])=[CH:5][C:6](=[O:13])[O:7]2
Reactant: CCCc1cc(=O)oc2cc(O)cc(O)c12
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: O=[N+]([O-])c1ccccc1
Solvent: ClCCCl
Product: CCCc1cc(=O)oc2c(C(C)=O)c(O)cc(O)c12
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 12.2 %

Procedure:
To a mixture of 5,7-dihydroxy-4-propyl-coumarin (2.06 g 9.36 mmol) and anhydrous AICI3 (2.53 g, 18.7 mmol) was added 1,2-dichloroethane (120 mL). The resulting suspension was heated to 75° C. with vigorous stirring. After 30 minutes of stirring, a brown slurry was obtained, then nitrobenzene was introduced into the mixture resulting in an orange colored solution. A solution of anhydrous AICI3 (2.53 g, 18.7 mmol) and acetic anhydride (0.88 mL, 9.36 mmol) in 1,2-dichloroethane (40 mL) was added dropwise over a period of 1-2 hours. After addition, the mixture was allowed to stir at 75° C. for another two hours and subsequently cooled to room temperature. The resulting mixture was poured into ice and 1 N HCl. The precipitated product was filtered and then taken into ethyl acetate and the aqueous solution was extracted throughly with ethyl acetate (3×100 mL). The combined ethyl acetate extracts were dried over Na2SO4 and the solvent was removed under reduced pressure. The resulting solid was purified by column chromatography (1:1 hexane/ethyl acetate) yielding 5,7-dihydroxy-8-acetyl-4-propyl-coumarin (0.30 g, 12%): mp. 221-224° C.; 1H NMR (DMSO-d6) δ 0.94 (t, 3H), 1.58 (sextet, 2H), 2.66 (s, 3H) 2.87 (t, 2H), 6.01 (s, 1H), 6.29 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:4][C:3]=1[C@:17]12[O:25][CH2:24][CH2:23][C@H:22]1[CH2:21][S:20][C:19]([NH:26]C(=O)OC(C)(C)C)=[N:18]2.C(O)(C(F)(F)F)=O>ClCCl>[NH2:26][C:19]1[S:20][CH2:21][C@@H:22]2[CH2:23][CH2:24][O:25][C@:17]2([C:3]2[CH:4]=[C:5]([NH:8][C:9](=[O:16])[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=3)[CH:6]=[CH:7][C:2]=2[F:1])[N:18]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(NC(=O)c4ccccn4)ccc3F)OCC[C@H]2CS1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1=N[C@@]2(c3cc(NC(=O)c4ccccn4)ccc3F)OCC[C@H]2CS1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52 %

Procedure:
To a solution of tert-butyl ((4aR,7aR)-7a-(2-fluoro-5-(picolinamido)phenyl)-4a,5,6,7a-tetrahydro-4H-furo[2,3-d][1,3]thiazin-2-yl)carbamate (Preparation 5, 12 mg, 0.025 mmol) in dichloromethane (254 μL) was added TFA (39.1 μL, 0.508 mmol) at rt, and the reaction mixture was stirred at rt for 3 h. The crude product was directly purified by prep TLC eluting with 90% CH2Cl2/9% MeOH/1% NH4OH to give the title compound (5 mg, 0.013 mmol, 52.9% yield) a colorless oil. 1H NMR (500 MHz, CHLOROFORM-d) δ 10.04 (s, 1H), 8.68-8.62 (m, 1H), 8.31 (dt, J=7.8, 1.0 Hz, 1H), 8.01 (ddd, J=8.9, 4.1, 2.9 Hz, 1H), 7.93 (td, J=7.7, 1.7 Hz, 1H), 7.72 (dd, J=6.9, 2.8 Hz, 1H), 7.51 (ddd, J=7.5, 4.8, 1.1 Hz, 1H), 7.08 (dd, J=10.9, 8.8 Hz, 1H), 4.11 (t, J=7.2 Hz, 3H), 3.50 (s, 1H), 3.15 (dd, J=12.8, 4.0 Hz, 1H), 2.97 (ddd, J=13.0, 7.5, 1.8 Hz, 1H), 2.77 (dd, J=7.0, 4.0 Hz, 1H), 2.22-1.98 (m, 2H). MS (M−1): 371.2.
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[CH:8][C:7]([F:11])=[CH:6][C:3]=1[CH:4]=O.C(O)(=O)[CH2:13][C:14]([OH:16])=[O:15]>>[F:1][C:2]1[C:9]([F:10])=[CH:8][C:7]([F:11])=[CH:6][C:3]=1[CH:4]=[CH:13][C:14]([OH:16])=[O:15]
Reactant: O=Cc1cc(F)cc(F)c1F
Reactant: O=C(O)CC(=O)O
Product: O=C(O)C=Cc1cc(F)cc(F)c1F

Procedure:
According to the previously described general procedure (GP1), Knoevenagel condensation (75° C.; 3h20) between 2,3,5-trifluorobenzaldehyde (9.730 g; 60.777 mmol) and malonic acid (12.016 g; 115.477 mmol) gave the product 3-(2,3,5-trifluoro-phenyl)-acrylic acid as a colorless solid (8.310 g; 68%). LC-MS: tR=0.84 min.; [M+H]+: no ionisation.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C@@H:17]1([NH2:27])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][CH2:18]1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][NH:27][C@@H:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][CH2:18]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N[C@H]1CCCc2ccccc21
Reactant: O=Cc1cccc(OCc2ccccc2)c1
Product: c1ccc(COc2cccc(CN[C@H]3CCCc4ccccc43)c2)cc1

Procedure:
3-(Benzyloxy)benzaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: [CH3:1][C:2]12[CH2:12][CH:6]3[CH2:7][C:8]([CH3:11])([CH2:10][C:4]([C:13]4(O)[CH:18]=[CH:17][CH:16]=[CH:15][CH2:14]4)([CH2:5]3)[CH2:3]1)[CH2:9]2.N1C=CC=CC=1.[F:26][C:27]([F:40])([F:39])[S:28]([O:31]S(C(F)(F)F)(=O)=O)(=[O:30])=[O:29].[Cl-].[Na+]>C(OCC)(=O)C>[CH3:11][C:8]12[CH2:7][CH:6]3[CH2:12][C:2]([CH3:1])([CH2:3][C:4]([C:13]4[CH:14]=[CH:15][C:16]([O:31][S:28]([C:27]([F:40])([F:39])[F:26])(=[O:30])=[O:29])=[CH:17][CH:18]=4)([CH2:5]3)[CH2:10]1)[CH2:9]2
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CC12CC3CC(C)(C1)CC(C1(O)C=CC=CC1)(C3)C2
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC12CC3CC(C)(C1)CC(c1ccc(OS(=O)(=O)C(F)(F)F)cc1)(C3)C2
Temperature: -15 °C
Yield: 88 %

Procedure:
Into a 100 ml four-necked flask equipped with a thermometer, an inlet for nitrogen gas and a stirrer, 4.0 g (0.0157 moles) of 4-(1-(3,5-dimethyladamantyl)phenol obtained above and 20 ml of pyridine were placed. A stream of nitrogen gas was introduced into the flask, and a solution was prepared under stirring. The obtained solution was cooled at −15° C. in an ice/methanol bath. Using a dropping funnel, trifluoromethanesulfonic acid anhydride was added dropwise. After the addition was completed, the obtained mixture was stirred at the room temperature for 2 hours. To the reaction fluid, 100 ml of ethyl acetate and 100 ml of a saturated aqueous solution of sodium chloride were added, and the obtained mixture was transferred to a separation funnel. The layer of ethyl acetate was taken out and washed twice with 100 ml of a saturated aqueous solution of sodium chloride. Then, ethyl acetate was removed by distillation under a reduced pressure using a rotary evaporator, and 5.4 g of 1-(1-(3,5-dimethyladamantyl)-4-trifluoromethane-sulfonyloxybenzene was obtained (the yield: 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH2:10][C:9]3=[N:12][CH:13]=[CH:14][N:8]3[CH2:7][C:6]=2[CH:15]=1.[CH3:16][C:17]1[CH:34]=[CH:33][CH:32]=[CH:31][C:18]=1[C:19]([NH:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1)=[O:20].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:26]([C:25]3[CH:24]=[CH:23][C:22]([NH:21][C:19](=[O:20])[C:18]4[CH:31]=[CH:32][CH:33]=[CH:34][C:17]=4[CH3:16])=[CH:30][CH:29]=3)=[O:27])[CH2:10][C:9]3=[N:12][CH:13]=[CH:14][N:8]3[CH2:7][C:6]=2[CH:15]=1
Reactant: Clc1ccc2c(c1)Cn1ccnc1CN2
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3nccn3Cc3cc(Cl)ccc32)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
As described for Example 125 a mixture of 1 mmol of 7-chloro-10,11-dihydro-5H-imidazo[2,1-c][1,4]benzodiazepine, 1.1 mmol of 4-[(2-methylbenzoyl)amino]benzoyl chloride and 1.5 mmol of triethylamine in 10 ml of dichloromethane is stirred at room temperature for 3 hours and worked up to give the desired product as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:17][C:16]3[C:11](=[N:12][CH:13]=[N:14][CH:15]=3)[N:10]=2)=[C:5]([O:18][CH2:19][CH2:20][S:21][CH3:22])[CH:4]=1.OO.C(=O)([O-])[O-:26].[K+].[K+]>C(O)(=O)C.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:17][C:16]3[C:11](=[N:12][CH:13]=[N:14][CH:15]=3)[N:10]=2)=[C:5]([O:18][CH2:19][CH2:20][S:21]([CH3:22])=[O:26])[CH:4]=1
Reactant: COc1ccc(-c2nc3ncncc3[nH]2)c(OCCSC)c1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(-c2nc3ncncc3[nH]2)c(OCCS(C)=O)c1
Reaction time: 3.5 h

Procedure:
One gram of 8-[4-methoxy-2-(2-methylmercapto-ethoxy)phenyl]purine was dissolved in 10 ml of glacial acetic acid and mixed with 0.5 ml of 30% hydrogen peroxide. After standing for 3.5 hours at room temperature, the reaction mixture was diluted with water and made alkaline by means of potassium carbonate. The precipitate was recrystallized from isopropanol/ethanol in a volume ratio of 1:1.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:8]1[C:12]2([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[O:11][CH2:10][CH2:9]1>C(OCC)C>[C:1]1([N:15]2[CH2:16][CH2:17][C:12]3([O:11][CH2:10][CH2:9][O:8]3)[CH2:13][CH2:14]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: C1CC2(CCN1)OCCO2
Reactant: O=C1CCCCC1
Solvent: CCOCC
Product: C1=C(N2CCC3(CC2)OCCO3)CCCC1

Procedure:
54 ml (0.5 mole) of cyclohexanone together with 200 ml (1.5 mole) of 1,4-dioxa-8-aza-spiro[4.5]decane III were dissolved in 0.5 l of diethyl ether and stirred for half an hour to form the compound 8-cyclohex-1-enyl-1,4-dioxa-8-aza-spiro[4.5]decane IV. 31 ml of titanium tetrachloride in 0.5 l of n-hexane were then added dropwise at 0° C. within 60 minutes. After the addition the reaction mixture was heated slowly to 20° C. and stirred for a further 24 hours. The precipitate formed was filtered off under suction and discarded. The filtrate was concentrated by evaporation and directly reacted further. The yield was 83 g (0.37 mole, 71%).
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][N:3]=1.[C:11]1([NH:17][C:18](=O)[CH3:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH3:19][C:18]1[N:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:2]2=[N:3][CH:4]=[CH:5][CH:6]=[C:7]2[N:8]=1
Reactant: CC(=O)Nc1ccccc1
Reactant: O=[N+]([O-])c1cccnc1Br
Product: Cc1nc2cccnc2n1-c1ccccc1
Yield: 52.6 %

Procedure:
The title compound was prepared with the analogous procedure described in example 3 using 2-Bromo-3-nitropyridine (101 mg, 0.5 mmol) and N-phenylacetamide (81 mg, 0.6 mmol) as starting materials to yield the title compound as pale yellow viscous oil (55 mg, 53%). 1H NMR (DMSO) δ 2.48 (s, 3 H), 7.24 (dd, 1 H), 7.53-7.63 (m, 5 H), 8.02 (d, 1 H), 8.20 (d, 1 H); 13C NMR δ 14.6, 118.3, 125.9, 127.4, 128.7, 129.3, 134.1, 134.3, 143.0, 148.7, 152.9. HRMS (FAB): cal. for C13H12N3 [M-FH+]: 210.1031; found: 210.1027.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]1[O:11][CH2:10][CH2:9][O:8]1.CCCCCC.C([Li])CCC.CN(C)[CH:25]=[O:26].[Cl-].[NH4+]>O1CCCC1>[O:8]1[CH2:9][CH2:10][O:11][CH:7]1[C:3]1[S:4][C:5]([CH:25]=[O:26])=[CH:6][C:2]=1[CH3:1]
Reactant: Cc1ccsc1C1OCCO1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(C=O)sc1C1OCCO1
Reaction time: 0.5 h
Yield: 88.8 %

Procedure:
To a solution of 2-(3-methylthiophen-2-yl)-1,3-dioxolane (3.198 g, 18.79 mmol) in anhydrous tetrahydrofuran (30 ml) was added dropwise 1.55M butyllithium hexane solution (12.1 ml, 18.8 mmol) at −78° C. After stirring for 30 min, anhydrous N,N-dimethylformamide (4.36 ml, 56.3 mmol) was added dropwise. After stirring at −78° C. for 1 hr, the reaction mixture was warmed, saturated aqueous ammonium chloride was added, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (FUJI SILYSIA CHEMICAL LTD. BW-300SP 80 g, ethyl acetate:hexane=1:5) to give 5-(1,3-dioxolan-2-yl)-4-methylthiophene-2-carbaldehyde (3.309 g, 16.69 mmol, yield 88.8%) as a brown oil.
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH:6]([OH:8])[CH3:7])[CH2:2][CH3:3].[C:9]([Si:13](Cl)([CH3:15])[CH3:14])([CH3:12])([CH3:11])[CH3:10].O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Si:13]([O:8][CH:6]([CH3:7])[CH2:5][NH:4][CH2:1][CH2:2][CH3:3])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:15])[CH3:14]
Reactant: CCCNCC(C)O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CCCNCC(C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 1-(propylamino)propan-2-ol (8.00 g, 68.3 mmol), tert-butylchlorodimethylsilane (10.9 g, 72.4 mmol), and catalytic amount of DMAP in CH2Cl2 (68 mL) at 0° C. was added dropwise TEA (9.61 ml, 68.3 mmol). The reaction mixture was warmed to room temperature and stirred for 20 h. Additional 1 mL of TEA was added and stirred for additional 20 h. Water (60 mL) was added. The layers were separated. The aqueous layer was extracted with EtOAc (1×). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude material that was filtered again to afford quantitatively 2-(tert-butyldimethylsilyloxy)-N-propylpropan-1-amine that was used directly without further purification.
Reaction SMILES: [CH3:1][S:2][C:3]1([NH:8][C:9](=[O:18])[CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6][NH:5][C:4]1=[O:7].C(OO)(=[O:21])C>O1CCOCC1.C(O)(=O)C>[CH3:1][S:2]([C:3]1([NH:8][C:9](=[O:18])[CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6][NH:5][C:4]1=[O:7])=[O:21]
Reactant: CSC1(NC(=O)COc2ccccc2)CNC1=O
Reactant: CC(=O)OO
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CS(=O)C1(NC(=O)COc2ccccc2)CNC1=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of (25) (175 mg) in dry dioxan (7 ml) was treated with a solution of peracetic acid in glacial acetic acid (0.99 ml of a 5.07% w/v solution). The mixture was stirred at room temperature for approximately 20 mins, then evaporated to dryness. The residue was evaporated once more from dry dioxan before drying thoroughly in vacuo. The residue was taken up in chloroform and chromatographed on a short column of silica gel eluting with 10% meOH/CHCl3 to give the product (26) (186 mg) a mixture of sulphoxide isomers (approximately 1:2) νmax(CHCl3) 3410, 1785, 1690, and 1490 cm-1, δppm (CDCl3) (90 MHz) 2.60 (major isomer) and 2.67 (minor isomer) (both s, together 3H), 3.79 and 4.12 (ABq, minor isomer, J8 Hz) and 3.87 and 4.01 (ABq, major isomer, J6Hz) (together 2H), 4.53 (minor isomer) and 4.60 (major isomer) both s, together 2H), 6.52 (s, 1H, exch.), 6.80 to 7.45 (m, 5H), 7.78 (s, 1H, exch.).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]3[N:15]([C:16]=2[C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)[N:18]=2)[CH:14]=[CH:13][S:12]3)=[CH:5][C:4]=1[O:30][CH3:31].CCN(C(C)C)C(C)C.[CH:41]1([S:44](Cl)(=[O:46])=[O:45])[CH2:43][CH2:42]1>C(Cl)Cl>[CH:41]1([S:44]([N:27]2[CH2:26][CH2:25][CH:24]([NH:23][C:19]3[N:18]=[C:17]([C:16]4[N:15]5[C:11]([S:12][CH:13]=[CH:14]5)=[N:10][C:9]=4[C:6]4[CH:7]=[CH:8][C:3]([F:2])=[C:4]([O:30][CH3:31])[CH:5]=4)[CH:22]=[CH:21][N:20]=3)[CH2:29][CH2:28]2)(=[O:46])=[O:45])[CH2:43][CH2:42]1
Reactant: COc1cc(-c2nc3sccn3c2-c2ccnc(NC3CCNCC3)n2)ccc1F
Reactant: O=S(=O)(Cl)C1CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(-c2nc3sccn3c2-c2ccnc(NC3CCN(S(=O)(=O)C4CC4)CC3)n2)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.7 %

Procedure:
The 4-[6-(4-fluoro-3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]-N-[piperidin-4-yl]pyrimidin-2-amine hydrochloride (0.25 g, 0.50 mmol) in methylene chloride (DCM) (12 ml) was cooled to 0° C. and was treated with Hunig's base (440 μl, 2.5 mmol). The mixture was kept at 0° C. for 30 minutes then the cyclopropyl-sulfonyl chloride (72 μl, 0.60 mmol) was added. The reaction mixture was stirred at room temperature for one hour. The mixture was diluted with methylene chloride (10 ml) and was washed water (2×10 ml) and a saturated aqueous sodium chloride solution (10 ml). The organic phase was dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography using a gradient (ethyl acetate/hexanes, 30-75%), affording 0.253 g (96%) of the title compound as a pale yellow solid. M.p.: 146-148° C. 400 MHz 1H NMR (DMSO-d6 at 60° C.) δ: 8.72 (br. s, 1H), 8.13 (d, J=5.1 Hz, 1H), 7.45 (d, J=4.3 Hz, 1H), 7.35 (dd, J=8.6, 2.0 Hz, 1H), 7.26 (dd, J=11.3, 8.2 Hz, 1H), 7.25 (br. S, 1H), 7.15 (ddd, J=8.2, 4.7, 2.0 Hz, 1H), 6.41 (d, J=5.1 Hz, 1H), 3.95-3.86 (m, 1H), 3.83 (s, 3H), 3.68-3.61 (m, 2H), 3.06-2.96 (m, 2H), 2.60-2.52 (m, 1H), 2.08-1.96 (m, 2H), 1.66-1.54(m, 2H), 1.04-0.94 (m, 4H). LCMS: 529 [M+H]. Calc. for C24H25N6O3S2F.0.13 water.0.7 diethyl ether: C, 54.31; H, 5.25; N, 14.18. Found C, 54.32; H, 4.89; N, 14.19.