Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C1C=CC(N)=CC=1)(=O)=O.[CH3:12][S:13]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[C:19]2=[O:26])(=[O:15])=[O:14].[CH:27]1[C:32]([NH:33][NH2:34])=[CH:31][CH:30]=[C:29]([S:35]([NH2:38])(=[O:37])=[O:36])[CH:28]=1.Cl>>[CH3:12][S:13]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[C:19]2=[O:26])(=[O:15])=[O:14].[CH3:12][S:13]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[C:19]2=[N:34][NH:33][C:32]1[CH:31]=[CH:30][C:29]([S:35]([NH2:38])(=[O:36])=[O:37])=[CH:28][CH:27]=1)(=[O:15])=[O:14]
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: CS(=O)(=O)c1ccc(N)cc1
Agent: CS(=O)(=O)c1ccc2c(c1)C(=O)C(=O)N2
Agent: Cl
Product: CS(=O)(=O)c1ccc2c(c1)C(=NNc1ccc(S(N)(=O)=O)cc1)C(=O)N2

Procedure:
5-Methylsulfonyl-1H-indole-2,3-dione was prepared from 4-methylsulfonylaniline according to Procedure A: 1H NMR (DMSO-d6): δ 3.21 (s, 3H), 7.07 (d, J=8.3 Hz, 1H), 7.92 (d, J=1.7 Hz, 1H), 8.05 (dd, J=8.2, 2.0 Hz, 1H), 11.46 (s, 1H); APCI-MS m/z 225 (M)−. The title compound was prepared from 5-methylsulfonyl-1H-indole-2,3-dione and 4-sulfonamidophenylhydrazine hydrochloride according to Procedure G: mp>250° C.; 1H NMR (DMSO-d6): δ 3.20 (s, 3H), 7.11 (d, J=8.3 Hz, 1H), 7.26 (s, 2H), 7.65 (d, J=8.9 Hz, 2H), 7.78 (d, J=8.7 Hz, 2H), 7.79 (dd, J=8.2, 1.9 Hz, 1H), 8.06 (d, J=1.6 Hz, 1H), 11.54 (s, 1H), 12.75 (s, 1H); APCI-MS m/z 394 (M)−. Anal. Calcd for C15H14N4O5S2.0.9H2O: C, 43.87; H, 3.88; N, 13.64; S, 15.62. Found: C, 43.96; H, 3.80; N, 13.58; S, 15.67.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C@H:8]1[CH2:13][CH2:12][C@@H:11]([NH:14][C:15]([C:17]2[C:18](Cl)=[N:19][CH:20]=[C:21]([F:23])[CH:22]=2)=[O:16])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:26][S:27][C:28]1[CH:29]=[C:30]([OH:34])[CH:31]=[CH:32][CH:33]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[C:1]([O:5][C:6](=[O:25])[NH:7][C@H:8]1[CH2:13][CH2:12][C@@H:11]([NH:14][C:15]([C:17]2[C:18]([O:34][C:30]3[CH:31]=[CH:32][CH:33]=[C:28]([S:27][CH3:26])[CH:29]=3)=[N:19][CH:20]=[C:21]([F:23])[CH:22]=2)=[O:16])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1cccc(O)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](NC(=O)c2cc(F)cnc2Cl)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](NC(=O)OC(C)(C)C)CC2)c1
Temperature: 65 °C
Reaction time: 18 h

Procedure:
{cis-4-[(2-Chloro-5-fluoro-pyridine-3-carbonyl)-amino]-cyclohexyl}-carbamic acid tert-butyl ester (5.44 g, 14.6 mmol), 3-methylsulfanylphenol (2.05 g, 14.6 mmol) and caesium carbonate (7.15 g, 21.9 mmol) were suspended in dimethylformamide (100 ml) and the reaction was heated to 65° C. and stirred at this temperature under nitrogen for 18 h, then at room temperature for 48 h. The reaction was cooled to room temperature, concentrated under reduced pressure and the residue was diluted with water (75 ml). It was then extracted with ethyl acetate (3×100 ml) and the combined organic extracts were washed with water (2×30 ml), brine (30 ml), dried over MgSO4 and the solvent removed under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with pentane:ether (50:50 changing to 45:55 then 40:60, by volume) to give (cis-4-{[-5-fluoro-2-(3-methylsulfanyl-phenoxy)-pyridine-3-carbonyl]-amino}-cyclohexyl)-carbamic acid tert-butyl ester (3.69 g) as a white solid.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH2:28]([N:30]1[CH:34]=[CH:33][N:32]=[C:31]1[C:35]1[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=1)[CH3:29]>>[CH2:28]([N:30]1[CH:34]=[CH:33][N:32]=[C:31]1[C:35]1[CH:41]=[CH:40][C:38]([NH:39]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:37][CH:36]=1)[CH3:29]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: CCn1ccnc1-c1ccc(N)cc1
Product: CCn1ccnc1-c1ccc(N/C(=C2\C(=O)Nc3cc(C(=O)OC)ccc32)c2ccccc2)cc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(1-ethyl-imidazol-2-yl)-aniline Rf value: 0.4 (silica gel, methylene chloride/methanol=10:1) C28H24N4O3
Reaction SMILES: [C:1]([CH:9]([CH2:13][CH3:14])C(O)=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15](Cl)(=[O:20])C(C)(C)C.[C:22]1([CH:28]2[CH2:32][O:31][C:30](=[O:33])[NH:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.S(=O)(=O)(O)O>ClCCl.CN(C)C=O.CN(C)C1C=CN=CC=1.C(N(CC)CC)C>[O:33]=[C:30]1[N:29]([C:15](=[O:20])[CH2:14][CH2:13][CH2:9][C:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:8])[CH:28]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:32][O:31]1
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCC(C(=O)O)C(=O)c1ccccc1
Reactant: O=C1NC(c2ccccc2)CO1
Agent: CN(C)c1ccncc1
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(CCCC(=O)N1C(=O)OCC1c1ccccc1)c1ccccc1
Reaction time: 0.08 h

Procedure:
10 g of benzoylbutyric acid and 12.5 ml of triethylamine are dissolved in 55 ml of dichloromethane. After 5 min at room temperature, 6.2 ml of pivaloyl chloride are added over a period of 30 min, and the mixture is stirred for 2 hours. 5.9 g of 4-phenyloxazolidin-2-one in 6 ml of dimethylformamide and 0.9 g of 4-(dimethylamino)pyridine are then added. The mixture is heated at reflux for about 7 hours (monitored by TLC). After the reaction has ended, the mixture is put into 15 ml of 2N sulfuric acid and stirred briefly, and the phases are then separated. The org. phase is washed with 5 percent strength bicarbonate solution and, after drying, concentrating and recrystallization from ethyl acetate/n-heptane, the product of molecular weight 337.4 (C20H19NO4); MS (DCl+): 338 (M+H+), is obtained. By the same route, optically active/enantiomerically enriched 2 is obtained when optically active/enantiomerically enriched 4-phenyloxazolidin-2-one is used.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[CH:23](C(OCC)=O)[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:12])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Li+].O>CS(C)=O.CCOC(C)=O>[CH2:1]([O:8][C:9]([N:11]([CH2:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:12])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc([N+](=O)[O-])cc1CN(C)C(=O)OCc1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)Cc1ccc([N+](=O)[O-])cc1CN(C)C(=O)OCc1ccccc1
Temperature: 130 °C
Reaction time: 3 h
Yield: 91.7 %

Procedure:
15A (2.668 g, 5.82 mmol) was dissolved in DMSO (30 mL), lithium chloride (0.493 g, 11.64 mmol) and water (0.105 mL, 5.82 mmol) were added. The reaction mixture was stirred at 130° C. for 3 h, cooled to rt, diluted with EtOAc (150 mL), washed with water (2×50 mL), brine (1×50 mL) and dried (Na2SO4). EtOAc was removed under reduced pressure and the residue was purified by flash chromatography (0-60% EtOAc/hexanes). Fractions were combined and concentrated under reduced pressure to give 15B (2.062 g, 92% yield) as a yellowish oil. MS (ESI) m/z: 387.2 [M+1]+. 1H NMR: (400 MHz, CDCl3) δ ppm 8.11 (1H, d, J=8.34 Hz), 8.06 (1H, br. s.), 7.28-7.46 (6H, m), 5.20 (2H, br. s.), 4.55-4.69 (2H, m), 4.13 (2H, d, J=6.82 Hz), 3.64-3.86 (2H, m), 2.92 (3H, s), 1.24 (3H, td, J=7.07, 2.53 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH:8]3[CH:11]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:12]([CH:14]=[O:15])=[N:13][N:7]3[C:6]=2[CH:22]=1.[CH2:23]([Mg]Cl)[CH3:24]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH:8]3[CH:11]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:12]([CH:14]([OH:15])[CH2:23][CH3:24])=[N:13][N:7]3[C:6]=2[CH:22]=1
Reactant: O=CC1=NN2c3cc(F)ccc3OCC2C1c1ccccc1
Reactant: CC[Mg]Cl
Solvent: C1CCOC1
Product: CCC(O)C1=NN2c3cc(F)ccc3OCC2C1c1ccccc1

Procedure:
A solution of racemic aldehyde (2-1) (0.03 g, 0.1 mmol) in THF (6 mL) at −78° C. was treated with a solution of ethylmagnesium chloride (0.05 mL of a 2M soln in THF). A heavy precipitate formed immediately. The reaction was quenched with water and the mixture extracted with EtOAc. The organic solution was washed with brine, dried over MgSO4, filtered, and concentrated. The residue was dissolved in MeCN (0.5 mL) and purified by reverse phase HPLC (YMC J-sphere H80 20×50 mm; eluted with 5-95% MeCN/water+0.1% TFA) to provide (2-2) as a mixture (˜2:1) of isomers. LRMS nm/z (M+H) 327.2 found, 327.2 required.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4](=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:5]([O-:7])=[O:6].[H-].[Na+].[F:14][C:15]([F:19])([F:18])CI.O.[CH3:21]N(C=O)C>>[CH3:21][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=1[S:2][CH2:1][C:15]([F:19])([F:18])[F:14]
Reactant: CN(C)C=O
Reactant: FC(F)(F)CI
Reactant: CSc1ccccc1C(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1ccccc1SCC(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Methylthiosalicylate (5.0 mL, 36 mmol) was added dropwise to a stirred suspension of NaH (60% oil dispersion, 1.43 g, 36 mmol) in dry DMF (30 ml,) at room temperature. The mixture was stirred in the dark under Ar for 30 min and was then cooled to 0° C. and treated with a solution of 1,1,1-trifluoro-2-iodoethane (3.0 mL, 30 mmol) in DMF (10 mL) via cannula. The reaction flask was covered with foil and was allowed to warm to room temperature while stirring overnight. Water was poured into the mixture which was then extracted with ether (3×150 mL). The combined ether extracts were washed with saturated aqueous Na2CO3 and brine, dried over MgSO4 filtered and concentrated in vacuo. Silica gel chromatography (isocratic elution with 10% EtOAc-hexanes) afforded the title compound as a pale yellow oil:
Reaction SMILES: Cl.[CH2:2]([N:4]([CH2:8][CH3:9])[CH2:5][CH2:6][SH:7])[CH3:3].[H-].[Na+].[H][H].C[O:15][C:16]([C:18]1[C:27]2[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=2[CH:21]=[CH:20][C:19]=1[NH:28][S:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1F)(=[O:31])=[O:30])=[O:17]>CN(C=O)C>[CH2:2]([N:4]([CH2:8][CH3:9])[CH2:5][CH2:6][S:7][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[S:29]([NH:28][C:19]1[CH:20]=[CH:21][C:22]2[CH2:23][CH2:24][CH2:25][CH2:26][C:27]=2[C:18]=1[C:16]([OH:17])=[O:15])(=[O:30])=[O:31])[CH3:3]
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccccc2F)ccc2c1CCCC2
Reactant: CCN(CC)CCS
Reactant: [H][H]
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC)CCSc1ccccc1S(=O)(=O)Nc1ccc2c(c1C(=O)O)CCCC2
Temperature: 72.5 °C
Reaction time: 8 h
Yield: 78.6 %

Procedure:
A suspension of 2-(diethylamino)ethanethiol hydrochloride (560 mg, 3.30 mmol) and 60% sodium hydride dispersion (224 mg, 10.18 mmol) was stirred in 3 mL of dry DMF until hydrogen evolution ceased. The mixture was treated with a solution of 2-([(2-fluorophenyl)sulfonyl]amino)-5,6,7,8-tetrahydro-1-napthalenecarboxylic acid methyl ester (200 mg, 0.55 mmol) in 1 mL of DMF, stirred at 70 to 75° C. overnight, and concentrated. The concentrate was purified by C18 reverse-phase HPLC using acetonitrile/water/0.1% TFA to provide the desired product (200 mg, 78.7%). MS (APCI) m/e 462.8 (M+H)+; 1H NMR (400 MHz, CD3OD) δ 7.89 (dd, 1H), 7.65 (dd, 1H), 7.57 (dt, 1H) 7.34 (dt, 1H), 7.18 (d, 1H), 7.00 (d, 1H), 3.34-3.51 (m, 4H), 3.29 (m, 2H), 3.25 (q, 4H), 2.65-2.77 (m, 4H), 1.70 (m, 4H), 1.28 (t, 6H).
Reaction SMILES: [Cl-:1].[Al+3].[Cl-].[Cl-].ClC(O[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=1[CH3:16])=O>>[CH3:16][C:10]1[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:9]=1[Cl:1]
Reactant: Cc1ccc(OC(=O)Cl)c(C)c1
Reactant: [Cl-]
Agent: [Al+3]
Product: Cc1ccc(Cl)c(C)c1
Temperature: 200 °C
Yield: 20 %

Procedure:
0.5 g of anhydrous aluminium chloride was added to 15 g of 2,4-dimethylphenyl chloroformate and the mixture was heated at 200° C. for 3 hours at normal pressure. The reaction mixture was cooled and worked up as described in Example 1. 2,4-Dimethylchlorobenzene was obtained in a yield of 20%, which is considerable despite the unfavourable substitution pattern.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13].[Cl:14][CH2:15][CH:16]([OH:26])[CH2:17][N:18]1[CH:23]([CH3:24])[CH2:22][CH2:21][CH2:20][CH:19]1[CH3:25].C(=O)([O-])[O-].[K+].[K+].CC(C)=O>CN(C)C=O>[ClH:14].[CH3:25][CH:19]1[CH2:20][CH2:21][CH2:22][CH:23]([CH3:24])[N:18]1[CH2:17][CH:16]([OH:26])[CH2:15][O:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccccc1Cc1cccs1
Reactant: CC1CCCC(C)N1CC(O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CC1CCCC(C)N1CC(O)COc1ccccc1Cc1cccs1
Product: Cl
Reaction time: 20 h
Yield: 37.9 %

Procedure:
A mixture of 1.9 g of 2-(2-thienylmethyl)phenol, 2.3 g of 1-chloro-3-(2,6-dimethylpiperidino)-2-propanol, 1.4 g of anhydrous potassium carbonate, 30 ml of acetone and 20 ml of dimethylformamide is refluxed with stirring for 20 hours. The insoluble matter is then filtered off, and the filtrate is concentrated. To the residue is added ether, and the ethereal solution is extracted with two 50 ml portions of 10% hydrochloric acid. The aqueous layer is made alkaline with sodium hydroxide, and the separated oil is extracted twice with ether. The ether layer is dried over anhydrous potassium carbonate, and the solvent is removed. The residue is purified by column chromatography and converted into the hydrochloride in the same manner as in above method (a) to give 1.5 g of 1-(2,6-dimethylpiperidino)-3-[2-(2-thienylmethyl)phenoxy]-2-propanol hydrochloride, melting at 152°-153°C.
Reaction SMILES: [Li+].[OH-].C[O:4][C:5](=[O:14])[CH2:6][CH:7]1[CH2:12][CH2:11][C:10](=[O:13])[CH2:9][CH2:8]1>>[O:13]=[C:10]1[CH2:11][CH2:12][CH:7]([CH2:6][C:5]([OH:14])=[O:4])[CH2:8][CH2:9]1
Reactant: COC(=O)CC1CCC(=O)CC1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)CC1CCC(=O)CC1

Procedure:
Prepared from LiOH hydrolysis of (4-Oxo-Cyclohexyl)-acetic acid methyl ester (commercially available).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[Cl-].[Ca+2].[Cl-].[Cl-].[Al+3].[Cl-].[Cl-].[C:16]1([CH3:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1C2C(=CC=CC=2)CCC1>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:19]2[CH:20]=[CH:21][C:16]([CH3:22])=[CH:17][CH:18]=2)=[CH:3][CH:4]=1
Reactant: Cc1ccc(N)cc1
Reactant: Cc1ccccc1
Agent: [Al+3]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: c1ccc2c(c1)CCCC2
Product: Cc1ccc(Nc2ccc(C)cc2)cc1
Temperature: 0 °C
Yield: 69.8 %

Procedure:
In a 500-ml four-necked flask were charged 56 ml of 1,2,3,4-tetrahydronaphthalene (boiling point: 207° C.) as a solvent and 91.1 g (0.83 mol) of p-toluidine, followed by the addition of 25.6 g (0.23 mol) of anhydrous calcium chloride and 30.8 g (0.23 mol) of anhydrous aluminum chloride under stirring. The resulting mixture was reacted at 210 to 220° C. for 3 hours under a nitrogen atmosphere. After cooling, the reaction mixture was added with 126 ml of toluene, followed by charging in 160 g of ice water. The resulting mixture was stirred and allowed to stand, and then the resulting water layer was separate out. The organic layer was washed successively with 150 ml of a 5% aqueous solution of hydrochloric acid, 100 ml of a 5% aqueous solution of sodium bicarbonate and 100 ml of water. After removal of the organic solvent by distillation under reduced pressure, 80 ml of methanol was added to the residue and the mixture was crystallized overnight at −3 to −8° C. The resulting crystals were collected by filtration, washed with 30 ml of methanol and then dried, whereby 57.1 g (yield: 69.8%) of the title compound was obtained as white crystals. As a result of HPLC. analysis (column: YMC-A-312, detection UV: 280 nm, flow rate: 1.0 ml/min, eluent: acetonitrile/water=8/2), the compound was found to have a purity of 99.8%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[C:17]3[N:34]=[CH:33][S:32][C:18]=3[N:19]=[C:20]([C:22]3[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[CH:24][CH:23]=3)[N:21]=2)[CH:6]=[C:7]([N:9]2[CH2:13][CH2:12][CH2:11][C@@H:10]2[CH3:14])[CH:8]=1.[OH-].[Na+]>O1CCOCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[C:17]3[N:34]=[CH:33][S:32][C:18]=3[N:19]=[C:20]([C:22]3[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:30][CH:31]=3)[N:21]=2)[CH:6]=[C:7]([N:9]2[CH2:13][CH2:12][CH2:11][C@@H:10]2[CH3:14])[CH:8]=1
Reactant: COC(=O)c1ccc(-c2nc(Nc3cc(OC)cc(N4CCC[C@@H]4C)c3)c3ncsc3n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(Nc2nc(-c3ccc(C(=O)O)cc3)nc3scnc23)cc(N2CCC[C@@H]2C)c1
Temperature: 30 °C
Yield: 43.3 %

Procedure:
The mixture of (S)-methyl 4-(7-(3-methoxy-5-(2-methylpyrrolidin-1-yl)phenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzoate (121 mg, 0.25 mmol) and NaOH (102 mg, 2.54 mmol) in dioxane (20 mL) and H2O (10 mL) was heated to 30° C. for 2 h. The reaction mixture was concentrated and the aqueous residue was adjusted to pH˜4 by the addition of conc. HCl. The solution was extracted with ethyl acetate (10 mL×3), then combined organics dried over Na2SO4 and concentrated to afford (S)-4-(7-(3-methoxy-5-(2-methylpyrrolidin-1-yl)phenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzoic acid (50 mg, crude) as yellow solid which was used to next step without purification. LC-MS: 462 [M+H]+, tR=1.699 min.
Reaction SMILES: C([O:3][C:4](=[O:41])[CH2:5][C@@H:6]([NH:19][C:20]1[C:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[F:32])=[CH:24][N:23]=[C:22]([N:33]([CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)[CH3:34])[N:21]=1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([N:16]([CH3:18])[CH3:17])=[O:15])=[CH:9][CH:8]=1)C.[OH-].[Na+]>CO.O>[F:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C:25]1[C:20]([NH:19][C@@H:6]([C:7]2[CH:8]=[CH:9][C:10]([O:13][C:14]([N:16]([CH3:17])[CH3:18])=[O:15])=[CH:11][CH:12]=2)[CH2:5][C:4]([OH:41])=[O:3])=[N:21][C:22]([N:33]([CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)[CH3:34])=[N:23][CH:24]=1
Reactant: CCOC(=O)C[C@@H](Nc1nc(N(C)C2CCCCC2)ncc1-c1ccccc1F)c1ccc(OC(=O)N(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(C)C(=O)Oc1ccc([C@@H](CC(=O)O)Nc2nc(N(C)C3CCCCC3)ncc2-c2ccccc2F)cc1
Temperature: 22 °C
Reaction time: 6 h

Procedure:
To a solution of (R)-3-(5-(2-fluorophenyl)-2-(N-cyclohexyl-N-methylamino)pyrimidin-4-ylamino)-3-(4-(dimethylaminocarbonyl)oxyphenyl)-propanoic acid ethyl ester (1.0 eq) in 3:1 MeOH/H2O was added 1M NaOH (2.5 eq). The mixture was stirred at 22° C. for 6 hr, and then the MeOH and H2O were evaporated. The residue was partitioned between Et2O and H2O, and then the separated aqueous layer was acidified to pH=3 by addition of 0.1 M H3PO4. The aqueous layer was extracted three times with 3:1 CHCl3/iPrOH, and then the CHCl3/iPrOH extracts were treated with MgSO4, filtered and evaporated to give (R)-3-(5-(2-fluorophenyl)-2-(N-cyclohexyl-N-methylamino)pyrimidin-4-ylamino)-3-(4-(dimethylaminocarbonyl)oxyphenyl)-propanoic acid.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]3[CH2:16][O:15]3)=[CH:10][N:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.[CH2:17]([NH2:20])[CH2:18][CH3:19].Cl.O>CS(C)=O>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[CH:10][C:11]([CH:14]([OH:15])[CH2:16][NH:20][CH2:17][CH2:18][CH3:19])=[CH:12][CH:13]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1
Reactant: CCCN
Reactant: Cc1ccc(C)n1-c1ccc(C2CO2)cn1
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Product: CCCNCC(O)c1ccc(-n2c(C)ccc2C)nc1
Temperature: 40 °C
Yield: 100 %

Procedure:
To the epoxide from example 40 (900 mg, 4.2 mmol) in DMSO (5 ml) was added propylamine (4 ml, 4.8 mmol) and the reaction mixture was heated to 40° C. for 4 days. The reaction mixture was then cooled and 3M HCl (aq) (10 ml) and water (10 ml) were added before washing with diethyl ether (2×10 ml). This organic layer was discarded. The aqueous layer was basified with NH4OH (5 ml) and extracted with ethyl acetate (3×10 ml). The organic extracts were combined and dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo to give the title compound as an oil (1.159 g, 4.2 mmol, 100%). 1H NMR (CDCl3, 400 MHz) δ: 0.93 (t, 3H), 1.62 (m, 2H), 2.11 (s, 6H), 2.69-2.82 (m, 3H), 3.06 (dd, 1H), 3.60 (bs, 2H), 4.92 (dd, 1H), 5.84 (s, 2H), 7.20 (d, 1H) 7.88 (d, 1H), 8.61 (s, 1H). LRMS: m/z 274 (M-H+).
Reaction SMILES: [OH-].[K+].[C:3](=S)=S.CO[C:8]1[CH:9]=[C:10](C2CO2)[CH:11]=[C:12](OC)[C:13]=1[O:14][CH2:15][O:16]C>CO>[CH3:10][CH2:9][CH2:8][CH2:13][CH2:12][CH3:11].[C:15]([O:14][CH2:13][CH3:8])(=[O:16])[CH3:3]
Reactant: S=C=S
Reactant: COCOc1c(OC)cc(C2CO2)cc1OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCCCC
Product: CCOC(C)=O
Temperature: 25 °C
Yield: 415 %

Procedure:
Powdered potassium hydroxide (1.75 g, 31.25 mmole) is dissolved in 3.0 ml methanol and carbon disulfide (2.85 g, 37.5 mmole) was added at 0° C. The reaction mixture is shaken vigorously and 3,5-dimethoxy-4-methoxymethoxyphenyloxirane (29) (3.0 g, 12.5 mmole) is added. The reaction is allowed to warm to room temperature at which point the reaction starts to reflux. The reaction is stirred at room temperature for 24 hours, and is quenched with ethyl acetate and 10% NaOH. The organic layer is washed with 3×40 ml 10% NaOH, 1×30 ml H2O, 2×30 ml ss NaCl, dried over MgSO4, and evaporated in vacuo to a yellow oil which is purified by flash column chromatography using 2:1 hexane/ethyl acetate. The product was recrystallized from hexane/ethyl acetate (4.52 g, 63% yield).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]#[N:13])=[C:10]2[C:5]([C:6](=[O:20])[C:7]([C:17]([OH:19])=[O:18])=[CH:8][N:9]2[CH:14]2[CH2:16][CH2:15]2)=[CH:4][C:3]=1[F:21].[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>O1CCOCC1>[C:12]([C:11]1[C:2]([N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[C:3]([F:21])[CH:4]=[C:5]2[C:10]=1[N:9]([CH:14]1[CH2:16][CH2:15]1)[CH:8]=[C:7]([C:17]([OH:19])=[O:18])[C:6]2=[O:20])#[N:13]
Reactant: C1CCNC1
Reactant: N#Cc1c(Cl)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Solvent: C1COCCO1
Product: N#Cc1c(N2CCCC2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12

Procedure:
3.05 g of the product from Example 1 and 2.5 ml of pyrrolidine are boiled in 50 ml of dioxane for 3 hours. The mixture is concentrated in vacuo and the residue is taken up in water. The mixture is rendered neutral with 1N HCl. The solid which has precipitated out is filtered off with suction, dried and stirred with acetonitrile. 1.8 g of the title compound with a melting point of 274°-276° C. are obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([S:14]([F:19])([F:18])([F:17])([F:16])[F:15])[CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])([O-])=O.CC(O)=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([S:14]([F:19])([F:15])([F:16])([F:17])[F:18])[CH:13]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: [H][H]
Reactant: COC(=O)c1cc([N+](=O)[O-])cc(S(F)(F)(F)(F)F)c1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1cc(N)cc(S(F)(F)(F)(F)F)c1
Yield: 92.3 %

Procedure:
3.0 g of methyl 3-nitro-5-pentafluorosulfanylbenzoate were dissolved in 50 ml of MeOH and 5 ml of HOAc and 200 mg of Pd/C (10%) were added. The mixture was hydrogenated under a standard pressure of hydrogen atmosphere for 20 h, then hydrogenation was effected under 6 bar of hydrogen for a further 2 days. The catalyst was filtered off and the solvent removed under reduced pressure to obtain 2.5 g of an amorphous solid.