Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Si:5]([CH3:38])([CH3:37])[O:6][C@H:7]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][C:9](=[CH:21][CH2:22]P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.[CH3:44][C@@H:45]([CH2:51][CH2:52][CH2:53][C:54]([CH3:61])([O:56][Si:57]([CH3:60])([CH3:59])[CH3:58])[CH3:55])[CH2:46][CH2:47][CH2:48][CH:49]=O>C1COCC1>[C:1]([Si:5]([CH3:37])([CH3:38])[O:6][C@H:7]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:18])[CH3:19])([CH3:15])[CH3:16])[CH2:10][C:9](=[CH:21][CH:22]=[CH:49][CH2:48][CH2:47][CH2:46][C@@H:45]([CH3:44])[CH2:51][CH2:52][CH2:53][C:54]([CH3:61])([O:56][Si:57]([CH3:58])([CH3:60])[CH3:59])[CH3:55])[CH2:8]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H](CCCC=O)CCCC(C)(C)O[Si](C)(C)C
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC(=CCP(=O)(c2ccccc2)c2ccccc2)C[C@@H](O[Si](C)(C)C(C)(C)C)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[C@H](CCCC=CC=C1C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)C1)CCCC(C)(C)O[Si](C)(C)C
Reaction time: 0.33 h

Procedure:
8.55 g of carefully dried (3R,5R)-[2-[3,5-bis-(t-butyldimethyl-silanyloxy)-cyclohexylidene]-ethyl]-diphenyl-phosphine oxide (Tetrahedron Lett. 32, 7663 (1991)) was dissolved in 90 ml of abs. THF and treated at -78° with 10.9 ml of nBuLi (1.6M, hexane). After 20 minutes, 2.27 g of (S)-5,9-dimethyl-9-trimethylsilanyloxy-decanal, dissolved in a small amount of THF, was added dropwise to the deep red solution. The mixture was kept for 0.5 h at -78° and for 4 h at ambient temperature. After quenching with crushed ice/ KH2PO4, the product was extracted twice with ether, washed with water and brine, dried over sodium sulfate and the solvents removed i.V. Flash chromatography (SiO2, hexane/ AcOEt) yielded in the less polar fractions 3.840 g of (R)-1-[(3R,5R)-3,5-bis-(tert-butyldimethyl-silanyloxy)-cyclohexylidene]-7,11-dimethyl-11-trimethylsilanyloxy-dodec-2-ene, as colorless oil, which was deprotected as described in the following paragraph. 2.40 g of phosphine oxide, which had been used in excess, were recovered in the more polar fractions.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:14]=[C:13]([C:23](=O)[CH3:24])[C:12]=2[OH:26])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:27]([C:29]([NH:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([OH:38])=[O:37])=[CH:34][CH:33]=1)=[S:30])[NH2:28].CN(C)C=O>Cl.O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:15]([CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:14]=[C:13]([C:23](=[N:28][NH:27][C:29]([NH:31][C:32]3[CH:40]=[CH:39][C:35]([C:36]([OH:38])=[O:37])=[CH:34][CH:33]=3)=[S:30])[CH3:24])[C:12]=2[OH:26])=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)c1nn(Cc2ccccc2)c(-c2ccc(C(C)(C)C)cc2)c1O
Reactant: NNC(=S)Nc1ccc(C(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(=NNC(=S)Nc1ccc(C(=O)O)cc1)c1nn(Cc2ccccc2)c(-c2ccc(C(C)(C)C)cc2)c1O
Yield: 70.3 %

Procedure:
1-[5-(4-tert-Butylphenyl)-1-benzyl-4-hydroxy-1H-pyrazol-3-yl]ethanone (0.218 mmol, 76 mg) and 4-hydrazinocarbonothioylaminobenzoic acid (0.218 mmol, 46 mg) were stirred with dimethylformamide (3.5 mL) and three drops of concentrated hydrochloric acid at room temperature for 22 hours. After addition of water, the precipitated yellow solid was recovered by filtration, washed with water and dried by means of a vacuum pump. The resulting solid was stirred with chloroform/n-hexane for a while, then recovered by filtration and dried by means of a vacuum pump to give the desired product as a pale yellow solid (83 mg, yield 70%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([NH2:11])[C:7]=1[C:8]([OH:10])=[O:9].[F:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=O)=[CH:15][CH:14]=1.[OH-].[Na+].S(Cl)(Cl)=O>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.ClCCCl>[F:1][C:2]1[C:7]2[C:8](=[O:10])[O:9][C:17]([C:16]3[CH:20]=[CH:21][C:13]([F:12])=[CH:14][CH:15]=3)=[N:11][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Nc1cccc(F)c1C(=O)O
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: ClCCCl
Product: O=c1oc(-c2ccc(F)cc2)nc2cccc(F)c12
Yield: 97.2 %

Procedure:
When 38.8 g of 6-fluoroanthranilic acid, 39 g of 4-fluorobenzoyl chloride, 20 g of 50% strength sodium hydroxide solution, 0.45 g of benzyltrimethylammonium chloride, 700 g of 1,2-dichloroethane and 32.7 g of thionyl chloride are used as starting materials, and the procedure described in Example 1 is employed, 62 g (96%) of 5-fluoro-2-(p-fluorophenyl)-4H-3,1-benzoxazin-4-one of melting point 189°-193° C. are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11](=[O:18])/[CH:12]=[CH:13]\[C:14]([O:16]C)=[O:15])=[CH:5][CH:4]=1.[OH-].[K+].P([O-])([O-])([O-])=O.C(OCC)(=O)C>CCOCC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6](/[CH:9]=[CH:10]/[C:11](=[O:18])/[CH:12]=[CH:13]\[C:14]([OH:16])=[O:15])=[CH:7][CH:8]=1
Reactant: COC(=O)/C=C\C(=O)/C=C/c1ccc(OC)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COc1ccc(/C=C/C(=O)/C=C\C(=O)O)cc1
Reaction time: 1 h

Procedure:
A solution of 1.70 g (6.9 mmol) of methyl (2Z,5E)-6-(4-methoxyphenyl)-4-oxo-2,5-hexadienoate in 20 ml of ether was treated while cooling with ice and stirring vigorously within about 15 minutes with 20 ml of 5% potassium hydroxide solution. The reaction mixture was stirred at 4° for 1 hour and then treated with 15 ml of phosphate buffer (pH=6.5) and 30 ml of ethyl acetate, whereupon the phases were separated. The aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulphate, filtered and evaporated. The solid residue was recrystallized from ethyl acetate/hexane and there was obtained (2Z,5E)-6-(4-methoxyphenyl)-4-oxo-2,5-hexadienoic acid as an orange colored powder of melting point 103.5°-104°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1.[CH3:11][S:12](Cl)(=[O:14])=[O:13]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][S:12]([CH3:11])(=[O:14])=[O:13])=[CH:5][CH:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(CN)cc1
Solvent: ClCCl
Product: COc1ccc(CNS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.5 %

Procedure:
To a solution of (4-methoxyphenyl)methanamine (1.317 g, 9.60 mmol) in CH2Cl2 (10 mL) was added methanesulfonyl chloride (0.34 mL, 4.36 mmol) dropwise. The mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with 50 mL CH2Cl2 washed with 1N H3PO4, 10% NaCl, dried over anhydrous mgSO4, filtered and concentrated in vacuo to give the title compound as a white solid (0.84 g, 89%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[CH2:17]([NH2:20])[CH2:18][CH3:19]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:20][CH2:17][CH2:18][CH3:19])[N:3]=1
Reactant: CCCN
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Solvent: CCN(CC)CC
Product: CCCNc1nc(Cl)nc2c1ncn2C1CCCC1

Procedure:
2-Chloro-6-(propylamino)-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, n-propylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: Cl.C(OC(=O)[NH:11][C:12]1([CH3:18])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)C1C=CC=CC=1.Br[C:21]1[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][N:22]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[CH3:30][S:27]([C:24]1[CH:25]=[CH:26][C:21]([N:15]2[CH2:14][CH2:13][C:12]([NH2:11])([CH3:18])[CH2:17][CH2:16]2)=[N:22][CH:23]=1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)c1ccc(Br)nc1
Reactant: CC1(NC(=O)OCc2ccccc2)CCNCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC1(N)CCN(c2ccc(S(C)(=O)=O)cn2)CC1
Yield: 72.6 %

Procedure:
A solution of (4-methyl-piperidin-4-yl)-carbamic acid benzyl ester hydrochloride salt (0.37 g, 1.3 mmol, Example 30B), 2-bromo-5-(methylsulfonyl)pyridine (0.27 g, 1.15 mmol) and diisopropylethylamine (0.7 mL) in dioxane (4 mL) in a sealed tube was heated to 80° C. for 16 hours. The mixture was cooled, concentrated under reduced pressure and purified by chromatography (silica gel, eluting with 5% hexane/ethyl acetate to 25% ethyl acetate/hexane) to provide the titled compound (0.225 g) as a white solid. MS (CI) m/z 404 (M+1)+; 1H NMR (300 MHz, CDCl3) δ ppm 8.63 (d, 1H), 7.86 (dd, 1H), 7.37 (m, 5H), 6.65 (d, 1H), 5.07 (s, 2H), 4.67 (s, 1H), 4.04-3.96 (m, 2H), 3.49-3.39 (m, 2H), 3.03 (s, 3H), 2.19-2.12 (m, 2H), 1.71-1.61 (m, 2H), 1.41 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([C:40]([OH:42])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:43][CH2:44][CH3:45])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:46]([CH2:48][NH2:49])[OH:47]>>[OH:47][CH2:46][CH2:48][NH:49][C:40]([CH:37]1[CH2:38][CH2:39][N:34]([C:32]([N:12]2[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=[C:11]2[C:8]2[CH:9]=[N:10][C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])=[CH:6][C:7]=2[O:43][CH2:44][CH3:45])=[O:33])[CH2:35][CH2:36]1)=[O:42]
Reactant: NCCO
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(C(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(C(=O)NCCO)CC1

Procedure:
In a manner analogous to the method described in example 163, 1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidine-4-carboxylic acid was coupled with ethanolamine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C37H46Cl2N5O4 [(M+H)+] 694.2922, observed 694.2918.
Reaction SMILES: [CH3:1][C:2](=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[CH:17]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]([CH3:28])[CH3:27])[C:21]=1[N:29]=[C:30]=[O:31])([CH3:19])[CH3:18].C([N-]C(C)C)(C)C.[Li+]>>[CH3:19][CH:17]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]([CH3:27])[CH3:28])[C:21]=1[NH:29][C:30](=[O:31])[CH2:1][C:2](=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH3:18]
Reactant: CCCCCCCCCCCCCC(C)=O
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: CCCCCCCCCCCCCC(=O)CC(=O)Nc1c(C(C)C)cccc1C(C)C

Procedure:
The title compound was prepared from 2-pentadecanone (3.0 g, 0.013 mol), 2,6-diisopropylphenyl isocyanate (2.64 g, 0.013 mol), and lithium diisopropylamide (0.013 mol) using the procedure described in Example 1. Purification by flash chromatography (silica gel, 15% EtOAc/hexane) yielded 1.92 g (0.004, 34%) of the desired product.
Reaction SMILES: [CH:1]1([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:22](O)=O)[CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:25][C:26](=[N:32][OH:33])[C:27]([O:29][CH2:30][CH3:31])=[O:28]>>[CH:1]1([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:22]3[O:33][N:32]=[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:25]=3)[CH2:9]2)=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(=O)C(N)=NO
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)C3CCCC3)C2)cc1
Product: CCOC(=O)c1noc(C2CC(c3ccc(CC)cc3)CN(C(=O)C3CCCC3)C2)n1

Procedure:
198 mg (0.60 mmol) of 1-(cyclopentylcarbonyl)-5-(4-ethylphenyl)piperidine-3-carboxylic acid (Example 7A) and 87 mg (0.66 mmol, 1.1 eq.) of ethyl 2-amino(hydroxyimino)ethanoate were reacted according to the General Method 1. Yield: 73 mg (27% of theory)
Reaction SMILES: [Br:1]Br.[CH2:3]([O:5][C:6](=[O:20])[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[CH:8]=1)[CH3:4].C(=O)(O)[O-].[Na+]>ClCCl.O>[CH2:3]([O:5][C:6](=[O:20])[C:7]1[C:12]([Br:1])=[CH:11][N:10]=[C:9]([N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[CH:8]=1)[CH3:4]
Reactant: BrBr
Reactant: CCOC(=O)c1ccnc(N2CCN(C)CC2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1cc(N2CCN(C)CC2)ncc1Br
Reaction time: 1 h
Yield: 37.4 %

Procedure:
A solution of 0.91 ml (17.7 mmol) Br2 was added dropwise to a solution of 2.95 g (11.8 mmol) 2-(4-methyl-piperazin-1-yl)-isonicotinic acid ethyl ester in 20 ml dichloromethane at 0° C.-4° C. Stirring was continued at room temperature for 1 h and 50 ml saturated sodium bicarbonate solution in water was added. The aqueous layer was separated and washed twice with dichloromethane. The combined organic layers were dried (magnesium sulfate) and evaporated. The residue was purified by chromatography to give 1.45 g (37%) of the title compound as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8]C(C)C)=[CH:6][C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])[N:14]=[C:13]2[O:26][CH3:27])=[C:4]([F:28])[CH:3]=1.S(=O)(=O)(O)O>>[Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:24])([F:25])[C:20]([F:23])([F:21])[F:22])[N:14]=[C:13]2[O:26][CH3:27])=[C:4]([F:28])[CH:3]=1
Reactant: COc1nc(C(F)(F)C(F)(F)F)cc(=O)n1-c1cc(OC(C)C)c(Cl)cc1F
Agent: O=S(=O)(O)O
Product: COc1nc(C(F)(F)C(F)(F)F)cc(=O)n1-c1cc(O)c(Cl)cc1F

Procedure:
using 1-(4-chloro-2-fluoro-5-isopropoxyphenyl)-2-methoxy-4-pentafluoroethyl-6(1H)-pyrimidinone with concentrated sulphuric acid at room temperature during 20 minutes there is obtained 1-(4-chloro-2-fluoro-5-hydroxyphenyl)-2-methoxy-4-pentafluoroethyl-6(1H)-pyrimidinone. m.p. 143°-145° C.;
Reaction SMILES: Cl.[C:2]([NH2:10])(=[NH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C[O-].[Na+].Br[CH:15]([CH3:28])[C:16]([C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1)=O>O1CCCC1>[C:3]1([C:2]2[NH:9][C:15]([CH3:28])=[C:16]([C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:19]=3)[N:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: N=C(N)c1ccccc1
Reactant: CC(Br)C(=O)c1ccc2ccccc2c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1[nH]c(-c2ccccc2)nc1-c1ccc2ccccc2c1

Procedure:
Benzamidine hydrochloride and an equimolar amount of sodium methylate were heated under reflux in tetrahydrofuran for 1 hour. After cooling, a tetrahydrofuran solution of an equimolar amount of 2-bromo-2′-propionaphthone was added dropwise thereto so that the temperature did not exceed 30° C., and then an equimolar amount of sodium methylate was further added, followed by heating under reflux for 1 hour. After removal of the solvent by distillation under reduced pressure, the residue was washed with water and subjected to recrystallization from acetonitrile to obtain grayish blue crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:20][C:21]2[N:26]=[C:25](O)[CH:24]=[CH:23][N:22]=2)[CH:5]=[C:6]([C:8]2[S:12][C:11]([C:13]([OH:19])([CH3:18])[C:14]([F:17])([F:16])[F:15])=[N:10][CH:9]=2)[CH:7]=1.P(Cl)(Cl)([Cl:30])=O>O1CCOCC1>[Cl:30][C:25]1[CH:24]=[CH:23][N:22]=[C:21]([NH:20][C:4]2[CH:5]=[C:6]([C:8]3[S:12][C:11]([C:13]([OH:19])([CH3:18])[C:14]([F:17])([F:15])[F:16])=[N:10][CH:9]=3)[CH:7]=[C:2]([CH3:1])[CH:3]=2)[N:26]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(Nc2nccc(O)n2)cc(-c2cnc(C(C)(O)C(F)(F)F)s2)c1
Solvent: C1COCCO1
Product: Cc1cc(Nc2nccc(Cl)n2)cc(-c2cnc(C(C)(O)C(F)(F)F)s2)c1
Temperature: 25 °C
Yield: 75.7 %

Procedure:
The product of Step 1 (145 mg, 0.37 mmol) was taken up in dioxane (2 mL) and phosphorus oxychloride (1.02 mL, 11 mmol) was added. The mixture was heated at reflux for 1.5 hours. The reaction was then cooled to room temperature, poured over ice, and quenched by dropwise addition of 10 N aqueous sodium hydroxide (until pH=8). Ethyl acetate was added and the layers were separated. The aqueous layer was extracted once more with ethyl acetate. The combined organics were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by Chromatography on silica gel (0-50% ethyl acetate/hexanes) to afford 114 mg (0.28 mmol, 75%) of 2-(5-{3-[(4-chloropyrimidin-2-yl)amino]-5-methylphenyl}-1,3-thiazol-2-yl)-1,1,1-trifluoropropan-2-ol as a white solid. MS ESI: [M+H]+ m/z 415.0. 1H NMR (500 MHz, DMSO-d6) δ 10.10 (s, 1H), 8.47 (d, J=5 Hz, 1H), 8.08 (s, 1H), 7.88 (s, 1H), 7.67 (s, 1H), 7.50 (s, 1H), 7.17 (s, 1H), 6.99 (d, J=5 Hz, 1H), 2.32 (s, 3H), 1.76 (s, 3H). rhSYK activity=+++
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1([CH3:18])[CH2:9][CH2:8][C:7]2[C:10]([CH3:17])=[C:11]([OH:16])[C:12]([CH3:15])=[C:13]([CH3:14])[C:6]=2[O:5]1.[CH3:19][NH:20][CH3:21].O.[ClH:23]>CN(C)C=O.C(O)(C)C>[ClH:23].[CH3:19][N:20]([CH3:21])[CH2:2][CH2:3][C:4]1([CH3:18])[CH2:9][CH2:8][C:7]2[C:10]([CH3:17])=[C:11]([OH:16])[C:12]([CH3:15])=[C:13]([CH3:14])[C:6]=2[O:5]1
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(CCBr)O2
Reactant: CNC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC(C)O
Solvent: O
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(CCN(C)C)O2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 12.53 g of 3,4-dihydro-2-(2-bromoethyl)-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol and liquid gaseous dimethylamine in 50 ml of dimethylformamide is stirred at room temperature for 16 hours. Water is added and the product is extracted with ethyl ether. The extract is washed with water, dried over anhydrous sodium sulfate, filtered and evaporated. One equivalent of hydrochloride acid in isopropanol is added and the resulting precipitate is recrystallized twice from isopropanol/water to yield 9.44 g of the title compound, mp 300° C.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:11])[NH:9][CH3:10])[C:5]([NH:12][C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:36]=[CH:35][C:27]([CH2:28][P:29](=[O:34])([OH:33])[O:30][CH2:31][CH3:32])=[CH:26][C:25]=3[O:37][CH3:38])[N:14]=2)=[CH:4][CH:3]=1.[CH2:39]([Sn:43]([CH2:57][CH2:58][CH2:59][CH3:60])([CH2:53][CH2:54][CH2:55][CH3:56])[C:44]1[N:45]=[N:46][N:47]([CH2:49][CH2:50][CH2:51]O)[CH:48]=1)[CH2:40][CH2:41][CH3:42].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>ClCCCl.C(Cl)Cl>[Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:11])[NH:9][CH3:10])[C:5]([NH:12][C:13]2[C:18]([C:19]([F:22])([F:20])[F:21])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:36]=[CH:35][C:27]([CH2:28][P:29](=[O:33])([O:34][CH2:51][CH2:50][CH2:49][N:47]4[CH:48]=[C:44]([Sn:43]([CH2:53][CH2:54][CH2:55][CH3:56])([CH2:39][CH2:40][CH2:41][CH3:42])[CH2:57][CH2:58][CH2:59][CH3:60])[N:45]=[N:46]4)[O:30][CH2:31][CH3:32])=[CH:26][C:25]=3[O:37][CH3:38])[N:14]=2)=[CH:4][CH:3]=1
Reactant: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)nc3C(=O)NC)n2)c(OC)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(CCCO)nn1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCC[Sn](CCCC)(CCCC)c1cn(CCCOP(=O)(Cc2ccc(Nc3ncc(C(F)(F)F)c(Nc4ccc(Br)nc4C(=O)NC)n3)c(OC)c2)OCC)nn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl hydrogen (4-{[4-{[6-bromo-2-(methylcarbamoyl)pyridin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (Compound 38C, 205 mg, 0.331 mmol), 3-[4-(tributylstannanyl)-1H-1,2,3-triazol-1-yl]propan-1-ol (Compound 64B, 165 mg, 0.397 mmol) and DIPEA (0.17 mL, 0.993 mmol) in 1,2-dichloroethane (8 mL) was added (benzotriazol-1-yloxy)tripyrrolidino-phosphonium hexafluorophosphate (517 mg, 0.993 mmol). The resulting mixture was stirred at rt overnight. The mixture was diluted with DCM (30 mL), washed with sat. aq. NaHCO3 (2×20 mL), brine (20 mL), and dried over anhydrous sodium sulfate. The solvents were evaporated under reduced pressure, and the residue was purified by silica gel chromatography (ISCO system: MeOH/DCM=0-3%) to give the desired product, which was used in the following step. MS (ESI): m/z 1018.86 [M+H]+. UPLC: tR=1.22 min (UPLC-SQD: very non-polar—2 min).
Reaction SMILES: [CH2:1](Br)[CH2:2][CH3:3].[C:5]([O:14]CC)(=[O:13])[C:6]1[C:7](=[CH:9][CH:10]=[CH:11][CH:12]=1)[OH:8].C(=O)([O-])[O-].[K+].[K+].C(OC1C=C(C=CC=1)C(O)=O)CC>>[CH2:1]([O:8][C:7]1[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=1[C:5]([OH:14])=[O:13])[CH2:2][CH3:3]
Reactant: CCOC(=O)c1ccccc1O
Reactant: CCCBr
Agent: CCCOc1cccc(C(=O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCOc1ccccc1C(=O)O

Procedure:
The reaction of propyl bromide and ethyl salicylate in the presence of potassium carbonate was performed as described for Compound 24 to give 2-Propoxy-benzoic acid as white powder. 1H-NMR (400 MHz, d6-DMSO): 12.56 (s, COOH); 7.61 (m, 1 arom. H); 7.45 (m, 1 arom. H); 7.07 (m, 1 arom. H); 6.96 (m, 1 arom. H); 3.96 (t, CH3CH2CH2O); 1.71 (m, CH3CH2CH2O); 0.96 (t, CH3CH2CH2O). 13C-NMR (100 MHz, d6-DMSO): 167.49 (—C═O); 157.41; 132.82; 130.51; 121.73; 119.91; 113.35; 69.63; 22.04; 10.39.
Reaction SMILES: CC([N:5]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][N:17]2[C:25]3[C:20](=[C:21]([CH:26]([F:28])[F:27])[CH:22]=[CH:23][CH:24]=3)[C:19]([N:29]([S:39]([C:42]3[S:43][C:44]([Cl:47])=[CH:45][CH:46]=3)(=[O:41])=[O:40])[S:30]([C:33]3[S:34][C:35]([Cl:38])=[CH:36][CH:37]=3)(=[O:32])=[O:31])=[N:18]2)[CH:11]=1)C(=O)[O-])(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:5][CH2:9][C:10]1[CH:11]=[C:12]([CH2:16][N:17]2[C:25]3[C:20](=[C:21]([CH:26]([F:27])[F:28])[CH:22]=[CH:23][CH:24]=3)[C:19]([N:29]([S:39]([C:42]3[S:43][C:44]([Cl:47])=[CH:45][CH:46]=3)(=[O:40])=[O:41])[S:30]([C:33]3[S:34][C:35]([Cl:38])=[CH:36][CH:37]=3)(=[O:32])=[O:31])=[N:18]2)[CH:13]=[CH:14][CH:15]=1
Reactant: CC(C)(C)N(Cc1cccc(Cn2nc(N(S(=O)(=O)c3ccc(Cl)s3)S(=O)(=O)c3ccc(Cl)s3)c3c(C(F)F)cccc32)c1)C(=O)[O-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCc1cccc(Cn2nc(N(S(=O)(=O)c3ccc(Cl)s3)S(=O)(=O)c3ccc(Cl)s3)c3c(C(F)F)cccc32)c1
Reaction time: 1 h
Yield: 54 %

Procedure:
1,1-Dimethylethyl[(3-{[3-{bis[(5-chloro-2-thienyl)sulfonyl]amino}-4-(difluoromethyl)-1H-indazol-1-yl]methyl}phenyl)methyl]carbamate (for a preparation see Intermediate 69) (60 mg, 0.079 mmol) was dissolved in dichloromethane (0.5 mL) and trifluoroacetic acid (0.125 mL) was added to the solution. and stirred for 1 h under nitrogen. The solution was concentrated under a stream of nitrogen and the off-white residue was dissolved in methanol and loaded onto a methanol conditioned sulphonic acid (SCX-2) cartridge (10 g). The cartridge was washed well with methanol, followed by 2M ammonia in methanol. Evaporation of the solvent from the ammoniacal fractions gave the title compound (26 mg, 54%) as a white solid. LCMS (System A) RT=1.11 min, ES+ve m/z 663/665 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([OH:12])[CH:3]=1.[C:13]([CH:17]1[CH2:22][CH2:21][CH:20](OS(C)(=O)=O)[CH2:19][CH2:18]1)([CH3:16])([CH3:15])[CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+].O>CC(O)(C)C.CC(=O)CC.CCOCC>[C:13]([CH:17]1[CH2:22][CH2:21][CH:20]([O:12][C:4]2[CH:3]=[C:2]([CH3:1])[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:19][CH2:18]1)([CH3:16])([CH3:15])[CH3:14]
Reactant: Cc1cc(O)cc2ccccc12
Reactant: CC(C)(C)C1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CC(C)(C)O
Solvent: O
Product: Cc1cc(OC2CCC(C(C)(C)C)CC2)cc2ccccc12
Temperature: 80 °C
Yield: 48.8 %

Procedure:
A mixture of 4-methyl-naphthalen-2-ol (0.60 g, 3.8 mmol), methanesulfonic acid 4-tert-butyl-cyclohexyl ester (1.9 g, 7.6 mmol) and cesium carbonate (3.7 g, 11 mmol) in t-BuOH (10 mL) and 2-butanone (7 mL) was heated at 80° C. overnight. After cooled to room temperature, the mixture was treated with water and ether. The organic phase was dried over MgSO4, filtered and concentrated. The crude was treated with methanol to give solid product (0.55 g, yield: 48%). ESI-MS: 297.20 (M+H)+.