Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[NH:21][C:22]([NH:24][C:25]1[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:26]=1[F:32])=[O:23])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[CH:12]=[C:13]([C:15](O)=[O:16])[S:14][C:7]=12.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:66]([NH:73][CH2:74][CH2:75][CH2:76][NH2:77])([O:68][C:69]([CH3:72])([CH3:71])[CH3:70])=[O:67].Cl>C(#N)C.O>[F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[NH:21][C:22]([NH:24][C:25]1[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:26]=1[F:32])=[O:23])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[CH:12]=[C:13]([C:15]([NH:77][CH2:76][CH2:75][CH2:74][NH:73][C:66](=[O:67])[O:68][C:69]([CH3:71])([CH3:70])[CH3:72])=[O:16])[S:14][C:7]=12
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc4cc(C(=O)O)sc34)cc2F)c1
Reactant: CC(C)(C)OC(=O)NCCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc4cc(C(=O)NCCCNC(=O)OC(C)(C)C)sc34)cc2F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxylic acid (300 mg, 0.66 mmol), HATU (277 mg, 0.73 mmol) and N,N-diisopropylethylamine (187 mg, 1.45 mmol) in anhydrous acetonitrile (10 ml) was stirred at room temperature for 30 minutes, followed by addition of N-Boc-1,3-propanediamine (172 mg, 0.99 mmol). The mixture was stirred for another 10 minutes and poured into 100 ml of water with vigorous stirring. 2M HCl was added dropwise until pH=5. The precipitates were filtered, washed with water and dried in vacuo to give tert-butyl {3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}carbamate as light yellow solid. Yield: 345 mg, 85%.
Reaction SMILES: [CH3:1][O:2][C:3]1([O:18][CH3:19])[CH2:8][CH2:7][CH:6]([CH:9]([NH:13][C:14](=[O:17])[CH:15]=[CH2:16])[CH2:10]C=C)[CH2:5][CH2:4]1.N1CCC1>ClCCCl>[CH3:19][O:18][C:3]1([O:2][CH3:1])[CH2:4][CH2:5][CH:6]([CH:9]2[NH:13][C:14](=[O:17])[CH:15]=[CH:16][CH2:10]2)[CH2:7][CH2:8]1
Reactant: C=CCC(NC(=O)C=C)C1CCC(OC)(OC)CC1
Agent: C1CNC1
Solvent: ClCCCl
Product: COC1(OC)CCC(C2CC=CC(=O)N2)CC1
Temperature: 50 °C

Procedure:
A solution of N-(1-(4,4-dimethoxycyclohexyl)but-3-en-1-yl)acrylamide (512 mg, 2.4 mmol), prepared in the previous step, and the Grubbs Generation II catalyst (97 mg, 0.11 mmol) in DCE (100 mL) was degassed and heated to 50° C. under argon for 2 hours. The reaction mixture was concentrated in vacuo and the residue purified by flash chromatography (silica gel, DCM→0-5% MeOH/ethyl acetate) to afford the product.
Reaction SMILES: [F:1][CH2:2][C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH2:17][F:18])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[O:6]C(C2C=CC=CC=2)=[N:4]1.Cl.C(OCC)(=O)C>ClCCl>[NH2:4][C@H:3]([CH2:2][F:1])[C@@H:7]([C:8]1[CH:9]=[CH:10][C:11]([S:14]([CH2:17][F:18])(=[O:16])=[O:15])=[CH:12][CH:13]=1)[OH:6]
Reactant: O=S(=O)(CF)c1ccc([C@H]2OC(c3ccccc3)=N[C@@H]2CF)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: N[C@H](CF)[C@H](O)c1ccc(S(=O)(=O)CF)cc1
Temperature: 25 °C
Yield: 899.7 %

Procedure:
A solution of sulfone 22 (1.47 g, 4.19 mmol) in dichloromethane (50 mL) was mixed with 6N HCl (40 mL). Dichloromethane was distilled out and the resulting white suspension was stirred at reflux for 14 hours. It was cooled to room temperature and treated with aqueous NaHCO3 to pH=8˜9. Extraction with dichloromethane (3×50 mL) afforded an oil residue which was subjected to flash chromatography (SiO2, hexanes/ethyl acetate=2:1 to ethyl acetate 100%) to provide 10 g of the desired product, as a light yellow oil. 1H NMR (400 MHz, CDCl3) 3.05-3.15 (m, 1H), 4.24-4.52 (m, 2H), 4.72 (d, J=6 Hz, 1H), 5.09 (s, 1H), 5.21 (s, 1H), 7.62 (d, J=9 Hz, 2H), 7.93 (d, J=9 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([Cl:11])[C:3]=1Cl.[CH3:13][C:14]1([CH3:24])[CH2:18][C:17]2[CH:19]=[CH:20][CH:21]=[C:22]([OH:23])[C:16]=2[O:15]1.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[Cl:11][C:4]1[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=[C:2]([Cl:1])[C:3]=1[O:23][C:22]1[C:16]2[O:15][C:14]([CH3:24])([CH3:13])[CH2:18][C:17]=2[CH:19]=[CH:20][CH:21]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)c(Cl)c1
Reactant: CC1(C)Cc2cccc(O)c2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC1(C)Cc2cccc(Oc3c(Cl)cc([N+](=O)[O-])cc3Cl)c2O1
Temperature: 25 °C

Procedure:
To a solution containing 32.83 g of 1,2,3-trichloro-5-nitrobenzene and 26.11 g of 2,3-dihydro-2,2-dimethyl-7-hydroxybenzofuran in 300 ml of methyl ethyl ketone under an atmosphere of nitrogen and at room temperature was added 21.98 g of anhydrous potassium carbonate. The reaction mixture was heated to reflux. Reflux was maintained for 30 hrs. The reaction mixture was cooled to room temperature and the solvents removed. The tan solid residue was dissolved in hot hexane containing a little ethyl acetate. This was filtered and the filtrate allowed to cool to room temperature then placed in freezer to cool further to promote crystallization. The crystals were collected and placed in a vacuum dessicator for drying. A second crop of crystals was obtained from the mother liquors. This afforded 29.2 g of pale tan crystals. mp 105°-110° C. NMR (CDCl3): 1.47 (s, 6H), 3.03 (s, 2H), 6.3-7.0 (m, 3H), 8.22 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][CH:11]([CH:13]([NH2:17])[CH:14]([CH3:16])[CH3:15])[CH3:12].O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:17][CH:13]([CH:14]([CH3:16])[CH3:15])[CH:11]([CH3:12])[CH3:10])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: CC(C)C(N)C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)C(N=Cc1ccc(Br)cc1)C(C)C
Yield: 94.9 %

Procedure:
A mixture of 4-bromobenzaldehyde (7.3 g, 40.0 mmol), 2,4-dimethylpent-3-ylamine (4.8 g, 41.4 mmol), and para-toluenesulfonic acid (0.05 g, 0.29 mmol) in 125 mL of toluene was heated under reflux while water was removed with a Dean-Stark trap. The toluene then was removed under vacuum and distillation of the remaining residue gave (4-bromobenzylidene)(1-isopropyl-2-methylpropyl)amine (10.71 g) as a clear colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[NH:15][NH:14][C:13](=[O:16])[CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].N1[C:22]([CH3:23])=[CH:21][C:20](C)=[CH:19][C:18]=1[CH3:25].C(Br)C1C=CC=CC=1>C1(C)C=CC=CC=1.ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[NH:15][N:14]([CH2:25][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:13](=[O:16])[CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2CC(=O)NN2)cc1OC
Reactant: Cc1cc(C)nc(C)c1
Agent: BrCc1ccccc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1ccc(C2CC(=O)N(Cc3ccccc3)N2)cc1OC

Procedure:
5 g of 5-(3,4-dimethoxyphenyl)-pyrazolin-3-one, prepared according to Example 1C, were suspended in 100 ml of toluene. First 3 ml of collidine and subsequently 3.6 ml of benzyl bromide were added dropwise to the suspension. After heating for 6 hours under reflux, the reaction mixture was cooled, and the precipitated crystals were filtered out and washed with isopropanol. The crystals obtained were dissolved in dichloromethane and washed with 2M citric acid. The organic phase was dried with magnesium sulfate and concentrated. For purification the residue was recrystallized from isopropanol. 4 g of 5-(3,4-dimethoxyphenyl)-2-benzyl-pyrazolin-3-one were obtained having a melting point of 165° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([NH:17][C:18]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:21]=[CH:20][C:19]=2[N+:30]([O-])=O)=[O:16])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6](=[O:33])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([NH:17][C:18]2[CH:23]=[C:22]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:21]=[CH:20][C:19]=2[NH2:30])=[O:16])=[CH:11][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)Nc2cc(-c3ccccc3)ncc2[N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1ccc(C(=O)Nc2cc(-c3ccccc3)ncc2N)cc1

Procedure:
To a suspension of tert-butyl(4-{[(3-nitro-6-phenylpyridin-4-yl)amino]carbonyl}benzyl)carbamate (30 mg, 0.067 mmoll) in MeOH (2 mL) was added Pd on carbon (˜10 mg) and the reaction flask was thoroughly flushed with H2. The reaction was then allowed to proceed at RT under a H2 balloon. During the course of reaction, the mixture becomes a homogenous solution. The reaction mixture was filtered through a silica gel pad and the silica gel was washed thoroughly with MeOH. The Me0H layer was concentrated and residue was purified by HPLC. 1H NMR (600 MHz. d6-DMSO) δ 9.78 (s, 1H), 8.15 (s, 1H), 7.96 (s, 1H), 7.91 (d, J=7.8 Hz, 2H), 7.87 (dd, J=8.4, 1.2 Hz, 2H), 7.48 (t, J=6 Hz, 1H), 7.37 (m, 4H), 7.27 (m, 1H), 5.32 (bs, 2H), 4.17 (d, J=6 Hz, 2H), 1.37 (s, 9H); MS: cal'd 419 (M+H)+, exp 419 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:14]([O-:16])=[O:15])=[C:6]2[C:11]=1[NH:10][CH:9]=[C:8]([CH3:12])[C:7]2=[O:13].CC1(C)C(C)(C)OB([C:25]2[CH2:30][CH2:29][CH:28]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:27][CH:26]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[CH3:12][C:8]1[C:7](=[O:13])[C:6]2[C:11](=[C:2]([C:25]3[CH2:30][CH2:29][CH:28]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:27][CH:26]=3)[CH:3]=[CH:4][C:5]=2[N+:14]([O-:16])=[O:15])[NH:10][CH:9]=1
Reactant: CCOC(=O)C1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Cc1c[nH]c2c(Br)ccc([N+](=O)[O-])c2c1=O
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: O
Solvent: C1COCCO1
Product: CCOC(=O)C1CC=C(c2ccc([N+](=O)[O-])c3c(=O)c(C)c[nH]c23)CC1
Temperature: 100 °C
Reaction time: 18 h
Yield: 67 %

Procedure:
A mixture of 8-bromo-3-methyl-5-nitroquinolin-4(1H)-one (Compound 304E, 700 mg, 2.47 mmol), ethyl 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)cyclohex-3-enecarboxylate (1.8 g, 6.43 mmol, commercially available or can be prepared according to WO2008/099221), Pd(PPh3)4 (20 mg), and Na2CO3 (1 g, 9.43 mmol) in 1,4-dioxane/H2O (150 mL, 4:1) was evacuated and purged with N2. The reaction mixture was stirred at 100° C. for 18 h under N2. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The material was purified by flash column chromatography to afford the desired compound (600 mg, yield: 67%). 1H NMR (DMSO-d6, 400 MHz): δ=1.22 (t, J=7.2 Hz, 3 H), 1.85 (m, 1 H), 1.96 (s, 3 H), 2.08 (m, 1 H), 2.26 (m, 1 H), 2.38-2.49 (m, 3 H), 2.78 (m, 1 H), 4.12 (q, J=7.2 Hz, 2 H), 5.84 (s, 1 H), 7.46 (d, J=8.0 Hz, 1 H), 7.58 (d, J=8.0 Hz, 1 H), 7.83 (d, J=6.0 Hz, 1 H), 10.94 (d, J=6.0 Hz, 1 H).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([O:23][N:24]1[CH:32]=[N:31][C:30]2[C:25]1=[N:26][CH:27]=[N:28][C:29]=2[N:33]1C(=O)C2=CC=CC=C2C1=O)[CH2:11][CH2:12][O:13][CH2:14][P:15]([O:20][CH2:21][CH3:22])([O:17][CH2:18][CH3:19])=[O:16])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CNN>ClCCl>[Si:1]([O:8][CH2:9][CH:10]([O:23][N:24]1[CH:32]=[N:31][C:30]2[C:25]1=[N:26][CH:27]=[N:28][C:29]=2[NH2:33])[CH2:11][CH2:12][O:13][CH2:14][P:15]([O:17][CH2:18][CH3:19])([O:20][CH2:21][CH3:22])=[O:16])([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2]
Reactant: CCOP(=O)(COCCC(CO[Si](C)(C)C(C)(C)C)On1cnc2c(N3C(=O)c4ccccc4C3=O)ncnc21)OCC
Agent: CNN
Solvent: ClCCl
Product: CCOP(=O)(COCCC(CO[Si](C)(C)C(C)(C)C)On1cnc2c(N)ncnc21)OCC
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
A solution of 9-[1-(t-butyldimethylsilyloxy)-4-(diethoxyphosphorylmethoxy)but-2-oxy]-6-phthalimidopurine (550 mg, 0.87 mmol) in dichloromethane (10 ml) was treated with methylhydrazine (0.05 ml, 0.96 mmol) and stirred for 30 min at 20° C. The reaction mixture was filtered, the solvent evaporated in vacuo and the residue chromatographed on silica, eluting with chloroform-methanol 40:1, affording 9-[1-(t-butyldimethylsilyloxy)-4-(diethoxyphosphorylmethoxy)-but-2-oxy]adenine (380mg, 87%) as a clear oil. νmax (film) 3340, 3200, 1730, 1650, 1600 and 1470 cm-1, δH (CDCl3) 0.04 (6H, s, CH3SiCH3), 0.87 (9H, s, (CH3)3CSi), 1.33 (6H, t, J7.1 Hz, 2×CH3CH2), 2.08 (2H, m, SiOCH2CHCH2), 3.80-3.90 (4H, m, CH2OSi+CH2P), 3.99 (2H, m, CH2OCH2P), 4.16 (4H, m, 2×CH3CH2), 4.61 (1H, m, CHON), 5.68 (2H, br.s, D2O exchangeable, NH2), 8.04 (1H, s, H- 2/H-8), 8.34 (1H, s, H-2/H-8); m/z (FAB+ve Ion), 526 (MNa+), 504 (MH+); Found: C, 47.35; H, 7.68; N, 13.67% C20H38N5O6PSi requires C, 47.50; H, 7.60; N, 13.91%.
Reaction SMILES: [CH2:1]1[C@:6]2([OH:10])[C:7]([O:9][C@@H:4]([CH2:5]2)[C@@H:3]([OH:11])[C@H:2]1[OH:12])=[O:8].C1C[O:16]CC1>Cl>[CH2:5]1[C@@H:4]([OH:9])[C@@H:3]([OH:11])[C@H:2]([OH:12])[CH2:1][C@@:6]1([C:7]([OH:16])=[O:8])[OH:10]
Reactant: O=C1O[C@H]2C[C@]1(O)C[C@H](O)[C@@H]2O
Reactant: C1CCOC1
Agent: Cl
Product: O=C(O)[C@]1(O)C[C@@H](O)[C@@H](O)[C@H](O)C1

Procedure:
A mixture of 10 g (9.6 mmol) 1,4-O-dicarbotrichloroethoxy-3-O-dicarbotrichloroethoxycaffeoyl quinide is stirred for 5 days at ambient temperature in 65 ml THF and 8 ml concentrated HCl. After separation of the THF and saturation with NaCl, the aqueous phase is extracted with 3×40 ml ethyl acetate. The combined extracts are then washed with brine and dried over sodium sulfate and the solvent is evaporated. Treatment of the residue with a mixture of 1 volume dichloromethane to 10 volumes hexane gives 9.5 g 1,4-O-dicarbotrichloroethoxy-3-O-dicarbotrichloroethoxycaffeoyl quinic acid (yield 93%) in the form of an amorphous solid.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]1[C:10]([C:11](OCC)=[O:12])=[C:9]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[N:8]=[C:7]([S:27][CH3:28])[N:6]=1.[NH4+].[OH-]>>[CH3:28][S:27][C:7]1[N:8]=[C:9]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:24])([F:25])[F:26])[CH:18]=2)[C:10]2[C:11](=[O:12])[NH:2][CH:3]=[CH:4][C:5]=2[N:6]=1
Reactant: CCOC(=O)c1c(/C=C/N(C)C)nc(SC)nc1Nc1cccc(C(F)(F)F)c1
Agent: [NH4+]
Agent: [OH-]
Product: CSc1nc(Nc2cccc(C(F)(F)F)c2)c2c(=O)[nH]ccc2n1

Procedure:
The title compound was prepared as described in Example 1f by starting from (E)-ethyl 4-(2-(dimethylamino)vinyl)-2-(methylthio)-6-(3-(trifluoromethyl)phenylamino)pyrimidine-5-carboxylate and 30% NH4OH solution and continuing until the reaction yield brown solids, 2-(methylthio)-4-(3-(trifluoro methyl)phenylamino)pyrido[4,3-d]pyrimidin-5(6H)-one (912 mg). MS m/z: 353.1 (M+H)+.
Reaction SMILES: [OH:1][C:2]1([C:15]2[S:16][C:17]([C:20]3[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([NH:27][C:28]4[N:33]=[C:32](/[CH:34]=[CH:35]/[CH2:36][O:37][CH3:38])[CH:31]=[CH:30][N:29]=4)[CH:21]=3)=[CH:18][N:19]=2)[CH2:7][CH2:6][CH:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1>CCO.[Pd]>[OH:1][C:2]1([C:15]2[S:16][C:17]([C:20]3[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([NH:27][C:28]4[N:33]=[C:32]([CH2:34][CH2:35][CH2:36][O:37][CH3:38])[CH:31]=[CH:30][N:29]=4)[CH:21]=3)=[CH:18][N:19]=2)[CH2:3][CH2:4][CH:5]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:6][CH2:7]1
Reactant: COC/C=C/c1ccnc(Nc2cc(C)cc(-c3cnc(C4(O)CCC(C(=O)OC(C)(C)C)CC4)s3)c2)n1
Agent: [Pd]
Solvent: CCO
Product: COCCCc1ccnc(Nc2cc(C)cc(-c3cnc(C4(O)CCC(C(=O)OC(C)(C)C)CC4)s3)c2)n1
Temperature: 23 °C
Reaction time: 1 h
Yield: 28.4 %

Procedure:
A solution of tert-butyl 4-hydroxy-4-{5-[3-({4-[(1E)-3-methoxyprop-1-en-1-yl]pyrimidin-2-yl}amino)-5-methylphenyl]-1,3-thiazol-2-yl}cyclohexanecarboxylate (100 mg, 0.19 mmol, 1.0 equiv) was dissolved in absolute EtOH (10 ml), deoxygenated, and treated with 10% Pd on carbon (50 mg, 0.47 mmol, 2.5 equiv). The mixture was deoxygenated further before being placed under hydrogen balloon and stirred for at 23° C. for 1 h. The reaction was 50% complete so it was maintained under H2 at 23° C. for another 1 h. The black mixture was filtered through a pad of Celite, which was then washed with EtOAc, dichloromethane, and MeOH. The filtrate was concentrated in vacuo, then purified by reverse-phase HPLC (acetonitrile/water gradient with 0.05% TFA present). The TFA salt was converted to the free base by partitioning between EtOAc (60 ml) and saturated aqueous NaHCO3 (70 ml). The organic layers were dried over MgSO4, filtered and concentrated to afford the title compound (29.1 mg, 27.5%) as a yellow-orange oil. MS ESI: [M+H]+ m/z 539.1. 1H NMR (500 MHz, CDCl3) δ 8.29 (d, J=3.4 Hz, 1H), 7.90 (m, 1H), 7.84 (s, 1H), 7.32 (s, 1H), 7.00 (s, 1H), 6.61 (m, 1H), 3.46-3.45 (m, 5H), 2.74-2.72 (m, 2H), 2.36 (s, 3H), 2.30 (m, 1H), 2.15-2.00 (m, 6H), 1.92-1.85 (m, 4H), 1.45 (s, 9H). rhSYK activity=++
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].FC(F)(F)S(O[C:22]1=[CH:23][C:24]2[C:25]([CH:30]([O:33][Si:34]([CH:41]([CH3:43])[CH3:42])([CH:38]([CH3:40])[CH3:39])[CH:35]([CH3:37])[CH3:36])[CH2:31][CH2:32]1)=[N:26][CH:27]=[CH:28][CH:29]=2)(=O)=O>C1(C)C=CC=CC=1.CO.C(OCC)(=O)C.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>[C:1]1([C:22]2=[CH:23][C:24]3[C:25]([CH:30]([O:33][Si:34]([CH:38]([CH3:40])[CH3:39])([CH:41]([CH3:43])[CH3:42])[CH:35]([CH3:36])[CH3:37])[CH2:31][CH2:32]2)=[N:26][CH:27]=[CH:28][CH:29]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)[Si](OC1CCC(OS(=O)(=O)C(F)(F)F)=Cc2cccnc21)(C(C)C)C(C)C
Reactant: OB(O)c1ccccc1
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: CO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)[Si](OC1CCC(c2ccccc2)=Cc2cccnc21)(C(C)C)C(C)C
Temperature: 80 °C

Procedure:
The mixture of phenylboronic acid (0.060 g, 0.495 mmol), sodium carbonate (0.382 mL, 0.764 mmol), (E)-9-(triisopropylsilyloxy)-8,9-dihydro-7H-cyclohepta[b]pyridin-6-yl trifluoromethanesulfonate (0.1922 g, 0.413 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.024 g, 0.021 mmol) in Toluene (5 mL) and MeOH (1 mL) was heat to 80° C. under N2 for 3 hours. LCMS showed no more starting material. The reaction was diluted with ethyl acetate and washed with water one time. The ethyl acetate layer was separated, dried (Na2SO4), filtered and concentrated to give the crude product. The crude was used as it is. MS (ESI)[M+H+]=394.32.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:7]([SH:9])[CH3:8].Cl[CH2:11][C:12]1[N:13]=[C:14]([CH:17]2[CH2:22][CH:21]([C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH3:30])=[CH:25][CH:24]=3)[CH2:20][N:19]([C:31]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[O:32])[CH2:18]2)[S:15][CH:16]=1>O1CCOCC1>[CH2:29]([C:26]1[CH:27]=[CH:28][C:23]([CH:21]2[CH2:22][CH:17]([C:14]3[S:15][CH:16]=[C:12]([CH2:11][S:9][CH2:7][CH3:8])[N:13]=3)[CH2:18][N:19]([C:31]([N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)=[O:32])[CH2:20]2)=[CH:24][CH:25]=1)[CH3:30]
Reactant: CCc1ccc(C2CC(c3nc(CCl)cs3)CN(C(=O)N3CCOCC3)C2)cc1
Reactant: CCS
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CCSCc1csc(C2CC(c3ccc(CC)cc3)CN(C(=O)N3CCOCC3)C2)n1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
73 mg (0.221 mmol) of caesium carbonate and 36 μl (0.442 mmol) of ethanethiol were added to a solution of 100 mg (about 0.184 mmol) of the compound from Example 141A in 1.5 ml of dioxane. The reaction mixture was stirred at 70° C. for 4 hours. Without any further work-up, the mixture was purified by preparative HPLC. Yield: 40 mg (47% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([CH2:17][CH2:18][CH2:19][CH2:20]OS(C)(=O)=O)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:26]([NH:28][CH2:29][CH2:30][OH:31])[CH3:27]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([CH2:17][CH2:18][CH2:19][CH2:20][N:28]([CH2:26][CH3:27])[CH2:29][CH2:30][OH:31])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CCNCCO
Reactant: CS(=O)(=O)OCCCCc1ccc2c(-c3ccc(Cl)cc3)nsc2c1
Product: CCN(CCO)CCCCc1ccc2c(-c3ccc(Cl)cc3)nsc2c1

Procedure:
According to the method in example 23, Methanesulfonic acid 4-[3-(4-chloro-phenyl)-benzo[d]isothiazol-6-yl]-butyl ester and 2-Ethylaminoethanol were converted to yield 2-({4-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-butyl}-ethyl-amino)-ethanol, MS: 389 (MH+, 1Cl).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][C:40]([OH:42])=O)=[CH:33][C:32]=2[CH3:43])=[C:28]([CH:44]([CH3:46])[CH3:45])[NH:27][N:26]=1)(=O)C.Cl.[NH2:48][CH2:49][CH2:50][CH2:51][CH2:52][C@H:53]([NH:57]C(OCC1C=CC=CC=1)=O)[C:54]([NH2:56])=[O:55].C(N1CCNCC1)C1C=CC=CC=1>>[NH2:57][C@H:53]([C:54](=[O:55])[NH2:56])[CH2:52][CH2:51][CH2:50][CH2:49][NH:48][C:40]([CH2:39][CH2:38][O:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][C:29]2[C:25]([O:24][C@@H:6]3[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]3[OH:4])=[N:26][NH:27][C:28]=2[CH:44]([CH3:46])[CH3:45])=[C:32]([CH3:43])[CH:33]=1)=[O:42]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCC(=O)O)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: NCCCC[C@H](NC(=O)OCc1ccccc1)C(N)=O
Agent: Cl
Agent: c1ccc(CN2CCNCC2)cc1
Product: Cc1cc(OCCC(=O)NCCCC[C@H](N)C(N)=O)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C

Procedure:
The title compound was prepared in a similar manner to that described in Example 99 using 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-carboxyethoxy)-2-methyl-phenyl]methyl}-5-isopropyl-1H-pyrazole and (S)-6-amino-2-(benzyloxycarbonylamino)hexanamide hydrochloride instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{2-[1-carboxy-1-(methyl)ethylcarbamoyl]ethoxy}-2-methyl-phenyl)methyl]-5-isopropyl-1H-pyrazole and 1-benzyl-piperazine, respectively.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:13][N:12]=[N:11][N:10]=2)[CH:5]=[C:6]([Br:8])[CH:7]=1.[C:14]1([CH:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH:20]([N:11]1[N:12]=[N:13][C:9]([C:4]2[CH:5]=[C:6]([Br:8])[CH:7]=[C:2]([Br:1])[CH:3]=2)=[N:10]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Brc1cc(Br)cc(-c2nnn[nH]2)c1
Reactant: OC(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Brc1cc(Br)cc(-c2nnn(C(c3ccccc3)c3ccccc3)n2)c1
Temperature: 100 °C
Yield: 85.1 %

Procedure:
A suspension of 5-(3,5-dibromophenyl)-1H-tetrazole (6.08 g, 20.00 mmol), diphenylmethanol (3.68 g, 20.00 mmol) and TsOH.H2O (0.38 g, 2.00 mmol) in toluene (50.0 mL) was heated to 100° C. until a clear solution was obtained. The solution was cooled to rt, and filtered. The filtration was concentrated, and the residue was purified by recrystallization in ether and hexane to afford 8.00 g (85%) of product as a white solid.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:12]2[C:25]([Cl:26])=[C:24]([CH3:27])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[N:21][CH:20]=[CH:19][N:18]=2)[N:16]=1>>[N:18]1[CH:19]=[CH:20][N:21]=[CH:22][C:17]=1[C:15]1[N:16]=[C:11]([NH:9][CH2:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:12]2[C:25]([Cl:26])=[C:24]([CH3:27])[S:23][C:13]=2[N:14]=1
Reactant: Cc1sc2nc(-c3cnccn3)nc(Cl)c2c1Cl
Reactant: NCCc1ccccc1
Product: Cc1sc2nc(-c3cnccn3)nc(NCCc3ccccc3)c2c1Cl

Procedure:
With the procedure of Example 1, the reaction of phenethylamine with 4-chloro-2-(pyrazin-2-yl)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-phenethylamino-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine.