Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[Li]CCCC.[CH3:11][C:12]([CH3:32])([CH3:31])[CH2:13][N:14]([CH2:23][C:24]1[CH:29]=[CH:28][C:27](I)=[CH:26][CH:25]=1)[C:15]1[CH:20]=[CH:19][N:18]=[C:17]([C:21]#[N:22])[N:16]=1.O>C1COCC1.[Cl-].[Cl-].[Zn+2].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>[CH3:11][C:12]([CH3:32])([CH3:31])[CH2:13][N:14]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[O:1][CH:5]=[CH:4][N:3]=2)=[CH:26][CH:25]=1)[C:15]1[CH:20]=[CH:19][N:18]=[C:17]([C:21]#[N:22])[N:16]=1
Reactant: c1cocn1
Reactant: CC(C)(C)CN(Cc1ccc(I)cc1)c1ccnc(C#N)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)CN(Cc1ccc(-c2ncco2)cc1)c1ccnc(C#N)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 4.2 %

Procedure:
To a solution of oxazole (0.5 ml, 7.2 mmoles) in 10 ml of THF at −78° C. is added BuLi (5.23 ml, 8.0 mmoles, 1.6 M solution in hexane). After 30 min, ZnCl2 (3.0g, 21.7 mmoles) and then a solution of 4-{(2,2-Dimethyl-propyl)-[4-iodo-benzyl]-amino}-pyrimidine-2-carbonitrile (2.9 g, 7.2 mmoles) in 10 ml of THF are added. The reaction mixture is warmed to 0° C. for 1 h. The reaction mixture is added to Pd(PPh3)4 (0.9 g, 0.8 mmoles) and heated to reflux. Water is added and is filtered through a pad of Celite which is wshed with AcOEt. The organic layer is extracted with AcOEt, washed with brine, dried over magnesum sulfate and concentrated. The crude product is purified by silica gel column chromatography to give 104 mg of desired 4-[(2,2-dimethyl-propyl)-(4-oxazol-2-yl-benzyl)-amino]-pyrimidine-2-carbonitrile in 16% yield.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[CH2:10]([CH:12]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:13][NH2:14])[CH3:11]>>[Cl:9][C:8]1[NH:7][C:5](=[N:14][CH2:13][CH:12]([CH2:10][CH3:11])[CH2:15][CH2:16][CH2:17][CH3:18])[N:4]=[C:2]([Cl:3])[N:1]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CCCCC(CC)CN
Product: CCCCC(CC)CN=c1nc(Cl)nc(Cl)[nH]1

Procedure:
Similarly to the process reported in example 1, the cyanuryl chloride was reacted with 2-ethyl-1-hexylamine, to obtain the corresponding intermediate 2,4-bischloro-6-(2-ethylhexyl)imino-1,3,5-triazine. Similarly to the process reported in examples 2 and 3, the latter was reacted with two equivalents of p-aminobenzoic acid to give the corresponding diacid, which was then converted to the corresponding diacyl chloride by the action of thionyl chloride.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([NH:5][C@@H:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[C@H:8]([OH:17])[CH2:7]1)=[O:4].[Li][CH2:21][CH2:22][CH2:23]C.C(Br)C=C>C1COCC1>[CH2:23]([O:17][C@H:8]1[C:9]2[C:14](=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[C@@H:6]([NH:5][C:3](=[O:4])[C:2]([F:18])([F:19])[F:1])[CH2:7]1)[CH:22]=[CH2:21]
Reactant: COc1ccc2c(c1)[C@@H](NC(=O)C(F)(F)F)C[C@H]2O
Reactant: [Li]CCCC
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCO[C@@H]1C[C@H](NC(=O)C(F)(F)F)c2cc(OC)ccc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
Step U (1): A solution of 2,2,2-trifluoro-N-((1S,3R)-3-hydroxy-6-methoxy-2,3-dihydro-1H-inden-1-yl)acetamide (enantiomer A, 2.65 g, 9.63 mmol) from step T (1) was cooled to −78° C. in THF. Added n-BuLi (7.7 mL, 19.3 mmol, 2.5M in Hex, Aldrich). Allowed the precipitous mixture to stir at −78° C. for 30 min. Added allyl bromide (4.6 mL, 48.2 mmol, Aldrich), warmed to rt and the reaction became homogeneous. The mixture was stirred for 18 h. Quenched with 1M HCl. Extracted with EtOAc. Washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography to afford 1.38 g (46% yield) of N-((1S,3R)-3-(allyloxy)-6-methoxy-2,3-dihydro-1H-inden-1-yl)-2,2,2-trifluoroacetamide as white solid. LC-MS (M+Na)+=337.9; [α]D −115.43 (c=6.79 mg/mL, dioxane); Anal. Calcd for C15H16F3NO3: C, 57.14; H, 5.11; N, 4.44. Found: C, 57.19; H, 4.88; N, 4.31. 1H NMR (500 MHz, CDCl3) δ ppm 1.55 (s, 2H) 2.09 (d, J=14.04 Hz, 1H) 2.61-2.73 (m, 1H) 3.80 (s, 2H) 4.06 (dd, J=3.05, 1.53 Hz, 2H) 4.79 (dd, J=5.49, 1.83 Hz, 1H) 5.19 (dd, J=10.53, 1.37 Hz, 1H) 5.28 (dd, J=17.24, 1.68 Hz, 1H) 5.39 (s, 1H) 5.83-5.97 (m, 1H) 6.85-6.98 (m, 2H) 7.32 (d, J=8.24 Hz, 1H).
Reaction SMILES: [C:1]([O:8]CC)(=O)[C:2]([O:4]CC)=O.[NH2:11][C:12]1[C:17]([NH2:18])=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:19]>FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.O>[CH3:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:12]=1[NH:11][C:2](=[O:4])[C:1](=[O:8])[NH:18]2
Reactant: Cc1cccc(N)c1N
Reactant: CCOC(=O)C(=O)OCC
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: O
Product: Cc1cccc2[nH]c(=O)c(=O)[nH]c12
Temperature: 80 °C
Reaction time: 2 h
Yield: 76.1 %

Procedure:
According to Step 1 of Reference Example 10-3, diethyl oxalate (4.5 mL, 33 mmol) and ytterbium trifluoromethanesulfonate (254 mg, 0.41 mmol) were added to 2,3-diaminotoluene (1.0 g, 8.2 mmol) and the mixture was stirred at 80° C. for 2 hours. After water was added to the reaction mixture, the precipitate was washed with ethanol. Thus, 5-methylquinoxaline-2,3(1H,4H)-dione (1.1 g, yield: 78%) was obtained.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[F:26][C:27]([F:39])([F:38])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34](Cl)(=[O:36])=[O:35]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([S:34]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[C:27]([F:26])([F:38])[F:39])(=[O:36])=[O:35])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(S(=O)(=O)c4ccccc4C(F)(F)F)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) and 2-(trifluoromethyl)benzenesulfonyl chloride as starting compounds. The crude product is purified by crystallization from methanol to yield the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][N:3]=1.O=S(Cl)Cl.[CH2:15](OCC)[CH3:16].[OH-].[Na+]>C(O)C.CO.C1COCC1>[CH2:15]([O:9][C:8](=[O:10])[C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=1)[CH3:16]
Reactant: CCOCC
Reactant: Nc1ccc(C(=O)O)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CO
Product: CCOC(=O)c1ccc(N)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
2-Amino-5-pyridinecarboxylic acid (25.0 g, 181 mmol) was suspended in ethanol (190 mL) and SOCl2 (15 mL, 206 mmol) was added. The mixture was refluxed for 10 hs and more SOCl2 (16 mL) was added. After 3 days with reflux (and more SOCl2 (10 mL) added each day), the reaction mixture was cooled to room temperature and diethyl ether was added. After 24 h at −20° C. the mixture was filtered. The crude salt was dissolved in methanol (214 mL) and a solution of NaOH (40.0 g, 23.5 mmol) in methanol (90 mL) was added. The reaction mixture was stirred for 1 h and THF (270 mL) was added. The reaction mixture was filtered through a plug of silica (THF/MeOH) and concentrated under reduced pressure to give 6-amino-nicotinic acid ethyl ester (36.2 g, 97%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:14]([O:16][CH3:17])=[O:15])[C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=2[CH:13]=1)([O-])=O.[N+](C1C2CCCCC=2C(C(OC)=O)=CC=1)([O-])=O>CO>[NH2:1][C:4]1[CH:5]=[C:6]([C:14]([O:16][CH3:17])=[O:15])[C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=2[CH:13]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])cc2c1CCCC2
Agent: COC(=O)c1ccc([N+](=O)[O-])c2c1CCCC2
Solvent: CO
Product: COC(=O)c1cc(N)cc2c1CCCC2
Temperature: 25 °C
Yield: 39 %

Procedure:
Methyl 3-nitro-5,6,7,8-tetrahydronaphthalene-1-carboxylate (see Zh Obshch Khim; 1948, 877-884; 1.4 g, 3 mmol), which was contaminated with its regioisomer methyl 4-nitro-5,6,7,8-tetrahydronaphthalene-1-carboxylate (1:1), was dissolved in methanol (50 mL). The solution was flushed with nitrogen whereupon Pd/C (5%) catalyst (0.19 g) was added. The mixture was stirred under H2 at room temperature until the consumption of gas ceased. The catalyst was removed by filtration and then the solvent was evaporated. The product was separated from its 4-amino regioisomer and by-products by chromatography on silica gel using CH2Cl2 and triethylamine (98:2). There was obtained 0.24 g (39%) of methyl 3-amino-5,6,7,8-tetrahydronaphthalene-1-carboxylate as an oil. 1H NMR (500 MHz, CDCl3): 1.7-1.8 (m, 4H), 2.7 (m, 2H), 2.9 (m, 2H), 3.8 (s, 3H), 6.6 (d, 1H), 7.0 (d, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([NH:16][CH2:17][C:18]2[CH:40]=[CH:39][C:21]([C:22]([N:24]3[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[NH:28][C:27]4[N:35]([CH3:38])[N:36]=[CH:37][C:26]=4[CH2:25]3)=[O:23])=[CH:20][C:19]=2[CH3:41])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:42].O1CCOCC1>>[ClH:42].[CH3:38][N:35]1[C:27]2[NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[N:24]([C:22](=[O:23])[C:21]3[CH:39]=[CH:40][C:18]([CH2:17][NH:16][C:14]([N:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)=[O:15])=[C:19]([CH3:41])[CH:20]=3)[CH2:25][C:26]=2[CH:37]=[N:36]1
Reactant: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CNC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CNC(=O)N1CCNCC1

Procedure:
A solution of 5-(4-(4-(tert-butyloxycarbonyl)piperazine-1-carbonylaminomethyl)-3-methylbenzoyl)-1-methyl-4,10-dihydropyrazolo[5,4-b][1,5]benzodiazepine (160 mg, 0.29 mmol) in 4N HCl/dioxan (15 ml) was stirred at room temperature for 30 min then concentrated in vacuo. The residue was azeotroped with diethyl ether to give a white solid identified as 1-methyl-5-(3-methyl-4-(piperazine-1-carbonylaminomethyl)-benzoyl)-4,10-dihydropyrazolo[5,4-b][1,5]hydrochloride (130 mg, 90%).
Reaction SMILES: [CH2:1]([Si:5](OC)([O:8][CH3:9])[O:6][CH3:7])[CH:2]([CH3:4])[CH3:3].[CH:12]1([Mg]Cl)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.CO>C(OCC)C>[CH2:1]([Si:5]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([O:8][CH3:9])[O:6][CH3:7])[CH:2]([CH3:4])[CH3:3]
Reactant: Cl[Mg]C1CCCCC1
Reactant: CO[Si](CC(C)C)(OC)OC
Solvent: CCOCC
Solvent: CO
Product: CO[Si](CC(C)C)(OC)C1CCCCC1

Procedure:
Under an inert gas, 152.0 g isobutyltrimethoxy silane (0.85 mol) was dissolved in 50 ml diethylether. While stirring, 667 ml of a 1.5 molar solution of cyclohexylmagnesiumchloride in ether was added dropwise to the solution at a rate to maintain a moderate reflux. At the end of the addition, the reaction was continued under reflux for several hours. After cooling the reaction mixture, 4.8 g methanol (0.15 mol) was added, stirred for a few minutes and then the resulting precipitate was removed by filtration. The filter cake was washed with several portions of diethylether. The solvent was then evaporated from the combined filtrates using a water aspirator. The remaining residue consisted of 192.7 g (98.4% of the theoretical yield) isobutylcyclohexyldimethoxysilane, which had a purity of 98% according to gas chromatography (GC). Isobutyldicyclohexylmethoxysilane was not detected by GC.
Reaction SMILES: C(OC([N:8]([CH:17]([C:19]#[C:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]2[O:31][N:30]=[C:29]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[CH2:28]2)[CH:22]=1)[CH3:18])[O:9]C(OC(C)(C)C)=O)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:38][C:35]1[CH:34]=[CH:33][C:32]([C:29]2[CH2:28][CH:27]([C:23]3[CH:22]=[C:21]([C:20]#[C:19][CH:17]([NH:8][OH:9])[CH3:18])[CH:26]=[CH:25][CH:24]=3)[O:31][N:30]=2)=[CH:37][CH:36]=1
Reactant: CC(C#Cc1cccc(C2CC(c3ccc(F)cc3)=NO2)c1)N(OC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C#Cc1cccc(C2CC(c3ccc(F)cc3)=NO2)c1)NO
Temperature: 0 °C
Yield: 69 %

Procedure:
To a solution of the product of Step 1, above (10, 0.5 g, 1.5 mmol), in triethylamine (4 ml) was added bis(triphenylphosphine)palladium (II) chloride (55 mg, 0.078 mmol) and N,O-bis(tert-butoxycarbonyl)-N-(3-butyn-2-yl)hydroxylamine (840 mg, 2.8 mmol) in triethylamine (1 ml) under a N2 atmosphere. The reaction mixture was stirred at 75° C. for 1.5 hours, then concentrated under reduced pressure. The residue was extracted with ethyl acetate (3×10 ml) and the organic layer was washed with 1N HCl (10 ml), saturated aqueous NaHCO3 (10 ml) and brine (10 ml). The combined extracts were dried over MgSO4 and concentrated under reduced pressure. The residue was chromatographed on silica gel (ethyl acetate:n-hexane=1:6) to give N,O-bis(tert-butoxycarbonyl)-[4-(3-[4,5-dihydro-3-(4-fluorophenyl)isoxazol-5-yl]phenyl)-3-butyn-2-yl]hydroxylamine. To a solution of the protected hydroxylamine thus obtained, in CH2Cl2 (3 ml) cooled to 0° C., was slowly added TFA (0.72 ml, 9.3 mmol). The reaction mixture was allowed to warm to room temperature over 2 hours. The reaction mixture was poured into ice cold saturated aqueous NaHCO3 (20 ml) and extracted with CH2Cl2 (3×15 ml). The combined extracts were washed with water (30 ml) and brine (30 ml) and were dried over MgSO4. After evaporation of solvent, the residue was chromatographed on silica gel (ethyl acetate:n-hexane=1:1) to give the title compound (11, 178 mg, 69% yield) as orange solids.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][CH:13]([C:15]([O:17]C)=[O:16])[CH2:12][CH2:11][N:10]2[C:19]([O:21][CH3:22])=[O:20])[CH:5]=[CH:6][C:7]=1[F:8].[Br-].[Li+]>C1COCC1.O>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][CH:13]([C:15]([OH:17])=[O:16])[CH2:12][CH2:11][N:10]2[C:19]([O:21][CH3:22])=[O:20])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COC(=O)C1CCN(C(=O)OC)C(c2ccc(F)c(F)c2)C1
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)N1CCC(C(=O)O)CC1c1ccc(F)c(F)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 90.1 %

Procedure:
Dimethyl 2-(3,4-difluorophenyl)piperidine-1,4-dicarboxylate (6.578 g, 21.00 mmol) was dissolved in THF (40 mL) and water (0.800 mL). Lithium bromide (14.59 g, 167.97 mmol) and TEA (11.71 mL, 83.98 mmol) were added and the reaction was stirred at 80° C. for 3 h. The reaction mixture was cooled to room temperature and some solvent evaporated in vacuo. EtOAc (150 mL) and water (150 mL) were added, shaken and the phases separated. The organic phase was extracted with water (150 mL). The combined aqueous phases were acidified with 3 M HCl to pH 1 and extracted with EtOAc (2×300 mL). The combined organic phases were dried with Na2SO4, filtered and evaporated in vacuo to yield 2-(3,4-difluorophenyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (5.66 g, 90%) as a light brown oil. MS m/z 298 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:41]=[CH:40][S:39][C:14]=3[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:36]=[CH:37][CH:38]=3)[C:21]([NH:23][C:24]3[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[C:26]([O:34][CH3:35])[CH:25]=3)=[O:22])[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH-].[Na+]>C1COCC1.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:41]=[CH:40][S:39][C:14]=3[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:36]=[CH:37][CH:38]=3)[C:21]([NH:23][C:24]3[CH:33]=[CH:32][C:27]([C:28]([OH:30])=[O:29])=[C:26]([O:34][CH3:35])[CH:25]=3)=[O:22])[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COC(=O)c1ccc(NC(=O)c2cccc(-c3nc(Nc4ccc(OC)c(OC)c4)c4ncsc4n3)c2)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(Nc2nc(-c3cccc(C(=O)Nc4ccc(C(=O)O)c(OC)c4)c3)nc3scnc23)cc1OC
Reaction time: 16 h
Yield: 30.7 %

Procedure:
To a stirred solution of methyl 4-(3-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzamido)-2-methoxybenzoate (100 mg, 0.175 mmol) in 20 mL of THF and 5 mL of methanol was added a solution of 1N NaOH (2 mL) at room temperature. After the addition, the reaction was stirred at this temperature for 16 hours. The solvent was evaporated and the residue was diluted with water and adjusted to pH=2 by HCl (aq.). The mixture was concentrated by rotary evaporation. The residue was purified by preparative HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 ml/inj, flow rate: 20 ml/min; wavelength: 214 nm and 254 nm; the gradient conditions are: 20% acetonitrile/80% water (0.1% TFA V/V) initially, and then proceed to 70% acetonitrile/30% water (0.1% TFA V/V) in a linear fashion after just 9 min.) to give 4-(3-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzamido)-2-methoxybenzoic acid (30 mg, 31%). 1H NMR (300 MHz, DMSO): δ 10.70 (s, 1H), 10.21 (s, 1H), 9.41 (s, 1H), 8.96 (s, 1H), 8.62 (d, 1H, J=7.5 Hz), 8.09 (d, 1H, J=7.8 Hz), 7.84 (s, 1H), 7.77-7.70 (m, 3H), 7.54 (d, 1H, J=8.4 Hz), 6.99 (d, 1H, J=9.0 Hz), 3.84 (s, 3H), 3.81 (s, 3H), 3.74 (s, 3H). LC-MS: 558 [M+H]+, tR=1.54 min. HPLC: 100% at 214 nm, 100% at 254 nm, tR=6.02 min.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([C:10]1[N:11]([CH3:31])[S:12](=[O:30])(=[O:29])[C:13]2[CH:28]=[CH:27][CH:26]=[CH:25][C:14]=2[C:15]=1S(C1C=CC=CC=1)(=O)=O)=[O:9].Cl.[OH2:33]>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([C:10]1[N:11]([CH3:31])[S:12](=[O:30])(=[O:29])[C:13]2[CH:28]=[CH:27][CH:26]=[CH:25][C:14]=2[C:15]=1[OH:33])=[O:9]
Reactant: O
Reactant: CN1C(C(=O)Nc2ccccn2)=C(S(=O)(=O)c2ccccc2)c2ccccc2S1(=O)=O
Agent: Cl
Product: CN1C(C(=O)Nc2ccccn2)=C(O)c2ccccc2S1(=O)=O
Yield: 91.1 %

Procedure:
2.36 g (0.005 mole) N-(2-pyridyl)-4-(benzenesulfonyl)-2-methyl-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide was dissolved in 50 ml water containing 1.0 g sodium hydroxide. After it was completely hydrolysed, the solution was neutralized with conc-hydrochloric acid to form precipitates. The obtained precipitates were filtered and recrystalized with methanol and N,N-dimethyl formamide and n-hexane to obtain 1.51 g of the title compound. Yield: 91%. m.p. 198°-201° C.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15]([O:24]COCCOC)=[C:14]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]>C(Cl)Cl.[Zn+2].[Br-].[Br-]>[C:31]1([C:14]2[CH:13]=[C:12]([O:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH:17]=[C:16]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:15]=2[OH:24])[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CCCCCCCCCCOc1cc(-c2ccccc2)c(OCOCCOC)c(-c2ccccc2)c1
Agent: [Br-]
Agent: [Zn+2]
Solvent: ClCCl
Product: CCCCCCCCCCOc1cc(-c2ccccc2)c(O)c(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 79.1 %

Procedure:
A mixture of 3,5-diphenyl-4-[(2-methoxyethoxy)methoxy]-phenyl decyl ether (0.880 g, 1.793 mmol) and ZnBr2 (2.019 g, 8.967 mmol) in methylene chloride (10 ml) under nitrogen was stirred at room temperature. After ˜48 h, the reaction mixture was concentrated in vac and the residue was taken up in EtOAc (60 ml) and saturated NaHCO3 solution (20 ml). The layers were shaken and separated and the organic layer was washed with saturated NaHCO3 solution (2×10 ml), water (3×10 ml), brine (1×10 ml), dried over Na2SO4, filtered and the filtrate concentrated in vac and dried. The residue was purified by flash chromatography (hexane and 1% EtOAc/Hex) to give the product as a light brown oil (0.571 g, 79%); 1H NMR (400 MHz, DMSO-d6) δ 0.83–0.88 (m, 3H), 1.20–1.36 (m, 12H), 1.36–1.45 (m, 2H), 1.65–1.73 (m, 2H), 3.96 (t, J=6.6 Hz, 2H), 6.77 (s, 2H), 7.31–7.36 (m, 2H), 7.40–7.45 (m, 4H), 7.54–7.58 (m, 4H), 7.80 (s, 1H); IR (film) 3550, 2940, 1600, 1460, 1180 cm−1; mass spectrum [EI], m/z 402 M+.
Reaction SMILES: [C:1]1([N:7]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([OH:21])(=[O:20])=[O:19])=[CH:15][CH:16]=3)[C:10](=O)[C:8]2=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:22].[K+]>>[S:18]([C:14]1[CH:15]=[CH:16][C:17]2[C:12](=[C:10]([C:8]([OH:22])=[O:9])[C:6]3[C:1]([N:7]=2)=[CH:2][CH:3]=[CH:4][CH:5]=3)[CH:13]=1)([OH:21])(=[O:20])=[O:19]
Reactant: [OH-]
Reactant: O=C1C(=O)N(c2ccccc2)c2ccc(S(=O)(=O)O)cc21
Agent: [K+]
Product: O=C(O)c1c2ccccc2nc2ccc(S(=O)(=O)O)cc12

Procedure:
The title compound can be prepared from N-phenyl isatin 5 sulfonic acid of example 11 and 10% KOH by heating for hours on a steam bath. The solution is filtered, then acidified to pH 1 and product is collected by filtration.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]([NH:30][C:31](=[O:41])[NH:32][CH:33]([C:37]([F:40])([F:39])[F:38])[C:34]([NH2:36])=O)([C:16]2[CH:21]=[C:20]([O:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])[CH:19]=[C:18]([F:29])[CH:17]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=1.CS(C)=O.[Cl-].CCN(CC)CC>C(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]([NH:30][C:31]([NH:32][CH:33]([C:34]#[N:36])[C:37]([F:39])([F:38])[F:40])=[O:41])([C:16]2[CH:21]=[C:20]([O:22][C:23]([F:28])([F:27])[CH:24]([F:25])[F:26])[CH:19]=[C:18]([F:29])[CH:17]=2)[CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:6][CH:7]=1
Reactant: NC(=O)C(NC(=O)N[C@@](Cc1ccccc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(Cl)cn1)C(F)(F)F
Agent: [Cl-]
Solvent: CS(C)=O
Solvent: O
Solvent: ClCCl
Product: N#CC(NC(=O)N[C@@](Cc1ccccc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(Cl)cn1)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-(3-((S)-1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)ureido)-3,3,3-trifluoropropanamide (15 mg, 0.024 mmol) in DCM (0.5 mL) was added DMSO (3.74 mg, 0.048 mmol). The reaction mixture was cooled to −78° C. and oxaly chloride (18.4 μL, 2M in DCM, 0.04 mmol) was added. After 15 min at −78° C., NEt3 (10 μL, 0.072 mmol) was added. The reaction mixture was stirred for 1 h and H2O was added to quench the reaction. The reaction mixture was concentrated and the crude mixture was purified by preparative HPLC Shimadzu-Phenomenex C18 column, 20×100 mm eluting with 30-100% MeOH (90% in H2O, 0.1% TFA) gradient over 12 min with flow rate 20 mL/min and UV detection at 220 nm. 1-((S)-1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3-(1-cyano-2,2,2-trifluoroethyl)urea was isolated as a pale yellow solid (7 mg, 50% yield). LCMS: RT=3.96 min [M+H] 593.11 (LCMS Method 1); NMR: 400 MHz 1H (CDCl3) 8.27 ppm, 1H, m; 7.72 ppm, 1H, m; 7.63 ppm, 1H, d, J=12.6 Hz; 7.12 ppm, 6H, m; 6.91 ppm, 1H, m; 6.52 ppm, 2H, dd, J=20.2, 6.8 Hz; 5.81 ppm, 2H, m; 5.23 ppm, 1H, dd, J=27.3, 10.1 Hz; 4.33 ppm, 1H, dd, J=12.9, 3.3 Hz; 3.52 ppm, 1H, m.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[CH:8]([NH:14][C:15]([NH:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=1[CH:20]=[N:21][NH:22]3)=[O:16])[CH2:7][CH2:6]2.[C:27](Cl)(=[O:29])[CH3:28].C(OCC)(=O)C>N1C=CC=CC=1>[C:27]([N:22]1[C:23]2[C:19](=[C:18]([NH:17][C:15]([NH:14][CH:8]3[C:9]4[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:11]([O:12][CH3:13])[CH:10]=4)[CH2:6][CH2:7]3)=[O:16])[CH:26]=[CH:25][CH:24]=2)[CH:20]=[N:21]1)(=[O:29])[CH3:28]
Reactant: COc1cc2c(cc1OC)C(NC(=O)Nc1cccc3[nH]ncc13)CC2
Reactant: CC(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1cc2c(cc1OC)C(NC(=O)Nc1cccc3c1cnn3C(C)=O)CC2
Temperature: 25 °C
Reaction time: 15 h
Yield: 38 %

Procedure:
To the solution of 1-(5,6-dimethoxy-indan-1-yl)-3-(1H-indazol-4-yl)-urea (0.1 g, 0.28 mmol) in pyridine (2 mL) was added acetyl chloride (0.5 mL) and mixture stirred for 15 hours at ambient temperature. The mixture was suspended with ethyl acetate and filtered. The precipitate was triturated with ether twice and dried to obtain 42 mg (38%) of desired product as a yellow solid. NMR (DMSO-d6): 8.98 (s, 1H), 8.72 (s, 1H), 7.60 (d, J 7.5 Hz, 1H), 7.32-7.18 (m, 2H), 6.90 (d, J 8 Hz, 2H), 6.53 (d, J 8 Hz, 1H), 5.16 (m, 1H), 3.76 (s, 3H), 3.72 (s, 3H), 3.00-2.70 (m, 5H), 2.43 (m, 1H), 1.82 (m, 1H). MS (DCI): 395 (M+1). Elemental: Calculated for C18H18N4O2.0.2H2O: C, 63.37; H, 5.67; N, 14.08. Found: C, 63.07; H, 5.49; N, 13.94.