Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[C:5](O)(=O)[C:6]1[C:7](=[CH:9][CH:10]=[CH:11][CH:12]=1)[SH:8].CO>ClC1C=CC=CC=1Cl>[NH:3]1[CH2:2][CH2:1][N:4]=[C:5]1[C:6]1[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=1[SH:8]
Reactant: O=C(O)c1ccccc1S
Reactant: NCCN
Solvent: CO
Solvent: Clc1ccccc1Cl
Product: Sc1ccccc1C1=NCCN1
Temperature: 60 °C
Reaction time: 8 h
Yield: 53.1 %

Procedure:
21.6 mL (0.323 mol) of ethylenediamine was added to a suspension of 20.0 g (0.112 mol) of thiosalicylic acid in 200 mL of 1,2-dichlorobenzene, and refluxed under nitrogen for 4 h then cooled to ca. 60° C. and 50 mL of methanol was added. The solution was allowed to stand at 22° C. overnight and the resulting yellow crystalline solid was collected and washed with ether to give 10.6 g of pure product.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:27]=[CH:26][CH:25]=[CH:24][C:4]=1[C:5]([N:7]1[CH2:11][C:10]2[CH2:12][N:13]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[CH2:14][C:9]=2[CH2:8]1)=[O:6].Cl.[S:31]1[C:35]([CH2:36][NH2:37])=[CH:34][N:33]=[CH:32]1>>[S:31]1[C:35]([CH2:36][NH:37][C:19](=[O:20])[C:18]2[CH:22]=[CH:23][C:15]([N:13]3[CH2:12][C:10]4[CH2:11][N:7]([C:5](=[O:6])[C:4]5[CH:24]=[CH:25][CH:26]=[CH:27][C:3]=5[C:2]([F:28])([F:1])[F:29])[CH2:8][C:9]=4[CH2:14]3)=[N:16][CH:17]=2)=[CH:34][N:33]=[CH:32]1
Reactant: NCc1cncs1
Reactant: O=C(O)c1ccc(N2CC3=C(CN(C(=O)c4ccccc4C(F)(F)F)C3)C2)nc1
Agent: Cl
Product: O=C(NCc1cncs1)c1ccc(N2CC3=C(CN(C(=O)c4ccccc4C(F)(F)F)C3)C2)nc1
Yield: 58 %

Procedure:
6-[5-(2-Trifluoromethylbenzoyl)-3,4,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl]nicotinic acid (50 mg, 0.124 mmol) were reacted with C-thiazol-5-ylmethylamine, hydrochloride analogously to example 3d. Yield: 58%, M+H+: 500.20.
Reaction SMILES: ClC1C=C(N[C@H](C2CC2)C(N[C@@H]2CCCN(C(OC(C)(C)C)=O)C2)=O)C=C(F)C=1.[Cl:30][C:31]1[CH:32]=[C:33]([NH:38][CH2:39][C:40]([NH:42][C@@H:43]2[CH2:48][CH2:47][CH2:46][N:45]([C:49](OC(C)(C)C)=O)[CH2:44]2)=[O:41])[CH:34]=[C:35]([Cl:37])[CH:36]=1.NC1C(C#N)=C(Cl)N=CN=1.[Cl:66][C:67]1[C:68]([NH2:74])=[N:69][CH:70]=[N:71]C=1Cl>>[NH2:74][C:68]1[N:69]=[CH:70][N:71]=[C:49]([N:45]2[CH2:46][CH2:47][CH2:48][C@@H:43]([NH:42][C:40](=[O:41])[CH2:39][NH:38][C:33]3[CH:34]=[C:35]([Cl:37])[CH:36]=[C:31]([Cl:30])[CH:32]=3)[CH2:44]2)[C:67]=1[Cl:66]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](NC(=O)CNc2cc(Cl)cc(Cl)c2)C1
Reactant: Nc1ncnc(Cl)c1Cl
Agent: CC(C)(C)OC(=O)N1CCC[C@@H](NC(=O)[C@H](Nc2cc(F)cc(Cl)c2)C2CC2)C1
Agent: N#Cc1c(N)ncnc1Cl
Product: Nc1ncnc(N2CCC[C@@H](NC(=O)CNc3cc(Cl)cc(Cl)c3)C2)c1Cl

Procedure:
The title compound of Example 140 was prepared in similar manner as described in Example 134 except the key intermediate (R)-tert-butyl 3-((R)-2-(3-chloro-5-fluorophenylamino)-2-cyclopropylacetamido)piperidine-1-carboxylate was replaced with (R)-tert-butyl 3-(2-(3,5-dichlorophenylamino)acetamido)piperidine-1-carboxylate and the 4-amino-6-chloropyrimidine-5-carbonitrile was substituted for 5,6-dichloropyrimidin-4-amine. 1H NMR (300 MHz, CD3OD) δ 7.91 (s, 1H), 6.51-6.63 (m, 1H), 6.34 (d, J=1.51 Hz, 2H), 3.93-4.10 (m, 1H), 3.47-3.57 (m, 3H), 3.20-3.31 (m, 2H), 2.76-3.01 (m, 1H), 1.72-1.85 (m, 2H), 1.54-1.67 (m, 2H). EIMS (m/z): calcd. for C17H19Cl3N6O (M+1H) 431. found 431.
Reaction SMILES: C(OC([N:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]2[C:10](=[CH:11][C:12]([NH:20][C:21]([C:23]3[C:24]([NH:29][CH2:30][C:31]4[C:39]5[C:34](=[N:35][CH:36]=[CH:37][CH:38]=5)[NH:33][CH:32]=4)=[N:25][CH:26]=[CH:27][CH:28]=3)=[O:22])=[CH:13][CH:14]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[CH3:18][C:16]1([CH3:19])[C:15]2[C:10](=[CH:11][C:12]([NH:20][C:21](=[O:22])[C:23]3[CH:28]=[CH:27][CH:26]=[N:25][C:24]=3[NH:29][CH2:30][C:31]3[C:39]4[C:34](=[N:35][CH:36]=[CH:37][CH:38]=4)[NH:33][CH:32]=3)=[CH:13][CH:14]=2)[CH2:9][NH:8][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1Cc2cc(NC(=O)c3cccnc3NCc3c[nH]c4ncccc34)ccc2C(C)(C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CNCc2cc(NC(=O)c3cccnc3NCc3c[nH]c4ncccc34)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4,4-Dimethyl-7-({2-[(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-amino]-pyridine-3-carbonyl}-amino)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (123 mg, 0.23 mmol) was treated with 10 mL of 1/1 TFA/CH2Cl2 solution and stirred at RT for 1 h. The volatiles were removed under reduced pressure and the residue was purified by flash column chromatography to obtain the titled compound as a white solid. MS (ES+): 427.1 (M+H)+. Calc'd for C25H26N6O—426.22.
Reaction SMILES: CN(C=O)C.[Cl:6][C:7]1[C:12]([OH:13])=[CH:11][C:10]([C:14]2[C:15](=[O:26])[N:16]([CH3:25])[C:17]([C:21]([F:24])([F:23])[F:22])=[C:18]([CH3:20])[CH:19]=2)=[C:9]([F:27])[CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:34](Br)[C:35]#[CH:36]>O>[Cl:6][C:7]1[C:12]([O:13][CH2:36][C:35]#[CH:34])=[CH:11][C:10]([C:14]2[C:15](=[O:26])[N:16]([CH3:25])[C:17]([C:21]([F:22])([F:23])[F:24])=[C:18]([CH3:20])[CH:19]=2)=[C:9]([F:27])[CH:8]=1
Reactant: Cc1cc(-c2cc(O)c(Cl)cc2F)c(=O)n(C)c1C(F)(F)F
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCOc1cc(-c2cc(C)c(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 60 °C
Reaction time: 2 h
Yield: 53.5 %

Procedure:
To 10 ml of DMF, 0.20 g (0.6 mmol) of 3-(4-chloro-2-fluoro-5-hydroxyphenyl)-1,5-dimethyl-6-trifluoromethyl-2(1H)-pyridone, 0.1 g (0.7 mmol) of potassium carbonate and 0.1 g (0.8 mmol) of propargyl bromide were added, followed by stirring at 60° C. for 2 hours. This reaction solution was poured into water and extracted with ethyl acetate. After washing with water, the organic layer was dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure, and then, the obtained residue was purified by silica gel column chromatography to obtain 0.12 g of the desired product (yield: 53%). Melting point: 107-108° C.
Reaction SMILES: S(=O)(=O)(O)O.[C:6]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16]C)[C:11]=1[CH3:18])(=O)C>O.C(O)C>[OH:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([O:9][CH3:6])[C:11]=1[CH3:18]
Reactant: COc1cccc(OC(C)=O)c1C
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCO
Product: COc1cccc(O)c1C
Temperature: 120 °C
Reaction time: 0.6 h
Yield: 87.7 %

Procedure:
A solution of 18.0 mL of concentrated sulfuric acid in 90 mL water was added to a solution of 4.69 g (26.0 mmol) of 2-acetoxy-6-methoxytoluene in 360 mL ethanol and heated and stirred on a 120° C. oil bath for 36 minutes. The reaction mixture which had been allowed to stand at room temperature overnight was transferred to a separatory funnel, extracted with 50 mL and 20 mL of toluene, and after the combined organic layers were washed with 30 mL of water, 30 mL of 5% sodium hydrogen carbonate aqueous solution and 30 mL of water twice, the solvent was evaporated to obtain 3.15 g of title compound.
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[C:8]([O:27][CH3:28])[CH:7]=1)C.[OH-].[K+].O>C(O)C>[CH3:28][O:27][C:8]1[CH:7]=[C:6]([CH2:5][C:4]([OH:29])=[O:3])[CH:11]=[CH:10][C:9]=1[O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCCCCCOc1ccc(CC(=O)OCC)cc1OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCCCCOc1ccc(CC(=O)O)cc1OC
Yield: 68 %

Procedure:
The title compound is prepared by the procedure of Example 64 using 60 g of product from Example 66, 24.84 g of potassium hydroxide, 45 ml of water and 650 ml of ethyl alcohol. The reaction is heated at reflux temperature for 41 hours. The residue is recrystallized from methylene chloride/hexane to give 38 g of the desired product as cream needles.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:16])[CH2:10][C:11]([O:13]CC)=O)=[C:4]([CH3:17])[CH:3]=1.[CH2:18]([NH2:22])[CH2:19][CH2:20][CH3:21]>O.C(O)C>[CH2:18]([NH:22][C:11](=[O:13])[CH2:10][C:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[CH3:17])=[O:16])[CH2:19][CH2:20][CH3:21]
Reactant: CCOC(=O)CC(=O)Nc1ccc(Br)cc1C
Reactant: CCCCN
Solvent: CCO
Solvent: O
Product: CCCCNC(=O)CC(=O)Nc1ccc(Br)cc1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 45 %

Procedure:
A mixture of 4.90 grams (0.02 mole) of ethyl 3-[(4-bromo-2-methylphenyl)amino]-3-oxopropanoate prepared in Example I (Compound No. 75), 358 grams (4.9 moles) of n-butylamine, 150 milliliters of ethanol and 5 drops of water was stirred at room temperature for about 16 hours. After this period, rotary evaporation gave a crude product as a white solid. The white solid was recrystallized from ethyl acetate-hexane to give 3.08 grams (0.009 mole) of N-butyl 3-[(4-bromo-2-methylphenyl)amino]-3-oxopropanamide having a melting point of 123° C.-125° C.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)=[O:7])=[CH:4][C:3]=1[NH:20][S:21]([C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[O:31][CH3:32])(=[O:23])=[O:22].Cl[C:34]1C=CC(OC)=C(S(Cl)(=O)=O)[CH:39]=1>>[CH2:34]([O:14][C:13](=[O:15])[C:12]1[CH:16]=[CH:17][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:18]=[CH:19][C:2]([Cl:1])=[C:3]([NH:20][S:21]([C:24]3[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=3[O:31][CH3:32])(=[O:23])=[O:22])[CH:4]=2)=[CH:10][CH:11]=1)[CH3:39]
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Cl
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Nc1cc(C(=O)Nc2ccc(C(=O)O)cc2)ccc1Cl
Product: CCOC(=O)c1ccc(NC(=O)c2ccc(Cl)c(NS(=O)(=O)c3cc(Cl)ccc3OC)c2)cc1

Procedure:
4-[4-Chloro-3-(5-chloro-2-methoxy-benzenesulfonylamino)-benzoylamino]-benzoic acid, MS (ISP): m/e=493.1 (M−H), was prepared in analogy to example 21, steps A to D. Step C was performed using 5-chloro-2-methoxy-benzenesulfonyl chloride and yielded 4-[4-chloro-3-(5-chloro-2-methoxy-benzenesulfonylamino)-benzoylamino]-benzoic acid ethyl ester, which was hydrolyzed in step D.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].Cl>C(O)C>[CH2:20]([O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: CCCCCCCCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1
Yield: 64 %

Procedure:
1.15 g of sodium hydroxide was dissolved in 100 ml of ethyl alcohol. Then, 2.0 g of 4-(4'-hydroxyphenyl) benzoic acid and 2.45 ml of 1-bromooctane were added to the solution and refluxed for 16 hours. 50 ml of 10% aqueous sodium hydroxide solution was added and refluxed for another 2 hours. After cooling, concentrated HCl was dropped into the solution until it was acidic. Filtration and recrystallization from ethyl alcohol gave 1.95 g of pure product (yield 64%).
Reaction SMILES: C(O)C.[Si]([O:21][CH2:22][CH2:23][C:24]1([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[N:28]([C:29]2[S:30][C:31]3[CH2:32][N:33]([CH3:38])[CH2:34][CH2:35][C:36]=3[N:37]=2)[N:27]=[C:26]([C:39]2[CH:44]=[C:43]([F:45])[CH:42]=[CH:41][C:40]=2[F:46])[S:25]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(#N)C>[F:46][C:40]1[CH:41]=[CH:42][C:43]([F:45])=[CH:44][C:39]=1[C:26]1[S:25][C:24]([CH2:23][CH2:22][OH:21])([C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[N:28]([C:29]2[S:30][C:31]3[CH2:32][N:33]([CH3:38])[CH2:34][CH2:35][C:36]=3[N:37]=2)[N:27]=1
Reactant: CN1CCc2nc(N3N=C(c4cc(F)ccc4F)SC3(CCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c3ccccc3)sc2C1
Solvent: CC#N
Solvent: CCO
Product: CN1CCc2nc(N3N=C(c4cc(F)ccc4F)SC3(CCO)c3ccccc3)sc2C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Preparation of 245-(2,5-difluorophenyl)-3-(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)ethanol: To a solution of 2-(2-(2-(tert-butyldiphenylsilyloxy)ethyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine (0.070 g, 0.098 mmol) in 2 mL of anhydrous acetonitrile was added HF-TEA (0.160 mL, 0.99 mmol). The solution was stirred at room temperature for 16 hours then slowly quenched with saturated NaHCO3 (20 mL). The mixture was extracted with EtOAc (3×10 mL) and the combined organic phases were washed with brine (10 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (0-1% MeOH/DCM) and the residue was dissolved in 2 mL of methanol and treated with 1N HCl/MeOH (2 mL). After stirring for 10 minutes, the solution was concentrated in vacuo. The residue was triturated with diethyl ether, filtered, washed with ether and dried in vacuo to afford the desired product as a yellow powder, 0.023 g, 42%. MS ESI (+) m/z 473 (M+1) detected; 1H NMR (400 MHz, CDCl3) δ 7.59 (m, 1H), 7.44 (d, 2H, J=7.5 Hz), 7.32 (m, 2H), 7.26 (m, 1H), 7.07 (m, 2H), 4.10 (m, 1H), 3.96 (m, 1H), 3.65 (m, 1H), 3.54 (q, 2H, J=30.2, 14.3 Hz), 2.83 (m, 1H), 2.72 (m, 2H), 2.57 (m, 2H), 2.48 (s, 3H) ppm.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH:6]([CH2:10][CH3:11])[C:7]([OH:9])=[O:8])=[O:4].CCN(C(C)C)C(C)C.[C:21](N1C=CN=C1)(N1C=CN=C1)=[S:22]>C1COCC1>[O:4]=[C:3]1[N:5]([CH:6]([CH2:10][CH3:11])[C:7]([OH:9])=[O:8])[C:21](=[S:22])[NH:1][CH2:2]1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: CCC(NC(=O)CN)C(=O)O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCC(C(=O)O)N1C(=O)CNC1=S
Yield: 38 %

Procedure:
To a mixture of 2-(2-aminoacetamido)butanoic acid (0.5 g, 3.12 mmol) and DIPEA (1.812 g, 14.05 mmol) in anhydrous THF 10 mL is added 1,1′-thiocarbonyldiimidazole (0.834 g, 4.68 mmol) and heated to reflux overnight. The resulting reaction mixture is concentrated to dry and the pure product 2-(5-oxo-2-thioxoimidazolidin-1-yl)butanoic acid (0.24 g, 1.187 mmol, yellow solid) is obtained by column chromatography using acetic acid/DCM, 0-5% ration solvent system. 1H-NMR (CD3OD/300 MHz): 5.21 (dd, J=10.5, 5.1 Hz, 1H), 4.09 (d, J=5.4 Hz, 2H), 2.25 (m, 2H), 0.90 (t, J=7.2 Hz, 3H). MS (ES+, m/z): 200.9 (M−, 100.0).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH:5]([NH:7][C:8]1[S:9][CH:10]=[C:11]([C:13](=[N:17][O:18][CH2:19][CH2:20]Br)[C:14]([OH:16])=[O:15])[N:12]=1)=[O:6].C(=O)(O)[O-].[Na+]>CN(C)C=O.O>[CH:5]([NH:7][C:8]1[S:9][CH:10]=[C:11]([C:13](=[N:17][O:18][CH2:19][CH2:20][N:1]=[N+:2]=[N-:3])[C:14]([OH:16])=[O:15])[N:12]=1)=[O:6]
Reactant: [N-]=[N+]=[N-]
Reactant: O=CNc1nc(C(=NOCCBr)C(=O)O)cs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCCON=C(C(=O)O)c1csc(NC=O)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 35.7 %

Procedure:
Sodium azide (14.87 g.) was added to a solution of 2-(2-formamidothiazol-4-yl)-2-(2- bromoethoxyimino)acetic acid (syn isomer, 15.7 g.) in N,N-dimethylformamide (100 ml.) and water (75 ml.), and stirred at room temperature for 2 days. To the resultant solution was added water (25 ml.) and adjusted to pH 8.0 with a saturated aqueous solution of sodium bicarbonate. The solution was washed with ethyl acetate (250 ml.). The solution was adjusted to pH 2.5 and extracted with ethyl acetate (350 ml.). The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was recrystalized from a solution of acetone and methylene chloride (3:1) repeatedly. The precipitates were collected by filtration to give 2-(2-formamidothiazol-4-yl)-2-(2-azidoethoxyimino)acetic acid (syn isomer, 4.95 g.).
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=3)=[CH:16][N:17]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C([Li])CCC.[C:30](=[O:32])=[O:31].Cl>O1CCCC1.O>[CH2:1]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:30]([OH:32])=[O:31])=[CH:20][CH:19]=3)=[CH:16][N:17]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: O=C=O
Reactant: CCCCCOc1ccc(-c2ncc(-c3ccc(Br)cc3)s2)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCCCOc1ccc(-c2ncc(-c3ccc(C(=O)O)cc3)s2)cc1
Temperature: -60 °C
Reaction time: 1 h
Yield: 80.9 %

Procedure:
A solution of 2-(4-pentyloxyphenyl)-5-(4-bromophenyl)thiazole (2.3 g) in dry tetrahydrofuran (60 ml) was cooled to −60° C., and a solution of n-butyllithium (1.66M in n-hexane, 4.46 ml) was added slowly to maintain the reaction temperature at −60° C. After stirring for 1 hour, a solution of n-butyllithium (1.66M in n-hexane, 1.0 ml) was additionally added. The reaction mixture was allowed to warm to −40° C. After stirring for 30 minutes, dry-ice (5 g) was added. The reaction mixture was allowed to warm to room temperature over 30 minutes. To the reaction mixture was added water (25 ml) and 0.5N-hydrochloric acid (100 ml), then extracted with dichloromethane (500 ml). The organic layer was washed with brine, and dried over magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure. The solids were slurried in acetonitrile, and collected by filtration to give 4-[2-(4-pentyloxyphenyl)thiazol-5-yl]benzoic acid (1.70 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][O:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=[CH:17][N:16]=2)=[CH:8][CH:7]=1.[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>N1C=CC=CC=1.C(OCC)(=O)C>[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]2[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][O:14][C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]=[CH:17][N:16]=3)=[CH:8][CH:7]=2)(=[O:33])=[O:32])=[CH:27][CH:26]=1
Reactant: OCCCCc1ccc(CCOc2ncnc3ccccc23)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)OCCCCc2ccc(CCOc3ncnc4ccccc34)cc2)cc1
Reaction time: 4 h

Procedure:
A 15 ml round bottom flask charged with 4-(2-(4-(4-hydroxybutyl)phenyl)ethoxy) quinazoline (0.25 g, 0.77 mmol) is dissolved in pyridine (5 ml). p-Toluenesulfonyl chloride (0.15 g, 0.79 mmol) is then added to it and the mixture stirred for 4 hours. The reaction mixture is diluted with ethyl acetate, washed with 5% copper sulfate solution and then with water and dried. After removing the solvent on the rotary evaporator the crude is purified by flash chromatography using silica gel (ethyl acetate/hexanes) to give the product.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11]C(=O)C(F)(F)F)[N:10]=2)[CH:7]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][N:21]=1.C([O-])([O-])=O.[Cs+].[Cs+].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.O1CCOCC1>[CH3:18][O:19][C:20]1[N:21]=[CH:22][C:23]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([CH:8]=[C:9]([NH2:11])[N:10]=3)[CH:7]=2)=[CH:24][CH:25]=1
Reactant: O=C(Nc1cn2cc(Br)ccc2n1)C(F)(F)F
Reactant: COc1ccc(B(O)O)cn1
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(-c2ccc3nc(N)cn3c2)cn1
Reaction time: 8 h

Procedure:
N-(6-Bromo-imidazo[1,2-a]pyridin-2-yl)-2,2,2-trifluoro-acetamide (Intermediate A1, step 3) (0.84 g, 2.72 mmol), 2-methoxy-5-pyridineboronic acid (0.50 g, 3.27 mmol) and dry 1,4-dioxane (10 ml) are placed in a microwave vial and purged with Argon. Pd(PPh3)4 (0.16 g, 0.14 mmol) is added followed by a solution of Cs2CO3 in water (2.66 g, 8.16 mmol in 3 ml). The reaction mixture is heated using microwave radiation at 150° C. for 45 minutes and then left overnight at room temperature. The mixture is filtered through Celite® (filter agent) and washed through with EtOAc (100 ml). The organic filtrate is washed with NaHCO3 (50 ml) and brine (50 ml), dried over MgSO4, filtered and concentrated in vacuo. Purification by flash chromatography on silica eluting with MeOH in DCM (1% increasing to 10%) affords the title compound. [MH+241.07].
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([N:10]2[CH2:15][CH2:14][CH:13]([NH2:16])[CH2:12][CH2:11]2)=[N:3][CH:2]=1.[N:17]1[CH:22]=[C:21]([C:23](O)=[O:24])[CH:20]=[N:19][CH:18]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:1]1[C:6]2=[N:7][CH:8]=[CH:9][C:5]2=[C:4]([N:10]2[CH2:11][CH2:12][CH:13]([NH:16][C:23]([C:21]3[CH:22]=[N:17][CH:18]=[N:19][CH:20]=3)=[O:24])[CH2:14][CH2:15]2)[N:3]=[CH:2]1
Reactant: NC1CCN(c2ncnc3[nH]ccc23)CC1
Reactant: O=C(O)c1cncnc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CCN(c2nc[nH]c3nccc2-3)CC1)c1cncnc1
Temperature: 25 °C

Procedure:
To a mixture of 1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinamine D2 (65.2 mg), 5-pyrimidinecarboxylic acid (37.2 mg, 0.300 mmol), HATU (137 mg, 0.360 mmol) and HOAt (24.50 mg, 0.180 mmol) in DMF (1.5 mL) was added DIPEA (252 μL, 1.440 mmol). The reaction mixture was stirred at room temperature until reaction was complete then solvent was removed in vacuo. The crude mixture was purified by MDAP using a high pH method to afford E14 (21 mg), 1H NMR (d6-DMSO) δ 11.70 (1H, brs), 9.30 (1H, s), 9.15 (2H, s), 8.65 (1H, d), 8.17 (1H, s), 7.17 (1H, d), 6.60 (1H, d), 4.65 (2H, dt), 4.15 (1H, m), 3.25 (2H, dt), 1.90 (2H, m), 1.55 (2H, m), MS(ES+) 324 [M+H]+.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[S:11][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH:18][CH:19]3[CH2:24][C:23]([CH3:26])([CH3:25])[NH:22][C:21]([CH3:28])([CH3:27])[CH2:20]3)[N:13]=2)=[CH:9][CH:8]=1.[O-]O.S(=O)(O)[O-:32].[Na+].[OH-].[Na+]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH3:1][S:2]([CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[S:11][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH:18][CH:19]3[CH2:24][C:23]([CH3:26])([CH3:25])[NH:22][C:21]([CH3:28])([CH3:27])[CH2:20]3)[N:13]=2)=[CH:9][CH:8]=1)=[O:32]
Reactant: O=S([O-])O
Reactant: CSCCCCc1ccc(-c2ccnc(NC3CC(C)(C)NC(C)(C)C3)n2)s1
Agent: [Na+]
Agent: [O-]O
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)CCCCc1ccc(-c2ccnc(NC3CC(C)(C)NC(C)(C)C3)n2)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Compound of Step C (650 mg, 1.55 mmol) was dissolved in 5 ml TFA and 3 ml DCM. At room temperature 79 mg (2.3 mmol) hydroperoxide 30% were added. This mixture was stirred at room temperature for 2 hours. Afterwards 10 ml 10% sodium bisulfite solution was added and stirring continued for 15 minutes. The solution was basified with 40% NaOH and extracted with EtOAc. The crude was purified by chromatography on silicagel (DCM/MeOH/ammonia:9/1/0.1). Yield: 0.35 g (50%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].Cl[C:9]1[N:14]=[N:13][C:12]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([F:31])=[C:20]([CH:30]=2)[C:21]([N:23]2[CH2:29][CH2:28][CH2:27][NH2+:26][CH2:25][CH2:24]2)=[O:22])=[C:11]([CH2:32][CH3:33])[CH:10]=1.CC([O-])=[O:36].[Na+]>CC(O)=O>[F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[CH2:32]([C:11]1[C:12]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([F:31])=[C:20]([CH:30]=2)[C:21]([N:23]2[CH2:29][CH2:28][CH2:27][NH2+:26][CH2:25][CH2:24]2)=[O:22])=[N:13][NH:14][C:9](=[O:36])[CH:10]=1)[CH3:33]
Reactant: CC(=O)[O-]
Reactant: CCc1cc(Cl)nnc1Cc1ccc(F)c(C(=O)N2CCC[NH2+]CC2)c1
Agent: O=C([O-])C(F)(F)F
Agent: [Na+]
Solvent: CC(=O)O
Product: CCc1cc(=O)[nH]nc1Cc1ccc(F)c(C(=O)N2CCC[NH2+]CC2)c1
Temperature: 25 °C

Procedure:
A mixture of B2, NaOAc (2 eq) and AcOH (0.16 M) was heated at reflux for 4 h. The reaction mixture was cooled down to RT and concentrated under reduced pressure. The crude was purified by preparative RP-HPLC, using H2O (0.1% TFA) and MeCN (0.1% TFA) as eluents (column: Water X-Terra C18). The pooled product fractions were lyophilized to give the title compound. 1H NMR (600 MHz, DMSO-d6) δ: 12.80 (1H, m), 8.84 (2H, s), 7.38-7.28 (3H, m), 6.66 (1H, s), 4.01 (2H, s), 3.85-3.7 (2H, m), 3.55 (1H, m), 3.36-3.32 (2H, m), 3.27 (1H, m), 3.20 (1H, m), 3.16 (1H, m), 2.45-2.42 (2H, m), 2.06 (1H, m), 1.90 (1H, m), 1.11-1.07 (3H, m). MS (ES) C19H23FN4O2 required: 358. found: 359 (M+H)+.