Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:7]=[C:8]([CH:20]([CH3:22])[CH3:21])[C:9]=1[NH:10][C:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([I:18])[CH:13]=1)([CH3:3])[CH3:2].CO[CH:31](OC)[CH2:32][NH2:33].C(C1C=C(C2C=CC=CC=2)C=C(C(C)C)C=1N1C=CN=C1C1C=CC=C(OC)C=1)(C)C>>[CH:1]([C:4]1[CH:5]=[C:6]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:7]=[C:8]([CH:20]([CH3:22])[CH3:21])[C:9]=1[N:10]1[CH:31]=[CH:32][N:33]=[C:11]1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([I:18])[CH:13]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cc(-c2ccccc2)cc(C(C)C)c1NC(=O)c1cccc(I)c1
Reactant: COC(CN)OC
Agent: COc1cccc(-c2nccn2-c2c(C(C)C)cc(-c3ccccc3)cc2C(C)C)c1
Product: CC(C)c1cc(-c2ccccc2)cc(C(C)C)c1-n1ccnc1-c1cccc(I)c1

Procedure:
The title compound was prepared from N-(3,5-diisopropyl-[1,1′-biphenyl]-4-yl)-3-iodobenzamide and 2,2-dimethoxyethanamine in substantially the same manner, as described in Synthesis of 1-(3,5-diisopropyl-[1,1′-biphenyl]-4-yl)-2-(3-methoxyphenyl)-1H-imidazole.
Reaction SMILES: [I-:1].[Na+].[OH-].[Na+].[Br:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12].[O-]Cl.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+].Cl>CO>[Br:5][C:6]1[CH:11]=[C:10]([I:1])[CH:9]=[CH:8][C:7]=1[OH:12]
Reactant: [I-]
Reactant: Oc1ccccc1Br
Agent: Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CO
Product: Oc1ccc(I)cc1Br
Temperature: 5 °C
Reaction time: 1 h
Yield: 52.1 %

Procedure:
Sodium iodide (14.2 g) and sodium hydroxide (3.8 g) were added to a solution of 2-bromophenol (XIX, 16.4 g) in methanol (250 mL). The resultant solution was chilled to 0° C. A commercial bleach solution (6% NaClO, 120 mL) was added drop wise at 0-3° C. over 2 h. After the addition, the reaction mixture was stirred for 1 h at 5° C., then treated with 10% sodium thiosulfate aqueous solution (100 mL) and acidified with concentrated HCl to pH 5-7. The mixture was extracted with EtOAc (150 mL×3). The combined organic layers were partitioned with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The resultant oil was purified by silica gel column chromatography; the product eluted with dichloromethane/hexane (2:3), to afford the desired product as a colorless solid (14.76 g, 52%).
Reaction SMILES: N[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5](O)=[CH:4][C:3]=1Cl.CN1CCN(C)C1=O.C(=O)([O-])[O-].[K+].[K+].C(N(CCCC)C1C=C(O)C=CC=1)CCC>O>[CH:9]1[C:8]2[C:7](=[O:17])[C:6]3[C:15](=[CH:2][CH:3]=[CH:4][CH:5]=3)[C:14](=[O:16])[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: Nc1c(Cl)cc(O)c2c1C(=O)c1ccccc1C2=O
Agent: CCCCN(CCCC)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCN(C)C1=O
Product: O=C1c2ccccc2C(=O)c2ccccc21
Temperature: 140 °C
Reaction time: 3 h

Procedure:
One part by weight of 1-amino-2-chloro-4-hydroxyanthraquinone, 10 parts by weight of 1,3-dimethyl-2-imidazolidinone, 1.0 part by weight of potassium carbonate and 1.0 part by weight of N,N-di-n-butyl-m-aminophenol were mixed at room temperature, and then heated to 140° C. While this temperature was maintained, the reaction was conducted for 3 hours. The reaction mixture was then cooled to room temperature, charged into 90 parts by weight of water, and extracted with toluene. After the solution was separated, toluene was distilled off under reduced pressure, and the residue was purified through silica gel column chromatography to obtain an anthraquinone compound as coloring matter No. 9 (yield 90%) in Table 1.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]#[N:21])=[C:7]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH:18]=O)[CH:17]=3)[N:8]2[CH3:11])=[CH:4][CH:3]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]#[N:21])=[C:7]([C:12]3[CH:17]=[C:16]([CH2:18][NH:32][S:29]([C:26]4[CH:25]=[CH:24][C:23]([F:22])=[CH:28][CH:27]=4)(=[O:31])=[O:30])[CH:15]=[N:14][CH:13]=3)[N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)c1ccc(F)cc1
Reactant: Cn1c(-c2cncc(C=O)c2)c(C#N)c2ccc(Cl)cc21
Product: Cn1c(-c2cncc(CNS(=O)(=O)c3ccc(F)cc3)c2)c(C#N)c2ccc(Cl)cc21

Procedure:
6-Chloro-2-(5-formyl-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile (Example 126) and 4-fluoro-benzenesulfonamide are processed according to the method described in Example 170 to give N-[5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-4-fluoro-benzenesulfonamide. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.74 (s, 3H), 4.23 (s, 2H), 7.33-7.41 (m, 3H), 7.72 (d, J=8.6 Hz, 1H), 7.82-7.88 (m, 2H), 7.95 (d, J=1.5 Hz, 2H), 8.44 (s, 1H), 8.62 (d, J=2.0 Hz, 1H), 8.73 (d, J=2.0 Hz, 1H). HRMS (ESI) m/z 455.0746 [(M+H)+ Calcd for C22H17ClFN4O2S: 455.0745].
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:39])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]([CH2:28][CH:29]=[C:30]([F:38])[C:31]([F:37])([F:36])[C:32]([F:35])([F:34])[F:33])[CH3:27].[BH4-].[Na+].[Cl-].[Na+]>CO>[F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C@@H:16]2[OH:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:39])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]([CH2:28][CH:29]=[C:30]([F:38])[C:31]([F:36])([F:37])[C:32]([F:33])([F:34])[F:35])[CH3:27]
Reactant: CN(CC=C(F)C(F)(F)C(F)(F)F)CCCCC[C@@H]1Cc2cc(O)ccc2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CN(CC=C(F)C(F)(F)C(F)(F)F)CCCCC[C@@H]1Cc2cc(O)ccc2[C@@H]2[C@@H]1[C@@H]1CC[C@H](O)[C@@]1(C)C[C@@H]2F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 12.9 %

Procedure:
1.86 g of 11β-fluoro-7α-{5-[(3,4,4,5,5,5-hexafluoro-pent-2-enyl)methylamino]pentyl}-3-hydroxyestra-1,3,5(10)-trien-17-one are dissolved in 15 ml of methanol and cautiously treated with 222 mg of sodium borohydride. After stirring at room temperature for 15 minutes, the mixture is added to saturated sodium chloride solution, extracted with methylene chloride, dried over magnesium sulphate and concentrated in vacuo. After chromatographing the crude product on silica gel using a hexane-ethyl acetate and an ethyl acetate-acetone gradient, 241 mg of 11β-fluoro-7α-{5-[(3,4,4,5,5,5-hexafluoropent-2-enyl)methyl-amino]pentyl}oestra-1,3,5(10)-triene-3,17β-diol of melting point 122° C. are obtained, [α]D=+47° (c=0.5 in CHCl3)
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[C@H:9]1[CH2:14][N:15]1[C:23]2[CH:22]=[CH:21][C:20]([C:24]#[N:25])=[CH:19][C:18]=2[C:17]2[CH2:26][C@H:27]([NH:29][C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31])[CH2:28][C:16]1=2)=O)(C)(C)C.Cl.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(O)C.O1CCOCC1.ClCCl>[CH:33]([O:32][C:30](=[O:31])[NH:29][C@@H:27]1[CH2:28][C:16]2[N:15]([CH2:14][C@@H:9]3[C@@H:10]([OH:13])[CH2:11][CH2:12][N:8]3[CH3:6])[C:23]3[CH:22]=[CH:21][C:20]([C:24]#[N:25])=[CH:19][C:18]=3[C:17]=2[CH2:26]1)([CH3:35])[CH3:34]
Reactant: CC(C)OC(=O)N[C@H]1Cc2c(n(C[C@@H]3[C@@H](O)CCN3C(=O)OC(C)(C)C)c3ccc(C#N)cc23)C1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCO
Product: CC(C)OC(=O)N[C@H]1Cc2c(n(C[C@@H]3[C@@H](O)CCN3C)c3ccc(C#N)cc23)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.9 %

Procedure:
A solution of (2R,3S)-2-((S)-7-cyano-2-isopropoxycarbonylamino-2,3-dihydro-1H-cyclopenta[b]indol-4-ylmethyl)-3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (3.10 g, 6.42 mmol) in ethanol (20 mL) is treated with 4 N hydrogen chloride in 1,4-dioxane (20 mL) and stirred at room temperature for 3 h. The resulted solution is concentrated in vacuo and suspended in ethyl acetate (200 mL) and treated with 2 N aqueous sodium hydroxide (70 mL). The organic layer is washed with brine, dried over sodium sulfate, and concentrated. The resulting residue is dissolved in chloroform (100 mL) and treated with formaldehyde (1.45 mL, 19.27 mmol) and sodium triacetoxyborohydride (4.25 g, 19.27 mmol). The resulting suspension is stirred overnight at room temperature. The suspension is treated with saturated sodium bicarbonate solution (40 mL) and stirred for 30 min. The resulting suspension is diluted with dichloromethane (100 mL) and washed with water (3×100 mL) and brine. The organic portion is dried over sodium sulfate, filtered, and concentrated to dryness. The resulting residue is purified by medium pressure liquid chromatography, eluting with methanol:chloroform (5:95). Fractions containing pure product are combined and concentrated to afford 1.6 g (63%) of the title compound. LC-ES/MS m/z 397.2 [M+H]+, TR=1.78 min.
Reaction SMILES: [O:1]=[C:2]1O[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:5][C:4]2[S:13][C:14]([CH2:16][CH2:17][CH3:18])=[CH:15][C:3]1=2.C([O-])(=O)C.[NH4+:23]>C(O)(=O)C>[O:1]=[C:2]1[NH:23][C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:5][C:4]2[S:13][C:14]([CH2:16][CH2:17][CH3:18])=[CH:15][C:3]1=2
Reactant: [NH4+]
Reactant: CCCc1cc2c(=O)oc(C(=O)OCC)nc2s1
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: CCCc1cc2c(=O)[nH]c(C(=O)OCC)nc2s1

Procedure:
The product of Procedure 85 is converted to the desired product by treatment with ethanolic ammonium acetate according to the method of Procedure 5 except that acetic acid is omitted. The product is recrystallized from ethanol, m.p. 169°-170° C.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[C:8]([NH:12]C(=O)C2C=C(C)C=NC=2)[CH:9]=[CH:10][CH:11]=1.[F:22][C:23]1[CH:24]=[CH:25][C:26]([C:29](Cl)=[O:30])=[N:27][CH:28]=1>>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[C:8]([NH:12][C:29]([C:26]2[CH:25]=[CH:24][C:23]([F:22])=[CH:28][N:27]=2)=[O:30])[CH:9]=[CH:10][CH:11]=1
Reactant: Cc1cncc(C(=O)Nc2cccc(C3OCCO3)c2)c1
Reactant: O=C(Cl)c1ccc(F)cn1
Product: O=C(Nc1cccc(C2OCCO2)c1)c1ccc(F)cn1

Procedure:
The subtitle compound is prepared according to the reaction 4.01a described above using 5-fluoropicolinoyl chloride: LC-MS A: tR=0.89 min; [M+H]+=289.29.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=2)[N:5]=[C:4](O)[CH:3]=1.O=P(Cl)(Cl)[Cl:21]>>[Cl:21][C:4]1[CH:3]=[C:2]([CH3:1])[N:7]=[C:6](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=2)[N:5]=1
Reactant: CSc1ccc(/C=C/c2nc(C)cc(O)n2)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: CSc1ccc(/C=C/c2nc(C)cc(Cl)n2)cc1
Yield: 92.9 %

Procedure:
In analogy to example 12c), by heating (E)-6-methyl-2-[2-(4-methylsulfanyl-phenyl)-vinyl]-pyrimidin-4-ol (2 g, 7.74 mmol) in POCl3 (14 ml, 0.15 mol) at 130° C. for 4.5 h there was obtained (E)-4-chloro-6-methyl-2-[2-(4-methylsulfanyl-phenyl)-vinyl]-pyrimidine (1.99 g, 93%) as an off-white solid. EI mass spectrum, m/e: 276.1 (M calculated for C14H13ClN2S: 276).
Reaction SMILES: [CH2:1]([Sn:5]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:20][CH2:21][CH2:22][CH3:23])[C:6]1[CH:7]=[C:8]([NH:12][C:13](=[O:19])/[CH:14]=[CH:15]\[C:16](O)=[O:17])[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4].C([O-])(=O)C.[Na+]>C(OC(=O)C)(=O)C>[CH2:1]([Sn:5]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:24][CH2:25][CH2:26][CH3:27])[C:6]1[CH:7]=[C:8]([N:12]2[C:16](=[O:17])[CH:15]=[CH:14][C:13]2=[O:19])[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(NC(=O)/C=C\C(=O)O)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CCCC[Sn](CCCC)(CCCC)c1cccc(N2C(=O)C=CC2=O)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78 %

Procedure:
N-(m tri-n butylstannylphenyl)maleamic acid prepared as described above (0.40 g, 0.83 mmol) was placed in acetic anhydride (6 mL). Sodium acetate (0.43 g) was added and the solution stirred for 15 minutes at room temperature. After the reaction became homogeneous, the reaction mixture was stirred for 3 hours at 120° C. The filtrate obtained from this brown mixture was evaporated to dryness under reduced pressure and the residue was dissolved in ethyl ether. The ether mixture was filtered and the filtrate was again evaporated to dryness The compound was obtained by flash chromatography on a 30×200 mm column of Kieselgel 60, 230-400 mesh, eluted with ethyl acetate/hexane (1:5) (100 mL) to yield ten fractions. Fractions 6-9 were combined to give the desired product as an orange oil (0.3, 78%): TLC (EtOAc/hexane, 1:5) Rf 0.30; 1H NMR (CDCl3), δ); 7.3-7.5 (multiplets, 4H, 4 aryl CH); 6.8 (singlet, 2H, 2 CHC=O); 0.9-1.6 (multiplets, 27H, 3×n-C4H9).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9](I)[O:10][C:3]=12.[C-:12]#[N:13].[K+]>CN(C=O)C.C(Cl)Cl.[Cu]I.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>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:12]#[N:13])[O:10][C:3]=12
Reactant: Clc1ccnc2cc(I)oc12
Reactant: [C-]#N
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#Cc1cc2nccc(Cl)c2o1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
In a sealed tube 7-chloro-2-iodofuro[3,2-b]pyridine (0.200 g, 0.72 mmol), KCN (0.093 g, 1.4 mmol), and copper (I) iodide (0.014 g, 0.072 mmol) were dissolved in 2 mL DMF. Pd(Ph3P)4(0.041 g, 0.036 mmol) was added, the tube was flushed with nitrogen, and the reaction in the tube was stirred overnight at 100° C. The reaction was cooled to RT, diluted with DCM, and washed with water. The aqueous layer was extracted with DCM, and the combined organic layers were washed with brine, dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (gradient elution 0-50% EtOAc:Hex) to afford 7-chlorofuro[3,2-b]pyridine-2-carbonitrile as a white solid. MS: M+H+=179.4.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][S:14]([CH2:17][C:18](NC1N=NN(CCCCCCCCCCCC)N=1)=[O:19])(=[O:16])=[O:15])([CH3:3])[CH3:2].[CH2:38]([OH:52])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51]>>[CH2:38]([O:52][C:18](=[O:19])[CH2:17][S:14](=[O:16])(=[O:15])[NH:13][C:5]1[C:6]([CH:10]([CH3:11])[CH3:12])=[CH:7][CH:8]=[CH:9][C:4]=1[CH:1]([CH3:3])[CH3:2])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51]
Reactant: CCCCCCCCCCCCCCO
Reactant: CCCCCCCCCCCCn1nnc(NC(=O)CS(=O)(=O)Nc2c(C(C)C)cccc2C(C)C)n1
Product: CCCCCCCCCCCCCCOC(=O)CS(=O)(=O)Nc1c(C(C)C)cccc1C(C)C

Procedure:
This compound was prepared in the same manner as for the title compound of Example 2, except that 2-DAT was replaced with tetradecanol, mp 53°-55° C.
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:11]=[CH:10][N:9]([CH3:12])[C:8](=[O:13])[CH:7]=1)=[O:5].[CH2:15]1COC[CH2:16]1>>[CH3:12][N:9]1[CH:10]=[CH:11][C:6]([C:4](=[O:5])[CH2:15][CH3:16])=[CH:7][C:8]1=[O:13]
Reactant: CON(C)C(=O)c1ccn(C)c(=O)c1
Reactant: C1CCOC1
Product: CCC(=O)c1ccn(C)c(=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
To a solution of N-methoxy-N,1-dimethyl-2-oxo-1,2-dihydropyridine-4-carboxamide (200 mg, 1.0 eq) in 10 mL anhydrous THF was added 3 M EtBrMg (0.7 mL, 2 eq) slowly at 0° C. The reaction was stirred at rt for 1 h., quenched with sat NH4Cl (aq), and extracted with CH2Cl2. The extract was dried, concentrated, and purified by column chromatography to give the desired product (105 mg, 62% yield). 1H NMR (400 MHz, CDCl3) δ 7.35 (d, J=6.8 Hz, 1H), 7.06 (d, J=2.0 Hz, 1H), 6.61 (dd, J=6.8 Hz, 1.6 Hz, 1H), 3.57 (s, 3H), 2.89 (q, J=7.2 Hz, 2H), 1.20 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]([S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:15])=[N:10][CH:9]=1)([CH3:6])[C:3]([OH:5])=[O:4].[F:32]C1C=C(CCBr)C=CC=1.C(OC(=O)C(SC1SC(N)=NC=1)(C)C)C>>[F:32][C:21]1[CH:20]=[C:19]([CH2:18][CH2:17][N:16]([C@H:25]2[CH2:26][CH2:27][C@H:28]([CH3:31])[CH2:29][CH2:30]2)[C:14](=[O:15])[NH:13][C:11]2[S:12][C:8]([S:7][C:2]([CH3:1])([CH3:6])[C:3]([OH:5])=[O:4])=[CH:9][N:10]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(Sc1cnc(NC(=O)N(CCc2ccccc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Reactant: Fc1cccc(CCBr)c1
Agent: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Product: CC(C)(Sc1cnc(NC(=O)N(CCc2cccc(F)c2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 2-methyl-2-{2-[3-(trans-4-methyl-cyclohexyl)-3-phenethyl-ureido]-thiazol-5-ylsulfanyl}-propionic acid using 2-(3-fluorophenyl)ethylbromide and 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:7].C([Li])(C)(C)C.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH3:29])([CH3:28])[CH2:21][C:22](=[O:27])[C:23]([F:26])([F:25])[F:24])=[CH:16][CH:15]=1>C1COCC1>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH3:29])([CH3:28])[CH2:21][C:22]([CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)([OH:27])[C:23]([F:25])([F:26])[F:24])=[CH:16][CH:15]=1
Reactant: CC(C)(CC(=O)C(F)(F)F)c1ccc(Cl)cc1
Reactant: Cc1ccccn1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(CC(O)(Cc1ccccn1)C(F)(F)F)c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A mixture of 2-picoline in 1 mL of THF was cooled down to −78° C. tert-Butyl lithium (1.7 M in pentanes, 0.2 mL (0.34 mmol)) was added dropwise over 5 minutes. The mixture stirred at −78° C. for 15 minutes, and then a solution of 40 mg of 4-(4-chlorophenyl)-1,1,1-trifluoro-4-methylpentan-2-one in 0.5 mL of THF was added. Stirring continued at −78° C. for 20 minutes. The reaction was quenched with 0.5 N HCl and extracted three times with EtOAc. The organic layers were combined and washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography to yield 9.6 mg of the title compound as a light yellowish oil.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[C:19]([F:26])[C:18]=1[F:27])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[N:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=2)=[C:19]([F:26])[C:18]=1[F:27])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: OB(O)c1ccc(OCc2ccccc2)c(F)c1F
Reactant: Brc1cnc(Br)nc1
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: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: Fc1c(OCc2ccccc2)ccc(-c2ncc(Br)cn2)c1F
Yield: 26.5 %

Procedure:
A reaction of 14 mmol of 2,5-dibromopyrimidine, 17 mmol of 4-benzyloxy-2,3-difluorophenylboronic acid, 34 mmol of sodium carbonate and 0.14 mmol of tetrakis(triphenylphosphine)palladium(0) in 100 ml of toluene, 50 ml of ethanol and 50 ml of water is carried out analogously to the procedure indicated for precursor 3. Purification by recrystallization from 2-propanol gives 1.4 g (26%) of a colorless solid, m.p. 138° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:9])[CH:8]=1)[NH2:5].C([Li])CCC.C[Si](Cl)(C)C.[S:20]1[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]1.Cl>O1CCCC1.C(OCC)C>[NH2:5][C:4]1[CH:3]=[C:2]([F:1])[C:8]([C:23]2([OH:26])[CH2:24][CH2:25][S:20][CH2:21][CH2:22]2)=[C:7]([F:9])[CH:6]=1
Reactant: O=C1CCSCC1
Reactant: Nc1cc(F)cc(F)c1
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: Nc1cc(F)c(C2(O)CCSCC2)c(F)c1
Reaction time: 0.5 h

Procedure:
3,5-Difluoroaniline (12.9 g, 0.1 M) in dry tetrahydrofuran (400 ml) was stirred and cooled under nitrogen to −78°. n-Butyllithium (1.6M in hexanes, 131 ml, 0.21 M) was run in slowly over 15 minutes, maintaining the temperature below −65°. Stirring was continued at the same temperature for 30 minutes, then trimethylsilyl chloride (22.8 g, 0.21 M) in tetrahydrofuran (100 ml) was added dropwise over 15 minutes. The temperature was then allowed to rise to ambient, and the mixture stirred overnight. After recooling to −78°, further n-butyllithium (1.6M in hexanes, 68.8 ml, 0.11 M) was added dropwise below −70°, and stirring continued for 5 hours to form anion. A solution of tetrahydrothiopyran-4-one (12.5 g, 0.107 M) in tetrahydrofuran (80 ml) was added dropwise, keeping the temperature below −70°, and the temperature allowed to warm to ambient overnight. The mixture was cooled in an ice-bath and acidified to pH<1 by slow addition of hydrochloric acid (1M, ˜500 ml). After stirring 15 minutes, diethyl ether (1 L) was added, and the phases separated. The organic layer was washed with hydrochloric acid (1M, 200 ml), and the combined aqueous layers made basic with concentrated ammonia solution, then extracted with diethyl ether (600 ml). The extract was washed with water (100 ml), brine (100 ml), dried (magnesium sulfate) and evaporated. After dissolving the residue in dichloromethane, the desired product was precipitated by the addition of isohexane (17.4 g). MS (Negative ES): 244 (M—H—) for C11H13F2NOS
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1.Cl[C:18]1[N:19]=[N:20][C:21]([N:24]2[CH:28]=[C:27]([CH3:29])[N:26]=[CH:25]2)=[CH:22][CH:23]=1.CCN(C(C)C)C(C)C.O>CS(C)=O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[CH:11]2[CH2:16][CH2:15][N:14]([C:18]3[N:19]=[N:20][C:21]([N:24]4[CH:28]=[C:27]([CH3:29])[N:26]=[CH:25]4)=[CH:22][CH:23]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc2c(c1)N(C1CCNCC1)CC2
Reactant: Cc1cn(-c2ccc(Cl)nn2)cn1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cn(-c2ccc(N3CCC(N4CCc5ccc(F)cc54)CC3)nn2)cn1
Temperature: 180 °C

Procedure:
To a mixture of 6-fluoro-1-(piperidin-4-yl)indoline (128 mg, 0.5 mmol), 3-chloro-6-(4-methylimidazol-1-yl)pyridazine (78 mg, 0.4 mmol) in DMSO (1.5 mL) was added DIPEA (0.25 mL, 1.5 mmol). The resulting mixture was sealed and heated at 180° C. for 1.5 h under microwave irradiation. The resulting mixture was then poured into H2O (30 mL) and the aqueous layer was extracted with 10% CH2Cl2/Et2O (80 mL×4). The combined organic layer was dried (Na2SO4) and filtered. The solvent was removed and the resulting residue was purified by column (dry loading) using EtOAc then 3% MeOH/EtOAc as the eluent to yield 6-fluoro-1-(1-(6-(4-methyl-1H-imidazol-1-yl)pyridazin-3-yl)piperidin-4-yl)indoline.
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH2:23]([O:27][C:28]1[CH:34]=[CH:33][C:31](O)=[CH:30][CH:29]=1)[CH2:24][CH2:25][CH3:26]>O1CCCC1.C(N(CC)CC)C>[CH2:23]([O:27][C:28]1[CH:34]=[CH:33][C:31]([O:19][C:18](=[O:20])[C:17]2[CH:16]=[CH:15][C:14]([O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][O:6][C:1](=[O:5])[C:2]([CH3:4])=[CH2:3])=[CH:22][CH:21]=2)=[CH:30][CH:29]=1)[CH2:24][CH2:25][CH3:26]
Reactant: C=C(C)C(=O)OCCCCCCOc1ccc(C(=O)O)cc1
Reactant: CCCCOc1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=C(C)C(=O)OCCCCCCOc1ccc(C(=O)Oc2ccc(OCCCC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
6.1 g of 4-(6-methacryloyloxyhexyloxy)benzoic acid were converted to the acid chloride in a manner similar to example 6. This substance was taken up in 100 ml of tetrahydrofuran (THF) and added dropwise at 0° to 5° C. to a stirred solution of 3.3 g of hydroquinone monobutyl ether in 100 ml of THF and 4 ml of triethylamine. The mixture was stirred for a further 3 hours at room temperature and the triethylamine hydrochloride was then filtered out. The filtrate was evaporated to dryness and the residue dissolved in 50 ml of dichloromethane. The solution was washed several times with water, dried with sodium sulphate and the solvent then distilled off. The crude product so obtained was purified by column chromatography and recrystallisation from n-hexane.