Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])([CH3:7])[C@H:2]([C:4]([OH:6])=O)[CH3:3].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH2:49]([O:56][C:57]([C@@H:59]1[CH2:63][C@H:62]([NH:64][C:65]([O:67][CH2:68][CH:69]2[C:81]3[CH:80]=[CH:79][CH:78]=[CH:77][C:76]=3[C:75]3[C:70]2=[CH:71][CH:72]=[CH:73][CH:74]=3)=[O:66])[CH2:61][N:60]1[C:82](=[O:91])[C@@H:83]([NH2:90])[CH:84]1[CH2:89][CH2:88][CH2:87][CH2:86][CH2:85]1)=[O:58])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>CN(C=O)C>[CH2:49]([O:56][C:57]([C@@H:59]1[CH2:63][C@H:62]([NH:64][C:65]([O:67][CH2:68][CH:69]2[C:81]3[CH:80]=[CH:79][CH:78]=[CH:77][C:76]=3[C:75]3[C:70]2=[CH:71][CH:72]=[CH:73][CH:74]=3)=[O:66])[CH2:61][N:60]1[C:82](=[O:91])[C@@H:83]([NH:90][C:4](=[O:6])[C@@H:2]([N:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH3:7])[CH3:3])[CH:84]1[CH2:89][CH2:88][CH2:87][CH2:86][CH2:85]1)=[O:58])[C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1
Reactant: N[C@H](C(=O)N1C[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C[C@H]1C(=O)OCc1ccccc1)C1CCCCC1
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](C(=O)N[C@H](C(=O)N1C[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C[C@H]1C(=O)OCc1ccccc1)C1CCCCC1)N(C)C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
To a solution of Boc-N-Me-Ala-OH (351 mg, 1.73 mmol) in DMF at 0° C. was added DIPEA (1.27 mL, 8.85 mmol) and HATU (626 mg, 1.65 mmol). After 30 min, (2S,4S)-1-((S)-2-amino-2-cyclohexyl-acetyl)-4-(9H-fluoren-9-ylmethoxycarbonylamino)-pyrrolidine-2-carboxylic acid benzyl ester hydrochloride (0.97 g, 1.57 mmol) was added, the cooling bath removed and the reaction stirred for 1 h. The mixture was diluted with ethyl acetate, washed with saturated ammonium chloride solution, saturated sodium bicarbonate solution, water, and brine and dried over anhydrous magnesium sulfate. Concentration gave (2S,4S)-1-{(S)-2-[(S)-2-(tert-butoxycarbonyl-methyl-amino)-propionylamino]-2-cyclohexyl-acetyl}-4-(9H-fluoren-9-ylmethoxycarbonylamino)-pyrrolidine-2-carboxylic acid benzyl ester (1.2 g) as an oil that was used without further purification or characterization.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[C:10]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:11][CH:12]=[CH:13][CH:14]=1.[CH3:21][S:22]([C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[C:28]([OH:30])=O)(=[O:24])=[O:23].[NH4+].[Cl-]>C(Cl)Cl>[CH3:21][S:22]([C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[C:28]([N:2]([CH3:1])[C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[C:10]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:11][CH:12]=[CH:13][CH:14]=1)=[O:30])(=[O:23])=[O:24]
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Reactant: CNc1cnccc1-c1cccnc1OCC(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: CN(C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1)c1cnccc1-c1cccnc1OCC(F)(F)F

Procedure:
The title compound was prepared in analogy to example 90, from methyl-[2-(2,2,2-trifluoro-ethoxy)-[3,4]bipyridinyl-3′-yl]-amine and 3-(methylsulfonyl)-5-(trifluoromethyl)-benzoic acid (example 114, intermediate a) after a reaction time of 18 hours. The reaction mixture was poured on saturated aqueous NH4Cl solution and CH2Cl2 and the layers were separated. The aqueous layer was extracted three times with CH2Cl2. The organic layers were dried over MgSO4, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 20 g column using an MPLC (ISCO) system eluting with EtOAc (isocratic). Further purification by preparative HPLC (Gemini NX column) using a gradient of MeOH:water (containing 0.1% formic acid) (20:80 to 98:2). Colorless foam (41%). MS (ESI): m/z=534.09 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC(=O)[NH:14][CH:15]([C:26]([N:28]1[CH2:31][C:30]([O:39][CH2:40][CH2:41][CH2:42][CH3:43])([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[CH3:38])[CH2:29]1)=[O:27])[CH:16]([OH:25])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)(C)(C)C>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:14][CH:15]([CH:16]([OH:25])[C:17]1[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=1)[C:26]([N:28]1[CH2:31][C:30]([O:39][CH2:40][CH2:41][CH2:42][CH3:43])([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[CH3:38])[CH2:29]1)=[O:27]
Reactant: CCCCOC1(c2ccccc2C)CN(C(=O)C(NC(=O)OC(C)(C)C)C(O)c2ccc(OC)cc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCOC1(c2ccccc2C)CN(C(=O)C(N)C(O)c2ccc(OC)cc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10 ml of trifluoroacetic acid are added to a solution containing 1.4 g (2.8 mmol) of tert-butyl[1-(3-butoxy-3-o-tolylazetidine-1-carbonyl)-2-hydroxy-2-(4-methoxy-phenyl)ethyl]carbamate in 20 ml of dichloromethane. After stirring for 1 hour at ambient temperature, the reaction medium is concentrated. 1.5 g of 2-amino-1-(3-butoxy-3-o-tolylazetidin-1-yl)-3-hydroxy-3-(4-methoxy-phenyl)propan-1-one trifluoroacetate are obtained in the form of a beige powder with a quantitative yield.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[C:5]1[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]Br)[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][C:6]=1[O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]Br)[CH3:2].[C:33]([O-:36])(=[O:35])[CH3:34].[K+]>[Cl-].C[N+](CCCCCCCC)(CCCCCCCC)CCCCCCCC.C(#N)C>[CH2:1]([O:3][C:4](=[O:32])[C:5]1[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:35][C:33](=[O:36])[CH3:34])[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][C:6]=1[O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][O:32][C:4](=[O:3])[CH3:5])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: CCOC(=O)c1cc(OCCCCCCBr)c(C(=O)OCC)cc1OCCCCCCBr
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cc(OCCCCCCOC(C)=O)c(C(=O)OCC)cc1OCCCCCCOC(C)=O

Procedure:
50.0 g (86.0 mmol) diethyl-2,5-bis-(6-bromohexoxy)terephthalate, 84.5 g (861 mmol) potassium acetate and 4.4 g (11 mmol) methyl trioctyl ammonium chloride (Aliquat 336®, tricaprylyl methyl ammonium chloride, Fluka, CAS 5137.55.3) in 500 ml absolute acetonitrile are heated under reflux in a nitrogen atmosphere for 48 hours. After distilling off the solvent, the reaction mixture is taken up in 1200 ml ethyl acetate and washed three times with water (3×300 ml). The organic phase is dried over MgSO4 and the solvent is then distilled off. 1000 ml petroleum ether is added to the residual, oily residue and the product crystallizing out after 16 hours at -20° C. is recrystallized from petroleum ether/ethyl acetate.
Reaction SMILES: [NH2:1][C:2]1[N:23]=[C:22](Cl)[CH:21]=[CH:20][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[S:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1)=[O:5].C1C=CC(CC(NC[NH:36][C@H:37]([C:48](O)=[O:49])CC2C=CC([N+]([O-])=O)=CC=2)=O)=CC=1.C(CN)O>CS(C)=O.C(N(C(C)C)CC)(C)C.[Cl-].[Na+].O>[NH2:1][C:2]1[N:23]=[C:22]([NH:36][CH2:37][CH2:48][OH:49])[CH:21]=[CH:20][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[S:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1)=[O:5]
Reactant: O=C(Cc1ccccc1)NCN[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Reactant: Nc1nc(Cl)ccc1C(=O)NCc1ccc(Oc2ccccc2)s1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: NCCO
Product: Nc1nc(NCCO)ccc1C(=O)NCc1ccc(Oc2ccccc2)s1
Temperature: 135 °C
Yield: 76 %

Procedure:
2-Amino-6-chloro-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide described in Example A-101 (170 mg, 0.47 mmol) was dissolved in a mixture solution of dimethylsulfoxide (2 mL) and diisopropylethylamine (1 mL), ethanolamine (0.428 mL, 7.1 mmol) was added thereto, followed by heating in a sealed tube for 15 hours 20 minutes (oil bath temperature: 135° C.). The reaction mixture was allowed to room temperature, poured into brine, and the solution was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, then concentrated, the obtained residue was purified by NH silica gel column chromatography (ethyl acetate:hexane=2:1), and the title compound (138 mg, 0.36 mmol, 76%) was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[N:15]1([CH2:20][C:21](O)=O)[CH:19]=[CH:18][N:17]=[CH:16]1.P(Cl)(Cl)(Cl)=O.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[N:15]1([CH2:20][C:21]2[N:8]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:3]3=[N:4][CH:5]=[CH:6][CH:7]=[C:2]3[N:1]=2)[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: O=C(O)Cn1ccnc1
Reactant: Nc1cccnc1Nc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: c1ccc(-n2c(Cn3ccnc3)nc3cccnc32)cc1
Yield: 26.9 %

Procedure:
To a solution of 3-amino-2-anilinopyridine (2.0 g) and 2-(imidazol-1-yl)acetic acid (1.56 g) in pyridine (20 ml) was dropwise added phosphorus oxychloride (1.91 g) and the mixture was refluxed for 30 minutes. The reaction mixture was poured into saturated aqueous sodium bicarbonate and extracted three times with ethyl acetate. The combined extract was washed with saturated aqueous sodium chloride and dried over magnesium sulfate. The solvent was removed under reduced pressure to give a residue, which was subjected to column chromatography on silica gel (20 g) eluting with a mixture of dichloromethane and ethanol. The fractions containing the desired compound were combined and evaporated in vacuo. The resultant crystal was recrystallized from a mixture of ethyl acetate and n-hexane to give 2-(imidazol-1-yl)methyl-3-phenyl-3H-imidazo[4,5-b]pyridine (0.8 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]1.Cl.[NH2:15][OH:16]>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][C:10](=[N:15][OH:16])[CH2:9][CH2:8]1
Reactant: NO
Reactant: O=C1CCN(CCCCCO)CC1
Agent: Cl
Product: OCCCCCN1CCC(=NO)CC1

Procedure:
1-(5-Hydroxypentyl)-4-piperidone oxime is prepared from 1-(5-hydroxypentyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: [C:1]([CH2:3][C@H:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C@@H:5]1[NH:10]C(=O)OC(C)(C)C)#[N:2]>CO.Cl.O1CCOCC1>[NH2:10][C@H:5]1[CH2:6][CH2:7][CH2:8][CH2:9][C@@H:4]1[CH2:3][C:1]#[N:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@@H]1CC#N
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: N#CC[C@H]1CCCC[C@@H]1N

Procedure:
A solution tert-butyl N-[(1S,2R)-2-(cyanomethyl)cyclohexyl]carbamate (2 g) in MeOH (40 mL) and 4 M HCl in dioxane (20 mL) was stirred at room temperature for 2 hours and concentrated in vacuo to provide the title compound as a yellow oil, which was used for the subsequent step without further purification.
Reaction SMILES: [C:1](O)(=O)C.[CH3:5][C:6]1[C:21]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])=[C:9]2[NH:10][C:11]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=[CH:12][C:13](=[O:14])[N:8]2[N:7]=1.C[Si](C=[N+]=[N-])(C)C>ClCCl.CO>[CH3:1][N:7]1[N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]3[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=3)[N:10]=[C:9]2[C:21]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])=[C:6]1[CH3:5]
Reactant: Cc1ccccc1Cc1c(C)nn2c(=O)cc(-c3ccncc3)[nH]c12
Reactant: CC(=O)O
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClCCl
Solvent: CO
Product: Cc1ccccc1Cc1c(C)n(C)n2c(=O)cc(-c3ccncc3)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.5 %

Procedure:
To a solution of 2-methyl-3-(2-methylbenzyl)-5-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one acetate (500 mg, 1.281 mmol) in dichloromethane/methanol (30 mL/15 mL) was added trimethylsilyldiazomethane (1.3 mL, 2.561 mmol). The mixture was stirred at room temperature for 16 h. Then the mixture was concentrated under reduced pressure. The residue was purified by a silica gel chromatography to give the titled compound (223 mg, 51%); LC/MS: MS (ES+) m/e 345 (MH+); 1H NMR (300 MHz, CDCl3) δ ppm 2.27 (s, 3H), 2.42 (s, 3H), 4.04 (s, 2H), 4.24 (s, 3H), 6.51 (s, 1H), 7.10-7.20 (m, 4H), 7.88 (d, J=5.7 Hz, 2H), 8.70 (d, J=5.7 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].I[CH:12]([CH3:14])[CH3:13].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH:12]([CH3:14])[CH3:13])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(Cl)cc1C=O
Yield: 78.8 %

Procedure:
5-Chloro-2-hydroxy-benzaldehyde (3 g, 19.16 mmol),2-Iodo-propane (4.88 g, 28.74 mmol) and K2CO3 (4 g, 28.74 mmol) was mixed in anhydrous DMF. The reaction tube was placed into the cavity of a focused monomode microwave reactor and the contents of the flask were irradiated for 30 min at 100° C. Then the solution was filtered and the filtration was concentrated to obtain the crude product (3 g). The crude product was used into next step reaction without further purification.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9]C)=O)[CH2:3][CH2:2]1.CC(C)C(=O)[CH2:14][C:15]#[N:16]>>[O:9]=[C:7]([CH:4]1[CH2:3][CH2:2][O:1][CH2:6][CH2:5]1)[CH2:14][C:15]#[N:16]
Reactant: COC(=O)C1CCOCC1
Reactant: CC(C)C(=O)CC#N
Product: N#CCC(=O)C1CCOCC1
Yield: 24 %

Procedure:
Prepared from methyl tetrahydropyran-4-carboxylate (3 g, 20.80 mmol) according to the method described for 4-methyl-3-oxopentanenitrile in Example 122A Step 1, to afford 3-oxo-3-(tetrahydro-2H-pyran-4-yl)propanenitrile as a yellow oil (760 mg, 24%) which was used in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 3.96-4.05 (m, 2H), 3.52 (s, 1H), 3.42-3.50 (m, 2H), 2.82 and 2.59 (2×m, 1H), 1.67-1.90 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]3[C:10]([CH2:11][N:12]([CH3:14])[CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[C@H:15]1[CH2:20][CH2:19][C@H:18]([O:21][CH:22]([CH3:25])[CH2:23]O)[CH2:17][CH2:16]1.COCCN(S(F)(F)[F:38])CCOC>ClCCl>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]3[C:10]([CH2:11][N:12]([CH3:14])[CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[C@H:15]1[CH2:20][CH2:19][C@H:18]([O:21][CH:22]([CH3:25])[CH2:23][F:38])[CH2:17][CH2:16]1
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: CC(CO)O[C@H]1CC[C@H](c2nnc3n2-c2ccc(Cl)cc2CN(C)C3)CC1
Solvent: ClCCl
Product: CC(CF)O[C@H]1CC[C@H](c2nnc3n2-c2ccc(Cl)cc2CN(C)C3)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (RS)-trans-2-[4-(8-chloro-5-methyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulen-1-yl)-cyclohexyloxy]-propan-1-ol (0.055 g, 0.14 mmol) in dichloromethane (2 ml) was added [bis(2-methoxyethyl)-amino]sulfur trifluoride (0.031 ml, 0.17 mmol) at 0-5° C. Stirring at room temperature for 18 h was followed by addition of further [bis(2-methoxyethyl)-amino]sulfur trifluoride (0.016 ml, 0.08 mmol) and stirring for 4 h. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate solution (30 ml) and ethyl acetate (30 ml). The layers were separated and the aqueous layer was extracted with two 30-ml portions of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. Flash-chromatography with n-heptane/2-propanol as eluent gave the title compound (0.020 g, 36%) as white solid. MS m/e: 393 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C:16]1[CH:17]=[N:18][C:19]([N:22]2[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]2)=[CH:20][CH:21]=1.[Cl:29][C:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[C:32]([F:45])[C:31]=1[OH:46]>>[Cl:29][C:30]1[CH:35]=[C:34]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C:16]2[CH:17]=[N:18][C:19]([N:22]3[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH2:27]3)=[CH:20][CH:21]=2)[CH:33]=[C:32]([F:45])[C:31]=1[OH:46]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(N2CCN(C)CC2)nc1
Product: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1Nc1ccc(N2CCN(C)CC2)nc1
Yield: 31.5 %

Procedure:
Following general procedure D, [1-(6-bromo-4-(6-(4-methylpiperazin-1-yl)pyridin-3-ylamino)quinolin-3-yl)ethanone (50 mg, 0.113 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (34 mg, 0.124 mmol) to afford the desired product (18 mg, 31%) as a yellow-orange solid: 1H NMR (500 MHz, CD3OD) δ 9.08 (s, 1H), 8.07 (d, J=3 Hz, 1H), 7.91 (s, 2H), 7.82 (s, 1H), 7.49 (dd, J=12, 2.0 Hz, 1H), 7.00-6.92 (m, 3H), 3.66 (t, J=10 Hz, 4H), 2.77 (s, 3H), 2.62 (t, J=10 Hz, 4H), 2.39 (s, 3H); ESI MS m/z 506, [C27H25ClFN5O2+H]+; HPLC 98.9% (AUC), tR=14.39 min.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:31]=[CH:30][C:9]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][C:18]4[NH:17][C:16]5[CH:21]([CH2:24][C:25]([O:27]CC)=[O:26])[CH2:22][CH2:23][C:15]=5[C:14]=4[CH:13]=3)=[CH:8][C:7]=2[C:32]([F:35])([F:34])[F:33])[CH2:3][CH2:2]1.[Li+].[OH-]>O1CCOCC1.CCOC(C)=O>[CH:1]1([CH2:4][O:5][C:6]2[CH:31]=[CH:30][C:9]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][C:18]4[NH:17][C:16]5[CH:21]([CH2:24][C:25]([OH:27])=[O:26])[CH2:22][CH2:23][C:15]=5[C:14]=4[CH:13]=3)=[CH:8][C:7]=2[C:32]([F:35])([F:33])[F:34])[CH2:3][CH2:2]1
Reactant: CCOC(=O)CC1CCc2c1[nH]c1ccc(OCc3ccc(OCC4CC4)c(C(F)(F)F)c3)cc21
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=C(O)CC1CCc2c1[nH]c1ccc(OCc3ccc(OCC4CC4)c(C(F)(F)F)c3)cc21
Reaction time: 3 h

Procedure:
To a solution of ethyl 2-(7-(4-(cyclopropylmethoxy)-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (22.9 mg, 0.047 mmol) in dioxane was added 1M LiOH (0.188 mL, 0.188 mmol). The reaction mixture was stirred 3 h, taken up in EtOAc and washed with 1 M HCl. The EtOAc extract was dried over MgSO4 and concentrated. The residue was purified by preparative HPLC/MS to give the title compound as a solid. LCMS m/z=460.3 [M±H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.30-0.38 (m, 2H), 0.52-0.59 (m, 2H), 1.17-1.27 (m, 1H), 2.03-2.13 (m, 1H), 2.35 (dd, J=15.98, 8.91 Hz, 1H), 2.59-2.76 (m, 4H), 3.99 (d, J=6.69 Hz, 2H), 5.05 (s, 2H), 6.69 (dd, J=8.84, 2.40 Hz, 1H), 6.91 (d, J=2.53 Hz, 1H), 7.19 (d, J=8.72 Hz, 1H), 7.24 (d, J=8.46 Hz, 1H), 7.62-7.71 (m, 2H), 10.45 (s, 1H).
Reaction SMILES: FCC1[N:4]=[N:5][N:6]([CH2:8][N:9]2[C:19]3[C:14](=[CH:15][C:16]([S:20]([N:23]4[CH2:27][CH2:26][CH2:25][C@H:24]4[CH2:28][O:29][C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=4[F:37])(=[O:22])=[O:21])=[CH:17][CH:18]=3)[C:12](=[O:13])[C:10]2=[O:11])C=1.[F:38][CH2:39][CH2:40][CH2:41][C:42]#[CH:43].FCC#C>>[F:38][CH2:39][CH2:40][CH2:41][C:42]1[N:4]=[N:5][N:6]([CH2:8][N:9]2[C:19]3[C:14](=[CH:15][C:16]([S:20]([N:23]4[CH2:27][CH2:26][CH2:25][C@H:24]4[CH2:28][O:29][C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=4[F:37])(=[O:22])=[O:21])=[CH:17][CH:18]=3)[C:12](=[O:13])[C:10]2=[O:11])[CH:43]=1
Reactant: C#CCCCF
Reactant: O=C1C(=O)N(Cn2cc(CF)nn2)c2ccc(S(=O)(=O)N3CCC[C@H]3COc3ccc(F)cc3F)cc21
Agent: C#CCF
Product: O=C1C(=O)N(Cn2cc(CCCF)nn2)c2ccc(S(=O)(=O)N3CCC[C@H]3COc3ccc(F)cc3F)cc21

Procedure:
is prepared according for the procedure for compound 6, with the exception that 5-fluoropent-1-yne is used in place of the (3-fluoroprop-1-yne). For the preparation of [18F]8, 5-[18F]fluoropent-1-yne is used in place of 3-fluoroprop-1-yne.
Reaction SMILES: [OH-].[K+].SCC(O)=O.[CH2:8]([N:15]([CH2:28][CH2:29][C:30]1[N:31]([C@@H:36]2[CH2:45][C:44]3[C:39](=[C:40]([F:47])[CH:41]=[C:42]([F:46])[CH:43]=3)[O:38][CH2:37]2)[C:32](=[S:35])[NH:33][CH:34]=1)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CO>O.CS(C)=O>[CH2:8]([NH:15][CH2:28][CH2:29][C:30]1[N:31]([C@@H:36]2[CH2:45][C:44]3[C:39](=[C:40]([F:47])[CH:41]=[C:42]([F:46])[CH:43]=3)[O:38][CH2:37]2)[C:32](=[S:35])[NH:33][CH:34]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)N(CCc1c[nH]c(=S)n1[C@H]1COc2c(F)cc(F)cc2C1)Cc1ccccc1
Agent: O=C(O)CS
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CS(C)=O
Solvent: O
Product: Fc1cc(F)c2c(c1)C[C@@H](n1c(CCNCc3ccccc3)c[nH]c1=S)CO2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 96 %

Procedure:
To a solution of potassium hydroxide (5M aqueous solution, 52.5 ml, 263 mmol) in water at 10° C. was added dropwise 2-mercaptoacetic acid (8.30 ml, 119 mmol). The resulting solution was stirred at room temperature for 10 minutes and a solution of (R)—N-benzyl-N-(2-(3-(6,8-difluorochroman-3-yl)-2-thioxo-2,3-dihydro-1H-imidazol-4-yl)ethyl)-2-nitrobenzenesulfonamide (28 g, 47.7 mmol) in DMSO (150 ml) was added dropwise over 20 minutes. During the addition of KOH, an exothermic event was observed. The resulting slurry was stirred at 40° C. under HPLC control for 3 h. The reaction was then cooled to 20° C. and methanol (105 ml) was added followed by water (45 ml). The resulting slurry was aged for 30 minutes at 20° C. and then filtered. The beige solid was successively washed with water/MeOH (9:1) (100 ml), water (200 ml) and finally methyl tert-butyl ether (MTBE) (50 ml), dried to give (R)-5-(2-(benzylamino)ethyl)-1-(6,8-difluorochroman-3-yl)-1H-imidazole-2(3H)-thione (compound RY′, 18.3 g, 12.35 mmol, 96% yield).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:12][CH:11]=2)[C:5]([C:21]#[N:22])=[C:4]([SH:23])[N:3]=1.C(=O)(O)[O-].[Na+].Cl[CH2:30][C:31]1[N:32]=[C:33]([NH2:36])[S:34][CH:35]=1.O>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:14][CH:15]=2)[C:5]([C:21]#[N:22])=[C:4]([S:23][CH2:30][C:31]2[N:32]=[C:33]([NH2:36])[S:34][CH:35]=2)[N:3]=1
Reactant: COCCOc1ccc(-c2c(C#N)c(N)nc(S)c2C#N)cc1
Reactant: Nc1nc(CCl)cs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1ccc(-c2c(C#N)c(N)nc(SCc3csc(N)n3)c2C#N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 mg (0.31 mmol) of 2-amino-4-[4-(2-methoxyethoxy)phenyl]-6-sulphanyl-pyridine-3,5-dicarbonitrile are dissolved in 1 ml of DMF. 103 mg (1.23 mmol) of sodium bicarbonate and 68.3 mg (0.46 mmol) of 4-chloromethyl-2-amino-1,3-thiazole are then added. The suspension is shaken at RT overnight, and water is added. The precipitate is filtered off with suction, washed with ethanol and diethyl ether and dried at 40° C. under reduced pressure. This gives 115.9 mg (86.2% of theory) of product.
Reaction SMILES: [C:1]12([CH2:11][CH2:12][C:13]3[NH:17][C:16]([CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[N:15][C:14]=3[C:24](O)=[O:25])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C[O:28][C:29](=[O:38])[C:30]1[CH:35]=[C:34]([NH2:36])[CH:33]=[CH:32][C:31]=1[F:37]>>[C:1]12([CH2:11][CH2:12][C:13]3[NH:17][C:16]([CH:18]4[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]4)=[N:15][C:14]=3[C:24]([NH:36][C:34]3[CH:33]=[CH:32][C:31]([F:37])=[C:30]([CH:35]=3)[C:29]([OH:38])=[O:28])=[O:25])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C(O)c1nc(C2CCCCC2)[nH]c1CCC12CC3CC(CC(C3)C1)C2
Reactant: COC(=O)c1cc(N)ccc1F
Product: O=C(O)c1cc(NC(=O)c2nc(C3CCCCC3)[nH]c2CCC23CC4CC(CC(C4)C2)C3)ccc1F

Procedure:
5-(2-Adamantan-1-yl-ethyl)-2-cyclohexyl-1H-imidazole-4-carboxylic acid (Example 252) was reacted with 5-amino-2-fluoro-benzoic acid methyl ester according to the procedure of Example 20, step d. The methyl ester was hydrolysed using the same procedure as in Example 36, step d to afford the title compound. 1H NMR (300 MHz, d6-DMSO) 10.79 (1H, br s), 8.32 (1H, dd), 7.97 (1H, m), 7.32 (1H, m), 2.91 (3H, m), 1.98-1.34 (27H, m). The acid was converted to the N-methyl-D-glucamine salt and lyophilised from water/dioxan. Found: C, 56.04; H, 8.48; N, 7.28%. C36H53FN4O8.4.5 mols H2O requires: C, 56.16; H, 8.12; N, 7.28%.