Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH2:19][CH2:20][O:21][CH3:22].[N:23]1([C:29](Cl)=[O:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH2:19][CH2:20][O:21][CH3:22])[N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:29]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[O:30])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCN
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCNC(=O)N1CCOCC1
Yield: 77.4 %

Procedure:
Using the general method of Example 143, 1-(3-aminopropyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.50 g, 5.01 mmol) was reacted with 4-morpholinecarbonyl chloride (830 mg, 5.51 mmol) to provide 1.6 g of N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}morpholine-4-carboxamide as a white powder, m.p. 194-196° C. Analysis: Calculated for C21H28N6O3: %C, 61.15; %H, 6.84; %N, 20.37; Found: %C, 60.82; %H, 6.94; %N, 20.34.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]#[N:9])[CH:2]=1.[NH2:10][C:11]1[N:16]=[C:15]([NH2:17])[C:14]([CH:18]=O)=[CH:13][N:12]=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:8]([NH2:9])=[N:17][C:15]3[N:16]=[C:11]([NH2:10])[N:12]=[CH:13][C:14]=3[CH:18]=2)[CH:2]=1
Reactant: N#CCc1cccnc1
Reactant: Nc1ncc(C=O)c(N)n1
Product: Nc1ncc2cc(-c3cccnc3)c(N)nc2n1

Procedure:
The procedure of Example 1 was followed to react 3-pyridylacetonitrile and 2,4-diamino-5-pyrimidine-carboxaldehyde to afford the title compound; mp 317°-319° C. (dec).
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])[NH:8][N:7]=[CH:6]2.C1(C(N)C2CCCCC2)CCCCC1.[CH3:28][Si:29]([CH2:32][CH2:33][O:34][CH2:35]Cl)([CH3:31])[CH3:30].CCOC(C)=O>C1COCC1>[CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][C:9]2[C:5](=[CH:6][N:7]([CH2:35][O:34][CH2:33][CH2:32][Si:29]([CH3:31])([CH3:30])[CH3:28])[N:8]=2)[CH:4]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: COc1cc2cn[nH]c2cc1OC
Agent: NC(C1CCCCC1)C1CCCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc2cn(COCC[Si](C)(C)C)nc2cc1OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The title compound was prepared in a similar manner as described by G. Luo et al., J. Org. Chem. 2006, 71, 5392-5395: To a solution of 5,6-dimethoxyindazole [7746-30-7] (356 mg, 2.00 mmol) in THF (20 mL) was added dicyclohexylmethylamine (0.51 mL, 2.40 mmol) followed by SEM-Cl (0.43 mL, 2.40 mmol). The mixture was stirred at RT for 24 h, followed by dilution with EtOAc and quench with 1N aqueous NaOH solution. The layers were separated and the organic layer was washed with water and brine, then dried (Phase separator) and evaporated. The residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc 4:1 to 1:1) to separate from the regioisomer 5,6-dimethoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole and to provide the title compound. TLC, Rf (c-hexane/EtOAc 1:1)=0.37; MS (LC/MS): 309 [M+H; tR (HPLC conditions k): 3.70 min.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([CH2:9][S:10]([CH3:13])(=[O:12])=[O:11])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:14]1([C:2]2[CH:8]=[C:7]([CH2:9][S:10]([CH3:13])(=[O:12])=[O:11])[CH:6]=[CH:5][C:3]=2[NH2:4])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OB(O)c1ccccc1
Reactant: CS(=O)(=O)Cc1ccc(N)c(Br)c1
Product: CS(=O)(=O)Cc1ccc(N)c(-c2ccccc2)c1

Procedure:
2-bromo-4-(methylsulfonylmethyl)aniline and benzene boronic acid can be combined to form 2-phenyl-4-(methylsulfonylmethyl)aniline,
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17].[CH2:19]([O:21][C:22]([CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[O:23])[CH3:20].N1C=CC=CC=1>O1CCOCC1>[CH2:19]([O:21][C:22]([CH:24]1[CH2:29][CH2:28][N:27]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=3)=[CH:4][C:3]=2[N+:16]([O-:18])=[O:17])[CH2:26][CH2:25]1)=[O:23])[CH3:20]
Reactant: CC1CC(=O)NN=C1c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CCOC(=O)C1CCNCC1
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: CCOC(=O)C1CCN(c2ccc(C3=NNC(=O)CC3C)cc2[N+](=O)[O-])CC1
Temperature: 0 °C

Procedure:
2.68 g (10 mmol) of 6-(4-chloro-3-nitro-phenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone are boiled under reflux with 3.14 g (20 mmol) of piperidine-4-carboxylic acid ethyl ester and 0.81 ml (10 mmol) of pyridine in 50 ml of dioxane for 5 hours. The reaction mixture is then poured out on 200 ml of ice water and suction filtered to separate the solid, and the filter cake is then washed with water.
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])/[CH:9]=[C:10](\[CH3:14])/[C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1.C(N(CC)CC)C.[H][H]>C(OC(C)C)(=O)C.[Pd]>[C:1]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:9][C@H:10]([CH3:14])[C:11]([OH:13])=[O:12])=[CH:5][CH:6]=1
Reactant: C/C(=C\[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)C
Product: C[C@@H](C[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O

Procedure:
To a suspension of (E)-(S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpent-2-enoic acid 3(ii-b) (10 g, 26.2 mmol) and triethylamine (3.6 ml, 26.2 mmol) in isopropyl acetate is added palladium on carbon (1 g, 10% loading). Hydrogen atmosphere is then applied for 5 h. Upon filtering off the catalyst, the solvent is removed in vacuo to give the title compound {3(i-d): 3(i-c) 80:20 ratio; 3(i-d): 3(i-c) 99.9:0.1 ratio upon recrystallization; as determined by HPLC analysis}.
Reaction SMILES: [OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:3]([CH3:14])[O:4][C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1.Br[C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[C:26]([CH3:32])[CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:3]([CH3:14])[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[C:26]([CH3:32])[CH:25]=2)=[CH:7][CH:6]=1
Reactant: Cc1cc(Br)ccc1C#N
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@H](O)CCc1cccnc1
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
Product: Cc1cc(-c2ccc(O[C@@H](C)[C@H](O)CCc3cccnc3)cc2)ccc1C#N
Temperature: 90 °C
Yield: 59.3 %

Procedure:
Prepared according to the method described in Example 12b) from (1S,2R)-4-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy)benzeneboronic acid (0.150 g, Example 33), 4-bromo-2-methylbenzonitrile (0.301 g), 2M aqueous sodium carbonate (0.50 ml) and tetrakis(triphenylphosphine)palladium (0) (0.025 g) in ethanol (3 ml). The reaction mixture was heated at 90° C. for 4 hours. After cooling, the solution was concentrated under reduced pressure, taken up in ethanol and concentrated again (twice). The residue was triturated with acetone and then filtered through silica gel. The filtrate was concentrated under reduced pressure, dissolved in dichloromethane, filtered and purified by normal-phase HPLC eluting with a gradient of 0-25% ethanol in dichloromethane to give an oil which crystallised under high vacuum over 24 hours. Trituration with diethyl ether resulted in isolation of the title compound as a solid (0.11 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[CH2:17][CH2:18][CH2:19][N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1.CN(C=O)C.C([O-])([O-])=O.[K+].[K+]>Cl.CC(OC)(C)C>[N:20]1([CH2:19][CH2:18][CH2:17][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3([C:14]#[N:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: N#CC1(c2ccc(O)cc2)CCOCC1
Reactant: ClCCCN1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: N#CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Yield: 51.6 %

Procedure:
4-(4-Hydroxy-phenyl)-tetrahydro-pyran-4-carbonitrile (2 g, 9.86 mmol), 1-(3-chloro-propyl)-pyrrolidine (2.33 g, 15.78 mmol), DMF (40 ml) and K2CO3 (5.45 g, 39.44 mmol) were reacted together according to general procedure E. The crude reaction product was diluted with 2M HCl solution (200 ml) and washed with ethyl acetate (3×50 ml). The aqueous phase was basified to pH 14 with 2M NaOH (200 ml) and extracted with ethyl acetate (4×50 ml). The combined organic extracts were dried over MgSO4, filtered, washed with ethyl acetate and concentrated in vacuo to give a white solid. The solid was slurried in TBME (15 ml) and heptane (15 ml), filtered, washed with heptane (8 ml) and dried on the filter for 2 hours to give the title compound as a white solid (1.6 g, 53%). 1H NMR (400 MHz, DMSO-d6) δ7.43 (d, 2H), 6.99 (d, 2H), 4.08-3.94 (m, 4H), 3.64 (dt, 2H), 2.57-2.47 (m, 2H), 2.46-2.36 (m, 4H), 2.12-1.94 (m, 4H), 1.87 (p, 2H), 1.73-1.62 (m, 4H).
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)CCC2C=CC=CC=2)=[O:15])=[N:10][CH:9]=1)([CH3:6])[C:3]([OH:5])=[O:4].Br[CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[C:37]([O:43][CH3:44])[CH:36]=1.C(OC(=O)C(SC1SC(N)=NC=1)(C)C)C>>[CH3:44][O:43][C:37]1[CH:36]=[C:35]([CH2:34][CH2:33][N:16]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:14](=[O:15])[NH:13][C:11]2[S:12][C:8]([S:7][C:2]([CH3:6])([CH3:1])[C:3]([OH:5])=[O:4])=[CH:9][N:10]=2)[CH:40]=[CH:39][C:38]=1[O:41][CH3:42]
Reactant: CC(C)(Sc1cnc(NC(=O)N(CCc2ccccc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Reactant: COc1ccc(CCBr)cc1OC
Agent: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Product: COc1ccc(CCN(C(=O)Nc2ncc(SC(C)(C)C(=O)O)s2)[C@H]2CC[C@H](C)CC2)cc1OC

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 1-(2-bromo-ethyl)-3,4-dimethoxy-benzene and 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[CH3:14][S:15]SC>>[CH3:14][S:15][C:8]1[CH:9]=[CH:10][CH:11]=[C:3]([C:2]([F:12])([F:13])[F:1])[C:4]=1[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1ccccc1C(F)(F)F
Reactant: CSSC
Product: CSc1cccc(C(F)(F)F)c1C(=O)O

Procedure:
The title compound, white solid, MS: m/e=191.1 [(M−CO2H)−], was prepared in accordance with the general method of intermediate E from 2-(trifluoromethyl)benzoic acid and dimethyl disulfide.
Reaction SMILES: C([O:5][N:6]1[C:15](=[O:16])[C:14]2[CH:17]=[C:18]([N+:20]([O-:22])=[O:21])[CH:19]=[C:12]3[C:13]=2[C:8](=[CH:9][CH:10]=[C:11]3[N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:7]1=[O:28])(C)(C)C.C(O)(C(F)(F)F)=O>O>[OH:5][N:6]1[C:15](=[O:16])[C:14]2[CH:17]=[C:18]([N+:20]([O-:22])=[O:21])[CH:19]=[C:12]3[C:13]=2[C:8](=[CH:9][CH:10]=[C:11]3[N:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)[C:7]1=[O:28]
Reactant: CC(C)(C)ON1C(=O)c2ccc(N3CCCC3)c3cc([N+](=O)[O-])cc(c23)C1=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C1c2ccc(N3CCCC3)c3cc([N+](=O)[O-])cc(c23)C(=O)N1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.7 %

Procedure:
A mixture of 2-t-butyloxy-5-nitro-7-(pyrrolidin-1-yl)-benzo[de]isoquinoline-1,3-dione (0.09 g, 0.23 mmol, from Example D3-B) and TFA was stirred at room temperature for 4 hours and poured into water. The solid was filtered and washed with acetone to give (0.06 g, 80%) of the title compound, mp 290-291° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([NH:23][C:24]2[CH:25]=[C:26]([C:36]([F:39])([F:38])[F:37])[CH:27]=[C:28]([N:30]3[CH:34]=[N:33][C:32]([CH3:35])=[CH:31]3)[CH:29]=2)=[O:22])=[CH:6][C:7]=1[NH:8][C:9]1[N:10]=[CH:11][CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[N:19][CH:20]=2)[N:14]=1.[C:40]([OH:47])(=[O:46])/[CH:41]=[CH:42]\[C:43]([OH:45])=[O:44]>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([NH:23][C:24]2[CH:25]=[C:26]([C:36]([F:38])([F:39])[F:37])[CH:27]=[C:28]([N:30]3[CH:34]=[N:33][C:32]([CH3:35])=[CH:31]3)[CH:29]=2)=[O:22])=[CH:6][C:7]=1[NH:8][C:9]1[N:10]=[CH:11][CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[N:19][CH:20]=2)[N:14]=1.[C:40]([O-:47])(=[O:46])/[CH:41]=[CH:42]\[C:43]([O-:45])=[O:44]
Reactant: O=C(O)/C=C\C(=O)O
Agent: Cc1cn(-c2cc(NC(=O)c3ccc(C)c(Nc4nccc(-c5cccnc5)n4)c3)cc(C(F)(F)F)c2)cn1
Product: O=C([O-])/C=C\C(=O)[O-]
Temperature: 5 °C
Reaction time: 8 h

Procedure:
Nilotinib base (0.300 g, 0.57 mmol) was dissolved in TFE (2 mL) at 40° C. to obtain a mixture. The mixture was stirred and added to a solution of maleic acid (0.132 g, 1.13 mmol) in TFE (1 mL) at 40° C. The resulting solution was stirred for about 4 h and subsequently cooled to 5° C. The mixture was kept at 5° C. overnight and then a sample (1 mL) was taken from the mixture and evaporated to dryness under reduced pressure at 40° C. to give amorphous Nilotinib maleate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](/[C:8](=[CH:14]/[N:15](C)C)/[C:9]([O:11]CC)=O)[CH:5]=[N:6][CH:7]=1.[NH:18]([C:20]1[N:25]=[CH:24][C:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:22][CH:21]=1)N.C1(C)C=CC(S(O)(=O)=O)=CC=1.[ClH:44]>C(O)C.O1CCOCC1>[ClH:44].[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9](=[O:11])[N:18]([C:20]3[N:25]=[CH:24][C:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:22][CH:21]=3)[NH:15][CH:14]=2)[CH:5]=[N:6][CH:7]=1
Reactant: CCOC(=O)/C(=C\N(C)C)c1cncc(Br)c1
Reactant: CC(C)(C)OC(=O)c1ccc(NN)nc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: CC(C)(C)OC(=O)c1ccc(-n2[nH]cc(-c3cncc(Br)c3)c2=O)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
500 mg (1.7 mmol) of the compound from Example 9A and 350 mg (1.7 mmol) of the compound from Example 15A are dissolved in 2 ml of ethanol, and 58 mg (0.3 mmol) of p-toluenesulfonic acid are added. The mixture is heated under reflux for 24 h and then cooled to RT, and 0.5 ml of a 4 N solution of hydrogen chloride in dioxane is added. The mixture is stirred at RT for 30 min. The precipitate is filtered off, washed with ethanol and diethyl ether and dried under high vacuum.
Reaction SMILES: C(N(CC)CC)C.[OH:8][C:9]1[N:13]=[C:12]([O:14][CH2:15][CH3:16])[S:11][N:10]=1.[CH:17]([N:19]=[C:20]=[O:21])=[CH2:18]>C(OC(C)C)(C)C>[CH:17]([NH:19][C:20]([N:10]1[C:9](=[O:8])[N:13]=[C:12]([O:14][CH2:15][CH3:16])[S:11]1)=[O:21])=[CH2:18]
Reactant: CCOc1nc(O)ns1
Reactant: C=CN=C=O
Solvent: CC(C)OC(C)C
Solvent: CCN(CC)CC
Product: C=CNC(=O)n1sc(OCC)nc1=O
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 69.8 %

Procedure:
1 ml of triethylamine was added to a solution of 14.6 g of 3-hydroxy-5-ethoxy-1,2,4-thiadiazole in 250 ml of isopropyl ether and after 5 minutes, 8 g of vinyl isocyanate were added. The mixture was stirred for 30 minutes at 20° C and was vacuum filtered and the recovered precipitate was washed, dried and crystallized from ethyl acetate to obtain 15 g of 2-(N-vinylcarbamoyl)-5-ethoxy-1,2,4-thiadiazole-3-one melting at 123° C.
Reaction SMILES: F[CH2:2][C:3]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:7]=1.[F:38][CH2:39]CC#C.FCC#C>>[F:38][CH2:39][CH2:2][C:3]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:7]=1
Reactant: O=C1C(=O)N(Cn2cc(CF)nn2)c2ccc(S(=O)(=O)N3CCC[C@H]3COc3ccc(F)cc3F)cc21
Reactant: C#CCCF
Agent: C#CCF
Product: O=C1C(=O)N(Cn2cc(CCF)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 4-fluorobut-1-yne is used in place of the (3-fluoroprop-1-yne). For the preparation of [18F]7, 4-[18F]fluorobut-1-yne is used in place of 3-fluoroprop-1-yne.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:17])=O>>[F:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([Cl:17])=[O:5]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1F
Reactant: O=C(Cl)C(=O)Cl
Product: O=C(Cl)c1cc([N+](=O)[O-])ccc1F

Procedure:
Prepared by then method of Example 15a), from 2-fluoro-5-nitrobenzoic acid (2.0 g, 11.0 mmol) and oxalyl chloride (2.89 ml, 33.0 mmol) the subtitle compound was obtained. The product was used directly in the next step without purification.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:14][N:13]([CH2:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:17])[C:12](=[O:25])[CH2:11][N:10]([S:26]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)(=[O:28])=[O:27])[C:9]1=[O:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N[C:38]1C=CC=CC=1.CNC1C=CC=CC=1>>[CH2:1]([CH:8]1[CH2:14][N:13]([CH2:15][C:16]([N:18]([CH3:38])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:17])[C:12](=[O:25])[CH2:11][N:10]([S:26]([C:29]2[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=2)(=[O:28])=[O:27])[C:9]1=[O:36])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccccc1
Reactant: O=C(CN1CC(Cc2ccccc2)C(=O)N(S(=O)(=O)c2ccc(Cl)cc2)CC1=O)Nc1ccccc1
Solvent: CNc1ccccc1
Product: CN(C(=O)CN1CC(Cc2ccccc2)C(=O)N(S(=O)(=O)c2ccc(Cl)cc2)CC1=O)c1ccccc1

Procedure:
Instead of the starting material compound of Example 270, that is, aniline, N-methylaniline was used for the similar procedure as in Example 270 to obtain the title compound.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][CH:25]=[C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12].C1C(=O)N([Br:40])C(=O)C1>C(#N)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([Br:40])=[C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1csc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)n1
Solvent: CC#N
Product: CCOC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)sc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To compound 34A in acetonitrile was added 1.05 eq of NBS. The reaction mixture was stirred at rt for 2 hours. The solvent was removed, and the residue was purified by column chromatography on silica gel eluting with 3:2 hexanes/EtOAc to provide the desired product: MS (ESI(+)): 544 (M+H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH3:15])[CH2:10][CH:9]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:23][O:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH:9]1[CH2:10][CH:11]([O:14][CH3:15])[CH2:12][CH2:13][NH:8]1
Reactant: COc1ccccc1C1CC(OC)CCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccccc1C1CC(OC)CCN1
Temperature: 20 °C
Reaction time: 2 h
Yield: 95.6 %

Procedure:
To a solution of N-(tert-butoxycarbonyl)-2-(2-methoxyphenyl)-4-methoxypiperidine (864 mg, 2.67 mmol) in CH2Cl2 at 0° C. was added TFA (9.6 mL) and the resulting solution was stirred at 0-40° C. for 2 hours. TFA was removed in vacuo, and the residue was stirred with 40 mL of 1:1 mixture of CH2Cl2 and 1N NaOH for 20 minutes. The layers were separated and the aqueous layer was extracted with CH2Cl2 (3×15 ml). The combined organic layers were washed with brine, dried over MgSO4, and concentrated in vacuo to afford the title compound as a light brown oil (565 mg). 1H NMR (CDCl3, 400 MHz) δ: 3.82 (3H, s, OMe), 3.37 (3H, s, OMe).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([C:17]4([C:23](O)=[O:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)(=[O:16])=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:3][CH2:2]1.S(Cl)(Cl)=O.C[N:36](C)C=O>>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([C:17]4([C:23]([NH2:36])=[O:24])[CH2:18][CH2:19][O:20][CH2:21][CH2:22]4)(=[O:16])=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:26][C:27]([CH3:28])([CH3:29])[CH3:30])[CH2:3][CH2:2]1
Reactant: CC(C)(C)Cc1nc2cc(S(=O)(=O)C3(C(=O)O)CCOCC3)ccc2n1CC1CC1
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CC(C)(C)Cc1nc2cc(S(=O)(=O)C3(C(N)=O)CCOCC3)ccc2n1CC1CC1
Yield: 92 %

Procedure:
A mixture of 4-{[1-(cyclopropylmethyl)-2-(2,2-dimethylpropyl)-1H-benzimidazol-5-yl]sulfonyl}tetrahydro-2H-pyran-4-carboxylic acid (Step B, 288 mg, 0.66 mmol), thionyl chloride and N,N-dimethylformamide (few drops) was stirred under reflux for 3 h. After concentration, the residue was dissolved in dichloromethane (10 mL) and aqueous ammonia (1 mL) was added. The mixture was stirred at room temperature for 4 days. Water was added and the organic layer was separated. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by pTLC (hexane:ethyl acetate=1:10 as eluent) to give the title compound (264 mg, 92%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[C:11]3[CH:17]=[CH:16][NH:15][C:12]3=[N:13][CH:14]=2)[O:3]1.[H-].[Na+].Cl[CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27].Cl>O1CCCC1.O>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:18])([CH3:1])[O:3][B:4]([C:9]2[CH:10]=[C:11]3[CH:17]=[CH:16][N:15]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:12]3=[N:13][CH:14]=2)[O:5]1
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Reactant: C[Si](C)(C)CCOCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)OB(c2cnc3c(ccn3COCC[Si](C)(C)C)c2)OC1(C)C

Procedure:
5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (1.01 g) was dissolved in tetrahydrofuran (10 ml). After the atmosphere was replaced with nitrogen, the solution was ice-cooled. 55% Sodium hydride (216 mg) was added and the mixture was stirred under ice-cooling for 20 minutes. Then, [2-(chloromethoxy)ethyl](trimethyl)silane (875 μl) was added and the mixture was stirred at room temperature for 15.5 hours. The reaction solution was diluted by adding water thereto, neutralized with 1 N hydrochloric acid (0.85 ml) and extracted with ethyl acetate three times. The organic layer was washed with water once and then with brine and dried over anhydrous sodium sulfate, and the solvent was evaporated. The brown oil was purified by silica gel column chromatography (developed with ethyl acetate-hexane) to give the title compound (691 mg) as a colorless oil.
Reaction SMILES: [CH2:1]([NH:19][CH:20]1[O:28][C@H:27]([CH2:29][OH:30])[C@@H:25]([OH:26])[C@H:23]([OH:24])[C@H:21]1[OH:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH2:31]([N:43]=[C:44]=[O:45])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]>O1CCCC1.C(O)C>[CH2:1]([N:19]([CH:20]1[O:28][C@H:27]([CH2:29][OH:30])[C@@H:25]([OH:26])[C@H:23]([OH:24])[C@H:21]1[OH:22])[C:44]([NH:43][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[O:45])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCN=C=O
Reactant: CCCCCCCCCCCCCCCCCCNC1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCCN(C(=O)NCCCCCCCCCCCC)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O

Procedure:
9 g of the compound from Example 1 are suspended in 160 ml of tetrahydrofuran and 40 ml of ethanol. 4.3 g of dodecyl isocyanate, dissolved in 20 ml of tetrahydrofuran, are added dropwise to this suspension in the course of 20 minutes. When the reaction has ended, the mixture is evaporated in vacuo and the resulting syrup is purified by column chromatography (mobile phase methylene chloride/methanol, 15:1)