Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:41])[O:9][CH2:10][CH:11]([O:34][C:35]1[CH:39]=[C:38]([CH3:40])[O:37][N:36]=1)[CH2:12][O:13][C:14](=[O:33])[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].[S:42]1[CH:46]=[CH:45][N:44]=[CH:43]1>>[Br-:1].[CH2:16]([NH:15][C:14]([O:13][CH2:12][CH:11]([O:34][C:35]1[CH:39]=[C:38]([CH3:40])[O:37][N:36]=1)[CH2:10][O:9][C:8]([NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N+:44]1[CH:45]=[CH:46][S:42][CH:43]=1)=[O:41])=[O:33])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCCCCCCCCCCCNC(=O)OCC(COC(=O)NCCCCCBr)Oc1cc(C)on1
Reactant: c1cscn1
Product: CCCCCCCCCCCCCCCCCNC(=O)OCC(COC(=O)NCCCCC[n+]1ccsc1)Oc1cc(C)on1
Product: [Br-]

Procedure:
33(b) 0.388 g of the title compound was prepared, as a powder, by reacting 0.600 g of (2RS)-3-(N-heptadecylcarbamoyloxy)-2-(5-methyl-3-isoxazolyloxy)propyl N-(5-bromopentyl)carbamate [prepared as described in step (a) above] with 0.66 ml of thiazole by a similar procedure to that described in Example 25(b).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@H:3]([CH2:11][N:12]2[C:16]([CH2:17][C:18]3[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=3)=[CH:15][N:14]=[CH:13]2)[NH:2]1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH2:34][C:35](O)=[O:36])[CH:31]=[CH:32][CH:33]=1.ON1C2C=CC=CC=2N=N1.C(Cl)CCl.CN1CCOCC1>CN(C=O)C>[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH2:34][C:35]([N:2]2[C@H:3]([CH2:11][N:12]3[C:16]([CH2:17][C:18]4[CH:19]=[CH:20][C:21]([C:22]#[N:23])=[CH:24][CH:25]=4)=[CH:15][N:14]=[CH:13]3)[CH2:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:1]2)=[O:36])[CH:31]=[CH:32][CH:33]=1
Reactant: COc1cccc(CC(=O)O)c1
Reactant: N#Cc1ccc(Cc2cncn2C[C@@H]2Cc3ccccc3CN2)cc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: COc1cccc(CC(=O)N2Cc3ccccc3C[C@H]2Cn2cncc2Cc2ccc(C#N)cc2)c1

Procedure:
The same proceedure as described in step D of Example 8 above was used to mix 4-{3-[(S)-1,2,3,4-tetrahydro-isoquinolin-3-yl-methyl]-3H-imidazol-4-yl-methyl}-benzonitrile (0.16 g, 0.487 mmol), 3-methoxyphenylacetic acid (0.081 g, 0.487 mmol), 1-hydroxybenzotriazole (0.075 g, 0.487 mmol), EDC (0.093 g, 0.487 mmol) and N-methylmorpholine (0.2 ml, 1.95 mmol) in 5 ml DMF. The title compound was obtained.
Reaction SMILES: Br[CH:2]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=O.[C:22]([NH2:25])(=[S:24])[CH3:23].N1C=CC=CC=1>C(O)C>[F:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:25]=[C:22]([CH3:23])[S:24][C:2]=2[C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CC(N)=S
Reactant: CS(=O)(=O)c1ccc(C(Br)C(=O)c2ccc(F)cc2)cc1
Solvent: CCO
Solvent: c1ccncc1
Product: Cc1nc(-c2ccc(F)cc2)c(-c2ccc(S(C)(=O)=O)cc2)s1
Yield: 31.1 %

Procedure:
To 2-bromo- 1-(4-fluorophenyl)-2-(4-(methylsulfonyl)phenyl)ethanone (1.10 g) in ethanol (15.0 mL) were added thioacetamide (0.266 g) and pyridine (0.300 mL). After refluxing for 2 h, the reaction mixture was extracted with EtOAc, 25% NH4OAc and purified by flash chromatography (50% EtOAc in hexane then 90% Et2O in hexane) to yield the title compound (0.320 g).
Reaction SMILES: CC1N=C(N2C(=O)N(CC3C=CC(C(F)(F)F)=CC=3)N=C2)SC=1C(O)=O.[F:27][CH:28]([F:52])[O:29][C:30]1[CH:51]=[CH:50][C:33]([CH2:34][N:35]2[C:39](=[O:40])[N:38]([C:41]3[S:42][C:43]([C:47](O)=[O:48])=[C:44]([CH3:46])[N:45]=3)[CH:37]=[N:36]2)=[CH:32][CH:31]=1.[N:53]1[CH:58]=[CH:57][CH:56]=[C:55]([CH2:59][NH2:60])[CH:54]=1>>[F:52][CH:28]([F:27])[O:29][C:30]1[CH:31]=[CH:32][C:33]([CH2:34][N:35]2[C:39](=[O:40])[N:38]([C:41]3[S:42][C:43]([C:47]([NH:60][CH2:59][C:55]4[CH:54]=[N:53][CH:58]=[CH:57][CH:56]=4)=[O:48])=[C:44]([CH3:46])[N:45]=3)[CH:37]=[N:36]2)=[CH:50][CH:51]=1
Reactant: Cc1nc(-n2cnn(Cc3ccc(OC(F)F)cc3)c2=O)sc1C(=O)O
Reactant: NCc1cccnc1
Agent: Cc1nc(-n2cnn(Cc3ccc(C(F)(F)F)cc3)c2=O)sc1C(=O)O
Product: Cc1nc(-n2cnn(Cc3ccc(OC(F)F)cc3)c2=O)sc1C(=O)NCc1cccnc1
Yield: 49 %

Procedure:
Following the procedure as described in Example 21, making variations as required to replace 4-methyl-2-(5-oxo-1-(4-(trifluoromethyl)benzyl)-1H-1,2,4-triazol-4(5H)-yl)thiazole-5-carboxylic acid with 2-(1-(4-(difluoromethoxy)benzyl)-5-oxo-1,2,4-triazol-4(5H)-yl)-4-methylthiazole-5-carboxylic acid to react with pyridin-3-ylmethanamine, the title compound was obtained as a white solid in 49% yield: mp 151-152° C. (ethyl acetate/hexane); 1H NMR (300 MHz, CDCl3) δ 8.55 (br s, 2H), 8.23 (s, 1H), 7.72-7.63 (m, 1H), 7.43-7.30 (m, 2H), 7.29-7.20 (m, 1H), 7.12-7.00 (m, 2H), 6.78 (t, J=5.6 Hz, 1H), 6.46 (t, JH-F=73.8 Hz, 1H), 4.94 (s, 2H), 4.57 (d, J=5.6 Hz, 2H), 2.61 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 161.7, 153.4, 151.1, 150.9, 149.9, 149.2, 148.9, 135.8, 132.2, 130.0, 129.9, 121.7, 119.9, 119.2, 115.7, 112.3, 48.9, 41.6, 17.2; MS (ES+) m/z 473.3 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:44]=[CH:43][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29]([NH:31][CH2:32][CH2:33][CH2:34][NH:35]C(=O)OC(C)(C)C)=[O:30])[CH:25]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11].FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:35][CH2:34][CH2:33][CH2:32][NH:31][C:29]([C:26]1[CH:25]=[C:24]([C:20]2[CH:19]=[C:18]([O:17][C:16]3[CH:15]=[CH:14][C:13]([NH:12][C:10]([NH:9][C:3]4[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=4[F:1])=[O:11])=[CH:44][CH:43]=3)[CH:23]=[CH:22][N:21]=2)[NH:28][CH:27]=1)=[O:30]
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NCCCNC(=O)OC(C)(C)C)c[nH]4)c3)cc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NCCCN)c[nH]4)c3)cc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of tert-butyl (3-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}propyl)carbamate (70 mg, 0.12 mmol) in 10 ml of methylene chloride was added 1 ml of trifluoroacetic acid. The mixture was stirred at room temperature for 2 hours and evaporated to dryness under reduced pressure. The residue was re-dissolved in MeOH (5 ml) and poured into 100 ml of water with vigorous stirring. Saturated NaHCO3 solution was added until pH=8-9. The precipitates were filtered, washed with water and dried in vacuo to give N-(3-aminopropyl)-5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide as yellow solid. Yield: 40 mg, 63%.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH:22]=O)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[NH2:24][CH:25]1[CH2:30][CH2:29][CH:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:27][CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][NH:24][CH:25]2[CH2:30][CH2:29][CH:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:35])([CH3:37])[CH3:36])[CH2:27][CH2:26]2)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5]
Reactant: CC(C)(C)OC(=O)NC1CCC(N)CC1
Reactant: O=Cc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NC1CCC(NCc2ccc(Cl)c(C(=O)NCC34CC5CC(CC(C5)C3)C4)c2)CC1
Yield: 50.1 %

Procedure:
Prepared according to the method described in Example 31b from 2-chloro-5-formyl-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (0.30 g, Example 31a), (4-aminocyclohexyl)-carbamic acid, 1,1-dimethylethyl ester (0.194 g, Journal of Organic Chemistry, 1996, 61(25), 8811-8818), sodium triacetoxyborohydride (0.135 g) and 1,2-dichloroethane (10 ml). The residue was purified by chromatography over silica gel eluting with ethyl acetate: iso-hexane (1:1) then ethyl acetate: ethanol (95:5) to give the subtitle compound as a colourless oil (0.24 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[CH2:12][N:11]([CH3:13])[C:10](=[O:14])[CH2:9]2)=[CH:4][CH:3]=1.C1C(=O)N([Br:22])C(=O)C1.C(=O)(O)[O-].[Na+]>C(#N)C.CCOC(C)=O>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[CH2:12][N:11]([CH3:13])[C:10](=[O:14])[CH2:9]2)=[CH:4][C:3]=1[Br:22]
Reactant: O=C1CCC(=O)N1Br
Reactant: CN1CC(c2ccc(N)nc2)CC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CN1CC(c2cnc(N)c(Br)c2)CC1=O
Reaction time: 0.25 h

Procedure:
To 4-(6-aminopyridin-3-yl)-1-methylpyrrolidin-2-one (90 mg, 0.377 mmol) in Acetonitrile 3 mL) in ice bath was added NBS (60.3 mg, 0.339 mmol). The reaction mixture was stirred in ice bath for 15 min and room temperature for 30 min. LC-MS shows mixture of SM and product. Added 0.1 equiv. more of NBS and stirred another 1h at room temperature. Reaction mixture was diluted with EtOAc and added 2 mL of Satd sodium bicarbonate. Stirred 10 min. The organic layer was separated, dried over sodium sulfate, filtered and evaporated. Proceed for next step (73%). LCMS (m/z): 270.2/272.2 (MH+), 0.302 min.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:13]2[O:14][CH2:15][C:16]([CH3:19])([CH3:18])[N:17]=2)([CH3:12])[CH3:11])=[CH:6][CH:5]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:26]([O:28][CH2:29][CH2:30][N:31]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=[C:32]1[CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)[CH3:27]>CO>[CH3:18][C:16]1([CH3:19])[CH2:15][O:14][C:13]([C:10]([C:7]2[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][N:43]3[CH2:44][CH2:45][CH:40]([C:32]4[N:31]([CH2:30][CH2:29][O:28][CH2:26][CH3:27])[C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=5[N:33]=4)[CH2:41][CH2:42]3)=[CH:5][CH:6]=2)([CH3:12])[CH3:11])=[N:17]1
Reactant: CC1(C)COC(C(C)(C)c2ccc(CCCl)cc2)=N1
Reactant: CCOCCn1c(C2CCNCC2)nc2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CCOCCn1c(C2CCN(CCc3ccc(C(C)(C)C4=NC(C)(C)CO4)cc3)CC2)nc2ccccc21
Yield: 125.4 %

Procedure:
In a reaction vessel, 2-{1-[4-(2-chloro-ethyl)-phenyl]-1-methyl-ethyl}-4,4-dimethyl-4,5-dihydro-oxazole (1.9 g) prepared in the Example 9, sodium carbonate (0.8 g), 1-(2-ethoxyethyl)-2-piperidin-4-yl-1H-benzoimidazole (2.0 g) prepared in the Example 12 and methyl alcohol (20 mL) were introduced, and the mixture was reacted for 14 hours under reflux condition to obtain 2-[1-(2-{4-[1-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-1-methyl-ethyl]-phenyl}-ethyl)-piperidin-4-yl]-1-(2-ethoxy-ethyl)-1H-benzoimidazole (4.4 g, yield 87%, HPLC purity 98% or more).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[CH:6]=[C:5]2[CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C([O-])(=O)/C=[CH:26]/[C:27]([O-])=[O:28]>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=1)[CH:6]=[C:5]2[CH:18]1[CH2:23][CH2:22][N:21]([CH2:26][CH2:27][OH:28])[CH2:20][CH2:19]1
Reactant: O=C([O-])/C=C/C(=O)[O-]
Reactant: Fc1ccc(-n2cc(C3CCNCC3)c3cc(Cl)ccc32)cc1
Product: Cl
Product: OCCN1CCC(c2cn(-c3ccc(F)cc3)c3ccc(Cl)cc23)CC1

Procedure:
5-chloro-1-(4-fluorophenyl)-3-(4-piperidyl)-1H-indole, fumarate, 10, MP: 196°-201° C.
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH:16]([C:18]3[N:19]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH:20]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)[N:22]=3)[OH:17])=[CH:8]2)=[CH:4][CH:3]=1.CCCCCC.C(OCC)(=O)C>ClCCl.O=[Mn]=O>[Cl:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16]([C:18]3[N:19]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:34])([CH3:35])[CH3:36])[CH:20]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)[N:22]=3)=[O:17])=[CH:8]2)=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCn1cc(-c2ccccn2)nc1C(O)c1cn(Cc2ccc(Cl)cc2)c2ccccc12
Agent: O=[Mn]=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1cc(-c2ccccn2)nc1C(=O)c1cn(Cc2ccc(Cl)cc2)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 0.1 %

Procedure:
A mixture of [1-(4-chloro-benzyl)-1H-indol-3-yl]-[4-pyridin-2-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-methanol (10 mg, 18.4 mmol) and MnO2 (0.2 g, 2.3 mmol) in dichloromethane (5 mL) was stirred at room temperature for two hours. Flash silica gel chromatography (2:1 hexane/ethyl acetate) afforded the oxidized product [1-(4-chloro-benzyl)-1H-indol-3-yl]-[4-pyridin-2-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-methanone as a syrup (10 mg, 100%). 1H NMR (CDCl3) δ−0.02 (s, 9H), 0.99 (t, 2H, J=7), 3.68 (t, 2H, J=7), 5.40 (s, 2H), 5.99 (s, 2H), 7.15-7.40 (m, 9H), 7.75 (t, 1H, J=4), 7.85 (d, 1H, J=6), 8.00 (s, 1H), 8.60(d, 1H, J=6), 9.00 (s, 1H)ppm; ESMS calcd for (C30H31ClN4O2Si): 542.2; found: 543.2 (M+H)+.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]([CH3:9])([CH3:8])[C:6]#[N:7].[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CCCCCC.CN(C=O)C.O>[CH2:10]([O:3][CH2:4][C:5]([CH3:9])([CH3:8])[C:6]#[N:7])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C#N)CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCCCCC
Product: CC(C)(C#N)COCc1ccccc1
Temperature: -10 °C
Yield: 95 %

Procedure:
A solution of 60% sodium hydride (367.1 mg, 15.3 mmol) was washed with hexane (3×2 mL) and suspended in DMF (2 mL). The suspension was cooled to -10° C. and then a mixture of 3-hydroxy-2,2-dimethylpropanenitrile (1.4 g, 13.9 mmol) and DMF (8 mL) was added. The mixture was cooled 2.5 hour with stirring stirred at -10° to -5° C. and then benzyl bromide (1.7 mL, 13.9 mmol) was added. The mixture was cooled 2 hours with stirring at -5° C., diluted with water (10 mL) and extracted with diethyl ether (3×10 mL). The combined extracts were washed with water (1×10 mL) and brine (1×10 mL), dried (MgSO4) and concentrated to give 3-benzyloxy-2,2-dimethylpropanenitrile (2.5 g, 13.2 mmol).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[OH:15])[CH:10]=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[F:24][CH:25]([F:27])Cl>CN(C)C=O>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH:25]([F:27])[F:24])[CH:10]=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: FC(F)Cl
Reactant: O=Cc1ccc(O)c(OC2CCCC2)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OC(F)F)c(OC2CCCC2)c1

Procedure:
A solution of 3-cyclopentyloxy-4-hydroxybenzaldehyde (5.1 g) in dimethylformamide (50 mL) is treated with potassium carbonate (4.83 g) and potassium iodide (1.2 g) and the solution is heated at 70-75° C. whilst difluorochloromethane is bubbled though it at a slow rate, during 5 hours. Water (100 mL) is added and the mixture is extracted with ethyl acetate (2×100 mL). The combined organic extracts are dried over magnesium sulfate and concentrated to give a brown oil. The oil is subjected to flash chromatography, eluting with a mixture of diethyl ether and pentane (1:4 v/v), to give 3-cyclopentyloxy-4-difluoromethoxybenzaldehyde, in the form of a pale yellow oil (4.7 g). [NMR (CDCl3): 9.92(s,1H);7.5-7.24(m,3H); 6.34-5.96(t,1H); 4.9(m,1H);2.0-1.6(m,8H)].
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][OH:14].[CH3:15][O:16][C:17]([C:19]1[S:23][N:22]=[C:21](O)[CH:20]=1)=[O:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:15][O:16][C:17]([C:19]1[S:23][N:22]=[C:21]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])[CH:20]=1)=[O:18]
Reactant: COC(=O)c1cc(O)ns1
Reactant: Cc1onc(-c2ccccc2)c1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(OCc2c(-c3ccccc3)noc2C)ns1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
To a solution of (5-methyl-3-phenyl-isoxazol-4-yl)-methanol (350 mg, 2.2 mmol) in THF (30 mL) was added 3-hydroxy-isothiazole-5-carboxylic acid methyl ester (416 mg, 2.2 mmol) and triphenylphosphine (692 mg, 2.4 mmol) at 0° C. under an argon atmosphere. Then diethyl azodicarboxylate (˜40% in toluene, 1.05 mL, 2.4 mmol) was added and the reaction mixture was stirred overnight at room temperature. Concentration and purification by chromatography (silica, heptane:ethyl acetate=9:1 to 0:1) afforded the title compound (567 mg, 78%) as a colourless oil. MS: m/e=331.1 [M+H]+.
Reaction SMILES: [Br:1][CH2:2][C:3]([NH:5][C:6]1[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:7]=1[F:13])=[O:4].[N:14]12[CH2:21][CH2:20][CH:17]([CH2:18][CH2:19]1)[C@@H:16]([O:22][C:23]([C:25]1([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:24])[CH2:15]2>CC#N>[Br-:1].[F:13][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([F:12])[C:6]=1[NH:5][C:3]([CH2:2][N+:14]12[CH2:21][CH2:20][CH:17]([CH2:18][CH2:19]1)[C@@H:16]([O:22][C:23]([C:25]1([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:24])[CH2:15]2)=[O:4]
Reactant: O=C(CBr)Nc1c(F)cccc1F
Reactant: O=C(O[C@H]1CN2CCC1CC2)C1(c2ccccc2)CCCCCC1
Solvent: CC#N
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C1(c3ccccc3)CCCCCC1)C2)Nc1c(F)cccc1F
Product: [Br-]
Temperature: 25 °C
Reaction time: 19 h
Yield: 46.5 %

Procedure:
A mixture of 2-bromo-N-(2,6-difluoro-phenyl)-acetamide (Example 38a) (42 mg) and 1-phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (Example 14e) (50 mg) in MeCN (1 mL) was stirred at room temperature for 19 h. A further 20 mg 2-bromo-N-(2,6-difluoro-phenyl)-acetamide was added and stirring continued for another 22 h. The volatiles were evaporated and the residue was purified by silica gel chromatography eluting with 0-10% MeOH/dichloromethane to give the title compound (41 mg) as a colourless foam.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[C:10](O)([CH3:12])[CH3:11].[F:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:25]([C:26]([OH:28])=[O:27])=[CH:24][N:23]=[C:22]2[S:29]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:17][CH:16]=1.[CH3:49][CH2:50]OC(C)=O>C(Cl)Cl.[I-].[Zn+2].[I-]>[F:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]2[C:25]([C:26]([O:28][CH2:49][CH3:50])=[O:27])=[CH:24][N:23]=[C:22]2[S:29][C:10]([C:3]2[C:4]([F:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[F:1])([CH3:12])[CH3:11])=[CH:19][CH:20]=1
Reactant: CCOC(C)=O
Reactant: O=C(O)c1cnc(SC(c2ccccc2)(c2ccccc2)c2ccccc2)n1-c1ccc(F)cc1
Reactant: CC(C)(O)c1c(F)ccc(F)c1F
Agent: [I-]
Agent: [Zn+2]
Solvent: ClCCl
Product: CCOC(=O)c1cnc(SC(C)(C)c2c(F)ccc(F)c2F)n1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(2,3,6-trifluorophenyl)propan-2-ol (74) (0.73 g, 3.8 mmol) and ethyl 1-(4-fluorophenyl)-2-mercapto-1H-imidazole-5-carboxylate (6) (1.12 g, 4.2 mmol) in CH2Cl2 (5 mL) was added zinc iodide (1.7 g, 5.3 mmol) at room temperature. The mixture was stirred at room temperature overnight. The reaction was diluted with EtOAc and washed with 0.5 N NaOH, water, brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel to afford ethyl 1-(4-fluorophenyl)-2-((2-(2,3,6-trifluorophenyl)propaN-2-yl)thio)-1H-imidazole-5-carboxylate. (75).
Reaction SMILES: [ClH:1].C([N:9]1[CH2:13][C:12]([F:15])([F:14])[C:11]([F:17])([F:16])[CH2:10]1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[ClH:1].[F:16][C:11]1([F:17])[C:12]([F:15])([F:14])[CH2:13][NH:9][CH2:10]1
Reactant: FC1(F)CN(Cc2ccccc2)CC1(F)F
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: FC1(F)CNCC1(F)F

Procedure:
A solution of 1-benzyl-3,3,4,4-tetrafluoro-pyrrolidine hydrochloride (23.8 grams, 88 mmol) in ethanol (300 mL) containing 10% palladium on carbon was treated with hydrogen in a Parr shaker at 45 psi for 3 hours. The mixture was filtered through Celite®, the filtrate was concentrated to dryness. The residue was triturated with ether and the solid was collected and dried (13.4 grams, 85%, (melting point: 193-196° C.). 1H NMR (400 MHz, D2O) 3.93 (m, 4H), 7.26-7.41 (m, 5H). 19F NMR (376 MHz, D2O) δ−122.25 (m)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[F:9].[Cl:10]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>ClC1C=CC=CC=1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][Cl:10])=[CH:4][C:3]=1[F:9]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cnc(Cl)c(F)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: Clc1ccccc1
Product: Fc1cc(CCl)cnc1Cl
Reaction time: 16 h
Yield: 52.6 %

Procedure:
1.00 g (6.87 mmol) of 6-chloro-5-fluoro-3-methylpyridine (F. L. Setliff, Organic Preparations and Procedures International 1971, 3, 217-222), 1.01 g (7.56 mmol) of N-chlorosuccinimide and 0.11 g (0.69 mmol) of 2,2′-azobis(2-methylpropannitrile) in 100 ml of chlorobenzene are boiled under reflux for 2 days. During this reaction, after about 16 hours and 32 hours, a further 1.01 g (7.56 mmol) of N-chlorosuccinimide and 0.11 g (0.69 mmol) of 2,2′-azobis(2-methylpropannitrile) are added in each case. The reaction mixture is washed with saturated aqueous sodium sulphite solution and sodium bicarbonate solution and then dried over sodium sulphite and concentrated under reduced pressure. Column chromatography of the residue on silica gel (silica gel 60-Merck, particle size: 0.04 to 0.063 mm) using the mobile phase mixture ethyl acetate:cyclohexane (1:20) gives 0.65 g (53% of theory) of 6-chloro-3-chloromethyl-5-fluoropyridine.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([CH3:7])[CH2:3]1.Cl[C:9]1[C:14]([C:15]#[N:16])=[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([C:23]#[N:24])=[C:11]([S:25][CH2:26][C:27]2[N:28]=[C:29]([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=3)[S:30][CH:31]=2)[N:10]=1>C1COCC1>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([C:29]2[S:30][CH:31]=[C:27]([CH2:26][S:25][C:11]3[C:12]([C:23]#[N:24])=[C:13]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:14]([C:15]#[N:16])=[C:9]([O:1][CH:2]4[CH2:6][CH2:5][N:4]([CH3:7])[CH2:3]4)[N:10]=3)[N:28]=2)=[CH:33][CH:34]=1
Reactant: N#Cc1c(Cl)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccccc1
Reactant: CN1CCC(O)C1
Solvent: C1CCOC1
Product: CN1CCC(Oc2nc(SCc3csc(-c4ccc(Cl)cc4)n3)c(C#N)c(-c3ccccc3)c2C#N)C1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
25 μl (0.229 mmol) of 3-hydroxy-N-methylpyrrolidine are initially charged in 0.5 ml of THF, the mixture is cooled to 0° C., 249 μl (0.249 mmol) of phosphazene base P(4)-t-Bu (1M in THF) are added and the mixture is stirred at this temperature for 10 minutes. 120 mg (0.208 mmol) of the compound from Example 3A are then added, and the mixture is stirred at RT overnight. The reaction mixture is then purified by preparative HPLC (addition of 0.15% hydrochloric acid). This gives 38 mg of the impure target compound. This is dissolved in dichloromethane and washed twice with 1N hydrochloric acid, once with water and once with saturated aqueous sodium chloride solution. After drying over sodium sulphate, the organic phase is concentrated on a rotary evaporator and the crude product is purified once more by preparative HPLC (addition of 0.15% hydrochloric acid).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1.[CH2:15]([O:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH2:26])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([O:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH:26][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Cc1cc(Cl)nc(-c2ccccn2)n1
Reactant: Nc1cccc(OCc2ccccc2)c1
Product: Cc1cc(Nc2cccc(OCc3ccccc3)c2)nc(-c2ccccn2)n1

Procedure:
The title compound was prepared from 4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (100 mg, 0.486 mmol) and 3-benzyloxyaniline (97 mg, 0.486 mmol) similar to Example 13 and isolated as a yellow oil (161 mg, 90%). 1H NMR (CDCl3): 8.78-8.76 (m, 1H), 8.48-8.45 (m, 1H), 7.79-7.74 (m, 1H), 7.68 (s, 1H), 7.42-7.29 (m, 6H), 7.24 (t, J=8.1 Hz, 1H), 7.10 (s, 1H), 6.92 (dd, J=0.8, 8.0 Hz, 1H), 6.77-6.74 (m, 1H), 6.58 (s, 1H), 5.04 (s, 2H), 2.42 (s, 3H).