Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:17]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=2)[NH2:28])[CH2:21][CH2:20]1>>[F:16][C:13]1[CH:14]=[CH:15][C:10]([C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:28][C:27]4[CH:29]=[CH:30][CH:31]=[C:25]([N:22]5[CH2:21][CH2:20][N:19]([CH3:18])[CH2:24][CH2:23]5)[CH:26]=4)[N:17]=3)[CH:9]=[CH:8][CH:7]=2)=[CH:11][CH:12]=1
Reactant: CN1CCN(c2cccc(N)c2)CC1
Reactant: Fc1ccc(-c2cccn3nc(Cl)nc23)cc1
Product: CN1CCN(c2cccc(Nc3nc4c(-c5ccc(F)cc5)cccn4n3)c2)CC1

Procedure:
[8-(4-Fluoro-phenyl)-[1,2,4]-triazolo[1,5-a]pyridin-2-yl]-[3-(4-methyl-piperazin-1-yl)-phenyl]-amine was prepared from 2-chloro-8-(4-fluoro-phenyl)-[1,2,4]-triazolo[1,5-a]pyridine (0.185 g, 0.747 mmol) and 3-(4-methylpiperazin-1-yl)aniline (0.171 g, 0.896 mmol) in a manner analogous to Example 311a and 311b with purification method from 313 to give product (0.155 g, 52%): MP=194-196° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.56 (s, 1H), 8.78 (d, 1H), 8.20 (m, 2H), 7.85 (d, 1H), 7.50 (s, 1H), 7.35 (m, 2H), 7.10 (m, 3H), 6.45 (m, 1H), 3.12 (m, 4H), 2.46 (m, 4H), 2.23 (s, 3H). MS=403 (MH)+.
Reaction SMILES: Cl.[N:2]1([CH2:9][C:10]([OH:12])=O)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[NH2:13][C@@H:14]([CH2:32][O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[CH:20][CH:19]=1)=[O:16]>>[N:2]1([CH2:9][C:10]([NH:13][C@@H:14]([CH2:32][O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:15]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[CH:22][CH:23]=2)=[O:16])=[O:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: O=C(O)CN1CCCCCC1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Product: O=C(CN1CCCCCC1)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 52.2 %

Procedure:
Proceeding as in Example 1, but substituting 2-(azepan-1-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 128, (S)-2-(2-(azepan-1-yl)acetamido)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide (21.7 mg, 52.2%); Major isomer: 1H-NMR (400 MHz, DMSO-D6): 10.22 (s, 1H), 7.99 (d, 1H), 7.60 (d, 2H), 7.27-7.33 (m, 5H), 7.19-7.23 (m, 2H), 6.99-7.04 (m, 4H), 4.70 (m, 1H), 4.52 (s, 2H), 3.67-3.79 (m, 2H), 3.10 (m, 2H), 2.51-2.63 (m, 4H), 1.55-1.60 (m, 8 h). MS (EI) for C30H34FN3O4. found 520.6 (MH+).
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].C[O-].[Na+].Cl.[Cl:10][C:11]([C:13]1[C:17]([CH3:18])=[CH:16][N:15]([C:19]2[CH:28]=[CH:27][CH:26]=[C:25]3[C:20]=2[CH:21]=[CH:22][CH:23]=[N:24]3)[CH:14]=1)=[O:12]>CO>[ClH:10].[NH:4]([C:11]([C:13]1[C:17]([CH3:18])=[CH:16][N:15]([C:19]2[CH:28]=[CH:27][CH:26]=[C:25]3[C:20]=2[CH:21]=[CH:22][CH:23]=[N:24]3)[CH:14]=1)=[O:12])[C:3]([NH2:5])=[NH:2]
Reactant: N=C(N)N
Reactant: Cc1cn(-c2cccc3ncccc23)cc1C(=O)Cl
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cc1cn(-c2cccc3ncccc23)cc1C(=O)NC(=N)N
Reaction time: 2 h
Yield: 40.8 %

Procedure:
1.06 g (11.18 mmol) of guanidine hydrochloride is added to a solution of 0.604 g (11.18 mmol) of sodium methoxide in 50 mL of methanol at a temperature in the region of 20° C. under an argon atmosphere. After stirring for 2 hours at this temperature, the mixture is concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up in 25 mL of 1,2-dimethoxyethane, and 0.57 g (1.86 mmol) of 3-chlorocarbonyl-4-methyl-1-(quinolin-5-yl)-1H-pyrrole hydrochloride is added. After stirring for 2 hours at a temperature in the region of 20° C., the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa). The residue is triturated in 25 mL of water and then filtered, giving a gum, which is triturated again in 20 mL of water and filtered. The residue is purified by chromatography on silica gel [eluent: chloroform/methanol (80/20 by volume)]. After the fractions containing the expected product have been concentrated to dryness under reduced pressure, the residue is dissolved in ethyl acetate, and excess 4 M hydrochloric ether is added. After the reaction mixture has been stirred at room temperature for one hour, the precipitate formed is isolated by filtration, giving 0.25 g of 3-guanidinocarbonyl-4-methyl-1-(quinolin-5-yl)-1H-pyrrole hydrochloride in the form of a yellow solid melting at 240° C. Mass spectrum (EI): m/e 293 (M+.) (base peak).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH3:19])=[C:6]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)=[O:10])[CH:7]=1.[C:20]1(=[O:26])[O:25][C:23](=[O:24])[CH2:22][CH2:21]1>N1C=CC=CC=1>[CH3:19][O:18][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:20](=[O:26])[CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:7][C:6]=1[NH:8][C:9]([NH:11][C:12]1[CH:17]=[N:16][CH:15]=[CH:14][N:13]=1)=[O:10]
Reactant: COc1ccc(N)cc1NC(=O)Nc1cnccn1
Reactant: O=C1CCC(=O)O1
Solvent: c1ccncc1
Product: COc1ccc(NC(=O)CCC(=O)O)cc1NC(=O)Nc1cnccn1
Yield: 48.7 %

Procedure:
A solution of 1-(5-amino-2-methoxyphenyl)-3-pyrazin-2-yl-urea (Compound 14, Example 4) (260 mg, 1 mmol), and succinic anhydride (131 mg, 1.3 mmol) in dry pyridine (10 mL) was stirred 16 h at room temperature. The resulting solid was collected by filtration and triturated with chloroform, and dried in vacuo to afford the off-white product (175 mg, 50%). 1H NMR (300 Mhz, d6-DMSO) δ: 10.15 (s, 1H), 10.05 (s, 1H), 9.87 (s, 1H), 8.90 (s, 1H), 8.33 (s, 2H), 8.24 (s, 1H), 7.42 (dd, J=8.8, 2.2 Hz, 1H), 6.96 (d, J 8.8 Hz, 1H), 3.87 (s, 3H), 2.54 (br s, 4H).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:24]=[CH:23][C:22]3[CH2:21][C@@H:20]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=4)[C:19]4[CH:33]=[CH:34][CH:35]=[CH:36][C:18]=4[C:17]=3[N:16]=2)=[CH:10][CH:9]=1)(=O)=O.[CH3:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>C(N(CC)CC)C>[ClH:31].[Cl:32][C:27]1[CH:26]=[C:25]([C@H:20]2[C:19]3[CH:33]=[CH:34][CH:35]=[CH:36][C:18]=3[C:17]3[N:16]=[C:15]([NH:14][C:11]4[CH:12]=[CH:13][C:8]([CH2:7][CH2:6][N:41]5[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]5)=[CH:9][CH:10]=4)[N:24]=[CH:23][C:22]=3[CH2:21]2)[CH:30]=[CH:29][C:28]=1[Cl:31]
Reactant: CN1CCNCC1
Reactant: CS(=O)(=O)OCCc1ccc(Nc2ncc3c(n2)-c2ccccc2[C@H](c2ccc(Cl)c(Cl)c2)C3)cc1
Solvent: CCN(CC)CC
Product: CN1CCN(CCc2ccc(Nc3ncc4c(n3)-c3ccccc3[C@H](c3ccc(Cl)c(Cl)c3)C4)cc2)CC1
Product: Cl

Procedure:
This was synthesized by using (S)-4-(6-(3,4-dichlorophenyl)-5,6-dihydrobenzo[h]quinazolin-2-ylamino)phenethyl methanesulfonate, N-methyl piperazine and triethylamine as described in general procedure 2 to give a yellow solid. M.p.=236-238° C. 1H NMR 400 MHz (DMSO-d6) δ 9.63 (s, 1H) 8.33-8.29 (m, 2H), 7.79 (d, J=8.0 Hz, 2H), 7.52-7.47 (m, 4H), 7.24 (d, J=8.8 Hz, 2H), 7.10 (m, 1H), 7.03-7.00 (dd, J=2.4, 8.8 Hz, 1H), 4.46 (t, J=6.4 Hz, 1H), 3.82-2.99 (m, 15H), 2.82 (s, 3H). LCMS m/e 544 (M+H).
Reaction SMILES: [NH2:1][C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].[NH:13](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:14]([C:27](OC1C(F)=C(F)C(F)=C(F)C=1F)=[O:28])[CH2:15][CH2:16][CH2:17][CH2:18][NH:19]C(OC(C)(C)C)=O.[C:58]([OH:82])(=O)[CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][C:67]#[C:68][C:69]#[C:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH3:80].C(N=C=NCCCN(C)C)C>CN(C)C=O>[C:58]([O:12][CH2:11][CH:9]1[CH:7]([OH:8])[CH:5]([OH:6])[CH:3]([OH:4])[CH:2]([NH:1][C:27](=[O:28])[CH:14]([NH2:13])[CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])[O:10]1)(=[O:82])[CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][C:67]#[C:68][C:69]#[C:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH3:80]
Reactant: N[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Reactant: CCCCCCCCCCC#CC#CCCCCCCCCC(=O)O
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)Oc1c(F)c(F)c(F)c(F)c1F
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Product: CCCCCCCCCCC#CC#CCCCCCCCCC(=O)OCC1OC(NC(=O)C(N)CCCCN)C(O)C(O)C1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-Amino-1-deoxy-β-D-galactose (180 mg, 1 mmol), and Fmoc-Lys(Boc)-OPfp (650 mg, 1 mmol) were dissolved in 4 ml dry dimethylformamide and stirred at room temperature overnight. The solvent was removed in vacuo, the residue was redissolved in acetonitrile/water (1:1), filtered and purified by reversed phase chromatography (Lobar RP8B, acetonitrile/water 50:50 and 65:35). The relevant fractions were collected, concentrated in vacuo, and the product was characterised by NMR. The purified product (1 g, 1 mmol), 10,12-tricosadiynoic acid (350 mg, 1 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide are dissolved in 10 ml dry dimethylformamide and stirred at room temperature overnight. The solvent is removed in vacuo, the residue redissolved in chloroform/methanol (95:5), filtered and purified by straight phase chromatography on a CHROMATOTRON. The relevant fractions are collected, concentrated in vacuo, and the product is characterised by NMR. The protecting groups of the α-ε amino groups are removed by standard reactions. Boc is removed by treatment with trifluoroacetic acid/methylene chloride for 30 minutes. The solvent is removed in vacuo. Fmoc is removed by treating the residue with 20% piperidine in dimethylformamide for 30 minutes, and the solvent is removed in vacuo. The final product is purified by reversed phase chromatography (Lobar RP8B).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]([N:8]([C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1)[CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])=[O:7].O1CCCC1.Cl.Cl.[CH2:29]([O:31][C:32]1[CH:33]=[C:34]([CH:51]=[CH:52][CH:53]=1)[CH2:35][N:36]1[C:40]2=[N:41][CH:42]=[N:43][C:44]([N:45]3[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]3)=[C:39]2[CH:38]=[N:37]1)[CH3:30].C([BH3-])#N>C(O)(=O)C.C(N(CC)CC)C>[CH2:29]([O:31][C:32]1[CH:33]=[C:34]([CH:51]=[CH:52][CH:53]=1)[CH2:35][N:36]1[C:40]2=[N:41][CH:42]=[N:43][C:44]([N:45]3[CH2:46][CH2:47][N:48]([CH2:18][C:17]4[CH:20]=[CH:21][C:14]([N:8]([C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[O:7])[CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])=[CH:15][CH:16]=4)[CH2:49][CH2:50]3)=[C:39]2[CH:38]=[N:37]1)[CH3:30]
Reactant: COCCOC(=O)N(CCN(C)C)c1ccc(C=O)cc1
Reactant: CCOc1cccc(Cn2ncc3c(N4CCNCC4)ncnc32)c1
Agent: Cl
Agent: [BH3-]C#N
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: CCOc1cccc(Cn2ncc3c(N4CCN(Cc5ccc(N(CCN(C)C)C(=O)OCCOC)cc5)CC4)ncnc32)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 106 %

Procedure:
To 4-[N-[(2-methoxyethoxy)carbonyl]-N-[2-(dimethylamino)ethyl]amino]-benzaldehyde (90 mg, compound obtained in Reference Example 97) is added successively tetrahydrofuran (1.5 mL), 1-(3-ethoxybenzyl)-4-(1-piperazinyl)-1H-pyrazolo[3,4-d]pyrimidine dihydrochloride (100 mg), triethylamine (90 μL), acetic acid (73 μL) and macroporous triethylammoniummethylpolystylenecyanoborohydride (MP-Cyanoborohydride 2.04 mmol/g, Argonaut Technology). The mixture is shaken at room temperature for 18 hours by using a parallel synthesizer (MiniBlock; Mettler Toledo). The reaction mixture is separated and the residual resin is washed with tetrahydrofuran (×3). The washings and the reaction solution are combined and concentrated. The resultant crude product is purified by flash column chromatography on silica gel (Solvent; ethyl acetate:chloroform=1:0→0:1) to give 1-(3-ethoxybenzyl)-4-[4-[4-[N-[(2-methoxyethoxy)carbonyl]-N-[2-(dimethylamino)ethyl]-amino]benzyl]piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine (159 mg, yield; 38%) as an amorphous powder. MS (APCI) m/z: 617 [M+H]+
Reaction SMILES: C([O:8][NH:9][C:10](=[O:38])[CH2:11][CH:12]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH2:36][CH3:37])[CH:28]=1)[N:13]1[C:17](=[O:18])[C:16]2=[C:19]([N+:23]([O-])=O)[CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:26])C1C=CC=CC=1.CCOCC>C(OCC)(=O)C.CO.[Pd]>[NH2:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:15]2[C:14]([N:13]([CH:12]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH2:36][CH3:37])[CH:28]=3)[CH2:11][C:10]([NH:9][OH:8])=[O:38])[C:17](=[O:18])[C:16]=12)=[O:26]
Reactant: CCOc1cc(C(CC(=O)NOCc2ccccc2)N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)ccc1OC
Agent: [Pd]
Solvent: CCOCC
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOc1cc(C(CC(=O)NO)N2C(=O)c3cccc(N)c3C2=O)ccc1OC
Reaction time: 72 h
Yield: 64.1 %

Procedure:
A mixture of N-benzyloxy-3-(3-ethoxy-4-methoxyphenyl)-3-(3-nitrophthalimido)propionamide (1.32 g, 2.54 mmol) and 10% Pd/C (230 mg) in ethyl acetate/methanol (150 mL each) was shaken under 50-60 psi of H2. After 3 days, the suspension was filtered through a pad of Celite, and the pad washed with methanol (75 mL) and methylene chloride (75 mL). The filtrate was concentrated in vacuo to give an oil. The oil was stirred with ether (20 mL) to afford 3-(3-aminophthalimido)-3-(3-ethoxy-4-methoxyphenyl)-N-hydroxypropionamide as a yellow solid (650 mg, 64% yield): mp, 143.0-145.0° C.; 1H NMR (DMSO-d6) δ1.39 (t, J=6.9 Hz, 3H, CH3), 3.16 (d, J=7.8 Hz, 2H, CH2), 3.79 (s, 3H, CH3), 4.05 (q, J=6.9 Hz, 2H, CH2), 5.68 (t, J=7.8 Hz, 1H, NCH), 6.55 (br s, 2H, NH2), 6.98-7.08 (m, 5H, Ar), 7.47-7.53 (m, 1H, Ar), 8.88 (br s, 1H, OH), 10.66 (1H, NH); 13C NMR (DMSO-d6) δ14.70, 34.37, 49.65, 55.47, 63.75, 108.64, 110.68, 111.77, 112.39, 119.61, 121.40, 131.69, 132.03, 135.19, 146.48, 147.65, 148.47, 166.14, 167.81, 169.18; Anal Calcd for C20H21N3O6: C, 60.14; H, 5.30; N, 10.52. Found: C, 59.76; H, 5.21; N, 10.30.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].[Li][CH2:8]CCC.[Si:12]([O:29][C@@H:30]1[CH2:47][CH2:46][C@@:45]2([CH3:48])[C@@H:32]([CH2:33][CH2:34][C@@H:35]3[C@@H:44]2[CH2:43][CH2:42][C@@:40]2([CH3:41])[C@H:36]3[CH2:37][CH2:38][C@@H:39]2[CH:49]=[O:50])[CH2:31]1)([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.IC>C1COCC1>[CH3:1][Si:2]([CH3:4])([CH3:3])[C:5]#[C:6][CH:49]([O:50][CH3:8])[C@H:39]1[CH2:38][CH2:37][C@H:36]2[C@H:35]3[C@H:44]([CH2:43][CH2:42][C@:40]12[CH3:41])[C@:45]1([CH3:48])[C@H:32]([CH2:31][C@H:30]([O:29][Si:12]([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:47][CH2:46]1)[CH2:33][CH2:34]3
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(C)[Si](O[C@@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](C=O)CC[C@@H]32)C1)(c1ccccc1)c1ccccc1
Reactant: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: COC(C#C[Si](C)(C)C)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of trimethylsilylacetylene (0.066 mL, 0.48 mmol) in anhydrous THF (2 mL) at 0° C. was added a solution of n-BuLi (0.3 mL, 0.48 mmol) 1.6 M in hexanes and the resulting mixture was stirred for 2 h. Subsequently, the mixture was cooled to −78° C. and a solution of 3α-(t-butyldiphenylsilyloxy)-5α-androstan-17β-carboxaldehyde (90 mg, 0.16 mmol) in THF (2 mL) was added and the mixture was stirred at this temperature for 3 h after which iodomethane (0.1 mL, 1.6 mmol) was added and the resulting mixture was stirred at RT for 24 h. Quenching of the reaction by the addition of NH4Cl was followed by extraction with ethyl acetate. The organic layer was washed with water, brine, dried with (Na2SO4) and the solvent was evaporated in vacuo. Subsequent purification of the residue with flash column chromatography using petroleum ether/ethyl acetate 95/5 as eluent afforded the desired compound named above. Separation of the two epimers was accomplished with preparative thin layer chromatography using petroleum etherlacetone 98/2 as eluent.
Reaction SMILES: [Br-].[F:2][CH2:3][CH2:4][CH2:5][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.CC([O-])(C)C.[K+].[C:36]([C:38]1[CH:43]=[CH:42][C:41]([C@H:44]2[CH2:49][CH2:48][C@H:47]([CH:50]=O)[CH2:46][CH2:45]2)=[CH:40][CH:39]=1)#[N:37]>O>[F:2][CH2:3][CH2:4][CH:5]=[CH:50][C@H:47]1[CH2:48][CH2:49][C@H:44]([C:41]2[CH:42]=[CH:43][C:38]([C:36]#[N:37])=[CH:39][CH:40]=2)[CH2:45][CH2:46]1
Reactant: FCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N#Cc1ccc([C@H]2CC[C@H](C=O)CC2)cc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc([C@H]2CC[C@H](C=CCCF)CC2)cc1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
A mixture of (3-fluoropropyl)triphenylphosphonium bromide (10.0 g, 24.8 millimols) with THF (50 ml) was cooled down to -20° C., followed adding t-BuOK (3.1 g, 27.3 millimols) to the mixture, stirring the resulting mixture for 30 minutes, dropwise adding to the mixture, a THF (60 ml) solution of trans-4-(4-cyanophenyl)cyclohexanecarbaldehyde (5.8 g, 27.3 millimols) so as to keep the temperature at -20° C. or lower, stirring the mixture at the same temperature for 2 hours, adding water (50 ml) to the reaction product after completion of the reaction, extracting the product with ethyl acetate (300 ml), three times washing the resulting organic layer with water, drying it over anhydrous magnesium sulfate, distilling off the solvent under reduced pressure, and subjecting the residue to silica gel column chromatography (eluent: toluene), to obtain raw 4-(trans-4-(4-fluorobutenyl)cyclohexyl)benzonitrile (5.0 g).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH3:5][O:6][C:7]1([CH2:10][CH2:11][N:12]2[CH2:16][CH2:15][NH:14][C:13]2=[O:17])[CH2:9][CH2:8]1.N1C=CC=CC=1.[CH3:24][N:25]1[CH:29]=[C:28]([C:30]2[CH:35]=[C:34]([O:36][C:37]3[CH:38]=[CH:39][C:40]([NH2:43])=[N:41][CH:42]=3)[CH:33]=[CH:32][N:31]=2)[CH:27]=[N:26]1>C(Cl)Cl.O>[CH3:5][O:6][C:7]1([CH2:10][CH2:11][N:12]2[CH2:16][CH2:15][N:14]([C:13]([NH:43][C:40]3[CH:39]=[CH:38][C:37]([O:36][C:34]4[CH:33]=[CH:32][N:31]=[C:30]([C:28]5[CH:27]=[N:26][N:25]([CH3:24])[CH:29]=5)[CH:35]=4)=[CH:42][N:41]=3)=[O:17])[C:1]2=[O:2])[CH2:8][CH2:9]1
Reactant: Cn1cc(-c2cc(Oc3ccc(N)nc3)ccn2)cn1
Reactant: O=C(Cl)Cl
Reactant: COC1(CCN2CCNC2=O)CC1
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC1(CCN2CCN(C(=O)Nc3ccc(Oc4ccnc(-c5cnn(C)c5)c4)cn3)C2=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24 %

Procedure:
A 0° C. solution of phosgene (20% in toluene, 0.711 mL, 0.980 mmol) in DCM (6 mL) was treated slowly drop-wise with a solution of Example B9 (0.129 g, 0.700 mmol) and pyridine (0.113 mL, 1.400 mmol) in DCM (2 mL), warmed to RT, stirred for 0.5 h, then concentrated to dryness. The residue was dissolved in DCM (2 mL), added to a 0° C. solution of Example A2 (0.058 g, 0.218 mmol) and TEA (0.091 mL, 0.654 mmol) in DCM (1 mL), warmed to RT and stirred for 0.5 h. The mixture was treated with water, stirred for 15 min and the layers separated. The organic layer was washed with additional water (2×), dried over MgSO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford 3-(2-(1-methoxycyclopropyl)ethyl)-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide (25 mg, 24%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.99 (s, 1 H), 8.37 (d, J=5.7 Hz, 1 H), 8.25 (s, 1 H), 8.22 (d, J=2.9 Hz, 1 H), 8.07 (d, J=9.0 Hz, 1 H), 7.96 (d, J=0.7 Hz, 1 H), 7.72 (dd, J=9.0, 2.9 Hz, 1 H), 7.22 (d, J=2.4 Hz, 1 H), 6.69 (dd, J=5.7, 2.4 Hz, 1 H), 3.84 (s, 3 H), 3.80 (m, 2 H), 3.50 (m, 2 H), 3.34 (m, 2 H), 3.17 (s, 3 H), 1.77 (t, J=7.4 Hz, 2 H), 0.67 (m, 2 H), 0.42 (m, 2 H); MS (ESI) m/z: 478.2 (M+H+).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].[H-].[Na+].I[CH2:10][CH2:11][CH2:12][CH:13]1[S:17][C:16]2[C:18]([CH3:28])=[C:19]([O:24][CH2:25][O:26][CH3:27])[C:20]([CH3:23])=[C:21]([CH3:22])[C:15]=2[O:14]1.O>CN(C)C=O>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][O:5][CH2:10][CH2:11][CH2:12][CH:13]1[S:17][C:16]2[C:18]([CH3:28])=[C:19]([O:24][CH2:25][O:26][CH3:27])[C:20]([CH3:23])=[C:21]([CH3:22])[C:15]=2[O:14]1
Reactant: CN(C)CCO
Reactant: COCOc1c(C)c(C)c2c(c1C)SC(CCCI)O2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1c(C)c(C)c2c(c1C)SC(CCCOCCN(C)C)O2
Temperature: 50 °C

Procedure:
210 mg of 2-dimethylaminoethanol were dissolved in 3 ml of dimethylformamide, and then 100 mg of a 50% w/w oily suspension of sodium hydride were added to the solution. This reaction mixture was then heated for 1 hour at 50° C. The reaction mixture was then cooled with ice, and a solution of 900 mg of 2-(3-iodopropyl)-5-methoxymethoxy-4,6,7-trimethyl-1,3-benzoxathiole (prepared as described in Example 86) in 2 ml of dimethylformamide was added dropwise, while stirring. After completion of the dropwise addition, the temperature of the reaction mixture was gradually raised, and then the mixture was heated for a further 2 hours at 50° C. The reaction mixture was then poured into water, and the resulting precipitate was extracted with benzene. The extract was washed with water and dried over anhydrous sodium sulfate. The benzene was distilled off under reduced pressure. The residual crude oily reaction product was separated by silica gel column chromatography. The fraction eluted with benzene was removed, while the fraction eluted with a 20:1 by volume mixture of ethyl acetate and triethylamine was subjected to silica gel Lobar column chromatography, eluted with the same eluent, to give the title compound.
Reaction SMILES: ClN1C=C[CH:5]=[CH:4]N1.Cl[C:9]1[CH:10]=[CH:11][C:12](=[O:16])N(C)[CH:14]=1.ClC1N=NC(C(C)(C)C)=CC=1.Cl[C:29]1[N:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=1>N1C=CC=CC=1>[CH3:36][O:35][C:32]1[N:31]=[N:30][C:29]([C:14]2[CH:5]=[CH:4][C:11]([CH:12]=[O:16])=[CH:10][CH:9]=2)=[CH:34][CH:33]=1
Reactant: COc1ccc(Cl)nn1
Reactant: ClN1C=CC=CN1
Reactant: Cn1cc(Cl)ccc1=O
Agent: CC(C)(C)c1ccc(Cl)nn1
Solvent: c1ccncc1
Product: COc1ccc(-c2ccc(C=O)cc2)nn1

Procedure:
The following compounds were synthesized in the same procedures as in the Preparation Example 2 except for using 2-chloropyridazine, 5-chloro-1-methyl-1,2-dihydro-2-oxopyridine, 3-chloro-6-tert-butylpyridazine, 5-chloro-2-(3,4-dimethoxyphenyl)methyl)pyridine respectively instead of 3-chloro-6-methoxypyridazine.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[NH:11][N:10]=[C:9]([SH:12])[N:8]=2)=[CH:3][CH:2]=1.[CH3:13]C(C)([O-])C.[K+].CI>CN(C=O)C.O>[CH3:13][S:12][C:9]1[N:8]=[C:7]([C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)[NH:11][N:10]=1
Reactant: CC(C)(C)[O-]
Reactant: Sc1n[nH]c(-c2ccncc2)n1
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: CSc1n[nH]c(-c2ccncc2)n1
Temperature: 50 °C
Yield: 45.7 %

Procedure:
A suspension of 5-(4-pyridyl)-1H-1,2,4-triazole-3-thiol (Aldrich) (4 g, 22.4 mmol) and .potassium t-butoxide (2.89 g, 25.8 mmol) in DMF (30 mL) was stirred at room temperature under argon until a homogeneous solution resulted. Methyl iodide (1.48 mL 23.8 mmol) was added and the reaction mixture was heated to 50° C. in an oil bath for 16 h. The reaction mixture was diluted with water, extracted with EtOAc, the organic extract was washed with water and dried (MgSO4). The solid obtained on concentration was filtered from hot ethyl acetate to obtain 3-methylthio-5-(4-pyridyl)-1H-1,2,4-triazole (1.97 g).