Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C=C.[C:3]1([CH2:9][C:10]([NH:12][C@@H:13]2[C:40](=[O:41])[N:15]3[C:16]([C:28]([O:30][CH2:31][C:32]4[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=4)=[O:29])=[C:17](OS(C(F)(F)F)(=O)=O)[CH2:18][S:19][C@H:14]23)=[O:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:42](N(C(C)C)CC)(C)[CH3:43]>C(OCC)(=O)C>[O:41]=[C:40]1[N:15]2[C@H:14]([S:19][C@@H:18]3[C:17](=[C:16]2[C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)=[O:29])[CH2:43][CH2:42]3)[C@@H:13]1[NH:12][C:10](=[O:11])[CH2:9][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COc1ccc(COC(=O)C2=C(OS(=O)(=O)C(F)(F)F)CS[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: C=C
Solvent: CCOC(C)=O
Product: COc1ccc(COC(=O)C2=C3CC[C@@H]3S[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Reaction time: 18 h
Yield: 60.6 %

Procedure:
Ethylene was bubbled into a solution of p-methoxybenzyl (6R,7R)-7-phenylacetamido-3-(trifluoromethanesulphonyloxy)ceph-3-em-4-carboxylate (0.50 g, 0.852 mmol) in ethyl acetate (500 ml) whilst a solution of diisopropylethylamine (0.15 ml, 0.852 mmol) in ethyl acetate (100 ml) was added dropwise over 2 h. After completion of the addition the mixture was left to stand for 18 h then the solvent was evaporated under reduced pressure. The residue was chromatographed to give the title compound (0.24 g, 61%), (Found: M+, 464.1411. C25H24N2O5S requires M, 464.1406); νmax (CH2Cl2) 1786, 1722, 1686, 1604 cm-1 ; δH (CDCl3) 2.08 (1H, m), 2.46 (1H, dtd, J 10.4, 9.3, 3.2), 3.16 (1H, dtd, J 15.8, 9.4, 1.6), 3.28 (1H, ddt, J 15.8, 8.8, 3.0). 3.63 (2H, ABq, J 16.1), 3.80 (3H, s), 4.32 (1H, dddd, J 9.3, 8.2, 2.8, 1.5), 4.94 (1H, d, J 5.0), 5.18 (2H, ABq, J 11.9), 5.76 (1H, d, J 8.8, 5.0), 5.97 (1H, d, J 8.8), 6.87 (2H, d, J 8.7), 7.26 (7H, m).
Reaction SMILES: C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[CH3:15][S:16]([O:19][C@H:20]1[CH2:24][N:23]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=2)=[O:26])[C@H:22]([C:38]([OH:40])=O)[CH2:21]1)(=[O:18])=[O:17].[OH:41][CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1>O1CCCC1>[OH:41][CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][N:47]([C:38]([C@@H:22]2[CH2:21][C@H:20]([O:19][S:16]([CH3:15])(=[O:18])=[O:17])[CH2:24][N:23]2[C:25]([O:27][CH2:28][C:29]2[CH:30]=[CH:31][C:32]([N+:35]([O-:37])=[O:36])=[CH:33][CH:34]=2)=[O:26])=[O:40])[CH2:46][CH2:45]1
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](C(=O)O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: OCCN1CCNCC1
Agent: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@H]1C[C@@H](C(=O)N2CCN(CCO)CC2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 0.08 h

Procedure:
0.21 ml of triethylamine, followed by 0.19 ml of pivaloyl chloride, were added dropwise at -20° C. to a solution of 0.5 g of trans-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)-L-proline in 5 ml of dry tetrahydrofuran, and the resulting mixture was stirred at the same temperature for 5 minutes. A solution of 0.25 of 1-(2-hydroxyethyl)piperazine in 3 ml of dry tetrahydrofuran was then added, and the reaction mixture was stirred at the same temperature for 30 minutes, after which the solvent was removed by distillation under reduced pressure. The resulting residue was worked up and purified in a similar manner to that described in step 54(a)(ii), to give 0.42 g of the title compound, as a powder. The infrared absorption spectrum and nuclear magnetic resonance spectrum of the product were identical with those of the compound obtained as described in step 54(a)(ii) above.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:9][CH2:10][C:11]#[CH:12])=[N:4][C:5](Cl)=[N:6][CH:7]=1.[NH2:13][C:14]1[CH:15]=[C:16]([CH:21]=[C:22]([NH2:24])[CH:23]=1)[C:17]([O:19][CH3:20])=[O:18].Cl>CO>[CH3:20][O:19][C:17](=[O:18])[C:16]1[CH:21]=[C:22]([NH:24][C:5]2[N:4]=[C:3]([O:9][CH2:10][C:11]#[CH:12])[C:2]([Br:1])=[CH:7][N:6]=2)[CH:23]=[C:14]([NH2:13])[CH:15]=1
Reactant: C#CCOc1nc(Cl)ncc1Br
Reactant: COC(=O)c1cc(N)cc(N)c1
Agent: Cl
Solvent: CO
Product: C#CCOc1nc(Nc2cc(N)cc(C(=O)OC)c2)ncc1Br
Temperature: 65 °C
Reaction time: 8 h
Yield: 60.4 %

Procedure:
A mixture of 5-bromo-2-chloro-4-(prop-2-ynyloxy)pyrimidine (15 g), methyl 3,5-diaminobenzoate (45 g) and concentrated hydrochloric acid (15 ml) in methanol (600 ml) was stirred at 65° C. for 8 h. After concentration to half the volume water was added and the precipitate collected by filtration. The precipitate then was treated with sodium hydroxide solution (1 n) and dichloromethane. The organic phase then was washed with water and brine, dried (Na2SO4) and evaporated to dryness to give the title compound (13.8 g).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:20]([OH:41])[CH2:21][NH:22][C:23]2([CH2:26][CH2:27][N:28]3[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[C:31]([CH3:39])([CH3:38])[O:30][C:29]3=[O:40])[CH2:25][CH2:24]2)[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:41][CH:20]([C:11]1[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=[C:9]([OH:8])[CH:10]=1)[CH2:21][NH:22][C:23]1([CH2:26][CH2:27][N:28]2[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[C:31]([CH3:39])([CH3:38])[O:30][CH:29]2[OH:40])[CH2:25][CH2:24]1
Reactant: [H][H]
Reactant: CC1(C)OC(=O)N(CCC2(NCC(O)c3cc(OCc4ccccc4)cc4c3OCC(=O)N4)CC2)c2ccccc21
Agent: [Pd]
Solvent: CO
Product: CC1(C)OC(O)N(CCC2(NCC(O)c3cc(O)cc4c3OCC(=O)N4)CC2)c2ccccc21

Procedure:
590 mg (1.06 mmol) of 1-(2-{1-[2-(6-benzyloxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-2-hydroxyethlamino]cyclopropyl}ethyl)-4,4-dimethyl-1,4-dihydrobenzo[d][1,3]oxazin-2-one is dissolved in 30 mL of methanol and hydrogenated in the presence of palladium on charcoal (10%) at ambient temperature and 3 bar hydrogen pressure. Yield: 180 mg (36%); mass spectroscopy: [M+H]+=468.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][NH:18][C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[NH:22][C:21](=[O:29])[N:20]=3)=[CH:13][CH:12]=2)=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:4].[OH-].[Na+].Cl>CO>[O:29]=[C:21]1[N:20]=[C:19]([NH:18][CH2:17][C:14]2[CH:15]=[CH:16][C:11]([C:6]3[C:5]([C:3]([OH:4])=[O:2])=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:12][CH:13]=2)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22]1
Reactant: COC(=O)c1ccccc1-c1ccc(CNc2nc(=O)[nH]c3ccccc23)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccccc1-c1ccc(CNc2nc(=O)[nH]c3ccccc23)cc1
Temperature: 25 °C
Yield: 63.9 %

Procedure:
To a solution of 0.26 g of 4'-[[(1,2-dihydro-2-oxo-4-quinazolinyl)amino]methyl][1,1'-biphenyl]-2-carboxylic acid methyl ester in 5.0 mL of methanol was added 15 mL of 0.1N aqueous sodium hydroxide. The solution was warmed to ~90° C. for 3 days. After cooling to room temperature the solution was neutralized with 0.1N HCl and the resulting precipitate was filtered off and washed with water. After drying, the solid was purified on silica gel chromatography to yield 0.160 g (64%) of the desired product. The product was characterized as its sodium salt: 1H NMR (DMSO-d6, 400 MHz) δ10.69 (s, 1H), 9.00 (t, J=5.8 Hz, 1H), 8.11 (d, J=8.0 Hz, 1H), 7.52 (m, 1H), 7.41 (d, J=8.2 Hz, 2H), 7.28 (m, 3H), 7.14 (m, 5 H), 4.68 (d, J=5.6 Hz, 2H); negative FAB MS m/e 392 (M--H); 370 (M--Na). Anal. Calcd for C22H16N3NaO3.1H2O: C, 64.23; H, 4.41; N, 10.21. Found: C, 64.43; H, 4.19; N, 9.82.
Reaction SMILES: C([O:4][CH2:5][CH:6]([NH:12][C:13]([C:15]1[C:20]([I:21])=[C:19]([NH:22][C:23](=[O:30])[C@@H:24]([O:26]C(=O)C)[CH3:25])[C:18]([I:31])=[C:17]([C:32]([NH:34][CH:35]([CH2:41][O:42]C(=O)C)[CH2:36][O:37]C(=O)C)=[O:33])[C:16]=1[I:46])=[O:14])[CH2:7][O:8]C(=O)C)(=O)C.O.[OH-].[Na+]>CO>[OH:42][CH2:41][CH:35]([NH:34][C:32]([C:17]1[C:18]([I:31])=[C:19]([NH:22][C:23](=[O:30])[C@@H:24]([OH:26])[CH3:25])[C:20]([I:21])=[C:15]([C:13]([NH:12][CH:6]([CH2:7][OH:8])[CH2:5][OH:4])=[O:14])[C:16]=1[I:46])=[O:33])[CH2:36][OH:37]
Reactant: CC(=O)OCC(COC(C)=O)NC(=O)c1c(I)c(NC(=O)[C@H](C)OC(C)=O)c(I)c(C(=O)NC(COC(C)=O)COC(C)=O)c1I
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[C@H](O)C(=O)Nc1c(I)c(C(=O)NC(CO)CO)c(I)c(C(=O)NC(CO)CO)c1I
Temperature: 50 °C
Reaction time: 4 h

Procedure:
(S)-N,N′-Bis[2-acetyloxy-1-[(acetyloxy)methyl]ethyl]-5-[(2-acetyloxy-1-oxopropyl)amino]-2,4,6-triiodo-1,3-benzenedicarboxamide (4.9 g, 5 mmol) prepared in Example 4 is admixed with deionized water (30 mL) and methanol (30 mL). The suspension is warmed to 50° C., then 2 M NaOH (12.8 mL) is dripped therein over a period of 4 hours, keeping the pH of the mixture in the range of from 0 to 11. The solution is purified on ion exchange resins columns and the neutral eluate thus obtained is concentrated under vacuum and the residue is crystallized from ethanol to give the compound of the title (2.8 g, 3.6 mmol)
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][C:20]([C:23]([O:25]C)=[O:24])=[CH:21][N:22]=2)[CH2:14][CH2:13]1)=[O:10].[OH-].[Li+].O.Cl>C1COCC1>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:13][CH2:14][N:15]([C:18]2[S:19][C:20]([C:23]([OH:25])=[O:24])=[CH:21][N:22]=2)[CH2:16][CH2:17]1)=[O:10]
Reactant: COC(=O)c1cnc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1[nH]c(C(=O)NC2CCN(c3ncc(C(=O)O)s3)CC2)c(Cl)c1Cl
Temperature: 25 °C

Procedure:
Methyl 2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-1,3-thiazole-5-carboxylate (Example 320, 250 mg, 0.60 mmol) was dissolved in THF (3 ml). 2 N lithium hydroxide solution in water (3 ml, 6.00 mmol) was added and the mixture was refluxed for 1 hr. The mixture was cooled to room temperature and acidified with 10% HCl solution. The mixture was extracted with EtOAc and organic layer was washed with water twice, dried over sodium sulfate and concentrated to give the desired product. The crude material was dissolved in DMF and purified by semi-preparative reverse phase HPLC eluting with acetonitrile/water (0.1% TFA). The desired fraction were collected and concentrated affording the title compound (28 mg).
Reaction SMILES: [CH:1]12C[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[NH:8][C:9](=[O:31])[C@H:10]([CH3:30])[CH2:11][C@H:12]([OH:29])[C@@H:13]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(N)CCCCC1>>[CH:2]1([NH:8][C:9](=[O:31])[C@H:10]([CH3:30])[CH2:11][C@H:12]([OH:29])[C@@H:13]([NH:21][C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:1][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)NC1CC2CCC1C2
Solvent: NC1CCCCC1
Product: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)NC1CCCCC1

Procedure:
Prepared in an analogous manner to D3 using cyclohexylamine instead of (±)exo-norbornylamine.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([O:20][C:17]2[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Br
Reactant: COc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Oc2ccc(Cl)cc2[N+](=O)[O-])cc1
Temperature: 80 °C
Yield: 67.8 %

Procedure:
1-Bromo-4-chloro-2-nitrobenzene (10 g, 42.2 mmol) was added to a solution of 4-methoxyphenol (5.3 g, 42.2 mmol), and K2CO3 (14.5 g, 105 mmol) in DMF (50 mL). The mixture was heated at 80° C. for 16 h. The reaction was poured into water. The aqueous phase was extracted with ethyl acetate and the combined phases were washed with water, brine, and dried over sodium sulfate, filtered and concentrated under vacuum giving the crude title compound. The crude product was purified by silica gel chromatography eluting with (hexanes/ethyl acetate 90:10) to give the title compound (8.0 g, 67%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([N+:29]([O-:31])=[O:30])=[C:11]([F:28])[CH:12]=[C:13]([CH:15](C(OCC)=O)[C:16]([O:18][C:19](C)(C)[CH3:20])=[O:17])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]1[C:10]([N+:29]([O-:31])=[O:30])=[C:11]([F:28])[CH:12]=[C:13]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C(=O)OC(C)(C)C)c1cc(F)c([N+](=O)[O-])c(OCc2ccccc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)Cc1cc(F)c([N+](=O)[O-])c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 70.6 %

Procedure:
In methylene chloride (30 ml) was dissolved tert-butyl ethyl 5-benzyloxy-3-fluoro-4-nitrophenylmalonate (2.89 g, 6.67 mmol) . To the resulting solution was added trifluoroacetic acid (30 ml). The resulting mixture was stirred at room temperature for 3.5 hours. The reaction mixture was distilled under reduced pressure to remove the solvent. The residue was neutralized with an aqueous saturated solution of sodium bicarbonate, followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from ethyl acetate/hexane (1/5) eluate fractions, ethyl 5-benzyloxy-3-fluoro-4-nitrophenylacetate (1.57 g, 70%) was obtained as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[OH:25])[C:5]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:6].Cl[S:27]([C:30]1[CH:38]=[CH:37][C:33]([C:34]([OH:36])=[O:35])=[C:32]([OH:39])[CH:31]=1)(=[O:29])=[O:28].[K+].[Br-]>>[Br:1][C:2]1[CH:3]=[C:4]([C:5](=[O:6])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:22]=[CH:23][C:24]=1[O:25][S:27]([C:30]1[CH:38]=[CH:37][C:33]([C:34]([OH:36])=[O:35])=[C:32]([OH:39])[CH:31]=1)(=[O:29])=[O:28]
Reactant: O=C(NCCCCCCCCc1ccccc1)c1ccc(O)c(Br)c1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Agent: [Br-]
Agent: [K+]
Product: O=C(NCCCCCCCCc1ccccc1)c1ccc(OS(=O)(=O)c2ccc(C(=O)O)c(O)c2)c(Br)c1

Procedure:
The title compound was prepared as a white solid (0.388 g, 40%) from 3-bromo-4-hydroxy-N-(8-phenyloctyl)benzamide and 4-chlorosulfonyl-2-hydroxy-benzoic acid using a procedure similar to step 3 of Example 179. 1H NMR (DMSO-d6) δ 8.57 (bt, 1H); 8.50 (d, 1H); 7.99 (dd, 1H); 7.86 (dd, 1H); 7.38–7.32 (m, 3H); 7.26–7.10 (m, 5H); 3.50 (bs, 2H); 3.20 (dd, 2H); 2.53 (t, 2H); 1.50 (m, 4H); 1.28 (m, 8H); IR (KBr) 3480, 3350, 2950, 2850, 1900, 1690, 1630, 1600, 1580, 1540, 1480, 1450, 1360, 1285, 1250, 1205, 1180, 1110, 1080, 1040, 930, 860 cm−1; mass spectrum [(+)APCI], m/z 604 (M+H)+; Anal. Calcd. for C28H30BrNO7S: C, 55.63; H, 5.00; N, 2.32. Found: C, 54.33; H, 5.11; N, 1.95.
Reaction SMILES: [C:1](O)(=[O:23])[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][CH2:18][CH2:19][C:20](O)=[O:21].C1COCC1.O.C([O-])(O)=O.[Na+]>O>[CH2:20]([OH:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:23]
Reactant: O=C(O)CCCCCCCCCCCCCCCCCCC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: OCCCCCCCCCCCCCCCCCCCCO

Procedure:
Icosane-1,20-diol was synthesized according to Yoon et al., J. Org. Chem. 1973, 38(16), 2786-2792. Briefly, under N2 atmosphere to 25 g eicosanedioic acid 100 ml THF was added. Then 474.5 ml of borane/THF complex was added dropwise over 1.5 hours. The mixture was refluxed over night before 200 ml THF/H2O 1:1 were added dropwise. Under further stirring 100 g NaHCO3 dissolved in 250 ml H2O was added and two hours later 1000 ml H2O was added to the mixture and the precipitate was removed by filtration. At the next day and the day after next a white precipitate was removed by filtration from the mixture, dried and recrystallized from acetic acid ethyl ester. The product was characterized by thin layer chromatography and 1H-NMR.
Reaction SMILES: C([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH2:11][C:10]1([F:27])[F:26])C1C=CC=CC=1>CO.[Pd]>[F:27][C:10]1([F:26])[CH:9]([NH2:8])[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[CH2:11]1
Reactant: Fc1ccc(OCCCN2CCC(NCc3ccccc3)C(F)(F)C2)cc1
Agent: [Pd]
Solvent: CO
Product: NC1CCN(CCCOc2ccc(F)cc2)CC1(F)F
Temperature: 25 °C
Reaction time: 15 h
Yield: 90.9 %

Procedure:
In a dry pressure vessel, 0.83 g (2.2 mmol) of benzyl-{3,3-difluoro-1-[3-(4-fluoro-phenoxy)propyl]piperidin-4-yl}amine 15 was dissolved in 10 mL of methanol. After adding 0.33 g (40 wt %) of Pd/C (10%) at 0° C., the mixture was stirred during 15 hours at room temperature under hydrogen pressure of 480 kPa. The mixture was filtered over diatomaceous earth. The solvent was evaporated in vacuo to yield 0.57 g (2.0 mmol; 90% yield) of 3,3-difluoro-1-[3-(4-fluorophenoxy)propyl]piperidin-4-amine 16 as a yellow oil.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][C:29]=1[CH3:30])[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:13]=[C:12]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[C:11]=1[O:25][CH3:26])=[O:8])=[N+:2]=[N-:3].[C:31]([C:33]1[CH:34]=[CH:35][C:36]([NH:39][CH3:40])=[N:37][CH:38]=1)#[CH:32]>>[C:16]([C:14]1[CH:13]=[C:12]([NH:20][S:21]([CH3:24])(=[O:22])=[O:23])[C:11]([O:25][CH3:26])=[C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:27]=[CH:28][C:29]([CH3:30])=[C:4]([N:1]3[CH:32]=[C:31]([C:33]4[CH:38]=[N:37][C:36]([NH:39][CH3:40])=[CH:35][CH:34]=4)[N:3]=[N:2]3)[CH:5]=2)[CH:15]=1)([CH3:18])([CH3:19])[CH3:17]
Reactant: C#Cc1ccc(NC)nc1
Reactant: COc1c(NC(=O)c2ccc(C)c(N=[N+]=[N-])c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Product: CNc1ccc(-c2cn(-c3cc(C(=O)Nc4cc(C(C)(C)C)cc(NS(C)(=O)=O)c4OC)ccc3C)nn2)cn1

Procedure:
Example 19 was prepared from 3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide and (5-ethynyl-pyridin-2-yl)-methyl-amine in the same manner as Example 15. ESI MS m/z 564 [C28H33N7O4S+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH:18]2[CH2:20][CH2:19]2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:5]2=[N:21][CH:22]=[C:23]([C:24]#[N:25])[N:4]2[N:3]=1.[NH2:26][C:27]1[C:28]([Cl:40])=[CH:29][C:30]([CH2:35][CH2:36][C:37](=[O:39])[CH3:38])=[C:31]([CH:34]=1)[C:32]#[N:33].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].O1CCOCC1>[Cl:40][C:28]1[CH:29]=[C:30]([CH2:35][CH2:36][C:37](=[O:39])[CH3:38])[C:31]([C:32]#[N:33])=[CH:34][C:27]=1[NH:26][C:2]1[N:7]=[C:6]([N:8]([CH:18]2[CH2:19][CH2:20]2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:5]2=[N:21][CH:22]=[C:23]([C:24]#[N:25])[N:4]2[N:3]=1
Reactant: COc1ccc(CN(c2nc(Cl)nn3c(C#N)cnc23)C2CC2)cc1
Reactant: CC(=O)CCc1cc(Cl)c(N)cc1C#N
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: COc1ccc(CN(c2nc(Nc3cc(C#N)c(CCC(C)=O)cc3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Temperature: 90 °C
Yield: 75.2 %

Procedure:
2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (150 mg, 0.423 mmol), 5-amino-4-chloro-2-(3-oxobutyl)benzonitrile (104 mg, 0.465 mmol), palladium (II) acetate (28.5 mg, 0.127 mmol), DPPF (23.4 mg, 0.042 mmol), Xantphos (24.5 mg, 0.042 mmol), and cesium carbonate (207 mg, 0.643 mmol) were combined in a 20 dram vial and dioxane (2 mL) was added. The vial was evacuated and backfilled with N2 3×, then heated at 90° C. for 1.5 h. The reaction was cooled to room temperature and the reaction mixture was filtered through celite, rinsing with EtOAc. The solvent was removed in vacuo and the material was purified by ISCO Companion (0-100% EtOAc/Hexane). 2-((2-chloro-5-cyano-4-(3-oxobutyl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl) amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (172 mg) was obtained as a yellow foam.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][C:7]([F:11])=[CH:8][CH:9]=2)[N:4]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:3]=1.CC1(C)C(C)(C)OB([C:29]2[CH:30]=[N:31][N:32]([C:34]3[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=3)[CH:33]=2)O1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:11][C:7]1[CH:6]=[C:5]2[C:10]([C:2]([C:29]3[CH:30]=[N:31][N:32]([C:34]4[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=4)[CH:33]=3)=[CH:3][N:4]2[S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:9][CH:8]=1
Reactant: CC1(C)OB(c2cnn(-c3ccncc3)c2)OC1(C)C
Reactant: O=S(=O)(c1ccccc1)n1cc(Br)c2ccc(F)cc21
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: O=S(=O)(c1ccccc1)n1cc(-c2cnn(-c3ccncc3)c2)c2ccc(F)cc21
Yield: 96.4 %

Procedure:
A mixture of 3-bromo-6-fluoro-1-(phenylsulfonyl)-1H-indole (Intermediate 2; 317 mg; 0.9 mmol) and 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)pyridine (Intermediate 9; 485 mg; 1.80 mmol), Pd2 dba3 (48 mg; 0.05 mmol) and X-phos (96 mg; 0.20 mmol), and K3PO4 (954 mg; 4.5 mmol) in 1,4-dioxane (8 mL) and water (1 mL) was flushed with argonand reacted at 125° C. for 25 minutes in a microwave reactor. The reaction mixture was filtered through Celite, washed with EtOAc (50 mL), concentrated, and purified by a silica gel chromatography (petroleum ether/EtOAc=1/1) to afford 363 mg (96%) of the title compound as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][C:9]1[CH:10]=[C:11]([CH:26]=[C:27]([O:29][CH2:30][CH2:31][NH:32][C:33]2[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=2)[CH:28]=1)[C:12]([N:14]([CH:23]([CH3:25])[CH3:24])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=O)=[O:13].C[N:40](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.N>CN(C=O)C.O1CCOCC1>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:20]([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][N:14]([CH:23]([CH3:25])[CH3:24])[C:12](=[O:13])[C:11]1[CH:26]=[C:27]([O:29][CH2:30][CH2:31][NH:32][C:33]2[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=2)[CH:28]=[C:9]([CH3:8])[CH:10]=1)(=[O:22])[NH2:40]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1cc(OCCNc2ccncc2)cc(C(=O)N(CCCCCC(=O)O)C(C)C)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(OCCNc2ccncc2)cc(C(=O)N(CCCCCC(N)=O)C(C)C)c1
Reaction time: 8 h

Procedure:
To a solution of 6-[{3-methyl-5-[2-(pyridin-4-ylamino)-ethoxy]-benzoyl}-(isopropyl)-amino]-hexanoic acid trifluoroacetate (0.022 g) in DMF (1 ml) was added HATU® (0.039 g), DIPEA (0.018 ml) and 0.5M ammonia in 1,4-dioxane solution (0.2 ml). The mixture was stirred overnight. The reaction mixture was evaporated under reduced pressure, the residue obtained was subjected to preparative hplc to give the title compound as a colourless oil (0.008 g).