Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:43]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.[N:44]([C:47]1[CH:52]=[CH:51][CH:50]=[C:49]([C:53]([F:56])([F:55])[F:54])[CH:48]=1)=[C:45]=[O:46]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:43]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[N:37]1[CH2:42][CH2:41][N:40]([C:45]([NH:44][C:47]2[CH:52]=[CH:51][CH:50]=[C:49]([C:53]([F:54])([F:55])[F:56])[CH:48]=2)=[O:46])[CH2:39][CH2:38]1
Reactant: Clc1cnc2nc1Nc1ccc(N3CCNCC3)c(c1)CCc1cccc(c1)N2
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cccc(C(F)(F)F)c1)N1CCN(c2ccc3cc2CCc2cccc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 44 %

Procedure:
The desired compound was prepared according to the procedure of Example D41 using 6-chloro-12-piperazin-1-yl-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene bis(trifluoroacetate) and 1-isocyanato-3-(trifluoromethyl)benzene as the starting materials in 44% yield. LCMS for C30H28ClF3N7O (M+H)+: m/z=594.0. 1H NMR (400 MHz, DMSO-d6): δ 9.67 (br s, 1H), 9.55 (br s, 1H), 8.94 (s, 1H), 8.18 (s, 1H), 7.95-7.92 (m, 2H), 7.77-7.75 (m, 2H), 7.47 (dd, J=8.0, 8.0 Hz, 1H), 7.27 (d, J=7.8 Hz, 1H), 7.14-7.02 (m, 3H), 6.88-6.85 (m, 2H), 3.64 (br s, 4H), 3.01 (s, 4H), 2.85-2.82 (m, 4H).
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.C(N(CC)C(C)C)(C)C.Cl[CH2:22][C:23]1[CH:39]=[CH:38][C:26]([CH2:27][NH:28][S:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)(=[O:31])=[O:30])=[CH:25][CH:24]=1>>[N:10]1[C:11]2[CH:2]([NH:1][CH2:22][C:23]3[CH:24]=[CH:25][C:26]([CH2:27][NH:28][S:29]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=4)(=[O:30])=[O:31])=[CH:38][CH:39]=3)[CH2:3][CH2:4][CH2:5][C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: NC1CCCc2cccnc21
Reactant: O=S(=O)(NCc1ccc(CCl)cc1)c1ccccn1
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(NCc1ccc(CNC2CCCc3cccnc32)cc1)c1ccccn1

Procedure:
Reaction of 8-amino-5,6,7,8-tetrahydroquinoline (200 mg, 1.35 mmol), N,N-diisopropylethylamine (157 μL, 0.90 mmol) and pyridine-2-sulfonic acid 4-chloromethyl-benzylamide (266 mg, 0.90 mmol) for 3 h at 50° C. followed by column chromatography on silica gel (CH2Cl2/MeOH/NH4OH 98:1:1) gave AMD9426 (150 mg, 41%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 1.68-1.79 (m, 2H), 1.97-2.03 (m, 1H), 2.12-2.20 (m, 1H), 2.69-2.84 (m, 3H), 3.77-3.81 (m, 2H), 3.92 (d, 1H, J=12.0 Hz), 4.20 (br s, 2H), 7.05 (dd, 1H, J=7.5, 4.8 Hz), 7.15 (d, 2H, J=7.8 Hz), 7.25 (d, 2H, J=7.8 Hz), 7.36 (d, 1H, J=7.5 Hz), 7.39-7.44 (m, 1H), 7.82 (ddd, 1H, J=7.8, 7.8, 1.5 Hz), 7.92 (d, 1H, J=7.8 Hz), 8.36 (d, 1H, J=3.9 Hz), 8.59 (d, 1H, J=4.2 Hz); 13C NMR (75.5 MHz, CDCl3) δ 20.09, 28.94, 29.23, 47.80, 51.75, 57.87, 122.25, 122.63, 126.94, 128.45 (2C), 128.88 (2C), 132.88, 135.25, 137.30, 138.35, 147.68, 147.15, 150.34, 157.75, 157.95. ES-MS m/z 409 (M+H). Anal. Calcd. for C22 H24N4O2S•0.2 H2O•0.3CH2Cl2: C, 61.21; H, 5.76; N, 12.80; S, 7.33; 0, 8.04. Found: C, 60.82; H, 5.73; N, 12.42; S, 7.30; O, 8.14.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[CH:26]([O:29][C:30]1[C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][CH:33]=[CH:32][N:31]=1)([CH3:28])[CH3:27]>CN(C=O)C>[CH:26]([O:29][C:30]1[C:35]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N:8]([CH3:25])[C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)=[CH:34][CH:33]=[CH:32][N:31]=1)([CH3:28])[CH3:27]
Reactant: CC(C)Oc1ncccc1B1OC(C)(C)C(C)(C)O1
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1Br
Solvent: CN(C)C=O
Product: CC(C)Oc1ncccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 25, from N-(4-bromo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 25, intermediate a) and 2-isopropoxypyridine-3-boronic acid pinacol ester (CAS RN 848243-25-4) and using DMF as reaction solvent. Off-white solid (13%). MS (ESI): m/z=483.8 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:5]([O:7][C:8](=[O:9])[C:3]=12)=O.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=1.C(O)(=O)C>O>[OH:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:3]=1[C:8](=[O:9])[N:20]([CH2:19][C:18]1[CH:21]=[CH:22][C:15]([O:14][CH3:13])=[CH:16][CH:17]=1)[C:5]2=[O:7]
Reactant: COc1ccc(CN)cc1
Reactant: O=C1OC(=O)c2c(O)cccc21
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(CN2C(=O)c3cccc(O)c3C2=O)cc1
Temperature: 100 °C
Yield: 81.1 %

Procedure:
A mixture of 3-hydroxyphthalic anhydride (543 mg, 3.31 mmol), 4-methoxybenzylamine (0.43 mL, 3.31 mmol) and acetic acid (3 mL) was heated at 100° C. for 4 hours. The mixture was allowed to cool and diluted with water (20 mL). The white solid was collected by filtration, washed well with water and dried to give the title compound (760 mg, 81%). 1H NMR (DMSO-d6) 11.03 (1H, s), 7.61 (1H, dd), 7.28 (1H, d), 7.23-7.19 (3H, m), 6.89-6.86 (2H, m), 4.63 (2H, s), 3.71 (3H, s). MS: [M−H+] 282.
Reaction SMILES: [ClH:1].Cl.Cl.[NH:4]1[CH:8]=[C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[CH:18][C:19]([C:21]4[CH:22]=N[CH:24]=[CH:25][CH:26]=4)=[CH:20][C:15]=3[CH2:14][N:13]([C:27](=[O:32])[C:28](F)(F)F)[CH:12]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:11]2)[N:6]=[CH:5]1.[CH3:40]NC>CN(C=O)C>[ClH:1].[C:27]([N:13]1[CH2:14][C:15]2[CH:20]=[C:19]([C:21]3[CH:22]=[CH:40][CH:24]=[CH:25][CH:26]=3)[CH:18]=[CH:17][C:16]=2[N:10]([CH2:9][C:7]2[N:6]=[CH:5][NH:4][CH:8]=2)[CH2:11][C@H:12]1[CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)(=[O:32])[CH3:28]
Reactant: O=C(N1Cc2cc(-c3cccnc3)ccc2N(Cc2c[nH]cn2)CC1Cc1ccccc1)C(F)(F)F
Reactant: CNC
Agent: Cl
Solvent: CN(C)C=O
Product: CC(=O)N1Cc2cc(-c3ccccc3)ccc2N(Cc2c[nH]cn2)C[C@H]1Cc1ccccc1

Procedure:
A solution of Compound B (7 g) and dimethylamine (2.0 M in THF, 75 mL, 150 mmol) in DMF (150 mL) was warmed to 80° C. (sealed tube) for 30 hr. The DMF was removed. The residue was passed through a short silica gel colum (5% MeOH, 0.5% NH4OH in CH2Cl2). The eluant was evaporated and the residue was purified by reverse phase preparative HPLC (gradient of aqueous methanol with 0.1% TFA) and converted to the HCl salt to provide Compound C as an off white solid (5.0 g, 60% from Compound D of Example 226) MS: (M+H)+ 544
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)[CH:9]=2)[N:5]=[C:4]([C:21]#[N:22])[N:3]=1.Cl.[NH2:24][OH:25].CCN(C(C)C)C(C)C>CCO>[OH:25][NH:24][C:21]([C:4]1[N:3]=[C:2]([CH3:1])[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N:14]3[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]3)[CH:9]=2)[N:5]=1)=[NH:22]
Reactant: NO
Reactant: Cc1nc(C#N)nn1Cc1cccc(N2CCN(C)CC2)c1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(C(=N)NO)nn1Cc1cccc(N2CCN(C)CC2)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 5-methyl-1-(3-(4-methylpiperazin-1-yl)benzyl)-1H-1,2,4-triazole-3-carbonitrile (120 mg, 0.40 mmol) in EtOH (2 mL) was added hydroxylamine hydrochloride (31 mg, 0.44 mmol) and DIPEA (141 μL, 0.81 mmol). The reaction was stirred at 80° C. for 2 h before the solvent was removed under reduced pressure. The crude product was used without further purification. MS (ES+) C16H23N7O requires: 329 found: 330 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C(=O)([O-])[O-].[K+].[K+].Br[CH:19]([Cl:21])[CH3:20]>CC(=O)CC>[Cl:21][CH2:19][CH2:20][O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: CC(Cl)Br
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=[N+]([O-])c1cc(OCCCl)ccc1Cl
Temperature: 25 °C

Procedure:
To a 500 mL 3-neck round-bottom flask was added 4-chloro-3-nitro-phenol (10 g, 0.058 mol), potassium carbonate (20 g, 0.14 mol), bromochloroethane (34.5 g, 0.24 mol) and 2-butanone (200 mL). The mixture was mechanically stirred and heated to reflux for 20 hours under nitrogen then allowed to cool to room temperature and the solids were filtered. The solvent was evaporated under vacuum and the oil dissolved in diethyl ether (300 mL) and washed with 10% sodium hydroxide. The organic layer was dried over anhydrous magnesium sulfate, filtered and the solvent removed under vacuum. The product was dissolved in 1:1 methylene chloride-hexanes and filtered through a short pad silica. Upon concentration and standing 12.9 g (94.8.% %) of light yellow crystalline solid was afforded: mp 46°-48° C.; MS EI m/e 235, 237, 239 (M+); 1H NMR (400 MHz, DMSO-d6) δ 3.95 (t, 2H, J=5.2 Hz), 4.36 (t, 2H, J=5.2 Hz), 7.32 (dd, 1H, J=3.2, J=8.9 Hz), 7.66, (d, 1H, J=9 Hz), 7.69, (d, 1H, J=3.2 Hz).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:33][CH2:32][C:12]3([N:16]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=4)[C:15](=[O:24])[N:14]=[C:13]3[NH:25][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.CC(C)([O-])C.[Na+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:86]([NH2:93])[C:87]1[CH:92]=[CH:91][CH:90]=[CH:89][CH:88]=1.FC(F)(F)C([O-])=O.FC(F)(F)C([O-])=O.C(NC1[NH+]=CC(C[NH+]2CCC3(N(C4C=CC=C(F)C=4)C(=O)N=C3NC3CCCCC3)CC2)=CC=1)C1C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH2:86]([NH:93][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:33][CH2:32][C:12]3([N:16]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=4)[C:15](=[O:24])[N:14]=[C:13]3[NH:25][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1)[C:87]1[CH:92]=[CH:91][CH:90]=[CH:89][CH:88]=1
Reactant: O=C1N=C(NC2CCCCC2)C2(CCN(Cc3ccc(Br)nc3)CC2)N1c1cccc(F)c1
Reactant: NCc1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: O=C1N=C(NC2CCCCC2)C2(CCN(Cc3ccc(NCc4ccccc4)nc3)CC2)N1c1cccc(F)c1
Temperature: 110 °C

Procedure:
To a 600 μL dried degassed toluene suspension of 27 mg (0.052 mmol) 8-[(6-bromopyridin-3-yl)methyl]-4-(cyclohexylamino)-1-(3-fluorophenyl)-1,3,8-triazaspiro[4.5]dec-3-en-2-one (8-1, prepared in the same manner as Intermediate 5-3), 9 mg (0.094 mmol) sodium t-butoxide, 2 mg (0.003 mmol) racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP), and 2 mg (0.003 mmol) tris(dibenzylideneacetone)dipalladium (0) was added 29 μL (0.262 mmol) benzylamine. The reaction vessel was capped and warmed to 110° C. overnight. The clear toluene layer was decanted and the residue extracted (2× hot toluene). The combined organic extracts were concentrated to dryness in vacuo, the residue dissolved in 900 μL DMF and purified by preparative HPLC (5→95% CH3CN/H2O over 30 m, 0.05% added TFA, C18 PRO YMC 20×150 mm) to afford, after lyophilization, 8-{[6-(benzylamino)pyridinium-3-yl]methyl}-4-(cyclohexylamino)-1-(3-fluorophenyl)-2-oxo-1,3-diaza-8-azoniaspiro[4.5]dec-3-ene bis(trifluoroacetate) as a white fluffy solid. 1H NMR (CD3OD with K2CO3, 400 MHz): δ 7.70 (s, 1H), 7.34 (m, 5H), 7.23 (m, 2H), 7.08 (m, 3H), 6.47 (d, J=8.60 Hz, 1H), 4.49 (s, 2H), 3.77 (m, 1H), 3.28 (s, 2H), 2.68 (m, 2H), 2.12 (m, 4H), 2.00 (m, 4H), 1.80 (m, 2H), 1.68 (m, 1H), 1.33 (m, 5H). High resolution mass spec (FT/ICR): calc M+H=541.3086. found 541.3103
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:9]2[N:10]([CH3:26])[CH:11]=[C:12]([C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)=[O:16])[C:13](=[O:14])[C:8]=2[S:7][C:6]=1[CH2:27][N:28]([CH2:30][C@@H:31]([OH:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)[CH3:29])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[NH2:1][CH2:4][C:5]1[C:9]2[N:10]([CH3:26])[CH:11]=[C:12]([C:15]([NH:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=3)=[O:16])[C:13](=[O:14])[C:8]=2[S:7][C:6]=1[CH2:27][N:28]([CH2:30][C@@H:31]([OH:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)[CH3:29]
Reactant: CN(Cc1sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c2c1CN=[N+]=[N-])C[C@@H](O)c1ccccn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CN(Cc1sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c2c1CN)C[C@@H](O)c1ccccn1
Yield: 78.6 %

Procedure:
A solution of 111 mg of 3-(azidomethyl)-N-(4-chlorobenzyl)-2-{[[(2R)-2-hydroxy-2-pyridin-2-ylethyl](methyl)amino]methyl}-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide and 58 mg of triphenylphosphine in 2 mL of THF containing 5 drops of water is stirred overnight, then concentrated under reduced pressure with CHCl3/MeOH azeotrope. Flash chromatography on silica gel using 4-10% methanolic ammonia in CH2Cl2 provides 83.1 mg of the amine as a white solid. Recrystallization from acetonitrile furnishes white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:10][C:9]2[C:4](=[C:5]([CH3:15])[C:6]([CH3:14])=[C:7]([CH:12]=O)[C:8]=2[CH3:11])[CH2:3]1.O.[OH-].[Na+].Cl.[CH3:21][C:22]([CH3:24])=[O:23]>>[CH3:1][C:2]1([CH3:16])[CH2:3][C:4]2[C:9](=[C:8]([CH3:11])[C:7]([CH3:12])=[C:6]([CH:14]=[CH:21][C:22](=[O:23])[CH3:24])[C:5]=2[CH3:15])[CH2:10]1
Reactant: CC(C)=O
Reactant: Cc1c(C)c2c(c(C)c1C=O)CC(C)(C)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)C=Cc1c(C)c(C)c2c(c1C)CC(C)(C)C2
Yield: 79 %

Procedure:
To a solution of 26.8 g of the 2,2,4,6,7-pentamethylindan-5-carboxaldehyde in 93 ml of absolute acetone was added 46 ml of water and 50 g of 2% NaOH. After refluxing for 20 hours, the solution was acidified with 2N HCl and extracted with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica-gel column chromatography to afford 25.36 g of the title compound as yellow solid.
Reaction SMILES: [NH2:1][CH:2]([CH2:8][C:9]1[CH:14]=[C:13]([F:15])[C:12]([F:16])=[CH:11][C:10]=1[F:17])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[C:18]([OH:28])(=[O:27])[C@@H:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[OH:20].O>C(O)(C)C>[C:18]([OH:28])(=[O:27])[C@@H:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[OH:20].[NH2:1][C@H:2]([CH2:8][C:9]1[CH:14]=[C:13]([F:15])[C:12]([F:16])=[CH:11][C:10]=1[F:17])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)CC(N)Cc1cc(F)c(F)cc1F
Agent: O=C(O)[C@H](O)c1ccccc1
Solvent: CC(C)O
Solvent: O
Product: COC(=O)C[C@H](N)Cc1cc(F)c(F)cc1F
Temperature: 77.5 °C
Reaction time: 0.25 h
Yield: 80 %

Procedure:
The methyl(3RS)-3-amino-4-(2,4,5-trifluorophenyl)butanoate (260 gm, 1.05 mol) (29) was charged in isopropanol (6.0 vol, 1.56 Ltr) at 25-30° C. and the reaction mixture was stirred for 15 minutes to give a clear solution. After 15 minutes stirring, controlled addition of a solution of (R)-(−)-mandelic acid [2.0 eq, 320 gm in 6.0 vol, 1.56 Ltr of isopropanol] was carried out. After completion of the addition, the reaction mixture was stirred at 25-30° C. for 3 hours to give enantiomerically enriched crude methyl(3R)-3-amino-4-(2,4,5-trifluorophenyl)butanoate (R)-(−)-mandelate as a white coloured product. The product was filtered, washed with isopropanol (1.0 vol, 260 ml), and dried in a vacuum oven at 40-45° C. for 4-5 hours to give enantiomerically enriched crude methyl(3R)-3-amino-4-(2,4,5-trifluorophenyl)butanoate (R)-(−)-mandelate (135 gm, molar yield: 64%). The dried enantiomerically enriched crude methyl(3R)-3-amino-4-(2,4,5-trifluorophenyl)butanoate (R)-(−)-mandelate product (135 gm) was charged in isopropanol (20.0 vol, 2.7 Ltr) at 25-30° C. and the white suspension was further heated at 75-80° C. for 0.5 hour to give a partially clear solution. The partially clear solution was made clear by the addition of water (2.0 vol, 270.0 ml) at 75-80° C. The clear solution was further stirred for 0.5 hour. After stirring for 0.5 hour, the clear solution was gradually cooled to 0-5° C. within 3 hours to give enantiomerically enriched pure methyl(3R)-3-amino-4-(2,4,5-trifluorophenyl)butanoate (R)-(−)-mandelate (30) as white coloured product. The product was filtered, washed with isopropanol (1.0 vol, 135.0 ml), and dried in a vacuum oven at 40-45° C. for 4-5 hours.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@@H:11]([C:15](O)=[O:16])[CH2:10]2)=[CH:5][C:4]=1[C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:20]=2[N:19]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:52]1([CH2:58][CH2:59][NH2:60])[CH2:57][CH2:56][O:55][CH2:54][CH2:53]1.C([O-])(O)=O.[Na+]>ClCCl>[N:52]1([CH2:58][CH2:59][NH:60][C:15]([C@@H:11]2[CH2:12][CH2:13][CH2:14][N:9]([C:6]3[CH:7]=[CH:8][C:3]([Cl:2])=[C:4]([C:18]4[NH:22][C:21]5[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:20]=5[N:19]=4)[CH:5]=3)[CH2:10]2)=[O:16])[CH2:57][CH2:56][O:55][CH2:54][CH2:53]1
Reactant: NCCN1CCOCC1
Reactant: Cc1ccc2[nH]c(-c3cc(N4CCC[C@@H](C(=O)O)C4)ccc3Cl)nc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: Cc1ccc2[nH]c(-c3cc(N4CCC[C@@H](C(=O)NCCN5CCOCC5)C4)ccc3Cl)nc2c1
Temperature: 35 °C
Yield: 41.5 %

Procedure:
Method O—Step a To a vial with (R)-1-[4-Chloro-3-(5-methyl-1H-benzoimidazol-2-yl)-phenyl]-piperidine-3-carboxylic acid hydrochloride (obtained as described in general method 3,4, step e) (0.10 g, 0.25 mmol), HATU (0.10 g, 0.26 mmol), TEA (0.07 mL, 0.53 mmol) and 2-morpholin-4-yl-ethylamine (0.04 mL, 0.33 mmol), dichloromethane (2 mL) was added and the reaction mixture was heated at 35° C. overnight. Reaction was cooled to room temperature, saturated NaHCO3 solution (2 mL) was added with stirring, the organic layer recovered by filtration through phase separator, and the solvent removed under reduced pressure. The crude was purified by SCX and flash chromatography (eluent; gradient cyclohexane:ethylacetate from 100:0 to 3:1) to obtain 0.05 g of the title compound (42%).
Reaction SMILES: C([O:3][C:4](=[O:17])[C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]([N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[CH:6]=1)C.[ClH:18]>>[ClH:18].[CH2:15]([N:12]([CH2:13][CH3:14])[C:7]1[CH:6]=[C:5]([CH:10]=[C:9]([CH3:11])[N:8]=1)[C:4]([OH:17])=[O:3])[CH3:16]
Reactant: CCOC(=O)c1cc(C)nc(N(CC)CC)c1
Agent: Cl
Product: CCN(CC)c1cc(C(=O)O)cc(C)n1

Procedure:
A solution of 2-diethylamino-6-methyl-isonicotinic acid ethyl ester (6.39 g, 27.0 mmol) in 6 N aq. HCl (100 mL) is stirred at 80° C. for 72 h before the solvent is removed in vacuo. The remaining solid is dried under high vacuum to give 2-diethylamino-6-methyl-isonicotinic acid hydrochloride (6.96 g) as a yellow solid; LC-MS: tR=0.53 min, [M+H]+=209.09; 1H NMR (D6-DMSO): δ 1.17 (t, J=6.8 Hz, 6H), 2.51 (s, 3H), 3.68 (q, J=6.3 Hz, 4H), 6.96 (s, 1H), 7.15 (s br, 1H).
Reaction SMILES: [P:1](=[O:5])([OH:4])([OH:3])[OH:2].[O-2].[O-2].[O-2].[O-2].[O-2].[V+5:11].[V+5]>>[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[V+5:11].[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[V+5:11].[V+5:11]
Reactant: O=P(O)(O)O
Agent: [V+5]
Agent: [O-2]
Product: O=P([O-])([O-])[O-]
Reaction time: 72 h

Procedure:
32 g of 85% phosphoric acid was thoroughly mixed with 10 g of vanadium pentoxide. The mixture was left to stand for 3 days. The mixture was then washed with methyl alcohol to remove unreacted phosphoric acid. The product was dried and calcined in air at 500° C. for 3 hours.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[C:19]([Cl:21])[N:18]=[C:17]([Cl:22])[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>C(O)C.Cl.O1CCOCC1>[ClH:21].[ClH:21].[Cl:22][C:17]1[N:16]=[C:15]([NH:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:20]=[C:19]([Cl:21])[N:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(Cl)nc(Cl)n2)CC1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: Clc1cc(NC2CCNCC2)nc(Cl)n1

Procedure:
A solution of 4-(2,6-dichloro-pyrimidin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (3.1 g, 8.93 mmol) in ethanol (40 mL) and 4 M HCl in dioxane (70 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 247.3 [M+H]+.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[CH3:6][CH2:7][O:8][C:9]([CH:11]1[CH2:15][CH2:14][CH:13]([CH2:16][NH:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[N:12]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[O:10].CN1CCOCC1>ClCCl>[CH3:6][CH2:7][O:8][C:9]([CH:11]1[CH2:15][CH2:14][CH:13]([CH2:16][N:17]([CH2:18][C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[C:2]([O:4][CH3:5])=[O:3])[N:12]1[C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])=[O:10]
Reactant: COC(=O)Cl
Reactant: CCOC(=O)C1CCC(CNCC(=O)OC(C)(C)C)N1C(=O)OC(C)(C)C
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCOC(=O)C1CCC(CN(CC(=O)OC(C)(C)C)C(=O)OC)N1C(=O)OC(C)(C)C
Yield: 88.3 %

Procedure:
Methyl chloroformate (0.065 mL, 0.85 mmol) was added to a solution of 5-[(tert-butoxycarbonylmethyl-amino)-methyl]-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (300 mg, 0.77 mmol) and 4-methylmorpholine (0.12 mL, 1.2 mmol) in dichloromethane (10 mL) at 0° C. After 15 minutes the mixture was diluted with dichloromethane (30 mL) and washed with water (15 mL), saturated ammonium chloride (15 mL) and saturated sodium chloride (15 mL). The organic phase was dried over sodium sulfate and the solvent was removed under reduced pressure to provide 5-[(tert-butoxycarbonylmethyl-methoxycarbonyl-amino)-methyl]-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (304 mg, 0.68 mmol, 88%). C21H36N2O8 calculated 444.3, observed [M+1]+445.3; rt=2.58 min.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][OH:5].[OH-].[Na+].[CH2:9]([C:11]1([CH2:15]Br)[CH2:14][O:13][CH2:12]1)[CH3:10].CCCCCCC>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH2:9]([C:11]1([CH2:15][O:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:6])[CH2:14][O:13][CH2:12]1)[CH3:10]
Reactant: CCC1(CBr)COC1
Reactant: OCCCCO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCCC
Product: CCC1(COCCCCO)COC1
Temperature: 50 °C
Yield: 66.4 %

Procedure:
1,4-Butanediol (270 g (3.0 mol)), 96% sodium hydroxide (36 g (0.86 mol)) and tetrabutylammonium bromide (3.6 g (11.2 mmol)) were added to a glass flask having an inner volume of 1,000 ml equipped with a stirrer, a thermometer, a dropping funnel and an reflux condenser, and the mixture was warmed to 50° C. Subsequently 3-ethyl-3-bromomethyloxetane (108 g (0.6 mol)) synthesized by the same method as in Reference Example 4 was dropwise added while keeping the liquid temperature at 50-60° C. After the completion of the reaction, heptane (100 ml) and water (100 ml) were added to the reaction liquid (a bisoxetane ether compound generated in the amount of only 3% (an analysis value by a gas chromatography)), and a liquid separation was performed. Subsequently, a resultant aqueous layer was extracted with toluene (200 ml) three times. An extract (a toluene layer) was washed with water (50 ml), and the resultant was concentrated under reduced pressure. After the completion of drying, it was filtered and a resultant filtrate was concentrated under reduced pressure to give, as a colorless liquid, 3-ethyl-3-(4-hydroxybutyl)oxymethyloxetane (75 g) having a purity of 95% (an analysis value by a gas chromatography) (an isolated yield based on 3-ethyl-3-bromomethyloxetane: 63%).
Reaction SMILES: C([C:4]1[CH:13]=[CH:12][C:7]([O:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:5]=1)(C)C.[CH2:14]([C:21]1C=CC=CC=1OCCO)[CH2:15]CCCCC>>[CH:14]([C:6]1[CH:5]=[CH:4][CH:13]=[CH:12][C:7]=1[O:8][CH2:9][CH2:10][OH:11])([CH3:21])[CH3:15]
Reactant: CC(C)c1ccc(OCCO)cc1
Reactant: CCCCCCCc1ccccc1OCCO
Product: CC(C)c1ccccc1OCCO

Procedure:
2-(4-isopropylphenoxy)ethanol or 2-(heptyl-phenoxy)ethanol