Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH2:7][NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[N+:16]([C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)([O-:18])=[O:17].C(N(C(C)C)CC)(C)C>CN(C)C1C=CN=CC=1.ClCCl>[N+:16]([C:19]1[CH:20]=[CH:21][C:22]([C:23]([N:6]2[CH2:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH2:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=3)=[O:24])=[CH:26][CH:27]=1)([O-:18])=[O:17]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: c1ccc2c(c1)CNc1ccccc1C2
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(c1ccc([N+](=O)[O-])cc1)N1Cc2ccccc2Cc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.8 %

Procedure:
A mixture of 2.34 g (12 mmol) of 6,11-dihydro-5H-dibenz[b,e]azepine, 2.23 g (12 mmol) of 4-nitrobenzoyl chloride, 1.94 g (15 mmol) of diisopropylethylamine and 70.5 mg of 4-(dimethylamino)pyridine in 25 ml of dichloromethane is stirred at room temperature for 2 hours, refluxed for 3 hours and allowed to stand at room temperature for 2 days. The mixture is washed with water, 1N sodium bicarbonate, water, 1N HCl, brine and dried (Na2SO4). The solvent is removed to give 4.0 g of solid. Trituration with ethyl acetate and filtering gives 2.85 g of off-white crystals, m.p. 185°-188° C.
Reaction SMILES: C(C1C=CC(C(Cl)=O)=CC=1)CCCCCCC.[CH2:18]([C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].S(Cl)(Cl)=O.[CH3:39][CH:40]([CH2:58][CH3:59])[CH2:41][O:42][C:43]([C:45]1[CH:50]=[CH:49][C:48]([C:51]2[CH:56]=[CH:55][C:54](O)=[CH:53][CH:52]=2)=[CH:47][CH:46]=1)=[O:44]>C1(C)C=CC=CC=1.N1C=CC=CC=1>[CH3:39][CH:40]([CH2:58][CH3:59])[CH2:41][O:42][C:43]([C:45]1[CH:50]=[CH:49][C:48]([C:51]2[CH:56]=[CH:55][C:54]([O:31][C:30](=[O:32])[C:29]3[CH:28]=[CH:27][C:26]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:34][CH:33]=3)=[CH:53][CH:52]=2)=[CH:47][CH:46]=1)=[O:44]
Reactant: CCCCCCCCc1ccc(C(=O)O)cc1
Reactant: CCC(C)COC(=O)c1ccc(-c2ccc(O)cc2)cc1
Agent: CCCCCCCCc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: CCCCCCCCc1ccc(C(=O)Oc2ccc(-c3ccc(C(=O)OCC(C)CC)cc3)cc2)cc1

Procedure:
p-n-Octylbenzoic acid chloride prepared from 7 g of p-n-octylbenzoic acid and excess thionyl chloride was dissolved in toluene, and the solution was admixed with a pyridine solution of 8.3 g of said 4-hydroxy-4'-biphenylcarboxylic acid 2-methylbutyl ester for reaction at 80° C. for 3 hours. The crude product was obtained in the same manner as described in Example 1 and recrystallized twice from ethyl acetate to obtain p-n-octylbenzoic acid 4'-(2-methylbutoxycarbonyl)-4-biphenylyl ester.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][NH2+:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:10])(=[O:9])[N:8]=1.[CH3:23][NH:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][N:33]=1)[C:28](O)=[O:29]>>[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][N:18]3[C:28]([C:27]3[CH:31]=[CH:32][N:33]=[C:25]([NH:24][CH3:23])[CH:26]=3)=[O:29])=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:9])(=[O:10])[N:8]=1
Reactant: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCC[NH2+]3)c21
Reactant: CNc1cc(C(=O)O)ccn1
Agent: Cl
Product: CNc1cc(C(=O)N2CCCC[C@@H]2COc2cccc3c2C(N)=NS(=O)(=O)N3)ccn1

Procedure:
Prepared as in Example 15 from (R)-2-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidinium hydrochloride (Example 15a) and 2-(methylamino)isonicotinic acid. 1H NMR (400 MHz, DMSO-d6) δ 1.41 (m, 1H), 1.52-1.74 (m, 4H), 1.83 (m, 1H), 2.74 (d, 3H, J=4.6 Hz,), 3.19 (m, 1H), 3.40 (m, 1H), 4.19 (dd, 1H, J=9.9, 3.6 Hz,), 4.65 (t, 1H, J=10.1 Hz,), 5.20 (m, 1H), 6.30 (s, 1H), 6.61 (m, 2H), 6.88 (d, 1H, J=8.5 Hz), 7.46 (t, 1H, J=8.6 Hz,), 7.83 (br s, 1H), 8.01 (d, 1H, J=5.4 Hz,), 8.30 (br s, 1H), 10.93 (s, 1H). MS 445 (MH+).
Reaction SMILES: [NH2:1][C@H:2]([CH:10]=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH:12](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[CH2:13][C:14](O)=[O:15].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CN(C)C=O.ClCCl>[NH2:1][C@H:2]([C:10]([NH:12][CH2:13][CH:14]=[O:15])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)CNC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: N[C@H](C=O)Cc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N[C@@H](Cc1ccccc1)C(=O)NCC=O

Procedure:
Similar to comparative example 4, CTC-Phe-H was synthesized by the solid phase reaction method using CTC as a solid phase carrier. Then, to dichloromethane (2 ml) were added CTC-Phe-H (110 mg (0.145 mmol)), Fmoc-Gly-OH (120 mg (0.4 mmol)), HBTU (165 mg (0.4 mmol)), HOBt (60 mg (0.4 mmol)), dimethylformamide (1 ml) and diisopropylethylamine (75 μl (0.4 mmol)), respectively, and the mixture was stirred to react at room temperature for 2 hours. After the reaction, the solid phase was washed with dimethylformamide (3×2 ml), methanol (3×2 ml) and dichloromethane (3×2 ml), respectively. Subsequently, to the solid phase was added the previously prepared Fmoc deprotection solution (dimethylformamide:piperidine:DBU=96:2:2) (2 ml), and the mixture was stirred to react at room temperature for 1 hour to obtain CTC-Phe-Gly-H. This CTC-Phe-Gly-H was dissolved in dichloromethane (2 ml), and Fmoc-Ala-OH.H2O (130 mg (0.4 mmol)), HBTU (165 mg (0.4 mmol)), HOBt (60 mg (0.4 mmol)), dimethylformamide (1 ml) and diisopropylethylamine (75 μl (0.4 mmol)) were added, respectively, and the mixture was stirred to react at room temperature for 2 hours. After the reaction, the solid phase was washed with dimethylformamide (3×2 ml), methanol (3×2 ml), and dichloromethane (3×2 ml), respectively. Subsequently, to the solid phase was added the previously prepared Fmoc deprotection solution (dimethylformamide:piperidine:DBU=96:2:2) (2 ml), and the mixture was stirred to react at room temperature for 1 hour to obtain CTC-Phe-Gly-Ala-H.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5]2[N:6]([N:8]=[CH:9][CH:10]=2)[CH:7]=1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[H-].[Na+]>CN(C=O)C.C(OCC)C>[CH2:12]([O:11][C:4]1[C:5]2[N:6]([N:8]=[CH:9][CH:10]=2)[CH:7]=[C:2]([Br:1])[CH:3]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: Oc1cc(Br)cn2nccc12
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Brc1cc(OCc2ccccc2)c2ccnn2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
6-bromopyrazolo[1,5-a]pyridin-4-ol (1.10 g, 5.16 mmol) and benzyl bromide (0.676 ml, 5.68 mmol) were dissolved in DMF (20 ml) at 0° C. NaH (413 mg, 10.3 mmol, 60 wt %) was added in one portion and the mixture was allowed to stir at 0° C. After 30 minutes, additional benzyl bromide 0.068 ml, 0.57 mmol) was added and the mixture was allowed to stir 30 minutes at 0° C. The reaction mixture was diluted in diethyl ether, washed with saturated aqueous sodium hydrogen carbonate and brine then dried over magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate/isohexane gradient) to afford 4-(benzyloxy)-6-bromopyrazolo[1,5-a]pyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([NH2:11])=[O:10])[CH:5]=[N:6][C:7]=1[Cl:8].CO[C:14](OC)([N:16]([CH3:18])[CH3:17])[CH3:15]>>[CH3:17][N:16]([CH3:18])[C:14](=[N:11][C:9]([C:4]1[CH:5]=[N:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)=[O:10])[CH3:15]
Reactant: COC(C)(OC)N(C)C
Reactant: NC(=O)c1cnc(Cl)c(Cl)c1
Product: CC(=NC(=O)c1cnc(Cl)c(Cl)c1)N(C)C
Temperature: 120 °C
Yield: 42 %

Procedure:
A mixture of 5,6-dichloro-3-pyridinecarboxamide (4.0 g, 0.02 mol), dimethylacetamide dimethyl acetal (8 mL) was heated in an oil bath at 120° C. for three hours. The reaction mixture was cooled to room temperature and the solid recrystallised from ethyl acetate:hexane in the presence of activated carbon to give the desired product (2.3 g, 42%) as an orange solid.
Reaction SMILES: Cl[C:2](OC1C=CC([N+]([O-])=O)=CC=1)=[O:3].[NH2:14][C@H:15]([CH2:35][C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=1)[C:16]([N:18]1[CH2:23][CH2:22][C:21]([C:30](=[O:34])[CH2:31][CH2:32][CH3:33])([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:20][CH2:19]1)=[O:17].[NH4+].[OH-].Cl.Cl.[NH:48]1[CH:52]=[C:51]([CH2:53][CH2:54][NH2:55])[N:50]=[N:49]1.C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[C:30]([C:21]1([CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]2)[CH2:22][CH2:23][N:18]([C:16](=[O:17])[C@H:15]([NH:14][C:2]([NH:55][CH2:54][CH2:53][C:51]2[N:50]=[N:49][NH:48][CH:52]=2)=[O:3])[CH2:35][C:36]2[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=2)[CH2:19][CH2:20]1)(=[O:34])[CH2:31][CH2:32][CH3:33]
Reactant: CCCC(=O)C1(C2CCCCC2)CCN(C(=O)[C@H](N)Cc2ccc(OC)cc2)CC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: NCCc1c[nH]nn1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCC(=O)C1(C2CCCCC2)CCN(C(=O)[C@@H](Cc2ccc(OC)cc2)NC(=O)NCCc2c[nH]nn2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 32.3 %

Procedure:
30 mg (0.15 mmol) of 4-nitrophenyl chloroformate are added, at 0° C., to 57 mg (0.14 mmol) of 1-{1-[(R)-2-amino-3-(4-methoxyphenyl)propionyl]-4-cyclohexylpiperidin-4-yl}butan-1-one (cf. preparation 2-3) dissolved in 2 ml of DCM. The reaction mixture is stirred for 4 hours at room temperature. The reaction is stopped by adding aqueous NH4OH solution and the organic compounds are extracted with DCM. The organic phase is then washed with water and dried over MgSO4, filtered and concentrated. The oil obtained is dissolved in DMF at 80° C., and 52 mg (0.28 mmol) of 2-(1H-[1,2,3]triazol-4-yl)ethylamine dihydrochloride and 0.1 ml (0.72 mmol) of triethylamine are then added. The reaction mixture is stirred at 80° C. for 10 minutes. After cooling to room temperature, dichloromethane is added and the organic phase is washed with 1N sodium hydroxide. The organic phase is dried over MgSO4, filtered and concentrated. The crude product obtained is chromatographed on silica gel (eluent: 93/7 DCM/MeOH). 25 mg of 1-[(R)-2-(4-butyryl-4-cyclohexylpiperidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-[2-(1H-[1,2,3]triazol-4-yl)ethyl]urea are obtained in the form of a white solid in a yield of 32%.
Reaction SMILES: [CH3:1][NH2:2].[CH2:3]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][C:7]=1[CH:16]=O)[CH2:4][CH3:5].[BH4-].[Na+]>CO>[CH3:1][NH:2][CH2:16][C:7]1[CH:8]=[CH:9][C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]=1[CH2:3][CH2:4][CH3:5]
Reactant: CN
Reactant: CCCc1c(C=O)ccc2ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCc1c(CNC)ccc2ccccc12
Reaction time: 18 h
Yield: 89 %

Procedure:
A solution of 2.0 M methylamine in methanol (20 mL) was added to 1-propyl-naphthalene-2-carbaldehyde (0.983 g, 4.95 mmol) under N2 and allowed to stir for 18 h. The solution was concentrated under reduced pressure. Then the resulting dark yellow oil was solvated in EtOH (20 mL) under N2. To the solution was added NaBH4 (0.187 g, 4.95 mmol) and the mixture allowed to stir for 6.5 h. The reaction was concentrated under reduced pressure, then solvated in 1 N NaOH (20 mL) and extracted with Et2O (3×50 mL). The organics were combined, washed with brine (2×100 mL), dried over Na2SO4, filtered and concentrated to yield the title compound (0.94 g, 89%) as a yellow oil: 1H NMR (300 MHz, DMSO-d6) δ 7.87-7.73 (m, 4H), 7.51-7.43 (m, 3H), 3.53 (m, 1H), 2.09 (s, 3H), 1.70-1.52 (m, 2H), 1.26-1.12 (m, 2H), 0.87-0.79 (m, 3H).
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]1=O.[NH2:15][C:16]([NH2:18])=[S:17]>CCO>[C:8]1([CH:4]2[C:3]3[N:15]=[C:16]([NH2:18])[S:17][C:2]=3[CH2:7][CH2:6][CH2:5]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NC(N)=S
Reactant: O=C1C(Br)CCCC1c1ccccc1
Solvent: CCO
Product: Nc1nc2c(s1)CCCC2c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.9 %

Procedure:
A solution of 2-bromo-6-phenyl-cyclohexanone (4.32 g, 17 mmol) and thiourea (1.18 g, 16 mmol) in EtOH (150 mL) was heated to reflux for 12 hours. The solvent was evaporated, diethyl ether was added to the residue and stirred at room temperature for 1 hour, the solid filtered off and washed with diethylether. The solid was dissolved in ethyl acetate and the organic phase was washed three times with sodium carbonate solution. The organic phase was dried over sodium sulfate, the solvent was evaporated to give the title compound as a white solid (3.46 g, 88%). MS ISP (m/e): 231.1 [(M+H)+].
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:8]([CH2:9][OH:10])=[N:7][CH:6]=[N:5]1.Cl[C:12]1[C:13]([C:29]2([CH3:35])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:14][C:15]2[N:16]([C:18]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=3[F:28])=[N:19][N:20]=2)[N:17]=1>CN(C)C=O>[F:28][C:22]1[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:21]=1[C:18]1[N:16]2[N:17]=[C:12]([O:10][CH2:9][C:8]3[N:4]([CH3:3])[N:5]=[CH:6][N:7]=3)[C:13]([C:29]3([CH3:35])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:14][C:15]2=[N:20][N:19]=1
Reactant: Cn1ncnc1CO
Reactant: CC1(c2cc3nnc(-c4ccc(F)cc4F)n3nc2Cl)CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ncnc1COc1nn2c(-c3ccc(F)cc3F)nnc2cc1C1(C)CCCCC1
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% dispersion in oil, 13 mg, 0.33 mmol) was added to a stirred solution of (2-methyl-2H-1,2,4-triazol-3-yl)methanol (prepared using the conditions described in EP-A-421210; 37 mg, 0.33 mmol) in anhydrous N,N-dimethylformamide (5 ml) at room temperature under nitrogen. This was stirred for 30 mins and 6-chloro-3-(2,4-difluorophenyl)-7-(1-methylcyclohexyl)-1,2,4-triazolo[4,3-b]pyridazine (100 mg, 0.275 mmol) in N,N-dimethylformamide (3 ml) was then added and the mixture stirred for a further 60 minutes. The reaction was quenched with water (20 ml) and stirred for an additional 60 minutes. The precipitated solid was collected by filtration and washed with water. The solid was dissolved in dichloromethane (20 ml), filtered and evaporated. The residue was recrystallised from ethyl acetate/hexane to give the title compound (38 mg): m.p.=196° C.; 1H NMR (360 MHz, CDCl3) δ1.32 (3H, s), 1.33-1.66 (6H, m), 1.72-1.81 (2H, m), 1.93-2.03 (2H, m), 3.87 (3H, s), 5.50 (2H, s), 7.00-7.14 (2H, m), 7.83-7.90 (1H, m), 7.91 (1H, s), 8.00 (1H, s MS (ES+) m/e 440 [MH]+; Anal. Found: C, 59.74; H, 5.23; N, 22.10. C22H23F2N7O requires: C, 60.13; H, 5.27; N, 22.31%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15]([C:17]2[C:21]([NH:22][C:23]([NH2:25])=[O:24])=[CH:20][N:19]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)[CH:18]=2)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:33][O:34][CH2:35][CH2:36][CH2:37]N.C(OCC)(=O)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15]([C:17]2[C:21]([NH:22][C:23]([NH:25][CH2:37][CH2:36][CH2:35][O:34][CH3:33])=[O:24])=[CH:20][N:19]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)[CH:18]=2)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCCN
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](NC(=O)c2cn(-c3cccc(F)c3)cc2NC(N)=O)C1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COCCCNC(=O)Nc1cn(-c2cccc(F)c2)cc1C(=O)N[C@H]1CCCN(C(=O)OC(C)(C)C)C1
Yield: 71 %

Procedure:
Following general method 6, employing (S)-3-{[1-(3-fluorophenyl)-4-ureido-1H-pyrrole-3-carbonyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester and 3-methoxy-propylamine afforded the crude desired product. Column chromatography (silica, 12 g column, ISCO, 0-60% ethyl acetate in DCM) afforded the title compound as a glass (100 mg, 71%). LCMS (method B): RT=3.67 min, M+H+=518.
Reaction SMILES: C(O[C:6](=[O:22])[NH:7][CH:8]1[CH2:11][N:10]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[CH:14][N:13]=2)[CH2:9]1)(C)(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(OC([NH:51][C@@H:52]([CH2:56][C:57]1[CH:62]=[CH:61][C:60]([Cl:63])=[CH:59][CH:58]=1)C(O)=O)=O)(C)(C)C.C(O)(C(F)(F)F)=O>Cl.CN(C=O)C.C(Cl)Cl>[NH2:51][C@H:52]([CH2:56][C:57]1[CH:62]=[CH:61][C:60]([Cl:63])=[CH:59][CH:58]=1)[C:6]([NH:7][CH:8]1[CH2:9][N:10]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[CH:14][N:13]=2)[CH2:11]1)=[O:22]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(Cl)cc1)C(=O)O
Reactant: CC(C)(C)OC(=O)NC1CN(c2ncnc3ccccc23)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: N[C@H](Cc1ccc(Cl)cc1)C(=O)NC1CN(c2ncnc3ccccc23)C1
Temperature: 80 °C
Reaction time: 3 h
Yield: 35.7 %

Procedure:
The (1-quinazolin-4-yl-azetidin-3-yl)-carbamic acid tert-butyl ester (390 mg, 1.30 mmol) was dissolved in 7 mL, of 4M HCl and allowed to stir at 80° C. to completion after three hours. The aqueous solution was washed with ether (discarded), and the aqueous layer was concentrated in vacuo to afford the de-protected intermediate as a white solid. The flask containing this solid was charged with HOBt (193 mg, 1.43 mmol), EDCI (274 mg, 1.43 mmol), and the 2(S)-tert-butoxycarbonylamino-3-(4-chlorophenyl)-propionic acid (389 mg. 1.30 mmol). The mixture was suspended/dissolved in 12.0 mL of DMF and treated with TEA (905 μL, 6.49 mmol). The mixture was allowed to stir for four hours to completion. The contents were partitioned between ethyl acetate and diluted NaHCO3 solution. The aqueous was extracted with ethyl acetate, and the organics were combined. The organic was washed with water, brine, separated, dried over MgSO4, filtered, and concentrated in vacuo to afford the crude Boc-intermediate as a white solid. The material was dissolved in 7 mL of DCM and treated with 4.0 mL of TFA. After two hours, the reaction solution was concentrated in vacuo to afford a pale yellow oil. The contents were partitioned between ethyl acetate and diluted NaHCO3 solution. The aqueous was extracted with ethyl acetate, and the organics were combined. The organic was washed with brine, separated, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by chromatography (silica gel eluted with 9:1 MeOH:DCM) to afford the pure 2(R)-amino-3-(4-chlorophenyl)-N-(1-quinazolin-4-yl-azetidin-3-yl)-propionamide as a colorless oil (177 mg, 30%). 1H NMR (CDCl3, 400 MHz) δ 8.60 (s, 1H), 8.02 (brs, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.75 (d, J=8.8 Hz, 1H), 7.72 (t, J=8.4 Hz, 1H), 7.40 (t, J=7.6 Hz, 1H), 7.29 (d, J=8.4 Hz, 1H), 7.15 (d, J=8.4 Hz, 1H), 4.85 (m, 3H), 4.29 (dd, J=15.6, 5.6 Hz, 2H), 3.64 (dd, J=8.8, 4.0 Hz, 1H), 3.22 (dd, J=13.6, 4.0 Hz, 1H), 2.78 (dd, J=14.0, 8.8 Hz, 1H). LCMS (APCI+) m/z 382 [M+H]+; Rt=0.76 min.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[Br:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19](Cl)=[O:20])=[CH:14][CH:13]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:19](=[O:20])[CH2:18][C:15]2[CH:16]=[CH:17][C:12]([Br:11])=[CH:13][CH:14]=2)[CH:5]=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: COc1cccc(Cl)c1Cl
Reactant: O=C(Cl)Cc1ccc(Br)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: COc1ccc(C(=O)Cc2ccc(Br)cc2)c(Cl)c1Cl
Reaction time: 17 h

Procedure:
To a stirred mixture of 2,3-dichloroanisole (73.5 g., 0.414 mole), 4-bromophenylacetyl chloride (105 g., 0.456 mole) and carbon disulfide (300 ml.) is added portionwise aluminum chloride (60.9 g., 0.456 mole) with cooling at 0°-5° C. The reaction mixture is left at 25° C. for 17 hours, then flushed with nitrogen, and the solid residue treated with crushed ice and 12N hydrochloric acid (80 ml.) to give 147.7 g. of 2,3-dichloro-4-(4-bromophenyl)acetylanisole which melts at 163°-164.5° C. after crystallization from benzene:hexane, 1:1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+].O>[Fe].C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCc1ccc(N)cc1
Reaction time: 3 h
Yield: 90 %

Procedure:
(4-Nitro-benzyl)-carbamic acid tert-butyl ester (6.34 g, 25.1 mmol), iron powder (6.5 g, 116 mmol), ammonium formate (130.0 g, 206 mmol), H2O (75 mls), and toluene (75 mls) were combined and heated to reflux. After 3 hrs the reaction mixture was allowed to cool and filtered through Celite with thorough washing with EtOAc. The filtrate was transferred to a separatory funnel and the phases separated. The organic phase was further washed with H2O (1×), sat'd NaCl (1×), dried (Na2SO4), and concentrated in vacuo to give (4-amino-benzyl)-carbamic acid tert-butyl ester (5.02 g, 90% yield). LC/MS Calcd for [M+H]+ 223.1. found 167.1 (minus t-butyl).
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]([CH2:14][CH2:15][N:16]([CH3:22])[CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[C:25](N1C=CN=C1)(N1C=CN=C1)=[O:26].[CH3:37][N:38]([CH2:40][C:41]1[O:50][C:44]([CH2:45][S:46][CH2:47][CH2:48][NH2:49])=[CH:43][CH:42]=1)[CH3:39]>>[CH3:39][N:38]([CH2:40][C:41]1[O:50][C:44]([CH2:45][S:46][CH2:47][CH2:48][NH:49][C:25]([NH:21][CH2:20][CH2:19][CH2:18][CH2:17][N:16]([CH2:15][CH2:14][N:7]([CH2:6][C:5]2[CH:23]=[CH:24][C:2]([F:1])=[CH:3][CH:4]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH3:22])=[O:26])=[CH:43][CH:42]=1)[CH3:37]
Reactant: CN(CCCCN)CCN(Cc1ccc(F)cc1)c1ccccn1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CN(C)Cc1ccc(CSCCN)o1
Product: CN(C)Cc1ccc(CSCCNC(=O)NCCCCN(C)CCN(Cc2ccc(F)cc2)c2ccccn2)o1

Procedure:
Preparation is effected analagously to Example 63, using 0.50 g (1.5 mmol) of N-[2-[N-(4-fluorobenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,4-butanediamine and the equimolar amounts of 1,1'-carbonyldiimidazole and 2-[[5-[(dimethylamino)methyl]furfuryl]thio]ethylamine as starting materials. Working up by chromatography analogously to Example 1 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel. int. [%])=571 ([M+H]+, 109 (100); IR (KBr): 1640 cm-1 (C=O). For further analysis, a portion of the compound is converted into the tartaric acid salt in an ethanol/ether solvent mixture; m.p.: 74° C. (ethanol/ether).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[CH:15][CH:14]=[N:13]2)=[CH:8][CH:7]=1)[CH3:2].[H-].[Na+].[Cl-].[Na+].[H][H].[CH3:24]I>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[CH:15][CH:14]=[N:13]2)=[CH:8][CH:7]=1)[CH3:24])[CH3:2]
Reactant: [H][H]
Reactant: CI
Reactant: CCOC(=O)Cc1ccc(-n2cccn2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)c1ccc(-n2cccn2)cc1

Procedure:
2.3 g (10 mmoles) of 4-(pyrazol-1-yl)phenylacetic acid ethyl ester are dissolved in 20 ml of dimethylformamide; 240 mg (10 mmoles) of sodium hydride are added, under nitrogen, with good cooling (ice, sodium chloride) and vigorous stirring is effected until hydrogen evolution subsides. A solution of 1.5 g of methyl iodide and 5 ml of dimethyl formamide is then added dropwise, and stirring at room temperature is subsequently effected over night. The reaction mixture is poured onto water and extracted with diethyl ether. The ethereal solution is concentrated to yield 2-[4-(pyrazol-1-yl)phenyl]propionic acid ethyl ester as oil.