Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](Cl)=[N:7][N:6]=[CH:5]2.[NH:13]1[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:13]1[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14]1)=[N:7][N:6]=[CH:5]2
Reactant: Clc1nncc2cc(Br)ccc12
Reactant: OC1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OC1CCN(c2nncc3cc(Br)ccc23)C1
Temperature: 180 °C
Reaction time: 0.33 h

Procedure:
The mixture of 6-bromo-1-chlorophthalazine (Example 1, 0.12 g, 0.5 mmol), pyrrolidin-3-ol (0.08 mL, 1.0 mmol) and potassium carbonate (0.07 g, 0.5 mmol) in 5 mL acetonitrile was added to a glass microwave reaction vessel. The reaction mixture was stirred and heated in a Smith Synthesizer® microwave reactor (Personal Chemistry, Inc., Upssala, Sweden) at 180° C. for 20 min. After about 20 min., all starting material was converted to product (M+1=294, 296). The mixture was concentrated under vacuum and purified via flash chromatography (silica gel) eluting with a gradient of 2% 2 M ammonia in MeOH/DCM to 6% 2M ammonia in MeOH/DCM to give 0.13 1-(6-bromophthalazin-1-yl)pyrrolidin-3-ol as yellow solid. Found MS (ES+): 294, 296(M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([C:18]3[C:19]4[CH:31]=[CH:30][C:29](=[O:32])[N:28]([C:33]5[C:38]([F:39])=[CH:37][CH:36]=[CH:35][C:34]=5[F:40])[C:20]=4[N:21]=[C:22](S(C)(=O)=O)[N:23]=3)[CH:12]=2)=[O:9])=[CH:4][CH:3]=1.[NH2:41][CH:42]1[CH2:47][CH2:46][N:45](C(OC(C)(C)C)=O)[CH2:44][CH2:43]1>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([C:18]3[C:19]4[CH:31]=[CH:30][C:29](=[O:32])[N:28]([C:33]5[C:38]([F:39])=[CH:37][CH:36]=[CH:35][C:34]=5[F:40])[C:20]=4[N:21]=[C:22]([NH:41][CH:42]4[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]4)[N:23]=3)[CH:12]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(NC(=O)c2ccc(Cl)nc2)cc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Product: Cc1ccc(NC(=O)c2ccc(Cl)nc2)cc1-c1nc(NC2CCNCC2)nc2c1ccc(=O)n2-c1c(F)cccc1F

Procedure:
The title compound was prepared as described in Example 2 from 6-chloro-N-{3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylphenyl}-3-pyridinecarboxamide and 1,1-dimethylethyl 4-amino-1-piperidinecarboxylate: LC-MS m/z 602 (M+H)+, 1.75 min (ret time).
Reaction SMILES: [OH:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([N+:14]([O-:16])=[O:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH2:17](Br)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].CN(C)P(=O)(N(C)C)N(C)C.C1OC1C>C(N(CC)CC)C>[CH3:13][O:12][C:11]1[C:2]([O:1][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:3]2[C:8](=[C:9]([N+:14]([O-:16])=[O:15])[CH:10]=1)[N:7]=[CH:6][CH:5]=[CH:4]2
Reactant: COc1cc([N+](=O)[O-])c2ncccc2c1O
Reactant: CCCCCCCCBr
Agent: CC1CO1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCN(CC)CC
Product: CCCCCCCCOc1c(OC)cc([N+](=O)[O-])c2ncccc12
Yield: 80.2 %

Procedure:
A stirred mixture of 5-hydroxy-6-methoxy-8-nitroquinoline, (6.6 g, 0.03 mole), n-octylbromide (6.7 g, 0.035 mole) and hexamethylphosphoric triamide (10 ml) was maintained at 125°-130°, under N2, while a mixture of triethylamine (1 ml) and propylene oxide (6 ml) was added in small portions during 3 hr. The mixture was cooled and extracted with petroleum ether (bp 20°-40°) (3×100 ml). The extracts were discarded. The petroleum ether-insoluble, semi-solid residue was dissolved in 300 ml of diethyl ether and washed with water, dilute sodium hydroxide and water. The ethereal solution was dried and concentrated in vacuo to leave 8 g of pale brown solid. Crystallization from boiling petroleum ether (20°-40°) (carbon) gave 7.5 g (75%) of the 5-octoxyquinoline derivative, mp 52°-54°. An additional crystallization from petroleum ether did not change the melting point.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][NH:18][C:19]2[CH:24]=[C:23]([CH3:25])[N:22]=[C:21](Cl)[N:20]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>C(O)C.[Pd]>[CH3:25][C:23]1[N:22]=[CH:21][N:20]=[C:19]([NH:18][CH2:17][CH:14]2[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]2)[CH:24]=1
Reactant: Cc1cc(NCC2CCN(C(=O)OCc3ccccc3)CC2)nc(Cl)n1
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(NCC2CCNCC2)ncn1
Reaction time: 6 h

Procedure:
A mixture of 4-[(2-chloro-6-methyl-pyrimidin-4-ylamino)-methyl]-piperidine-1-carboxylic acid benzyl ester (EXAMPLE 57, 0.50 g, 1.33 mmol), Pd/C (10%, 0.05 g) in absolute ethanol (15 mL) was vigorously stirred under 1 atm H2 for 6 h. Filtered and concentrated, the reaction gave 4-[(6-methyl-pyrimidin-4-ylamino)-methyl]-piperidine. M.S. (M+1): 207.30
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21](Cl)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:25]1[CH:29]=[CH:28][C:27]([NH:30]C(=O)OC(C)(C)C)=[N:26]1>CN(C1C=CN=CC=1)C.CC#N>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21]([N:25]3[CH:29]=[CH:28][C:27]([NH2:30])=[N:26]3)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cc[nH]n1
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CC(C)(C)c1nc2cc(S(=O)(=O)n3ccc(N)n3)ccc2n1CC1CCOCC1
Yield: 18.9 %

Procedure:
Following the same procedure in Example 1, Step A, using 2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (1.46 g, 3.93 mmol), tert-butyl 1H-pyrazol-3-ylcarbamate (0.80 g, 4.33 mmol) (see following step B for preparation), and DMAP (1.47 g, 12.0 mmol) in MeCN (40 mL). The crude product was purified by MPLC using EtOAc on silica gel to give 0.31 g (19%) of a white solid as the title compound. 1H NMR (400 MHz, DMSO-D6) δ 1.25-1.44 (m, 4 H), 1.46 (s, 9 H), 2.05-2.24 (m, 1 H), 3.15 (m, 2 H), 3.77 (m, 2 H), 4.28 (d, J=7.03 Hz, 2 H), 5.38 (s, 2 H), 5.78 (d, J=2.93 Hz, 1 H), 7.63 (dd, J=8.79, 1.76 Hz, 1 H), 7.82 (d, J=8.59 Hz, 1 H), 7.97 (d, J=1.76 Hz, 1 H), 8.00 (d, J=2.93 Hz, 1 H); MS (ESI) (M+H)+=417.8; Anal. Calcd for C20H27N5O3S+1.30 TFA+0.10 EtOAc (575.78): C, 48.19; H, 5.09; N, 12.16. Found: C, 48.12; H, 5.02; N, 12.29.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH:6]1[N:11]2[CH:12]=[C:13]([N+:15]([O-])=O)[CH:14]=[C:10]2[C:9](=[O:18])[NH:8][CH2:7]1)[CH3:2].[ClH:20]>C(O)C.[Pd]>[ClH:20].[CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH:6]1[N:11]2[CH:12]=[C:13]([NH2:15])[CH:14]=[C:10]2[C:9](=[O:18])[NH:8][CH2:7]1)[CH3:2]
Reactant: CCOC(=O)CC1CNC(=O)c2cc([N+](=O)[O-])cn21
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CC1CNC(=O)c2cc(N)cn21
Yield: 97.4 %

Procedure:
To a solution of ethyl(7-nitro-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl)acetate (V, where R1=OCH2CH3) (0.55 g, 2.1 mmol) in ethanol 100% (20 mL) was added hydrochloric acid (4 M solution in 1,4-dioxane, 0.52 mL, 2.1 mmol). The reaction mixture was stirred at room temperature in the presence of Pd—C (10%) (0.11 g), under hydrogen atmosphere (50 psi). After 7 h the solid was filtered through celite (washed with ethanol) and the solvent evaporated under vacuum, to obtain compound ethyl(7-amino-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl)acetate hydrochloride (I) as a light-brown solid (0.56 g, 98% yield), used without further purification in the next steps. Very hygroscopic product. To be stored for a short time and under inert gas atmosphere.
Reaction SMILES: [C:1](ON=O)(C)([CH3:3])[CH3:2].C(Br)C=C.[N+:12]([C:15]1[CH:21]=[CH:20][C:18](N)=[CH:17][C:16]=1[C:22]([F:25])([F:24])[F:23])([O-:14])=[O:13].NC1C=CC=CC=1>CC#N>[CH2:3]([C:18]1[CH:20]=[CH:21][C:15]([N+:12]([O-:14])=[O:13])=[C:16]([C:22]([F:25])([F:24])[F:23])[CH:17]=1)[CH:1]=[CH2:2]
Reactant: Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Reactant: CC(C)(C)ON=O
Solvent: Nc1ccccc1
Solvent: C=CCBr
Solvent: CC#N
Product: C=CCc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Temperature: 14 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
To a solution of t-butylnitrite (535 μl, 4.5 mmol) and allyl bromide (3.9 ml, 45.0 mmol) in CH3CN (3 ml), 4-nitro-3-trifluoromethylaniline (618 mg, 3.0 mmol) was added during 20 minutes, while maintaining the temperature of the reaction mixture between 13-15° C. At the end of the addition of the aniline, extra t-butylnitrite (180 μl, 1.5 mmol) was added to the reaction mixture which then was stirred at 25° C. for one hour. The volatile material in the reaction mixture was removed at reduced pressure. Column chromatography (heptane-ethyl acetate 97:3) gave 430 mg (62%) of allyl-4-nitro-3-trifluoromethylbenzene as a light yellow oil. 1H NMR (CDCl3, 400 MHz) δ 7.86, (d, 1H, J=8.3 Hz), 7.65, (d, 1H, J=1.2 Hz), 7.55, (dd, 1H, J=8.3, 1.4 Hz), 6.00-5.89, (m, 1H), 5.26-5.14, (m, 2H), 3.54, (d, 2H, J=6.7 Hz); 13C NMR (CDCl3, 100 MHz) δ 146.5, 135.0, 133.3, 128.5, (q, J=5.0 Hz), 125.8, 124.4, 124.1, 123.8, 121.1, 118.8, 40.0; Anal HRMS Calcd. for C10H8F3NO2 (M): 231.0507. Found: 208.0499.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:21])[NH:10][C:11]1[CH:20]=[CH:19][C:14]2[O:15][CH2:16][CH2:17][O:18][C:13]=2[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[Br:27][CH2:28]/[CH:29]=[CH:30]/[CH2:31]Br>C1COCC1>[CH2:1]([O:8][C:9](=[O:21])[N:10]([CH2:31][CH:30]=[CH:29][CH2:28][Br:27])[C:11]1[CH:20]=[CH:19][C:14]2[O:15][CH2:16][CH2:17][O:18][C:13]=2[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc2c(c1)OCCO2)OCc1ccccc1
Reactant: BrC/C=C/CBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N(CC=CCBr)c1ccc2c(c1)OCCO2
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 39.3 %

Procedure:
A solution of (2,3-dihydro-benzo[1,4]dioxin-6-yl)-carbamic acid benzyl ester (5 g, 17.5 mmol) in dry THF (85 mL) was cooled to −78° C. At this temperature n-BuLi (2.5M solution in hexanes, 14 mL) was added dropwise and the clear solution stirred at −78° C. for 20 min. A solution of E-1,4-dibromobut-2-ene (4.9 g, 23 mmol) in THF (42 mL) was added dropwise and the mixture slowly allowed to warm to rt. The mixture was poured on water and extracted with EA. The combined org. extracts were dried over MgSO4 and concentrated. The product was purified by FC (Hept/EA 9:1, 4:1) and obtained as a greenish oil (2.88 g, 38% yield) which was used as such in the next step despite some contaminations with starting material.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:3]=1/[CH:4]=[CH:5]/[C:6]1[CH:14]=[CH:13][C:9]([N:10](C)[CH3:11])=[CH:8][CH:7]=1.N#CBr>>[Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:3]=1/[CH:4]=[CH:5]/[C:6]1[CH:14]=[CH:13][C:9]([NH:10][CH3:11])=[CH:8][CH:7]=1
Reactant: CN(C)c1ccc(/C=C/c2c(F)cccc2Cl)cc1
Agent: N#CBr
Product: CNc1ccc(/C=C/c2c(F)cccc2Cl)cc1

Procedure:
The procedure used to prepare 4 cc was repeated using 1 g (3.63 mmol) of 4x and 764 mg (7.26 mmol, 2 equiv) of cyanogen bromide to afford a product that was purified by chromatography using 1:5 EtOAc-hexane to afford 400 mg (42%) of 4dd as a yellow solid: mp 43-45° C. 1H NMR (DMSO-d6): δ 7.37-7.31 (m, 3H), 7.27-7.21 (m, 2H), 7.18 (d, 1H, J=16.4 Hz), 6.88 (d, 1H, J=16.4 Hz), 6.56 (d, 2H, J=8.8 Hz), 6.04 (q, 1H, J=5.2 Hz), 2.71 (d, 3H, J=5.2 Hz). 13C NMR (DMSO-d6): δ 160.75 (d, J=248.0 Hz), 150.98, 137.24 (d, J=12.2 Hz), 133.30 (d, J=6.1 Hz), 128.49 (two C), 128.33 (d, J=9.9 Hz), 126.28 (d, J=3.1 Hz), 124.73 (d, J=14.5 Hz), 124.40, 115.54 (d, J=22.9 Hz), 113.12 (d, J=2.2 Hz), 112.11 (two C), 29.94. MS: m/z (%) 261 (100), 227 (15), 213 (25). Anal. Calcd for C15H13Cl FN: C, 68.84; H, 5.01. Found: C, 68.67; H, 5.05.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.O[CH:10]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1.Cl>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:10]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:11][CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([C:21]3[CH:22]=[C:23]([NH:27][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[CH:24]=[CH:25][CH:26]=3)[CH2:17][CH2:16]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(O)c3ccccc3)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(Oc3ccc(Cl)cc3)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 4-chlorophenol and N-{3-[1-(5-hydroxy-5-phenylpentyl)-4-piperidinyl]phenyl}-2-methylpropanamide: 1H NMR (400 MHz, CDCl3), HCl salt δ 7.72–6.72 (m, 13H), 5.12–5.04 (m, 1H), 3.66–3.52 (m, br, 2H), 3.01–2.83 (br, 2H), 2.68–2.62 (m, br, 2H), 2.62–2.48 (m, br, 4H), 2.04–1.82 (m, br, 6H), 1.62–1.40 (m, br, 2H), 1.25 (d, 6H, J=7.2 Hz); ESMS m/e: 519.1 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C@@:6]12[CH2:24][C@H:23]1[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][C@H:15]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:14](=[O:33])[N:13]1[C@@H:9]([CH2:10][C@@H:11]([O:34][C:35]([N:37]3[CH2:45][C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH2:38]3)=[O:36])[CH2:12]1)[C:8](=[O:46])[NH:7]2)=[O:5])C.O[Li].O>C(Cl)Cl.CO>[C:29]([O:28][C:26]([NH:25][C@@H:15]1[C:14](=[O:33])[N:13]2[C@@H:9]([CH2:10][C@@H:11]([O:34][C:35]([N:37]3[CH2:38][C:39]4[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=4)[CH2:45]3)=[O:36])[CH2:12]2)[C:8](=[O:46])[NH:7][C@@:6]2([C:4]([OH:5])=[O:3])[C@@H:23]([CH2:24]2)[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: CCOC(=O)[C@@]12C[C@H]1C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](OC(=O)N3Cc4ccccc4C3)C[C@H]1C(=O)N2
Agent: [Li]O
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1CCCCCC=C[C@@H]2C[C@@]2(C(=O)O)NC(=O)[C@@H]2C[C@@H](OC(=O)N3Cc4ccccc4C3)CN2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
The macrocyclic ester 11 (60 mg, 0.092 mmol) was dissolved in 0.9 mL of a mixed solvent (THF/MeOH/H2O 2:1:1), followed by addition of LiOH—H2O (23 mg, 6 equiv). The mixture was stirred at rt for overnight. After 18 h, TLC (DCM/MeOH 9:1) showed a clean new spot with a lower Rf. The reaction was concentrated down to almost dryness and partitioned between 1N aq. HCl (15 mL) and DCM (20 mL). The aqueous layer was extracted with DCM (2×10 mL). The organic layers were combined, dried over Na2SO4 and concentrated down, giving the desired compound as a light brownish foamy powder (50 mg, 87%). 1H NMR (CDCl3, 500 MHz) 1.21-1.44 (m, 8H), 1.32 (s, 9H), 1.54-1.62 (m, 2H), 1.78-1.88 (m, 2H), 2.04-2.13 (m, 1H), 2.16-2.23 (m, 1H), 2.24-2.36 (m, 2H), 2.66-2.74 (m, 1H), 3.87-3.90 (m, 1H), 4.15 (d, J=11.0 Hz, 1H), 4.37-4.43 (m, 1H), 4.61-4.77 (m, 5H), 5.18 (t, J=10.3 Hz, 1H), 5.24-5.31 (m, 1H), 5.40-5.45 (m, 1H), 5.58-5.66 (m, 1H), 7.11-7.30 (m, 4H). MS m/e 611.0 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:23])[N:10]([C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][S:19][CH2:20][CH2:21]O)[CH2:14][CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.CS([Cl:28])(=O)=O.N1C=CC=CC=1.O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:23])[N:10]([C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][S:19][CH2:20][CH2:21][Cl:28])[CH2:14][CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CN(C(=O)Oc1ccc(Cl)cc1)[C@H]1CC[C@H](CSCCO)CC1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(C(=O)Oc1ccc(Cl)cc1)[C@H]1CC[C@H](CSCCCl)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 645 mg (corresponds to 1.65 mmol) of trans-[4-(2-Hydroxy-ethylsulfanylmethyl)-cyclohexyl]-methyl-carbamic acid 4-chloro-phenyl ester in 12 ml CH2Cl2 was treated at 0° C. with 0.14 ml (1.82 mmol) methanesulfonylchloride, 0.20 ml (2.45 mmol) pyridine and 202 mg (1.65 mmol) DMAP. The reaction mixture was warmed up over night to room temperature. Water (2 ml) was added and the reaction was stirred for 5 min. After extraction with aqueous 10% KHSO4/Et2O (3×), the organic phases were washed with aqueous saturated NaHCO3 (2×), aqueous 10% NaCl, dried over Na2SO4 and evaporated to yield 650 mg (quantitative) trans-[4-(2-Chloro-ethylsulfanylmethyl)-cyclohexyl]-methyl-carbamic acid 4-chloro-phenyl ester, MS: 376 (MH+, 2Cl).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:20][CH:19]([OH:21])[CH2:18]3)=[O:16])[CH2:12][CH:11]([C:22](O)=[O:23])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.O[N:38]=[C:39]([O:41][CH2:42][CH3:43])[NH2:40]>CN(C=O)C.O1CCOCC1>[CH2:42]([O:41][C:39]1[N:40]=[C:22]([CH:11]2[CH2:10][CH:9]([C:6]3[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=3)[CH2:14][N:13]([C:15]([N:17]3[CH2:20][CH:19]([OH:21])[CH2:18]3)=[O:16])[CH2:12]2)[O:23][N:38]=1)[CH3:43]
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CC(O)C3)C2)cc1
Reactant: CCOC(N)=NO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CCOc1noc(C2CC(c3ccc(CC)cc3)CN(C(=O)N3CC(O)C3)C2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 80.0 mg (0.241 mmol) of the carboxylic acid from Example 14A in 0.97 ml of DMF and 1.93 ml of 1,4-dioxane were added, at 60° C., 99.8 mg (0.615 mmol) of 1,1′-carbonyldiimidazole, and the mixture was stirred for 3 h. Subsequently, the mixture was admixed with 50.1 mg (0.481 mmol) of ethyl N′-hydroxyimidocarbamate [G. Zinner, G. Nebel, Arch. Pharm. 1970, 303, 385-390] and then stirred at RT for 2 h and then at 120° C. for 2.5 h. The reaction solution was concentrated under reduced pressure and purified directly by means of preparative HPLC. Yield: 33.1 mg (33% of theory)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12](O)=[O:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CSC.B.Cl>C1COCC1>[OH:13][CH2:12][CH:10]1[CH2:11][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CSC
Product: CC(C)(C)OC(=O)N1CC(CO)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (2.0 g) in THF (30 ml) was added borane-dimethyl sulfide complex (4.0 ml; 10.0 M as borane) under ice-cooled bath, and the mixture was stirred for 8 hours at room temperature. 1 N HCl (10 ml) was added dropwise to the mixture under ice-cooled bath, and THF was removed under reduced pressure. The whole residue was extracted with EtOAc, and the extract was washed with brine and dried over MgSO4. Concentration under reduced pressure gave tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate (1.6 g).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[NH:4][N:3]=1.[OH-].[Na+].[CH3:18][N:19]=[C:20]=[S:21].Cl>O1CCCC1>[NH2:1][C:2]1[N:3]([C:20]([NH:19][CH3:18])=[S:21])[N:4]=[C:5]([CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[N:6]=1
Reactant: CN=C=S
Reactant: Nc1n[nH]c(C=Cc2ccc(Cl)cc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CNC(=S)n1nc(C=Cc2ccc(Cl)cc2)nc1N
Yield: 69 %

Procedure:
The synthesis method of Example 7-(3) was applied. The compound (4.00 g) obtained in (2) above, 0.67N sodium hydroxide (30 ml), methyl isothiocyanate (1.52 g) and tetrahydrofuran (30 ml) were used as reagents and the mixture was reacted at room temperature for 4 hours. After the reaction, the mixture was neutralized with 2N hydrochloric acid. The resulting substance was collected by filtration and washed with water and hexane-ethyl acetate to give 3.67 g of white crystals (yield 69%).
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]([CH2:12][CH2:13][NH2:14])=[N:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:15][C:16]([F:32])([F:31])[C:17]1[O:21][N:20]=[C:19]([C:22]2[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=2)[C:25](O)=[O:26])[N:18]=1>>[C:1]1([C:7]2[S:11][C:10]([CH2:12][CH2:13][NH:14][C:25](=[O:26])[C:24]3[CH:28]=[CH:29][CH:30]=[C:22]([C:19]4[N:18]=[C:17]([C:16]([F:32])([F:31])[F:15])[O:21][N:20]=4)[CH:23]=3)=[N:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: NCCc1ncc(-c2ccccc2)s1
Product: O=C(NCCc1ncc(-c2ccccc2)s1)c1cccc(-c2noc(C(F)(F)F)n2)c1
Yield: 5 %

Procedure:
This compound was synthesized from 2-(5-phenylthiazol-2-yl)ethanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (7 mg, yield 5%). 1H NMR (400 MHz, MeOD) δ 8.60-8.59 (t, J=1.4 Hz, 1H), 8.31-8.28 (dt, J=7.8 Hz, 1.4 Hz, 1H), 8.08-8.05 (dt, J=7.9 Hz, 1.3 Hz, 1H), 7.96 (s, 1H), 7.72-7.68 (t, J=7.9 Hz, 1H), 7.61-7.59 (m, 2H), 7.43-7.39 (m, 2H), 7.36-7.32 (m, 1H), 3.85-3.82 (t, J=6.9 Hz, 2H), 3.40-3.36 (t, J=6.8 Hz, 2H). MS (ESI) m/z: Calculated for C21H15F3N4O2S: 444.09. found: 445.0 (M+H)+.
Reaction SMILES: O.[OH-].[Li+].[C:4]([C:8]([CH2:10][N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:14][CH:13]([NH:28][C:29]([NH:31][C:32]2[CH:37]=[C:36]([C:38]([O:40]C)=[O:39])[CH:35]=[C:34]([C:42]([O:44]C)=[O:43])[CH:33]=2)=[O:30])[C:12]1=[O:46])=[O:9])([CH3:7])([CH3:6])[CH3:5]>O1CCCC1>[C:4]([C:8]([CH2:10][N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]([CH:22]2[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]2)[CH2:14][CH:13]([NH:28][C:29](=[O:30])[NH:31][C:32]2[CH:33]=[C:34]([C:42]([OH:44])=[O:43])[CH:35]=[C:36]([CH:37]=2)[C:38]([OH:40])=[O:39])[C:12]1=[O:46])=[O:9])([CH3:7])([CH3:5])[CH3:6]
Reactant: COC(=O)c1cc(NC(=O)NC2CN(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)cc(C(=O)OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)CN1C(=O)C(NC(=O)Nc2cc(C(=O)O)cc(C(=O)O)c2)CN(C2CCCCC2)c2ccccc21
Temperature: 50 °C
Reaction time: 2 h
Yield: 74.3 %

Procedure:
Aqueous lithium hydroxide monohydrate (420 mg) solution (20 ml) was added to a solution of 1-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-[3,5-bis(methoxycarbonyl)phenyl]urea (593 mg) in tetrahydrofuran (20 ml), the mixture was stirred at 50° C. for 2 hours. After allowed to cool, the reaction mixture was concentrated under reduced pressure, the residue was acidified with 1N hydrochloric acid, extracted with the mixed solvent of chloroform and methanol (5:1), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, Isopropyl alcohol was added to the residue, crystals so precipitated were collected by filtration, to thereby obtain 420 mg of the title compound (Yield: 74%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH:10]=1)[C:5]([OH:7])=[O:6].Cl.[CH3:18]N(C)CCCN=C=NCC>CO.CCOCC.CN(C1C=CN=CC=1)C.CCOC(C)=O>[CH3:18][O:6][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH:10]=[C:2]([NH2:1])[CH:3]=1
Reactant: Nc1cc(C(=O)O)cc(N2CCCC2=O)c1
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COC(=O)c1cc(N)cc(N2CCCC2=O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.3 %

Procedure:
To a solution of 3-amino-5-(2-oxo-pyrrolidin-1-yl)-benzoic acid (D6) (2.2 g, 10 mmol, 1 equiv) in MeOH/Et2O (1:1, 20 ml) was added 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (2.3 g, 12 mmol, 1.2 equiv), DMAP (112 mg, 1 mmol, 0.1 equiv) and the resulting mixture was stirred at room temperature for 16 h then diluted with AcOEt. The organic phase was washed with saturated aqueous NaHCO3 solution, dried over MgSO4 and concentrated in vacuo. The residue was triturated with Et2O to give 3-amino-5-(2-oxo pyrrolidin-1-yl)-benzoic acid methyl ester (D4a) (1.6 g, 68%) as a white solid.