Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:9]1[CH:19]=[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:17]([O:28][CH3:29])=[CH:16][C:10]=1[C:11]([O:13]CC)=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C(O)C.Cl>C(OCC)(=O)C>[C:1]([C:9]1[CH:19]=[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:17]([O:28][CH3:29])=[CH:16][C:10]=1[C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(OC)c(OCc2ccccc2)cc1C(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)O)c(C(=O)c2ccccc2)cc1OCc1ccccc1
Yield: 99 %

Procedure:
A mixture of ethyl 2-benzoyl-4-benzyloxy-5-methoxy-benzoate (reference example 11-1) (947 mg), a 2 mol/L aqueous solution of sodium hydroxide (3.64 mL) and ethanol (12 mL) was stirred at 70° C. for 3 hours. Ethyl acetate and 2 mol/L hydrochloric acid were added to the mixture. The separated organic layer was washed with water and brine successively, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (0.87 g).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][O:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:42]=[C:43]([CH:52]=[CH:53][CH:54]=2)[O:44][CH2:45][CH2:46][O:47]S(C)(=O)=O)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:55][NH:56][CH3:57].C1C[O:61]CC1>>[CH:46]([OH:47])=[O:61].[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][O:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:54]=[CH:53][CH:52]=[C:43]([O:44][CH2:45][CH2:46][N:56]([CH3:57])[CH3:55])[CH:42]=2)[N:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: C[C@H]1COCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCOS(C)(=O)=O)c4)c4ccccc43)cn12
Reactant: C1CCOC1
Reactant: CNC
Product: C[C@H]1COCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCN(C)C)c4)c4ccccc43)cn12
Product: O=CO
Temperature: 50 °C
Yield: 34 %

Procedure:
To a solution of Intermediate 141c (0.19 mmol) in THF (2.0 mL) was added dimethylamine (2M in MeOH, 1.9 mL, 3.8 mmol) and the reaction was heated to 50° C. in a sealed tube overnight. The crude reaction mixture was partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by FCC on silica, using a gradient of 0-10% [2M NH3 in MeOH] in DCM, followed by MDAP (Method 7) purification, to give the title compound (50 mg, 34%). LCMS (Method 5): Rt 3.33 min, m/z 708 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.83 (3H, d, J=5.7 Hz), 1.23 (9H, s), 1.78-1.92 (2H, m), 1.94-2.04 (1H, m), 2.04-2.12 (1H, m), 2.16 (6H, s), 2.59 (2H, t, J=5.7 Hz), 2.94 (1H, ddd, J=12.2, 7.3, 4.7 Hz), 3.16 (1H, dt, J=12.2, 3.3), 3.35-3.43 (2H, m), 3.72-3.80 (2H, m), 3.81-3.87 (1H, m), 4.04 (2H, t, J=5.7 Hz), 4.77 (1H, td, J=8.5, 5.9 Hz), 5.50 (1H, t, J=4.1 Hz), 6.28 (1H, s), 6.90-6.94 (1H, m), 7.01-7.09 (3H, m), 7.14-7.18 (1H, dd, J=9.8, 2.1 Hz), 7.20-7.26 (2H, m), 7.26-7.30 (1H, m), 7.30-7.38 (2H, m), 7.62 (1H, d, J=9.8 Hz), 7.78 (1H, d, J=1.8 Hz), 8.09 (1H, s), 8.12 (1.4H, s).
Reaction SMILES: [N+:1]([CH:4]([CH3:8])[CH:5]([OH:7])[CH3:6])([O-:3])=[O:2].N1C=CN=C1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>CN(C)C=O>[N+:1]([CH:4]([CH3:8])[CH:5]([O:7][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH3:6])([O-:3])=[O:2]
Reactant: CC(O)C(C)[N+](=O)[O-]
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(O[Si](C)(C)C(C)(C)C)C(C)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 6 h
Yield: 101.3 %

Procedure:
2.4 g (20 mmol) of 3-nitro-2-butanol was dissolved in 10 ml of dimethylformamide, 4.08 g (60 mmol) of imidazole and 4.52 g (30 mmol) of tert-butyldimethylsilyl chloride were added under ice cooling, and the mixture was stirred at room temperature for 6 hours. After the reaction, the reaction solution was poured into 100 ml of ice water, and the mixture was extracted with diethyl ether. The organic layer was washed successively with 2N hydrochloric acid, saturated sodium bicarbonate solution and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane-benzene=10:1) to give 4.73 g of 3-nitro-2-(tert-butyldimethylsilyloxy)butane as a colorless oil (yield: quantitative).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[NH:10][N:9]=1)=[O:7])[CH3:4].[F:23][C:24]([F:35])([F:34])[CH2:25]OS(C(F)(F)F)(=O)=O.ClCCl>CN(C=O)C>[CH2:3]([O:5][C:6]([C:8]1[N:9]([CH2:25][C:24]([F:35])([F:34])[F:23])[N:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:15][CH:14]=2)[CH:12]=1)=[O:7])[CH3:4]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)nn1CC(F)(F)F
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 56.8 %

Procedure:
Sodium hydride (55% dispersion in mineral oil, 203 mg, 5 mmol) was added to an ice cooled solution of 5-(4-trifluoromethyl-phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester (1 g, 4 mmol; PCT Int. Appl. (2003), WO 2004000785 A2) in DMF (60 ml) under an argon atmosphere. The solution was stirred for 10 min at 0° C. and for 40 min at ambient temperature. Trifluoroethyltriflate (1.07 g, 5 mmol) was added and the mixture was stirred for 3 h at ambient temperature. The solution was cooled to 0° C., 1 N HCl/ice water 1/2 and dichloromethane were added. The aqueous layer was extracted two times with dichloromethane, the combined extracts were washed with brine/ice water 1/1 and dried over sodium sulfate. Evaporation of the solvent under reduced pressure gave yellow crystals which were purified by column chromatography (silica gel, n-heptane/AcOEt) to yield 833 mg (2.27 mmol, 65%) of the title compound as colorless crystals.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:13])[CH:11]=2)[C:6]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[CH2:18][CH2:17]2)=[O:15])=[CH:5]1.[S:29](Cl)([CH3:32])(=[O:31])=[O:30].C(N(CC)CC)C>C(Cl)Cl>[Cl:13][C:10]1[CH:11]=[C:12]2[C:7]([C:6]([C:14]([N:16]3[CH2:17][CH2:18][N:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[F:28])[CH2:20][CH2:21]3)=[O:15])=[CH:5][N:4]2[CH2:3][CH2:2][NH:1][S:29]([CH3:32])(=[O:31])=[O:30])=[CH:8][CH:9]=1
Reactant: CS(=O)(=O)Cl
Reactant: NCCn1cc(C(=O)N2CCN(c3ccccc3F)CC2)c2ccc(Cl)cc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)NCCn1cc(C(=O)N2CCN(c3ccccc3F)CC2)c2ccc(Cl)cc21

Procedure:
[1-(2-Amino-ethyl)-6-chloro-1H-indol-3-yl]-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone (preparation described herein), was treated with mesylchloride (1.05 eq) and triethylamine (1.05 eq) in CH2Cl2 under argon at RT to give after purification by prep. HPLC the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11](=O)[CH3:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:14]1(=[O:21])[CH2:19][CH2:18][CH2:17][C:16](=O)[CH2:15]1.C([O-])(=O)C.[NH4+:26]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:15]3[C:14](=[O:21])[CH2:19][CH2:18][CH2:17][C:16]=3[NH:26][C:11]([CH3:12])=[CH:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: [NH4+]
Reactant: O=C1CCCC(=O)C1
Reactant: CC(=O)C=Cc1ccc(Cl)c(Cl)c1
Agent: CC(=O)[O-]
Solvent: CCO
Product: CC1=CC(c2ccc(Cl)c(Cl)c2)C2=C(CCCC2=O)N1
Yield: 36.3 %

Procedure:
A mixture of 1-(3,4-dichlorophenyl)but-1-en-3-one (5.0 g), 1,3-cyclohexanedione (2.71 g), ammonium acetate (2.70 g) and ethanol (75 mL) was heated at reflux for ten hours. The reaction was worked up as described in Example 8, and recrystallization from ethyl acetate-hexane yielded the title compound (2.6 g) as an off-white solid, mp 199°-201° C.; NMR: 1.74 (s,3, CH3), 1.84-1.88 (m,2, CH2), 2.14-2.19 (m,2, CH2), 2.41-2.46 (m,2, CH2), 4.42 (d,1, J=4.7, CH), 4.59 (d,1, J=4.7, CH), 7.12 (dd,1, J=8.3,2.0, Ar), 7.31 (d,1, J=2.0, Ar), 7.48 (d,1, J=8.3, Ar), 8.55 (s,1, NH); (CI, CH4) MS: m/z=308(M+1). Analysis for C16H15Cl2NO: Calculated C, 62.35; H, 4.91; N, 4.54; Found: C, 62.03; H, 5.09; N, 4.44.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:8][CH2:7][CH2:6][NH:5][C:4]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:3]1=2.N1C=CC=CC=1.[Cl:23][CH2:24][C:25](Cl)=[O:26]>CN(C)C1C=CN=CC=1.ClCCCl>[Cl:23][CH2:24][C:25]([N:5]1[CH2:6][CH2:7][CH2:8][C:2]([CH3:16])([CH3:1])[C:3]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:4]1=2)=[O:26]
Reactant: O=C(Cl)CCl
Reactant: CC1(C)CCCNc2cc([N+](=O)[O-])ccc21
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CC1(C)CCCN(C(=O)CCl)c2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5,5-Dimethyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[b]azepine (0.837 g, 3.80 mmol), pyridine (0.408 mL, 5.04 mmol) and 4-dimethylaminopyridine (14.4 mg, 0.118 mmol) were dissolved in anhydrous 1,2-Dichloroethane (9.0 mL) before adding chloroacetyl chloride (0.403 mL, 5.07 mmol). The reaction was stirred at room temperature for 3 hours, washed sequentially with 1 N HCl, water, saturated sodium bicarbonate solution and brine. The organic phase was dried with magnesium sulfate, filtered and concentrated under reduced pressure. The residue was triturated with ether (6 mL×2) to yield a crude brown solid, 2-Chloro-1-(5,5-dimethyl-8-nitro-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl)-ethanone. LCMS: m/z=297.42 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].N1C=CC=C[CH:11]=1.[C:16]([O:19][C:20]([CH3:25])(C)[C:21](Cl)=[O:22])(=[O:18])[CH3:17]>C(Cl)Cl>[Cl:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:21](=[O:22])[CH:20]([O:19][C:16](=[O:18])[CH3:17])[CH2:25][CH3:11]
Reactant: Nc1ccc(I)cc1Cl
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Reactant: c1ccncc1
Solvent: ClCCl
Product: CCC(OC(C)=O)C(=O)Nc1ccc(I)cc1Cl
Temperature: 2.5 °C

Procedure:
2-Chloro-4-iodoaniline (5 g) was dissolved in DCM (100 ml) and cooled to 0-5° C. in an ice bath. Pyridine (2.1 ml) was added followed by dropwise addition of 2-acetoxy-2-methylpropanoyl chloride (3.44 ml) and the mixture was allowed to warm to ambient temperature over 15 hours. The solvent was removed by evaporation and the residue was purified by flash chromatography eluting with 10-50% ethyl acetate/hexane to give the title compound (7.5 g) as a solid. Mp 156-158° C.; NMR (CDCl3): 1.7 (s. 6H), 2.2 (s, 3H), 7.6 (d, 1H), 7.7 (d, 1H), 8.2 (d, 1H), 8.4 (s, 1H); MS (ESP−): 380.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](F)=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:28]([N:30]2[CH2:33][C:32]([F:35])([F:34])[CH2:31]2)=[O:29])=[O:8])[CH2:5][CH2:4]1)#[N:2].Cl.Cl.[CH:38]1([N:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH2:40][CH2:39]1>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([N:44]4[CH2:45][CH2:46][N:41]([CH:38]5[CH2:40][CH2:39]5)[CH2:42][CH2:43]4)=[CH:19][C:18]=3[C:24]([F:25])([F:26])[F:27])(=[O:15])=[O:16])[CH2:11][C@H:10]2[C:28]([N:30]2[CH2:31][C:32]([F:35])([F:34])[CH2:33]2)=[O:29])=[O:8])[CH2:4][CH2:5]1)#[N:2]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(F)cc3C(F)(F)F)C[C@H]2C(=O)N2CC(F)(F)C2)CC1
Reactant: C1CN(C2CC2)CCN1
Agent: Cl
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(N4CCN(C5CC5)CC4)cc3C(F)(F)F)C[C@H]2C(=O)N2CC(F)(F)C2)CC1

Procedure:
The title compound was prepared in analogy to Example 127 using (1R,2R,4R)-2-(3,3-Difluoro-azetidine-1-carbonyl)-4-(4-fluoro-2-trifluoromethyl-benzenesulfonyl)-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (Example 118) and 1-cyclopropylpiperazine-bis-hydrochloric acid. White solid. MS (EI): 630.2 (M+H)+.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:43])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH2:22][CH:23]2[CH2:27][CH2:26][NH:25][CH2:24]2)[CH:17]=[C:16]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:15]3=[O:33])=[C:8]([C:34]2[S:35][CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[N:38]=2)[CH:7]=1)[CH3:2].Cl.O.[N:46]1([CH2:52][CH:53]=O)[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1.C([BH3-])#N>CO>[CH2:1]([NH:3][C:4](=[O:43])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH2:22][CH:23]2[CH2:27][CH2:26][N:25]([CH2:53][CH2:52][N:46]4[CH2:51][CH2:50][O:49][CH2:48][CH2:47]4)[CH2:24]2)[CH:17]=[C:16]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:15]3=[O:33])=[C:8]([C:34]2[S:35][CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[N:38]=2)[CH:7]=1)[CH3:2]
Reactant: O=CCN1CCOCC1
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)OCC)cn3CC2CCNC2)cn1
Agent: Cl
Agent: [BH3-]C#N
Solvent: CO
Solvent: O
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)OCC)cn3CC2CCN(CCN3CCOCC3)C2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.4 %

Procedure:
A vial was charged with ethyl 6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-4-oxo-1-(pyrrolidin-3-ylmethyl)-1,4-dihydroquinoline-3-carboxylate (Example 239, 700 mg, 1.14 mmol), morpholin-4-yl-acetaldehyde monohydrate hydrochloride (260 mg, 1.39 mmol) and methanol (10 mL). MP-cyanoborohydride beads (730 mg, 1.71 mmol) were added and the resulting mixture was allowed to stir at room temperature overnight. The reaction went to completion based on LC. The mixture was filtered and the beads were washed with methanol. The filtrate was concentrated under reduced pressure and purified by Analogix SF15-24 g column eluting with dichloromethane/methanol system to give a light yellow solid (310 mg, 37.4%).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:20]([OH:22])=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[C:1]([NH:8][C@H:9]([C:20]([N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[O:22])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Reactant: C1COCCN1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)N1CCOCC1
Yield: 96 %

Procedure:
In substantially the same manner as in Example 5, morpholine (290 μl) was condensed with Boc-p-nitro-L-phenylalanine (996 mg, Bachem Fein Chemikalien AG, Switzerland) to give N-(Boc-p-nitro-L-phenylalanyl)morpholine (1.22 g) as a white powder (yield 96%). After Boc group elimination with 4N HCl/ethyl acetate, the product was condensed with (2S,3S)-ethyl hydrogen trans-epoxysuccinate as obtained in Reference Example 8 (465 mg) to yield the title compound (compound 71; 878 mg) as a white powder (yield 81%).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[CH2:3][N:4]=[C:5]([NH2:20])[NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18]C)=O)[N:11]=1.[CH3:23][NH2:24]>>[CH3:23][NH:24][C:16](=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12][C:10]1[N:11]=[C:7]([NH:6][C:5]([NH2:20])=[N:4][CH2:3][C:2]([F:1])([F:22])[F:21])[S:8][CH:9]=1
Reactant: COC(=O)CCCCc1csc(NC(N)=NCC(F)(F)F)n1
Reactant: CN
Product: CNC(=O)CCCCc1csc(NC(N)=NCC(F)(F)F)n1
Reaction time: 48 h
Yield: 85 %

Procedure:
A mixture of methyl 5-[2-(2-[2,2,2-trifluoroethyl]guanidino)thiazol-4-yl]valerate (0.4 g.) and ethanolic methylamine (33% w/v, 60 ml.) was allowed to stand at room temperature for 2 days. The mixture was then evaporated to dryness and the residue recrystallised from EtOAc/ether to give N-methyl-5-[2-(2-[2,2,2-trifluoroethyl]guanidino)thiazol-4-yl]valeramide (yield 85%), m.p. 122°-126°.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:15]=[C:16]([CH:33]=[CH:34][CH:35]=1)[O:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)=[O:25])[CH2:20][CH2:19]1.[CH:36]1([CH2:42]O)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)[Cl:64]>C1COCC1>[ClH:64].[CH:36]1([CH2:42][O:13][C:14]2[CH:15]=[C:16]([CH:33]=[CH:34][CH:35]=2)[O:17][CH:18]2[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)=[O:25])[CH2:22][CH2:23]2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: OCC1CCCCC1
Reactant: ClC(Cl)Cl
Reactant: O=C(Oc1cccnc1)N1CCC(Oc2cccc(O)c2)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cl
Product: O=C(Oc1cccnc1)N1CCC(Oc2cccc(OCC3CCCCC3)c2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Diethyl azodicarboxylate (0.35 ml, 40% Tol solution) was dropwise added to a THF (5 ml) solution containing 3-pyridyl 4-(3-hydroxyphenoxy)-1-piperidinecarboxylate (160 mg), cyclohexylmethanol (87 mg) and triphenylphosphine (200 mg), at 0° C., followed by stirring at room temperature for 24 hours. The reaction solution was diluted with chloroform, washed with aqueous saturated sodium hydrogencarbonate solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane:EtOAc=1:1 (v/v)). The resulting oil was dissolved in EtOAc (5 ml), 4 M hydrogen chloride/EtOAc solution (1 ml) was added thereto, followed by stirring at room temperature. The solvent was evaporated under reduced pressure, and the precipitated solid was washed with EtOAc/2-propanol and dried under reduced pressure to obtain 3-pyridyl 4-[3-(cyclohexylmethoxy)phenoxy]-1-piperidinecarboxylate hydrochloride (94 mg).
Reaction SMILES: [CH2:1]([N:4]([C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)[N:5]1[C:13]2[C:8](=[CH:9][C:10]([OH:14])=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)[CH2:2][CH3:3].[C:21](N1C=CN=C1)([N:23]1C=CN=C1)=[O:22].C(O)(=O)C.[CH2:37]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH2:40][CH2:39][NH:38]1>O1CCCC1>[CH2:37]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH2:40][CH2:39][N:38]1[NH:23][C:21](=[O:22])[O:14][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[N:5]([N:4]([CH2:1][CH2:2][CH3:3])[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)[CH:6]=[CH:7]2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCCN(c1ccncc1)n1ccc2cc(O)ccc21
Reactant: c1ccc2c(c1)CCNC2
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCN(c1ccncc1)n1ccc2cc(OC(=O)NN3CCc4ccccc4C3)ccc21
Reaction time: 24 h
Yield: 135.6 %

Procedure:
To a solution of 1-(propyl-4-pyridinylamino)-1H-indol-5-ol (2.5 g) in 40 ml of tetrahydrofuran was added 1,1'-carbonyldiimidazole (1.83 g) and this mixture was stirred for 24 hours. Then 3.5 ml of glacial acetic acid was added to the reaction mixture. Then 1,2,3,4-tetrahydroisoquinoline (1.49 g) in 10 ml of tetrahydrofuran which had been acidified with 0.60 ml of glacial acetic acid was added to the reaction mixture dropwise. This was stirred for 24 hours and then the reaction mixture was quenched with water, basified with saturated sodium carbonate solution and extracted with ethyl acetate. The organic layer was washed with water and dried (sat. NaCl, anhy. MgSO4). After filtration, the solvent was evaporated to yield an oil (5.6 g) which was eluted with 5% methanol/dichloromethane on a silica gel column via HPLC. The desired fractions were concentrated to yield an oil (4.2 g). This material was dissolved in pentane/ether (1:1), whereupon a solid precipitated out of the solution. This material was collected to yield a solid, 2.6 g, m.p. 141°-143° C.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH2:6][C:7]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=O)=[O:5].[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O>[CH2:15]([NH:22][C:7]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][C:4]([O:3][CH2:2][CH3:1])=[O:5])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)CC(=O)CC(=O)OCC
Reactant: NCc1ccccc1
Solvent: O
Product: CCOC(=O)C=C(CC(=O)OCC)NCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 83.4 %

Procedure:
To 50.00 g (0.247 mol) of diethyl acetonedicarboxylate was added dropwise 31.79 g (0.297 mol) of benzylamine at such a rate that reaction temperature was kept below 50° C. The reaction mixture was stirred at room temperature for 12 hours and poured into H2O, extracted twice with ether, dried (MgSO4) and concentrated in vacuo affording 60.00 g of a yellow-green oil. Crude was purified by HPLC using 10% ethyl acetate/cyclohexane affording 46.2 g of a yellow semi solid. This was kugelrohr distilled at 53 Pa and collected at a pot temperature of 148°-150° C. to give 39.4 g (55%) of enamine diester as a beige crystalline solid; mp 34°-36° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([Cl:9])[N:3]=1.[C:10](O)(=[O:18])[C:11]1[C:12](=[CH:14][CH:15]=[CH:16][CH:17]=1)[OH:13].S(Cl)(Cl)=O.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[C:7]([NH:8][C:10](=[O:18])[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[OH:13])=[CH:6][CH:5]=[C:4]([Cl:9])[N:3]=1
Reactant: Nc1ccc(Cl)nc1Cl
Reactant: O=C(O)c1ccccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: O=C(Nc1ccc(Cl)nc1Cl)c1ccccc1O
Temperature: 90 °C

Procedure:
A suspension of 60.3g (0.37 mole) 2,6-dichloro-3-aminopyridine and salicylic acid 61g (0.44 mole) in 300 mL of toluene were heated to reflux for one hour. The reaction mixture was cooled at 90° C. and 34.2 ml (0.47 mole) of thionyl chloride was slowly added. After the addition the reaction mixture was refluxed for 3 hours, then cooled to room temperature. To the reaction mixture was added a solution containing 20g NaOH in 740 mL of H2O. The organic phase was separated and washed with water. The organic phase was treated with charcoal, filtered and the filtrate treated with CO2, the brownish precipitate was filtered off. Recrystallization from isopropyl alcohol gave 63.3g (60.5%) mp 179°-186° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=2)=[O:20])=[CH:14][CH:13]=1.C(OC([N:40](C(OC(C)(C)C)=O)[C@H:41]([C:47](O)=[O:48])[CH2:42][CH2:43][CH2:44][CH2:45][NH2:46])=O)(C)(C)C>>[ClH:28].[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([NH:21][C:19](=[O:20])[NH:18][C:15]2[CH:14]=[CH:13][C:12]([N:7]3[CH:6]=[N:5][C:4]4[C:8]3=[N:9][CH:10]=[N:11][C:3]=4[NH:2][C:47](=[O:48])[C@@H:41]([NH2:40])[CH2:42][CH2:43][CH2:44][CH2:45][NH2:46])=[CH:17][CH:16]=2)=[CH:23][C:24]=1[C:29]([F:31])([F:32])[F:30]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@@H](CCCCN)C(=O)O
Reactant: Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: Cl
Product: NCCCC[C@H](N)C(=O)Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1

Procedure:
The title compound can be synthesized from 1-[4-(6-aminopurin-9-yl)phenyl]-3-(4-chloro-3-(trifluoromethyl)phenyl)urea hydrochloride and di-tert-butoxycarbonyl-L-lysine by using the same method as in Example 96.