Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:15]#[CH:16])([CH3:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[CH:23]=[C:22](I)[C:21]([OH:25])=[CH:20][N:19]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[O:25][C:21]3=[CH:20][N:19]=[C:18]([Cl:17])[CH:23]=[C:22]3[CH:16]=2)([CH3:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CC1(C)CCN(C(=O)OC(C)(C)C)CC1
Reactant: Oc1cnc(Cl)cc1I
Product: CC(C)(C)OC(=O)N1CCC(C)(c2cc3cc(Cl)ncc3o2)CC1

Procedure:
The title compound is prepared from 4-ethynyl-4-methyl-piperidine-1-carboxylic acid tert-butyl ester and 2-chloro-5-hydroxy-4-iodo-pyridine following a procedure analogous to that described for Intermediate 5. LC (method 4): tR=1.76 min; Mass spectrum (ESI+): m/z=351/353 (Cl) [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:13][C:12](=[O:14])[NH:11][CH:10]=[C:9]2[C:15]([OH:17])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:21])=O.CN(C=O)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:13][C:12](=[O:14])[NH:11][CH:10]=[C:9]2[C:15]([Cl:21])=[O:17])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C1C[C@@H](c2ccc(F)cc2)C(C(=O)O)=CN1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C1C[C@@H](c2ccc(F)cc2)C(C(=O)Cl)=CN1
Reaction time: 2 h

Procedure:
To a cooled (ice-bath) suspension of 150 mg (0.63 mmol) of (S)-4-(4-fluoro-phenyl)-6-oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid in 15 mL of CH2Cl2 were added 0.081 mL (0.956 mmol) of oxalyl chloride, followed by a drop of DMF. The mixture was allowed to reach room temperature with stirring over two hours. Solvents were evaporated in in vacuo, and methylene chloride was added and solvent was removed in vacuo. Methynele chloride (10 mL) was again added and removed in vacuo, and the residue dried in high vacuum for 20 minutes to give (S)-4-(4-fluoro-phenyl)-6-oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid chloride, which was dissolved in 8 mL of dry CH3CN and transferred to a sealable tube under Argon atmosphere. DIPEA 0.22 mL (1.26 mmol), DMAP (few crystals) were added, followed by 6-amino-5-ethylquinoline (60 mg 0.348 mmol). The tube was sealed and heated with stirring to 120° C. for 24 hours. The tube contents were cooled to room temperature, saturated aqueous NaHCO3 solution (10 mL) was added and product extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with CH2Cl2/MeOH/NH4OH (100/10/1) to give 30 mg (22.2%) of (S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid (5-ethyl-quinolin-6-yl)-amide as a pale yellow foam. MS (ESI): m/z 389 (M+H)+.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]=[C:11]=[S:12])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH:13]([NH:16][CH2:17][C:18](O)=[O:19])([CH3:15])[CH3:14].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[C:18](=[O:19])[CH2:17][N:16]([CH:13]([CH3:15])[CH3:14])[C:11]3=[S:12])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: S=C=Nc1ccc2c(c1)CCC2
Reactant: CC(C)NCC(=O)O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)N1CC(=O)N(c2ccc3c(c2)CCC3)C1=S
Yield: 36.1 %

Procedure:
The title compound was prepared by the procedure described in Example 45 using 17.5 g of indan-5-yl-isothiocyanate, 21.2 g of N-isopropyl glycine, 21.0 g of triethyl amine, and 300 mL of chloroform. Crystallization from ethanol afforded the title compound (9.9 g) as a white solid, m.p. 178°-180° C. Anal. Calcd. for. C15H18N2O S: C, 56.66; H, 6.61; N, 10.21. Found: C, 56.70; H, 6.67; N, 10.22. Mass spectrum (EI, M.+) m/z 274.
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[CH:18]=[C:17]([Br:19])[C:16]([F:20])=[CH:15][C:14]=1[F:21].CN(C)[CH:24]=[O:25]>C(OCC)C>[Br:19][C:17]1[C:16]([F:20])=[CH:15][C:14]([F:21])=[C:13]([CH:18]=1)[CH:24]=[O:25]
Reactant: CN(C)C=O
Reactant: Fc1cc(F)c(Br)cc1Br
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: O=Cc1cc(Br)c(F)cc1F
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 61.1 %

Procedure:
A 1.6 M solution of butyl lithium in hexane (114 mL, 182 mmol) is added to a −78° C. solution of 1,5-dibromo-2,4-difluorobenzene (41.3 g, 152 mmol) in diethyl ether (290 mL). Dimethylformamide (14.4 g, 198 mmol) is added and the reaction is stirred at −78° C. for 15 minutes. The reaction is quenched with 1 N HCl (300 mL), is diluted with water, and extracted three times with ethyl acetate. The organic layer is dried over sodium sulfate and the solvent is removed under reduced pressure to give crude material that is purified by silica gel chromatography with a linear gradient of 0% to 50% CH2Cl2 in hexanes over 30 minutes to give the title compound (20.51 g, 61%). GC-MS m/e (79Br/81Br) 220, 222.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[N:4]=1.C([O:17][C:18](=[O:30])[CH:19]([CH3:29])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([Cl:28])[CH:22]=1)C>>[Cl:28][C:23]1[CH:22]=[C:21]([CH2:20][CH:19]([CH3:29])[C:18]([OH:30])=[O:17])[CH:26]=[CH:25][C:24]=1[O:27][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[N:4]=1
Reactant: ClCc1cccc(SC2CCCC2)n1
Reactant: CCOC(=O)C(C)Cc1ccc(O)c(Cl)c1
Product: CC(Cc1ccc(OCc2cccc(SC3CCCC3)n2)c(Cl)c1)C(=O)O
Yield: 78.5 %

Procedure:
2-Chloromethyl-6-cyclopentylsulfanyl-pyridine (37 mg, 0.16 mmol) obtained in Step C of Preparation Example 27 and 3-(3-chloro-4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester (43 mg, 0.17 mmol) obtained in Step B of Preparation Example 46 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (51 mg, 85%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C@:10]([OH:18])([CH:15]([CH3:17])[CH3:16])[CH2:11][C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.Cl.C[C@@H](N)C1C=CC=CC=1.C(O)(C)C>CCOC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C@@:10]([OH:18])([CH:15]([CH3:16])[CH3:17])[CH2:11][C:12]([OH:14])=[O:13])=[CH:6][CH:7]=1
Reactant: CC(C)[C@@](O)(CCc1ccc(F)cc1)CC(=O)O
Agent: C[C@@H](N)c1ccccc1
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CC(C)[C@](O)(CCc1ccc(F)cc1)CC(=O)O
Temperature: 25 °C

Procedure:
The mother liquors from the isolation of the G-11 (R) enantiomer were combined, treated with 1N HCl and extracted with EtOAc. The organic phase was washed with brine, dried (MgSO4), filtered and concentrated to liberate the free β-hydroxy acid. HPLC analysis indicated the isolated material was 79% (S):21% (R). β-Hydroxy acid G-11 (22.6 g, 89.0 mmol) was dissolved in 250 mL EtOAc and treated with (R)-α-methylbenzylamine (9.17 g, 75.64 mmol). The resulting mixture was placed on a steam bath, heated to reflux, diluted with additional ˜100 mL EtOAc, and treated with hot isopropanol until solids completely dissolved. The solution was allowed to cool to room temperature slowly overnight and then cooled to −10 to −15° C. Cold EtOAc was added; the solids were filtered off and washed with cold EtOAc and Et2O to yield the title compound. The free acid was obtained by treating the salt with 1N HCl followed by extraction with EtOAc. The organic phased was washed with brine, dried (MgSO4), filtered and concentrated to afford the resolved β-hydroxy acid. HPLC analysis of isolated solid (as the free acid): (AS chiralpak column, 1 mL/min., 98% Hexanes:2% IPA:+0.1% Formic acid)
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:5].[Br:15]Br.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.CCCCCC.C(OCC)(=O)C>ClC1C=CC=CC=1>[Br:15][CH2:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:5]
Reactant: CCOC(=O)C(=O)c1ccccc1C
Reactant: BrBr
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: Clc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)C(=O)c1ccccc1CBr
Temperature: 0 °C
Yield: 9.9 %

Procedure:
To a solution of ethyl 2-methylbenzoylformate (10 g) in chlorobenzene (50 ml) were added a solution of bromine (10 g) in chlorobenzene (20 ml) and a suspension of 25%-hydrous benzoyl peroxide (1 g) in chlorobenzene (10 ml) over 2 hours and the mixture was heated under reflux for 1 hour. The reaction mixture was cooled with ice-water and filtered through a pad of celite. The filtrate was concentrated under reduced pressure to give a yellow oil. The oil was subjected to silica gel column chromatography (eluent: hexane/ethyl acetate=20/1) to give the desired ethyl 2-(bromomethyl)benzoylformate (1.4 g, yield: 10%).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([C:14]([OH:16])=O)=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH3:26])=[CH:20][CH:19]=2)[CH2:3][CH2:2]1.CN(C(ON1N=N[C:37]2[CH:38]=[CH:39][CH:40]=[N:41][C:36]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:51][CH2:52]N(C(C)C)C(C)C.C1(CN)CCCCC1.Cl>CN(C=O)C.CCOC(C)=O.C(OCC)C>[CH:40]1([N:41]([CH3:36])[C:14]([C:12]2[CH:11]=[CH:10][C:9]3[N:5]([CH2:4][CH:1]4[CH2:3][CH2:2]4)[C:6]([CH2:17][C:18]4[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH3:26])=[CH:22][CH:23]=4)=[N:7][C:8]=3[CH:13]=2)=[O:16])[CH2:39][CH2:38][CH2:37][CH2:52][CH2:51]1
Reactant: CCOc1ccc(Cc2nc3cc(C(=O)O)ccc3n2CC2CC2)cc1
Reactant: CCN(C(C)C)C(C)C
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: NCC1CCCCC1
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOc1ccc(Cc2nc3cc(C(=O)N(C)C4CCCCC4)ccc3n2CC2CC2)cc1
Reaction time: 0.17 h
Yield: 91.5 %

Procedure:
1-(Cyclopropylmethyl)-2-(4-ethoxybenzyl)-1H-benzimidazole-5-carboxylic acid (80 mg, 0.228 mmol) was dissolved in DMF (2 mL) and then HATU (104 mg, 0.274 mmol) was added followed by DIPEA (48 μL, 0.274 mmol). After stirring for 10 min; cyclohexylmethyl amine (0.456 mmol) was added and the resulting mixture was stirred overnight. The mixture was diluted with EtOAc (50 mL), washed with saturated NaHCO3 (2×10 mL) and then H2O (2×10 mL), dried over MgSO4, and concentrated to give a crude amide. The crude residue was purified by silica gel column chromatography to give pure product which was treated with 1 M HCl solution in diethyl ether to form a HCl salt as white solids (93 mg, 78%). 1H NMR (400 MHz, CD3OD): δ 7.66 (s, 1H), 7.58 (d, J=8.0 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H), 7.16 (d, J=8.6 Hz, 2H), 6.84 (d, J=8.6 Hz, 2H), 4.30 (s, 2H), 4.10–4.04 (m, 5H), 3.96 (q, J=7.6 Hz, 2H), 3.66–3.54 (m, 1H), 1.90–1.50 (m, 10H), 1.33 (t, J=7.6 Hz, 3H), 1.10–0.98 (m, 1H), 0.50–0.42 (m, 2H), 0.32–0.27 (m, 2H). MS (ESI) (M+H)+=446. Anal. Calcd for C28H35N3O2.2.2HCl: C, 63.96; H, 7.13; N, 7.99. Found: C, 64.11; H, 7.24; N, 7.73.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([O:22][CH3:23])[CH:16]=1)=O)(C)(C)C.CO[C:26]([CH3:28])=[CH2:27].FC(F)(F)C(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(=O)(O)[O-].[Na+]>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([N:14]([CH:26]([CH3:28])[CH3:27])[CH2:13][C@@H:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)=[CH:16][C:17]=1[O:22][CH3:23]
Reactant: C=C(C)OC
Reactant: COc1cc(NC[C@@H]2CCCN2C(=O)OC(C)(C)C)ccc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(N(C[C@@H]2CCCN2)C(C)C)ccc1Cl
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-2-[(4-chloro-3-methoxy-phenylamino)-methyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.68 g, 2.0 mmol) were added 2-methoxypropene (0.216 g, 3.0 mmol), trifluoracetic acid (0.228 g, 2.0 mmol) and sodium triacetoxyborohydride (0.64 g, 3.0 mmol). The mixture was stirred overnight at 60° C. Saturated sodium bicarbonate solution (10 ml) was added and the mixture was extracted with ethyl acetate (3×30 ml). The combined organic layers were dried with magnesium sulphate, filtered and concentrated in vacuo. The residue was dissolved in dichloromethane (3 ml) and trifluoroacetic acid (3 ml) was added. Solvent and access trifluoroacetic acid was evaporated, diisopropylethylamine (1 ml) was added to liberate the free base and the mixture was purified by flash chromatography (column: Isolute® Flash-NH2 from Separtis; eluent: ethyl acetate/heptane 1:1) to yield a light yellow oil, (0.185 g, 33%); MS (ISP): 283.5, 285.2 ((M+H)+.).
Reaction SMILES: N#N.[C:3]([C:6]1[CH:7]=[C:8]([CH:18]=[CH:19][CH:20]=1)[CH2:9][C:10]1[O:11][CH:12]=[C:13]([C:15](Cl)=[O:16])[N:14]=1)(=[O:5])[CH3:4].[N-:21]=[N+:22]=[N-:23].[Na+]>CC(C)=O.O>[C:3]([C:6]1[CH:7]=[C:8]([CH:18]=[CH:19][CH:20]=1)[CH2:9][C:10]1[O:11][CH:12]=[C:13]([C:15]([N:21]=[N+:22]=[N-:23])=[O:16])[N:14]=1)(=[O:5])[CH3:4]
Reactant: CC(=O)c1cccc(Cc2nc(C(=O)Cl)co2)c1
Reactant: [N-]=[N+]=[N-]
Agent: N#N
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)c1cccc(Cc2nc(C(=O)N=[N+]=[N-])co2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of the crude 2-(3-acetyl-benzyl)-oxazole-4-carbonyl chloride in dry acetone (13.5 mL) was cooled to 0° C. and a solution of sodium azide (210 mg, 3.20 mmol) in H2O (1.7 mL) was added dropwise. The reaction mixture was stirred at 0° C. for 1 h. The mixture was concentrated under reduced pressure (coevaporation with toluene) then dissolved in CH2Cl2 and filtered. The filtrate was concentrated under reduced pressure to give the title compound as an orange oil. LC-MS-conditions 02: tR=0.91 min [M+AcCN+H]+=312.31.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH2:5].S([O-])([O-])(=O)=O.CS[C:13]([NH2:25])=[NH+:14][CH2:15][CH2:16][S:17][CH2:18][C:19]1[N:20]=[CH:21][NH:22][C:23]=1[CH3:24].CS[C:28]([NH2:40])=[NH+:29][CH2:30][CH2:31][S:32][CH2:33][C:34]1[N:35]=[CH:36][NH:37][C:38]=1[CH3:39]>O>[CH3:39][C:38]1[NH:37][CH:36]=[N:35][C:34]=1[CH2:33][S:32][CH2:31][CH2:30][N:29]=[C:28]([NH2:40])[NH:1][CH2:2][CH2:3][CH2:4][NH:5][C:13]([NH2:25])=[N:14][CH2:15][CH2:16][S:17][CH2:18][C:19]1[N:20]=[CH:21][NH:22][C:23]=1[CH3:24]
Reactant: NCCCN
Reactant: CSC(N)=[NH+]CCSCc1nc[nH]c1C
Agent: O=S(=O)([O-])[O-]
Solvent: O
Product: Cc1[nH]cnc1CSCCN=C(N)NCCCNC(N)=NCCSCc1nc[nH]c1C

Procedure:
1,3-Diaminopropane (0.37 g) was added to a solution of S-methyl-N-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]thiouronium sulphate (2.93 g) in water (10 ml) and the mixture was heated under reflux for 2 hours. Following concentration the residue was converted into the picrate with an aqueous solution of sodium picrate. Recrystallisation from ethanol afforded the title compound as the dipicrate (1.1 g) m.p. 114-6°.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:17])[C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].[F:18][C:19]([F:33])([F:32])[C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH:23]=O.O>CO>[F:18][C:19]([F:32])([F:33])[C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([C:28]([F:31])([F:29])[F:30])[CH:27]=1)[CH2:23][NH:1][C@@H:2]([CH3:17])[C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4]
Reactant: C[C@H](N)[C@H](O)c1ccc(O)c(NS(C)(=O)=O)c1
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: O
Solvent: CO
Product: C[C@H](NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@H](O)c1ccc(O)c(NS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 66.2 %

Procedure:
To a solution of the amine (4) (107 mg, 0.41 mmol) and 3,5-bis(trifluoromethyl)benzaldehyde (90 μL, 0.54 mmol) in methanol (4 mL) was added borane-pyridine complex (130 μL, 1.24 mmol) at 40° C. and the resulting mixture was stirred for 1.5 hours. The reaction mixture was cooled to room temperature and water was added thereto, followed by extraction with a mixed solvent (ethyl acetate:methanol=10:1) and subsequent washing of the organic layer with saturated brine. The organic layer was dried and concentrated and the obtained crude product was purified by amine silica gel column chromatography (eluent; chloroform:methanol=7:1) to obtain the desired amine (6) as a white solid (132 mg, Yield: 66%).
Reaction SMILES: [C:1]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH:25]1[C:30]([N+:31]([O-:33])=[O:32])=[CH:29][CH:28]=[C:27](O)[CH:26]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C.CN(C)C=O>[N+:31]([C:30]1[CH:25]=[CH:26][C:27]([O:23][C:22](=[O:24])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:1]([O:3][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:2])=[CH:28][CH:29]=1)([O-:33])=[O:32]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: O=C(O)CCCCCCCCCCNC(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(CCCCCCCCCCNC(=O)OCc1ccccc1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 55.7 %

Procedure:
In a solvent mixture (120 ml) of ethyl acetate and N,N-dimethylformamide (5:1) was dissolved N-carbobenzoxy-11-aminoundecanoic acid (10.1 g, 30 m mols) and p-nitrophenol (4.59 g, 33 m mols), followed by addition of N,N'-dicyclohexylcarbodiimide (6.80 g, 33 m mols). The mixture was stirred at room temperature for 15 hours, after which the precipitate was filtered off. The solvent was distilled off and the residue was crystallized in petroleum ether, recovered by filtration and recrystallized from ethyl acetate-petroleum ether. By the above procedure there was obtained 7.65 g of N-carbobenzoxy-11-aminoundecanoic acid p-nitrophenyl ester. m.p. 72°-73° C.; Rf1 =0.94.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([O:11][CH:12]([F:14])[F:13])[CH:3]=1.[CH2:15](O)[CH:16]([OH:19])[CH2:17][CH3:18]>>[F:14][CH:12]([F:13])[O:11][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[C:8]1([CH3:9])[O:19][CH:16]([CH2:17][CH3:18])[CH2:15][O:10]1
Reactant: CC(=O)c1ccc(Cl)cc1OC(F)F
Reactant: CCC(O)CO
Product: CCC1COC(C)(c2ccc(Cl)cc2OC(F)F)O1
Temperature: 25 °C

Procedure:
12.8 parts of 1-(4-chloro-2-difluoromethoxyphenyl)ethan-1-one and 10.4 parts of 1,2-butanediol are heated under reflux for 12 hours in 100 ml of abs. toluene in the presence of 0.2 part of p-toluene-sulfonic acid as catalyst, while removing the water of reaction with a water separator. The reaction mixture is cooled to room temperature and then washed with 2×100 ml of water, dried over sodium sulfate and filtered. The solvent is removed by evaporation and the residual oil is purified by high-vacuum distillation; b.p. 78°-80° C./0.04 mbar.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.ClC(Cl)(O[C:41](=[O:47])[O:42][C:43](Cl)(Cl)Cl)Cl.[F:49][C:50]1[CH:60]=[CH:59][C:53]([O:54][CH2:55][CH2:56]CO)=[CH:52][CH:51]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:41](=[O:47])[O:42][CH2:43][CH2:56][CH2:55][O:54][C:53]2[CH:59]=[CH:60][C:50]([F:49])=[CH:51][CH:52]=2)=[CH:18][CH:17]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OCCCOc1ccc(F)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(Oc3ccc(NC(=O)OCCCOc4ccc(F)cc4)cc3)c2cc1OC
Temperature: 25 °C
Yield: 52.1 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (59 mg) was added to toluene/triethylamine=10/1 (6 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (89 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3-(4-fluorophenoxy)-1-propanol (51 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (51 mg, yield 49%).
Reaction SMILES: C1(O[C:8](=[O:40])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[C:20]([C:22]4[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=4[S:29]([CH3:32])(=[O:31])=[O:30])[N:19]=[C:18]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][C@@H:34]4[CH3:39])[N:17]=3)=[CH:12][CH:11]=2)C=CC=CC=1.[NH2:41][CH2:42][C:43]([NH2:45])=[O:44]>>[F:28][C:26]1[CH:25]=[CH:24][C:23]([S:29]([CH3:32])(=[O:31])=[O:30])=[C:22]([C:20]2[N:19]=[C:18]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][C@@H:34]3[CH3:39])[N:17]=[C:16]([C:13]3[CH:12]=[CH:11][C:10]([NH:9][C:8](=[O:40])[NH:41][CH2:42][C:43]([NH2:45])=[O:44])=[CH:15][CH:14]=3)[CH:21]=2)[CH:27]=1
Reactant: NCC(N)=O
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)cc(-c2cc(F)ccc2S(C)(=O)=O)n1
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NCC(N)=O)cc2)cc(-c2cc(F)ccc2S(C)(=O)=O)n1

Procedure:
Method as described for example 58 using (S)-phenyl(4-(6-(5-fluoro-2-(methylsulfonyl)phenyl)-2-(3-methylmorpholino)pyrimidin-4-yl)phenyl)carbamate (intermediate 32) (100 mg, 0.18 mmol) and 2-aminoacetamide (20 mg, 0.27 mmol). The reaction mixture was purified by prep HPLC at low pH to afford the title compound as a yellow solid. (4 1 mg, 43%)
Reaction SMILES: [NH2:1][NH:2][C:3]([NH:5][NH2:6])=[S:4].[N+:7]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH2:20][CH3:21])C(O)=O)=[CH:12][CH:11]=1)([O-:9])=[O:8].[N+]([C:25]1C=C(B(O)O)C=CC=1)([O-])=O>C1(C)C=CC=CC=1>[NH2:6][N:5]1[C:3]([SH:4])=[N:2][N:1]=[C:25]1[CH2:21][CH2:20][CH2:16][C:13]1[CH:12]=[CH:11][C:10]([N+:7]([O-:9])=[O:8])=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: NNC(=S)NN
Reactant: CCC(C(=O)O)c1ccc([N+](=O)[O-])cc1
Solvent: Cc1ccccc1
Product: Nn1c(S)nnc1CCCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h
Yield: 647.5 %

Procedure:
To a mixture of 4.9 g (47 mmol) of thiocarbohydrazide and 9.8 g (47 mmol) of 4-nitrophenylbutanoic acid in 30 mL of toluene was added 0.8 g (4.7 mmol) of 3-nitrobenzeneboronic acid. The mixture was heated at reflux for 24 hr. The reaction was cooled and the reaction mixture was allowed to settle. The supernatant liquid was decanted. To the residual solid was added 50 mL of acetonitrile. The mixture was stirred for 30 minutes. The solid was collected, rinsed with 10 mL of acetonitrile and dried in vacuo to yield 8.5 g (65.4%) of the desired product as a white sandy material. All the analytical data confirmed the assigned structure.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[C:12]([NH:19][C:20]([C:22]4[N:23]=[CH:24][S:25][CH:26]=4)=[O:21])[CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:6]=[CH:7][CH:8]=1)=O.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[BH4-].[Na+]>C1COCC1.C(O)C.C(O)(=O)C>[O:30]1[CH2:31][CH2:32][N:27]([CH2:1][C:3]2[CH:4]=[C:5]([C:9]3[CH:18]=[CH:17][C:16]4[C:11](=[C:12]([NH:19][C:20]([C:22]5[N:23]=[CH:24][S:25][CH:26]=5)=[O:21])[CH:13]=[CH:14][CH:15]=4)[N:10]=3)[CH:6]=[CH:7][CH:8]=2)[CH2:28][CH2:29]1
Reactant: C1COCCN1
Reactant: O=Cc1cccc(-c2ccc3cccc(NC(=O)c4cscn4)c3n2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C(Nc1cccc2ccc(-c3cccc(CN4CCOCC4)c3)nc12)c1cscn1
Reaction time: 18 h
Yield: 71.2 %

Procedure:
A solution of N-(2-(3-formylphenyl)quinolin-8-yl)thiazole-4-carboxamide (54 mg, 0.150 mmol) and morpholine (37 μL, 0.450 mmol) in a mixture of THF (4 mL) and Ethanol (8 mL) was added Na(OAc)3BH (95 mg, 0.450 mmol). The reaction was stirred 18 hours, and NaBH4 (17 mg, 3 eq) and acetic acid (500 uL) and the reaction was stirred for 2 hours. The reaction was quenched with water/methanol mixture, concentrated to dryness, and diluted with CH2Cl2. The resulting solution was washed with 1N NaOH, water, brine, dried (Na2SO4) and concentrated. The crude material was purified by silica gel column chromatography (0 to 10% methanol gradient in CH2Cl2 modified with 0.1% triethylamine). The product was lyophilized in a mixture of acetonitrile/water to obtain N-(2-(3-(morpholinomethyl)phenyl)quinolin-8-yl)thiazole-4-carboxamide (46 mg, 71% yield). MS (ESI) calcd for C24H22N4O2S (m/z): 430.15. found: 431 [M+1].