Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][NH:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[O:19][CH3:20].[F:22][C:23]([F:38])([F:37])[C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[N:32]=1)[C:27](O)=[O:28]>>[CH3:1][O:2][C:3](=[O:21])[CH2:4][N:5]([C:27]([C:26]1[CH:30]=[C:31]([C:33]([F:34])([F:35])[F:36])[N:32]=[C:24]([C:23]([F:38])([F:22])[F:37])[CH:25]=1)=[O:28])[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[O:19][CH3:20]
Reactant: O=C(O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Reactant: COC(=O)CNc1cnccc1-c1ccc(F)cc1OC
Product: COC(=O)CN(C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1)c1cnccc1-c1ccc(F)cc1OC

Procedure:
The title compound was prepared in analogy to example 90, from [4-(4-fluoro-2-methoxy-phenyl)-pyridin-3-ylamino]-acetic acid methyl ester and 2,6-bis(trifluoromethyl)isonicotinic acid (Key Organics Ltd.) after a reaction time of 72 hours. The compound was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 20:80). Colorless solid (46%). MS (ESI): m/z=532.109 [M+H]+.
Reaction SMILES: [C:1]([N:3]=[C:4](SC)[NH:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH2:7]1)#[N:2].[CH:18]([NH2:21])([CH3:20])[CH3:19]>C(#N)C>[C:1]([N:3]=[C:4]([NH:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH2:7]1)[NH:21][CH:18]([CH3:20])[CH3:19])#[N:2]
Reactant: CSC(=NC#N)NC1CCCc2ccccc21
Reactant: CC(C)N
Solvent: CC#N
Product: CC(C)NC(=NC#N)NC1CCCc2ccccc21
Reaction time: 154 h

Procedure:
A solution of 30.0 g of N'-cyano-N-(1,2,3,4-tetrahydro-1-naphthyl)-S-methylisothiourea and 40 ml of isopropylamine in 300 ml of acetonitrile was heated at reflux with stirring for 154 hours. The solvent and excess isopropylamine were removed by evaporation in vacuo, leaving the crude product as a tacky, white solid. Crystallization from isopropyl acetate followed by a recrystallization from a mixture of isopropyl acetate and 2-propanol gave 5.13 g of N"-cyano-N-isopropyl-N'-(1,2,3,4-tetrahydro-1-naphthyl)guanidine as a white, crystalline solid, mp 170.5°-172.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])/[C:5](=[N:7]/[OH:8])/[NH2:6].[NH2:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](O)=O)=[CH:19][CH:18]=1.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.CCN(C(C)C)C(C)C>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[N:6]=[C:21]([C:20]3[CH:24]=[CH:25][C:17]([NH2:16])=[CH:18][CH:19]=3)[O:8][N:7]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: CC(C)Oc1ccc(/C(N)=N/O)cc1Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1ccc(-c2noc(-c3ccc(N)cc3)n2)cc1Cl
Temperature: 150 °C
Yield: 50.6 %

Procedure:
(Z)-3-chloro-N′-hydroxy-4-isopropoxybenzimidamide (1 g, 4.37 mmol), 4-aminobenzoic acid (0.660 g, 4.81 mmol), HOBT (0.737 g, 4.81 mmol), DCC (0.992 g, 4.81 mmol) and DIEA (1.680 ml, 9.62 mmol) were combined in a microwave vial. The reaction mixture was heated in the microwave for 20 minutes at 150° C. The reaction mixture was filtered to remove the urea formed in the reaction and the solvent was removed in vacuo. The crude material was purified by FCC (50% ethyl acetate/heptane) to afford 4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)aniline (729 mg, 2.211 mmol, 50.6% yield) as an off white solid: LCMS (Table A, Method b) 3.00 min, (M+H)+ 330.13.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH3:9])[C:5]([C:11]#[C:12][C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[CH3:20])=[CH:4][N:3]=1.C([O-])(=O)C.[Na+].Cl.[NH2:27][OH:28]>C(O)C.ClC(Cl)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8](=[N:27][OH:28])[CH3:9])[C:5]([C:11]#[C:12][C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[CH3:20])=[CH:4][N:3]=1
Reactant: NO
Reactant: CC(=O)c1cc(Cl)ncc1C#Cc1cc(F)ccc1C
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: CC(=NO)c1cc(Cl)ncc1C#Cc1cc(F)ccc1C
Temperature: 70 °C

Procedure:
A mixture of 1-(2-chloro-5-((5-fluoro-2-methylphenyl)ethynyl)pyridin-4-yl)ethanone (700 mg, 2.0 mmol), sodium acetate (320 mg, 3.9 mmol), and hyroxylamine hydrochloride (254 mg, 3.65 mmol) in ethanol (11 mL) and dichloroethane (1.6 mL) was heated at 70° C. for 15 minutes. The cooled reaction mixture was evaporated in vacuo to afford a residue that was redissolved in ethyl acetate (150 mL) and washed with water (100 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a white solid that was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:33])[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:34]1([NH:37][C:38]([C:40]2[N:41]=[C:42](Br)[S:43][CH:44]=2)=[O:39])[CH2:36][CH2:35]1.C([O-])(O)=O.[Na+].CN(C=O)C>CO>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:33])[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:42]2[S:43][CH:44]=[C:40]([C:38](=[O:39])[NH:37][CH:34]3[CH2:36][CH2:35]3)[N:41]=2)[CH:19]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC1CC1)c1csc(Br)n1
Reactant: CC1(C)OB(c2cccc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)c2)OC1(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(NC1CC1)c1csc(-c2cccc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)c2)n1
Temperature: 70 °C

Procedure:
A solution of (S)-2-[3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylcarbamoyl]-pyrrolidine-1-carboxylic acid benzyl ester (90 mg, 0.2 mmol), 2-Bromo-thiazole-4-carboxylic acid cyclopropylamide (1 eq., 49 mg), Pd[P(Ph)3]4 (5 mol %, 10 mg), in methanol (4 mL), NaHCO3 (sat. aq., 600 uL) and DMF (800 uL) was degassed and heated to 70° C. overnight in a sealed vial. The reaction was cooled, filtered and the solvents removed. The resulting mixture was redissolved in 5 ml of 90% DMF, 10% water with 0.1% TFA and purified by reverse phase HPLC to give the products. Yield 11.1 mg. MS: 491.3 (M+H). H1-NMR (DMSO-d6): δ (ppm) 10.2 (s, 1H), 8.4-8.2 (m, 2H), 7.8-7.0 (m, 10H), 6.5 (m, 2H), 5.1-4.9 (m, 2H), 4.4 (m, 1H), 2.8 (m, 1H), 2.3 (m, 1H), 1.9 (m, 3H), 0.7-0.6 (m, 4H).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[S:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[O:20]([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25]Br)[CH3:21]>>[CH3:21][O:20][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][N:7]1[C:8]([S:9][C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]1=[O:18]
Reactant: COc1cccc(CBr)c1
Reactant: CCc1c(Sc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Product: CCc1c(Sc2cc(C)cc(C)c2)n(Cc2cccc(OC)c2)c(=O)[nH]c1=O
Yield: 44.1 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenyl)thio-2,4-pyrimidinedione and 3-methoxylbenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (175 mg, yield: 44.1%).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)=[CH:18][CH:17]=1.[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38].CO>C(OCC)(=O)C>[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:33]3[CH2:32][CH2:31][N:30]([CH:22]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=4)[C:19]4[CH:18]=[CH:17][C:16]([Cl:15])=[CH:21][CH:20]=4)[CH2:35][CH2:34]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: Clc1ccc(C(c2ccc(Cl)cc2)N2CCNCC2)cc1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 1-(bis(4-chlorophenyl)methylpiperazine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 82% overall yield. mp 123°-124°. FDMS m/e=510 (M+ of free base). α[D]589 =-8.46(c=0.89, methanol).
Reaction SMILES: [F:1][C:2]1[C:7]2[CH2:8][CH2:9][N:10]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH2:11][CH2:12][C:6]=2[C:5]([OH:19])=[CH:4][CH:3]=1.S(Cl)([Cl:23])(=O)=O>C1(C)C=CC=CC=1.C(NC(C)C)(C)C>[Cl:23][C:4]1[CH:3]=[C:2]([F:1])[C:7]2[CH2:8][CH2:9][N:10]([C:13](=[O:18])[C:14]([F:16])([F:17])[F:15])[CH2:11][CH2:12][C:6]=2[C:5]=1[OH:19]
Reactant: O=S(=O)(Cl)Cl
Reactant: O=C(N1CCc2c(O)ccc(F)c2CC1)C(F)(F)F
Solvent: CC(C)NC(C)C
Solvent: Cc1ccccc1
Product: O=C(N1CCc2c(F)cc(Cl)c(O)c2CC1)C(F)(F)F
Temperature: 60 °C
Reaction time: 2 h
Yield: 89.1 %

Procedure:
Dissolve 9-fluoro-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (1.0 g, 3.6 mmol) in toluene (36 mL) with diisopropylamine (41 μL, 0.29 mmol). Warm to 60° C. and add dropwise a solution of sulfuryl chloride (0.32 mL, 3.97 mmol) in toluene (10 mL). After 2 h, wash the mixture with brine, dry the organic layer over Na2SO4 and evaporate onto silica gel. Purify by chromatography on silica gel eluting with EtOAc/hexane (0:1 to 1:0) to obtain the desired intermediate (1.0 g, 92%). MS (ES+) m/z: 312 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:12][N:13]([CH3:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:11]=1)[C:5]([O:7]C)=[O:6].O.[OH-].[Li+]>CO.O1CCCC1>[CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:12][N:13]([CH3:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:11]=1)[C:5]([OH:7])=[O:6]
Reactant: CCCCCN(C)Cc1cc(C)cc(C(=O)OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCCCCN(C)Cc1cc(C)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of methyl 3-methyl-5-{[methyl(pentyl)amino]methyl}benzoate (120 mg, 0.46 mmol) in methanol (2 mL), tetrahydrofuran (1 mL), and water (1 mL) is added lithium hydroxide (191 mg, 4.6 mmol), and the reaction mixture stirred at room temperature for 2 h. The reaction mixture is concentrated under reduced pressure, dissolved in methylene chloride, filtered, and the filtrate concentrated under reduced pressure to provide the title compound. ESI MS m/z 250 [M+H]+.
Reaction SMILES: [CH:1](=[O:10])[C:2]1[C:3]([O:8]C)=[CH:4][CH:5]=[CH:6][CH:7]=1.[C:11](Cl)([CH3:14])([CH3:13])[CH3:12].[Cl-].[Al+3].[Cl-].[Cl-].ClCCl>CCOCC.O>[OH:8][C:3]1[CH:4]=[CH:5][C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:7][C:2]=1[CH:1]=[O:10]
Reactant: CC(C)(C)Cl
Reactant: COc1ccccc1C=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)c1ccc(O)c(C=O)c1
Temperature: 25 °C
Reaction time: 2.25 h
Yield: 40.3 %

Procedure:
To an ice-cold stirred mixture of o-anisaldehyde (50 ml, 326 mmol) and tert-butylchloride (80 ml, 735 mmol) was added aluminum chloride (40 g, 300 mmol). The reaction mixture became thick. Dry dichloromethane (100 ml) and aluminum chloride (60 g, 450 mmol) were added carefully with cooling. Once the reaction became less vigorous the reaction mixture was stirred at room temperature for 2.25 h. Ice (50 g) and subsequently ice-cold water (100 ml) were added carefully and the mixture was left to stir for 20 min. water (250 ml) and ether (550 ml) were added. The aqueous layer was removed and the organic layer was washed with water (3×250 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by distillation under reduced pressure and the fraction (b.p. 80°-86° C., 0.55-0.65 mm Hg) collected to yield (6) as a colourless oil (23.4 g, 40%). Preparation of 2-methoxy-5-tert-butylbenzaldehyde (5) To a solution of (6) (5.01 g, 28.1 mmol) in dry DMF (25 ml) was added a solution of tetra-n-butylammonium hydroxide in methanol (1.0M, 28.5 ml, 28.5 mmol). Methyl iodide (25 ml, 399 mmol) was added and the solution was stirred ac reflux for 1.5 h and then allowed to cool. Ether (250 ml) and water (250 ml) were added. The aqueous layer was removed and the organic layer was washed with water (3×250 ml), brine (250 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography over silica (dichloromethane/petroleum ether [60/80]; 4:1) to yield a colourless oil of (5) (4.36 g, 81%); δH (CDCl3) 1.29 (9 H, s, tert-butyl), 3.88 (3 H, s, OCH3), 6.95 (1 H, d, J=8.8 Hz, H3), 7.56 (1 H, dd, J=8.8, 2,7 Hz, H4), 7.83 (1 H, d, J=2.7 Hz, H6), and 10.44 (1 H, s, CHO).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH2:3][CH2:2]1.[N-:12]=[N+]=[N-].[Na+]>OS(O)(=O)=O>[O:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4](=[O:11])[NH:12][CH2:3][CH2:2]1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1CCOc2ccccc21
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C1NCCOc2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 59.5 %

Procedure:
To a solution containing 4-chromanone (1, 2 g, 13.4 mmol) in 15 mL conc H2SO4 at 0° C. was added sodium azide (1.131 g, 17.4 mmol) and the reaction mixture was stirred initially at 0° C. for 1 hour and then stirred at room temperature for 2 hours. The reaction was quenched by the slow addition of water and then subsequently basified with 10% NaOH. The aqueous solution was extracted with ether (2×150 mL). The combined ether layers were dried (Na2SO4) and filtered. The solvent was removed under vacuo and the crude product was recrystallized from EtOAc/hexanes to afford 1.3 g, 61% of 2 as white needles. mp 118°-120° C. 1H NMR (CDCl3) d 8.0 (d, 1 H ArH), 7.6-7.7 (bs, 1H, NH), 7.4 (t, 1H, ArH), 7.2 (t, 1H ArH), 7.0 (d, 1H, ArH), 4.4 (t, 2H, CH2), 3.5 (t, 2H, CH2). EIMS M+ 163 (98), 134 (99), 105 (100).
Reaction SMILES: Cl.[NH2:2][C:3]1[S:4][CH:5]=[C:6]([CH2:8]Cl)[N:7]=1.[C:10]1([CH:16]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>CN(C)C=O>[NH2:2][C:3]1[S:4][CH:5]=[C:6]([CH2:8][N:21]2[CH2:22][CH2:23][CH:18]([O:17][CH:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:19][CH2:20]2)[N:7]=1
Reactant: Nc1nc(CCl)cs1
Reactant: c1ccc(C(OC2CCNCC2)c2ccccc2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1nc(CN2CCC(OC(c3ccccc3)c3ccccc3)CC2)cs1
Temperature: 25 °C
Yield: 70.4 %

Procedure:
A stirred mixture of 2-amino-4-chloromethylthiazole hydrochloride (0.7 g), 4-(diphenylmethoxy)piperidine (0.78 g) and triethylamine (1.82 ml) in N,N-dimethylformamide (7.8 ml) was heated at 40° C. to 45° C. for 5 hours. After cooling to ambient temperature, the reaction mixture was filtered. The filtrate was poured into water (50 ml) and extracted with ethyl acetate (80 ml×2). The extract was washed with a saturated aqueous solution of sodium chloride (30 ml) and dried over magnesium sulfate. The solvent was distilled off and the residue was subjected to column chromatography on silica gel (30 g) and eluted with a mixture of chloroform and methanol (10:1 V/V). The fractions containing the object compound were combined and concentrated under reduced pressure to give 2-amino-4-[4-(diphenylmethoxy)piperidinomethyl]thiazole (0.78 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[C:4]([F:15])[CH:3]=1.N1C=CC=CC=1.Cl[C:23]([O:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[O:24].C(OCC)(=O)C>ClCCl>[F:15][C:4]1[CH:3]=[C:2]([NH:1][C:23](=[O:24])[O:25][CH2:26][CH:27]([CH3:29])[CH3:28])[CH:7]=[CH:6][C:5]=1[N:8]1[CH:9]=[CH:10][C:11](=[O:14])[CH2:12][CH2:13]1
Reactant: Nc1ccc(N2C=CC(=O)CC2)c(F)c1
Reactant: CC(C)COC(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)COC(=O)Nc1ccc(N2C=CC(=O)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 72.6 %

Procedure:
To a cold (0° C.) stirring solution of the aniline from step 4 (62.0 g, 300.7 mmol) and pyridine (29.1 ml, 360.8 mmol) in dichloromethane (1095 ml) is added isobutyl chloroformate (42.9 ml, 330.7 mmol), and the mixture is stirred at ambient temperature for 90 min. Upon completion of the reaction the solvent is removed in vacuo, and the residual material is redissolved in dichloromethane (800 ml) and ethyl acetate (1100 ml). The mixture is washed with 10% aqueous HCl (1100 ml), and aqueous layer is extracted with 1:9/dichloromethane:ethyl acetate (1100 ml). The organic layers are combined and washed with brine (1100 ml). The organic layer is dried over MgSO4 and filtered. The filtrate is concentrated in vacuo. The residual material is recrystallized in 1:9/dichloromethane:ethyl acetate to afford 66.9 g (72% yield) of the title compound as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ 0.93 (d, 6 H), 1.93 (m, 1 H), 2.47 (m, 2 H), 3.84 (m, 2 H), 3.89 (m, 2 H), 4.96 (d, 1 H) 7.29 (m, 2 H), 7.48 (m, 2 H), 9.92 (brs, 1 H).
Reaction SMILES: [C:1](=[O:6])=[N:2][C:3](Cl)=[O:4].[CH3:7][C:8]1[O: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)=[N:10][C:9]=1[CH2:23][O:24][C:25]1[CH:26]=[C:27](/[C:31](/[CH2:36][CH3:37])=[CH:32]/[CH2:33][NH:34][OH:35])[CH:28]=[CH:29][CH:30]=1.Cl>C1COCC1>[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH2:23][O:24][C:25]1[CH:26]=[C:27](/[C:31](/[CH2:36][CH3:37])=[CH:32]/[CH2:33][N:34]2[C:3](=[O:4])[NH:2][C:1](=[O:6])[O:35]2)[CH:28]=[CH:29][CH:30]=1
Reactant: O=C=NC(=O)Cl
Reactant: CC/C(=C\CNO)c1cccc(OCc2nc(-c3ccc(C(F)(F)F)cc3)oc2C)c1
Agent: Cl
Solvent: C1CCOC1
Product: CC/C(=C\Cn1oc(=O)[nH]c1=O)c1cccc(OCc2nc(-c3ccc(C(F)(F)F)cc3)oc2C)c1
Reaction time: 0.5 h
Yield: 63.7 %

Procedure:
N-(Chlorocarbonyl)isocyanate (0.37 ml, 4.63 mmol) was added dropwise to a cold (-5° C.) mixture of (E)-N-(3-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-pent-2-enyl)-hydroxylamine (2.0 g, 4.63 mmol) in THF (20 ml). The mixture was stirred for 30 minutes, then poured into HCl (1N) and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography on acid washed (5% H3PO4 /MeOH) silica gel (hexane/EtOAc 3/1) gave a white solid (1.48 g, 64% yield, mp 66°-67° C.).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7](OS(C(F)(F)F)(=O)=O)[CH:8]=2)[NH:3]1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=1B(O)O.[C:35]1([CH2:41][CH2:42][SH:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=1[C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[NH:3][C:2]([CH3:1])([CH3:21])[CH:11]=[C:10]2[CH2:12][S:43][CH2:42][CH2:41][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COc1ccc(OC)c(B(O)O)c1
Reactant: CC1=CC(C)(C)Nc2ccc(OS(=O)(=O)C(F)(F)F)cc21
Reactant: SCCc1ccccc1
Product: COc1ccc(OC)c(-c2ccc3c(c2)C(CSCCc2ccccc2)=CC(C)(C)N3)c1

Procedure:
Trifluoromethanesulfonic acid 2,2,4-trimethyl-1,2-dihydroquinolin-6-yl ester was coupled with 2,5-dimethoxyphenylboronic acid. Bromination and coupling reaction with 2-phenylethanethiol gave 43 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH2:17])[CH2:15][CH3:16])[N:5]=[C:4]([CH3:18])[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].[OH:24][CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][C:30]=1[O:38][CH3:39]>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH:17][C:33](=[O:34])[C:32]2[CH:36]=[CH:37][C:29]([O:28][CH2:27][CH2:26][CH2:25][OH:24])=[C:30]([O:38][CH3:39])[CH:31]=2)[CH2:15][CH3:16])[N:5]=[C:4]([CH3:18])[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: COc1cc(C(=O)O)ccc1OCCCO
Reactant: CCOC(=O)c1c(C)nc2cccc(OC[C@@H](N)CC)c2c1N
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@H](CC)NC(=O)c3ccc(OCCCO)c(OC)c3)c2c1N

Procedure:
Prepared as in Example 24a from (S)-ethyl 4-amino-5-(2-aminobutoxy)-2-methylquinoline-3-carboxylate (Example 97b) and 4-(3-hydroxypropoxy)-3-methoxybenzoic acid (Baraldi, P. G. et al. J. Med. Chem. 1999, 42, 5131) as brown solid (41%). MS 526 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)[CH:3]=1.[Li][CH2:20]CCC.C[Si](C)(C)[O:26][C@@H:27]1[C@@H:32]([O:33][Si](C)(C)C)[C@H:31]([O:38][Si](C)(C)C)[C@@H:30]([CH2:43][O:44][Si](C)(C)C)[O:29][C:28]1=[O:49].Cl.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C1COCC1.C1(C)C=CC=CC=1.CO>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C@@:28]2([O:49][CH3:20])[C@H:27]([OH:26])[C@@H:32]([OH:33])[C@H:31]([OH:38])[C@@H:30]([CH2:43][OH:44])[O:29]2)=[CH:3][C:4]=1[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[CH:12][CH:11]=1
Reactant: C[Si](C)(C)OC[C@H]1OC(=O)[C@H](O[Si](C)(C)C)[C@@H](O[Si](C)(C)C)[C@@H]1O[Si](C)(C)C
Reactant: [Li]CCCC
Reactant: CCOc1ccc(Cc2cc(Br)ccc2Cl)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOc1ccc(Cc2cc([C@]3(OC)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Temperature: -65 °C
Reaction time: 0.5 h

Procedure:
To a solution of Example 1B (200 g, 0.614 mol) in anhydrous toluene/THF (1.2 L, 2:1 (v/v)) was added n-BuLi (2.5 M in hexane, 295 mL) dropwise at −65° C. The reaction was stirred at −65° C. for 30 min. Then the mixture was transferred by a cannula to a solution of (3R,4S,5R,6R)-3,4,5-tris(trimethylsilyloxy)-6-((trimethylsilyloxy)methyl)tetrahydro-2H-pyran-2-one) (373 g, 0.798 mol) in toluene (1.2 L) at −65° C. The mixture was stirred at −65° C. until starting material was consumed (2 h). The reaction was quenched with hydrochloric acid (36˜38%, 113 mL, 1.35 mol) in methanol (800 mL), and stirred at room temperature overnight. The reaction was neutralized with saturated sodium bicarbonate to pH 7.5 and the organic phase was separated and the aqueous phase was extracted with ethyl acetate (2×3.0 L). The combined organic layers were washed with brine (2×2.0 L), dried over sodium sulfate and concentrated. The residue was dissolved in hot toluene (600 mL) and poured into n-hexane (2.0 L) with vigorous stirring. After stirring for 1 h, the mixture was filtered and the filter cake was dried under vacuum to give the desired product as a white solid. This solid was used without further purification in the next step. MS ESI (m/z) 439 [M+1]+.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[C:5]([N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)(=[O:8])[CH2:6][CH3:7]>C1(C)C=CC=CC=1>[Cl:4][C:1]([N:12]1[CH2:13][CH2:14][N:9]([C:5](=[O:8])[CH2:6][CH3:7])[CH2:10][CH2:11]1)=[O:2]
Reactant: CCC(=O)N1CCNCC1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: CCC(=O)N1CCN(C(=O)Cl)CC1
Temperature: -5 °C
Yield: 98.8 %

Procedure:
A solution of phosgene (45.0 g.) in anhydrous toluene (500 cm3) and 1-propionylpiperazine (129.0 g.) are added simultaneously to anhydrous toluene (500 cm3), while the temperature is maintained at about -5° C. 1-Chlorocarbonyl-4-propionylpiperazine (92.0 g.), m.p. about 45° C., is thus obtained. After one hour's stirring at 2° C., the 1-propionylpiperazine hydrochloride formed is separated by filtration and, after evaporation of the filtrate under reduced pressure (20 mm.Hg) 1-chlorocarbonyl-4-propionyl-piperazine is obtained.