Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7](C(C2C(O)=CC3C(C)(C)CCC(C)(C)C=3C=2)=O)=[CH:6][CH:5]=1.[OH-].[K+].BrCCCCCC>CS(C)=O>[C:3]([OH:27])(=[O:2])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C(=O)c2cc3c(cc2O)C(C)(C)CCC3(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCCCCCBr
Solvent: CS(C)=O
Product: O=C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A solution of the 4-[(3-hydroxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]benzoic acid methyl ester (from Example 7, 433 mg, 1.18 mmol) in DMSO (2 mL) was treated with KOH (1.5 mmol) at 0° C. and allowed to warm to ambient temperature over 1 h. The yellow solution was cooled again to 0° C. and treated with a solution of bromohexane (156 mL, 1.30 mmol) in DMSO (1 mL) and allowed to warm to ambient temperature and stirred for 10 h. The reaction was quenched with saturated aqueous NH4Cl. The aqueous solution was adjusted to pH=3 with 1M HCl and extracted with EtOAc, 3×. The organic layers were combined and washed with water (2×) and brine. The organic solution was dried (NaSO4), filtered, and concentrated. Purification by silica gel radial chromatography (20:1=hexane:Et2O) gave 4-[2-hexyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]benzoic acid, 317 mg (62%) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ8.14 (½ABq, J=8.4 Hz, 2H, ArH), 7.84 (½ABq, J=8.4 Hz, 2H, ArH), 7.47 (s, 1H, ArH), 6.81 (s, 1H, ArH), 3.80 (t, J=6.2 Hz, 2H, OCH2), 1.17 (m, 4H, 2CH2), 1.34 (m, 2H, CH2), 1.32 (s, 6H, 2CH3), 1.28 (s, 6H, 2CH3), 1.11 (m, 4H, 2CH2), 0.95 (m, 2H, CH2), 0.80 (t, J=7.1 Hz, 3H, CH3). The hexyloxyketo acid (87 mg, 0.19 mmol) in EtOH (2 mL) was converted into the oxime derivative as described in Example 4 to provide, after recrysallization (CH2Cl2/hexanes), 4-[(3-hexyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]benzoic acid oxime (114), 312 mg (60%) as a white solid: mp 197-199° C. (d); 1H NMR (400 MHz, CDCl3) δ8.14 (½ABq, J=8.5 Hz, 2H, ArH), 7.57 (½ABq, J=8.5 Hz, 2H, ArH), 7.22 (s, 1H, ArH), 6.85 (s, 1H, ArH), 3.82 (t, J=6.3 Hz, 2H, OCH2), 1.70 (m, 4H, 2CH2), 1.45 (m, 2H, CH2), 1.32 (s, 6H, 2CH3), 1.25 (s, 6H, 2CH3), 1.13 (m, 6H, 3CH2), 0.80 (t, J=6.8 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3) δ155.7, 153.8, 147.8, 141.1, 137.0, 130.3, 129.9, 128.4, 127.0, 118.5, 110.0, 68.3, 35.3, 35.0, 34.8, 33.8, 31.9, 31.8, 31.4, 29.0, 25.4, 22.5, 13.9.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C=C.C=CC1C=CC=CC=1.C(C1C=CC=CC=1[C:23]([OH:25])=[O:24])=C>C(C1C=CC=CC=1S(O)(=O)=O)CCCCCCCCCCC>[CH:2]([C:3]1[CH:8]=[CH:7][C:6]([C:23]([OH:25])=[O:24])=[CH:5][CH:4]=1)=[CH2:1]
Reactant: C=Cc1ccccc1
Reactant: C=Cc1ccccc1C(=O)O
Agent: C=C
Agent: CCCCCCCCCCCCc1ccccc1S(=O)(=O)O
Product: C=Cc1ccc(C(=O)O)cc1
Reaction time: 0.08 h
Yield: 3062.6 %

Procedure:
40 g of an ethylene styrene interpolymer (35 wt percent Copolymer Styrene, 6.0 wt percent a tactic Polystyrene, ESI-2) was added to a Brabender mixer at 190° C. To the polymer melt, 1.2 g (8 mmol) of powdered vinylbenzoic acid was added. Finally, 107 μL of dodecylbenzenesulfonic acid was added and the molten mixture blended at 80 rpm for 5 minutes. After the allotted time, the Brabender was opened and the tan polymer melt was removed to yield 36.3 g of product. A 300 mg portion of the polymer was pressed between teflon sheets into a thin, clear, and creasable film at 210 C with 20,000 lbs of load. Analysis of the film by infrared spectroscopy showed a broad peak at 3500 to 3000 cm−1 due to the carboxylic acid group and a carbonyl stretch at 1695 cm−1. Dissolution of the polymer in warm xylene (15 mL/g of polymer) followed by precipitation into methanol did not change the IR spectrum of the product indicating that the vinylbenzoic acid was indeed grafted to the ethylene styrene copolymer and that the product was not simply a physical mixture of the two components.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([CH:9]=O)=[CH:7][CH:6]=[CH:5][C:4]=1[C:11]1[N:15]=[C:14]([C:16]2[CH:17]=[CH:18][C:19]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH:23]=2)[C:21]#[N:22])[S:13][N:12]=1)[CH3:2].[NH:28]1[CH2:31][CH:30]([C:32]([OH:34])=[O:33])[CH2:29]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CO>[C:21]([C:20]1[CH:23]=[C:16]([C:14]2[S:13][N:12]=[C:11]([C:4]3[C:3]([CH2:1][CH3:2])=[C:8]([CH2:9][N:28]4[CH2:31][CH:30]([C:32]([OH:34])=[O:33])[CH2:29]4)[CH:7]=[CH:6][CH:5]=3)[N:15]=2)[CH:17]=[CH:18][C:19]=1[O:24][CH:25]([CH3:27])[CH3:26])#[N:22]
Reactant: O=C(O)C1CNC1
Reactant: CCc1c(C=O)cccc1-c1nsc(-c2ccc(OC(C)C)c(C#N)c2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCl
Product: CCc1c(CN2CC(C(=O)O)C2)cccc1-c1nsc(-c2ccc(OC(C)C)c(C#N)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.4 %

Procedure:
To a solution of 5-[3-(2-ethyl-3-formylphenyl)-1,2,4-thiadiazol-5-yl]-2-[(1-methylethyl)oxy]benzonitrile (D46) (110 mg) in dichloromethane (DCM) (5 mL) and methanol (5.00 mL) was added 3-azetidinecarboxylic acid (147 mg) and acetic acid (0.050 mL). The resulting solution was stirred at room temperature for overnight. Sodium triacetoxyborohydride (185 mg) was added and the reaction solution was stirred for 2 h. The solvent was removed in vacuo and the residue was purified by Mass Directed AutoPrep to give 1-{[3-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazol-3-yl)-2-ethylphenyl]methyl}-3 azetidinecarboxylic acid (E17) (37 mg) as a TFA salt (white solid). δH (DMSO-d6, 400 MHz): 1.03 (3H, t), 1.31 (6H, d), 2.93 (2H, q), 3.60 (1H, m), 4.22 (4H, m), 4.52 (2H, s), 4.89 (1H, m), 7.38 (1H, t), 7.42 (1H, d), 7.51 (1H, s br), 7.82 (1H, d), 8.27 (1H, dd), 8.42 (1H, d), 10.20 (1H, s br), 13.13 (1H, br s). δF (DMSO-d6, 376 MHz): −73.7. MS (ES): C26H26N4O3S requires 462. found 463.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][N:7]1[CH3:12].[C:17]([O:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)(=[O:19])[CH3:18]>N1C=CC=CC=1>[C:17]([O:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:1][C:2]2[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=2[CH2:4][CH2:5][CH:6]2[CH2:11][CH2:10][CH2:9][CH2:8][N:7]2[CH3:12])=[O:26])=[CH:23][CH:22]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)Oc1ccc(C(=O)Cl)cc1
Reactant: CN1CCCCC1CCc1ccccc1N
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(C(=O)Nc2ccccc2CCC2CCCCN2C)cc1

Procedure:
Reaction of 2-(o-aminophenethyl)-1-methylpiperidine with p-acetoxybenzoyl chloride in pyridine according to Example 1 provides 4-acetoxy-2'-[2-(1-methyl-2-piperidyl)ethyl]benzanilide. Analytically pure product is obtained by crystallization from isopropyl ether, m.p. 88°-108°C. (corr.). The broad melting point of the analytically pure material is due to the polymorphism.
Reaction SMILES: [ClH:1].Cl.N1CCOC(CN[C:11]([C:13]2[N:14]=[N:15][C:16]([CH2:32][CH2:33][CH2:34][CH3:35])=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)=[CH:21][CH:20]=3)[CH:18]=2)=[O:12])C1.[CH3:36][N:37]1[CH:42]2[CH2:43][CH2:44][CH:38]1[CH2:39][CH:40]([NH2:45])[CH2:41]2.C(N(C(C)C)C(C)C)C>C1COCC1.C(OCC)C>[ClH:1].[ClH:1].[CH3:36][N:37]1[CH:42]2[CH2:43][CH2:44][CH:38]1[CH2:39][CH:40]([NH:45][C:11]([C:13]1[N:14]=[N:15][C:16]([CH2:32][CH2:33][CH2:34][CH3:35])=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]4[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]4)=[CH:21][CH:20]=3)[CH:18]=1)=[O:12])[CH2:41]2
Reactant: CCCCc1nnc(C(=O)NCC2CNCCO2)cc1-c1ccc(OC2CCCCC2)cc1
Reactant: CN1C2CCC1CC(N)C2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCc1nnc(C(=O)NC2CC3CCC(C2)N3C)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazine-3-carboxylic acid pentafluorophenyl ester hydrochloride (Example 90, 0.108 mmol, 60 mg), 8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylamine (0.05 mL), ethyl-diisopropyl-amine (0.2 mL) in THF (2.0 mL) may be stirred at room temperature for 3 h. The reaction mixture may be diluted with diethyl ether, washed with water and 2 M aq. sodium hydroxide solution and dried over magnesium sulfate. The crude product may be purified by column chromatography on silica gel using 2-5% 2 M ammonia in MeOH in DCM and treated with 4 N HCl in dioxane. The organic solvents may be removed under reduced pressure, and the product dried overnight under high vacuum to provide the free base of the title compound. 1H NMR (free base, 400 MHz, CDCl3) δ 8.72 (1 H, d), 8.09 (1 H, s), 7.27 (2 H, d), 7.01 (2 H, d), 4.30-4.36 (2 H, m), 3.20 (2 H, bs), 3.08 (2 H, t), 2.32 (3 H, s), 1.26-2.35 (22 H, m), 0.87 (3 H, t).
Reaction SMILES: [CH2:1]([C:3]1([C:8]2[S:9][CH:10]=[C:11]([CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][OH:22])=[C:17]([CH2:23][OH:24])[CH:16]=3)[CH:12]=2)OCC[O:4]1)[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O.O>[OH:24][CH2:23][C:17]1[CH:16]=[C:15]([CH2:14][CH2:13][C:11]2[CH:12]=[C:8]([C:3](=[O:4])[CH2:1][CH3:2])[S:9][CH:10]=2)[CH:20]=[CH:19][C:18]=1[CH2:21][OH:22]
Reactant: CCC1(c2cc(CCc3ccc(CO)c(CO)c3)cs2)OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: CCC(=O)c1cc(CCc2ccc(CO)c(CO)c2)cs1

Procedure:
In a manner similar to that of Example 6(g), by reaction of 5.3 g (15 mmol) of (4-{2-[2-(2-ethyl-[1,3]dioxolan-2-yl)-4-thienyl]ethyl}-2-hydroxymethyl-phenyl)methanol with a solution of para-toluenesulphonic acid in an acetone/water mixture, the desired product is obtained in the form of a white powder (m=4 g; Y=86%).
Reaction SMILES: [N:1]1([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:5][CH2:4][C:3]2([C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([C:14]([O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])=[O:15])[CH2:6]2)[CH2:2]1.[Br:30]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(O)(C)(C)C.O>[Br:30][C:11]1[CH:12]=[C:13]2[C:3]3([CH2:4][CH2:5][N:1]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:2]3)[CH2:6][N:7]([C:14]([O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:20])[CH3:21])=[O:15])[C:8]2=[CH:9][CH:10]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCC2(C1)CN(C(=O)OCC[Si](C)(C)C)c1ccccc12
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)N1CCC2(C1)CN(C(=O)OCC[Si](C)(C)C)c1ccc(Br)cc12
Temperature: 60 °C
Reaction time: 15 h
Yield: 71 %

Procedure:
1-(2-(Trimethylsilyl)ethyl) 1′-tert-butyl spiro[indoline-3,3′-pyrrolidine]-1,1′-dicarboxylate (15.2 g, 36.5 mmol) was dissolved in t-butanol (240 mL) and water (40 mL). Thereafter, N-bromosuccinimide (7.9 g, 44.4 mmol) was added to the above obtained solution at room temperature, and the thus obtained mixture was then stirred at 60° C. for 15 hours. Thereafter, an aqueous solution of sodium thiosulfate was added to the reaction solution, and the mixed solution was then extracted with ethyl acetate. The organic layer was washed with brine, and was then dried over anhydrous sodium sulfate, followed by concentration in vacuo. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain 1-(2-(trimethylsilyl)ethyl) 1′-tert-butyl 5-bromospiro[indoline-3,3′-pyrrolidine]-1,1′-dicarboxylate (12.9 g, 71%) in the form of a white amorphous product.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]2[C:13]3[C:18]([O:19][CH2:20][C:3]=12)=[CH:17][C:16]([OH:21])=[CH:15][CH:14]=3.[Cl:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1>>[Cl:22][C:23]1[CH:28]=[C:27]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=3)[N:5]=[C:4]3[C:13]4[C:18]([O:19][CH2:20][C:3]=23)=[CH:17][C:16]([OH:21])=[CH:15][CH:14]=4)[CH:26]=[CH:25][CH:24]=1
Reactant: Oc1ccc2c(c1)OCc1c-2nc2ccc(O)cc2c1Br
Reactant: OB(O)c1cccc(Cl)c1
Product: Oc1ccc2c(c1)OCc1c-2nc2ccc(O)cc2c1-c1cccc(Cl)c1
Yield: 94 %

Procedure:
This compound was prepared from 7-bromo-3,9-dihydroxy-6H-chromeno[4,3-b]quinoline (7) using 3-chlorophenylboronic acid according to method M. Orange powder; Yield: 94%; mp 162-165° C. (dec.); 1H-NMR (400 MHz, DMSOd-6) δ 5.01 (s, 2H), 6.36 (d, J=2.3 Hz, 1H), 6.60 (dd, J=8.5, 2.2 Hz, 1H), 6.61 (d, J=2.6 Hz, 1H), 7.26 (dd, J=9.1, 2.6 Hz, 1H), 7.35 (m, 1H), 7.50 (d, J=1.0 Hz, 1H), 7.64 (dd, J=3.9, 1.6, Hz, 2H), 7.90 (d, J=9.1 Hz, 1H), 8.15 (d, J=8.8 Hz, 1H), 9.86 (s, 1H), 9.98 (s, 1H); MS (ESI) m/z 374/376 ([M−H]−), 376/378 ([M+H]+); HRMS (ESI+) calcd for C22H14ClNO3 376.0735 ([M+H]+). Found: 376.0721.
Reaction SMILES: [ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@@H:5]3[NH2:12])[CH2:3]1)[CH2:9]2.[CH:13]1[CH:18]=[C:17]2[CH:19]=[C:20]([C:22](O)=[O:23])[S:21][C:16]2=[CH:15][CH:14]=1.N>>[ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@@H:5]3[NH:12][C:22]([C:20]3[S:21][C:16]4[CH:15]=[CH:14][CH:13]=[CH:18][C:17]=4[CH:19]=3)=[O:23])[CH2:3]1)[CH2:9]2
Reactant: O=C(O)c1cc2ccccc2s1
Reactant: NC1C2CC3CC1CN(C3)C2
Agent: Cl
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1cc2ccccc2s1

Procedure:
Prepared from (4s)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine hydrochloride and thianaphthene-2-carboxylic acid (Aldrich) according to methods A and C; yield 57 mg, 0.16 mmol (50%): 1H NMR (300 MHz, methanol-d4) δ 1.98 (d, J=13 Hz, 2H), 2.20 (s, 1H), 2.36 (d, J=14 Hz, 2H), 2.49 (s, 2H), 3.57 (s, 2H), 3.67 (d, J=2 Hz, 4H), 4.42 (s, 1H), 7.39-7.50 (m, 2H), 7.88-7.96 (m, 2H), 8.12 (s, 1H); MS (DCI/NH3) m/z 313 (M+H)+; Anal. C18H20N2OS.HCl 0.12H2O: C, H, N.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:27]([F:30])([F:29])[F:28])[O:16][CH2:15][N:14]=[C:13]2[C:17]2[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[C:19]([CH3:26])[CH:18]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:52][N:53]1[CH2:58][CH2:57][CH2:56][N:55]([CH2:59][C:60]([F:63])([F:62])[F:61])[C:54]1=[O:64]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:27]([F:28])([F:29])[F:30])[O:16][CH2:15][N:14]=[C:13]2[C:17]2[CH:25]=[CH:24][C:20]([C:21]([NH:52][N:53]3[CH2:58][CH2:57][CH2:56][N:55]([CH2:59][C:60]([F:61])([F:63])[F:62])[C:54]3=[O:64])=[O:22])=[C:19]([CH3:26])[CH:18]=2)[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: Cc1cc(C2=NCOC2(c2cc(Cl)cc(C(F)(F)F)c2)C(F)(F)F)ccc1C(=O)O
Reactant: NN1CCCN(CC(F)(F)F)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: Cc1cc(C2=NCOC2(c2cc(Cl)cc(C(F)(F)F)c2)C(F)(F)F)ccc1C(=O)NN1CCCN(CC(F)(F)F)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-2,5-dihydro-1,3-oxazol-4-yl]-2-methylbenzoic acid (50 mg, 0.11 mmol, 1.00 equiv), dichloromethane (20 mL), EDCI (25 mg, 0.13 mmol, 1.20 equiv), HOBt (18 mg, 0.13 mmol, 1.20 equiv), TEA (30 mg, 0.30 mmol, 3.00 equiv), 1-amino-3-(2,2,2-trifluoroethyl)-1,3-diazinan-2-one (22 mg, 0.11 mmol, 1.00 equiv). The resulting solution was stirred overnight at room temperature. The resulting solution was diluted with 40 mL of DCM. The resulting mixture was washed with 3×20 mL of brine. The mixture was dried over anhydrous sodium sulfate. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1). This resulted in 12 mg (17.2%) of 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-2,5-dihydro-1,3-oxazol-4-yl]-2-methyl-N-[2-oxo-3-(2,2,2-trifluoroethyl)-1,3-diazinan-1-yl]benzamide as a white solid. (ES, m/z): 631 [M+H]+ 1H-NMR (CDCl3, ppm): 7.82 (s, 1H), 7.76-7.73 (m, 2H), 7.69 (s, 1H), 7.61-7.50 (m, 3H), 4.14 (d, J=18.6 Hz, 1H), 4.07-3.98 (m, 2H), 3.80-3.69 (m, 3H), 3.58-3.52 (m, 2H), 2.51 (s, 3H), 2.25-2.17 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[C:8]([C:9](O)=[O:10])=[CH:7][N:6]=[CH:5][CH:4]=1.S(Cl)([Cl:16])=O.CN(C)C=O>C1C=CC=CC=1>[F:1][C:2]([F:13])([F:12])[C:3]1[C:8]([C:9]([Cl:16])=[O:10])=[CH:7][N:6]=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cnccc1C(F)(F)F
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: O=C(Cl)c1cnccc1C(F)(F)F
Yield: 90.1 %

Procedure:
4-Trifluoromethylnicotinic acid (50.09 g, 0.262 mol) was suspended in benzene (250 ml), and thionyl chloride (38.2 ml, 0.524 mol) and N,N-dimethylformamide (0.1 ml) were added. The mixture was refluxed for 3 hours. The reaction mixture was concentrated, and the residue was distilled under reduced pressure to obtain 49.45 g (yield 90.1%) of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:66])[C@H:3]1[CH2:63][C@@H:62]([CH3:64])[O:61][CH:5]([O:6][C@@H:7]2[C@@H:23]([CH3:24])[C:22](=[O:25])[C@@H:21]([CH3:26])[C:20](=[O:27])[O:19][C@H:18]([CH2:28][CH3:29])[C@:17]3([CH2:30][O:31][Si](C(C)(C)C)(C)C)[C@H:13]([N:14]([CH2:40][CH2:41][CH2:42][CH2:43][N:44]4[CH:48]=[C:47]([C:49]5[CH:50]=[N:51][CH:52]=[CH:53][CH:54]=5)[N:46]=[CH:45]4)[C:15](=[O:39])[O:16]3)[C@@H:12]([CH3:55])[C:11](=[O:56])[C@H:10]([CH3:57])[CH2:9][C@:8]2([O:59][CH3:60])[CH3:58])[C@@H:4]1[OH:65].C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>O1CCCC1>[CH3:66][N:2]([CH3:1])[C@H:3]1[CH2:63][C@@H:62]([CH3:64])[O:61][CH:5]([O:6][C@@H:7]2[C@@H:23]([CH3:24])[C:22](=[O:25])[C@@H:21]([CH3:26])[C:20](=[O:27])[O:19][C@H:18]([CH2:28][CH3:29])[C@:17]3([CH2:30][OH:31])[C@H:13]([N:14]([CH2:40][CH2:41][CH2:42][CH2:43][N:44]4[CH:48]=[C:47]([C:49]5[CH:50]=[N:51][CH:52]=[CH:53][CH:54]=5)[N:46]=[CH:45]4)[C:15](=[O:39])[O:16]3)[C@@H:12]([CH3:55])[C:11](=[O:56])[C@H:10]([CH3:57])[CH2:9][C@:8]2([O:59][CH3:60])[CH3:58])[C@@H:4]1[OH:65]
Reactant: CC[C@H]1OC(=O)[C@H](C)C(=O)[C@H](C)[C@@H](OC2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(OC)C[C@@H](C)C(=O)[C@H](C)[C@H]2N(CCCCn3cnc(-c4cccnc4)c3)C(=O)O[C@]12CO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC[C@H]1OC(=O)[C@H](C)C(=O)[C@H](C)[C@@H](OC2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(OC)C[C@@H](C)C(=O)[C@H](C)[C@H]2N(CCCCn3cnc(-c4cccnc4)c3)C(=O)O[C@]12CO
Reaction time: 48 h
Yield: 48 %

Procedure:
To (3aR,4R,7R,9R,10R,11R,13 R,15R,15aR)-3a-({[tert-butyl(dimethyl)silyl]-oxy}methyl)-4-ethyl-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxo-1-[4-(4-pyridin-3-yl-1H-imidazol-1-yl)butyl]tetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl 3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside (1 eq) in tetrahydrofuran was added acetic acid (2 eq) and tetrabutylammonium fluoride/1.0M in tetrahydrofuran (2 eq). After standing for 48 hours, ethyl acetate was added and the solution was washed with NaHCO3(sat.), NaCl(sat.), dried over MgSO4, filtered, and concentrated. Purification by RP HPLC afforded (3aR,4R,7R,9R,10R,11R,13R,15R,15aR)-4-ethyl-3a-(hydroxymethyl)-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxo-1-[4-(4-pyridin-3-yl-1H-imidazol-1-yl)-butyl]tetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl 3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside (48% yield) as a white solid. MH+(828.50).
Reaction SMILES: [F:1][C:2]1[C:3]2[CH:4]=[CH:5][CH:6]=[N:7][C:8]=2[C:9]2[O:15][CH2:14][CH2:13][O:12][C:10]=2[CH:11]=1.[CH2:16]([I:19])[CH:17]=[CH2:18]>C1(C)C=CC=CC=1>[I-:19].[F:1][C:2]1[C:3]2[CH:4]=[CH:5][CH:6]=[N+:7]([CH2:18][CH:17]=[CH2:16])[C:8]=2[C:9]2[O:15][CH2:14][CH2:13][O:12][C:10]=2[CH:11]=1
Reactant: C=CCI
Reactant: Fc1cc2c(c3ncccc13)OCCO2
Solvent: Cc1ccccc1
Product: C=CC[n+]1cccc2c(F)cc3c(c21)OCCO3
Product: [I-]
Temperature: 25 °C
Yield: 78.8 %

Procedure:
6-fluoro-2,3-dihydro[1,4]dioxino[2,3-h]quinoline (2.78 g, 13.6 mmol) and allyl iodide (2.5 ml, 27.2 mmol) in toluene (50 ml) under argon was heated at 90° C. than at 120° C. for 5 h. The reaction was cooled to rt, the solvent decanted and the solid dried in the vacuum oven at 40° C. overnight to afford the desired product (4 g, 80%).
Reaction SMILES: [CH3:1][C:2]([NH:5][CH2:6][CH:7]([OH:12])[C:8]([Cl:11])([Cl:10])[Cl:9])([CH3:4])[CH3:3].Cl[C:14]([O:16][CH3:17])=[O:15].C(N(CC)CC)C>ClCCl>[CH3:4][C:2]([N:5]([CH2:6][CH:7]([OH:12])[C:8]([Cl:11])([Cl:10])[Cl:9])[C:14](=[O:15])[O:16][CH3:17])([CH3:1])[CH3:3]
Reactant: CC(C)(C)NCC(O)C(Cl)(Cl)Cl
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N(CC(O)C(Cl)(Cl)Cl)C(C)(C)C

Procedure:
3-(1,1-Dimethylethylamino)-1,1,1-trichloro-2-propanol can then be reacted with methyl chloroformate at about -70° to +70° C. in the presence of an acid acceptor such as triethylamine in a solvent such as dichloromethane to produce methyl (1,1-dimethylethyl)-(3,3,3-trichloro-2-hydroxypropyl)carbamate.
Reaction SMILES: C(O[CH:4]([O:15]CC)[C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[N+:12]([O-:14])=[O:13])C.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>CN(C)C=O>[ClH:11].[N+:12]([C:6]1[CH:7]=[CH:8][C:9]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[CH:10][C:5]=1[CH:4]=[O:15])([O-:14])=[O:13]
Reactant: C1CNCCN1
Reactant: CCOC(OCC)c1cc(Cl)ccc1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: Cl
Product: O=Cc1cc(N2CCNCC2)ccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 4 h
Yield: 64.4 %

Procedure:
2-Nitro-5-chlorobenzaldehyde diethyl acetal (138 g) was dissolved in 750 ml of dimethylformamide (DMF) and to the solution was added 250 g of anhydrous piperazine and stirred at 80° C. for 4 hours. After removing excessive piperazine and DMF by evaporation under reduced pressure, and a dilute aqueous sodium hydroxide solution was added to the residue to dissolve. Then, the solution was extracted with methylene chloride. The methylene chloride layer was washed with water and dried over sodium sulfate followed by removal of the solvent by distillation. To the residue was added 850 ml of isopropyl alcohol to dissolve, and to the solution was added 65 ml of concentrated hydrochoric acid and heated under reflux for 1 hour. After cooling, the crystals which precipitated were collected by filtration to give 93 g of 2-nitro-5-piperazinylbenzaldehyde hydrochloride, m.p. 195°-201° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=3)=[N:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl.[Cl:31][CH2:32][CH2:33][CH2:34][NH2:35]>O.C(Cl)(Cl)Cl>[Cl:31][CH2:32][CH2:33][CH2:34][NH:35][S:20]([C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:7]2[C:6]3[C:11](=[CH:12][C:3]([Cl:2])=[CH:4][CH:5]=3)[N:10]=[CH:9][N:8]=2)=[CH:15][CH:16]=1)(=[O:22])=[O:21]
Reactant: O=S(=O)(Cl)c1ccc(Nc2ncnc3cc(Cl)ccc23)cc1
Reactant: NCCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=S(=O)(NCCCCl)c1ccc(Nc2ncnc3cc(Cl)ccc23)cc1
Reaction time: 1 h
Yield: 60 %

Procedure:
4-(7-Chloro-4-quinazolinylamino)benzenesulphonyl chloride hydrochloride (11.7 g, 0.03 mole) was added portionwise to a well stirred mixture of sodium carbonate (45 g) in water (350 ml) and 3-chloropropylamine hydrochloride (3.9 g, 0.03 mole) in chloroform (350 ml) was added at 10° C. After about 1 hour at room temperature, the mixture was filtered and the solid was washed with water and then dried to give 7.4 g of the title compound. A sample was recrystallised from a mixture of ethanol and water to give the title compound, m.p. 168°-171° C.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]3([CH3:18])[CH:12]4[CH2:16][C:15]([CH3:17])([C:9]3([CH3:19])[C:8]=2[CH:20]=1)[CH2:14][CH2:13]4)=[O:3].C1(C=CC(C2C=CC=CC=2)=O)C=CC=CC=1.[CH2:37]([O:39][C:40]([C:42]1[CH:43]=[C:44]([CH:47]=O)[S:45][CH:46]=1)=[O:41])[CH3:38]>>[CH3:17][C:15]12[CH2:16][CH:12]([C:10]3([CH3:18])[C:9]1([CH3:19])[C:8]1[CH:20]=[C:4]([C:2](=[O:3])/[CH:1]=[CH:47]/[C:44]4[S:45][CH:46]=[C:42]([C:40]([O:39][CH2:37][CH3:38])=[O:41])[CH:43]=4)[CH:5]=[CH:6][C:7]=1[O:11]3)[CH2:13][CH2:14]2
Reactant: CC(=O)c1ccc2c(c1)C1(C)C3(C)CCC(C3)C1(C)O2
Reactant: CCOC(=O)c1csc(C=O)c1
Agent: O=C(C=Cc1ccccc1)c1ccccc1
Product: CCOC(=O)c1csc(/C=C/C(=O)c2ccc3c(c2)C2(C)C4(C)CCC(C4)C2(C)O3)c1

Procedure:
2.70 g (10 mmol) of the methyl ketone obtained in Example 3 were converted to chalcone in the presence of 1.7 g of 4-(ethoxycarbonyl)thiophenecarbaldehyde under the conditions described in Example 8 to yield, after recrystallization in ethyl acetate, 2.2 g (52%) of the expected compound, melting at 149°-151° C.