Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[N:7]2[CH2:8][CH2:9][NH:10][CH2:11][C:6]2=[C:5]([C:12]([O-:14])=O)[N:4]=1.[CH2:17]([NH2:19])[CH3:18]>>[CH2:17]([NH:19][C:12]([C:5]1[N:4]=[C:3]([C:2]([F:1])([F:16])[F:15])[N:7]2[CH2:8][CH2:9][NH:10][CH2:11][C:6]=12)=[O:14])[CH3:18]
Reactant: O=C([O-])c1nc(C(F)(F)F)n2c1CNCC2
Reactant: CCN
Product: CCNC(=O)c1nc(C(F)(F)F)n2c1CNCC2
Temperature: 50 °C
Reaction time: 12 h

Procedure:
3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylate 3b (1 g, 4 mmol) was dissolved in 40 mL of ethylamine solution (60%). After stirring at 50° C. for 12 hours, the reaction mixture was concentrated under reduced pressure to obtain the crude N-ethyl-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxamide 7a (1.15 g) as a white solid. The product was used directly in the next reaction without purification.
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]2[C:13]([S:14](Cl)(=[O:16])=[O:15])=[C:12]([Cl:18])[CH:11]=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>C1COCC1>[C:1]([C:5]1[O:6][C:7]2[C:13]([S:14]([N:30]3[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]3)(=[O:16])=[O:15])=[C:12]([Cl:18])[CH:11]=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCNCC1
Reactant: CC(C)(C)c1nc2ccc(Cl)c(S(=O)(=O)Cl)c2o1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN1CCN(S(=O)(=O)c2c(Cl)ccc3nc(C(C)(C)C)oc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.5 %

Procedure:
To a solution of 2-tert-butyl-6-chloro-benzooxazole-7-sulfonyl chloride (2.69 g, 8.73 mmol) and triethylamine (2.44 mL, 17.5 mmol) in THF (60 mL) at 0° C. was added 1-methylpiperazine (0.98 mL, 8.83 mmol). The reaction was warmed to room temperature and allowed to stir overnight. The solution was concentrated and then diluted with water and extacted with ethyl acetate (3 times). The combined organic layers were dried with MgSO4, filtered, and concentrated. Flash chromatography (80% ethyl acetate/20% Ethanol) on silica gel gave the title compound (2.45 g, 76%). EI-MS m/z 372(M+H)+.
Reaction SMILES: Br[CH:2]([CH:22]([CH3:24])[CH3:23])[C:3]([O:5]C(C#N)C1C=CC=C(OC2C=CC=CC=2)C=1)=[O:4].[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[I-].[K+].S(=O)(=O)(O)O>CN(P(N(C)C)(N(C)C)=O)C>[C:26]1([NH:25][C@H:2]([C:3]([OH:5])=[O:4])[CH:22]([CH3:24])[CH3:23])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)C(Br)C(=O)OC(C#N)c1cccc(Oc2ccccc2)c1
Reactant: Nc1ccccc1
Agent: O=S(=O)(O)O
Agent: [I-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(C)[C@H](Nc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 90 h

Procedure:
To m-phenoxy-α-cyanobenzyl α-bromoisovalerate (2.0 g, 0.0052 mole) in 4 ml of HMPT, at 24°, is added aniline (1.5 g, 0.016 mole) and potassium iodide (21 mg). The reaction is stirred at 65° for 90 hours and then cooled and poured into ice-water (20 ml) plus 2 N sulfuric acid (10 ml). The reaction is worked up as in Example 4 and purified by preparative TLC to give the m-phenoxy-α-cyanobenzyl ester of N-phenylvaline.
Reaction SMILES: II.Br[CH2:4][CH2:5][CH:6]=[CH2:7].[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=1/[CH:19]=[N:20]/[S:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22]>C1COCC1>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=1[C@@H:19]([NH:20][S:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22])[CH2:7][CH2:6][CH:5]=[CH2:4]
Reactant: C=CCCBr
Reactant: CC(C)(C)S(=O)/N=C/c1cc(C(F)(F)F)ccc1Br
Agent: II
Solvent: C1CCOC1
Product: C=CCC[C@H](NS(=O)C(C)(C)C)c1cc(C(F)(F)F)ccc1Br
Temperature: 40 °C
Yield: 64.9 %

Procedure:
To a 100 mL three-neck RBF equipped with stir bar and condenser was added Mg (excess), catalytic iodine, THF (20 mL), followed by 4-bromobut-1-ene (4.55 g, 33.7 mmol) in small increments. The mixture was heated to 40° C. for 1 hour. The reaction was cooled to room temperature and the freshly made Grignard reagent was added via syringe into a 250 mL RBF with N-{(E)-[2-bromo-5-(trifluoromethyl)phenyl]methylidene}-2-methylpropane-2-sulfinamide (8.0 g, 22.5 mmol) in THF (100 mL). Upon completion, the reaction was quenched with saturated aqueous NH4Cl and partitioned with ethyl acetate. The organic was dried over sodium sulfate, filtered, concentrated and purified by column chromatography to yield N-{(1S)-1-[2-bromo-5-(trifluoromethyl)phenyl]pent-4-en-1-yl}-2-methylpropane-2-sulfinamide (6.0 g, 14.6 mmol). 1H NMR (500 MHz, CDCl3) δ7.72 (m, 2H), 7.42 (d, J=8.2 Hz, 1H), 5.87 (m, 1H), 5.13 (m, 2H), 5.02 (m, 1H), 2.24 (m, 1H), 2.18 (m, 1H), 2.08 (m, 1H), 1.98 (m, 1H), 1.27 (s, 9H).
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11](/[CH:14]=[CH:15]/[C:16]3[S:17][CH:18]=[C:19]([CH:21]([CH3:23])[CH3:22])[N:20]=3)[CH:12]=2)[C:7](=[O:24])[C:6]([C:25]([OH:27])=O)=[CH:5]1.C([N:30](CC)CC)C.ClC(OCC)=O.N>CN(C)C=O.C(OCC)(=O)C>[F:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11](/[CH:14]=[CH:15]/[C:16]3[S:17][CH:18]=[C:19]([CH:21]([CH3:23])[CH3:22])[N:20]=3)[CH:12]=2)[C:7](=[O:24])[C:6]([C:25]([NH2:30])=[O:27])=[CH:5]1
Reactant: CC(C)c1csc(/C=C/c2ccc3c(=O)c(C(=O)O)cn(CCF)c3c2)n1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: N
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)c1csc(/C=C/c2ccc3c(=O)c(C(N)=O)cn(CCF)c3c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
The 1-(2-fluoroethyl)-7-[(E)-2-(4-isopropyl-1,3-thiazol-2-yl)-1-ethenyl]-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (174 mg, 0.450 mmol) obtained in (B) was dissolved in dimethylformamide (3 ml), added with triethylamine (0.126 ml, 0.900 mmol) and ethyl chloroformate (0.086 ml, 0.900 mmol) under ice cooling, and then the mixture was stirred for 1 hour. The reaction mixture was warmed to room temperature, stirred for 30 minutes and further stirred at 0° C. for 1 hour. The reaction mixture was added with concentrated aqueous ammonia (0.15 ml) and stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate and washed successively with aqueous citric acid, saturated aqueous sodium hydrogencarbonate and saturated brine and dried over anhydrous magnesium sulfate. Then, the solvent was evaporated to obtain the title compound (164 mg, 94%) as pale yellow solid.
Reaction SMILES: [CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:32])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:33]([C:36]([CH3:38])=[CH2:37])[CH2:34][CH2:35][C@:5]1([NH:39][CH2:40][CH2:41][NH:42][S:43]([CH3:46])(=[O:45])=[O:44])[CH2:4][CH2:3]2.[CH2:47](S(Cl)(=O)=O)[CH2:48]C>>[CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:32])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:21])([CH3:22])[C:14]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:33]([C:36]([CH3:38])=[CH2:37])[CH2:34][CH2:35][C@:5]1([NH:39][CH2:40][CH2:41][NH:42][S:43]([CH2:46][CH2:47][CH3:48])(=[O:45])=[O:44])[CH2:4][CH2:3]2
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCNS(C)(=O)=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CCCS(=O)(=O)Cl
Product: C=C(C)[C@@H]1CC[C@]2(NCCNS(=O)(=O)CCC)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described above for the synthesis of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(methylsulfonamido)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid using propane-1-sulfonyl chloride as the reagent in Step 1. The product was isolated as a white solid (9 mg, 49%). LCMS: m/e 679.48 (M+H)+, 2.34 min (method 11). 1H NMR (500 MHz, CHLOROFORM-d) δ 9.36 (br. s., 1H), 8.00 (d, J=8.4 Hz, 2H), 7.25 (d, J=8.2 Hz, 2H), 6.81 (br. s., 1H), 6.04 (br. s., 1H), 5.31-5.19 (m, 1H), 4.86 (s, 1H), 4.73 (s, 1H), 3.85-3.67 (m, 1H), 3.54 (d, J=14.7 Hz, 1H), 3.38-3.18 (m, 2H), 3.15-3.07 (m, 2H), 2.80 (td, J=11.2, 5.9 Hz, 1H), 2.26-0.95 (m, 24H), 1.71 (s, 3H), 1.20 (s, 3H), 1.12 (t, J=7.4 Hz, 3H), 1.05 (s, 3H), 0.97 (s, 3H), 0.96 (s, 3H), 0.94 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([NH2:9])=[O:8])[CH2:3][CH2:2]1.Br[C:11]([CH3:18])([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13]>>[NH2:9][C:7]([CH:4]1[CH2:5][CH2:6][N:1]([C:11]([CH3:18])([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:2][CH2:3]1)=[O:8]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: NC(=O)C1CCNCC1
Product: CCOC(=O)C(C)(C)N1CCC(C(N)=O)CC1

Procedure:
The title compound was prepared according to the procedure described in the Example 17 from piperidine-4-carboxamide and ethyl 2-bromo-2-methylpropanoate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[C:9](/[C:27]([F:30])([F:29])[F:28])=[CH:10]\[C:11]([C:13]2[CH:25]=[CH:24][C:16]([C:17]([NH:19][CH:20]3[CH2:23][S:22][CH2:21]3)=[O:18])=[C:15]([CH3:26])[CH:14]=2)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(O)(=[S:33])C.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([SH:33])([C:27]([F:30])([F:29])[F:28])[CH2:10][C:11]([C:13]2[CH:25]=[CH:24][C:16]([C:17]([NH:19][CH:20]3[CH2:23][S:22][CH2:21]3)=[O:18])=[C:15]([CH3:26])[CH:14]=2)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(O)=S
Reactant: Cc1cc(C(=O)/C=C(\c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)NC1CSC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)CC(S)(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)NC1CSC1
Temperature: 25 °C
Reaction time: 41 h

Procedure:
To 4-[(E)-3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-2-methyl-N-thietan-3-yl-benzamide (500 mg) was added thioacetic acid (6 eq.) and triethylamine (4 μL). The solution was stirred under argon at room temperature for 41 hours. To this mixture was added a minimum of dichloromethane and then isolute. The suspension was evaporated under vacuo. The residue was purified by chromatography on silica gel (eluent: cyclohexane/ethyl acetate) to give:
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:8][CH:7]1[C:9]1[CH:14]=[C:13]([F:15])[C:12]([O:16]CC2C=CC=CC=2)=[C:11]([F:24])[CH:10]=1)=[O:5])[CH3:2]>CCO.[Pd]>[CH2:1]([O:3][C:4]([CH:6]1[CH2:8][CH:7]1[C:9]1[CH:10]=[C:11]([F:24])[C:12]([OH:16])=[C:13]([F:15])[CH:14]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CC1c1cc(F)c(OCc2ccccc2)c(F)c1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1CC1c1cc(F)c(O)c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.9 %

Procedure:
2-(4-Benzyloxy-3,5-difluoro-phenyl)-cyclopropane-carboxylic acid ethyl ester (0.65 g, 1.96 mmol) obtained in Step A was dissolved in EtOH (15 mL), and 10% Pd/C (65 mg) was added thereto. The mixture was stirred at room temperature under hydrogen atmosphere for 3 hours. The reactant was filtered by using celite and concentrated under reduced pressure to obtain the title compound (0.46 g, 97%).
Reaction SMILES: P([O-])([O-])([O-])=O.[OH:6][CH:7]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9].[OH-].[Na+]>O>[OH:6][C@H:7]([CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C(O)CCc1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)[C@H](O)CCc1ccccc1
Yield: 48.7 %

Procedure:
A 3 L three-neck, round-bottom flask equipped with a mechanical stirrer, an electrode connected to a pH control unit and an addition tube connected to a peristaltic pump, was charged with 450 ml of deionized water, 50 ml of 0.05M aqueous phosphate buffer (pH 7.0) and 52.0 g of racemic ethyl 2-hydroxy-4-phenylbutanoate. The mixture was stirred for several minutes to make certain that the pH remained constant at 7.0. Then, 0.67 g (20,000 units) of Pseudomonas lipase enzyme (P-30, Amano International Enzyme Co., Inc., Troy, Va.) was added and the hydrolysis was allowed to proceed at pH 7.0 and room temperature, with stirring. The pH was kept constant by adding 1.0N aqueous sodium hydroxide solution via the peristaltic pump, which was activated by the pH control unit. The reaction was discontinued at 50% conversion when 125 ml of 1.0N aqueous sodium hydroxide solution had been added (at the 24 hour mark). The reaction mixture was then extracted with 3 portions of 200 ml (600 ml total) of diethyl ether. The combined organic layers were dried over anhydrous sodium sulfate and the solvent was removed at 45° C. under 70 mm Hg of vacuum, to provide 25.3 g of ethyl (2R)-2-hydroxy-4-phenylbutanoate (48.5% yield; 97% of theory), which was 91% enantiomerically pure (α)D25 -7.8° (c 1.0, EtOH). The aqueous layer was acidified to pH 2 with 3N hydrochloric acid and extracted with 3×200 ml of diethyl ether. The combined organic layers were dried over anhydrous sodium sulfate and the solvent was removed at 45° C. and 70 mm Hg to give 20.8 g of (2S)-2-hydroxy-4-phenylbutanoic acid (46% yield; 92% of theory), which was 90.8% enantiomerically pure. (α)D25 +7.6° (c 1.0, EtOH), m.p. 109°-110° C.
Reaction SMILES: [ClH:1].[Cl:2]CCCO[C:7]1[CH:8]=[CH:9][C:10]2[C:19]([CH:20]=1)=[N:18][C:17]1[C:12](=[CH:13][CH:14]=[C:15](OCCCCl)[CH:16]=1)[CH:11]=2.[CH2:26]([NH2:30])[CH2:27][CH2:28][CH3:29]>>[ClH:2].[ClH:1].[ClH:2].[CH2:26]([NH:30][CH2:13][CH2:12][CH2:11][C:15]1[CH:14]=[CH:13][C:12]2[C:17]([CH:16]=1)=[N:18][C:19]1[C:10](=[CH:9][CH:8]=[C:7]([CH2:15][CH2:16][CH2:17][NH:18][CH2:19][CH2:10][CH2:9][CH3:8])[CH:20]=1)[CH:11]=2)[CH2:27][CH2:28][CH3:29]
Reactant: ClCCCOc1ccc2cc3ccc(OCCCCl)cc3nc2c1
Reactant: CCCCN
Agent: Cl
Product: CCCCNCCCc1ccc2cc3ccc(CCCNCCCC)cc3nc2c1

Procedure:
The compound is prepared from 3,6-bis(3-chloropropoxy)acridine hydrochloride and n-butylamine as described in Example 15, giving 2.0 g. of the desired product as orange crystals, m.p. 247°-249° C.
Reaction SMILES: [C:1]1([CH:7]([CH2:22][CH3:23])[C:8]([O:10]C(=O)C(C2C=CC=CC=2)CC)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1>C(OCC)C>[C:1]1([CH:7]([CH2:22][CH3:23])[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCC(C(=O)OC(=O)C(CC)c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCC(C(=O)O)c1ccccc1
Yield: 91.5 %

Procedure:
A solution of 2,3-isopropylidene-D(+)-ribono-1,4-lactone (188 mg) and 2-phenylbutyric anhydride (310 mg) in d5 -pyridine (0.35 ml) was monitored by 1H n.m.r. until reaction was complete (1.5 hours). The mixture was dissolved in diethyl ether (20 ml), partitioned with aqueous hydrochloric acid (2×20 ml, 1M) and aqueous sodium hydroxide (2×10 ml, 1M). The combined alkaline extracts were acidified with 10M hydrochloric acid to pH 2, extracted with diethyl ether (2×10 ml) and the dried (MgSO4) ether extracts concentrated in vacuo to give (+)2-phenylbutyric acid (150 mg), [α]D25 +31° (c=1.0, benzene).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:38])[C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)[C:20]([O:33][CH2:34][CH2:35][OH:36])=[C:19]([Br:37])[CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC(Cl)(Cl)[C:41]([N:43]=C=O)=[O:42]>C(Cl)Cl>[Br:37][C:19]1[C:20]([O:33][CH2:34][CH2:35][O:36][C:41](=[O:42])[NH2:43])=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:30])[F:31])[CH:24]=2)[CH:22]=[C:17]([C:16](=[O:38])[NH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:18]=1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: O=C(NCCCCCCCCc1ccccc1)c1cc(Br)c(OCCO)c(-c2cccc(C(F)(F)F)c2)c1
Solvent: ClCCl
Product: NC(=O)OCCOc1c(Br)cc(C(=O)NCCCCCCCCc2ccccc2)cc1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 62.1 %

Procedure:
To a solution of N-(8-phenyl-octyl)-3-bromo-5-(m-trifluoromethylphenyl)-4-(2-hydroxyethoxy)-benzamide (0.463 g, 0.78 mmol, 1 eq) in CH2Cl2 (10 mL) was added trichloroacetyl isocyanate (0.100 mL, 0.84 mmol, 1.1 eq) The reaction was stirred at rt 15 minutes and oven-dried alumina was added. The reaction was stirred overnight at rt and concentrated in vacuo. The residue was purified by flash chromatography (30 to 60% EtOAc:hexane) to afford the title compound (0.308 g, 62%) as a oil. 1H NMR (DMSO-d6) δ 8.56 (bt, 1H); 8.13 (d, 1H); 7.89 (m, 3H); 7.72 (dd, 1H); 7.24 (m, 2H); 7.14 (m, 3H); 6.40 (bs, 2H); 3.90 (dd, 2H); 3.70 (dd, 2H); 3.23 (dd, 2H); 2.52 (t, 2H); 1.25 (m, 4H); 1.27 (m, 8H); IR (KBr) 3330, 2920, 2850, 1720, 1640, 1600, 1550, 1460, 1410, 1330, 1180, 1120 cm−1; mass spectrum [(+)ESI], m/z 635/637 (M+H)+; Anal. Calcd. for C31H34BrF3N2O4: C, 58.59; H, 5.39; N, 4.41. Found: C, 57.26; H, 5.46; N, 4.38.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=[CH:13][C:14]2[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][CH:15]=2)[C:10](O)=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].P(Cl)(Cl)(Cl)(Cl)[Cl:23]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:9](=[CH:13][C:14]2[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][CH:15]=2)[C:10]([Cl:23])=[O:11])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CSc1ccc(C=C(C(=O)O)c2ccc(F)c(F)c2)cc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: CSc1ccc(C=C(C(=O)Cl)c2ccc(F)c(F)c2)cc1
Reaction time: 1 h
Yield: 102.2 %

Procedure:
A mixture of 2-(3,4-difluorophenyl)-3-[4-(methylthio)phenyl]acrylic acid (12 g) and phosphorus pentachloride (9.0 g) in dichloromethane (120 ml) was stirred for 1 hour. The solvent was evaporated to give a solid of 2-(3,4-difluorophenyl)-3-[4-(methylthio)phenyl]acryloyl chloride (13 g).
Reaction SMILES: [N:1]([C@@H:4]([CH3:18])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15](O)=[O:16])[CH:13]=2)[CH:8]=[N:7]1)=[N+:2]=[N-:3].C1C=CC2N(O)N=[N:25]C=2C=1.CCN=C=NCCCN(C)C.N.O1CCOCC1.[Cl-].[NH4+]>CN(C=O)C>[N:1]([C@@H:4]([CH3:18])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([NH2:25])=[O:16])[CH:13]=2)[CH:8]=[N:7]1)=[N+:2]=[N-:3]
Reactant: On1nnc2ccccc21
Reactant: C[C@@H](Cn1ncc2ccc(C(=O)O)cc21)N=[N+]=[N-]
Agent: CCN=C=NCCCN(C)C
Agent: N
Agent: [Cl-]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: C[C@@H](Cn1ncc2ccc(C(N)=O)cc21)N=[N+]=[N-]
Reaction time: 18 h
Yield: 191.1 %

Procedure:
To the product from Step A (0.17 g, 0.64 mmol) in DMF (5 mL) was added HOBT (0.041 g, 0.30 mmol), and EDCI (0.18 g, 0.96 mmol), followed by a solution of ammonia in dioxane (0.5 M, 0.18 g, 0.96 mmol). After 18 h, a saturated aqueous solution of ammonium chloride (20 mL) was added. The mixture was extracted with ethyl acetate (3×50 mL) and the combined extracts were washed with brine, dried and evaporated. The residue was purified by chromatography (silica, 50% ethyl acetate in hexane, ethyl acetate) to give an oil (0.14 g, 92%): MS (ES) m/z 245 (M+); 1H NMR (CDCl3) 8.11 (1H, s), 8.08 (1H, s), 7.81 (1H, d, J=8.0 Hz), 7.52 (1H, d, J=8.0 Hz), 4.43 (2H, m), 4.15 (1H, m), 1.36 (3H, d, J=8.0 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][C:4]=1[CH2:10][C:11]1[N:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]2=[N:13][C:12]=1[C:20](OCC)=[O:21].[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1.CCCCCC>[Br:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([CH2:10][C:11]2[N:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]3=[N:13][C:12]=2[CH2:20][OH:21])[CH:5]=1
Reactant: CCOC(=O)c1nc2ccccn2c1Cc1cc(Br)ccc1OC
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(Br)cc1Cc1c(CO)nc2ccccn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
A solution of 3.69 g (9.5 mmol) of ethyl 3-[(2-methoxy-5-bromophenyl)methyl]-imidazolo[1,2-a]pyridine-2-carboxylate in 50 mL tetrahydrofuran is cooled to −78° C. and treated with 25.0 mL (25.0 mmol) of diisobutylaluminum hydride, 1M in hexane. After 1 hr the reaction is allowed to warm up to room temperature and carefully quenched by addition of 25 mL 1M sodium hydroxide. The mixture is extracted with 3×40 mL ethyl acetate and the combined extracts washed with 50 mL brine and dried over anhydrous MgSO4 and the solvent removed in vacuo to afford 3.0 g (91% yield) {3-[(5-bromo-2-methoxyphenyl)methyl]-imidazolo[1,2-a]pyridin-2-yl}methan-1-ol.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCN(CC)CC.[Br:27][C:28]1[CH:61]=[CH:60][C:31]([C:32]([NH:34][NH:35][C:36](=[O:59])[C@H:37]([NH:48][C:49]2[CH:54]=[CH:53][C:52]([C:55]#[N:56])=[C:51]([Cl:57])[C:50]=2[CH3:58])[C@@H:38]([O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[CH3:39])=O)=[CH:30][CH:29]=1>C(Cl)Cl>[Br:27][C:28]1[CH:29]=[CH:30][C:31]([C:32]2[O:59][C:36]([C@H:37]([NH:48][C:49]3[CH:54]=[CH:53][C:52]([C:55]#[N:56])=[C:51]([Cl:57])[C:50]=3[CH3:58])[C@@H:38]([O:40][Si:41]([C:44]([CH3:46])([CH3:47])[CH3:45])([CH3:42])[CH3:43])[CH3:39])=[N:35][N:34]=2)=[CH:60][CH:61]=1
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(Br)cc2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(Br)cc3)o2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88.5 %

Procedure:
To a solution of triphenylphosphine (4.23 g, 16.1 mmol) in DCM (200 mL) was added 12 (4.1 g, 16.2 mmol) at 0° C. After 12 was dissolved completely, Et3N (4.5 mL, 32.3 mmol) was added, followed by a solution of 4-bromo-N′-((2R,3S)-3-(tert-butyldimethylsilyloxy)-2-(3-chloro-4-cyano-2-methylphenylamino)butanoyl)-benzohydrazide (4.68 g, 8.1 mmol) in DCM (100 mL). The reaction mixture was allowed to warm to room temperature and stirred for additional 15 min. The reaction was quenched with saturated sodium thiosulfate (50 mL) and diluted with DCM (400 mL). The organic layer was separated and washed with water, brine, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by flash chromatography to provide the title compound (4.03 g, 89%), which was used directly in the next step
Reaction SMILES: [CH3:1][C:2](O)([CH2:5][C:6](C)=[CH2:7])[CH:3]=C.C([O:12][CH2:13][CH3:14])C>O1CCCC1>[CH3:3][C:2](=[CH2:1])[CH2:5][CH2:6][CH2:7][C:13](=[O:12])[CH3:14]
Reactant: CCOCC
Reactant: C=CC(C)(O)CC(=C)C
Solvent: C1CCOC1
Product: C=C(C)CCCC(C)=O

Procedure:
A mixture of 3,5-dimethylhexa-1,5-dien-3-ol (0.126 g; 10-3 mol) and dichloro-bis-(benzonitrile)-palladium(II) (0.0153 g; 0.04.10-3 mol) in tetrahydrofuran (7.5 cc) is kept at a temperature of the order of 20° C. under an inert atmosphere. After a reaction time of 5 hours, diethyl ether (50 cc) is added and the reaction mixture is then washed with water (7×10 cc). After drying of the organic layer over magnesium sulphate and evaporation of the solvent under reduced pressure (20 mm Hg; 2.7 kPa), 6-methylhept-6-en-2-one (0.125 g) is obtained, which has the following characteristics:
Reaction SMILES: [CH:1]([C:3]1[N:7]2[CH:8]=[CH:9][C:10]3[C:11](=[O:23])[C@H:12]([OH:22])[C@@H:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[NH:14][C:15]=3[C:6]2=[N:5][C:4]=1[CH3:24])=[O:2].[BH4-].[Na+]>CO>[OH:2][CH2:1][C:3]1[N:7]2[CH:8]=[CH:9][C:10]3[C@@H:11]([OH:23])[C@H:12]([OH:22])[C@@H:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[NH:14][C:15]=3[C:6]2=[N:5][C:4]=1[CH3:24]
Reactant: Cc1nc2c3c(ccn2c1C=O)C(=O)[C@H](O)[C@@H](c1ccccc1)N3
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1nc2c3c(ccn2c1CO)[C@@H](O)[C@H](O)[C@@H](c1ccccc1)N3
Reaction time: 0.5 h
Yield: 70.5 %

Procedure:
0.07 g of (8R,9R)-3-formyl-8-hydroxy-2-methyl-7-oxo-9-phenyl-7,8,9,10-tetrahydro-imidazo[1,2-h][1,7]naphthyridine are dissolved in 5 ml of dry methanol, and 0.1 g of sodium borohydride is added. The mixture is stirred for 30 min and concentrated in vacuo. The oily residue is partitioned between water and chloroform. The organic layer is separated, dried over anhydrous sodium sulfate and concentrated. The product is purified by flash chromatography on silica gel (eluent: dichloromethane/methanol 9/1) to give 0.05 g of the title compound as a semi solid.