Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[C:3]1([OH:13])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.Cl[CH2:15][C:16]([OH:18])=[O:17]>O>[C:3]1([O:13][CH2:15][C:16]([OH:18])=[O:17])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: Oc1cccc2ccccc12
Reactant: O=C(O)CCl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)COc1cccc2ccccc12
Yield: 64.2 %

Procedure:
To a solution of potassium hydroxide (2.98 g, 52.1 mmol) in H2O (35 mL) was added 1-naphthol (3.08 g, 21.4 mmol), followed by 2-chloroacetic acid (2.32 g, 24.7 mmol). The resulting mixture was heated at reflux for 3 h, then allowed to cool and extracted with EtOAc. The aqueous phase was made acidic by the addition of 3N HCl and extracted with EtOAc. The organic phase from the acidic extraction was washed with saturated aqueous NaCl. The solvent was removed in vacuo to provide the title compound (2.78 g, 64%).
Reaction SMILES: C([Li])CCC.[Br:6][C:7]1[CH:12]=[CH:11][C:10](I)=[CH:9][CH:8]=1.[C:14]([N:21]1[CH2:26][CH2:25][CH2:24][C:23](=[O:27])[CH2:22]1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>C1COCC1>[C:17]([O:16][C:14]([N:21]1[CH2:26][CH2:25][CH2:24][C:23]([C:10]2[CH:11]=[CH:12][C:7]([Br:6])=[CH:8][CH:9]=2)([OH:27])[CH2:22]1)=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Reactant: Brc1ccc(I)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(O)(c2ccc(Br)cc2)C1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 55.7 %

Procedure:
n-Butyllithium (2.5 M in hexanes, 8.2 mL, 20.5 mmol) was added over 10 min to a solution of 1-bromo-4-iodobenzene (5.79 g, 20.5 mmol) in THF (100 mL) at −78° C. After 15 min, a solution of 1-boc-3-piperidone (3.71 g, 18.6 mmol) in THF (10 mL) was added and the resultant reaction mixture was left to stir at −78° C. for 1 h, then warmed to 0° C. and quenched by the addition of saturated aqueous ammonium chloride (50 mL). The mixture was allowed to warm to ambient temperature and partitioned between ethyl acetate (400 mL) and water (150 mL). The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The resultant residue was purified by flash chromatography (silica, 80 g column, ISCO, 0-100% ethyl acetate in cyclohexane) to afford the title compound as a colourless gum (3.69 g, 56%). 1H NMR (CDCl3, 300 MHz): 7.52-7.46 (m, 2H); 7.42-7.36 (m, 2H); 4.16-3.87 (m, 2H); 3.13 (d, J=13.7 Hz, 1H); 2.92-2.77 (m, 1H); 2.03-1.53 (m, 4H); 1.47 (s, 9H).
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[S:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[CH2:10][C:11]([O:13][CH3:14])=[O:12].Cl[CH:16](Cl)[O:17]C.Cl>ClCCl.O>[CH:16]([C:9]1[S:5][C:6]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:8]=1)=[O:17]
Reactant: COC(Cl)Cl
Reactant: COC(=O)Cc1cccs1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: COC(=O)Cc1ccc(C=O)s1
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 90.4 %

Procedure:
To a suspension of aluminium trichloride (853 mg, 6.4 mmol) in dichloromethane (4 mL) at −10° C. was added a solution of methyl 2-(2-thienyl)acetate (500 mg, 3.2 mmol) in dichloromethane (3 mL). The resulting solution was stirred at −10° C. for 10 minutes. A solution of dichloro(methoxy)methane (434 μL, 4.8 mmol) in dichloromethane (3 mL) was then added dropwise over 30 minutes. The reaction mixture was stirred at −10° C. for 1 h. The resulting solution was poured into a flask containing water (20 mL), crushed ice and concentrated HCl (1 mL) and stirred vigorously for 30 minutes. The solution was washed with dichloromethane (3×20 mL) and the combined organic phases washed with aqueous saturated sodium bicarbonate (30 mL) followed by brine (30 mL). The phases were separated over a hydrophobic frit and concentrated in vacuo to give the title compound as a red oil (533 mg, 91%) which was used in the next step without further purification.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:25]([OH:27])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.[CH2:28]([O:30][CH2:31][CH2:32][C:33](=[N:35]O)[NH2:34])[CH3:29]>>[CH2:28]([O:30][CH2:31][CH2:32][C:33]1[N:35]=[C:25]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:6][CH2:5][S:4][CH2:3][CH2:2]3)=[O:8])[CH2:10]2)[O:27][N:34]=1)[CH3:29]
Reactant: CCOCCC(N)=NO
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCSCC2)C1
Product: CCOCCc1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCSCC3)C2)n1

Procedure:
According to General Method 6A, 600 mg (1.491 mmol) of the compound from Example 16A and 320 mg (approx. 1.983 mmol) of 3-ethoxy-N′-hydroxypropanimidamide were reacted Yield: 343 mg (46% of theory)
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([F:15])=[C:13](F)[C:12]([N+:17]([O-:19])=[O:18])=[C:11]([F:20])[C:10]=1[F:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([O-:25])[CH:23]=[CH2:24].[Na+]>C(#N)C>[CH2:1]([O:8][C:9]1[C:10]([F:21])=[C:11]([F:20])[C:12]([N+:17]([O-:19])=[O:18])=[C:13]([O:25][CH2:22][CH:23]=[CH2:24])[C:14]=1[F:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1c(F)c(F)c(OCc2ccccc2)c(F)c1F
Reactant: C=CC[O-]
Agent: [Na+]
Solvent: CC#N
Product: C=CCOc1c(F)c(OCc2ccccc2)c(F)c(F)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
30.1 g of the 1-benzyloxy-4-nitro-2,3,5,6-tetra-fluorobenzene prepared as described in Example 4 (0.1 mol) are dissolved in 250 ml of dry acetonitrile in a three-neck flask fitted with reflux condenser and stirrer, and 8 g of sodium prop-2-enolate (0.1 mol) are added in portions to the solution. The reaction mixture is stirred at room temperature for 1 hour and then refluxed for 24 hours. The reaction solution is then filtered via a fluted filter, and the crude product is extracted by shaking with 150 ml of ethyl acetate and 300 ml of water. The organic phase is washed three times with water, dried over sodium sulfate and evaporated to half in a rotary evaporator. The precipitated reaction product is then recrystallized from a mixture of n-hexane and methylene chloride (volume ratio 1:1) and then dried for 48 hours under nitrogen at 40° C./10 mbar in a vacuum drying cabinet.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:15]=[C:14]([C:16]4[S:17][C:18]([C:27]([F:30])([F:29])[F:28])=[C:19]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[CH:20]=4)[O:13][N:12]=3)[CH:9]=2)[NH:4][CH:3]=1.Br[CH2:32][CH2:33][C:34]([O-:36])=[O:35].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:15]=[C:14]([C:16]4[S:17][C:18]([C:27]([F:30])([F:28])[F:29])=[C:19]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[CH:20]=4)[O:13][N:12]=3)[CH:9]=2)[N:4]([CH2:32][CH2:33][C:34]([OH:36])=[O:35])[CH:3]=1
Reactant: FC(F)(F)c1sc(-c2nc(-c3ccc4[nH]cc(Cl)c4c3)no2)cc1-c1ccccc1
Reactant: O=C([O-])CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(O)CCn1cc(Cl)c2cc(-c3noc(-c4cc(-c5ccccc5)c(C(F)(F)F)s4)n3)ccc21
Temperature: 131 °C
Reaction time: 1.5 h
Yield: 23 %

Procedure:
D8 (86 mg), 3-bromopropionate (52 mg), Cs2CO3 (126 mg) and DMF (1 ml) were placed in a microwave vial and stirred at 131° C. in the microwave reactor for 1.5 hours. The reaction mixture was then evaporated to dryness and treated with 2M aq. NaOH and EtOH (20 ml). This solution was stirred at 50° C. for 4 hours and then neutralised with HCl and evaporated to remove the EtOH. The aqueous solution was then extracted twice with EtOAc and the combined extracts evaporated. The residue was dissolved in DMSO, filtered, treated with MeCN causing precipitation of the product which was filtered and washed with MeCN to give the title compound (23 mg) as an off-white solid. δH (d6-DMSO, 400 MHz): 2.47-2.57 (solvent+2H) 4.37 (2H, t), 7.51-7.59 (5H, m), 7.72 (1H, s), 7.76 (1H, d), 7.89 (1H, d), 8.17 (1H, s), 8.25 (1H, s). MS (ES): C24H16ClF3N3O2S requires 517; found 516 (M−H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][C@H:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13])=[O:10].[CH2:20]1[CH2:30][CH2:29][N:28]2C(=NC[CH2:26][CH2:27]2)CC1.C(Br)(Br)(Br)Br.N1CCCCC1>C1COCC1.C(OCC)C.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]([N:28]1[CH2:27][CH2:26][CH2:20][CH2:30][CH2:29]1)[C:9]([O:11][C@H:12]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH3:13])=[O:10]
Reactant: C[C@H](OC(=O)Cc1ccccc1F)c1ccccc1
Reactant: C1CCC2=NCCCN2CC1
Agent: BrC(Br)(Br)Br
Solvent: C1CCNCC1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: C[C@H](OC(=O)[C@@H](c1ccccc1F)N1CCCCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 11.1 %

Procedure:
To a solution of (S)-1-phenylethyl 2-(2-fluorophenyl)acetate (5.00 g, 19.4 mmol) in THF (1200 mL) at 0° C. was added DBU (6.19 g, 40.7 mmol) and the solution was allowed to warm to room temperature while stirring for 30 minutes. The solution was then cooled to −78° C. and a solution of CBr4 (13.5 g, 40.7 mmol) in THF (100 mL) was added and the mixture was allowed to warm to −10° C. and stirred at this temperature for 2 hours. The reaction mixture was quenched with saturated aq. NH4Cl and the layers were separated. The aqueous layer was back-extracted with ethyl acetate (2×) and the combined organic phases were washed (H2O, brine), dried (Na2SO4), filtered, and concentrated in vacuo. To the residue was added piperidine (5.73 mL, 58.1 mmol) and the solution was stirred at room temperature for 24 hours. The volatiles were then concentrated in vacuo and the residue was purified by silica gel chromatography (BIOTAGE®/0-30% diethyl ether-hexane) to provide a pure mixture of diastereomers (2:1 ratio by 1H NMR) as a yellow oil (2.07 g, 31%), along with unreacted starting material (2.53 g, 51%). Further chromatography of the diastereomeric mixture (BIOTAGE®/0-10% diethyl ether-toluene) provided the title compound as a colorless oil (0.737 g, 11%). 1H NMR (400 MHz, CD3OD) δ 7.52 (ddd, J=9.4, 7.6, 1.8 Hz, 1H), 7.33-7.40 (m, 1), 7.23-7.23 (m, 4H), 7.02-7.23 (m, 4H), 5.86 (q, J=6.6 Hz, 1H), 4.45 (s, 1H), 2.39-2.45 (m, 4H), 1.52-1.58 (m, 4H), 1.40-1.42 (m, 1H), 1.38 (d, J=6.6 Hz, 3H). LCMS: Anal, Calcd. for C21H24FNO2: 341; found: 342 (M+H)+.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[NH:6]1[C:15]2[C:10](=[CH:11][N:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][C:7]1=O.[OH-].[Na+]>CCOC(C)=O>[Cl:3][C:7]1[CH:8]=[CH:9][C:10]2[C:15](=[CH:14][CH:13]=[N:12][CH:11]=2)[N:6]=1
Reactant: O=c1ccc2cnccc2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Clc1ccc2cnccc2n1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
A mixture of phosphoryl trichloride (5.17 ml, 56.5 mmol) and 1,6-naphthyridin-2(1H)-one (112) (1.65 g, 11.29 mmol, Alfa Aesar) was stirred at 70° C. for 16 h. The reaction mixture was cooled to RT and was poured onto 150 g of ice carefully. EtOAc (50 mL) was added and the mixture was treated carefully with about 30 mL of 5 M NaOH until the final pH is persistently >10. The mixture was vigorously mixed, then transferred into a separatory funnel. The EtOAc layer was then separated and dried and re-suspended in 30 mL of DCM, the insoluble solids were filtered off. The filtrate was loaded onto a silica gel pad and flushed with 30% EtOAc in hexanes to give a solid after drying. The solid was initially white but changed color to yellow after drying on the high vacuum line over night. Yield; 1.19 g, 64%. The material (113) was used directly in the next step without any further purification.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([CH3:34])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[F:37][C:38]([F:48])([F:47])[C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][CH:46]=1)[CH2:42][NH2:43]>>[CH3:34][C:23]1[CH:22]=[C:21]([C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:43][CH2:42][C:41]4[CH:44]=[CH:45][CH:46]=[C:39]([C:38]([F:47])([F:48])[F:37])[CH:40]=4)=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:20])[CH:26]=[CH:25][C:24]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33]
Reactant: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)cc1C
Reactant: NCc1cccc(C(F)(F)F)c1
Product: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccc(C(F)(F)F)c4)n3Cc3ccccc32)cc1C

Procedure:
The title compound was synthesized in the manner of Example 13 from 2,2,2-trichloro-1-{10-[(2,2′-dimethyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 6 and 3-trifluoromethylbenzylamine, m.p. 171-173° C. MS [(+)ESI, m/z]: 592 [M+H]+
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]([C:23]3[CH:32]=[C:31]([N+:33]([O-:35])=[O:34])[CH:30]=[CH:29][C:24]=3[C:25]([O:27]C)=[O:26])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+]>CO>[C:1]1([C:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]([C:23]3[CH:32]=[C:31]([N+:33]([O-:35])=[O:34])[CH:30]=[CH:29][C:24]=3[C:25]([OH:27])=[O:26])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)N(CCCCN1CC=C(c2ccccc2)CC1)c1cc([N+](=O)[O-])ccc1C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCOC(=O)N(CCCCN1CC=C(c2ccccc2)CC1)c1cc([N+](=O)[O-])ccc1C(=O)O
Temperature: 50 °C
Reaction time: 2 h
Yield: 102.3 %

Procedure:
To a stirred solution of methyl 2-[N-{4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl}-N-ethoxycarbonylamino]-4-nitrobenzoate (1.58 g) in methanol (16 ml) was added 2N potassium hydroxide (5.0 ml). After stirring for 2 hours at 50° C., methanol was evaporated in vacuo. The residue was diluted with water, acidified with 3N hydrochloric acid, extracted with chloroform. The extract was washed with brine, dried over magnesium sulfate, and evaporated. Crude 2-[N-{4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl}-N-ethoxycarbonylamino]-4-nitrobenzoic acid (1.57 g) was obtained as an amorphous.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([CH3:35])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[C:30]([CH3:34])=[N:31][NH:32][CH:33]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)(C(C)(C)C)(C)C.Cl>CO>[CH3:35][C:10]1([CH2:9][OH:8])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:24]=[CH:25][C:26]([C:29]5[C:30]([CH3:34])=[N:31][NH:32][CH:33]=5)=[CH:27][CH:28]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1
Reactant: Cc1n[nH]cc1-c1ccc(C2(c3nnc4n3CCSC(C)(CO[Si](C)(C)C(C)(C)C)C4)CC2)cc1
Agent: Cl
Solvent: CO
Product: Cc1n[nH]cc1-c1ccc(C2(c3nnc4n3CCSC(C)(CO)C4)CC2)cc1
Yield: 68 %

Procedure:
A solution of the compound (213 mg, 0.42 mmol) obtained in Example 76-1) and 4 M hydrochloric acid (1,4-dioxane solution, 3 mL) in methanol (6 mL) was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure, a 5 M aqueous sodium hydroxide solution (10 mL) was added to the residue, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel chromatography (ethyl acetate:methanol=20:80) to obtain the title compound (113 mg, 68%) as a colorless solid.
Reaction SMILES: [OH:1][C:2]1([C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.Cl.[NH:18]1[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)=[O:24])[CH2:19]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[OH:1][C:2]1([C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)[CH2:7][CH2:6][CH:5]([N:18]2[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:35])[F:36])[CH:29]=3)=[O:24])[CH2:19]2)[CH2:4][CH2:3]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: COc1ccc(C2(O)CCC(=O)CC2)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cn1

Procedure:
4-Hydroxy-4-(6-methoxy-pyridin-3-yl)-cyclohexanone, as prepared in Step B of this example, (300 mg, 1.36 mmol) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide HCl salt, as prepared in Step D of this example, (460 mg, 1.36 mmol) in DCM (5 mL) were treated with TEA (1 mL, 7.12 mmol) for 10 min followed by NaBH(OAc)3 (860 mg, 4.07 mmol) for another 4 hours at room temperature. The reaction was quenched with saturated sodium bicarbonate. The organic layer was separated and the aqueous layer was extracted 3 times with chloroform and IPA “cocktail” (˜3:1, v/v). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated to give the crude product, which was then purified by a CombiFlash® system using ethyl acetate and 7N NH3 in MeOH as eluent (from pure ethyl acetate to 5% 7N NH3 in MeOH in ethyl acetate) to afford two title compounds as white solids: a less polar isomer, and a more polar isomer.
Reaction SMILES: [NH2:1][C@@H:2]([CH:5]([CH3:7])[CH3:6])[CH2:3][OH:4].[CH:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O.CC1C=CC(S(O)(=O)=O)=CC=1.[B-]C#N.[Na+].[BH4-].[Na+]>C1C=CC=CC=1.CO>[CH2:8]([NH:1][C@@H:2]([CH:5]([CH3:7])[CH3:6])[CH2:3][OH:4])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=Cc1ccccc1
Reactant: CC(C)[C@H](N)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [B-]C#N
Agent: [BH4-]
Solvent: CO
Solvent: c1ccccc1
Solvent: O
Product: CC(C)[C@@H](CO)NCc1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of (S)-2-amino-3-methylbutan-1-ol (10.0 g, 97 mmol), benzaldehyde (10.34 mL, 102 mmol), and 4-methylbenzenesulfonic acid hydrate (3.69 mg, 0.019 mmol) in benzene (300 mL) was refluxed (80° C.) for 15 h with a Dean-Stark trap (ca. 2 mL water was collected). The solution was concentrated (leaving a pale yellow solid) and redissolved in methanol (200 mL). The methanol solution was cooled in an ice bath then treated with sodium cyanotrihydroborate (7.31 g, 116 mmol). The ice bath was removed and the mixture was stirred for 30 min (50% conversion). NaBH4 (3 g, 79.3 mmol) were added and stirring continued at room temperature for 20 min. The mixture was concentrated. The remaining residue was taken up in ethyl acetate (200 mL) then washed with saturated NaHCO3 (100 mL) then brine (100 mL). The organic layer was dried (MgSO4), filtered, then concentrated to give (S)-2-(benzylamino)-3-methylbutan-1-ol as a colorless oil. This oil was dissolved in dichloromethane (300 mL). N-ethyl-N-isopropylpropan-2-amine (67.5 mL, 388 mmol) was added. The flask was flushed with nitrogen, and the mixture was cooled in a dry-ice/acetone bath. Thionyl chloride (7.78 mL, 107 mmol) was added dropwise, maintaining the internal temperature between −60° C. and −30° C. After addition was complete, the cooling bath was removed and the mixture gradually warmed to room temperature over 1 h. The mixture was concentrated. The residue was purified by silica gel flash column chromatography to give the title compound (18 g) as an orange oil (mixture of epimers). LCMS m/z=240.0 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:8][N:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10](Cl)=[O:11]>>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:1][C:10](=[O:11])[N:9]([CH3:8])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:3]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: Oc1cccnc1
Product: CN(C(=O)Oc1cccnc1)c1ccccc1

Procedure:
The title product was prepared from 3-hydroxypyridine and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC. (94%, colourless oil).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9]([C:11]1[C:12]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH3:31])=[CH:13][CH:14]=[C:15]2[C:20]=1[NH:19][C:18](=[O:21])[C:17]([CH3:23])([CH3:22])[NH:16]2)=O.Cl>O1CCCC1.O.C(OCC)(=O)C>[OH:8][CH2:9][C:11]1[C:12]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH3:31])=[CH:13][CH:14]=[C:15]2[C:20]=1[NH:19][C:18](=[O:21])[C:17]([CH3:22])([CH3:23])[NH:16]2
Reactant: COC(=O)c1c(-c2ccccc2OC)ccc2c1NC(=O)C(C)(C)N2
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccccc1-c1ccc2c(c1CO)NC(=O)C(C)(C)N2
Temperature: 0 °C
Reaction time: 3 h
Yield: 61 %

Procedure:
Lithium aluminium hydride (26.0 mg, 0.64 mmol) was suspended in anhydrous tetrahydrofuran (0.5 mL) under nitrogen atmosphere. An anhydrous tetrahydrofuran solution (1.5 mL) of 8-methoxycarbonyl-7-(2-methoxyphenyl)-3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference Compound No. 2-1, 108 mg, 0.32 mmol) was added thereto at 0° C., and stirred for 3 hours at the same temperature. After ethyl acetate (3 mL) and water (3 mL) were added dropwise successively, ethyl acetate (30 mL), water (30 mL) and 1N aqueous hydro chloride solution (5 mL) were added thereto, and the mixture was partitioned. After the water layer was extracted with ethyl acetate (20 mL), the organic layer was combined. The organic layer was washed with water (50 mL, 2 times) and saturated brine (50 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (61.0 mg) as a pale yellow amorphous product. (Yield 61%)
Reaction SMILES: [OH:1][C:2]([CH3:18])([CH3:17])[CH2:3][CH2:4][CH2:5][CH:6]([CH3:16])[CH2:7][CH:8]=[CH:9][C:10]([CH3:15])=[CH:11][C:12]([OH:14])=O.[CH2:19]([Li])[CH3:20].[Cl-].[NH4+]>C1C=CC=CC=1.CCOCC>[OH:1][C:2]([CH3:18])([CH3:17])[CH2:3][CH2:4][CH2:5][CH:6]([CH3:16])[CH2:7][CH:8]=[CH:9][C:10]([CH3:15])=[CH:11][C:12](=[O:14])[CH2:19][CH3:20]
Reactant: [Li]CC
Reactant: CC(C=CCC(C)CCCC(C)(C)O)=CC(=O)O
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccccc1
Solvent: CCOCC
Product: CCC(=O)C=C(C)C=CCC(C)CCCC(C)(C)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3.35 g. of 11-hydroxy-3,7,11-trimethyldodeca-2,4-dienoic acid in 50 ml. ether at -20°C under nitrogen is added dropwise 59.1 ml. of a 0.67 molar solution of ethyllithium in benzene. The reaction mixture is allowed to warm to room temperature and is stirred overnight. The reaction mixture is then taken up in a mixture of ether and saturated aqueous ammonium chloride. The organic layer is separated, is washed with saturated aqueous ammonium chloride, 5% aqueous sodium bicarbonate, water, and saturated sodium chloride, is dried over calcium sulfate, and the solvent is removed to yield 13-hydroxy-5,9,13-trimethyltetradeca-4,6-dien-3-one which is purified by preparative thin layer chromatography (50% ether/hexane).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]([F:16])([F:15])[F:14])=[C:11]([CH3:17])[C:10]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[F:25])=[C:9]1[C:26]([O:28]CC)=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>O.CCO>[CH2:1]([N:8]1[C:12]([C:13]([F:14])([F:15])[F:16])=[C:11]([CH3:17])[C:10]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[F:25])=[C:9]1[C:26]([OH:28])=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(-c2ccc(Cl)cc2F)c(C)c(C(F)(F)F)n1Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1c(-c2ccc(Cl)cc2F)c(C(=O)O)n(Cc2ccccc2)c1C(F)(F)F
Temperature: 25 °C

Procedure:
To a mixture of ethyl 1-benzyl-3-(4-chloro-2-fluorophenyl)-4-methyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylate (1.55 g, 3.5 mmol) in H2O (20 mL) and EtOH (20 mL) was added NaOH (2.82 g, 71 mmol) and the mixture stirred at reflux for 2 h. The reaction mixture cooled to room temperature and concentrated. The reaction mixture was acidified using aqueous 5N HCl and the solids which had been formed were filtered off to give 1.45 g (100%) of ACI-04 as an off white solid.