Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:7]=[CH:6][NH:5][CH:4]=1)=[O:2].[H-].[Na+].[C:10]([NH:13][CH2:14][CH:15]1[O:19][N:18]=[C:17]([C:20]2[CH:25]=[CH:24][C:23](F)=[C:22]([F:27])[CH:21]=2)[CH2:16]1)(=[O:12])[CH3:11]>CN(C)C=O.C(OCC)(=O)C>[F:27][C:22]1[CH:21]=[C:20]([C:17]2[CH2:16][CH:15]([CH2:14][NH:13][C:10](=[O:12])[CH3:11])[O:19][N:18]=2)[CH:25]=[CH:24][C:23]=1[N:5]1[CH:6]=[CH:7][C:3]([CH:1]=[O:2])=[CH:4]1
Reactant: CC(=O)NCC1CC(c2ccc(F)c(F)c2)=NO1
Reactant: O=Cc1cc[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)NCC1CC(c2ccc(-n3ccc(C=O)c3)c(F)c2)=NO1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55.9 %

Procedure:
3-Formylpyrrole (628 mg) is dissolved in 12 ml dimethylformamide in a 50 ml one neck round bottom flask under nitrogen. The solution is cooled to 0° C., is treated with 60% sodium hydride (554 mg), and the mixture is stirred 30 minutes at room temperature. The solution is treated with (-)-5-(acetamidomethyl)-3-(3,4-difluorophenyl)-isoxazoline (Step 1, Example 11) (1.52 g), and the reaction is stirred 6 hours at 65° C. The reaction is cooled, is diluted with 100 ml ethyl acetate, and is washed with 4×25 ml 50% saturated sodium chloride. The organics are dried over anhydrous potassium carbonate and are concentrated in vacuo to a yellow oil. The crude material is chromatographed over 75 g silica gel (230-400 mesh) eluting with 3% methanol/dichloromethane and after a 200 ml forerun collecting 9 ml fractions. Fractions 48-69 are combined and concentrated to give 1.10 g (56%) of the title compound as a white solid, mp 155-156° C., [α]25D -69° (c 0.61, ethanol).
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].[Na].C(OCC)(=O)CC(OCC)=O.[CH3:17][CH:18]([CH3:24])[CH:19]=[CH:20][C:21](=[O:23])[CH3:22].[OH-].[K+].Cl>O.C(O)C>[CH:18]([CH:19]1[CH2:20][C:21](=[O:23])[CH2:22][C:2](=[O:1])[CH2:3]1)([CH3:24])[CH3:17]
Reactant: CC[O-]
Reactant: CC(=O)C=CC(C)C
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CCOC(=O)CC(=O)OCC
Product: CC(C)C1CC(=O)CC(=O)C1
Yield: 40 %

Procedure:
To a fresh solution of sodium ethoxide prepared from 23 g (1.0 mole) of sodium and 700 ml of absolute ethanol is added 168.2 g (1.05 mole) of diethyl malonate and 114.24 g (1.02 mole) of distilled 5-methyl-3-hexene-2-one. The mixture is refluxed for 1 hour; an additional 125 ml of ethanol added; and refluxing continued for two more hours. A solution of 123.4 g of potassium hydroxide in a 600 ml of water is then added and the reaction mixture refluxed for 6 hours. The mixture is then neutralized with 12% hydrochloric acid to pH 4. The ethanol is distilled and the mixture treated with three 15 g portions of activated charcoal. The hot reaction mixture is filtered through filter aid after acidification to pH 2. The product is extracted with hot isopropyl ether (700 ml). Cooling of the isopropyl ether layer results in 60.5 g (40% yield) of the product, m.p. 52°- 65° C.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[F:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1>>[F:28][C:29]1[CH:34]=[C:33]([C:2]2[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=[C:6]([CH:21]=2)[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[O:8])[CH:32]=[CH:31][CH:30]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2cccc(F)c2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 57 using (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 35.1) and (3-fluorophenyl)boronic acid to afford an off-white solid. HPLC (Condition 4) tR=5.48 min, UPLC-MS (Condition 3) tR=1.17 min, m/z=462.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.72 (m, J=3.90 Hz, 1H) 1.77-1.89 (m, 1H) 2.86 (d, J=11.34 Hz, 1H) 3.12-3.27 (m, 2H) 3.40 (m, J=7.40 Hz, 1H) 4.09-4.22 (m, 1H) 4.82 (d, J=3.52 Hz, 1H) 7.15-7.28 (m, 3H) 7.34 (d, J=1.00 Hz, 2H) 7.41-7.53 (m, 1H) 7.77-7.90 (m, 2H) 7.99 (d, J=2.30 Hz, 1H) 8.73 (d, J=2.35 Hz, 1H) 10.15 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[N:11][C:10]2[C:5](=[CH:6][C:7]([N+:17]([O-:19])=[O:18])=[CH:8][C:9]=2[CH2:15][OH:16])[N:4]=1.[H-].[Na+].[C:22]([O:26][C:27](=[O:30])[CH2:28]Br)([CH3:25])([CH3:24])[CH3:23]>O1CCCC1>[C:22]([O:26][C:27](=[O:30])[CH2:28][O:16][CH2:15][C:9]1[CH:8]=[C:7]([N+:17]([O-:19])=[O:18])[CH:6]=[C:5]2[C:10]=1[N:11]=[C:12]([O:13][CH3:14])[C:3]([O:2][CH3:1])=[N:4]2)([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COc1nc2cc([N+](=O)[O-])cc(CO)c2nc1OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1nc2cc([N+](=O)[O-])cc(COCC(=O)OC(C)(C)C)c2nc1OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
300 mg (1.13 mmol) of 2,3-dimethoxy-5-hydroxymethyl-7-nitro-quinoxaline are placed in 8 ml of tetrahydrofuran and cooled to 0° C. 52 mg (1.05 equiv.) of approximately 55% NaH in oil are added and the mixture is stirred for 30 minutes at 0° C. 0.2 ml (1.5 equiv.) of bromo-acetic acid tert-butyl ester is added and after 20 minutes the ice-bath is removed. The reaction mixture is stirred at room temperature for 20 hours, diluted with water and extracted with ethyl acetate. The combined organic phases are washed once with brine, dried over magnesium sulfate and concentrated by evaporation. The residue is chromatographed (SiO2, ethyl acetate/petroleum ether 1:3) and the title compound is obtained in the form of a solid (340 mg).
Reaction SMILES: Cl.CN(C)[CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7].[C:15]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[O-]CC.[Na+]>C(O)C>[C:15]([CH:23]([CH2:4][CH2:5][C:6](=[O:7])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:24]([O:26][CH2:27][CH3:28])=[O:25])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: CN(C)CCC(=O)c1ccccc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(CCC(=O)c1ccccc1)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.6 %

Procedure:
To a stirred mixture of 2.14 g of β-dimethylaminopropiophenone hydrochloride and 1.92 g of ethyl benzoylacetate in 30 cc of ethanol was added in small portions 1.36 g of sodium ethoxide at room temperature. The resulting mixture was stirred at room temperature for 30 minutes and then heated under reflux for 1 hour. After cooling, the solvent was distilled off and water was added to the residue. The aqueous layer was acidified with 1N HCl, and extracted twice with chloroform. The combined organic layer was washed with a saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was distilled off and the crude product thus obtained was purified by a silica gel column chromatography (eluent: ethyl acetate/hexane=1/5) to obtain 2.45 g of compound G. Yield: 75.5%.
Reaction SMILES: [N:1]1([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[C:9]([C:15]([F:18])([F:17])[F:16])[CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:19][C@@H:20]1[CH2:25][NH:24][CH2:23][CH2:22][N:21]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].ClCCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[CH3:19][C@@H:20]1[CH2:25][N:24]([CH2:11][C:10]2[CH:13]=[CH:14][C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[CH:8][C:9]=2[C:15]([F:18])([F:17])[F:16])[CH2:23][CH2:22][N:21]1[C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27]
Reactant: O=Cc1ccc(N2CCOCC2)cc1C(F)(F)F
Reactant: C[C@@H]1CNCCN1C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: C[C@@H]1CN(Cc2ccc(N3CCOCC3)cc2C(F)(F)F)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.3 %

Procedure:
A 100 mL round-bottom flask was charged with 4-(morpholin-4-yl)-2-(trifluoromethyl)benzaldehyde (1.00 g, 3.86 mmol, 1.00 equiv), tert-butyl (2R)-2-methylpiperazine-1-carboxylate (0.850 g, 4.24 mmol, 1.10 equiv), 1,2-dichloroethane (20 mL). The mixture was stirred for 30 min at room temperature. Sodium triacetoxyborohydride (2.40 g, 11.3 mmol, 3.00 equiv) was added. The resulting solution was stirred overnight at room temperature, diluted with H2O (10 mL), extracted with dichloromethane (3×10 mL). The organic layers were combined and washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (20/80) to provide 1.70 g (99% yield) of tert-butyl (2R)-2-methyl-4-[[4-(morpholin-4-yl)-2-(trifluoromethyl)phenyl]methyl]piperazine-1-carboxylate as yellow oil. LCMS (ESI, m/z): 444 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:16]3[NH:17][C:18]4[C:23]([C:24]=3[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:12]=2)[C:7]=1[Br:30].[CH3:32]C([O-])(C)C.[K+].CI.[H-].[Na+]>C1COCC1>[Br:30][C:7]1[C:8]2[C:13](=[CH:12][C:11]([C:16]3[N:17]([CH3:32])[C:18]4[C:23]([C:24]=3[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:10][CH:9]=2)[CH:14]=[CH:15][C:6]=1[O:5][CH2:4][C:3]([OH:2])=[O:31]
Reactant: CCCCCc1c(-c2ccc3c(Br)c(OCC(=O)OC)ccc3c2)[nH]c2ccccc12
Reactant: CC(C)(C)[O-]
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CCCCCc1c(-c2ccc3c(Br)c(OCC(=O)O)ccc3c2)n(C)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.6 %

Procedure:
To a stirred solution of {[1-bromo-6-(3-pentyl-1H-indol-2-yl)-2-naphthyl]oxy}acetic acid methyl ester (0.410 g, 0.853 mmol) in THF (20 mL) at 0° C. was added KOt-Bu (0.105 g, 0.938 mmol) followed by MeI (0.064 mL, 1.02 mmol). The reaction was warmed to rt and let stir for 1 h. It appeared by TLC and MS that all the starting material was gone; however, two polar acids (one N—Me and one N—H) had been generated due to hydrolysis in these basic conditions. After concentration, the residue was taken up in DMF (20 mL). Added NaH (0.075 g, 60% by wt., 1.88 mmol) followed by excess MeI to convert all intermediate to one acid (N—Me). After 1 h, the reaction mixture was concentrated and then diluted with EtOAc (200 mL) and 1 N HCl (20 mL). The organic layer was washed with H2O (20 mL) and brine (20 mL) and then dried (Na2SO4). After concentration, the residue was purified by preparatory plate chromatography (10% MeOH:CHCl3) to afford the product (0.232 g, 57%) as a yellowish-orange foamy solid, mp>73° C. (decomp.); 1H NMR (DMSO-d6) δ 0.73 (t, J=7.0 Hz, 3H), 1.11-1.20 (m, 4H), 1.50-1.58 (m, 2H), 2.66 (t, J=7.3 Hz, 2H), 3.58 (s, 3H), 4.93 (s, 2H), 7.07 (t, J=7.6 Hz, 1H), 7.19 (t, J=7.1 Hz, 1H), 7.42-7.48 (m, 2H), 7.58 (d, J=7.9 Hz, 1H), 7.68 (dd, J=1.7, 8.7 Hz, 1H), 7.99 (s, 1H), 8.04 (d, J=9.0 Hz, 1H), 8.21 (d, J=8.7 Hz, 1H), 11.95-14.75 (bs, 1H); IR (neat) 3050, 2955, 2925, 2850, 1725, 1670, 1600, 1480, 1470, 1430, 1370, 1325, 1275, 1220, 1190, 1145, 1095, 1015, 980, 925, 895, 830, 800, 765, 735, 700, and 665 cm−1; mass spectrum [(+) ESI], m/z 480/482 (M+H)+;
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([CH:17]=[CH2:18])[CH:14]=[C:13]2[C:19]#[N:20])=[CH:8][CH:7]=1)=O)C.[BH4-].[Li+]>O1CCCC1>[OH:3][CH2:4][C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH:16]=[C:15]([CH:17]=[CH2:18])[CH:14]=[C:13]2[C:19]#[N:20])=[CH:10][CH:11]=1
Reactant: C=Cc1cc(C#N)n(-c2ccc(C(=O)OCC)cc2)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=Cc1cc(C#N)n(-c2ccc(CO)cc2)c1
Yield: 68 %

Procedure:
A mixture of 1-(4-ethoxycarbonylphenyl)-4-vinylpyrrole- 2-carbonitrile (1.59 g) and lithium borohydride (78.4 mg) in tetrahydrofuran (30 ml) was refluxed for 3 hours. To the pale green solution was added lithium borohydride (78.4 mg) and the mixture was refluxed for 3 hours. The cooled mixture was quenched with saturated aqueous ammonium chloride solution and diethyl ether was added. The separated organic layer was washed with saturated aqueous ammonium chloride solution, dried, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluted by 2% methanol in dichloromethane to yield 1-(4-hydroxymethylphenyl)-4-vinylpyrrole-2-carbonitrile (910 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([C:11]([O:13]C)=[O:12])[S:10][C:5]2=[N:4][CH:3]=1.[OH-].[Na+]>C1COCC1.C(O)C.Cl>[Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([C:11]([OH:13])=[O:12])[S:10][C:5]2=[N:4][CH:3]=1
Reactant: COC(=O)c1cc2nc(Cl)cnc2s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1cc2nc(Cl)cnc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.9 %

Procedure:
To a solution of methyl 2-chlorothieno[3,2-b]pyrazine-6-carboxylate 22 (1.23 g, 5.38 mmol) in THF (10 mL) and ethanol (10 mL) was added a solution of 2N sodium hydroxide (13.45 mL, 26.9 mmol). The reaction was stirred at rt for 1 h. The reaction mixture was poured in 2N HCl solution and the resulting precipitate was collected, washed with water and dried to give crude 2-chlorothieno[3,2-b]pyrazine-6-carboxylic acid 23 (1.027 g, 89%). NMR (400 MHz, DMSO-d6) 8.18 (s, 1H), 8.90 (s, 1H).
Reaction SMILES: C([O:3][C:4](=[O:22])/[CH:5]=[CH:6]/[CH:7]=[CH:8]/[CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1)C.O[Li].O>CCO>[C:18]([O:17][C:15]([N:12]1[CH2:13][CH2:14][CH:9](/[CH:8]=[CH:7]/[CH:6]=[CH:5]/[C:4]([OH:22])=[O:3])[CH2:10][CH2:11]1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: CCOC(=O)/C=C/C=C/C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li]O
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(/C=C/C=C/C(=O)O)CC1
Temperature: 50 °C
Yield: 98.2 %

Procedure:
A solution of the above ethyl ester (22) (2.60 g, 8.4 mmol) in absolute EtOH (30 mL) was added LiOH—H2O (720 mg, 17 mmol, in 10 mL of water). The reaction was heated to 50° C. for 1 h, then concentrated to remove excess EtOH. After acidification with 5% citric acid (50 mL), the product was extracted with EtOAc (2×100 mL). The combined organic extracts were washed with brine (100 mL), dried (MgSO4) and concentrated to give a white solid (23) (2.32 g, 98%). 1H NMR (500 MHz, CDCL3) δ 7.31 (dd, J=15.5, 11.0 Hz, 1H), 6.18 (dd, J=15.5, 11.0 Hz, 1H), 6.08 (dd, J=15.5, 7.0 Hz, 1H), 5.80 (d, J=15.5 Hz, 1H), 4.10 (m, 2H), 2.75 (m, 2H), 2.25 (m, 1H), 1.70 (m, 2H) 1.44 (s, 9H), 1.33 (m, 2H); MS (ESI−) m/z 280.74 (M−H+).
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:19]=[C:20]([CH:25]=[CH:26][C:27]=2[F:28])[C:21]([O:23][CH3:24])=[O:22])[CH2:14][C@H:13]1[O:29][CH3:30])=O)C1C=CC=CC=1>[C].[Pd]>[NH2:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:19]=[C:20]([CH:25]=[CH:26][C:27]=2[F:28])[C:21]([O:23][CH3:24])=[O:22])[CH2:14][C@H:13]1[O:29][CH3:30]
Reactant: COC(=O)c1ccc(F)c(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)c1
Agent: [Pd]
Product: COC(=O)c1ccc(F)c(N2CC[C@H](N)[C@H](OC)C2)c1
Yield: 26.6 %

Procedure:
The same operation as in Example (160c) was performed using methyl cis(±)-3-(4-{[(benzyloxy)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-fluorobenzoate obtained in Example (181a) (101 mg, 0.24 mmol) and a 10% palladium-carbon catalyst (100 mg), to obtain 18 mg of the title compound as a colorless oily substance (26%). The resulting compound was used for the next reaction without purification.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:5][O:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH2:19]([O:21][C:22](=[O:36])[CH2:23][NH:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=1[O:34][CH3:35])[CH3:20].C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>CN(C=O)C.O>[CH3:35][O:34][C:27]1[CH:28]=[C:29]([O:32][CH3:33])[CH:30]=[CH:31][C:26]=1[CH2:25][N:24]([CH2:2][C:3]1[C:4]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:5][O:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:23][C:22]([O:21][CH2:19][CH3:20])=[O:36]
Reactant: CCOC(=O)CNCc1ccc(OC)cc1OC
Reactant: CCOC(=O)c1onc(-c2ccncc2)c1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1c(-c2ccncc2)noc1C(=O)OCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 21 %

Procedure:
Ethyl 4-(bromomethyl)-3-(pyridin-4-yl)isoxazole-5-carboxylate (1.5 g, 4.82 mmol) was dissolved in 20 mL of DMF. N-(2,4-dimethoxybenzyl)glycine ethyl ester (1.22 g, 4.82 mmol) and potassium carbonate (1.33 g, 9.65 mmol) were added, and the mixture was stirred at room temperature for 16 h. EtOAc (100 mL) and water (100 mL) were added and the aqueous layer was extracted with additional EtOAc. The combined organic layer was washed with water and brine, and dried over MgSO4. After solvent was removed in vacuo, the crude was purified by flash chromatography (0-50% EtOAc/hexanes) to give 0.49 g of the title compound. MS: (+) m/z 484.48 (M+1).
Reaction SMILES: [CH:1]1[CH:20]=[CH:19][C:17](=[O:18])/[C:3](=[CH:4]\[NH:5][CH2:6][CH2:7][NH:8]/[CH:9]=[C:10]2\[C:11]([CH:13]=[CH:14][CH:15]=[CH:16]\2)=[O:12])/[CH:2]=1.N#N.C(=O)=O>O>[CH:4](=[N:5][CH2:6][CH2:7][N:8]=[CH:9][C:10]1[C:11](=[CH:13][CH:14]=[CH:15][CH:16]=1)[OH:12])[C:3]1[C:17](=[CH:19][CH:20]=[CH:1][CH:2]=1)[OH:18]
Reactant: O=C1C=CC=C/C1=C/NCCN/C=C1/C=CC=CC1=O
Agent: N#N
Agent: O=C=O
Solvent: O
Product: Oc1ccccc1C=NCCN=Cc1ccccc1O

Procedure:
Approximately 0.6 g of SALEN ligand dissolved in 1 ml water was loaded into each reactor tube of the Multiclave™, and 5 ml of 4:1 (weight ratio) water/EO was added at 100° C. The reactor was blanketed with 250 psig of N2. The experiment with the same SALEN ligand dissolved in 5 ml of water and treated with carbon dioxide over the weekend at room temperature was repeated but with 250 psig of CO2 as blanket gas.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([O:21][CH3:22])[C:14](Br)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH2:32]1COC[CH2:33]1>O>[C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([O:21][CH3:22])[C:14]([CH2:32][CH3:33])=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(Br)c1OC
Reactant: C1CCOC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCc1ccc(CS(=O)(=O)c2ccccc2)c(C(=O)OC)c1OC
Temperature: 140 °C

Procedure:
A mixture of methyl 6-(benzenesulphonylmethyl)-3-bromo-2-methoxybenzoate (Intermediate 65, 1.31 g) and potassium phosphate (2.02 g) in THF (9 ml) and water (4.5 ml) was degassed and palladium chloride dppf adduct with DCM (0.134 g) and triethyl borane (1M solution in THF, 4.6 ml) were added. The mixture was stirred and heated in the microwave at 140° C. for 18 minutes. The mixture was partitioned between ethyl acetate and water and the organic layer was separated, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 5-40% to give methyl 6-(benzenesulphonylmethyl)-3-ethyl-2-methoxybenzoate (0.754 g) as a colourless oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[N:14][O:15][CH2:16][C:17]2[N:18]=[C:19](N)[S:20][CH:21]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:5][N:4]=[N:3]1.[Br-:23].[Na+].C(ON=O)(C)(C)C>CC#N.[Cu]Br>[Br:23][C:19]1[S:20][CH:21]=[C:17]([CH2:16][O:15][N:14]=[C:7]([C:6]2[N:2]([CH3:1])[N:3]=[N:4][N:5]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:18]=1
Reactant: [Br-]
Reactant: Cn1nnnc1C(=NOCc1csc(N)n1)c1ccccc1
Agent: [Cu]Br
Agent: CC(C)(C)ON=O
Agent: [Na+]
Solvent: CC#N
Product: Cn1nnnc1C(=NOCc1csc(Br)n1)c1ccccc1
Temperature: 80 °C
Yield: 73 %

Procedure:
To a stirred suspension of 4-[({[(1-methyl-1H-tetrazol-5-yl)(phenyl)methylene]amino}oxy)methyl]-1,3-thiazol-2-amine (41 g, 130 mmol, 1 eq.) in 2000 ml of MeCN, were added sodium bromide (40.1 g, 390 mmol, 3 eq.), Copper (I) bromide (18.65 g, 130 mmol, 1 eq.) and t-Butylnitrite (16.38 g, 143 mmol, 1.1 eq.). The reaction was slowly heated to 80° C. for 1 h and allowed to cool. MeCN was evaporated and 500 ml water/1000 ml DCM were added to the residue. The crude was triturated, filtered through “celite” plug and washed with further 500 ml of EtOAc. The organic layers were combined, dried over MgSO4, and evaporated to give N-[(2-bromo-1,3-thiazol-4-yl)methoxy]-1-(1-methyl-1H-tetrazol-5-yl)-1-phenylmethanimine (36 g, 69% yield, 10:1 mixture of stereoisomers) as a brown viscous oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[Cl:34])[C:5]([NH:7][C:8]1[CH:30]=[CH:29][C:11]([CH2:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([CH2:22][C:23]([O:25]CC)=[O:24])[C:14]=2[CH3:28])=[CH:10][CH:9]=1)=[O:6].O.[OH-].[Li+].O1CCCC1.CO>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[Cl:34])[C:5]([NH:7][C:8]1[CH:30]=[CH:29][C:11]([CH2:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([CH2:22][C:23]([OH:25])=[O:24])[C:14]=2[CH3:28])=[CH:10][CH:9]=1)=[O:6]
Reactant: CCOC(=O)Cn1c(C)c(Cc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cc2)c2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1c(Cc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cc2)c2ccccc2n1CC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
Into a dry reaction vessel, ethyl 2-[3-[4-(3,4-dichlorobenzamido)benzyl]-2-methyl-1H-indol-1-yl]acetate (691 mg, 1.39 mmol), lithium hydroxide monohydrate (176 mg, 4.19 mmol), 10 mL tetrahydrofuran, 10 mL methanol, 10 mL water were weighed, and stirred at room temperature for 1 h. The reaction was monitored to be complete by TLC. The solvent was rotate evaporated. It was adjusted to pH=3-4 with 2 N HCl solution. It was filtered, and the filter cake was washed with 20 mL methanol to obtain the product as a white solid 551 mg, at a yield of 84.9%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([Br:13])=[CH:11][N:10]([CH3:14])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[F:22][C:23]([F:36])([F:35])[O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32](O)=[O:33])=[CH:27][CH:26]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[Br:13][C:12]1[C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:32](=[O:33])[CH2:31][C:28]3[CH:29]=[CH:30][C:25]([O:24][C:23]([F:35])([F:22])[F:36])=[CH:26][CH:27]=3)[CH:7]=[CH:6][CH:5]=2)=[N:9][N:10]([CH3:14])[CH:11]=1
Reactant: Cn1cc(Br)c(-c2cccc(N)c2)n1
Reactant: O=C(O)Cc1ccc(OC(F)(F)F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1cc(Br)c(-c2cccc(NC(=O)Cc3ccc(OC(F)(F)F)cc3)c2)n1
Temperature: 70 °C
Yield: 67.6 %

Procedure:
A solution of 3-(3-aminophenyl)-4-bromo-1-methylpyrazole (35 mg, 0.14 mmol) and triethylamine (23 μL, 0.17 mmol) in DMF (0.5 mL) was added in one portion to a stirred solution of 4-trifluoromethoxyphenylacetic acid (31 mg, 0.14 mmol), HBTU (53 mg, 0.14 mmol) and HOBT (19 mg, 0.14 mmol) in DMF (1 mL). The mixture was heated at 70° C. for 24 h and then quenched with aqueous sodium bicarbonate solution. Ethyl acetate was added and the organic phase separated, washed with water (×3), brine, dried (MgSO4) and evaporated. Chromatography on flash silica (50%EtOAc/hexane) gave the title compound as a colourless solid (43 mg, 68%), m.p. 141.2-142.5° C. (EtOAc/hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:12])[CH:11]=1)[C:5](OC)=[O:6].[CH3:13][NH2:14]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:12])[CH:11]=1)[C:5]([NH:14][CH3:13])=[O:6]
Reactant: COC(=O)c1cc(Cl)cc(Cl)c1
Reactant: CN
Product: CNC(=O)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl 3,5-dichlorobenzoate (2-D) (1.07 g, 5.0 mmol) was suspended in a vigorously stirring solution of methylamine (40%/H2O, 5.0 mL). After heating gently for 10 min, the mixture was stirred at room temperature for 18 h. The mixture was extracted with methylene chloride and the extract dried (MgSO4) to provide 3,5-dichloro-N-methylbenzamide (2-E).