Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:10]([OH:12])=O)[N:8]=1)=[O:2].CN(C)C=O.P(Cl)(Cl)(Cl)=O.[NH2:31][CH:32]1[C:59](=[O:60])[N:34]2[C:35]([C:56]([OH:58])=[O:57])=[C:36]([CH2:39][S:40][C:41]3[N:45]([CH2:46][CH2:47][NH:48][C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[N:44]=[N:43][N:42]=3)[CH2:37][S:38][C@H:33]12>CC(C)=O.O1CCCC1>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:10]([NH:31][CH:32]2[C:59](=[O:60])[N:34]3[C:35]([C:56]([OH:58])=[O:57])=[C:36]([CH2:39][S:40][C:41]4[N:45]([CH2:46][CH2:47][NH:48][C:49]([O:51][C:52]([CH3:54])([CH3:55])[CH3:53])=[O:50])[N:44]=[N:43][N:42]=4)[CH2:37][S:38][C@H:33]23)=[O:12])[N:8]=1)=[O:2]
Reactant: CCOC(=O)CON=C(C(=O)O)c1csc(NC=O)n1
Reactant: CC(C)(C)OC(=O)NCCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Solvent: CC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CCNC(=O)OC(C)(C)C)CS[C@H]12)c1csc(NC=O)n1
Yield: 85.7 %

Procedure:
2-(2-Formamidothiazol-4-yl)-2-ethoxycarbonylmethoxyiminoacetic acid (syn isomer, 1.32 g.), N,N-dimethylformamide (447 mg.), phosphoryl chloride (939 mg.), 7-amino-3-[1-(2-tert-butoxycarbonylaminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (3.0 g.), tetrahydrofuran (13 ml.) and 50% aqueous acetone (30 ml.) were treated in a similar manner to that of Example 11-(1) to give 7-[2-(2-formamidothiazol-4-yl)-2-ethoxycarbonylmethoxyiminoacetamido]-3-[1-(2-tert-butoxycarbonylaminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 2.78 g.).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][NH2:10])[CH2:4][CH2:3]1.[Br:11][C:12]1[CH:17]=[CH:16][C:15](I)=[C:14]([CH3:19])[CH:13]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(O)CO>C(O)(C)C.[Cu]I>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([NH:10][CH2:9][CH2:8][N:5]2[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH2:4]2)=[C:14]([CH3:19])[CH:13]=1
Reactant: CC1CCN(CCN)CC1
Reactant: Cc1cc(Br)ccc1I
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CC(C)O
Product: Cc1cc(Br)ccc1NCCN1CCC(C)CC1

Procedure:
5.00 g (35.00 mmol) of 2-(4-methylpiperidin-1-yl)ethylamine was added under argon to a mixture of 10.39 g (35.00 mmol) of 4-bromo-1-iodo-2-methylbenzene, 0.33 g (1.75 mmol) of CuI, 30.0 g (141.00 mmol) of potassium phosphate, and 4.34 g (70.00 mmol) of ethylene glycol in 35 mL of isopropanol and the mixture was refluxed for 15 hours. The reaction mixture was evaporated down in vacuo and the residue taken up in EtOAc. The organic phase was washed with 5% aqueous ammonia, dried over magnesium sulfate, and evaporated down in vacuo. The crude product was purified by column chromatography (silica gel, EtOAc). Yield: 1.20 g (11% of theoretical); C15H23BrN2 (M=311.261); calc.: molpeak (M+H)+: 311/313 (Br); found: molpeak (M+H)+: 311/313 (Br); HPLC-MS: 4.24 minutes (method B).
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22]([N+:24]([O-])=O)[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:18]([CH3:19])[CH:17]=[N:16][CH:15]=3)[S:13][C:6]=12.[BH4-].[Na+].[NH4+].[OH-]>CO.C1COCC1.Cl>[F:1][C:2]1[CH:23]=[C:22]([NH2:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:18]([CH3:19])[CH:17]=[N:16][CH:15]=3)[S:13][C:6]=12
Reactant: Cn1cncc1-c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Agent: Cl
Agent: [BH4-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: Cn1cncc1-c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Reaction time: 0.25 h
Yield: 52.2 %

Procedure:
To a stirring mixture of the nitro compound 17 (0.96 g, 2.59 mmol) and NiCl2.6H2O (1.24 g, 5.22 mmol) in MeOH/THF (26 mL/39 mL) at 0° C., NaBH4 (0.341 g, 9.01 mmol) was added portion wise. The reaction mixture was stirred for 15 minutes, quenched with 1M HCl (10 mL) and concentrated under reduced pressure to form a green residue, which was then dissolved in 1M HCl (250 mL) and basified with NH4OH. The cloudy suspension was extracted with EtOAc, the organic layer was collected, filtered, washed with water and then dried over anhydrous Na2SO4. Evaporation of this solution afforded title compound 18 as brown solid (0.46 g, 52% yield), which was used in the next step without additional purification. MS (m/z): 341.1 (M+H).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].CC1(C)O[C:17](=[O:18])[CH2:16][C:14](=[O:15])[O:13]1>C1(C)C=CC=CC=1>[C:14]([CH2:16][C:17]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([OH:10])=[O:9])=[O:18])([OH:15])=[O:13]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: Nc1ccccc1C(=O)O
Solvent: Cc1ccccc1
Product: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Yield: 89.3 %

Procedure:
Anthranilic acid (181 g, 1.32 mol) and Meldrum's acid (200 g, 1.39 mol) in toluene (1.50 L) were treated according to Procedure 1. 2-[(Carboxyacetyl)amino]benzoic acid (263 g, 89%) was obtained as a colourless solid; mp 171-173° C., lit. [21] 178-180° C.; δH (500 MHz, DMSO-d6) 3.45 (br s, 2H, CH2), 7.16 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.59 (td, J4,5=J5,6=8.0, J3,5=1.5 Hz, 1H, H5), 7.97 (dd, J3,4=8.0, J3,5=1.5 Hz, 1H, H3), 8.44 (d, J5,6=8.0 Hz, 1H, H6), 11.27 (s, 1H, NH), 12.83 (br s, 1H, CO2H), 13.57 (br s, 1H, CO2H); δC (125 MHz, DMSO-d6) 45.0, 117.0, 120.3, 123.1, 131.2, 134.1, 140.4, 164.9, 169.1, 169.3.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH2:4].C(=O)(O)[O-].[Na+].Br[CH2:16][C:17]([O:19][CH3:20])=[O:18]>ClCC(OC)=O>[CH3:20][O:19][C:17](=[O:18])[CH2:16][NH:4][C:3]1[C:2]([F:1])=[CH:8][CH:7]=[CH:6][C:5]=1[F:9]
Reactant: Nc1c(F)cccc1F
Reactant: COC(=O)CBr
Agent: COC(=O)CCl
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)CNc1c(F)cccc1F
Reaction time: 16 h

Procedure:
A suspension of 2,6-difluoroaniline (15.0 g) and sodium bicarbonate (19.5 g) in methyl chloroacetate (15.2 ml) was stirred at 90°-100° under nitrogen for 16 h. Methyl bromoacetate (11.0 ml) and sodium bicarbonate (9.75 g) were added, and the suspension was stirred at 90°-100° for a further 5 h. Work up according to the method of Intermediate 11 gave an oil (14.7 g) which was purified by FCC eluting with system A (1:8) to give the title compound (8.27 g) as an oil, t.l.c. (System A, 1:8) Rf 0.3.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([N+:17]([O-])=O)[CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#[N:9].[Cl-].[Ca+2].[Cl-]>C(O)C.O>[NH2:17][C:15]1[CH:14]=[CH:13][C:3]([O:4][C:5]2[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=2)[C:8]#[N:9])=[C:2]([Cl:1])[CH:16]=1
Reactant: N#Cc1cccc(Oc2ccc([N+](=O)[O-])cc2Cl)c1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: N#Cc1cccc(Oc2ccc(N)cc2Cl)c1
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3-(2-chloro-4-nitrophenoxy)benzonitrile (2.0 g) in ethanol/water (9:1, 40 mL) was added calcium chloride (90%, 449 mg), and the mixture was stirred at 100° C. for 10 min. Reduced iron (90%, 2.7 g) was added at room temperature, and the mixture was stirred at 100° C. for 5 hrs.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([CH2:9]P(=O)(OCC)OCC)#[N:8].[F:18][C:19]1[CH:20]=[C:21]([C@H:26]2[CH2:28]O2)[CH:22]=[CH:23][C:24]=1[F:25].O>C1(C)C=CC=CC=1>[F:18][C:19]1[CH:20]=[C:21]([C@@H:26]2[CH2:28][C@H:9]2[C:7]#[N:8])[CH:22]=[CH:23][C:24]=1[F:25]
Reactant: Fc1ccc([C@H]2CO2)cc1F
Reactant: CCOP(=O)(CC#N)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: N#C[C@@H]1C[C@H]1c1ccc(F)c(F)c1
Temperature: 75 °C

Procedure:
Potassium t-butoxide (21.5 g) and toluene (150 mL) were charged into a reaction vessel. Diethyl cyanomethylphosphonate (34.8 g) was added to the mixture with stirring and mixture was heated to 70-80° C. Then a mixture of (2S)-2-(3,4-difluorophenyl) oxirane (29 g) in toluene (150 mL) was slowly added to above reaction mass at 75-80° C. over a period of 30 minutes and the mixture was maintained for 11-12 hours for completion of reaction as monitored by TLC. After completion of reaction, mixture was cooled to 25-30° C. and water (300 mL) was added, the layers were separated. The aqueous layer was back extracted with toluene (150 mL). The organic layers were combined and washed with water (300 mL). The combined organic layer was subjected to complete distillation under vacuum at below 55-60° C. to afford the compound which was purified by column chromatography to afford the title compound of about 97% HPLC purity.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([Sn](C)(C)C)=[N:9][N:10]2[CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])=[CH:6][CH:5]=1)([O-:3])=[O:2].I[N:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[N:28]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[CH2:27]1>[Cu]I.C1COCC1>[N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:27]3[N:28]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:41])([CH3:42])[CH3:40])[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[N:26]=3)=[N:9][N:10]2[CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: C[Si](C)(C)CCOCN1CN(I)c2ccccc21
Reactant: C[Si](C)(C)CCOCn1nc([Sn](C)(C)C)c2ccc([N+](=O)[O-])cc21
Agent: [Cu]I
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1nc(-c2nc3ccccc3n2COCC[Si](C)(C)C)c2ccc([N+](=O)[O-])cc21
Yield: 82.2 %

Procedure:
6-Nitro-1-[2-(trimethyl-silanyl)-ethoxymethyl]-3-(trimethyl-stannanyl)-1-H-indazole (7.50 g, 16.4 mmol), 3-iodo-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1-H-benzimidazole (6.50 g, 17.4 mmol), and copper(I) iodide (313 mg, 1.64 mmol) were combined with dry THF (150 mL) in a flask purged with argon. Tetrakis(triphenylphosphine)palladium(0) was added, and the reaction stirred at reflux under argon for 23 h. The reaction was cooled and adsorbed directly onto silica gel (˜16 g). Purification by silica gel chromatography (4% to 15% ethyl acetate/hexanes) gave 7.28 g (82%) of 6-nitro-1-[2-(trimethyl-silanyl)-ethoxymethyl]-3-{1-[2-(trimethyl-silanyl)-ethoxymethyl]-1-H-benzoimidazol-2-yl}-1-H-indazole as a light yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.91 (d, 1 H, J=9.0 Hz), 8.59 (d, 1 H, J=1.8 Hz), 8.22 (dd, 1 H, J=8.7, 1.8 Hz), 7.92–7.89 (m, 1 H), 7.66–7.62 (m, 1 H), 7.40–7.36 (m, 2 H), 6.24 (s, 2 H), 5.90 (s, 2 H), 3.68–3.59 (m, 4 H), 0.94 (t, 2 H, J=8.1 Hz), 0.86 (t, 2 H, J=8.1 Hz), −0.04 (s, 9 H), −0.15 (s, 9 H). Anal. (C26H37N5O4Si2) C, H, N. Calculated: C, 57.85; H, 6.91; N, 12.97. Found: C, 57.60; H, 6.81; N, 12.82.
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:6][CH2:5][CH2:4][C:3]1=O.[C:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])#[N:10].C([O-])(=O)C.[NH4+].[Na+].[Cl-]>C1(C)C=CC=CC=1.C(O)(=O)C>[C:9](/[C:11](=[C:3]1\[C:2]([CH3:8])([CH3:1])[CH2:6][CH2:5][CH2:4]\1)/[C:12]([O:14][CH2:15][CH3:16])=[O:13])#[N:10]
Reactant: CC1(C)CCCC1=O
Reactant: CCOC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)/C(C#N)=C1\CCCC1(C)C
Yield: 26.7 %

Procedure:
2,2-dimethylcyclopentanone (5 g, 44.6 mmol, 1 equiv.) was dissolved in toluene (100 mL). Then, ethyl 2-cyanoacetate (5.04 g, 44.6 mmol, 1 equiv.), ammonium acetate (2.4 g, 31.2 mmol, 0.7 equiv.) and acetic acid (2.8 mL) were added in the mixture at room temperature. The mixture was refluxed for 20 hours. 10% NaCl solution (100 mL) was added in the mixture. Then, the organic layer was washed by water (50 mL) and brine (50 mL), dried by sodium sulfate and filtered. The organic layer was concentrated and the residue was purified by column chromatography to give (E)-ethyl 2-cyano-2-(2,2-dimethylcyclopentylidene)acetate (2.47 g, 32%) as a colorless oil. MS: m/z 208 (M+H)+.
Reaction SMILES: Cl.Cl.[N:3]1([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][O:21][C:22]4[CH:26]=[CH:25][O:24][N:23]=4)[O:17][C:16]3=[O:27])=[CH:11][C:10]=2[F:28])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[C:29](Cl)(=[O:31])[CH3:30]>>[C:29]([N:6]1[CH2:5][CH2:4][N:3]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][O:21][C:22]4[CH:26]=[CH:25][O:24][N:23]=4)[O:17][C:16]3=[O:27])=[CH:11][C:10]=2[F:28])[CH2:8][CH2:7]1)(=[O:31])[CH3:30]
Reactant: CC(=O)Cl
Reactant: O=C1O[C@@H](COc2ccon2)CN1c1ccc(N2CCNCC2)c(F)c1
Agent: Cl
Product: CC(=O)N1CCN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)CC1

Procedure:
The title compound was prepared using essentially the method of Example 73, starting from 3-(4-(piperazin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one dihydrochloride (0.59 g, 1.35 mmol) and acetyl chloride. Purification by chromatography, eluting with a gradient increasing in polarity from 0 to 2.5% MeOH in dichloromethane gave the desired product (142 mg).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][O:23][C:24]2[CH:33]=[C:32]3[C:27]([C:28]([O:34][C:35]4[CH:36]=[C:37]5[C:41](=[CH:42][CH:43]=4)[NH:40][C:39]([CH3:44])=[CH:38]5)=[N:29][CH:30]=[N:31]3)=[CH:26][C:25]=2[O:45][CH3:46])[CH2:17][CH2:16]1)=O)(C)(C)C>ClCCl>[CH3:46][O:45][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][C:24]=1[O:23][CH2:22][CH2:21][N:18]1[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]1)[N:31]=[CH:30][N:29]=[C:28]2[O:34][C:35]1[CH:36]=[C:37]2[C:41](=[CH:42][CH:43]=1)[NH:40][C:39]([CH3:44])=[CH:38]2
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCCN1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCCN1CCNCC1
Reaction time: 1 h
Yield: 80.6 %

Procedure:
TFA (8 ml) was added to a solution of 7-{2-[4-(tert-butoxycarbonyl)piperazin-1-yl]ethoxy}-6-methoxy-4-[(2-methyl-1H-indol-5-yl)oxy]quinazoline (2.75 g) in dichloromethane (30 ml) at 0° C. and the reaction mixture was stirred at this temperature for 1 hour before being concentrated in vacuum in a cold bath (˜20° C.). Cold water was added to the residue and the pH was adjusted to 10.5 with 1N sodium hydroxide. After several extractions with dichloromethane, the combined organic layers were dried over magnesium sulphate, filtered and concentrated in vacuum to give 6-methoxy-4-[(2-methyl-1H-indol-5-yl)oxy]-7-[2-(piperazin-1-yl)ethoxy]quinazoline (1.8 g) as a white solid.
Reaction SMILES: [F:1][CH:2]([F:29])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=[O:28])[CH2:12][CH2:13][C:14]1[N:15]=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([OH:27])[CH:20]=2)[O:17][CH:18]=1.Br[CH:31]([CH3:33])[CH3:32]>>[F:29][CH:2]([F:1])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=[O:28])[CH2:12][CH2:13][C:14]1[N:15]=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH:31]([CH3:33])[CH3:32])[CH:20]=2)[O:17][CH:18]=1
Reactant: CC(C)Br
Reactant: COc1ccc(-c2nc(CCC(=O)c3ccccc3OCC(F)F)co2)cc1O
Product: COc1ccc(-c2nc(CCC(=O)c3ccccc3OCC(F)F)co2)cc1OC(C)C

Procedure:
Using the compound obtained in Example 272 and 2-bromopropane, white powdery 1-[2-(2,2-difluoroethoxy)phenyl]-3-[2-(3-isopropoxy-4-methoxyphenyl)oxazol-4-yl]propan-1-one was obtained following the procedure of Example 3.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:27])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=3[O:25][CH3:26])[CH2:11][CH2:12][C:13]=2[C:14]=1[OH:15])=[O:4].[NH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH3:26][O:25][C:18]1[CH:19]=[C:20]([O:23][CH3:24])[CH:21]=[CH:22][C:17]=1[CH2:16][N:10]1[C:9](=[O:27])[C:8]2[CH:7]=[N:6][C:5]([C:3]([NH:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:4])=[C:14]([OH:15])[C:13]=2[CH2:12][CH2:11]1
Reactant: COC(=O)c1ncc2c(c1O)CCN(Cc1ccc(OC)cc1OC)C2=O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1ccc(CN2CCc3c(cnc(C(=O)NCCC(=O)O)c3O)C2=O)c(OC)c1
Temperature: 25 °C
Yield: 33.3 %

Procedure:
A mixture of 7-(2,4-dimethoxy-benzyl)-4-hydroxy-8-oxo-5,6,7,8-tetrahydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (19 mg, 0.051 mmol), β-alanine (605 mg, 6.79 mmol), and NaOMe solution (10 mL, 5.11, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water, and 1 M HCl was added with vigorous stirring until pH about 1. The organic layer was dried over MgSO4 and concentrated. The crude was first purified by silica gel chromatography (5-80% EtOAc/hexanes+2% AcOH), and the product isolated was then dissolved in saturated NaHCO3. The aqueous solution was washed with ether, acidified to pH about 1 with 4 M HCl, and the resulting precipitate was collected by filtration and dried under vacuum to give 7.3 mg of the title compound. MS: (+) m/z 430.27 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[N:12][C:13]([O:21][CH2:22][C:23]([O:25]CC)=[O:24])=[CH:14][C:15]=2[C:17]([F:20])([F:19])[F:18])[N:10]([CH3:28])[N:9]=1.C1COCC1.O[Li].O.Cl>CCO.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[N:12][C:13]([O:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:14][C:15]=2[C:17]([F:20])([F:19])[F:18])[N:10]([CH3:28])[N:9]=1
Reactant: CCOC(=O)COc1cc(C(F)(F)F)c2c(-c3ccccc3F)nn(C)c2n1
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: Cn1nc(-c2ccccc2F)c2c(C(F)(F)F)cc(OCC(=O)O)nc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
To a solution of ethyl 2-(3-(2-fluorophenyl)-1-methyl-4-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yloxy)acetate (180 mg, 0.45 mmol) in a mixture of EtOH, THF and water (2 ml/1 ml/0.5 ml) was added LiOH.H2O (76.1 mg, 1.81 mmol). The reaction mixture was stirred for 1 h at rt. Aqueous HCl was then added to adjust the reaction mixture to pH ˜2. The resulting precipitate was filtered off and washed twice with pentane (2×10 mL). The obtained solid was dried under vacuum to furnish 130 mg (78%) of the title compound. [1H-NMR (CDCl3, 300 MHz) δ 7.58-6.95 (m, 5H), 5.25 (s, 2H), 4.15 (s, 3H); LCMS RtA=1.681 min; [M+H]+=370.1]
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2([OH:21])[CH2:20][CH2:19][C:14]3(OCC[O:15]3)[CH2:13][CH2:12]2)=[N:9][CH:10]=1)[CH3:3].Cl.C([O-])(O)=O.[Na+]>C1COCC1>[CH3:3][N:2]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2([OH:21])[CH2:20][CH2:19][C:14](=[O:15])[CH2:13][CH2:12]2)=[N:9][CH:10]=1)[CH3:1]
Reactant: CN(C)Cc1ccc(C2(O)CCC3(CC2)OCCO3)nc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)Cc1ccc(C2(O)CCC(=O)CC2)nc1
Reaction time: 2 h
Yield: 51.4 %

Procedure:
8-{5-[(Dimethylamino)methyl]pyridin-2-yl}-1,4-dioxaspiro[4,5]decan-8-ol (0.85 g, 2.9 mmol) was dissolved in 10 mL of THF and 10 mL of 2 N HCl solution was added. After being stirred for two hours, the reaction mixture was neutralized to pH˜8-9 by addition of a saturated NaHCO3 aqueous solution and extracted twice using EtOAc. The combined extracts were dried and concentrated to obtain 0.37 g of white solid (51% yield), MS: 249.2 (M++1).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:23][CH2:22][C:21]([C:31]([O:33]C)=[O:32])=[CH:20][C:19]=3[CH:35]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CO.C1COCC1>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:23][CH2:22][C:21]([C:31]([OH:33])=[O:32])=[CH:20][C:19]=3[CH:35]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.2 %

Procedure:
In methanol (25 ml) and THF (25 ml) was dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-1-phenyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.37 g). To the solution was added 1N sodium hydroxide solution (7.5 ml), and the mixture was stirred at room temperature overnight, concentrated, neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated to give 7-[4-(2-butoxyethoxy)phenyl]-1-phenyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.27 g) as yellow crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.C(N(C(C)C)C(C)C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C.O>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C@@H:12]([CH:13]([CH3:14])[CH3:15])[C:16]([N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1COCCN1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.2 %

Procedure:
To a solution of N-[(benzyloxy)carbonyl]-L-valine (1.26 g) and morpholine (0.479 g) and N-ethyl-N-(1-methylethyl)propan-2-amine (0.711 g) in DMF (20 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.90 g) at room temperature. The reaction mixture was stirred at room temperature overnight, the reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate/hexane, and the insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure to give the title compound (1.53 g).
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:9][C:10]1[CH:24]=[CH:23][CH:22]=[CH:21][C:11]=1[C:12]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)=[O:13]>C(OC)(C)(C)C>[F:9][C:10]1[CH:24]=[CH:23][CH:22]=[CH:21][C:11]=1[C:12]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[OH:13]
Reactant: O=C(c1ccc(F)cc1)c1ccccc1F
Reactant: Br[Mg]c1ccccc1
Solvent: COC(C)(C)C
Product: OC(c1ccccc1)(c1ccc(F)cc1)c1ccccc1F
Temperature: 25 °C

Procedure:
Phenylmagnesium bromide (1.83 mL, 5.5 mmol) was added dropwise to a tirring solution of 2,4′-difluorobenzophenone (1.09 g, 5.0 mmol) in t-butylmethyl ether (12 mL) at room temperature (“rt,”˜25° C.). After the addition was complete the reaction was heated at reflux for 3 h. The solution was cooled to rt and was poured in to ice cold 1.0 M HCl (aq) (20 mL). The organics were extracted with EtOAc (3×10 mL) and dried (Na2SO4). Concentration under reduced pressure gave the desired product (2-fluorophenyl)-(4-fluorophenyl)phenylmethanol as a pale brown oil which was used in the next reaction without any further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].[CH2:36](Br)[CH:37]=[CH2:38]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH2:38][CH:37]=[CH2:36])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]
Reactant: COc1cc2c(cc1O)CCN(CC(=O)NCc1ccccc1)C2Cc1ccc(OC)c(OC)c1
Reactant: C=CCBr
Product: C=CCOc1cc2c(cc1OC)C(Cc1ccc(OC)c(OC)c1)N(CC(=O)NCc1ccccc1)CC2

Procedure:
prepared by reaction of 2-[l-(3,4-dimethoxy-benzyl)-6-hydroxy-7-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide with allyl bromide