Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:4]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[N:5][C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][C:8]=1[CH:9]([CH3:11])[CH3:10])#[CH:2].[I:25]I>C([SnH](CCCC)CCCC)CCC.CCOCC.CC(N=NC(C#N)(C)C)(C#N)C>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:4]2[C:3](/[CH:1]=[CH:2]/[I:25])=[C:8]([CH:9]([CH3:11])[CH3:10])[CH:7]=[C:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:5]=2)=[CH:19][CH:20]=1
Reactant: II
Reactant: C#Cc1c(C(C)C)cc(-c2ccccc2)nc1-c1ccc(F)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: CCOCC
Product: CC(C)c1cc(-c2ccccc2)nc(-c2ccc(F)cc2)c1/C=C/I
Temperature: 120 °C
Reaction time: 2.5 h
Yield: 49 %

Procedure:
A mixture of 3-Ethynyl-2-(4-fluorophenyl)-4-(1-methylethyl)-6-phenylpyridine (700 mg, 2.22 mmol) (the preparation of which is described in Example 14) and AIBN (11 mg) in tri-n-butylstannyl hydride (1.40 ml) was rapidly heated to 120° C. After 5 minutes of heating, the temperature of the reaction was raised to 140° C. and approximately 12 mg of AIBN was added to the reaction mixture every 0.5 hour thereafter. After 2.5 hours, the mixture was cooled to room temperature, diluted with Et2O (20 ml) and treated with solid I2 (2.00 gm, 7.9 mmol). The dark reaction mixture was stirred for one hour, then quenched with 60 ml saturated NaHCO3 containing 4 gm Na2SO3. The layers were shaken and separated. The ethereal layer was washed with brine, dried (Na2 SO4), filtered and stripped to yield a yellow oil. The oil was chromatographed twice (Merck SiO2, 5% EtOAc in hexane (1st) then 3% EtOAc in hexane (2nd)) to (E)-2-(4-Fluorophenyl)-3-(2-iodoethenyl)-4-(1-methylethyl)-6-phenyl-pyridine as a foam which solidified (671 mg). Recrystallization of the solid from hot hexane gave 482 mg of (E)-2-(4-Fluorophenyl)-3-(2-iodoethenyl)-4-(1-methylethyl)-6-phenyl-pyridine. An additional 100 mg of 2 was obtained from the mother liquor to give a total of 582 mg (59%) product.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[Br:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19]Br)=[C:15]([F:21])[CH:14]=1.C(=O)([O-])[O-].[K+].[K+].CO>CN(C=O)C.O>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][O:8][C:6]2[CH:5]=[CH:4][C:3]([C:9](=[O:11])[CH3:10])=[C:2]([OH:1])[CH:7]=2)=[C:15]([F:21])[CH:14]=1
Reactant: CC(=O)c1ccc(O)cc1O
Reactant: Fc1cc(Br)ccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: CC(=O)c1ccc(OCc2ccc(Br)cc2F)cc1O
Yield: 75.4 %

Procedure:
1-(2,4-dihydroxyphenyl)ethanone (25.3 g, 0.17 mol) and 4-bromo-1-bromomethyl-2-fluorobenzene (44.6 g, 0.17 mol) were dissolved in DMF (150 mL). Potassium carbonate (11.8 g, 0.09 mol) was added to the solution under ice-cooled conditions, and the mixture was stirred under ice-cooled conditions and further stirred at room temperature for 12 hours. Again, potassium carbonate (11.8 g, 0.09 mol) was added to the mixture under ice-cooled conditions, and the mixture was stirred under ice-cooled conditions for 30 minutes and further stirred at room temperature for 12 hours. Methanol (100 mL) was added to this reaction solution, and the mixture was stirred at 80° C. for 1 hour. Thereafter, water (150 mL) was added to the mixture, and precipitated crystals were filtered and washed with methanol. The crystals were vacuum-dried at 60° C. for 2 hours, yielding 1-[4-(4-bromo-2-fluorobenzyloxy)-2-hydroxyphenyl]ethanone (43.5 g, yield: 75%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:17]([NH2:18])=[CH:16][C:15]([C:19](=[O:24])[NH:20][CH:21]3[CH2:23][CH2:22]3)=[CH:14][N:13]=2)[CH2:8][CH2:7]1)[CH3:2].[Cl:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](Cl)=[O:31]>C(#N)C>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:17]([NH:18][C:30](=[O:31])[C:29]3[CH:33]=[CH:34][CH:35]=[C:27]([Cl:26])[CH:28]=3)=[CH:16][C:15]([C:19](=[O:24])[NH:20][CH:21]3[CH2:22][CH2:23]3)=[CH:14][N:13]=2)[CH2:8][CH2:7]1)[CH3:2]
Reactant: CCOC(=O)CC1CCN(c2ncc(C(=O)NC3CC3)cc2N)CC1
Reactant: O=C(Cl)c1cccc(Cl)c1
Solvent: CC#N
Product: CCOC(=O)CC1CCN(c2ncc(C(=O)NC3CC3)cc2NC(=O)c2cccc(Cl)c2)CC1
Reaction time: 8 h
Yield: 52.7 %

Procedure:
A mixture of 0.39 g (0.90 mmol) of (3′-amino-5′-cyclopropylcarbamoyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-acetic acid ethyl ester in acetonitrile (5 mL) is treated with 0.14 mL (1.1 mmol) of 3-chlorobenzoyl chloride. The mixture is stirred overnight and then concentrated under reduced pressure. The residue is taken up into water and extracted with ethyl acetate. The combined organic phase is washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by flash silica gel chromatography to provide 0.23 g (52%) of [3′-(3-chloro-benzoylamino)-5′-cyclopropylcarbamoyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-acetic acid ethyl ester as a colorless foam.
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][O:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:32])([F:31])[C:15]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])([OH:22])[CH2:16][N:17]3[CH:21]=[N:20][N:19]=[N:18]3)=[N:12][CH:13]=2)=[C:4](F)[CH:3]=1.BrCC1C=CC(Cl)=CC=1>>[Cl:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][O:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:32])([F:31])[C:15]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])([OH:22])[CH2:16][N:17]3[CH:21]=[N:20][N:19]=[N:18]3)=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: OC(Cn1cnnn1)(c1ccc(F)cc1F)C(F)(F)c1ccc(OCc2ccc(Cl)cc2F)cn1
Agent: Clc1ccc(CBr)cc1
Product: OC(Cn1cnnn1)(c1ccc(F)cc1F)C(F)(F)c1ccc(OCc2ccc(Cl)cc2)cn1

Procedure:
Compound 4 was prepared in a similar manner to compound 1 from 1-(bromomethyl)-4-chlorobenzene to afford a syrup (0.04 g, 0.08 mmol, 28.7%). 1H NMR (500 MHz, CDCl3): δ 8.73 (s, 1H), 8.23 (d, J=2.0 Hz, 1H), 7.51 (d, J=8.5 Hz, 2H), 7.40 (d, J=8.5 Hz, 2H), 7.34-7.29 (m, 2H), 7.28 (dd, J=9.0, 3.0 Hz, 1H), 6.77-6.73 (m, 1H), 6.67 (t, J=7.0 Hz, 1H), 5.55 (d, J=14 Hz, 1H), 5.09 (s, 2H), 5.08 (d, J=14.5 Hz, 2H). MS (ESI): m/z 494.1 [M++1]. HPLC: 99.43%.
Reaction SMILES: Cl[CH:2]1[CH:11]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:10]2[CH2:21][CH2:22][CH:3]1[C:4]1[C:9]2=[CH:8][CH:7]=[CH:6][CH:5]=1.C1CCN2C(=NCCC2)CC1.Cl>C1COCC1>[C:15]1([S:12]([C:11]2[CH:10]3[CH2:21][CH2:22][CH:3]([CH:2]=2)[C:4]2[C:9]3=[CH:8][CH:7]=[CH:6][CH:5]=2)(=[O:14])=[O:13])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=S(=O)(c1ccccc1)C1C2CCC(c3ccccc32)C1Cl
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: O=S(=O)(C1=CC2CCC1c1ccccc12)c1ccccc1
Reaction time: 0.5 h
Yield: 97.8 %

Procedure:
A solution of 0.3 g (0.91 mmol) of the obtained 2-chloro-1,2,3,4-tetrahydro-3-phenylsulfonyl-1,4-ethanonaphthalene and 15 ml of anhydrous THF was cooled to 0° C., added with 2.5 ml of 1,8-diazabicyclo[5.4.0]-7-undecene and stirred for 30 minutes. The solution is then added with a dilute hydrochloric acid solution, extracted with chloroform, washed with distilled water, an aqueous saturated sodium bicarbonate solution and saturated saline and dried with anhydrous sodium sulfate. The product was purified with silica gel column chromatography (chloroform) to obtain 1,4-dihydro-2-phenylsulfony-1,4-ethanonaphthalene (0.264 g, 0.89 mmol, yield: 98%).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[I-].C[S+](C)(C)=O.[O:13]1[CH2:18][CH2:17][CH2:16][O:15][CH:14]1[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[S:26][C:27]3[CH:33]=[C:32]([C:34]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=4)=[CH2:35])[CH:31]=[CH:30][C:28]=3[N:29]=2)=[C:21]([F:42])[CH:20]=1.CCOC(C)=O>CS(C)=O.C1COCC1>[O:15]1[CH2:16][CH2:17][CH2:18][O:13][CH:14]1[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[S:26][C:27]3[CH:33]=[C:32]([C:34]4([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=5)[CH2:1][CH2:35]4)[CH:31]=[CH:30][C:28]=3[N:29]=2)=[C:21]([F:42])[CH:20]=1
Reactant: CC(C)(C)[O-]
Reactant: C=C(c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2c1)c1ccccn1
Agent: C[S+](C)(C)=O
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: Fc1cc(C2OCCCO2)ccc1-c1nc2ccc(C3(c4ccccn4)CC3)cc2s1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Potassium t-butoxide (36 mg, 0.32 mmol) was added to a solution of trimethyl-sulfoxonium iodide (440 mg, 0.48 mmol) in DMSO to make a 1M solution of ylide. This reaction mixture was stirred for 10 min at RT, then a portion of it (0.64 mL, 0.64 mmol) was added to a solution of 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-6-(1-(pyridine-2-yl)vinyl)-benzo[d]thiazole (134 mg, 0.32 mmol) in THF (0.5 mL). The reaction mixture was stirred overnight, EtOAc was added, and the mixture was washed with water several times, then dried over MgSO4. After concentrating under vacuum, the resulting oil was purified by silica gel chromatography to give 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-6-(1-(pyridine-2-yl)-cyclopropyl)benzo[d]thiazole. MS (ESI) m/z: Calculated: 432.1; Observed: 433.1 (M++1).
Reaction SMILES: CO[C:3]([C:5]1[C:10](=[O:11])[N:9]([CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[N:8]2[CH:19]=[C:20]([Cl:22])[CH:21]=[C:7]2[C:6]=1[OH:23])=[O:4].[NH2:24][C@H:25]([C:27]([OH:29])=[O:28])[CH3:26].C[O-].[Na+]>>[Cl:22][C:20]1[CH:21]=[C:7]2[C:6]([OH:23])=[C:5]([C:3]([NH:24][C@@H:25]([CH3:26])[C:27]([OH:29])=[O:28])=[O:4])[C:10](=[O:11])[N:9]([CH2:12][C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[N:8]2[CH:19]=1
Reactant: COC(=O)c1c(O)c2cc(Cl)cn2n(Cc2cccnc2)c1=O
Reactant: C[C@H](N)C(=O)O
Agent: C[O-]
Agent: [Na+]
Product: C[C@H](NC(=O)c1c(O)c2cc(Cl)cn2n(Cc2cccnc2)c1=O)C(=O)O

Procedure:
Prepared according to the reaction condition used in Example 19 step a) from 6-chloro-4-hydroxy-2-oxo-1-pyridin-3-ylmethyl-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid methyl ester, L-alanine and NaOMe. ESI (m/z): 391 (M+H)+.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[OH-].[K+].C1(C)C=CC(S(O[CH2:21][CH:22]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH3:23])(=O)=O)=CC=1>C(O)C>[CH2:25]([O:24][CH:22]([CH3:21])[CH2:23][O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: Oc1ccc(O)cc1
Reactant: CCCCCCCCCCCCOC(C)COS(=O)(=O)c1ccc(C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCCCOC(C)COc1ccc(O)cc1
Reaction time: 2.5 h

Procedure:
11.1 g of hydroquinone, 3.1 g of 85% KOH and 100 ml of ethanol were mixed and the reaction was carried out for 2.5 hours. 10.7 g of (2'-dodecyloxypropyl) p-toluenesulfonate was added dropwise and after the reaction was carried out at 60° C. for 3 hours and by heating under reflux for 7.0 hours, ethanol was evaporated. The residue was diluted with 200 ml of water, acidified with a small amount of hydrochloric acid and then extracted with 500 ml of hexane, followed by recrystallization. Yield: 1.1 g (12%). Optical rotation [α]D26° =-8.6°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:21]=[C:20]2[C:11]([N:12]3[C:17]([CH2:18][O:19]2)=[N:16][NH:15][C:14](=[O:22])[C@H:13]3[CH3:23])=[CH:10][CH:9]=1.C1C(=O)N([Br:31])C(=O)C1>C(O)(C(F)(F)F)=O>[Br:31][C:9]1[CH:10]=[C:11]2[C:20](=[CH:21][C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])[O:19][CH2:18][C:17]1[N:12]2[C@H:13]([CH3:23])[C:14](=[O:22])[NH:15][N:16]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: C[C@@H]1C(=O)NN=C2COc3cc(-c4ccccc4F)ccc3N21
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1C(=O)NN=C2COc3cc(-c4ccccc4F)c(Br)cc3N21
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.1 %

Procedure:
To a solution of (R)-7-(2-fluoro-phenyl)-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (2.4 g, 7.71 mmol) in TFA (20 mL) was added NBS (1.37 g, 7.71 mmol) in portions. The reaction mixture was stirred at ambient temperature for 3 h then concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 10-50% EtOAc in petroleum ether) to give (R)-6-bromo-7-(2-fluoro-phenyl)-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (2.2 g, 73%) as a colorless solid. 1H NMR (400 MHz, CDCl3) δ 8.23 (brs, 1H), 7.45-7.36 (m, 1H), 7.30-7.11 (m, 5H), 6.99 (s, 1H), 4.74-4.69 (m, 1H), 4.69-4.55 (m, 2H), 1.58 (d, J=6.8 Hz, 3H).
Reaction SMILES: [C:1]([C:3](=[C:7](SC)[S:8][CH3:9])[C:4]([NH2:6])=[O:5])#[N:2].FC(F)(F)C(O)=O.[CH:19]1([NH:22][C:23](=[O:33])[C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([NH:31][NH2:32])[CH:25]=2)[CH2:21][CH2:20]1.C(N(C(C)C)CC)(C)C>C(O)C>[NH2:2][C:1]1[N:31]([C:26]2[CH:25]=[C:24]([C:23](=[O:33])[NH:22][CH:19]3[CH2:21][CH2:20]3)[CH:29]=[CH:28][C:27]=2[CH3:30])[N:32]=[C:7]([S:8][CH3:9])[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NN
Reactant: CSC(SC)=C(C#N)C(N)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: CSc1nn(-c2cc(C(=O)NC3CC3)ccc2C)c(N)c1C(N)=O
Temperature: 65 °C

Procedure:
To a solution of 2-cyano-3,3-bis-methylsulfanyl-acrylamide 12 (100 mg, 0.574 mmol) in ethanol (5 ml) was added N-cyclopropyl-3-hydrazino-4-methyl-benzamide trifluoroacetic acid salt (0.183 g, 0.574 mmol) and diisopropylethylamine (0.100 ml, 0.574 mmol). The mixture was heated to 65° C. for 18 h. The mixture was cooled to room temperature. Solvents were removed in vacuo. EtOAc was added to the residue and a solid precipitated. The solid was collected on a fitted funnel and was washed with EtOAc and ether to give the desired 5-amino-1-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-3-methylsulfanyl-1H-pyrazole-4-carboxylic acid amide 13. HPLC (4 minute 10-90 gradient) tR 1.98 min; MS m/z 439.08 [M+H]+; 1H NMR (DMSO-d6, 500 MHz) δ 8.47 (d, J=3.7, 1H), 7.90 (d, J=7.9, 1 H), 7.78 (s, 1H), 7.49 (d, J=8.0, 1H), 6.81 (bs, 2H), 6.30 (s, 2H), 2.86 (m, 1H), 2.45 (s, 3H), 2.11 (s, 3H), 0.68 (m, 2H), 0.57 (m, 2H) ppm.
Reaction SMILES: [N:1](=[C:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1)O.[C:13](OC(=O)C)(=[O:15])[CH3:14].[O:20]1CCCC1>[Pd]>[C:13]([NH:1][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]1=[O:20])(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: C1CCOC1
Reactant: ON=C1CCc2ccccc2C1
Agent: [Pd]
Product: CC(=O)NC1CCc2ccccc2C1=O

Procedure:
A slurry of 2-oximino-3,4-dihydronaphthalen-[1(2H)-one (8.75 gm, 0.05 m) acetic anhydride (25 ml), tetrahydrofuran (150 ml) and Pd/C (10%, 500 mg) was hydrogenated on a Parr apparatus for 3 hours. The catalyst was removed by filtration through diatomaceous earth. The organic solvents were evaporated under reduced pressure (20 mm) to yield the product as an oil, which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:32][CH3:33])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[N:28]=[C:27]([C:29](O)=[O:30])[CH:26]=[CH:25][CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.[Br:64][C:65]1[CH:66]=[C:67]([CH2:73][NH2:74])[CH:68]=[CH:69][C:70]=1[O:71][CH3:72]>ClCCl>[Br:64][C:65]1[CH:66]=[C:67]([CH2:73][NH:74][C:29]([C:27]2[CH:26]=[CH:25][CH:24]=[C:23]([C:21]([NH:20][CH2:19][C:10]3[C:11]([NH:12][CH:13]4[CH2:14][CH2:15][O:16][CH2:17][CH2:18]4)=[C:6]4[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]4=[N:8][C:9]=3[CH2:32][CH3:33])=[O:22])[N:28]=2)=[O:30])[CH:68]=[CH:69][C:70]=1[O:71][CH3:72]
Reactant: COc1ccc(CN)cc1Br
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)O)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(OC)c(Br)c2)n1
Reaction time: 1.5 h
Yield: 121.5 %

Procedure:
To a suspension of 6-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-2-pyridinecarboxylic acid (30 g, 66.3 mmol) in a 1 L round-bottom flask in dichloromethane (DCM) (300 mL) was added triethylamine (46.2 mL, 331 mmol) giving a solution to which was added TBTU (31.9 g, 99 mmol). The mixture became cloudy and was then stirred at room temperature under nitrogen for 5 min when 1-[3-bromo-4-(methyloxy)phenyl]methanamine hydrochloride (18.42 g, 72.9 mmol) was added. After 1.5 h the reaction was worked up. The mixture was partitioned between dichloromethane and water and the aqueous layer extracted well with dichloromethane. The combined organics were washed with saturated sodium bicarbonate, brine, dried (MgSO4), filtered and evaporated to give 52.41 g (121%) of a golden foam. The crude product was purified on a 750 g Companion XL silica cartridge, eluting with 20-100% of {1% MeOH in EtOAc) in dichloromethane over 12 column volumes. The fractions were checked by HPLC and product fractions were combined and solvent evaporated to give 30.15 g (˜65%) of a cream foam that lab HPLC showed to be 97.2% pure (ret time 2.11 min) LC-MS m/z 650, 652 (M+H)+, 1.03 min (ret time).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[C:17]([CH2:18][OH:19])=[C:16]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.C(N(CC)CC)C>ClCCl.CS(C)=O>[Cl:7][C:8]1[C:17]([CH:18]=[O:19])=[C:16]([C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1
Reactant: OCc1c(Cl)nc2ccccc2c1-c1ccc(F)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=Cc1c(Cl)nc2ccccc2c1-c1ccc(F)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 90.5 %

Procedure:
To a solution of oxalyl chloride (2.88 ml, 1.3 equivalents), in 25 ml of dichloromethane at -78° C. under nitrogen is added dropwise a solution of dimethylsulfoxide (DMSO) (4.70 ml, 2.6 equivalents) in 25 ml of dichloromethane. After addition, the mixture is stirred for 15 minutes at -78° C. and then a solution of 2-chloro-4-(4-fluorophenyl)-3-quinolinemethanol (7.30 g) in 50 ml dichloromethane and 20 ml dimethyl sulfoxide is added dropwise. The resulting mixture is stirred at -78° C. for one hour and then quenched by adding triethylamine (17.7 ml, 5.0 equivalents), and removing the cooling bath. A saturated aqueous solution of ammonium chloride is added. The organic layer is separated, washed with water, dried (magnesium sulfate), and evaporated to give 6.56 g of 2-chloro-4-(4-fluorophenyl)-3-quinolinecarboxaldehyde as a yellow solid; mp 168°-169.5° C.; 1H NMR (chloroform-d): δ 10.25 (s, 1H), 8.12 (d, 1H), 7.91-7.83 (m, 1H), 7.57-7.53 (m, 2H), 7.36-7.22 (m, 4H) ppm.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]([CH:14]([CH3:16])[CH3:15])[C:12](=[O:17])[O:11]C2=O)=[CH:5][CH:4]=1.O(C1N=C(CO)C=CC=1)C1C=CC=CC=1>>[F:1][C:2]([F:19])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C@H:13]([C:12]([OH:17])=[O:11])[CH:14]([CH3:16])[CH3:15])=[CH:5][CH:4]=1
Reactant: CC(C)C1C(=O)OC(=O)N1c1ccc(C(F)(F)F)cc1
Agent: OCc1cccc(Oc2ccccc2)n1
Product: CC(C)[C@H](Nc1ccc(C(F)(F)F)cc1)C(=O)O

Procedure:
In the same way, 3-(4-trifluoromethylphenyl)-4-isopropyloxazolidine-2,5-dione is reacted with (6-phenoxy-2-pyridyl)methanol to give the (6-phenoxy-2-pyridyl)methyl ester of N-(4-trifluoromethylphenyl)valine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:29])[CH2:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH2:27])[CH:22]=3)=[C:16]([F:28])[CH:15]=2)=[O:12])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:37]1([C:40](Cl)=[O:41])[CH2:39][CH2:38]1.[OH-].[Na+]>CN(C)C=O.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:29])[CH2:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:27][C:40]([CH:37]4[CH2:39][CH2:38]4)=[O:41])[CH:22]=3)=[C:16]([F:28])[CH:15]=2)=[O:12])=[CH:6][CH:7]=1
Reactant: Nc1cc(Oc2ccc(NC(=O)CC(=O)Nc3ccc(F)cc3)cc2F)ccn1
Reactant: O=C(Cl)C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(CC(=O)Nc1ccc(Oc2ccnc(NC(=O)C3CC3)c2)c(F)c1)Nc1ccc(F)cc1
Reaction time: 1 h
Yield: 53 %

Procedure:
N-(4-Fluorophenyl)-N′-[4-(2-aminopyridin-4-yloxy)-3-fluorophenyl]malonamide (34 mg) was dissolved in N,N-dimethylformamide (0.5 ml), and then triethylamine (0.047 ml) and cyclopropanecarbonyl chloride (0.016 ml) were added dropwise thereto under a nitrogen atmosphere at room temperature, followed by stirring for 1 hr. To the reaction mixture were added a 1 N aqueous solution of sodium hydroxide (1.5 ml) and methanol (1.0 ml), followed by stirring and extracting with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of ammonium chloride in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (FUJI Silysia NH, eluent; ethyl acetate). Fractions containing the target compound were concentrated to give a residue, which was then dried in vacuum to provide the titled compound (21.1 mg, 53%) as white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([N:12]1[CH2:17][CH2:16][C:15]2[S:18][CH:19]=[CH:20][C:14]=2[CH2:13]1)[C:9](N)=[O:10].OS(O)(=O)=O.[C:26](=O)([O-])[O-:27].[Na+].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([N:12]1[CH2:17][CH2:16][C:15]2[S:18][CH:19]=[CH:20][C:14]=2[CH2:13]1)[C:9]([O:27][CH3:26])=[O:10]
Reactant: O=C([O-])[O-]
Reactant: NC(=O)C(c1ccccc1Cl)N1CCc2sccc2C1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@H](c1ccccc1Cl)N1CCc2sccc2C1
Temperature: -2.5 °C
Reaction time: 0.5 h

Procedure:
5 g of (+)-(2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetamide was dissolved in 35 ml methanol and the solution was chilled to 0 to −5° C. 15 mL (0.28 mole) of conc. H2SO4 (98%) was added slowly in 1 hr maintaining the temperature till −5° C. After the completion of addition the reaction mixture was stirred at room temperature for 30 min. The solution was refluxed at 60° C. for 36 hrs. The reaction mixture was cooled to room temperature and the solvent was distilled off under reduced pressure. The residue was added to 200 mL chilled water was added and cooled to −5° C. The pH of reaction mixture was adjusted between 9 to 10 using aq. sodium carbonate. The residue was extracted with 100 mL ethyl acetate. The organic layer was dried over anhydrous Na2SO4, and evaporated under vacuum. The combined eluent was evaporated at reduced pressure to yield 3.2 g of purified product purified by column chromatography, using hexane: ethyl acetate (9:1) as eluent.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[N+:8]([C:11]1[CH:21]=[CH:20][C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[CH:12]=1)([O-:10])=[O:9].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:6]([O:5][C:3]([CH2:2][N:15]1[C:14]2[CH:20]=[CH:21][C:11]([N+:8]([O-:10])=[O:9])=[CH:12][C:13]=2[O:18][CH2:17][C:16]1=[O:19])=[O:4])[CH3:7]
Reactant: CCOC(=O)CBr
Reactant: O=C1COc2cc([N+](=O)[O-])ccc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CN1C(=O)COc2cc([N+](=O)[O-])ccc21
Yield: 71.4 %

Procedure:
Ethyl bromoacetate (18.4 g) was added dropwise at a temperature of 30° C. to 40° C. to a mixture of 7-nitro-2H-1,4-benzoxazin-3(4H)-one (19.4 g), potassium carbonate (15.2 g) and acetonitrile (100 ml), the mixture was refluxed under heating for 3 hours. When the reaction was completed, the liquor was filtered, the filtrate was distilled. Recrystallization of the resulting solid from toluene-hexane gave the desired 4-ethoxycarbonylmethyl-7-nitro-2H-1,4-benzoxazin-3(4H)-one (20 g). mp. 120.5°-121.5° C.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([CH2:12][C:13]([OH:15])=O)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]([O:20][C:21](=[O:25])[C@H:22]([CH3:24])[NH2:23])[CH:17]([CH3:19])[CH3:18]>>[CH2:16]([O:20][C:21](=[O:25])[C@H:22]([CH3:24])[NH:23][C:13](=[O:15])[CH2:12][C:10]1[S:9][N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:11]=1)[CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)COC(=O)[C@H](C)N
Reactant: O=C(O)Cc1nc(-c2ccccc2)ns1
Product: CC(C)COC(=O)[C@H](C)NC(=O)Cc1nc(-c2ccccc2)ns1

Procedure:
Following General Procedure I′ above, and using (3-phenyl-1,2,4-thiadiazol-5-yl)acetic acid (CAS# 90771-06-5) and alanine iso-butyl ester (prepared following General Procedure J′ above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.