Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH3:23])[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28]([NH2:30])=[O:29].O.[C:35]([OH:39])(=[O:38])[CH:36]=O>>[CH2:1]([O:8][C:9]([N:11]([CH3:23])[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH:36]([NH:24][C:25]2[CH:33]=[CH:32][CH:31]=[C:27]([C:28](=[O:29])[NH2:30])[CH:26]=2)[C:35]([OH:39])=[O:38])=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(CCc1ccc(B(O)O)cc1)C(=O)OCc1ccccc1
Reactant: NC(=O)c1cccc(N)c1
Reactant: O=CC(=O)O
Solvent: O
Product: CN(CCc1ccc(C(Nc2cccc(C(N)=O)c2)C(=O)O)cc1)C(=O)OCc1ccccc1
Yield: 76 %

Procedure:
Using a procedure analogous to that used to prepare 2D, 28D (400 mg, 1.3 mmol) was reacted with 3-aminobenzamide and glyoxylic acid monohydrate to afford 28E (661 mg, 76%) as a yellow solid. MS (ESI) m/z 462.32 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[CH:20]=[C:19]([C:21]3[CH:26]=[C:25](S(C)(=O)=O)[CH:24]=[CH:23][N:22]=3)[N:18]([C:31]3[CH:32]=[N:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=3)[N:17]=2)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:39]1[CH2:43][CH2:42][CH2:41][CH2:40]1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[CH:20]=[C:19]([C:21]3[CH:26]=[C:25]([N:39]4[CH2:43][CH2:42][CH2:41][CH2:40]4)[CH:24]=[CH:23][N:22]=3)[N:18]([C:31]3[CH:32]=[N:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=3)[N:17]=2)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(-n2nc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)cc2-c2cc(S(C)(=O)=O)ccn2)cn1
Reactant: C1CCNC1
Product: COc1ccc(-n2nc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)cc2-c2cc(N3CCCC3)ccn2)cn1
Yield: 96 %

Procedure:
A solution of 4-[1-(6-methoxy-3-pyridyl)-5-(4-methylsulfonyl-2-pyridyl)pyrazole-3-carbonyl]piperazine-1-carboxylic acid tert-butyl ester (0.186 g) obtained in Example 48 in pyrrolidine (3.7 mL) was stirred at 100° C. for 17 hours, and then the mixture was cooled in air. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was dried over sodium sulfate anhydrate. After filtration, the solvent was removed under reduced pressure. The residue was purified through silica gel column chromatography (chloroform-methanol), to thereby give the title compound as a solid (0.176 g, 96%).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH2:7])[N:4]([C:8]2[C:17]([F:18])=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=2)[N:3]=1.Br[CH2:20][C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[CH3:1][C:2]1[CH:6]=[C:5]([NH:7][CH2:20][C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=2)[N:4]([C:8]2[C:17]([F:18])=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=2)[N:3]=1
Reactant: Cc1cc(N)n(-c2cc3ccccc3cc2F)n1
Reactant: N#Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(NCc2ccc(C#N)cc2)n(-c2cc3ccccc3cc2F)n1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To the mixture of 3-methyl-1-(3-fluoro-2-naphthyl)-5-amino-1H-pyrazole (200 mg, 0.48 mmol) and 4-bromomethylbenzonitrile (140 mg, 0.72 mmol) in 5 mL DMF was added Cs2CO3 (234 mg, 0.72 mmol). The mixture was stirred for overnight at 50° C. It was diluted with 200 mL EtOAc, washed with water ×2, dried, evaporated in vacuuo, purified using flash column to afford 3-methyl-1-(3-fluoro-2-naphthyl)-5-((4-cyanophenyl)methylamino)-1H-pyrazole. ES-MS: (M+H)+357.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:5][C@@H:6]([CH3:17])[C@@H:7]([C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([F:16])[CH:10]=1)[OH:8])[CH3:4].[CH:18]1[CH:19]=[C:20]([CH2:23][NH:24][C:25]2[C:30]([C:31](O)=[O:32])=[CH:29][C:28]([S:34]([NH2:37])(=[O:36])=[O:35])=[C:27]([Cl:38])[CH:26]=2)[O:21][CH:22]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O.C1C=CC=CC=1.C1(C)C=CC=CC=1>[NH2:37][S:34]([C:28]1[C:27]([Cl:38])=[CH:26][C:25]([NH:24][CH2:23][C:20]2[O:21][CH:22]=[CH:18][CH:19]=2)=[C:30]([CH:29]=1)[C:31]([O:1][CH2:2][C@H:3]([NH:5][C@H:6]([CH3:17])[C@H:7]([C:9]1[CH:10]=[C:11]([F:16])[CH:12]=[C:13]([F:15])[CH:14]=1)[OH:8])[CH3:4])=[O:32])(=[O:35])=[O:36]
Reactant: NS(=O)(=O)c1cc(C(=O)O)c(NCc2ccco2)cc1Cl
Reactant: C[C@H](CO)N[C@@H](C)[C@H](O)c1cc(F)cc(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Product: C[C@H](COC(=O)c1cc(S(N)(=O)=O)c(Cl)cc1NCc1ccco1)N[C@H](C)[C@@H](O)c1cc(F)cc(F)c1

Procedure:
The free base of (rac)-(R*,S*)-2-((2-hydroxy-(R)-1-methylethyl)amino)-1-(3,5-difluorophenyl)propanol (21) (0.023 mole) and benzene (30 mL) (or toluene) is added to a round-bottomed flask. Furosemide (5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoic acid (10), (Aldrich) (0.025 mole), benzene (30 mL), and p-toluenesulfonic acid (0.026 mole) catalyst is added to the flask. A Dean-Stark trap is filled with benzene, and the contents of the flask is refluxed with stirring for several hours or until no additional water is collected in the trap. The reaction is cooled, extracted with sodium bicarbonate solution, washed with water, and then with a saturated sodium chloride solution. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo to give crude product, which may be purified by column chromatography on silica gel with hexanes/ethyl acetate as eluent. The fractions that contain pure product may be combined and spin evaporated in vacuo to give a solid that may be recrystallized to give (rac)-(R*,S*)-2-((2-(3,5-difluorophenyl)-2-hydroxy-1-methylethyl)amino)-(R)-2-methylethyl 5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoate (210). [See eg., Sandier et al., Organic Functional Group Preparations, p. 249 (1968)]
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=2)=[C:4]([NH2:15])[CH:3]=1.I[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-].[K+].N1[C:38]2[C:29](=[CH:30][CH:31]=[C:32]3[C:37]=2N=CC=C3)C=CC=1>C1(C)C=CC=CC=1.[Cu]Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([Br:14])=[CH:12][CH:13]=2)=[C:4]([N:15]([C:29]2[CH:38]=[CH:37][CH:32]=[CH:31][CH:30]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:3]=1
Reactant: c1cnc2c(c1)ccc1cccnc12
Reactant: Ic1ccccc1
Reactant: Nc1cc(Br)ccc1-c1ccc(Br)cc1
Agent: Cl[Cu]
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Brc1ccc(-c2ccc(Br)cc2N(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Yield: 835.7 %

Procedure:
4,4′-Dibromo-2-amino-1,1′-biphenyl (16.35 g, prepared according to Libman and Slack (1951) J. Chem. Soc., p. 2588), iodobenzene (26.52 g, 0.13 mol), flake potassium hydroxide (22.4 g, 0.35 mol), 1,10-phenanthroline (0.45 g), copper (I) chloride (0.25 g), and toluene (30 ml) were charged into a flask and stirred at reflux for 15 hours. The dark reaction mixture was cooled to room temperature and diluted with 200 ml of toluene. The toluene solution was washed with DI water, dried with magnesium sulfate, and evaporated. The dark residue obtained was recrystallized trice from hexane/toluene (4:1 volume) to yield 10 grams of white crystals to yield the desired monomer. 1H NMR (CDCl3): δ=6.8–7.5, multiple peaks.
Reaction SMILES: Cl[C:2]1[C:3]([C:11]([NH2:13])=[O:12])=[N:4][C:5]([CH2:9][CH3:10])=[C:6]([Cl:8])[N:7]=1.[F:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][C:21]=1[N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)[NH2:18].C(N(C(C)C)CC)(C)C.CN1CCCC1=O>O>[Cl:8][C:6]1[N:7]=[C:2]([NH:18][C:17]2[CH:19]=[CH:20][C:21]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)=[C:15]([F:14])[CH:16]=2)[C:3]([C:11]([NH2:13])=[O:12])=[N:4][C:5]=1[CH2:9][CH3:10]
Reactant: Nc1ccc(N2CCOCC2)c(F)c1
Reactant: CCc1nc(C(N)=O)c(Cl)nc1Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCc1nc(C(N)=O)c(Nc2ccc(N3CCOCC3)c(F)c2)nc1Cl
Yield: 66.1 %

Procedure:
A mixture of 3,5-dichloro-6-ethylpyrazine-2-carboxamide (600 mg), 3-fluoro-4-(morpholin-4-yl)aniline (500 mg), diisopropylethylamine (880 μL), and N-methylpyrrolidone (2.5 mL) was reacted in a microwave reaction device at 180° C. for 1 hour. After leaving to be cooled, to the reactant was added water, and the precipitated solid was collected by filtration and then washed with ethanol to obtain 5-chloro-6-ethyl-3-{[3-fluoro-4-(morpholin-4-yl)phenyl]amino}pyrazine-2-carboxamide (640 mg) as a yellow solid.
Reaction SMILES: C[C:2]1(C)CC2C=C(C=S(=O)=O)C=CC=2N(CC=C)[S:3]1(=[O:20])=[O:19].[Cl:22][CH2:23][CH2:24][N:25]1C2C=CC(SC)=CC=2C[N:27]([CH:37]([CH3:39])[CH3:38])[S:26]1(=[O:41])=[O:40].Cl[C:43]1[CH:48]=[CH:47][CH:46]=[C:45]([C:49](OO)=O)[CH:44]=1.[OH-].[Na+]>O.C(Cl)(Cl)Cl>[Cl:22][CH2:23][CH2:24][N:25]1[C:46]2[CH:47]=[CH:48][C:43]([S:3]([CH3:2])(=[O:20])=[O:19])=[CH:44][C:45]=2[CH2:49][N:27]([CH:37]([CH3:38])[CH3:39])[S:26]1(=[O:40])=[O:41]
Reactant: C=CCN1c2ccc(C=S(=O)=O)cc2CC(C)(C)S1(=O)=O
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc2c(c1)CN(C(C)C)S(=O)(=O)N2CCCl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)N1Cc2cc(S(C)(=O)=O)ccc2N(CCCl)S1(=O)=O
Reaction time: 0.25 h

Procedure:
A 500 mL 3 necked flask equipped thermometer, pressure equalised dropping funnel, nitrogen bubbler and magnetic stirrer bar was charged with 1-(2-chloroethyl)-3,4-dihydro-3-(1-methylethyl)-6-methylthio-1H-2,1,3-benzothiadiazine-2,2-dioxide (10.0 g, 0.0299 mol) and chloroform (200 ml). To this solution was added in one portion m-chloroperbenzoic acid (20.6 g, ˜4 equivalents, nominal purity 56-86%), this resulted in an exotherm which raised the temperature from 20° C. to 50° C. This solution was then stirred for 15 mins, water (100 ml) was added then 2M sodium hydroxide (100 ml). The organic layer was separated, washed again with 2M sodium hydroxide (100 ml), then water (100 ml) dried (MgSO4), filtered and the filtrate evaporated under reduced pressure to leave a white-cream foam, which was dried at 45° C. in vacuo to yield the product.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[C:17](OCC)(=[O:24])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].N1CCCCC1.C(OC(C)C)(C)C>>[Cl:16][C:13]1[CH:12]=[C:3]2[C:2](=[CH:15][CH:14]=1)[NH:1][C:17](=[O:24])[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:4]2[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: CCOC(=O)CC(=O)OCC
Solvent: C1CCNCC1
Solvent: CC(C)OC(C)C
Product: CCOC(=O)c1c(-c2ccccc2)c2cc(Cl)ccc2[nH]c1=O
Temperature: 170 °C
Yield: 79.3 %

Procedure:
A mixture of 2-amino-5-chlorobenzophenone (6.93 g), diethyl malonate (7.2 g) and piperidine (0.3 ml) was heated at 170° C. for 4 hours. After cooling, isopropyl ether was added to the mixture to obtain crystals of ethyl 6-chloro-1,2-dihydro-2-oxo-4-phenyl-3-quinolinecarboxylate (7.77 g, 79.3%). The crystals was recrystallized from ethanol to give pale-yellowish needles. mp 223°-224° C.
Reaction SMILES: [C:1]([C:4]1[CH:13]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=2[C:23]([F:26])([F:25])[F:24])[C:12]2[C:11](=[O:27])[NH:10][CH:9]=[CH:8][C:7]=2[NH:6][C:5]=1[CH3:28])(=[O:3])[CH3:2].FC(F)(F)S(O[CH2:35][CH3:36])(=O)=O.CO>C1COCC1>[CH2:35]([O:27][C:11]1[N:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[CH:13]([C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=1[C:23]([F:26])([F:25])[F:24])[C:4]([C:1](=[O:3])[CH3:2])=[C:5]([CH3:28])[NH:6]2)[CH3:36]
Reactant: CC(=O)C1=C(C)Nc2cc[nH]c(=O)c2C1c1ccc([N+](=O)[O-])cc1C(F)(F)F
Reactant: CCOS(=O)(=O)C(F)(F)F
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1nccc2c1C(c1ccc([N+](=O)[O-])cc1C(F)(F)F)C(C(C)=O)=C(C)N2
Reaction time: 0.17 h

Procedure:
976 mg (2.48 mmol) of 3-acetyl-2-methyl-4-[4-nitro-2-(trifluoromethyl)phenyl]-4,6-dihydro-1,6-naphthyridin-5(1H)-one are suspended in THF (60 ml), and 3 ml (3 mmol) of N′″-(tert-butyl)-N,N′,N″-tris[tris(dimethylamino)phosphoranylidene]phosphorimide triamide (phosphazene base P4-t-Bu; 1 M in hexane) are added. Then 389 μl (2.97 mmol) of ethyl trifluoromethanesulfonate are added to the dark red solution. The decolorized solution is stirred for a further 10 min and then mixed with methanol and concentrated. The residue is purified by preparative HPLC to result in 240 mg (23% of theory) of the title compound as a white solid.
Reaction SMILES: F[C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[C:9](=[N:19][OH:20])[CH:10]1[CH2:15][CH2:14][N:13]([C:16](=O)[CH3:17])[CH2:12][CH2:11]1.[OH-].[K+].C([C@@H]1[C@@H:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:28][N:27]([C@H:36]([CH:49]2[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]2)[C:37]([O:39]CC2C=CC(OC)=CC=2)=[O:38])[CH2:26]1)=O.[C:55](O)([C:57](F)(F)F)=[O:56].C1(OC)C=CC=CC=1>CCO>[CH2:55]([O:56][C:6]1[CH:5]=[CH:4][C:3]2[C:9]([CH:10]3[CH2:15][CH2:14][N:13]([CH2:16][C@@H:17]4[C@@H:29]([C:30]5[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=5)[CH2:28][N:27]([C@H:36]([CH:49]5[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]5)[C:37]([OH:39])=[O:38])[CH2:26]4)[CH2:12][CH2:11]3)=[N:19][O:20][C:2]=2[CH:7]=1)[CH3:57]
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](c3ccccc3)[C@@H](C=O)C2)cc1
Reactant: CC(=O)N1CCC(C(=NO)c2ccc(F)cc2F)CC1
Reactant: O=C(O)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: COc1ccccc1
Product: CCOc1ccc2c(C3CCN(C[C@H]4CN([C@@H](C(=O)O)C5CCCCC5)C[C@@H]4c4ccccc4)CC3)noc2c1

Procedure:
A solution of 1-(4-((2,4-difluorophenyl)-hydroxyimino-methyl)piperidin-1-yl)ethanone (from Step A) and KOH (45 wt. % solution) in EtOH was refluxed for 24 hours. The products were coupled with of α-(R)-(3-(R)-formyl-4-(S)-phenylpyrrolidin-1-yl)-cyclohexaneacetic acid, 4-methoxybenzyl ester (prepared above as Aldehyde 5) using a procedure analogous to that described in Example 89, Step C. The products were treated with TFA and anisole for 18 hours and concentrated under reduced pressure. The residue was purified by prep HPLC (Zorbax-RX C8 column, 30% CH3CN 15 min. and 100% CH3CN, 20 mL/min., 254 nm) to provide α-(R)-(3-(S)-((4-(6-ethoxy-benzo[d]isoxazol-3-yl)piperidin-1-yl)methyl)-4-(S)-phenylpyrrolidin-1-yl)-cyclohexaneacetic acid: ESI-MS 546 (M+1); HPLC A: 3.01 min.; and α-(R)-(3-(S)-((4-(6-fluoro-benzo[d]isoxazol-3-yl)piperidin-1-yl)methyl)-4-(S)-phenylpyrrolidin-1-yl)-cyclohexaneacetic acid: ESI-MS 520 (M+1); HPLC A: 2.88 min.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Mg].[F:13][C:14]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:15]=1[O:16][C:17]1[C:18]([N+:27]([O-:29])=[O:28])=[CH:19][C:20]([CH3:26])=[C:21]([CH:25]=1)[C:22](Cl)=[O:23].S(=O)(=O)(O)O>CCOCC.C(Cl)(Cl)(Cl)Cl.C(O)C>[F:13][C:14]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:15]=1[O:16][C:17]1[C:18]([N+:27]([O-:29])=[O:28])=[CH:19][C:20]([CH3:26])=[C:21]([CH:25]=1)[C:22]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])=[O:23]
Reactant: Cc1cc([N+](=O)[O-])c(Oc2ccc(F)cc2F)cc1C(=O)Cl
Reactant: CCOC(=O)CC(=O)OCC
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCO
Solvent: CCOCC
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(C(=O)OCC)C(=O)c1cc(Oc2ccc(F)cc2F)c([N+](=O)[O-])cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
A mixture of 5-(2,4-difluorophenoxy)-2-methyl-4-nitrobenzoic acid (1.4 g) and phosphorus pentachloride (1 g) in benzene (10 ml) was stirred for 1 hour at room temperature. The mixture was concentrated under reduced pressure to give an oil of 5-(2,4-difluorophenoxy)-2-methyl-4-nitrobenzoyl chloride (1.6 g). A solution of diethyl malonate (0.88 g) and ethanol (0.5 ml) in ether (5 ml) was added dropwise to a stirred solution of magnesium (132 mg), ethanol (0.2 ml), and carbon tetrachloride (0.3 ml) in ether (5 ml) at room temperature. The mixture was stirred for 1 hour at room temperature and refluxed for 30 minutes. To the resulting mixture was added dropwise a solution of 5-(2,4-difluorophenoxy)-2-methyl-4-nitrobenzoyl chloride (1.6 g) in ether (3 ml) at 5° C. The mixture was stirred for 2 hours at room temperature and refluxed for 1 hour. The reaction mixture was poured into 10% sulfuric acid (40 ml) and extracted with ethyl acetate. The extract was washed with water, dried, and concentrated to give an oil of diethyl 5-(2,4-difluorophenoxy)-2-methyl-4-nitrobenzoylmalonate (2.1 g).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][CH:14]=O)=[C:9]([O:16][CH3:17])[CH:8]=2)=[CH:5][N:4]=[C:3]1[CH3:18].CS(C1[N:24]=[CH:25][C:26]2[CH:32]=[CH:31][N:30]=[C:29]([NH:33][CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[C:27]=2[N:28]=1)(=O)=O>>[CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:24]=[CH:25][C:26]4[CH:32]=[CH:31][N:30]=[C:29]([NH:33][CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[C:27]=4[N:28]=3)=[C:9]([O:16][CH3:17])[CH:8]=2)=[CH:5][N:4]=[C:3]1[CH3:18]
Reactant: CC(C)(C)CNc1nccc2cnc(S(C)(=O)=O)nc12
Reactant: COc1cc(-c2cnc(C)n2C)ccc1NC=O
Product: COc1cc(-c2cnc(C)n2C)ccc1Nc1ncc2ccnc(NCC(C)(C)C)c2n1
Yield: 21 %

Procedure:
The title compound was prepared according to Example 40 using N-(4-(1,2-dimethyl-1H-imidazol-5-yl)-2-methoxyphenyl)formamide (Preparation 55) and 2-(methylsulfonyl)-N-neopentylpyrido[3,4-d]pyrimidin-8-amine (Preparation 47). The residue was purified by silica gel column chromatography eluting with 0-10% MeOH in EtOAc. The residue was purified by passage through a SCX-2 cartridge eluting with 100% MeOH-1M NH3 in MeOH. The residue was diluted with DCM (30 mL) and washed with 0.1M HCl (30 mL), dried (MgSO4) and concentrated in vacuo. The residue was further purified by SCX-2 cartridge eluting with 100% MeOH-1M NH3 in MeOH followed by silica gel column chromatography eluting with 0-7% MeOH in EtOAc to give the title compound (5.5 mg, 21%).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][O:7][C:8]2[CH:14]=[C:13]([CH3:15])[C:11]([NH2:12])=[C:10]([CH3:16])[CH:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:26]([CH2:30][C:31](Cl)=[O:32])([CH3:29])([CH3:28])[CH3:27].O>C(Cl)Cl>[F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][O:7][C:8]2[CH:14]=[C:13]([CH3:15])[C:11]([NH:12][C:31](=[O:32])[CH2:30][C:26]([CH3:29])([CH3:28])[CH3:27])=[C:10]([CH3:16])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)CC(=O)Cl
Reactant: Cc1cc(OCc2ccc(F)cc2)cc(C)c1N
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cc1cc(OCc2ccc(F)cc2)cc(C)c1NC(=O)CC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.7 %

Procedure:
To a solution of 4-(4-fluoro-benzyloxy)-2,6-dimethylaniline (0.20 g, 0.82 mmol) from above and triethylamine (125 mg, 1.24 mmol) in anhydrous methylene chloride (20 ml) was added dropwise tert-butylacetyl chloride (135 mg, 1 mmol) at 0° C. The reaction mixture was stirred at room temperature for 18 hours. Water was added to the reaction mixture, and the mixture was washed with saturated brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ISCO, hexane/EtOAc, 0-40%, 40 min) and recrystallized from hexane/EtOAc (5:1) to give 230 mg (82%) of the white solids. 1H NMR (DMSO-d6, 400 MHz): δ 8.92 (brs, 1H, exchangeable with D20, NH), 7.46 (dd, J=4.7 and 6.4 Hz, 2H), 7.19 (t, J=7.0 Hz, 2H), 6.70 (s, 2H), 5.02 (s, 2H), 2.16 (s, 2H), 2.08 (s, 6H), 1.03 (s, 9H). MS: 344 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)[C:11]([S:24][CH3:25])=[CH:10][N:9]=2)=[CH:4][CH:3]=1.ClCCl.ClC1C=CC=C(C(OO)=[O:37])C=1.[OH2:40]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:22])([F:23])[F:21])[CH:15]=3)[C:11]([S:24]([CH3:25])(=[O:37])=[O:40])=[CH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1cnc(-c2ccc(Cl)cc2)nc1-c1cccc(C(F)(F)F)c1
Reactant: O
Solvent: ClCCl
Product: CS(=O)(=O)c1cnc(-c2ccc(Cl)cc2)nc1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
1.5 g of 2-(4-chlorophenyl)-4-(3-trifluoromethylphenyl)-5-methylmercaptopyrimidine was added to 30 ml of dichloromethane. 2.0 g of m-chloroperbenzoic acid was added to the obtained reaction mixture under cooling in an ice-bath. Then, the resulting mixture was stirred at room temperature for 5 hours. After adding water, the mixture was extracted with dichloromethane. The organic phase was successively washed with a saturated aqueous solution of sodium sulfite and a saturated aqueous solution of sodium hydrogencarbonate. The solvent was distilled away under reduced pressure and the residue was subjected to column chromatography. Thus 1.5 g of 2-(4-chlorophenyl)-4-(3-trifluoromethylphenyl)-5-methanesulfonylpyrimidine was obtained (Compound 113).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].Cl[C:9]1[N:14]=[C:13]([F:15])[C:12]2[O:16][C:17]3[C:22]([C:23]4([C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[C:25]([NH2:32])=[N:24]4)[C:11]=2[CH:10]=1)=[CH:21][C:20]([C:33]1[C:34]([F:39])=[N:35][CH:36]=[CH:37][CH:38]=1)=[CH:19][CH:18]=3.[F:40][C:41]1[CH:46]=[C:45](B(O)O)[CH:44]=[CH:43][N:42]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:15][C:13]1[C:12]2[O:16][C:17]3[C:22]([C:23]4([C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[C:25]([NH2:32])=[N:24]4)[C:11]=2[CH:10]=[C:9]([C:45]2[CH:44]=[CH:43][N:42]=[C:41]([F:40])[CH:46]=2)[N:14]=1)=[CH:21][C:20]([C:33]1[C:34]([F:39])=[N:35][CH:36]=[CH:37][CH:38]=1)=[CH:19][CH:18]=3
Reactant: OB(O)c1ccnc(F)c1
Reactant: NC1=NC2(c3cc(-c4cccnc4F)ccc3Oc3c2cc(Cl)nc3F)c2ccccc21
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Product: NC1=NC2(c3cc(-c4cccnc4F)ccc3Oc3c2cc(-c2ccnc(F)c2)nc3F)c2ccccc21
Temperature: 100 °C
Yield: 48.1 %

Procedure:
A microwave vial was charged with 3-chloro-1-fluoro-7-(2-fluoropyridin-3-yl)spiro[chromeno[2,3-c]pyridine-5,1′-isoindol]-3′-amine 2,2,2-trifluoroacetate (43 mg, 0.077 mmol, step 3), 2-fluoropyridine-4-boronic acid (27.0 mg, 0.192 mmol, Aldrich), bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium(II) (5.43 mg, 7.67 μmol, Aldrich) and potassium phosphate (48.8 mg, 0.230 mmol, Aldrich). The vial was evacuated and backfilled with N2 gas (2×). Dioxane (0.6 mL) and water (0.2 mL) were added, and the vial was heated in the microwave for 30 min at 100° C. The reaction mixture was partitioned between EtOAc and water. The organic phase was separated and the solvent was removed under reduced pressure. The residue was purified by reversed-phase preparative HPLC using a Phenomenex Gemini column, 10 micron, C18, 110 Å, 100×50 mm, 0.1% TFA in CH3CN/H2O, gradient 10% to 100% over 20 min to obtain the title product (23 mg, 0.037 mmol, 48.3% yield) as a light-yellow solid. MS m/z=508.1 [M+H]+. Calculated for C29H16F3N5OC2HF3O2: 621.49 (TFA salt). 1H-NMR (300 MHz, MeOH) δ ppm 7.14 (t, J=1.61 Hz, 1H) 7.30-7.39 (m, 1H) 7.39-7.48 (m, 1H) 7.53-7.70 (m, 3H) 7.72-7.86 (m, 4H) 7.92 (ddd, J=9.94, 7.75, 1.90 Hz, 1H) 8.16 (d, J=4.97 Hz, 1H) 8.22 (d, J=5.41 Hz, 1H) 8.26-8.37 (m, 1H).