Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[NH:4][CH:5]([C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]([F:21])([F:20])[F:19])[CH2:13][CH:12]1[C:22]1[NH:23][CH:24]=[C:25]([C:27]2[CH:32]=[CH:31][C:30](Br)=[CH:29][CH:28]=2)[N:26]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:35][O:36][C:37](=[O:63])[NH:38][CH:39]([C:43]([N:45]1[CH2:49][CH2:48][CH2:47][CH:46]1[C:50]1[NH:51][C:52]([C:55]2[CH:60]=[CH:59][C:58]([C:61]#[CH:62])=[CH:57][CH:56]=2)=[CH:53][N:54]=1)=[O:44])[CH:40]([CH3:42])[CH3:41].C(N(CC)CC)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I.CN(C=O)C>[CH3:35][O:36][C:37](=[O:63])[NH:38][CH:39]([C:43]([N:45]1[CH2:49][CH2:48][CH2:47][CH:46]1[C:50]1[NH:51][C:52]([C:55]2[CH:60]=[CH:59][C:58]([C:61]#[C:62][C:30]3[CH:31]=[CH:32][C:27]([C:25]4[N:26]=[C:22]([CH:12]5[CH2:13][N:14]([CH2:17][C:18]([F:21])([F:19])[F:20])[CH2:15][CH2:16][N:11]5[C:9](=[O:10])[CH:5]([NH:4][C:3]([O:2][CH3:1])=[O:34])[CH:6]([CH3:8])[CH3:7])[NH:23][CH:24]=4)=[CH:28][CH:29]=3)=[CH:57][CH:56]=2)=[CH:53][N:54]=1)=[O:44])[CH:40]([CH3:42])[CH3:41]
Reactant: COC(=O)NC(C(=O)N1CCN(CC(F)(F)F)CC1c1nc(-c2ccc(Br)cc2)c[nH]1)C(C)C
Reactant: C#Cc1ccc(-c2cnc(C3CCCN3C(=O)C(NC(=O)OC)C(C)C)[nH]2)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)NC(C(=O)N1CCN(CC(F)(F)F)CC1c1nc(-c2ccc(C#Cc3ccc(-c4cnc(C5CCCN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)cc3)cc2)c[nH]1)C(C)C
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 8 %

Procedure:
{1-[2-[4-(4-Bromo-phenyl)-1H-imidazol-2-yl]-4-(2,2,2-trifluoro-ethyl)-piperazine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (98.7 mg, 0.181 mmol) was combined with (1-{2-[5-(4-Ethynyl-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (71.2 mg, 0.181 mmol) and Pd(PPh3)4 (21.5 mg, 0.018 mmol) under an argon atmosphere. DMF (degassed with Argon) was added followed by triethylamine (181 mg, 1.8 mmol) and copper(I) iodide (3.5 mg, 0.018 mmol). The mixture was heated at 80° C. After 20 minutes, volatiles were removed in vacuo and the crude material was semi-purified via chromatography on silica gel (eluent EtOAc w MeOH 10%/hexanes) and further purified via RP-HPLC (eluent: water/MeCN w 0.1% TFA) to yield the product [1-(2-{5-[4-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-4-(2,2,2-trifluoro-ethyl)-piperazin-2-yl]-1H-imidazol-4-yl}-phenylethynyl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (12.4 mg): LCMS-ESI+: calc'd for C44H52F3N9O6: 859.9 (M+). Found: 860.5 (M+H+); 1H-NMR: 300 MHz, (MeOH-d4) δ: 7.91-7.68 (m, 10H), 6.06 (m, 2H), 5.24 (m, 1H), 4.43 (m, 1H), 4.23 (d, J=7.8 Hz, 1H), 4.11 (m, 1H), 3.85 (m, 1H), 3.68 (s, 3H), 3.66 (s, 3H), 3.49-3.45 (m, 2H), 3.15-3.02 (m, 3H), 2.77 (m, 1H), 2.58 (m, 1H), 2.29-2.01 (m, 5H), 1.07-0.83 (m, 12H).
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[N:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:13])[CH:6]=1.[Cl-].[NH4+].C(OCC)(=O)C.O1CCCC1>C(O)C.O.[Fe]>[NH2:24][C:22]1[CH:21]=[CH:20][C:3]([O:4][C:5]2[N:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)=[O:13])[CH:6]=2)=[C:2]([F:1])[CH:23]=1
Reactant: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ncn1)N1CCCCC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1ccc(Oc2cc(NC(=O)N3CCCCC3)ncn2)c(F)c1
Temperature: 25 °C
Yield: 94.2 %

Procedure:
Piperidine-1-carboxylic acid [6-(2-fluoro-4-nitrophenoxy)pyrimidin-4-yl]amide (273 mg) was dissolved in ethanol (15 ml)-water (3 ml), and then electrolytic iron powder (275 mg) and ammonium chloride (550 mg) were added thereto, followed by heating under reflux for 30 min. The reaction mixture was cooled down to room temperature, and ethyl acetate-tetrahydrofuran (1:1) was then added thereto, followed by stirring. The reaction mixture was filtered through celite to remove an insoluble portion, which was washed with ethyl acetate and water. The organic layer of the filtrate was washed with water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; hexane:ethyl acetate=1:1 to 1:5). Fractions containing the target compound was concentrated under a reduced pressure, and dried in vacuum to provide the titled compound (235.8 mg, 94.1%) as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[Br:15].[N+](C1C=C(S([O-])(=O)=O)C=CC=1)([O-])=O.[Na+].[OH-].[Na+].Cl>O.C(O)(C)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[Br:15]
Reactant: Nc1ccc(C2=NNC(=O)CC2)cc1Br
Agent: Cl
Agent: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: Nc1ccc(-c2ccc(=O)[nH]n2)cc1Br

Procedure:
3 In a mixture of water and isopropanol (20 : 5) was suspended 0.45 g. of 6-(4-amino-3-bromophenyl)-4,5-dihydro-3(2H)pyridazinone, and to the resulting suspension were added 0.45 g. of sodium m-nitrobenzenesulfonate and 0.27 g. of sodium hydroxide. This mixture was then refluxed with heating for 3.5 hours and allowed to stand to cool. The mixture was neutralized with 6 N hydrochloric acid, and the precipitated yellow crystals were collected by filtration. The so obtained crystals were recrystallized from ethanol - acetone to give 0.4 g. of the desired product of m.p. 266° - 267° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14].C(=O)([O-])[O-].[Na+].[Na+].[N+:21]([C:24]1[CH:25]=[C:26]([CH:29]=[C:30]([N+:32]([O-:34])=[O:33])[CH:31]=1)[CH2:27][OH:28])([O-:23])=[O:22]>CN(C=O)C>[N+:21]([C:24]1[CH:25]=[C:26]([CH:29]=[C:30]([N+:32]([O-:34])=[O:33])[CH:31]=1)[CH2:27][O:28][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])([O-:23])=[O:22]
Reactant: OCCCCCCCCCCCCBr
Reactant: O=[N+]([O-])c1cc(CO)cc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(COCCCCCCCCCCCCO)cc([N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 12 h
Yield: 79.4 %

Procedure:
5.9 g (18.9 mmol) of 12-bromododecanol, 1.06 g (10 mmol) of sodium carbonate, 4.92 g of (25 mmol) of 3,5-dinitrobenzyl alcohol were dissolved in 50 mL of DMF and heated with stirring at 100° C. for 12 hours (under a nitrogen atmosphere). The reaction solution was poured into ice water to precipitate a solid, and the solid was recrystallized with methanol. Thus, 5.73 g (15 mmol) of 12-(3,5-dinitrobenzyloxy)-dodecanol was prepared. (The yield was 79%.)
Reaction SMILES: [N:1]([CH2:4][C:5]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)([CH2:8][CH2:9][O:10]C1CCCCO1)[C:6]#[N:7])=[N+:2]=[N-:3].C(=O)([O-])O.[Na+]>CO.Cl>[N:1]([CH2:4][C:5]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)([CH2:8][CH2:9][OH:10])[C:6]#[N:7])=[N+:2]=[N-:3]
Reactant: N#CC(CCOC1CCCCO1)(CN=[N+]=[N-])c1ccccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: N#CC(CCO)(CN=[N+]=[N-])c1ccccn1
Reaction time: 6 h
Yield: 95.2 %

Procedure:
To a solution of 4.72 g of the compound obtained in Step 3 in 100 ml of methanol was added 40 ml of IN HCl solution, and the resulting mixture was stirred for 6 hours. After the reaction was completed, the reaction solution was neutralized with sodium hydrogen carbonate solution, distilled under reduced pressure to remove methanol therefrom, and extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue thus obtained was purified by a silica gel column chromatography using a mixture of ethyl acetate and n-hexane of 1:2 to obtain 3.24 g of the title compound as an oil.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]=1[C:17]1[CH:22]=[CH:21][C:20]([CH:23]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH3:24])=[CH:19][CH:18]=1.B(Br)(Br)Br.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.C(N(CC)CC)C>ClCCl.O>[OH:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]=1[C:17]1[CH:22]=[CH:21][C:20]([CH:23]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH3:24])=[CH:19][CH:18]=1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(C(C)NC(=O)OC(C)(C)C)cc1
Agent: BrB(Br)Br
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(NC(=O)OC(C)(C)C)c1ccc(-c2c(O)ccc3[nH]c(=O)c4sccc4c23)cc1
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 1-(4-(8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl)ethylcarbamate (0.96 g, 2.1 mmol) in dichloromethane (15 mL) at 0° C. was added BBr3 (1.0 M in methylene chloride, 15 mL, 15 mmol) and the reaction was stirred at that temperature for 1 h and quenched by pouring onto water or ice-water. The precipitate was filtered and suspended in DMF (8 mL). Di-tert-butyl dicarbonate (0.85 g, 3.9 mmol) and triethylamine (1.1 mL, 7.8 mmol) were added and the mixture was stirred at rt for 2 h. Water was added and the precipitate was filtered and purified by column chromatography to afford the desired product as a solid: ESI MS m/z 437 [C24H24N2O4S+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[CH:16]=[N:17][CH:18]=[C:14]2[CH:13]=[CH:12][C:11]=1[C:19]([OH:21])=O.Cl.[NH2:23][O:24][CH2:25][C@@H:26]([OH:28])[CH3:27].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C1COCC1>[OH:28][C@@H:26]([CH3:27])[CH2:25][O:24][NH:23][C:19]([C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH:16]=[N:17][CH:18]=2)[C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[F:1])=[O:21]
Reactant: O=C(O)c1ccc2cncn2c1Nc1ccc(I)cc1F
Reactant: C[C@H](O)CON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C[C@H](O)CONC(=O)c1ccc2cncn2c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 11 %

Procedure:
To a solution of 5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid (130 mg, 0.33 mmol) in THF (1.7 mL) was added (S)-1-aminooxy-propan-2-ol hydrochloride (84 mg, 0.66 mmol), DIPEA (0.23 mL, 1.32 mmol), HOBt (88 mg, 0.66 mmol) and EDCI (126 mg, 0.66 mmol). After 18 hours stirring at ambient temperature, further (S)-1-aminooxy-propan-2-ol hydrochloride (84 mg, 0.66 mmol), DIPEA (0.23 mL, 1.32 mmol), HOBt (88 mg, 0.66 mmol) and EDCI (126 mg, 0.66 mmol) and THF (1.7 mL) were added. The reaction mixture was stirred at ambient temperature for a further 5 hours. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge. The cartridge was then washed with methanol and the desired compound was eluted using a 2M solution of ammonia in methanol. Appropriate fractions were combined and concentrated under reduced pressure and the residue azeotroped with dichloromethane. The resultant residue was subjected to flash chromatography (Si-PPC, gradient 0 to 10%, methanol in dichloromethane) to afford the title compound as a yellow solid (17 mg, 11%). LCMS (method A): RT=6.01 min, [M+H]+=471. 1H NMR (DMSO-d6): 8.07 (1 H, s), 7.58 (1 H, dd, J=10.71, 1.92 Hz), 7.43 (1 H, s), 7.38 (1 H, d, J=9.31 Hz), 7.31-7.28 (1 H, m), 6.89 (1 H, d, J=9.31 Hz), 6.35 (1 H, t, J=8.68 Hz), 3.69-3.60 (1 H, m), 3.45-3.38 (2 H, m), 0.96 (3 H, d, J=6.35 Hz).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([N:13]([CH:21]([CH3:23])[CH3:22])[C:14]1[CH:19]=[N:18][CH:17]=[C:16]([Cl:20])[N:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O.CN([CH:28]=[O:29])C>>[CH2:6]([N:13]([CH:21]([CH3:23])[CH3:22])[C:14]1[N:15]=[C:16]([Cl:20])[C:17]([CH:28]=[O:29])=[N:18][CH:19]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)N(Cc1ccccc1)c1cncc(Cl)n1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CC(C)N(Cc1ccccc1)c1cnc(C=O)c(Cl)n1
Reaction time: 0.25 h
Yield: 70 %

Procedure:
Phosphoryl chloride (5.6 mL) was added dropwise to DMF (12 mL) at 0° C. The mixture was stirred for 15 min, and a solution of N-benzyl-6-chloro-N-(1-methylethyl)pyrazin-2-amine (3.40 g) in DMF (3 mL) was added dropwise thereto. The mixture was stirred at 100° C. for 13 hr, water (50 mL) was added at 0° C., and the mixture was stirred at room temperature for 1 hr. The mixture was extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient: 5→20% ethyl acetate/hexane) to give the title compound (2.42 g, 70%) as a pale-yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]#[N:19])[CH:16]=3)[NH:11][N:10]=2)=[CH:5][CH:4]=1.[OH:20]O.[OH-].[Na+].Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([NH2:19])=[O:20])[CH:16]=3)[NH:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2n[nH]c3ccc(C#N)cc23)cc1
Reactant: OO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(-c2n[nH]c3ccc(C(N)=O)cc23)cc1
Temperature: 50 °C
Yield: 41.6 %

Procedure:
A mixture of 20 mg (0.080 mmol) of 3-(4-methoxyphenyl)-1H-indazole-5-carbonitrile, 0.428 mL of 95% denatured ethanol, 0.021 mL of H20, 0.32 mL of 30% aqueous hydrogen peroxide (aq. H202) and 0.032 mL of 6.0 N aq. NaOH (0.192 mmol, 2.4 equiv.) was heated at 50° C. for 3 h, and then acidified to pH=6.0 with 0.052 mL of 6.0 N 10 aq. HCl. The mixture was extracted with 2×EtOAc. The combined organics were washed with 2× sat. aq. NaHCO3, dried (Na2SO4), filtered, and concentrated affording the title compound (8.9 mg, 41.6% yield): 1H NMR (CDCl3/DMSO-d6) δ 12.5 (br s, 1H), 8.60 (s, 1H), 7.95 (d, 2H), 7.85 (d, 2H), 7.55 (d, 1H), 7.05 (d, 2H), 3.89 (s, 3H); ES-MS (m/z) 268 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4](Cl)[N:3]=1.[CH3:10][O-:11].[Na+]>CO>[NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:11][CH3:10])[N:3]=1
Reactant: C[O-]
Reactant: Nc1cc(Cl)nc(Cl)n1
Agent: [Na+]
Solvent: CO
Product: COc1nc(N)cc(Cl)n1

Procedure:
4-Amino-2,6-dichloropyrimidine (0.5 g.) was added to 30 ml. of a 1% solution of sodium methoxide in methanol. The resultant solution was heated at the reflux temperature for 2 hrs. The methanol was then removed by evaporaion and water was added to the residual oil. The precipitate that formed was filtered off, washed with water and dried at 100° C. at a pressure of 100 mm for 18 hrs. There was thus obtained 4-amino-6-chloro-2-methoxypyrimidine having a melting point at 124° C.
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][S:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:28]=4[F:35])=[C:23]([CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH:22]=3)(=[O:20])=[O:19])[CH:12]=2)[CH2:5][C:6]([O:8]CC)=[O:7])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>C(O)C>[CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][S:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:28]=4[F:35])=[C:23]([CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH:22]=3)(=[O:20])=[O:19])[CH:12]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:2][CH2:3]1
Reactant: CCOC(=O)CC(c1cccc(CS(=O)(=O)c2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)c1)C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(F)c(-c2ccc(S(=O)(=O)Cc3cccc(C(CC(=O)O)C4CC4)c3)cc2CC(C)(C)C)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 68.6 %

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(3-(((2′-fluoro-5′-methoxy-2-neopentyl-[1,1′-biphenyl]-4-yl)sulfonyl)methyl)phenyl)propanoate (204 mg) in ethanol (3.6 mL) was added 2N aqueous sodium hydroxide solution (898 μl) at room temperature, and the mixture was stirred at 50° C. for 2 hr. The reaction mixture was cooled to 0° C., neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (133 mg) as a white amorphous solid.
Reaction SMILES: [P:1]([O:8][CH2:9][CH3:10])([O:5]CC)[O:2][CH2:3][CH3:4].Br[CH2:12][C:13]1[S:17][C:16]([C:18]([OH:20])=[O:19])=[CH:15][CH:14]=1.[OH-].[Na+].ClCCl>C(O)C>[CH2:9]([O:8][P:1]([CH2:12][C:13]1[S:17][C:16]([C:18]([OH:20])=[O:19])=[CH:15][CH:14]=1)([O:2][CH2:3][CH3:4])=[O:5])[CH3:10]
Reactant: CCOP(OCC)OCC
Reactant: O=C(O)c1ccc(CBr)s1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: CCOP(=O)(Cc1ccc(C(=O)O)s1)OCC
Temperature: 160 °C
Yield: 89.9 %

Procedure:
189 g of triethyl phosphite was added to 84 g of 5-bromomethyl-2-thiophenecarboxylic acid obtained above, and the mixture was stirred with heating at 160° C. for 1 hour. The reaction mixture was dissolved in 200 ml of ethanol, and 190 ml of a 4N aqueous solution of sodium hydroxide was slowly added dropwise with ice-cooling and stirring. After stirring the resulting mixture at room temperature for 12 hours, 200 ml of dichloromethane was added for separating the reaction mixture. The obtained aqueous layer was mixed with 300 ml of a 30% aqueous solution of hydrochloric acid and subjected to extraction with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, giving 95 g of 5-[(diethoxyphosphoryl)methyl]-2-thiophenecarboxylic acid as colorless crystals having a melting point of 77-78° C.
Reaction SMILES: [C:1]1([N:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:23][C:24]1[CH:29]=[CH:28][C:27](Br)=[CH:26][C:25]=1[CH3:31].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:23][C:24]1[CH:29]=[CH:28][C:27]([C:11]2[CH:12]=[CH:13][C:8]([N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:9][CH:10]=2)=[CH:26][C:25]=1[CH3:31]
Reactant: OB(O)c1ccc(N(c2ccccc2)c2ccccc2)cc1
Reactant: Cc1cc(Br)ccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(-c2ccc(N(c3ccccc3)c3ccccc3)cc2)ccc1Br
Temperature: 80 °C
Yield: 67 %

Procedure:
A mixture of 4-diphenylaminophenyl boronic acid (1.25 g, 4.33 mmol), 2,5-dibromotoluene (2.16 g, 8.65 mmol), Pd(PPh3)4 (0.25 g, 0.22 mmol) and K2CO3 (1.38 g, 10 mmol) in dioxane/water (50 mL/9 mL) was degassed and heated at 80° C. for 15 hours. The resulting mixture was mixed with ethyl acetate/brine. The organic phase was dried over Na2SO4, loaded on silica gel, and purified by flash column (hexanes to hexanes/dichloromethane 9:1 to 4:1). The desired fraction was collected and concentrated. After removal of solvent, a white solid (Compound 18) was obtained (1.2 g, in 67% yield).
Reaction SMILES: C(Cl)(=O)C.[NH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([N:20]3[CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21]3)=[O:19])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.NC1C=C2C(=CC=1)CN(C(NC1C=[CH:46][C:45]([C:48](=[O:53])NCCC)=[CH:44]C=1)=O)C2>>[C:48]([N:5]1[CH2:6][CH2:7][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([N:20]3[CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21]3)=[O:19])=[CH:13][CH:12]=2)[CH2:9][CH2:10]1)(=[O:53])[CH:45]([CH3:46])[CH3:44]
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(N)cc3C2)cc1
Reactant: O=C(Nc1ccc(C2CCNCC2)cc1)N1Cc2ccccc2C1
Solvent: CC(=O)Cl
Product: CC(C)C(=O)N1CCC(c2ccc(NC(=O)N3Cc4ccccc4C3)cc2)CC1

Procedure:
The title compound was prepared as described in Example 278, substituting isobutyryl chloride for acetyl chloride and N-[4-(piperidin-4-yl)phenyl]-1,3-dihydro-2H-isoindole-2-carboxamide for 5-amino-N-(4-(propylcarbamoyl)phenyl)isoindoline-2-carboxamide. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.28 (s, 1H), 7.46-7.48 (m, 2H), 7.34-7.39 (m, 2H), 7.29-7.33 (m, 2H), 7.12-7.14 (m, 2H), 4.75-4.76 (bs, 4H), 4.53-4.58 (m, 1H), 4.03-4.07 (m, 1H), 3.06-3.14 (m, 1H), 2.86-2.93 (m, 1H), 2.67-2.74 (m, 1H), 2.53-2.61 (m, 1H), 1.75-1.84 (m, 2H), 1.45-1.56 (m, 1H), 1.33-1.45 (m, 1H), 1.03 (d, J=6.7 Hz, 3H), 1.00 (d, J=6.6 Hz, 3H); MS (ESI(−)) m/e 390 (M−H)−.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=O)[O:14]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]1([Li])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:14]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1OC2(CCCN(Cc3ccccc3)C2)c2ccccc21
Reactant: [Li]c1ccccc1
Product: c1ccc(CN2CCCC3(C2)OC(c2ccccc2)(c2ccccc2)c2ccccc23)cc1

Procedure:
Reaction of 1'-benzyl-1,3-dihydrospiro[isobenzofuran-1,3'-piperidine]-3-one with a large excess of phenyllithium by the method described in Example 1 provides off-white crystals, m.p. 144°-146°.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].C1(P(C(C)(C)C)C(C)(C)C)C=CC=CC=1.[CH3:22][C:23]1[CH:24]=[C:25](Cl)[CH:26]=[CH:27][C:28]=1[C:29]([F:32])([F:31])[F:30].C1(C(N)C2CCCCC2)CCCCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.CC(N(C)C)=O>[CH3:22][C:23]1[CH:24]=[C:25]([CH:26]=[CH:27][C:28]=1[C:29]([F:30])([F:31])[F:32])[CH:3]=[CH:2][C:1]([O:5][CH3:6])=[O:4]
Reactant: Cc1cc(Cl)ccc1C(F)(F)F
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1)C(C)(C)C
Solvent: O
Solvent: CC(=O)N(C)C
Product: COC(=O)C=Cc1ccc(C(F)(F)F)c(C)c1
Reaction time: 4 h
Yield: 86 %

Procedure:
0.619 g (7.2 mmol) of methyl acrylate, 38.7 mg (120 μmol) of NBu4Br, 6.7 mg (30 μmol) of palladium acetate and 26.7 mg (120 μmol) of phenyldi(t-butyl)phosphine are weighed into a Schlenk vessel. 1.17 g (6 mmol) of 3-methyl-4-trifluoromethylchlorobenzene and 1.53 ml (7.2 mmol) of dicyclohexylmethylamine and also 3.5 ml of dimethylacetamide are then added. The Schlenk vessel is placed in a heating bath at 130° C. and the contents are stirred. After 4 hours, the contents are poured into 30 ml of water and the product is extracted by shaking with t-butyl methyl ether. After drying the organic phase over MgSO4, the solvent is removed under reduced pressure and the product is isolated. Yellowish, crystalline solid. Yield: 86%, two products in a ratio of 99:1 (trans/cis products).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[O:12][C@H:13]([CH3:21])[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].CNN>C(Cl)Cl>[NH2:3][O:12][C@H:13]([CH3:21])[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: C[C@@H](ON1C(=O)c2ccccc2C1=O)C(=O)OC(C)(C)C
Agent: CNN
Solvent: ClCCl
Product: C[C@@H](ON)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of (R)-tert-butyl 2-((1,3-dioxoisoindolin-2-yl)oxy)propanoate (69.6 mg, 0.239 mmol) in DCM (478 μL) at 0° C. was added methyl hydrazine (12.8 μL, 0.239 mmol). After stirring for 3 h at 0° C., the solids were filtered off and the filtrate was concentrated in vacuo, affording the title compound (assumed quantitative) as a clear oil.