Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([NH:6]C(OC(C)(C)C)=O)=[CH:4][CH:3]=1.[F:16][C:17]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:18]=1[C:19](Cl)=[O:20]>>[NH2:6][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:15][C:14]=1[C:19]([C:18]1[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:17]=1[F:16])=[O:20]
Reactant: O=C(Cl)c1ccc(F)cc1F
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)cc1
Product: Nc1ccc(Cl)cc1C(=O)c1ccc(F)cc1F
Yield: 20 %

Procedure:
In a manner similar to that described above for compound 1aa, 4-Chloro-N-Boc-aniline and 2,4-difluoro-benzoyl chloride were converted to 1w (20% yield) MS m/z=268 (M+H).
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[Na+].[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][C@H:20]([CH:23]=O)[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][C@H:20]([CH:23]=[CH2:1])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](C=O)C1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A slurry of methyltriphenylphosphonium bromide (16.1 g, 45.2 mmol, 3.0 eq.) in THF (50 mL) was cooled to −78° C. 1M Sodium bis(trimethylsilyl)amide in THF (38.0 mL, 2.8 eq.) was added and the mixture was stirred for 30 minutes. A solution of (S)-3-formylpyrrolidine-1-carboxylic acid t-butyl ester (3.0 g, 15.0 mmol, 1.0 eq.) in THF (10 mL) was slowly added and the mixture was stirred at −78° C. for 2 hours. The mixture was warmed to room temperature over 3 hours and the reaction was quenched with half saturated NH4Cl (50 mL). The organic layer was washed with saturated aqueous NaCl (50 mL). The organic layer was collected, dried over MgSO4, filtered, and concentrated. The resulting oil was slurried in hexanes (50 mL) and the precipitate was filtered off. The filtrate was concentrated, diluted with hexanes (25 mL), and chilled at −20° C. overnight. The precipitate was filtered off and the filtrate was purified by column chromatography (0-100% EtOAc in hexanes) to yield (R)-3-vinylpyrrolidine-1-carboxylic acid t-butyl ester as an oil (2.1 g).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:25][CH2:24][C@@:23]2([CH3:26])[C@H:4](/[C:5](=[CH:29]/[CH3:30])/[C:6](=[O:28])[C@@H:7]3[C@@H:22]2[CH2:21][CH2:20][C@@:19]2([CH3:27])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:18])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH2:3]1.[H][H]>[Pd]>[OH:1][C@@H:2]1[CH2:25][CH2:24][C@@:23]2([CH3:26])[C@H:4]([C@@H:5]([CH2:29][CH3:30])[C:6](=[O:28])[C@@H:7]3[C@@H:22]2[CH2:21][CH2:20][C@@:19]2([CH3:27])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:18])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH2:3]1
Reactant: [H][H]
Reactant: C/C=C1\C(=O)[C@@H]2[C@H](CC[C@]3(C)[C@@H]([C@H](C)CCC(=O)O)CC[C@@H]23)[C@@]2(C)CC[C@@H](O)C[C@@H]12
Agent: [Pd]
Product: CC[C@H]1C(=O)[C@@H]2[C@H](CC[C@]3(C)[C@@H]([C@H](C)CCC(=O)O)CC[C@@H]23)[C@@]2(C)CC[C@@H](O)C[C@@H]12

Procedure:
reacting E/Z-3α-hydroxy-6-ethylidene-7-keto-5β-cholan-24-oic acid (5A) with Pd/C and hydrogen gas to form 3α-hydroxy-6α-ethyl-7-keto-5β-cholan-24-oic acid (6),
Reaction SMILES: Cl.[NH2:2][C:3]1([C:6]([NH:8][CH2:9][CH2:10][C:11]2[N:12]([CH3:30])[C:13](=[O:29])[C:14]3[C:19]([C:20]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:18][C:17]([O:27][CH3:28])=[CH:16][CH:15]=3)=[O:7])[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:38][O:39][C:40]1[CH:48]=[CH:47][C:43]([C:44](Cl)=[O:45])=[CH:42][CH:41]=1>CN(C)C=O>[CH3:38][O:39][C:40]1[CH:48]=[CH:47][C:43]([C:44]([NH:2][C:3]2([C:6]([NH:8][CH2:9][CH2:10][C:11]3[N:12]([CH3:30])[C:13](=[O:29])[C:14]4[C:19]([C:20]=3[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:18][C:17]([O:27][CH3:28])=[CH:16][CH:15]=4)=[O:7])[CH2:5][CH2:4]2)=[O:45])=[CH:42][CH:41]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: COc1ccc2c(=O)n(C)c(CCNC(=O)C3(N)CC3)c(-c3ccccc3)c2c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)NC2(C(=O)NCCc3c(-c4ccccc4)c4cc(OC)ccc4c(=O)n3C)CC2)cc1
Reaction time: 72 h

Procedure:
To a solution of 1-amino-N-[2-(6-methoxy-2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl]cyclopropanecarboxamide hydrochloride (30 mg, 0.117 mmol) in 3 mL of dimethylformamide was added triethylamine (0.049 mL, 0.35 mmol), followed by 4-(methoxy)benzoyl chloride (24 mg, 0.14 mmol). After 3 days, the mixture was concentrated in vacuo. Purification by preparative reversed phase HPLC provided the titled compound. ESI+MS: 526.0 [M+H]+.
Reaction SMILES: C(OC(NOS(C1C(C)=CC(C)=CC=1C)(=O)=O)=O)(C)(C)C.C(O)(C(F)(F)F)=O.[F:29][C:30]1[CH:35]=[CH:34][C:33]([C:36](=[N:44]O)[CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=2)=[CH:32][CH:31]=1>C(Cl)(Cl)Cl>[F:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:37]=[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][N:39]3[N:44]=2)=[CH:32][CH:31]=1
Reactant: ON=C(Cc1ccccn1)c1ccc(F)cc1
Agent: Cc1cc(C)c(S(=O)(=O)ONC(=O)OC(C)(C)C)c(C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: Fc1ccc(-c2cc3ccccn3n2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.6 %

Procedure:
Solid t-butoxycarbonyl-O-mesitylenesulfonylhydroxylamine (17.26 54.6 mmol) was added portionwise with stirring to TFA (50 ml) over 10 min then stirred for a further 30 minutes. The solution was poured onto ice (˜250 ml) and left until the ice melted. The resulting white solid was filtered off, washed with water, and dissolved in chloroform (200 ml). The solution was dried over 4 Å mol. sieves for 1.5 hours, filtered and 1-(4-fluorophenyl)-2-pyridin-2-ylethanone oxime (6.29 g 27.3 mmol) in chloroform (100 ml) was added. The reaction was stirred at room temperature for 18 hours, washed with water (2×50 ml) and dried. Removal of solvent gave a brown solid which was purified by biotage chromatography. Elution with cyclohexane/ethyl acetate (20/1) gave the title compound as a yellow solid (4.09 g 71%). MH+: 213; NMR: (CDCl3): δ 6.75 (2H, m) 7.10 (3H, m) 7.50 (1H, d) 7.95 (2H, m) 8.45 (1H, d).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[CH2:13](O)[CH3:14]>OS(O)(=O)=O>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1cc(F)cc(F)c1

Procedure:
5 g of 3,5-difluorophenylacetic acid are dissolved in 50 ml of ethanol and 3 ml of concentrated H2SO4, and the mixture is heated at reflux for two hours. The mixture is evaporated to dryness, neutralization is then carried out with a saturated K2CO3 solution, extraction is then carried out with AcOEt and the organic phase is evaporated to produce 5.0 g of the expected compound in the form of a colourless liquid.
Reaction SMILES: [OH:1][C@@H:2]([C:16]1[CH:21]=[CH:20][C:19](/[C:22](=[N:24]/O)/[NH2:23])=[CH:18][CH:17]=1)[CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][C@H:6]([CH2:10][C:11]([O:13]CC)=[O:12])[CH2:5]1.CCN(C(C)C)C(C)C.[C:35]1([C:41]2[C:45]([C:46]([F:49])([F:48])[F:47])=[C:44]([C:50](F)=[O:51])[O:43][N:42]=2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>C(#N)C.C(OCC)(=O)C>[OH:1][CH:2]([C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:24]=[C:50]([C:44]3[O:43][N:42]=[C:41]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:45]=3[C:46]([F:49])([F:48])[F:47])[O:51][N:23]=2)=[CH:18][CH:17]=1)[CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][C@H:6]([CH2:10][C:11]([OH:13])=[O:12])[CH2:5]1
Reactant: CCOC(=O)C[C@H]1CCCN(C[C@@H](O)c2ccc(/C(N)=N/O)cc2)C1
Reactant: O=C(F)c1onc(-c2ccccc2)c1C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: C1CCOC1
Product: O=C(O)C[C@H]1CCCN(CC(O)c2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)cc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of ethyl 2-((R)-1-((S)-2-hydroxy-2-(4-((Z)—N′-hydroxycarbamimidoyl)phenyl)ethyl)piperidin-3-yl)acetate (198 mg, 0.567 mmol) and DIEA (0.198 mL, 1.133 mmol) in acetonitrile (10 mL) was added 3-phenyl-4-(trifluoromethyl)isoxazole-5-carbonyl fluoride, Int-I-G (147 mg, 0.567 mmol). The reaction mixture was stirred at room temperature. After 1 hr, TBAF in THF (0.567 mL, 0.567 mmol) was added and the reaction mixture was stirred overnight. The reaction mixture was diluted with ethyl acetate and washed with H2O. The organic layer was dried with MgSO4, filtered, and concentrated. The resulting solids were purified on a silica gel cartridge using an EtOAc/hexanes gradient. Isolated fractions with correct mass by LCMS were concentrated in vacuo. The product was then treated with 6N HCl/MeCN at 50° C. overnight. The reaction mixture was filtered and purified by HPLC. HPLC conditions: PHENOMENEX® Luna C18 5 micron column (250×30 mm); 25-100% CH3CN/water (0.1% TFA); 25 minute gradient; 30 mL/min. Isolated fractions with correct mass were freeze-dried overnight to yield 107 mg of 2-((3R)-1-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidin-3-yl)acetic acid as a TFA salt. 1H NMR (400 MHz, MeOH-d3) δ ppm 8.13 (2H, d, J=8.35 Hz), 7.57-7.64 (4H, m), 7.44-7.55 (3H, m), 5.17 (1H, dd, J=9.23, 4.39 Hz), 3.81 (1H, d, J=11.86 Hz), 3.56 (1H, d, J=11.42 Hz), 3.24-3.31 (2H, m), 2.82-2.95(1H, m), 2.72 (1H, t, J=11.86 Hz), 2.16-2.40 (3H, m), 1.79-1.95 (3H, m), 1.10-1.34 (1H, m). MS (m+1)=543. HPLC Peak RT=3.26 minutes. Purity=98%.
Reaction SMILES: N[C:2]1[C:3](C)=[C:4]([CH:9]=[C:10](Br)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C1(=O)CCCC1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:9]=[CH:10][CH:11]=[CH:2][CH:3]=1
Reactant: COC(=O)c1cc(Br)cc(N)c1C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O=C1CCCC1
Solvent: CO
Product: COC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 142.8 %

Procedure:
To a stirred solution of methyl 3-amino-5-bromo-2-methylbenzoate (5 g, 20.57 mmol) and cyclopentanone (8.64 g, 102.8 mmol) in methanol (30 mL), acetic acid (2.46 g, 41.1 mmol) was added and reaction stirred at room temperature for 3 h. Then sodium cyanoborohydride (3.23 g, 51.4 mmol) was added and reaction stirred overnight. On completion, solvent was removed under reduced pressure and crude material was purified by column chromatography to afford methyl 5-bromo-3-(cyclopentylamino)-2-(methylbenzoate (4 g, 78.2%).
Reaction SMILES: Br[C:2]1[C:10]2[CH:11]=[C:12]3[C:20]([C:21]([CH3:23])([CH3:22])[C:9]=2[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:7]=2)=[C:19]1[C:14]([CH:15]=[CH:16][CH:17]=[CH:18]1)=[N:13]3.[C:30]1([N:36]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:37]2[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C1(C)C=CC=CC=1.C(O)C.C(=O)([O-])[O-].[K+].[K+]>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.O.C1(C)C=CC=CC=1>[CH3:22][C:21]1([CH3:23])[C:20]2[C:12]([N:13]=[C:14]3[C:19]=2[CH:18]=[CH:17][CH:16]=[CH:15]3)=[CH:11][C:10]2[C:2]([C:40]3[CH:41]=[CH:42][C:37]([N:36]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)=[CH:38][CH:39]=3)=[C:3]3[C:8]([C:9]1=2)=[CH:7][CH:6]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:5]=[CH:4]3
Reactant: CC1(C)C2=C(C=C3N=c4ccccc4=C31)C(Br)=C1C=CC(c3ccccc3)C=C12
Reactant: OB(O)c1ccc(N(c2ccccc2)c2ccccc2)cc1
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: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CC1(C)C2=C(C=C3N=c4ccccc4=C31)C(c1ccc(N(c3ccccc3)c3ccccc3)cc1)=C1C=CC(c3ccccc3)C=C12
Temperature: 73 °C
Reaction time: 5 h
Yield: 58.2 %

Procedure:
7-Bromo-12,12-dimethyl-10-phenyl-10,12-dihydroindeno[2,1-b]carbazole synthesized in Example 1 (2.0 g), 4-diphenylamino-phenylboronic acid (1.32 g), a toluene/ethanol (4/1, v/v) mixed solvent (15 ml), and a 2M potassium carbonate aqueous solution (3.4 ml) were added to a nitrogen-substituted reaction vessel and aerated with nitrogen gas for 30 min under ultrasonic irradiation. The mixture was heated after adding tetrakis(triphenylphosphine)palladium (0.26 g), and stirred at 73° C. for 5 hours. After the mixture was cooled to a room temperature, toluene (30 ml) and water (20 ml) were added to perform liquid separation in order to collect an organic layer. The organic layer was washed with saturated brine, dehydrated with anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (carrier: silica gel; eluent: toluene/n-hexane) to obtain a pale yellowish white powder of 12,12-dimethyl-10-phenyl-7-(4-diphenylamino-phenyl)-10,12-dihydroindeno[2,1-b]carbazole (1.6 g; yield 58.4%).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:17][CH:14]([CH:15]=[CH2:16])[CH:4]([CH:5]([O:10][CH2:11][O:12][CH3:13])[CH2:6][CH:7]=[N:8][OH:9])[O:3]1.C(N(CC)CC)C.Cl[O-].[Na+]>C(Cl)Cl.C(OCC)C>[CH3:1][C:2]1([CH3:18])[O:3][CH:4]2[CH:5]([O:10][CH2:11][O:12][CH3:13])[CH2:6][C:7]3[CH:15]([CH2:16][O:9][N:8]=3)[CH:14]2[O:17]1
Reactant: C=CC1OC(C)(C)OC1C(CC=NO)OCOC
Agent: [Na+]
Agent: [O-]Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCOC1CC2=NOCC2C2OC(C)(C)OC12
Temperature: 0 °C
Reaction time: 57 h
Yield: 0 %

Procedure:
4,5-(Dimethylmethylenedioxy)-3-methoxymethoxy-6-heptenal oxime (89.5 mg) was dissolved in 4 ml of methylene chloride, and 0.035 ml of triethylamine was added at 0° C. A 10 % sodium hypochlorite aqueous solution (2.6 ml) was added at 0° C., and the mixture was stirred at 0° C. for 57 hours. The reaction mixture was diluted with diethyl ether, and washed with saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution in sequence. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to provide 0.0 mg of 4,5-(dimethylmethylenedioxy)-6-(methoxymethoxy)-3,3a,4,5,6,7-hexahydro-2,1-benzoisooxazole having the following properties (yield 56%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4](I)[C:3]=1[Br:10].C1COCC1.[C:16]([Si:18]([CH3:21])([CH3:20])[CH3:19])#[CH:17]>CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Br:10][C:3]1[C:2]([Br:1])=[CH:7][CH:6]=[C:5]([F:8])[C:4]=1[C:17]#[C:16][Si:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: Fc1ccc(Br)c(Br)c1I
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1c(F)ccc(Br)c1Br
Temperature: 40 °C
Reaction time: 40 h
Yield: 79.4 %

Procedure:
A thick-walled glass vessel was charged with 1,2-dibromo-4-fluoro-3-iodobenzene (8.31 g, 21.88 mmol), Pd(PPh3)2Cl2 (0.768 g, 1.094 mmol), and CuI (0.292 g, 1.532 mmol) and sealed with a rubber septum. Anhyd THF (30 mL) and DIPA (30.8 mL, 219 mmol) were added via syringe and the mixture was degassed 10 min by sparging with N2 while immersed in an ultrasonic bath. Ethynyltrimethylsilane (3.40 mL, 24.07 mmol) was added via syringe and the septum was replaced with a PTFE bushing. The mixture was stirred in an oil bath at 40° C. After 40 h, the mixture was cooled, diluted with EtOAc and filtered through a pad of Celite. The filtrate was washed (satd NH4Cl×2, water, brine), dried over Na2SO4 and concentrated in vacuo. The residue was purified by low pressure liquid chromatography (silica gel, EtOAc/hexanes, gradient elution) affording ((2,3-dibromo-6-fluorophenyl)ethynyl)trimethylsilane (6.08 g, 17.37 mmol, 79% yield) as a yellow oil: 1H NMR (400 MHz, CDCl3) δ 7.53 (dd, J=8.9, 5.4 Hz, 1H), 6.95 (dd, J=8.9, 8.1 Hz, 1H), 0.29 (s, 9H); MS (GCMS EI) m/z 348 ([M]+, Br isotopes, 18%), 350 ([M]+, Br isotopes, 34%), 352 ([M]+, Br isotopes, 18%), 333 ([M-CH3]+, Br isotopes, 56%), 335 ([M-CH3]+, Br isotopes, 100%), 337 ([M-CH3]+, Br isotopes, 54%).
Reaction SMILES: Cl[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[O:3]1.O1CCCC1>[Ni].C(N(CC)CC)C>[C:4]1([C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:2][O:3]1)=[O:5]
Reactant: O=C1OC(Cl)c2ccccc21
Agent: [Ni]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1OCc2ccccc21
Temperature: 65 °C
Reaction time: 2 h
Yield: 88.5 %

Procedure:
A 1-liter lift magnet autoclave is charged with 110 g of 3-chlorophthalide, 10 g of nickel catalyst RCH 55/10 (commercial product of Farbwerke Hoechst AG) and 400 ml of tetrahydrofuran to which 66 g of triethylamine is added. After purging the air with nitrogen, hydrogen is pumped in to a pressure of 10 bars, and the temperature is raised, with stirring, to 65° C. The hydrogen consumption is compensated by additions in the range between 10 and 20 bars for a period of 41/2 hours. After the absorption of hydrogen ceases, the catalyst and precipitated salt are filtered out and the solvent is withdrawn. After distillation of the residue between 88° and 90° C. and 0.2 Torr, 77.5 g of phthalide is obtained, of a melting point of 71° C. (gas-chromatographic analysis 98.95%).
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[Cl:14]>C(#N)C>[Cl:14][C:6]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:5]=1[NH:2][NH2:3]
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Reactant: NN
Solvent: O
Solvent: CC#N
Product: NNc1ccc([N+](=O)[O-])cc1Cl
Temperature: 25 °C

Procedure:
59 g of hydrazine hydrate was dissolved in 712 ml of acetonitrile at room temperature under an atmosphere of nitrogen. A solution obtained by dissolving 46.3 g of 1,2-dichloro-4-nitrobenzene in 71 g of acetonitrile was added dropwisely to the obtained solution. After the addition had been completed, the obtained mixture was subjected to reflux by heat for 4 hours, and the reaction solution was concentrated. 500 g of water was added to the concentrate, and the produced crystals were filtered off. 200 g of acetonitrile was then added to the crystals, and the obtained mixture was subjected to reflux by heat for 30 minutes and then cooled with ice to room temperature. The produced crystals were filtered off (yield: 27 g).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]([O:14]COC)([CH2:12][F:13])[CH2:10][F:11].[Li]CCCC.[B:23](OC(C)C)(OC(C)C)[O:24]C(C)C>C1COCC1>[F:11][CH2:10][C:9]1([CH2:12][F:13])[O:14][B:23]([OH:24])[C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]1=2
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COCOC(CF)(CF)c1ccc(C)cc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)B(O)OC2(CF)CF
Temperature: -78 °C
Reaction time: 1 h
Yield: 60.5 %

Procedure:
To a solution of 2-bromo-1-(1,3-difluoro-2-(methoxymethoxy)propan-2-yl)-4-methylbenzene (1.2 g, 3.9 mmol) in THF (20 mL) at −78° C. was added n-BuLi (4 mL, 9.75 mmol) dropwise. The mixture was stirred at −78° C. for additional 1 h and then triisopropyl borate (1.5 g, 7.9 mmol) in 10 mL of THF was added below −70° C. The resulting mixture was kept stirring at −78° C. for 30 min and allowed to warm to rt and stirred overnight. Then it was quenched with aqueous NH4Cl and extracted with EA. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified on column chromatography to provide the product (0.5 g, yield 60%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10](=[O:25])[NH:11][N:12]=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:4][CH:3]=1.Br[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[C:29]([F:34])[CH:28]=1.N>>[F:33][C:30]1[CH:31]=[C:32]([N:11]2[C:10](=[O:25])[C:9]([CH2:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[C:14]([C:15]3[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=3)[CH:13]=[N:12]2)[CH:27]=[CH:28][C:29]=1[F:34]
Reactant: Fc1ccc(Br)cc1F
Reactant: CS(=O)(=O)c1ccc(-c2cn[nH]c(=O)c2Cc2ccc(F)cc2)cc1
Agent: N
Product: CS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)c(F)c3)c(=O)c2Cc2ccc(F)cc2)cc1

Procedure:
The title compound was prepared according to the method of Example 62 substituting 4-(4-fluorophenylmethyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and substituting 1-bromo-3,4-difluorobenzene in place of 4-iodo-1-fluorobenzene (yield: 0.085 g, 54%). mp 157-159° C. 1H NMR (300 MHz, DMSO d6) δ 3.30 (s, 3H), 3.88 (bs, 2H), 7.04 (m, 4H), 7.49-7.66 (m, 2H), 7.70 (m, 2H), 7.81 (m, 1H), 8.12 (s, 1H). MS (DCI/NH3) m/z 471 (M+H)+, 488 (M+NH4)+. Anal. calc. for C24H17F3N2O3S.0.25H2O: C, 60.69; H, 3.71; N, 5.84. Found: C, 6.39; H, 3.76; N, 5.81.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][OH:18])=[CH:13][C:12]=2[F:19])[CH:9]=1)[C:5]#[N:6].Cl[C:21]1[CH:31]=[C:25]2[N:26]([CH3:30])[CH2:27][CH2:28][CH2:29][N:24]2[C:23](=[O:32])[N:22]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][O:18][C:21]3[CH:31]=[C:25]4[N:26]([CH3:30])[CH2:27][CH2:28][CH2:29][N:24]4[C:23](=[O:32])[N:22]=3)=[CH:13][C:12]=2[F:19])[CH:9]=1)[C:5]#[N:6]
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Reactant: N#Cc1cc(F)cc(Oc2ccc(CO)cc2F)c1
Product: CN1CCCn2c1cc(OCc1ccc(Oc3cc(F)cc(C#N)c3)c(F)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from 3-fluoro-5-(2-fluoro-4-(hydroxymethyl)phenoxy)benzonitrile and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: C(OC(=O)[NH:10][C@H:11]([CH2:16][O:17][Si:18]([C:31]([CH3:34])([CH3:33])[CH3:32])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:12][CH:13]([CH3:15])[CH3:14])C1C=CC=CC=1>CO.[Pd]>[Si:18]([O:17][CH2:16][C@@H:11]([NH2:10])[CH2:12][CH:13]([CH3:14])[CH3:15])([C:31]([CH3:33])([CH3:34])[CH3:32])([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)C[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)C[C@H](N)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Yield: 84.4 %

Procedure:
A solution of [(1S)-1-(t-butyldiphenylsilyloxymethyl)-3-methylbutyl]carbamic acid benzyl ester (7.35 g, 15.0 mmol) (obtained as described in Reference Example 37(1)) in methanol (220 ml) was subjected to catalytic hydrogenation in the presence of 10% palladium on charcoal (7.35 g) at room temperature for 4 hours. After checking the completion of the reaction, the reaction mixture was filtered in order to remove the catalyst and the filtrate concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using methylene chloride:methanol (98:2→9:1) as the eluant to afford (1S)-1-(t-butyldiphenylsilyloxymethyl)-3-methylbutylamine (4.50 g, yield 84%) as a colorless oil.