Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:21]=[C:20]3[C:15]([N:16]([CH3:23])[CH2:17][C:18](=[O:22])[NH:19]3)=[CH:14][CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[H-].[Na+].[CH2:26](Br)[C:27]#[CH:28]>CN(C)C=O>[Cl:1][C:2]1[C:3]([C:12]2[CH:21]=[C:20]3[C:15]([N:16]([CH3:23])[CH2:17][C:18](=[O:22])[N:19]3[CH2:28][C:27]#[CH:26])=[CH:14][CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:7]=1
Reactant: CN1CC(=O)Nc2cc(-c3ncc(C(F)(F)F)cc3Cl)ccc21
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCN1C(=O)CN(C)c2ccc(-c3ncc(C(F)(F)F)cc3Cl)cc21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 2.0 g of 7-(3-chloro-5-trifluoromethylpyridin-2yl)-1,2,3,4-tetrahydro-4-methylquinoxalin-2-one in 35 ml of dimethylformamide was added dropwise to a suspension of 0.2 g of 80% strength by weight sodium hydride in 35 ml of anhydrous dimethylformamide. After stirring for 15 minutes, 0.73 g of propargyl bromide was added to the reaction mixture. After 18 hours at 23° C., the reaction mixture was poured into 300 ml of ice water and extracted three times with 100 ml of tert-butyl methyl ether each time, after which the combined organic phases were washed twice with 100 ml of water each time, dried over sodium sulfate and concentrated. Purification of the crude product was carried out by means of chromatography on silica gel (eluent: cyclohexane/ethyl acetate). Yield: 1.1 g (49%) of colorless crystals; m.p.: 128-129° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[S:16][C:15]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=3[C:13]=2[CH3:22])(=[O:11])=[O:10])=[C:4]([CH2:23][S:24][CH3:25])[CH:3]=1.[N:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1>COCCOC.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].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>[CH3:25][S:24][CH2:23][C:4]1[CH:3]=[C:2]([C:29]2[CH:30]=[CH:31][N:26]=[CH:27][CH:28]=2)[CH:7]=[CH:6][C:5]=1[NH:8][S:9]([C:12]1[S:16][C:15]2[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=2[C:13]=1[CH3:22])(=[O:11])=[O:10]
Reactant: OB(O)c1ccncc1
Reactant: CSCc1cc(Br)ccc1NS(=O)(=O)c1sc2ccc(F)cc2c1C
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: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: CSCc1cc(-c2ccncc2)ccc1NS(=O)(=O)c1sc2ccc(F)cc2c1C
Yield: 66.8 %

Procedure:
This compound was prepared in analogy to Example 2 starting from 5-fluoro-3-methyl-benzo[b]thiophene-2-sulfonic acid(4-bromo-2-methylsulfanylmethyl-phenyl)-amide (0.23 g) and 4-pyridineboronic acid (0.092 g) in 1,2-dimethoxyethane (10 ml), ethanol (2 ml) and 2 M aqueous sodium carbonate solution (2 ml) with tetrakis(triphenylphosphine)palladium (0.058 g) to obtain the title compound (0.153 g) as a brownish foam (0.153 g). MS (ISN): 457.2 (M−H)−
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=2[CH3:18])=[O:9])[CH:3]=1.[CH3:19][NH:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH:21]1([N:20]([CH3:19])[C:2]2[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=3[CH3:18])=[O:9])[CH:3]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: Cc1cc(O)ccc1NC(=O)c1cc(Cl)ncn1
Reactant: CNC1CCCCC1
Product: Cc1cc(O)ccc1NC(=O)c1cc(N(C)C2CCCCC2)ncn1

Procedure:
Following the general method as outlined in Example 20, starting from 6-chloro-N-(4-hydroxy-2-methylphenyl)pyrimidine-4-carboxamide (Intermediate 8) and N-methylcyclohexylamine (Aldrich), the title compound was obtained as a yellow solid after purification by column chromatography (silica) eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [C:1]1([Mg]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]([N:15]1[C@@H:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:18][O:17][C:16]1=[O:26])(=[O:14])/[CH:10]=[CH:11]/[CH2:12][CH3:13]>O1CCCC1>[C:20]1([C@H:19]2[CH2:18][O:17][C:16](=[O:26])[N:15]2[C:9](=[O:14])[CH2:10][C@H:11]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH3:13])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Cl[Mg]c1ccccc1
Reactant: CC/C=C/C(=O)N1C(=O)OC[C@@H]1c1ccccc1
Solvent: C1CCOC1
Product: CC[C@H](CC(=O)N1C(=O)OC[C@@H]1c1ccccc1)c1ccccc1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
To a suspension of copper (I) bromide dimethyl sulfide complex (12.4 g, 60.6 mmol) in dry tetrahydrofuran (150 mL) at −10° C. was added phenyl magnesium chloride solution (30.3 mL, 60.6 mmol, 2 M in tetrahydrofuran). The reaction mixture was stirred at −10° C. for 1 hour, then a solution of (S)-3-((E)-pent-2-enoyl)-4-phenyl-oxazolidin-2-one (9.9 g, 40.4 mmol) in tetrahydrofuran (100 mL) was added dropwise via cannula. The reaction mixture was stirred at −10° C. for 0.5 hours, then at room temperature for 2 hours. The mixture was quenched with saturated aqueous ammonium chloride solution (150 mL), concentrated under reduced pressure to half of its volume. The mixture was extracted with ethyl acetate (2×250 mL). The organic layer was separated, combined and dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography over silica gel eluted with 2:1 ethyl acetate/hexanes to give (S)-4-phenyl-3-((R)-3-phenyl-pentanoyl)-oxazolidin-2-one as a colorless oil which solidified on standing at room temperature (9.56 g, 73%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:8](=O)[NH:9][CH:10]=[CH:11][CH:12]=2)[CH:2]=1.[OH-].[Na+].P(Br)(Br)([Br:18])=O>>[Br:18][C:8]1[C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: O=c1[nH]cccc1-c1cccnc1
Reactant: O=P(Br)(Br)Br
Agent: [Na+]
Agent: [OH-]
Product: Brc1ncccc1-c1cccnc1

Procedure:
A mixture of 0.30 g of 3-(3-pyridinyl)-2(1H)pyridinone and 10 ml of phosphorus oxybromide was heated on a steam bath for 18 hours, then poured onto crushed ice and made alkaline with 10N sodium hydroxide. The resulting solid was collected, dissolved in methylene chloride and the solution passed through a short pad of hydrous magnesium silicate. The filtrate was concentrated and while boiling diluted with hexane. Concentration and chilling gave 2'-bromo-3,3'-bipyridine as white crystals, mp 97°-98° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[C:14]([S:18]([NH2:21])(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=2)[C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[CH3:28][O:29][C:30]1[N:35]=[C:34]([O:36][CH3:37])[CH:33]=[C:32]([N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[N:31]=1>N1C=CC=CC=1>[CH3:28][O:29][C:30]1[N:31]=[C:32]([N:38]2[CH2:43][CH2:42][N:41]([C:2]3[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]4[CH:13]=[C:14]([S:18]([NH2:21])(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=4)[C:3]=3[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:40][CH2:39]2)[CH:33]=[C:34]([O:36][CH3:37])[N:35]=1
Reactant: COc1cc(N2CCNCC2)nc(OC)n1
Reactant: NS(=O)(=O)c1cccc(-c2nc(C(F)(F)F)nc(Cl)c2-c2ccccc2)c1
Solvent: c1ccncc1
Product: COc1cc(N2CCN(c3nc(C(F)(F)F)nc(-c4cccc(S(N)(=O)=O)c4)c3-c3ccccc3)CC2)nc(OC)n1
Reaction time: 8 h

Procedure:
A solution of 3-[6-chloro-5-phenyl-2-(trifluoromethyl)pyrimidin-4-yl]benzenesulfonamide (0.1 g, 0.24 mmol) in pyridine (1.5 ml) was treated with 2,4-dimethoxy-6-piperazin-1-ylpyrimidine (0.081 g, 0.363 mmol) and the reaction mixture was stirred for 8 hours. Subsequently the reaction mixture was poured onto ice-cold water and extracted with ethyl acetate (25 ml). The organic layer was washed with brine and evaporated to furnish the title compound. 1H-NMR (CDCl3) δ: 3.39-3.41 (m, 4H), 3.51-3.52 (m, 4H), 3.87-3.88 (s, 6H), 7.07-7.09 (d, 2H), 7.20-7.26 (m, 3H), 7.30-7.32 (m, 1H), 7.47-7.61 (t, 1H), 7.64 (s, 1H), 7.82-7.87 (m, 2H); MS m/z: 601.8 (M+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([C:12]3[CH:13]=[C:14]([C:19]4[S:20][C:21]5[CH:27]=[CH:26][CH:25]=[C:24](C(F)(F)F)[C:22]=5[N:23]=4)[C:15]([NH2:18])=[N:16][CH:17]=3)[CH:9]=[N:8]2)[CH2:3][CH2:2]1.Cl[C:33]1SC2C=C(C#N)C=CC=2[N:37]=1>>[NH2:18][C:15]1[C:14]([C:19]2[S:20][C:21]3[CH:27]=[C:26]([C:33]#[N:37])[CH:25]=[CH:24][C:22]=3[N:23]=2)=[CH:13][C:12]([C:10]2[CH:9]=[N:8][N:7]([CH:4]3[CH2:3][CH2:2][NH:1][CH2:6][CH2:5]3)[CH:11]=2)=[CH:17][N:16]=1
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2c(C(F)(F)F)cccc2s1
Reactant: N#Cc1ccc2nc(Cl)sc2c1
Product: N#Cc1ccc2nc(-c3cc(-c4cnn(C5CCNCC5)c4)cnc3N)sc2c1

Procedure:
Following the procedure for 5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-3-(4-trifluoromethylbenzothiazol-2-yl)-pyridin-2-ylamine, but using 2-chloro-1,3-benzothiazole-6-carbonitrile, the title compound was obtained as yellow solid. MS (ES+): m/z=402.13 [MH+].
Reaction SMILES: C1COCC1.[CH2:6]([Si:9]([CH2:24][CH:25]=[CH2:26])([CH2:21][CH:22]=[CH2:23])[CH2:10][CH2:11][CH2:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1)[CH:7]=[CH2:8].[BH4-].[Na+].C(=O)([O-])O.[Na+]>CO>[CH2:24]([Si:9]([CH2:6][CH:7]=[CH2:8])([CH2:21][CH:22]=[CH2:23])[CH2:10][CH2:11][CH2:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][OH:18])=[CH:15][CH:14]=1)[CH:25]=[CH2:26]
Reactant: C=CC[Si](CC=C)(CC=C)CCCc1ccc(C=O)cc1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: C=CC[Si](CC=C)(CC=C)CCCc1ccc(CO)cc1
Reaction time: 3 h
Yield: 83 %

Procedure:
THF (25 ml) and methanol (MeOH) (25 ml) were added to 4-{3-(triallylsilyl)propyl}benzaldehyde (4) (11.0 g, 36.9 mmol) under a nitrogen atmosphere, the mixture was cooled to around 0° C. with ice, NaBH4 (2.8 g, 73.8 mmol) was added thereto, and the mixture was stirred for 3 hours. An aqueous solution of saturated sodium hydrogen carbonate was added to the reaction mixture. The aqueous layer was extracted with diethyl ether, and the combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under a reduced pressure to give a crude product. The crude product was purified by separating by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate=5/1) to give 4-{3-(triallylsilyl)propyl}benzyl alcohol (5) (yield amount: 9.2 g, yield: 84%), as shown in the following chemical reaction formula.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].S(Cl)([Cl:16])=O>C1C=CC=CC=1>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([Cl:16])=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=C(Cl)Cc1ccc([N+](=O)[O-])cc1
Yield: 91 %

Procedure:
To mixture of p-nitrophenylacetic acid (1 g, 5.5 mmol) in benzene (10 ml) was added thionyl chloride (0.8 ml) at room temperature. The reaction mixture was heated to reflux for 12 hr and then cooled. The excess thionyl chloride and benzene were removed in vacuo to obtain (4-nitro-phenyl)-acetyl chloride (1 g, 91%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:13]2[CH2:18][C@H:17]([C:19]3[O:23][NH:22][C:21](=[O:24])[CH:20]=3)[CH2:16][CH2:15][N:14]2C(OC)=O)[CH:5]=[C:6]([F:12])[C:7]=1[C:8]([F:11])([F:10])[F:9].Br>>[F:12][C:6]1[CH:5]=[C:4]([C@H:13]2[CH2:18][C@H:17]([C:19]3[O:23][NH:22][C:21](=[O:24])[CH:20]=3)[CH2:16][CH2:15][NH:14]2)[CH:3]=[C:2]([F:1])[C:7]=1[C:8]([F:9])([F:10])[F:11]
Reactant: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1c1cc(F)c(C(F)(F)F)c(F)c1
Agent: Br
Product: O=c1cc([C@@H]2CCN[C@@H](c3cc(F)c(C(F)(F)F)c(F)c3)C2)o[nH]1
Temperature: 25 °C
Reaction time: 20 h
Yield: 33.5 %

Procedure:
Trans-methyl 2-(3,5-difluoro-4-(trifluoromethyl)phenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (26 mg, 0.06 mmol) was dissolved in hydrogen bromide (33% in AcOH, 2 mL, 0.06 mmol) and stirred at room temperature for 20 h. The solvent was evaporated and the residue purified by preparative HPLC (Instrument: FractionLynx II, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-(trans-2-(3,5-difluoro-4-(trifluoromethyl)phenyl)piperidin-4-yl)isoxazol-3(2H)-one (7.00 mg, 31%). 1H NMR (600 MHz, dmso) δ 1.73-1.88 (m, 3H), 2.02-2.08 (m, 1H), 2.64-2.70 (m, 1H), 2.77-2.83 (m, 1H), 3.06-3.11 (m, 1H), 3.83-3.86 (m, 1H), 6.02 (s, 1H), 7.42 (d, 2H). HRMS Calcd for [C15H13F5N2O2+H]+: 349.0975. Found: 349.0983.
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[C:9]2[C:14](=[C:15](Br)[CH:16]=1)[N:13]=[CH:12][CH:11]=[CH:10]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[N+:18]([C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)([O-:20])=[O:19]>>[CH2:1]([C:7]1[CH:8]=[C:9]2[C:14](=[C:15]([C:25]3[CH:24]=[CH:23][CH:22]=[C:21]([N+:18]([O-:20])=[O:19])[CH:26]=3)[CH:16]=1)[N:13]=[CH:12][CH:11]=[CH:10]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1cc(Br)c2ncccc2c1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Product: CCCCCCc1cc(-c2cccc([N+](=O)[O-])c2)c2ncccc2c1

Procedure:
6-hexyl-8-bromoquinoline and 3-nitrobenzene boronic acid can be combined to form 6-hexyl-8-(3-nitrophenyl)quinoline,
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[O:6][CH2:7][CH2:8][CH2:9][N:10]1[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]2[C:11]1=[O:20])=[O:2].[CH2:24](O)[CH2:25][OH:26].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[O:2]1[CH2:24][CH2:25][O:26][CH:1]1[C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[O:6][CH2:7][CH2:8][CH2:9][N:10]1[C:11](=[O:20])[C:12]2=[CH:19][CH:18]=[CH:17][CH:16]=[C:13]2[C:14]1=[O:15]
Reactant: O=Cc1cccc(OCCCN2C(=O)c3ccccc3C2=O)c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: O=C1c2ccccc2C(=O)N1CCCOc1cccc(C2OCCO2)c1
Yield: 92.5 %

Procedure:
N-[3-(3-formylphenoxy)propyl]phthalimide (29 g) was dissolved in 400 ml of benzene, and 11.67 g of ethylene glycol and 1.8 g of p-toluenesulfonic acid were added, and the mixture was heated under reflux for 7 hours while water was removed by using a Dean-Stark trap. After the reaction, the reaction mixture was cooled and the benzene layer was washed successively with a 1N aqueous NaOH solution, water, and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 30.63 g (yield 92%) of N-{3-[3-(1,3-dioxolan-2-yl)phenoxy]propyl}phthalimide.
Reaction SMILES: [CH2:1]([N:4]([CH:10]([CH3:13])[CH:11]=O)[C:5](=[O:9])[O:6][CH2:7][CH3:8])[CH:2]=[CH2:3].O.[NH:15]([CH2:17]C(O)=O)[CH3:16]>C1(C)C=CC=CC=1>[CH3:16][N:15]1[CH2:17][CH2:3][CH:2]2[CH:11]1[CH:10]([CH3:13])[N:4]([C:5]([O:6][CH2:7][CH3:8])=[O:9])[CH2:1]2
Reactant: CNCC(=O)O
Reactant: C=CCN(C(=O)OCC)C(C)C=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)N1CC2CCN(C)C2C1C

Procedure:
18.5 g (0.1 mol) of ethyl N-allyl-N-(1-oxoprop-2-yl)-carbamate are heated under reflux overnight in a water separator with 9 g (0.1 mol) of sarcosine in 300 ml of toluene. The mixture is concentrated and the residue is distilled.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[C:5]([F:9])=[CH:4][C:3]=1[F:10].C([Li])CCC.[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=[O:21].[Cl-].[NH4+]>C(OCC)C.CCCCCC>[Br:8][C:6]1[C:5]([F:9])=[CH:4][C:3]([F:10])=[C:2]([CH:20]([C:19]2[CH:22]=[CH:23][CH:24]=[C:17]([F:16])[CH:18]=2)[OH:21])[CH:7]=1
Reactant: O=Cc1cccc(F)c1
Reactant: Fc1cc(F)c(Br)cc1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOCC
Product: OC(c1cccc(F)c1)c1cc(Br)c(F)cc1F
Temperature: -70 °C

Procedure:
A total of 2.02 g of 1,5-dibromo-2,4-difluorobenzene obtained in Production Example II-5-a was dissolved in 38 ml of diethyl ether, and 4.9 ml of a 1.58 M solution of n-butyllithium in hexane was added under stirring at −70° C. After stirring for 1 hour, 4.9 ml of m-fluorobenzaldehyde was added and the mixture was stirred for 15 minutes. Saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extracting with ethyl acetate. The resulting organic layer was washed with brine, dried over magnesium sulfate and the solvent was evaporated. The residue was purified and separated by silica gel column chromatography (ethyl acetate:hexane=1:10), to give 0.96 g of the title compound.
Reaction SMILES: Cl.Cl.[CH3:3][C@H:4]1[C:12]2[C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:10][CH:9]=[N:8][C:7]=2[C@@H:6]([OH:19])[CH2:5]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1C(C)=CC(C)=CC=1C.[C:53]([O:57][C:58]([N:60]1[C:64]([CH3:66])([CH3:65])[CH2:63][CH2:62][C@H:61]1[C@H:67]([C:71]1[CH:76]=[CH:75][C:74]([Cl:77])=[CH:73][C:72]=1[F:78])[C:68](O)=[O:69])=[O:59])([CH3:56])([CH3:55])[CH3:54]>C(Cl)Cl>[Cl:77][C:74]1[CH:75]=[CH:76][C:71]([C@@H:67]([C@H:61]2[N:60]([C:58]([O:57][C:53]([CH3:55])([CH3:54])[CH3:56])=[O:59])[C:64]([CH3:66])([CH3:65])[CH2:63][CH2:62]2)[C:68]([N:16]2[CH2:15][CH2:14][N:13]([C:11]3[C:12]4[C@H:4]([CH3:3])[CH2:5][C@@H:6]([OH:19])[C:7]=4[N:8]=[CH:9][N:10]=3)[CH2:18][CH2:17]2)=[O:69])=[C:72]([F:78])[CH:73]=1
Reactant: C[C@@H]1C[C@H](O)c2ncnc(N3CCNCC3)c21
Reactant: CC(C)(C)OC(=O)N1[C@H]([C@@H](C(=O)O)c2ccc(Cl)cc2F)CCC1(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: Cc1cc(C)nc(C)c1
Solvent: ClCCl
Product: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)[C@@H](c4ccc(Cl)cc4F)[C@@H]4CCC(C)(C)N4C(=O)OC(C)(C)C)CC3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.5 %

Procedure:
(5R,7R)-5-Methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride (0.109 g, 0.356 mmol; see Example 3, Step 12), HATU (0.123 g, 0.324 mmol), and collidine (0.171 mL, 1.30 mmol) were added to a solution of (S)-2-((S)-1-(tert-butoxycarbonyl)-5,5-dimethylpyrrolidin-2-yl)-2-(4-chloro-2-fluorophenyl)acetic acid (0.125 g, 0.324 mmol; prepared analogously to that described in Example B) in DCM (25 mL). The reaction was stirred overnight at room temperature. The reaction was partitioned between water (20 mL) and DCM (50 mL), and the layers were separated. The organics were washed with water (2×10 mL). The aqueous portion was back extracted with DCM (25 mL), dried (MgSO4) and concentrated to an oil that was purified by flash chromatography (5% MeOH/DCM) to give (S)-tert-butyl 5-((S)-1-(4-chloro-2-fluorophenyl)-2-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-oxoethyl)-2,2-dimethylpyrrolidine-1-carboxylate (0.116 g, 0.193 mmol, 59.5% yield). LC/MS=3.79 minutes, (APCI+) m/z=602 [M+H]+.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:12]([O:13][CH:14]([CH3:16])[CH3:15])=[C:11]([O:17][CH3:18])[CH:10]=[CH:9][C:6]=1[CH:7]=[O:8])([CH3:3])[CH3:2].[CH3:19][Li]>C(OCC)C>[CH:1]([O:4][C:5]1[C:12]([O:13][CH:14]([CH3:16])[CH3:15])=[C:11]([O:17][CH3:18])[CH:10]=[CH:9][C:6]=1[CH:7]([OH:8])[CH3:19])([CH3:3])[CH3:2]
Reactant: [Li]C
Reactant: COc1ccc(C=O)c(OC(C)C)c1OC(C)C
Solvent: CCOCC
Product: COc1ccc(C(C)O)c(OC(C)C)c1OC(C)C
Reaction time: 2 h
Yield: 84 %

Procedure:
To a solution of 22 (23.10 g, 91.56 mmol) in dry ethyl ether (150 mL) was added dropwise methyllithium (98.10 mL, 1.4 M in EtO2, 1.37.3 mmol) at 0° C. under nitrogen. The reaction mixture was stirred for 2 h allowing too reach room temperature. The reaction was slowly quenched with water, the phases were separated, and the aqueous phase was extracted with ethyl ether (3×150 mL). The combined organic solutions were dried over MgSO4 and concentrated over reduced pressure. Purification by flash column chromatography (silica gel, elution with hexanes/EtOAc: 80/20) provided the protected alcohol 20.62 g (76.77 mmol, 84%) as a pale yellow oil.
Reaction SMILES: [NH2-].[Na+].Cl[C:4]1[CH:9]=[C:8]([Cl:10])[N:7]=[C:6]([CH3:11])[N:5]=1.[NH2:12][C:13]1[S:14][C:15]([C:18]([NH:20][C:21]2[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:28])=[O:19])=[CH:16][N:17]=1.Cl>O.C1COCC1>[Cl:10][C:8]1[N:7]=[C:6]([CH3:11])[N:5]=[C:4]([NH:12][C:13]2[S:14][C:15]([C:18]([NH:20][C:21]3[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:28])=[O:19])=[CH:16][N:17]=2)[CH:9]=1
Reactant: Cc1nc(Cl)cc(Cl)n1
Reactant: Cc1cccc(Cl)c1NC(=O)c1cnc(N)s1
Agent: Cl
Agent: [NH2-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(Cl)cc(Nc2ncc(C(=O)Nc3c(C)cccc3Cl)s2)n1
Temperature: 7.5 °C
Reaction time: 0.21 h

Procedure:
Into a RBF 6.6 g of Sodium Amide was added at 30-35° C. under N2 atmosphere and stirring was done for 10-15 minutes. Then the reaction mass was cooled to 5-10° C. and 120.0 mL THF and 7.92 g 4,6-Dichloro-2-methyl pyrimidine were added to the reaction mass. Addition of 10.0 g 2-amino-N-(2-chloro-6-methyl phenyl)-5-thiazole carboxamide was then performed into the reaction mass. The reaction mass was stirred for ˜40 mins at 30-35° C. to get clear solution which was transferred to an addition dropper. At temperature of 5-10° C., the reaction mass was slowly added over 30 minutes, into another RBF having 40.0 mL THF. At the same temperature, the reaction mass was stirred for 1.0-1.5 hrs. Then the reaction mass temperature was increased to 30-35° C., where stirring was performed for 3 to 4 hrs. On completion of the reaction as verified by TLC, the reaction mass was cooled slowly to a temperature of 0-5° C. Then the reaction mass pH was adjusted to 3-4 by addition of 22.4 mL HCl and 240 mL water over 10-15 mins. The reaction mass was then stirred for 2.0-2.5 hrs at 0-5° C.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]1[CH:19]=[CH:18][C:6]([C:7]([C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=O)=[O:8])=[C:5]([CH3:20])[CH:4]=1.[CH3:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37]2[CH:42]=[CH:41][C:40]([CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[CH:39][CH:38]=2)=[CH:32][CH:31]=1>>[CH3:21][N:2]([CH3:1])[C:3]1[CH:19]=[CH:18][C:6]([C:7]2([N:36]([C:37]3[CH:38]=[CH:39][C:40]([CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[CH:41][CH:42]=3)[C:33]3[CH:32]=[CH:31][C:30]([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH3:22])=[CH:35][CH:34]=3)[C:9]3[C:10](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:11](=[O:13])[O:8]2)=[C:5]([CH3:20])[CH:4]=1
Reactant: Cc1cc(N(C)C)ccc1C(=O)c1ccccc1C(=O)O
Reactant: CCCCCCCCc1ccc(Nc2ccc(CCCCCCCC)cc2)cc1
Product: CCCCCCCCc1ccc(N(c2ccc(CCCCCCCC)cc2)C2(c3ccc(N(C)C)cc3C)OC(=O)c3ccccc32)cc1
Yield: 46.8 %

Procedure:
Following a procedure similar to that described in Example 1 but employing 5.7 g of 2-[4-(dimethylamino)-2-methylbenzoyl]benzoic acid and 8.0 g of 4,4'-dioctyldiphenylamine there was obtained 6.2 g of 3-[4-(dimethylamino)-2-methylphenyl]-3-[bis(4-octylphenyl)amino]phthalide, m.p. 172°-174° C. A toluene solution of the product contacted with acidic clay or phenolic resin developed a red-colored image.
Reaction SMILES: Cl.[NH2:2]O.[CH2:4]([O:6][C:7](=[O:39])[C:8](O)=[CH:9][C:10]([C:12]1[CH:17]=[C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:15]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:14][C:13]=1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:11])[CH3:5].O>C(O)C>[CH2:4]([O:6][C:7]([C:8]1[CH:9]=[C:10]([C:12]2[CH:17]=[C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:15]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:14][C:13]=2[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:11][N:2]=1)=[O:39])[CH3:5]
Reactant: NO
Reactant: CCOC(=O)C(O)=CC(=O)c1cc(C(C)(C)C)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc(-c2cc(C(C)(C)C)c(OCc3ccccc3)cc2OCc2ccccc2)on1
Yield: 89.1 %

Procedure:
Hydroxylamine hydrochloride (3.6 g, 52 mmol) was added to a solution of 4-(2,4-Bis-benzyloxy-5-tert-butyl-phenyl)-2-hydroxy-4-oxo-but-2-enoic acid ethyl ester (9.0 g, 18.5 mmol) in ethanol (75 ml) and the suspension heated under reflux for ˜4 hrs. The resulting solution was allowed to cool and poured into water (200 ml) to give an off-white precipitate. The solids were removed by filtration and taken up in dichloromethane (150 ml). The solution was washed with water (150 ml) and saturated aqueous sodium chloride solution (50 ml). The solution was dried over anhydrous sodium sulphate and concentrated to an off-white solid. Solids were washed with hexane and dried in vacuo (40° C.), to give 5-(2,4-bis-benzyloxy-5-tert-butyl-phenyl)-isoxazole-3-carboxylic acid ethyl ester as a pale brown powder (8.0 g, 89%).