Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:9]=[CH:10][C:2]1=2.CC(OC(C)=O)=O.[N+:23]([O-])([OH:25])=[O:24]>CC(O)=O>[N+:23]([C:9]1[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][C:3]2[O:4][CH2:5][CH2:6][O:1][C:2]=2[CH:10]=1)([O-:25])=[O:24]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)c1ccc2c(c1)OCCO2
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)c1cc2c(cc1[N+](=O)[O-])OCCO2
Temperature: 50 °C
Yield: 99 %

Procedure:
According to the procedure described in Example 6A Step 2, to a solution of ethyl 2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylate (1.42 g, 6.8 mmol) and Ac2O (3 mL), in AcOH (15 mL) was dropped fuming nitric acid (1 mL). The reacted ion was heated at 50° C. for 2 hours, to afford ethyl 7-nitro-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylate as a solid (1.720 g, 99%). 1H NMR (300 MHz, CDCl3) δ 7.51 (s, 1H), 7.18 (s, 1H), 4.36 (m, 6H), 1.33 (t, 3H).
Reaction SMILES: [C:1]1([C@H:11]([N:13]([CH2:21][CH:22]2[CH:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:25][NH:24][CH2:23]2)[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.ClCCl.[C:36]1([N:42]=[C:43]=[O:44])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(OCC)(=O)C>[NH:42]([C:43]([N:24]1[CH2:25][CH:26]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:22]([CH2:21][N:13]([C@@H:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[CH3:12])[C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:19])[CH3:17])[CH2:23]1)=[O:44])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=C=Nc1ccccc1
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CNCC1c1ccccc1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[C@H](c1cccc2ccccc12)N(CC1CN(C(=O)Nc2ccccc2)CC1c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.4 %

Procedure:
A mixture of 215 mg of tert-butyl [(1R)-1-(1-naphthyl)ethyl][(4-phenylpyrrolidin-3-yl)methyl]carbamate and 5 ml of dichloromethane was mixed with 119 mg of phenyl isocyanate and stirred at room temperature for 4 hours. The reaction solution was diluted with ethyl acetate and washed with water and 1 M hydrochloric acid. The organic layer was dried with anhydrous sodium sulfate and concentrated under a reduced pressure. The thus obtained residue was purified by a silica gel column chromatography (chloroform-methanol)to obtain 270 mg of crude tert-butyl {[1-(anilinocarbonyl)-4-phenylpyrrolidin-3-yl]methyl}[(1R)-1-(1-naphthyl)ethyl]carbamate as a colorless solid. The thus obtained compound was dissolved in 5 ml of ethyl acetate, mixed with 1 ml of 4 M hydrogen chloride/ethyl acetate and stirred overnight at room temperature. The resulting precipitate was collected by filtration to obtain 56 mg of 3-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-N,4-diphenylpyrrolidine-1-carboxamide hydrochloride as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[CH2:10]([NH2:13])[C:11]#[CH:12].C(=O)([O-])[O-].[K+].[K+].C1COCC1>O>[Cl:1][C:2]1[N:7]=[C:6]([NH:13][CH2:10][C:11]#[CH:12])[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: C#CCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C#CCNc1nc(Cl)ncc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.5 %

Procedure:
2,4,5-Trichloropyrimidine (500 mg, 2.7 mmol), propargyl amine (149 mg, 2.7 mmol), and potassium carbonate (373 mg, 2.7 mmol) were combined in a 30 ml reaction vial with 5 ml THF and stirred at room temperature overnight. The reaction was poured into 50 ml water and extracted with EtOAc (3×20 ml). The combined organic was dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield (2,5-dichloro-pyrimidin-4-yl)-prop-2-ynyl-amine (488 mg, 90%) as a yellow oil that crystallizes upon standing. This was used crude in the next reaction.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:9]=[CH:8][C:5]=1[C:6]#[N:7].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>O1CCCC1.CN(C)C=O>[C:6]([C:5]1[CH:8]=[CH:9][C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][C:4]=1[O:3][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])#[N:7]
Reactant: N#Cc1ccc(OCc2ccccc2)cc1O
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)COc1cc(OCc2ccccc2)ccc1C#N
Reaction time: 0.5 h
Yield: 80.3 %

Procedure:
9.7 g (0.20 mol) of 50% sodium hydride are slowly added portionwise to a solution of 46 g (0.20 mol) of 2-hydroxy-4-(phenylmethoxy)benzonitrile in a mixture of 450 ml of tetrahydrofuran and 450 ml of dimethylformamide. The mixture is stirred for 30 minutes and then 22.4 ml (0.20 mol) of ethyl bromoacetate are added dropwise. Reaction is allowed to take place for 30 minutes, the reaction mixture is then poured into ice-cold water and the product is extracted with ethyl acetate. The organic phase is then washed with water, dried over sodium sulphate and concentrated under reduced pressure. After trituration of the residue in diisopropyl ether, 50 g of product are obtained.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=O)[C:16]([CH3:23])([CH3:22])[CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>CO.P(=O)(O)(O)O.[OH-].[OH-].[Pd+2]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]([CH3:23])([CH3:22])[CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:14]=1
Reactant: [H][H]
Reactant: COC(=O)CC(C)(C)C(=O)c1ccc(OCc2ccccc2)cc1
Agent: [Pd+2]
Agent: O=P(O)(O)O
Agent: [OH-]
Solvent: CO
Product: COC(=O)CC(C)(C)Cc1ccc(O)cc1

Procedure:
A solution of the product of STEP 3 in methanol and phosphoric acid (catalytic amount) was shaken in Parr hydrogenation apparatus with 20% Pd(OH)2/C under 60 psi hydrogen pressure for 9 hours. The solution was filtered and filtrate concentrated in vacuo. An ether solution of the residue was treated with excess diazomethane in ether at 0° C. The resulting solution was concentrated in vacuo and the residue was purified by chromatography over silica gel using 10% ethyl acetate in hexane as eluant to provide the above compound as a colorless thick liquid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[N:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[F:11][CH:12]([F:26])[O:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([O:22][CH:23]([F:25])[F:24])[CH:21]=1)[CH:17]=[O:18].[OH-].[K+].O>CO>[F:11][CH:12]([F:26])[O:13][C:14]1[CH:15]=[C:16]([CH:17]([C:5]2[C:4]3[C:8](=[N:9][CH:10]=[C:2]([Br:1])[CH:3]=3)[NH:7][CH:6]=2)[OH:18])[CH:19]=[C:20]([O:22][CH:23]([F:24])[F:25])[CH:21]=1
Reactant: Brc1cnc2[nH]ccc2c1
Reactant: O=Cc1cc(OC(F)F)cc(OC(F)F)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: OC(c1cc(OC(F)F)cc(OC(F)F)c1)c1c[nH]c2ncc(Br)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.7 %

Procedure:
To 5-bromo-7-azaindole (67, 86.4 mg, 0.000438 mol) in methanol (10.0 mL) were added 3,5-bis-difluoromethoxy-benzaldehyde (529, 110.0 mg, 0.46 mmol) and potassium hydroxide (200.0 mg, 3.6 mmol) under an atmosphere of nitrogen. The reaction was stirred at room temperature overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give the compound as a white solid (530, 70 mg, 35%). MS (ESI) [M+H+]+=435.1, 437.1.
Reaction SMILES: [NH2:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][NH:4][N:3]=1.[H-].[Na+].Br[CH2:13][CH2:14][CH2:15]Br.ClCCl>CN(C=O)C>[N+:7]([C:6]1[CH:5]=[N:4][N:3]2[CH2:15][CH2:14][CH2:13][NH:1][C:2]=12)([O-:9])=[O:8]
Reactant: Nc1n[nH]cc1[N+](=O)[O-]
Reactant: BrCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cnn2c1NCCC2
Temperature: 0 °C
Yield: 87.7 %

Procedure:
A solution of 51.2 g (0.4 moles) 3-amino-4-nitropyrazole in 650 ml dried DMF is slowly added by drops to a suspension of 10 g (0.4 moles) sodium hydride in 200 ml dried DMF. After the reaction is concluded, 121 g (0.6 moles) 1,3-dibromopropane in 250 ml DMF are added. The mixture is then heated for 5 hours accompanied by reflux. After cooling, the preparation is reduced to dryness. When the residue is treated with 300 ml dichloromethane and subsequently cooled to 0° C. the product is precipitated out together with NaBr. The raw product is recrystallized from 1200 ml ethanol. 59 g (38%) ocher-colored crystals with a melting point of 251°-252° C. are obtained.
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:6]=1[N+:15]([O-])=O)([CH3:3])[CH3:2]>[Pd].C(OCC)(=O)C>[CH:1]([NH:4][C:5]1[C:6]([NH2:15])=[CH:7][C:8]([C:11]([F:13])([F:14])[F:12])=[CH:9][CH:10]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Nc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)Nc1ccc(C(F)(F)F)cc1N
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90.6 %

Procedure:
A mixture of 5.46 g of N-isopropyl-2-nitro-4-trifluoromethylaniline, 30 ml of ethyl acetate and 5% palladium charcoal (catalytic amount) was stirred for 1.5 hours at room temperature under a hydrogen atmosphere of about 1 atm. The reaction mixture was filtrated through Celite (registered trademark). The filtrate was washed with water, dried over sodium sulfate, then, concentrated under reduced pressure, to obtain 4.35 g of N1-isopropyl-4-trifluoromethylbenzene-1,2-diamine.
Reaction SMILES: S(Cl)(Cl)=O.[I:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1.[CH:15](O)([CH3:17])[CH3:16]>>[CH:15]([O:11][C:10](=[O:12])[C:9]1[CH:13]=[CH:14][C:6]([I:5])=[CH:7][CH:8]=1)([CH3:17])[CH3:16]
Reactant: O=C(O)c1ccc(I)cc1
Reactant: CC(C)O
Solvent: O=S(Cl)Cl
Product: CC(C)OC(=O)c1ccc(I)cc1
Temperature: 50 °C

Procedure:
Thionyl chloride (1.4 ml) was added to a solution of 4-iodobenzoic acid (3.72 g) in isopropanol (25 ml) and the reaction mixture heated at 50° C. for several hours. The reaction mixture was cooled to ambient temperature and evaporated. Methylene chloride was added to the residue and the mixture filtered. The filtrate was washed with saturated sodium bicarbonate solution, water, saturated brine, dried (MgSO4) and evaporated to give isopropyl-4-iodo-benzoate as an oil (1.5 g); NMR: 1.28-137(6H,d), 5.04-5.21(1H,m), 7.65-7.74(2H,d), 7.88-7.95(2H,d); m/z 291(M+H).
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:10]1[S:14][C:13]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)=[N:12][CH:11]=1>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.C(N(CC)CC)C>[C:1]1([C:7]#[C:8][C:10]2[S:14][C:13]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)=[N:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Ic1cnc(-c2cccs2)s1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: C(#Cc1cnc(-c2cccs2)s1)c1ccccc1
Yield: 71.4 %

Procedure:
In a manner similar to Step D of Example 1, the reaction of 1.3 gram (0.013 mole) of phenylacetylene, 50 ml of triethylamine, 3.2 grams (0.011 mole) of 5-iodo-2-(thien-2-yl)thiazole, 0.080 gram (1.1×10-4 mole) of dichlorobis(triphenylphosphine)palladium (II), and 0.022 gram (1.1×10-4 mole) of copper(I) iodide produced 2.1 grams of 1-phenyl-2-[2-(thien-2-yl)thiazol-5-yl]ethyne as a solid, m.p. 94°-96° C., Compound 22 of Table 1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH2:14](OC(=O)C1C=C(OCCOC)C(OCCOC)=CC=1N)C.S(Cl)(Cl)=O.C(=O)([O-])O.[Na+]>CO>[CH3:14][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([OH:1])[CH:3]=[CH:4][C:5]=1[N+:11]([O-:13])=[O:12]
Reactant: CCOC(=O)c1cc(OCCOC)c(OCCOC)cc1N
Reactant: O=C(O)c1cc(O)ccc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)c1cc(O)ccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 12 h

Procedure:
5-Hydroxy-2-nitro-benzoic acid (compound A′) (1.5 g) was dissolved in methanol (15 ml). Thionyl chloride (1.5 ml) was added dropwise to the solution on an ice bath, and the mixture was then stirred at 80° C. for 12 hr. After the completion of the reaction, the reaction solution was neutralized with a saturated aqueous sodium hydrogencarbonate solution, and was then subjected to separatory extraction with ethyl acetate. The organic layer was washed with saturated brine, was dried over sodium sulfate, and was then concentrated under the reduced pressure to give crude 5-hydroxy-2-nitro-benzoic acid methyl ester (1.1 g, crude yield 70%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[OH:20][C:21]1[C:30]2[C:25](=[N:26][C:27]([CH3:31])=[CH:28][CH:29]=2)[N:24]=[CH:23][C:22]=1[C:32](O)=[O:33]>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:19][C:32]([C:22]1[CH:23]=[N:24][C:25]2[C:30]([C:21]=1[OH:20])=[CH:29][CH:28]=[C:27]([CH3:31])[N:26]=2)=[O:33]
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Reactant: Cc1ccc2c(O)c(C(=O)O)cnc2n1
Product: Cc1ccc2c(O)c(C(=O)Nc3ccc(N4CCC(N5CCCC5C)C4)cc3C)cnc2n1

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 4-hydroxy-7-methyl-[1,8]naphthyridine-3-carboxylic acid. MS: 446.5 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](I)[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH2:17][CH2:18][CH3:19])=[O:15].[CH3:20][O:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:23]3[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:22]=3[O:21][CH3:20])[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH2:17][CH2:18][CH3:19])=[O:15]
Reactant: CCCNC(=O)c1nnc2c(I)c(F)ccc2c1N
Reactant: COc1cc(F)ccc1B(O)O
Product: CCCNC(=O)c1nnc2c(-c3ccc(F)cc3OC)c(F)ccc2c1N
Yield: 52.8 %

Procedure:
Using method A, 4-amino-7-fluoro-8-iodo-N-propyl-cinnoline-3-carboxamide (250 mg, 0.67 mmol) and (2-methoxy-4-fluorophenyl)boronic acid (227.1 mg, 1.336 mmol) were reacted to afford the title compound (131.7 mg, 53% yield) as an off-white solid. 1H NMR (500 MHz, CDCl3) δ 8.49 (bs, 1H), 7.89 (d×d, J=5.5 Hz, J=9.2 Hz, 1H), 7.52 (apparent triplet, J=8.9 Hz, 1H), 7.30 (m, 1H), 6.82 (d×d, J=2.4 Hz, J=8.5 Hz, 1H), 6.79 (d×d, J=2.4 Hz, J=12.8 Hz, 1H), 3.72 (s, 3H), 3.44 (q, J=6.7 Hz, J=13.4 Hz, 2H), 1.64 (apparent sextet, J=7.3 Hz, 2H), 0.99 (t, J=7.6 Hz, 3H). MS APCI, m/z=373 (M+H) HPLC 2.70 min.
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].[Br:8][C:9]1[N:14]=[C:13]([CH:15]=O)[CH:12]=[CH:11][CH:10]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(O)(=O)C>[Br:8][C:9]1[N:14]=[C:13]([CH2:15][N:4]([CH2:5][CH2:6][CH3:7])[CH2:1][CH2:2][CH3:3])[CH:12]=[CH:11][CH:10]=1
Reactant: CCCNCCC
Reactant: O=Cc1cccc(Br)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCCN(CCC)Cc1cccc(Br)n1
Temperature: 50 °C
Reaction time: 1 h
Yield: 72.9 %

Procedure:
Dipropylamine (7.4 mL, 54 mmol) and 6-bromopyridine-2-carbaldehyde (5.0 g, 27 mmol) were dissolved in 1,2-dichloroethane (50 mL). 2 drops of glacial acetic acid was added followed by sodium triacetoxyborohydride (11.4 g, 54 mmol). The reaction was stirred at 50° C. for 1 h. The reaction was cooled and quenched with water. The solution was diluted with saturated sodium bicarbonate and extracted with ethyl acetate (3 times). The organic layers were dried over magnesium sulfate, filtered and concentrated. Flash chromatography gave 5.34 g (73% yield) of product.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[ClH:10].[CH2:11]([OH:13])[CH3:12]>>[ClH:10].[F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6](=[NH:7])[O:13][CH2:11][CH3:12])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: CCO
Agent: Cl
Product: CCOC(=N)c1ccc(F)cc1

Procedure:
Ethyl 4-fluorobenzimidate hydrochloride was synthesized in the same manner as in Reference Example 2. That is, 4-fluorobenzonitrile (50.8 g, 0.407 mol) was treated with hydrogen chloride in ethanol (500 mL) to give 82.1 g (99%) of the target compound as colorless crystals.
Reaction SMILES: [C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17](B(O)O)=[CH:18]4)=[CH:13][C:12]=3[O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.I[C:33]1[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=1>>[C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:33]5[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=5)=[CH:18]4)=[CH:13][C:12]=3[O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: COC(=O)c1ccc(I)cc1
Reactant: OB(O)c1ccc2cc(OCc3ccccc3)c(C34CC5CC(CC(C5)C3)C4)cc2c1
Product: COC(=O)c1ccc(-c2ccc3cc(OCc4ccccc4)c(C45CC6CC(CC(C6)C4)C5)cc3c2)cc1
Yield: 33.5 %

Procedure:
Following the procedure of Example 1(c), but reacting 1.5 g (3.6 mmol) of 7-(1-adamantyl)-6-benzyloxy-2-naphthylboronic acid with 500 mg (1.9 mmol) of methyl 4-iodobenzoate, 320 mg (33%) of the compound were obtained, which compound had a melting point of 170°-3° C.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:24]3[C:19](=[CH:20][C:21]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:22][CH:23]=3)[C:18]([CH3:33])=[C:17]2[C:34]2[CH:39]=[CH:38][C:37]([O:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[CH:36][CH:35]=2)=[CH:11][CH:10]=1)(=O)=O.Cl.[F:49][CH2:50][C@@H:51]1[CH2:55][CH2:54][NH:53][CH2:52]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:26]([O:25][C:21]1[CH:20]=[C:19]2[C:24](=[CH:23][CH:22]=1)[N:16]([CH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][N:53]3[CH2:54][CH2:55][C@@H:51]([CH2:50][F:49])[CH2:52]3)=[CH:10][CH:11]=1)[C:17]([C:34]1[CH:35]=[CH:36][C:37]([O:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[CH:38][CH:39]=1)=[C:18]2[CH3:33])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: Cc1c(-c2ccc(OCc3ccccc3)cc2)n(Cc2ccc(OCCOS(C)(=O)=O)cc2)c2ccc(OCc3ccccc3)cc12
Reactant: FC[C@@H]1CCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1c(-c2ccc(OCc3ccccc3)cc2)n(Cc2ccc(OCCN3CC[C@@H](CF)C3)cc2)c2ccc(OCc3ccccc3)cc12
Temperature: 80 °C

Procedure:
A mixture of 2-(4-((5-(benzyloxy)-2-(4-(benzyloxy)phenyl)-3-methyl-1H-indol-1-yl)methyl)phenoxy)ethyl methanesulfonate, (R)-3-(fluoromethyl)pyrrolidine (Intermediate 8) and potassium carbonate in acetonitrile was degassed with three vacuum/N2 cycles. The reaction was heated at 80° C. for 10 hrs, allowed to cool to room temperature and then diluted with water (40 mL). The aqueous layer was extracted with ethyl acetate (2×40 mL) and the combined ethyl acetate extracts were then washed with water (40 mL), washed with brine (40 mL), dried (MgSO4), filtered, concentrated and purified by silica gel chromatography (0%-5% MeOH in DCM) to give 274 mg of (R)-5-(benzyloxy)-2-(4-(benzyloxy)phenyl)-1-(4-(2-(3-(fluoromethyl)pyrrolidin-1-yl)ethoxy)benzyl)-3-methyl-1H-indole. 1H NMR (400 MHz, DMSO-d6): δ 7.48 (d, 4H), 7.44-7.37 (m, 4H), 7.37-7.32 (m, 2H), 7.30 (d, 2H), 7.21 (d, 1H), 7.15-7.10 (m, 3H), 6.81 (dd, 1H), 6.74 (s, 4H), 5.17-5.10 (m, 6H), 4.33-4.30 (m, 1H), 4.22-4.18 (m, 1H), 3.94 (t, 2H), 2.70 (t, 2H), 2.56-2.40 (m, 3H), 2.60 (t, 1H), 2.36-2.31 (m, 1H), 2.16 (s, 3H), 1.86-1.76 (m, 1H), 1.40-1.30 (m, 1H). LCMS: 655.3 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.CC1(C)C(C)(C)OB([C:17]2[CH:18]=[C:19]([N:23]3[C:35]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[C:29]4[C:24]3=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:20]=[CH:21][CH:22]=2)O1.C([O-])(=O)C.[K+]>C1(C)C=CC=CC=1.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:8][C:4]1[CH:3]=[C:2]([C:21]2[CH:22]=[CH:17][CH:18]=[C:19]([N:23]3[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=4[C:30]4[C:35]3=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:20]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)c1
Reactant: CC1(C)OB(c2cccc(-n3c4ccccc4c4ccccc43)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Brc1cccc(-c2cccc(-n3c4ccccc4c4ccccc43)c2)c1

Procedure:
1,3-Dibromobenzene (16 g, 64.9 mmol), 9-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-9H-carbazole b(6.0 g, 11.6 mmol), potassium acetate (saturated solution of 6.6 g in water) and tetrakis(triphenylphosphine)palladium (0) (380 mg) are heated to reflux in 150 mL of toluene overnight under nitrogen atmosphere. After cooling down, evaporation and column chromatography 9-(3′-bromo-[1,1′-biphenyl]-3-yl)-9H-carbazole (5.8 g) is obtained.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH:17]=[C:16]([F:18])[C:15]([N:19]=CN(C)C)=[N:14][C:13]2=[O:24])(=[O:11])=[O:10])=[CH:5][CH:4]=1>O1CCOCC1>[NH2:19][C:15]1[C:16]([F:18])=[CH:17][N:12]([S:9]([C:6]2[CH:5]=[CH:4][C:3]([Cl:2])=[CH:8][CH:7]=2)(=[O:11])=[O:10])[C:13](=[O:24])[N:14]=1
Reactant: CN(C)C=Nc1nc(=O)n(S(=O)(=O)c2ccc(Cl)cc2)cc1F
Agent: Cl
Solvent: C1COCCO1
Product: Nc1nc(=O)n(S(=O)(=O)c2ccc(Cl)cc2)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.1 %

Procedure:
To an 8 mL screw-cap vial was added dioxane (9 mL), 1 N aqueous hydrochloric acid (HCl; 1 mL), and N′-[1-(4-chloro-benzenesulfonyl)-5-fluoro-2-oxo-1,2-dihydro-pyrimidin-4-yl]-N,N-dimethylformamidine (269 mg, 0.75 mmol). The mixture was shaken at room temperature for 16 h, evaporated under a stream of nitrogen, and partitioned between EtOAc and satd aq NaHCO3. The organic phase was dried over MgSO4, filtered, and evaporated to yield the title product as a white solid (196 mg, 86%): mp 174-178° C.; 1H NMR (300 MHz, CDCl3) δ 8.5 (br s, 1H), 8.08 (d, J=5.9 Hz, 1H), 8.04-7.98 (m, 2H), 7.55-7.49 (m, 2H), 5.9 (br s, 1H); ESIMS m/z 304 ([M+H]+).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[OH:34][CH2:35][C:36]1[CH:37]=[C:38]([S:42][C:43]2[CH:44]=[N:45][CH:46]=[C:47]([CH:50]=2)[C:48]#[N:49])[CH:39]=[CH:40][CH:41]=1.[OH:51][C:52]1[C:57]([CH3:58])=[C:56](O)[CH:55]=[CH:54][C:53]=1[C:60](=[O:62])[CH3:61]>C1COCC1>[C:60]([C:53]1[CH:54]=[CH:55][C:56]([O:34][CH2:35][C:36]2[CH:37]=[C:38]([S:42][C:43]3[CH:44]=[N:45][CH:46]=[C:47]([CH:50]=3)[C:48]#[N:49])[CH:39]=[CH:40][CH:41]=2)=[C:57]([CH3:58])[C:52]=1[OH:51])(=[O:62])[CH3:61]
Reactant: N#Cc1cncc(Sc2cccc(CO)c2)c1
Reactant: CC(=O)c1ccc(O)c(C)c1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)c1ccc(OCc2cccc(Sc3cncc(C#N)c3)c2)c(C)c1O
Yield: 50.5 %

Procedure:
Add triphenylphosphine (5.24 g, 20.0 mmol) and diisopropylazodicarboxylate (4.04 g, 20.0 mmol) to a solution of 5-(3-(hydroxymethyl)phenylthio)nicotinonitrile (4.84 g, 20.0 mmol) and 1-(2,4-dihydroxy-3-methylphenyl)ethanone (3.32 g, 20.0 mmol) in THF (100 mL). Stir the reaction for 24 h. Quench the reaction with water and extract with EtOAc. Dry, filter and concentrate. Purify the residue by flash chromatography on silica gel eluting with a mixture of EtOAc and hexanes (15:85 to 20:80) to give an off-white solid. Recrystallize the solid from a mixture of EtOAc and hexanes to afford the title compound (3.94 g, 50%): 1H NMR (CDCl3) δ 2.14 (s, 3H), 2.57 (s, 3H), 5.18 (s, 2H), 6.44 (d, J=9.0 Hz, 1H), 7.46-7.49 (m, 3H), 7.52 (s, 1H), 7.59 (d, J=9.0 Hz, 1H), 7.62-7.63 (m, 1H), 8.63-8.64 (m, 2H), 12.78 (s, 1H).