Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.[CH3:9][NH:10][CH2:11][CH2:12][OH:13]>C(O)C.O>[Cl:8][C:6]1[N:7]=[CH:2][N:3]=[C:4]([N:10]([CH3:9])[CH2:11][CH2:12][OH:13])[CH:5]=1
Reactant: CNCCO
Reactant: Clc1ccnc(Cl)n1
Solvent: CCO
Solvent: O
Product: CN(CCO)c1cc(Cl)ncn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 14.8 g (0.1 mmol) 2,4-dichloropyrimidine in 120 ml ethanol and 20 ml water, cooled to 0° C., 11.3 g (0.15 mol) 2-(N-methylamino)ethanol is added. The resulting mixture is stirred at room temperature for ½ h., then concentrated to dryness and finally partitioned between CH2Cl2 and a NaHCO3 saturated solution.
Reaction SMILES: CS(O)(=O)=O.CS(O)(=O)=O.[NH2:11][C:12]1[C:19](=[O:20])[N:15]2[CH2:16][CH2:17][CH2:18][N:14]2[C:13]=1[NH2:21].[NH2:22][C:23]1[CH:24]=[CH:25][C:26]([CH3:30])=[C:27]([OH:29])[CH:28]=1.N.OO>O.C(O)C>[NH2:21][C:13]1[N:14]2[CH2:18][CH2:17][CH2:16][N:15]2[C:19](=[O:20])[C:12]=1/[N:11]=[C:24]1/[C:23]([NH2:22])=[CH:28][C:27](=[O:29])[C:26]([CH3:30])=[CH:25]/1
Reactant: Nc1c(N)n2n(c1=O)CCC2
Reactant: Cc1ccc(N)cc1O
Agent: CS(=O)(=O)O
Agent: N
Agent: OO
Solvent: CCO
Solvent: O
Product: CC1=C/C(=N\c2c(N)n3n(c2=O)CCC3)C(N)=CC1=O

Procedure:
0.58 mmol of 2,3-diamino-6,7-dihydro-1H,5H-pyrazolo[1,2-a]pyrazol-1-one dimethane sulphonate was dissolved in a mixture of water and ethanol (7.5 ml/1.5 ml). This solution was admixed with 0.58 mmol of 5-amino-2-methyl phenol, then with 1.8 ml of concentrated aqueous ammonia, then with 9 ml of hydrogen peroxide.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]([O:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][CH2:10][OH:11])=[CH:12][CH:13]=1
Reactant: O=[N+]([O-])c1ccc(OCCO)cc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(OCCO)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.9 %

Procedure:
A solution of 2-(4-nitro-phenoxy)-ethanol (2.1 g, 12 mmol) in MeOH (30 mL) was flushed with argon and then charged with 10 wt % Pd/C (0.1 equiv by wt). The mixture was evacuated under house vacuum and then refilled with hydrogen from hydrogen balloon. The cycle was repeated again and the mixture stirred at room temperature for 2 h. The heterogeneous reaction mixture was filtered through a pad of Celite, washed with MeOH and concentrated in vacuo to furnish the title compound (1.8 g, 99%) as a brown solid. MS (ES+): m/z 154 (M+H)+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrBr.C(N(CC)CC)C.[CH3:29][C:30]1[CH:34]=[CH:33][N:32]([NH:35][C:36](=O)[C@@H:37]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[CH3:38])[C:31]=1[C:48](=[O:56])[NH:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1.N>ClCCl>[CH3:29][C:30]1[CH:34]=[CH:33][N:32]2[C:31]=1[C:48](=[O:56])[N:49]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:36]([C@@H:37]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[CH3:38])=[N:35]2
Reactant: Cc1ccn(NC(=O)[C@H](C)NC(=O)OC(C)(C)C)c1C(=O)Nc1ccccc1
Agent: BrBr
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccn2nc([C@H](C)NC(=O)OC(C)(C)C)n(-c3ccccc3)c(=O)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.9 %

Procedure:
Triphenylphosphine (6.8 g, 25.93 mmol) was dissolved in 50 mL dichloromethane. Bromine (1.33 mL, 25.97 mmol) was added dropwise and the reaction was stirred at room temperature for 30 min. Triethylamine (10.3 mL, 73.9 mmol) and (S)-tert-butyl (1-((3-methyl-2-(phenylcarbamoyl)-1H-pyrrol-1-yl)amino)-1-oxopropan-2-yl)carbamate (7.15 g, 18.5 mmol) suspended in 100 mL dichloromethane was added and the reaction mixture was stirred at 60° C. for 2 h. The mixture was concentrated to dryness and was re-dissolved in a pressure reactor with a solution of ammonia (7M in methanol, 350 mL, 2415 mmol). The mixture was heated at 100° C. for 32 h, then cooled at room temperature and evaporated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic layer was washed with water, brine and dried over sodium sulphate, filtered and concentrated. The residue was purified using Isolera® Purification System (0% to 50%, hexane-ethyl acetate) to obtain 0.95 g (14% yield) of the title compound as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6](/[CH:8]=[N:9]/[C:10]([CH3:13])([CH3:12])C)[CH:7]=1.[C:15]([C:17]1[CH:22]=[CH:21]C(C#C)=[CH:19][CH:18]=1)#[N:16].C(NC(C)C)(C)C>C1(C)C=CC=CC=1.[Cu]I.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>[Br:1][C:2]1[CH:7]=[C:6]2[C:5]([CH:13]=[C:10]([C:12]3[CH:21]=[CH:22][C:17]([C:15]#[N:16])=[CH:18][CH:19]=3)[N:9]=[CH:8]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)/N=C/c1cc(Br)ccc1I
Reactant: C#Cc1ccc(C#N)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: Cc1ccccc1
Solvent: CC(C)NC(C)C
Product: N#Cc1ccc(-c2cc3ccc(Br)cc3cn2)cc1

Procedure:
The product from Example 62D (3.6 mmol), 4-cyanophenylacetylene (4.3 mmol), CuI (0.2 mmol), PdCl2(PPh3)2 (0.1 mmol), and diisopropylamine (5.3 mmol) can be combined in toluene (15 mL) and processed as described in Example 62E to provide the title compound.
Reaction SMILES: [C:1]1([CH:7]([CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[C:8](O)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)C=O.C(Cl)(=O)C([Cl:24])=O>C(Cl)Cl>[C:1]1([CH:7]([CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[C:8]([Cl:24])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C(c1ccccc1)C1CCCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)C(c1ccccc1)C1CCCC1
Reaction time: 0.75 h

Procedure:
To a stirred solution of α-phenylcyclopentaneacetic acid (422 mg; 2.0 mmol) and a catalytic amount of dry dimethylformamide (ca. 20 uL) in 5 mL of dry methylene chloride under nitrogen at room temperature was added oxalyl chloride (1.5 mL of 2.0 M solution in methylene chloride) dropwise. After 45 minutes, the mixture was concentrated in vacuo to give crude α-phenylcyclopentaneacetyl chloride which was used immediately for Step 2.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[NH2:9][C@H:10]1[CH2:14][CH2:13][NH:12][CH2:11]1>C(O)(C)C>[Br:8][C:5]1[CH:4]=[N:3][C:2]([N:12]2[CH2:13][CH2:14][C@H:10]([NH2:9])[CH2:11]2)=[N:7][CH:6]=1
Reactant: N[C@H]1CCNC1
Reactant: Clc1ncc(Br)cn1
Solvent: CC(C)O
Product: N[C@H]1CCN(c2ncc(Br)cn2)C1
Reaction time: 4 h

Procedure:
Combine 2-chloro-5-bromopyrimidine (20.0 g, 1.0 eq) and isopropanol (200 mL). Add (S)-3-aminopyrrolidine (8.91 g, 1.0 eq) dropwise over about 30 minutes. Add isopropanol (10 mL) and heat to 50° C.-60′. After 4 hours, cool to 20° C.-25° C. over about 1 hour, stir for about 1 hour, and then collect the solid by filtration. Rinse the solid with isopropanol (2×25 mL) and dry under vacuum at about 40° C. to give (S)-1-(5-bromopyrimidin-2-yl)-pyrrolidine-3-amine as its hydrochloride salt.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C>[CH2:18]([O:10][C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:8][C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=2)=[CH:7][CH:6]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(OCc2ccccc2)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 4-hydroxy-phenyl acetic acid (10.0 g, 65.72 mmol) in DMF (70 mL) at rt were added Cs2CO3 (47.11 g, 144.5 mmol) and benzyl bromide (17.29 mL, 144.5 mmol). The reaction mixture was stirred overnight at room temperature, heated at 100° C. for 1 h and cooled to rt. The solvent was removed under reduced pressure and poured into H2O. The aqueous solution was extracted with ethyl acetate and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was recrystallization in hexanes to afford (4-benzyloxy-phenyl)acetic acid benzyl ester as a yellow solid. (20.5 g, 94%): 1H NMR (300 MHz, CDCl3): δ 7.25-7.34 (m, 10H), 7.14 (d, J=8.4 Hz, 2H), 7.02 (d, J=8.4 Hz, 2H), 5.50 (s, 2H), 5.12 (s, 2H), 3.61 (s, 2H); TLC conditions: Uniplate silica gel, 250 microns; mobile phase=ethyl acetate-hexanes (1:5); Rf=0.8.
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[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[NH2:19][CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:28][CH:29]=1)=[O:14]
Reactant: NCc1ccc(C(=O)O)cc1
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Product: O=C(O)c1ccc(CNC(=O)c2ccncc2Nc2ccc(I)cc2F)cc1

Procedure:
4-[({3-[(2-fluoro-4-iodophenyl)amino]isonicotinoyl}amino)methyl]benzoic acid was synthesized according to the procedure for General Method 1, outlined above, starting with 0.3 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.45 mmol of 4-aminomethylbenzoic acid. LC/MS [9.25 min; 492 (M+1)]
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH2:10](O)[CH2:11][CH2:12][OH:13].O>C1(C)C=CC=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]2[O:13][CH2:12][CH2:11][CH2:10][O:6]2)[CH:7]=[CH:8][CH:9]=1
Reactant: OCCCO
Reactant: O=Cc1cccc(Br)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Brc1cccc(C2OCCCO2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 102.8 %

Procedure:
A mixture containing 3-bromobenzaldehyde (135; 18.5 g, 100 mmol), propane-1,3-diol (9.1 g, 120 mmol) and TsOH (0.1 g) in toluene (200 mL) was stirred under reflux in a Dean-Stark water separator for 18 h. Upon cooling to room temperature, the mixture was washed with 5% aqueous Na2CO3 (200 mL), dried (Na2SO4) and concentrated under reduced pressure to afford essentially quantitative yield of crude 2-(3-bromophenyl)-1,3-dioxane 136 as a yellow oil (25 g).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=1[CH:4]=[S:5].Br[CH2:12][CH:13]1[CH2:15][CH2:14]1>>[CH:13]1([CH2:12][O:1][C:2]2[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=2[CH:4]=[S:5])[CH2:15][CH2:14]1
Reactant: Cc1ccc(O)c(C=S)c1
Reactant: BrCC1CC1
Product: Cc1ccc(OCC2CC2)c(C=S)c1

Procedure:
2-Hydroxy-5-methylthiobenzaldehyde was alkylated with bromomethylcyclopropane using a similar method to that of reference example 4 to give 2-cyclopropylmethoxy-5-methylthiobenzaldehyde.
Reaction SMILES: [NH2:1][C@@:2]1([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])[CH2:7][O:6][C@@H:5]([CH2:8][O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:4][C@H:3]1[CH2:17][OH:18].FC1C=C(F)C=CC=1[C@@]1(N[C:44]([NH:46][C:47](=[O:63])[O:48][CH2:49][CH:50]2[C:62]3[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=3[C:56]3[C:51]2=[CH:52][CH:53]=[CH:54][CH:55]=3)=[S:45])[C@H](CO)CCOC1>>[CH2:10]([O:9][CH2:8][C@@H:5]1[O:6][CH2:7][C@@:2]([NH:1][C:44]([NH:46][C:47](=[O:63])[O:48][CH2:49][CH:50]2[C:51]3[CH:52]=[CH:53][CH:54]=[CH:55][C:56]=3[C:57]3[C:62]2=[CH:61][CH:60]=[CH:59][CH:58]=3)=[S:45])([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])[C@H:3]([CH2:17][OH:18])[CH2:4]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(NC(=S)N[C@@]1(c2ccc(F)cc2F)COCC[C@H]1CO)OCC1c2ccccc2-c2ccccc21
Reactant: N[C@@]1(c2ccc(F)cc2F)CO[C@@H](COCc2ccccc2)C[C@H]1CO
Product: O=C(NC(=S)N[C@@]1(c2ccc(F)cc2F)CO[C@@H](COCc2ccccc2)C[C@H]1CO)OCC1c2ccccc2-c2ccccc21

Procedure:
Conversion of [(2R,4R,5S)-5-amino-2-[(benzyloxy)methyl]-5-(2,4-difluorophenyl)tetrahydro-2H-pyran-4-yl]methanol (C22) to the product was carried out according to the general procedure for the synthesis of 9H-fluoren-9-ylmethyl {[(3S,4R)-3-(2,4-difluorophenyl)-4-(hydroxymethyl)tetrahydro-2H-pyran-3-yl]carbamothioyl}carbamate (C12) in Example 1. The product was obtained as a white solid. Yield: 995 mg, 1.54 mmol, 75%. LCMS m/z 645.6 (M+1). 1H NMR (400 MHz, CDCl3), characteristic peaks: δ 3.52 (dd, J=10.3, 4.1 Hz, 1H), 3.64 (dd, J=10.2, 6.0 Hz, 1H), 4.46 (dd, half of ABX pattern, J=10.6, 6.9 Hz, 1H), 4.60 (AB quartet, JAB=12.0 Hz, ΔνAB=11.1 Hz, 2H), 6.73-6.81 (m, 1H), 6.86-6.92 (m, 1H), 7.20-7.25 (m, 1H), 7.42-7.48 (m, 2H), 7.54-7.59 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]([N:20]2[CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[C:25]([CH2:29][OH:30])[CH:26]=3)[CH2:21]2)=[O:19])[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[O-2].[O-2].[Mn+4].C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]([N:20]2[CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[C:25]([CH:29]=[O:30])[CH:26]=3)[CH2:21]2)=[O:19])[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N[C@H]1CC[C@H](C(=O)N2Cc3ccc(CO)cc3C2)CC1)OCc1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: O=Cc1ccc2c(c1)CN(C(=O)[C@H]1CC[C@H](NC(=O)OCc3ccccc3)CC1)C2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
20 g of manganese dioxide was added to 120 ml of a chloroform solution containing 4.0 g of N-benzyloxycarbonyl-trans-4-[(5-hydroxymethyl-2-isoindolinyl)carbonyl]cyclohexylamine, and the mixture was stirred at room temperature for 4 hours. Manganese dioxide was removed by filtration through Celite and the solvent was removed under reduced pressure. The residue was suspended in hexane-ethyl acetate and the crystals were collected by filtration to obtain N-benzyloxycarbonyl-trans-4-[(5-formyl-2-isoindolinyl)carbonyl]cyclohexylamine.
Reaction SMILES: [CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:43])[CH3:42])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@H:9]([CH3:47])[C:7](=[O:8])[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50].C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:62])(=O)=O)=CC=1>C(O)(=O)C.C1COCC1>[CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:42])[CH3:43])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@:9]([F:62])([CH3:47])[C:7](=[O:8])[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50]
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@](C)(F)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Reaction time: 2 h
Yield: 18.2 %

Procedure:
Erythromycin A (5 g, 6.813 mmole) was dissolved in glacial acetic acid (20 mL) at room temperature and stirred for 2 hours. N-fluorobenzenesulfonimide (2.2 g, 6.813 mmole) dissolved in THF (4 mL) was added and stirring continued for an additional 18 hours at 22° C. The reaction was worked up in the same manner as Example 1 to afford only 0.93 g (7% yield) of crude flurithromycin.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].Cl[CH2:20][CH2:21][OH:22]>C(O)C.C1C=CC=CC=1>[C:12]([C:7]1[CH:8]=[C:9]([S:11][CH2:20][CH2:21][OH:22])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:16])([CH3:15])([CH3:14])[CH3:13]
Reactant: OCCCl
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Agent: [K+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: CCO
Product: CC(C)(C)c1cc(SCCO)cc(C(C)(C)C)c1O

Procedure:
Using the equipment described in Example I, 2,6-ditertiary butyl-4-mercaptophenol (50 grams) was dissolved in 90 millimeters of ethanol (denatured alcohol) and 30 millimeters of benzene. A solution of 12 grams of KOH in 60 millimeters of ethanol was added under a nitrogen blanket. 2-Chloroethanol (19 grams) was slowly added dropwise at room temperature. The combination was reacted for three hours and then diluted with benzene and washed with water. The volatiles were then stripped off.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([OH:11])[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:7]=1)=[O:5])C.CO>O>[OH:11][C:9]1[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:10]=1
Reactant: CCOC(=O)c1cc(O)n(-c2ccccn2)n1
Solvent: O
Solvent: CO
Product: O=C(O)c1cc(O)n(-c2ccccn2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.6 %

Procedure:
To a suspension of 5-hydroxy-1-pyridin-2-yl-1h-pyrazole-3-carboxylic acid ethyl ester (351.6 mg, 1.5 mmol) in MeOH (5.0 mL, 120 mmol) at room temperature was added LiOH monohydrate (126.5 mg, 3.0 mmol), forming a clear solution. The solution was stirred at room temperature overnight. The solution was then concentrated. To the resulting residue was added 1N aqueous HCl to achieve pH˜2, forming a precipitate. Water (4.0 mL) was added and the resulting mixture was stirred at room temperature for 1 hour, then filtered. The solids were rinsed with water and dried under vacuum to yield the title compounds as a white solid (128 mg).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([C:14]2[CH:15]=[CH:16][C:17]([N:20](C)[C:21](=O)[O-])=[N:18][CH:19]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:21][NH:20][C:17]1[N:18]=[CH:19][C:14]([C:5]2[N:4]=[N:3][C:2]([NH2:1])=[N:7][C:6]=2[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:15][CH:16]=1
Reactant: CN(C(=O)[O-])c1ccc(-c2nnc(N)nc2-c2ccccc2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNc1ccc(-c2nnc(N)nc2-c2ccccc2)cn1
Yield: 71.4 %

Procedure:
6-(6-(Methylamino)pyridin-3-yl)-5-phenyl-1,2,4-triazin-3-amine (49.5 mg, 0.177 mmol, 71.4%) was prepared from 5-(3-amino-5-phenyl-1,2,4-triazin-6-yl)pyridin-2-yl(methyl)carbamate (vide supra), by BOC deprotection with trifluoroacetic acid (0.4 mL) in dichloromethane (1.6 mL) for 1 hour at room temperature.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:14][O:15][C:16]1[CH:25]=[C:24]2[C:19]([CH:20]=[CH:21][CH:22]=[C:23]2[CH2:26][CH2:27][NH:28][C:29](=[O:32])[CH2:30]Br)=[CH:18][CH:17]=1>CC(C)=O>[CH3:14][O:15][C:16]1[CH:25]=[C:24]2[C:19]([CH:20]=[CH:21][CH:22]=[C:23]2[CH2:26][CH2:27][NH:28][C:29](=[O:32])[CH2:30][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[CH:18][CH:17]=1
Reactant: C1COCCN1
Reactant: COc1ccc2cccc(CCNC(=O)CBr)c2c1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: COc1ccc2cccc(CCNC(=O)CN3CCOCC3)c2c1

Procedure:
0.01 mol of morpholine is dissolved under magnetic agitation in 50 ml of acetone, and 0.012 mol of triethylamine and 0.01 mol of N-[2-(7-methoxynaphth-1-yl) ethyl]-2-bromoacetamide are added. The mixture is refluxed for 1 hour under magnetic agitation. The precipitate formed is spun down and the filtrate is evaporated. The residue is taken up in alkaline water, and the precipitate - is spun down, washed, dried and recrystallized in a toluene/cyclohexane mixture.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)CC(=O)C>[CH:3]1([N:2]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:1])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: BrCc1ccccc1
Reactant: CNC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: CN(Cc1ccccc1)C1CCCCC1

Procedure:
The compound N-cyclohexyl-N-methylbenzylamine was synthesized by treatment of N-methylcyclohexylamine (1) [1.98 ml, 1.70 g, 0.015 moles] with benzyl bromide (2) [1.78 ml, 2.56 g, 0.015 moles] in the presence of potassium carbonate [2.28 g, 1.1 equivalents] in 4-methyl-2-pentanone (50 ml). The reaction mixture was heated under reflux overnight. After filtering the insoluble potassium salts, the filtrate was concentrated to dryness. The solid was dissolved in boiling 4-methyl-2-pentanone, treated with activated carbon, followed by hot filtration after which the purified compound precipitated upon cooling. It was collected by vacuum filtration. m.p. 173.5°-174.5° C. Proton NMR (CDCl3) reported downfield from TMS: 1.11-1.92 ppm multiplet 10 H cyclic alkyl ring, 2.65 ppm singlet 3 H N-methyl, 3.01-3.11 ppm multiplet 1 H tertiary proton, 4.19 ppm singlet 2 H benzylic --CH2 --, 7.44-7.80 ppm 5 H aromatic; C-13 nmr 131.12, 130.19, 129.08, 128.40, 63.11, 55.12, 35.23, 26.37, 25.06, 24.33. EI Mass Spec. M/e-(int) M+203 (28.4), M++1 204 (4.7), M++2 205 (0.2), 160 (70.7), 146 (10.6), 91 (100), 92 (7.1), 85 (5.6), 82 (5.2), 70 (17.6), 65 (24.7), 57 (5.7), 56 (5.3), 55 (15.0), 43 (3.6), 42 (32.3), 41 (20.1).
Reaction SMILES: O=P(Cl)(Cl)Cl.CN([CH:9]=[O:10])C.[CH3:11][CH2:12][O:13][C:14]([C@@H:16]1[CH2:20][CH:19]=[CH:18][N:17]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:15].[OH-].[Na+]>C(Cl)Cl>[CH3:11][CH2:12][O:13][C:14]([C@@H:16]1[CH2:20][C:19]([CH:9]=[O:10])=[CH:18][N:17]1[C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])=[O:15]
Reactant: CN(C)C=O
Reactant: CCOC(=O)[C@@H]1CC=CN1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CC(C=O)=CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
POCl3 (7.59 mL, 83 mmol) was added in 25 min at 0° C. under N2 atmosphere to DMF (6.39 mL, 83 mmol) and the mixture was stirred at RT for 20 min. Dry CH2Cl2 (150 mL) was added at 0° C., followed by a solution of (S)-2,3-dihydro-pyrrole-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (10 g, 41.4 mmol) in CH2Cl2 (50 mL). The mixture was stirred 30 min at RT until completion. The mixture was slowly poured into an ice cold aqueous solution of NaOH 10 N (150 mL) and extracted with CH2Cl2 (×3). The combined organic extracts were washed with brine (×2), with water, dried (Na2SO4), filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 9:1) to give the desired material as a yellow oil. Rf, TLC (c-hexane/EtOAc 4:1)=0.2; MS (UPLC-MS): 270 [M+H]+, 170 [M−Boc]−; tR (HPLC conditions f): 1.93 min.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.Br[CH2:13][C:14]#[N:15]>>[CH3:1][N:2]([CH3:11])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:13][C:14]#[N:15])[CH2:7][CH2:6]1
Reactant: N#CCBr
Reactant: CN(C)CCN1CCNCC1
Product: CN(C)CCN1CCN(CC#N)CC1

Procedure:
The title compound is synthesized by coupling of Dimethyl-(2-piperazin-1-yl-ethyl)-amine (commercially available from CHESS GmbH) and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a colorless oil; ES-MS: M+=197.2.