Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[C:16]1(O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OC(C)(C)C)=O)=O)(C)(C)C>C1COCC1>[O:1]([CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Oc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(COc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.2 %

Procedure:
tert-Butyl 4-(hydroxymethyl)piperidine-1-carboxylate (0.300 g, 1.393 mmol), phenol (0.122 mL, 1.393 mmol), triphenylphosphine (0.440 g, 1.672 mmol) and N-{[(tert-butoxy)carbonyl]imino}(tert-butoxy)formamide (0.390 g, 1.672 mmol) were combined in THF (4 mL) and stirred at room temperature for 18 h. The reaction mixture was concentrated under reduced pressure and purified by FCC (EtOAc: heptane, 1:1) to afford a white solid. This was further purified by trituration with diethyl ether to afford the title compound (0.289 g, 71%). Method B HPLC-MS: MH+ requires m/z=292 Found: m/z=235 (MH+-tBu), Rt=2.44 min (71%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1[NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13].[H-].[Na+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1[N:11]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[S:12]([C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)(=[O:14])=[O:13]
Reactant: COC(=O)c1cccc(Cl)c1NS(=O)(=O)c1ccc(OC)cc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc(Cl)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Reaction time: 0.5 h
Yield: 39 %

Procedure:
To a solution of 0.90 g (2.532 mmol) of the product of Example 2 in 10 mL of DMF was added 0.127 g (3.165 mmol) of 60% sodium hydride. The resulting mixture was stirred for 30 min at room temperatue and then 0.38 mL (3.165 mmol) of benzyl bromide was added. This reaction mixture was stirred overnight at room temperature, poured into water and then extracted with ether. The combined organics were washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo to provide a white solid which was recrystallized from EtOAc/liexanes to provide 0.44 g (39%) of the desired product as white crystals. CI Mass Spec: 446 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2[CH:12]=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[Cl:18][C:19]1[CH:20]=[CH:21][C:22]2[O:26][C:25]([NH:27][CH2:28][C@@H:29]3[C@H:34]([CH3:35])[CH2:33][CH2:32][CH2:31][NH:30]3)=[N:24][C:23]=2[CH:36]=1>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]2[O:26][C:25]([NH:27][CH2:28][C@@H:29]3[C@H:34]([CH3:35])[CH2:33][CH2:32][CH2:31][N:30]3[C:7]([C:6]3[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=3[C:11]3[CH:12]=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=3)=[O:9])=[N:24][C:23]=2[CH:36]=1
Reactant: C[C@@H]1CCCN[C@@H]1CNc1nc2cc(Cl)ccc2o1
Reactant: Cc1ccc(-c2ccc(C)nc2)c(C(=O)O)c1
Product: Cc1ccc(-c2ccc(C)nc2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2nc3cc(Cl)ccc3o2)c1

Procedure:
The title compound was prepared following the same general protocol as described in Example A1, using 5-methyl-2-(6-methylpyridin-3-yl)benzoic acid and 5-chloro-N-(((2S,3R)-3-methylpiperidin-2-yl)methyl)benzo[d]oxazol-2-amine. ESI-MS (m/z): 489 [M+1]+.
Reaction SMILES: [CH:1]1([CH2:4][C:5]([OH:7])=O)[CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH:44]([C:47]1[CH:52]=[CH:51][C:50]([NH:53][C:54]([CH:56]2[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]2)=[O:55])=[CH:49][CH:48]=1)([CH3:46])[CH3:45]>C(#N)C>[CH:44]([C:47]1[CH:48]=[CH:49][C:50]([NH:53][C:54]([CH:56]2[CH2:61][CH2:60][N:59]([C:5](=[O:7])[CH2:4][CH:1]3[CH2:2][CH2:3]3)[CH2:58][CH2:57]2)=[O:55])=[CH:51][CH:52]=1)([CH3:46])[CH3:45]
Reactant: CC(C)c1ccc(NC(=O)C2CCNCC2)cc1
Reactant: O=C(O)CC1CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)c1ccc(NC(=O)C2CCN(C(=O)CC3CC3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.3 %

Procedure:
Cyclopropylacetic acid (0.055 g) was dissolved in acetonitrile (6 ml), ethyl-diisopropyl-amine (0.129 g), BOP (0.221 g) was added at RT under an argon atmosphere and the mixture was stirred for 30 minutes at RT. Then piperidine-4-carboxylic acid (4-isopropyl-phenyl)-amide (0.123 g) in acetonitrile (2 ml) was added dropwise at RT and the reaction mixture was stirred for 12 h until completion of the reaction. It was then partitioned between ethyl acetate and aqueous 1M HCl, the layers were separated and the aqueous layer washed with 2M aqueous KHCO3 then dried over Na2SO4. The solvent was evaporated off, the residue purified by flash chromatography (AcOEt/heptane, gradient from 0 to 60%) to give 1-(2-cyclopropyl-acetyl)-piperidine-4-carboxylic acid (4-isopropyl-phenyl)-amide (0.158 g) as an off-white solid. MS (ESI): 329.17 (MH+).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([C:9]([OH:12])([CH3:11])[CH3:10])[CH2:5][CH2:4]1.[C:13](OC(=O)C)(=[O:15])[CH3:14]>>[C:13]([O:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([C:9]([OH:12])([CH3:10])[CH3:11])[CH2:5][CH2:4]1)(=[O:15])[CH3:14]
Reactant: CC(C)(O)C1CCC(CO)CC1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OCC1CCC(C(C)(C)O)CC1

Procedure:
treating 7,8-dihydroxy-p-menthane with acetic anhydride to give 7-acetoxy-8-hydroxy-p-menthane;
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.IC1C=CC=CC=1.I[C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1>>[C:22]([C:21]1[CH:24]=[CH:25][C:18]([O:9][C:4]2[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[CH:3]=2)=[CH:19][CH:20]=1)#[N:23]
Reactant: N#Cc1ccc(I)cc1
Reactant: Cc1cc(C)cc(O)c1
Solvent: Ic1ccccc1
Product: Cc1cc(C)cc(Oc2ccc(C#N)cc2)c1

Procedure:
Example 3.1 was repeated, replacing the phenol with 244 mg of 3,5-dimethylphenol (2 mmoles) and the iodobenzene with 595 mg of 4-iodobenzonitrile (2.6 mmoles), the latter being added at the same time as the 3,5-dimethylphenol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=O)[CH2:10][C:11]([C:13]2[N:14]=[CH:15][N:16]([C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:17]=2)=O)=[CH:4][CH:3]=1.[NH2:38][NH2:39].O>CCO.CC(O)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[NH:39][N:38]=[C:11]([C:13]3[N:14]=[CH:15][N:16]([C:18]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:17]=3)[CH:10]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=C(CC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)Cc1ccc(F)cc1
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: Fc1ccc(Cc2cc(-c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)n[nH]2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.5 %

Procedure:
To a mixture of 4-(4-fluorophenyl)-1-(1-trityl-1H-imidazol-4-yl)butane-1,3-dione (80 g, 0.165 mol) and anhydrous EtOH/AcOH (400 mL/100 mL) was added NH2NH2.H2O (80 mL, 0.96 mol) dropwise at 0° C. After the addition, the mixture was stirred at RT overnight. The solvent mixture was evaporated, the residue washed with anhydrous Et2O (4×250 mL) and the resulting precipitate was dried in oven to yield the title compound (58.8 g, 73.0%) as a yellow solid.
Reaction SMILES: [CH:1]1(C(Cl)=O)CCCCC1.[CH:10]1([C:16]([N:18]=[C:19]=[S:20])=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH3:34])[N:29]=[CH:28]N=[C:26]2[O:35][C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=1.C1(C)C=CC=CC=1>C(O)C>[CH:10]1([C:16]([N:18]=[C:19]=[S:20])=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.[CH:10]1([C:16]([NH:18][C:19]([NH:40][C:39]2[CH:41]=[CH:42][C:36]([O:35][C:26]3[C:25]4[C:30](=[CH:31][C:32]([O:33][CH3:34])=[C:23]([O:22][CH3:21])[CH:24]=4)[N:29]=[CH:28][CH:1]=3)=[CH:37][CH:38]=2)=[S:20])=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(Cl)C1CCCCC1
Agent: O=C(N=C=S)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)C4CCCCC4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
1-Cyclohexanecarbonyl isothiocyanate was prepared using commercially available 1-cyclohexanecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 1-Cyclohexanecarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (60 mg, yield 47%).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][C:6]1[C:15]2CO[CH2:12][O:11][C:10]=2[C:9]([CH3:16])=[CH:8][CH:7]=1.C[C:18](OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=[O:19]>C(OC(=O)C)(=O)C>[N+:1]([C:7]1[CH:8]=[C:9]([CH3:16])[C:10]2[O:11][CH2:12][CH2:18][O:19][C:15]=2[C:6]=1[CH3:5])([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(C)c2c1COCO2
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Solvent: CC(=O)OC(C)=O
Product: Cc1cc([N+](=O)[O-])c(C)c2c1OCCO2
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 1.12 mL of concentrated nitric acid in 20 mL of acetic arthydride is added dropwise to a stirred solution of 2.90 g of 5,8-dimethyl-1,3-benzodioxane in 70 mL of acetic anhydride at -5° C. After 15 minutes, the mixture is poured over 100 g of crushed ice and allowed to stir for 30 minutes as a white precipitate falls out of solution. The solid is filtered and taken up in ether, dried over magnesium sulfate and concentrated under reduced pressure to afford 3.1 g of 6-nitro-5,8-dimethyl-1,4-benzodioxane.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:44]([C:48]1[CH:65]=[CH:64][C:51]([CH2:52][NH:53][CH2:54][CH:55]([C:57]2[CH:62]=[CH:61][C:60]([Cl:63])=[CH:59][CH:58]=2)[CH3:56])=[CH:50][CH:49]=1)([CH3:47])([CH3:46])[CH3:45]>CN(C=O)C.O>[C:44]([C:48]1[CH:65]=[CH:64][C:51]([CH2:52][N:53]([CH2:54][CH:55]([C:57]2[CH:62]=[CH:61][C:60]([Cl:63])=[CH:59][CH:58]=2)[CH3:56])[C:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)=[O:12])=[CH:50][CH:49]=1)([CH3:45])([CH3:46])[CH3:47]
Reactant: O=C(O)c1cccc2cc[nH]c12
Reactant: CC(CNCc1ccc(C(C)(C)C)cc1)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(CN(Cc1ccc(C(C)(C)C)cc1)C(=O)c1cccc2cc[nH]c12)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 88.4 %

Procedure:
To a solution of 81 mg of 1H-indole-7-carboxylic acid (0.5 mmol) and 161 mg of TBTU (0.5 mmol) in 2 ml DMF, were added 0.43 ml (2.5 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 158 mg (0.5 mmol) [rac]-(4-tert-butyl-benzyl)-[2-(4-chloro-phenyl)-propyl]-amine in 3.5 ml DMF was added. After stirring for 22 h at rt, the reaction mixture was diluted with 50 ml water and extracted twice with EtOAc. The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (40 g silica gel; heptane/EtOAc 2:1) to give 203 mg (86%) of a off-white solid. MS(ISP) 459.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:11](=[O:16])[N:10]([CH2:17][C:18]([NH:20][NH2:21])=O)[N:9]=2)=[CH:4][CH:3]=1.Cl.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](N)=[NH:29]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:11](=[O:16])[N:10]([CH2:17][C:18]3[NH:29][C:28]([C:27]4[CH:31]=[CH:32][CH:33]=[C:25]([C:24]([F:23])([F:34])[F:35])[CH:26]=4)=[N:21][N:20]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: NNC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O
Reactant: N=C(N)c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: CN(C)C=O
Product: O=c1n(Cc2nnc(-c3cccc(C(F)(F)F)c3)[nH]2)nc(-c2ccc(Cl)cc2)n1C1CC1
Temperature: 150 °C
Reaction time: 0.75 h

Procedure:
100 mg (0.33 mmol) of the compound from Example 21A were dissolved in 1.6 ml of DMF, 109 mg (0.49 mmol) of 3-trifluoromethylbenzamidine hydrochloride were added and the mixture was stirred in a microwave oven at 150° C. for 45 min. After cooling, the reaction was concentrated under reduced pressure on a rotary evaporator and the residue that remained was purified chromatographically [Method 19]. This gave 70 mg (47% of theory) of the target compound as a colorless solid.
Reaction SMILES: [C:1]([N:9]=[C:10]=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[CH:14][Si](C)(C)C)=[N-]>C(#N)C>[C:2]1([C:1]2[O:8][CH2:14][C:10](=[O:11])[N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C=NC(=O)c1ccccc1
Solvent: CC#N
Product: O=C1COC(c2ccccc2)=N1
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
To a solution of benzoyl isocyanate (2 g, 12.2 mmol) in acetonitrile (40 mL) was added rapidly (diazomethyl)trimethylsilane (2M solution in hexane, 7.34 mL, 14.7 mmol) at 0-5° C., whereby the temperature rose to 15° C. (bubbling). The mixture was stirred at 0-5° C. for 1 h. Following solvent evaporation, the product was obtained after purification by flash chromatography (using silica gel and an ethyl acetate/heptane gradient) as yellow solid (1.84 g with 90% purity, 10.3 mmol, 84.0%) which was used without further purification for the next step.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:52]([CH3:54])[CH3:53])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[NH:15][C:16]([C:19]2[CH:20]=[C:21]3[C:33]4[C:34]5[C:24](=[CH:25][C:26]([C:35]6[NH:39][C:38]([C@@H:40]7[CH2:44][CH2:43][CH2:42][N:41]7C(OC(C)(C)C)=O)=[N:37][CH:36]=6)=[CH:27][C:28]=5[CH2:29][CH2:30][C:31]=4[CH:32]=2)[CH2:23][CH2:22]3)=[CH:17][N:18]=1)=[O:8])=[O:4].Cl.[CH3:56][O:57][C:58]([NH:60][C@@H:61]([CH:65]1[CH2:70][CH2:69][O:68][CH2:67][CH2:66]1)[C:62]([OH:64])=O)=[O:59].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:52]([CH3:54])[CH3:53])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[NH:15][C:16]([C:19]2[CH:32]=[C:31]3[C:33]4[C:34]5[C:28](=[CH:27][C:26]([C:35]6[NH:39][C:38]([C@@H:40]7[CH2:44][CH2:43][CH2:42][N:41]7[C:62](=[O:64])[C@@H:61]([NH:60][C:58](=[O:59])[O:57][CH3:56])[CH:65]7[CH2:70][CH2:69][O:68][CH2:67][CH2:66]7)=[N:37][CH:36]=6)=[CH:25][C:24]=5[CH2:23][CH2:22][C:21]=4[CH:20]=2)[CH2:29][CH2:30]3)=[CH:17][N:18]=1)=[O:8])=[O:4]
Reactant: COC(=O)N[C@H](C(=O)O)C1CCOCC1
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2cc3c4c(c2)CCc2cc(-c5cnc([C@@H]6CCCN6C(=O)OC(C)(C)C)[nH]5)cc(c2-4)CC3)[nH]1)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2cc3c4c(c2)CCc2cc(-c5cnc([C@@H]6CCCN6C(=O)[C@@H](NC(=O)OC)C6CCOCC6)[nH]5)cc(c2-4)CC3)[nH]1)C(C)C
Reaction time: 1 h
Yield: 26.9 %

Procedure:
To (S)-tert-butyl 2-(5-(7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-4,5,9,10-tetrahydropyren-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (55 mg, 0.08 mmol) in DCM (3 mL) was added HCl (4M in dioxane, 0.25 mL). The solution stirred for 1 h, and the solvent was removed. The intermediate was dissolved in DMF (2 mL). (S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid (16 mg, 0.08 mmol), HATU (29 mg, 0.08 mmol), and DIPEA (0.06 mL, 0.37 mmol) were added sequentially. The solution was stirred o/n and the mixture was purified by HPLC to yield product (17.9 mg). LCMS-ESI+: calc'd for C46H56N8O7: 832.99 (M+); Found: 833.25 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]2[C:19]([Cl:20])=[CH:18][N:17]=[C:16](Cl)[N:15]=2)[CH:8]=1.Cl.O.[OH-].[Na+]>COCCO.O1CCOCC1>[Cl:20][C:19]1[CH:18]=[N:17][C:16]2[NH:1][C:2]3[CH:24]=[CH:23][CH:22]=[C:4]([CH:3]=3)[CH2:5][NH:6][C:7]3[CH:8]=[C:9]([NH:13][C:14]=1[N:15]=2)[CH:10]=[CH:11][CH:12]=3
Reactant: Nc1cccc(CNc2cccc(Nc3nc(Cl)ncc3Cl)c2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: COCCO
Solvent: O
Product: Clc1cnc2nc1Nc1cccc(c1)NCc1cccc(c1)N2
Yield: 10.2 %

Procedure:
To a solution of N-(3-aminobenzyl)-N′-(2,5-dichloropyrimidin-4-yl)benzene-1,3-diamine (900 mg, 2.0 mmol) in 2-methoxyethanol (18 mL) was added 4.00 M of hydrogen chloride in 1,4-dioxane (1.88 mL). The resultant mixture was heated at 150° C. in the microwave for 5 min. After cooling, water and NaOH (12 N) were added to neutralize the mixture to pH=7. The aqueous layer was extracted with EtOAc four times. The combined organic layers were dried, filtered and concentrated. The residue was purified by silica gel column chromatography to give the desired product as an off-white powder (66 mg, 8%). LCMS for C17H15ClN5 (M+H)+: m/z=324.0.
Reaction SMILES: [C:1]([CH:3](P(=O)(OCC)OCC)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:2].[H-].[Na+].[C:20]12([CH:30]=O)[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]3)[CH2:21]1)[CH2:27]2.O>C1COCC1>[C:20]12([CH:30]=[C:3]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:1]#[N:2])[CH2:21][CH:22]3[CH2:28][CH:26]([CH2:25][CH:24]([CH2:23]3)[CH2:29]1)[CH2:27]2
Reactant: CCOP(=O)(OCC)C(C#N)c1ccccc1
Reactant: O=CC12CC3CC(CC(C3)C1)C2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N#CC(=CC12CC3CC(CC(C3)C1)C2)c1ccccc1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 28.3 %

Procedure:
A solution of diethyl 1-cyano-1-phenylmethylphosphonate (10.97 g, 43.3 mmol) in dry THF (60 mL) at 0° C. was treated with NaH (60% dispersion in oil, 1.7 g, 43.3 mmol), stirred at 0° C. for 40 min, warmed to room temperature for 20 min, treated with a solution of 1-adamantanecarboxaldehyde (3.56 g, 21.7 mmol) in dry THF (10 mL) and heated at 60° C. for 16 h. The reaction mixture was cooled, treated with water (50 mL), extracted with EtOAc (3×20 mL), the extracts washed with brine (40 mL), dried (MgSO4) and concentrated in vacuo. The resulting brown oil was purified by chromatography [SiO2, heptane-EtOAc (9:1)] and recrystallised (heptane) to give the product (1.62 g, 28%) as a white solid: mp 107-108° C; IR νmax (Nujol)/cm−1 2924, 2852, 2218, 1497, 1448, 1377, 1343, 1101, 910, 762, 750 and 689; NMR δH (400 MHz, CDCl3) 1.76 (6H, m), 1.99 (6H, m), 2.07 (3H, m), 6.50 (1H, s), 7.37 (3H, m) and 7.51 (2H, m); Anal. Calcd for C19H21N: C, 86.65; H, 8.04; N, 5.32. Found: C, 86.58; H, 8.09; N, 5.33.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:18]=[CH:19][CH:20]=2)[O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][NH2:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[NH:22][C:23](SC)=[CH:24][N+:25]([O-:27])=[O:26].Cl.[CH2:31](O)C>O>[CH3:31][N:17]([CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][C:10]1[CH:18]=[CH:19][CH:20]=[C:8]([CH2:7][N:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH:9]=1)[C:23]([NH2:22])=[CH:24][N+:25]([O-:27])=[O:26]
Reactant: NCCOCCOc1cccc(CN2CCCCC2)c1
Reactant: CNC(=C[N+](=O)[O-])SC
Reactant: CCO
Agent: Cl
Solvent: O
Product: CN(CCOCCOc1cccc(CN2CCCCC2)c1)C(N)=C[N+](=O)[O-]

Procedure:
A solution of 2-[2-[3-(1-piperidinylmethyl) phenoxy]ethoxy]ethanamine (0.4 g) and N-methyl-1-methylthio-2-nitro-etheneamine (0.24 g) in water (20 ml) and ethanol (20 ml) was stirred at 50° for 5h. The solution was diluted with water (20 ml) acidified to pH 1 with dilute hydrochloric acid and washed with ethyl acetate (2×50 ml). The aqueous solution was basified to pH 9 with potassium carbonate and extracted with ethyl acetate (3×50 ml). Evaporation of these organic extracts gave a yellow oil which solidified when triturated with cyclohexane. The solid was recrystallised from ethyl acetate (10 ml) to give the title compound as a white powder (0.17 g) m.p. 125.5°-126.5° .
Reaction SMILES: CO[C:3]1[CH2:4][CH2:5][CH:6]([CH3:10])[CH2:7][CH2:8][N:9]=1.[Cl-:11].[NH4+:12]>CCO>[ClH:11].[CH3:10][CH:6]1[CH2:7][CH2:8][NH:9][C:3](=[NH:12])[CH2:4][CH2:5]1
Reactant: [Cl-]
Reactant: COC1=NCCC(C)CC1
Reactant: [NH4+]
Solvent: CCO
Product: CC1CCNC(=N)CC1
Product: Cl
Yield: 81.2 %

Procedure:
The product of EXAMPLE 69 (750 mg, 5.3 mmol) in 3 mL of EtOH was reacted with ammonium chloride (285 mg, 5.3 mmol) by the method of EXAMPLE 27 to yield 700 mg (77%) of the title material.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1.[Cl:13][S:14](O)(=[O:16])=[O:15]>>[Cl:13][S:14]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10])(=[O:16])=[O:15]
Reactant: O=S(=O)(O)Cl
Reactant: COC(=O)Cc1cccc(F)c1
Product: COC(=O)Cc1cc(F)ccc1S(=O)(=O)Cl
Reaction time: 16 h

Procedure:
Methyl (3-fluorophenyl)acetate (1.51 g) was added dropwise to chlorosulphonic acid (7 mL) with stirring and ice cooling. The cooling bath was removed and the mixture was allowed to stand at room temperature for 16 hours before being carefully added to a mixture of ice and ethyl acetate. The organic layer was separated, washed with water, dried (MgSO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-20% to give methyl (2-chlorosulfonyl-5-fluorophenyl)acetate (1.42 g) as a white solid.
Reaction SMILES: [OH:1][C@H:2]([CH2:8][C:9](=[O:11])[O-:10])[CH2:3][N+:4]([CH3:7])([CH3:6])[CH3:5].[C:12]([Cl:31])(=[O:30])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>>[Cl-:31].[C:9]([CH2:8][C@@H:2]([O:1][C:12](=[O:30])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:3][N+:4]([CH3:7])([CH3:5])[CH3:6])([OH:10])=[O:11]
Reactant: C[N+](C)(C)C[C@H](O)CC(=O)[O-]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)Cl
Product: CCCCC/C=C\C/C=C\CCCCCCCC(=O)O[C@H](CC(=O)O)C[N+](C)(C)C
Product: [Cl-]

Procedure:
By processing L-carnitine and linoleoyl chloride in the same manner as described in Reference example 15, (R)-(3-carboxy-2-linoleoyloxypropyl)trimethylammonium chloride was obtained.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].O[CH2:7][CH2:8][C:9]1[S:10][C:11]2[CH:42]=[CH:41][CH:40]=[CH:39][C:12]=2[N:13]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:38])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:20][CH:19]=2)[C:14](=[O:16])[CH:15]=1>C(N(CC)CC)C>[CH3:1][S:2]([CH2:7][CH2:8][C:9]1[S:10][C:11]2[CH:42]=[CH:41][CH:40]=[CH:39][C:12]=2[N:13]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([NH:24][C:25](=[O:38])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[CH:22][CH:23]=2)[C:14](=[O:16])[CH:15]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(Nc1ccc(CN2C(=O)C=C(CCO)Sc3ccccc32)cc1)c1ccccc1-c1ccccc1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)CCC1=CC(=O)N(Cc2ccc(NC(=O)c3ccccc3-c3ccccc3)cc2)c2ccccc2S1

Procedure:
Methanesulfonyl chloride (0.04 ml, 0.55 mM) was added to Compound 23 as prepared in Example 22 (0.280 g, 0.55 mM) and triethylamine (0.15 ml, 1.1 mM) following the procedure described in Example 29 to give the solid product. m/z (MH+) 587.