Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[S:12])[NH:6][C:5]2=[O:13].[CH3:14][O-].[Na+].IC>CN(C=O)C.CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([S:12][CH3:14])[NH:6][C:5]2=[O:13]
Reactant: O=c1[nH]c(=S)[nH]c2ccc(Br)cc12
Reactant: C[O-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CO
Product: CSc1nc2ccc(Br)cc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90.3 %

Procedure:
To a solution of compound 4a (8.43 g, 32.8 mmol) in 130 mL of DMF was added a solution sodium methoxide (0.50 M, 32.8 mmol) in methanol (65.6 mL) and the mixture was stirred at room temperature for 15 minutes. Iodomethane (2.04 mL, 32.8 mmol) was added and the reaction mixture was stirred at room temperature for 22 hours. The solvents were evaporated under reduced pressure and the remaining solid was dissolved in 500 mL of EtOAc and washed with 400 mL of a saturated solution of aqueous NaHCO3. The organic layer was dried over MgSO4, concentrated under reduced pressure and precipitated from 50 mL of ethyl alcohol, to give 5a as a white solid (8.03 g, 90%). mp: 230° C.,
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].F[C:11]1[CH:19]=[N:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14]>>[NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:5][C:16]1[CH:17]=[N:18][CH:19]=[CH:11][C:12]=1[C:13]([OH:15])=[O:14]
Reactant: NCc1ccccc1N
Reactant: O=C(O)c1ccncc1F
Product: Nc1ccccc1CNc1cnccc1C(=O)O
Yield: 9 %

Procedure:
The title compound was prepared in 9% yield from 2-aminobenzylamine and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 3. 1H NMR (400 MHz, DMSO-d6): δ 8.16 (s, 1H), 7.82 (d, 1H, J=5.0 Hz), 7.56 (d, 1H, J=5.0 Hz), 7.05 (d, 1H, J=7.5 Hz), 6.97 (td, 1H, J=7.8, 1.4 Hz), 6.66 (d, 1H, J=7.9 Hz), 6.52 (td, 1H, J=7.4, 1.0 Hz), 4.35 (s, 2H). [M+H] calc'd for C13H13N3O2, 244; found 244.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[C:21](B1OC(C)(C)C(C)(C)O1)([CH3:23])=[CH2:22]>>[CH:21]([C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1)([CH3:23])[CH3:22]
Reactant: COc1cccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc12
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Product: COc1cccc2c(C(C)C)nc(Nc3cc(C)[nH]n3)cc12

Procedure:
Similar procedure as described in example 330 was used, starting from (1-Chloro-5-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and isopropenylboronic acid pinacol ester to give (1-Isopropyl-5-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 297(MH+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[NH2:20][N:21]1[CH:25]=[CH:24][CH:23]=[CH:22]1>>[CH2:17]1[CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:6]3[C:5]([F:19])=[CH:4][N:3]=[C:2]([NH:20][N:21]4[CH:25]=[CH:24][CH:23]=[CH:22]4)[N:7]=3)=[CH:10][C:11]=2[O:18]1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Reactant: Nn1cccc1
Product: Fc1cnc(Nn2cccc2)nc1Nc1ccc2c(c1)OCCO2

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-N-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine was reacted with 1-aminopyrrole to provide N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(1H-pyrrol-1-yl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.95 (s, 1H), 9.16 (s, 1H), 7.95 (d, 1H, J=3.5 Hz), 7.16-7.12 (m, 2H), 6.69 (dd, 2H, J=2.3 and 4.7 Hz), 6.61 (d, 1H, J=8.8 Hz), 5.99 (dd, 2H, J=2.3 and 4.7 Hz), 4.12-4.15 (m, 4H). LCMS: ret. time: 19.86 min.; purity: 92%; MS (m/e): 328 (MH+).
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([O:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH2:14][CH2:13]3)[CH:4]=1.[C:19]([C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20].CCOC(C)=O.O>C1COCC1>[C:19]([C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([N:15]2[C:16]3[C:12](=[CH:11][C:10]([O:9][C:5]4[CH:4]=[C:3]([NH:2][CH3:1])[N:8]=[CH:7][N:6]=4)=[CH:18][CH:17]=3)[CH2:13][CH2:14]2)=[O:31])=[CH:25][CH:24]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)c1ccc(N=C=O)cc1
Reactant: CNc1cc(Oc2ccc3c(c2)CCN3)ncn1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CNc1cc(Oc2ccc3c(c2)CCN3C(=O)Nc2ccc(C(C)(C)C)cc2)ncn1

Procedure:
A solution of 70 mg (0.3 mMol) 5-(6-methylamino-pyrimidin-4-yloxy)-2,3-dihydro-indole (Step 21.2) and 70 mg (0.4 mMol) 4-tert.butyl-phenylisocyanat in 2 ml THF is stirred for 75 min at rt. The reaction mixture is dissolved with EtOAc and water, the aqueous layer separated off and extracted twice with EtOAc. The organic phases are washed with water and brine, dried (Na2SO4) and concentrated. Column chromatography (SiO2; EtOAc/hexane 1:1→3:1→4:1) gives the title compound: MS: [M+1]+=418; TLC(EtOAc): Rf=0.20.
Reaction SMILES: C[C@@H]1[O:7][C@@H:6](OC[C@H]2O[C@@H](OC3C(=O)C4C(O)=CC(O)=CC=4OC=3C3C=CC(O)=C(O)C=3)[C@H](O)[C@@H](O)[C@@H]2O)[C@H](O)[C@H](O)[C@H]1O.CC1OC(OCC2OC(O[C:60]3[C:69](=[O:70])[C:68]4[C:63](=[CH:64][C:65]([OH:72])=[CH:66][C:67]=4[OH:71])[O:62][C:61]=3[C:73]3[CH:78]=[CH:77][C:76](O)=[C:75]([OH:80])[CH:74]=3)C(O)C(O)C2O)C(O)C(O)C1O.C1[C@H]2C3N(C[C@@H]1CNC2)C(=O)C=CC=3>>[CH3:6][O:7][C:76]1[CH:77]=[CH:78][C:73]([C@H:61]2[O:62][C:63]3[CH:64]=[C:65]([OH:72])[CH:66]=[C:67]([OH:71])[C:68]=3[C:69](=[O:70])[CH2:60]2)=[CH:74][C:75]=1[OH:80]
Reactant: C[C@@H]1O[C@@H](OC[C@H]2O[C@@H](Oc3c(-c4ccc(O)c(O)c4)oc4cc(O)cc(O)c4c3=O)[C@H](O)[C@@H](O)[C@@H]2O)[C@H](O)[C@H](O)[C@H]1O
Reactant: CC1OC(OCC2OC(Oc3c(-c4ccc(O)c(O)c4)oc4cc(O)cc(O)c4c3=O)C(O)C(O)C2O)C(O)C(O)C1O
Agent: O=c1cccc2n1C[C@@H]1CNC[C@H]2C1
Product: COc1ccc([C@@H]2CC(=O)c3c(O)cc(O)cc3O2)cc1O

Procedure:
rutin, 3-[[6-O-(6-Deoxy-α-L-mannopyranosyl)-β-D-glucopyranosyl]oxy]-2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-4H-1-benzopyran-4-one; rutoside; quercetin-3-rutinoside; 3,3′,4′,5,7-pentahydroxyflavone-3-rutinoside; melin; phytomelin; eldrin; ilixathin; sophorin; globularicitrin; paliuroside; osyritrin; osyritin; myrticolorin; violaquercitrin; Birutan; Rutabion; Rutozyd; Tanrutin;
Reaction SMILES: [C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:13][CH:8]2[C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B(F)(F)F.C[CH2:25][O:26]CC>CO>[OH:13][CH:8]([C:7]([O:26][CH3:25])([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)C1OC1(c1ccccc1)c1ccccc1
Reactant: CCOCC
Agent: FB(F)F
Solvent: CO
Product: COC(=O)C(O)C(OC)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
5 g (19.6 mmol) of methyl 3,3-diphenyl-2,3-epoxypropionate were dissolved in 50 ml of absolute methanol and, at 0° C., 0.1 ml of boron trifluoride etherate was added. The mixture was stirred at 0° C. for 2 h and at room temperature for a further 12 h. The solvent was distilled out, the residue was taken up in ethyl acetate, washed with sodium bicarbonate solution and water and dried over magnesium sulfate. After removal of the solvent by distillation there remained 5.5 g (88%) of a pale yellow oil.
Reaction SMILES: [C:1](=[S:3])=[S:2].[NH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][CH3:12])[N:6]=1.[CH2:13](OCC)[CH3:14]>C(#N)C.C(N(CC)CC)C>[CH2:11]([C:7]1[N:6]=[C:5]([NH:4][C:1](=[S:3])[S-:2])[CH:10]=[CH:9][CH:8]=1)[CH3:12].[CH2:13]([NH+:6]([CH2:5][CH3:10])[CH2:7][CH3:11])[CH3:14]
Reactant: S=C=S
Reactant: CCc1cccc(N)n1
Reactant: CCOCC
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC[NH+](CC)CC
Product: CCc1cccc(NC(=S)[S-])n1
Temperature: 20 °C
Reaction time: 20 h

Procedure:
A solution of carbon disulphide (17.5 cc) in anhydrous acetonitrile (19.5 cc) is added to a solution of 2-amino-6-ethylpyridine (27.0 g) in anhydrous triethylamine (60 cc) at a temperature of 25° C. After 20 hours stirring at 20° C., anhydous diethyl ether (250 cc) is added. After cooling for 1 hour at 2° C., the resulting crystals are filtered off, washed three times with anhydrous diethyl ether (240 cc) and dried under reduced pressure (20 mm.Hg) at 20° C. to give triethylammonium (6-ethylpyrid-2-yl)dithiocarbamate (42.0 g) melting at 75° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6].Cl[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]>C1COCC1>[CH2:14]([O:13][C:11](=[O:12])[NH:6][CH2:5][C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([NH2:1])[CH:3]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NCc1cccc(N)c1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: C1CCOC1
Product: Nc1cccc(CNC(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.1 %

Procedure:
To a solution of 3-aminobenzylamine (610 mg, 5 mmol) and TEA (1.01 g, 10 mmol) in 10 mL of THF at 0° C., was added benzyl chloroformate (936 mg, 5.5 mmol) dropwise. The mixture was stirred at rt for 30 min. The reaction was quenched with water and extracted with EtOAc (3×20 mL). The organic layer was washed with brine, dried (Na2SO4) and concentrated. Purification via flash chromatography (0 to 50% EtOAc in hexanes) gives 66A (911 mg, 71%). MS (ESI) m/z 257.3 (M+H)+.
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:7][O:8][CH:9]([O:12][CH3:13])[CH:10]=O>CO.O.[Pd]>[CH3:7][O:8][CH:9]([O:12][CH3:13])[CH2:10][NH:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCC1
Reactant: COC(C=O)OC
Agent: [Pd]
Solvent: O
Solvent: CO
Product: COC(CNC1CCCC1)OC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred solution of cyclopentanamine (5 g) in methanol (20 mL) was added 2,2-dimethoxyacetaldehyde 60% in water (8.86 mL) and the mixture stirred at ambient temperature for 5 h. A slurry of palladium on carbon (10%, 200 mg) in methanol (5 mL) was added and the mixture hydrogenated at 5 bar for 16 h. It was filtered and concentrated in vacuo to afford N-(2,2-dimethoxyethyl)cyclopentanamine (9.44 g) as a oil. 1H NMR (400 MHz, CDCl3) δ 4.47 (t, J=5.6 Hz, 1H), 3.39 (s, 6H), 3.05 (quintet, J=6.8 Hz, 1H), 2.72 (d, J=5.4 Hz, 2H), 1.89-1.80 (m, 2H), 1.73-1.62 (m, 2H), 1.58-1.48 (m, 2H), 1.36-1.27 (m, 2H)
Reaction SMILES: ClCC1C=CC(C#N)=CC=1.Br[CH2:12][CH:13]1[O:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[O:15][CH2:14]1.[CH2:23]([NH:30][C:31]([C:33]1[S:37][C:36]([N:38]2[CH2:42][CH2:41][NH:40][C:39]2=[O:43])=[N:35][C:34]=1[CH3:44])=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([NH:30][C:31]([C:33]1[S:37][C:36]([N:38]2[CH2:42][CH2:41][N:40]([CH2:12][CH:13]3[O:18][C:17]4[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=4[O:15][CH2:14]3)[C:39]2=[O:43])=[N:35][C:34]=1[CH3:44])=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCC1COc2ccccc2O1
Reactant: Cc1nc(N2CCNC2=O)sc1C(=O)NCc1ccccc1
Agent: N#Cc1ccc(CCl)cc1
Product: Cc1nc(N2CCN(CC3COc4ccccc4O3)C2=O)sc1C(=O)NCc1ccccc1
Yield: 3 %

Procedure:
Following the procedure as described in Example 23, making variations as required to replace 4-(chloromethyl)benzonitrile with 2-(bromomethyl)-2,3-dihydrobenzo[b][1,4]dioxine to react with N-benzyl-4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxamide, the title compound was obtained as an oil in 3% yield: 1H NMR (300 MHz, CDCl3) δ 7.35-7.31 (m, 5H), 6.88-6.87 (m, 4H), 5.89 (br s, 1 H), 4.57 (d, J=6.0 Hz, 2H), 4.43-4.39 (m, 1H), 4.33-4.28 (m, 1H), 4.17-3.97 (m, 3 H), 3.86-3.53 (m, 4H), 2.63 (s, 3H); MS (ES+) m/z 465.2 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:4]1.[C:16]([N:23]1[CH:27]=[CH:26]N=[CH:24]1)(N1C=CN=C1)=[O:17].[CH2:28]([CH:35]1CCNC[CH2:36]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C=O)C>[CH3:1][N:2]([CH3:15])[C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][C:11]([NH:14][C:16]([N:23]3[CH2:24][CH2:36][CH:35]([CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:26][CH2:27]3)=[O:17])=[CH:10][CH:9]=2)[CH2:4]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CN(C)[C@@H]1CCN(c2ccc(N)cn2)C1
Reactant: c1ccc(CC2CCNCC2)cc1
Solvent: CN(C)C=O
Product: CN(C)[C@@H]1CCN(c2ccc(NC(=O)N3CCC(Cc4ccccc4)CC3)cn2)C1
Temperature: 90 °C
Reaction time: 0.25 h

Procedure:
(R)-6-(3-Dimethylaminopyrrolidin-1-yl)pyridin-3-ylamine was added to a solution of carbonyldiimidazole (53 mg) in DMF (0.5 ml) at 0° C. After 15 minutes, 4-benzylpiperidine (57 mg) was added and the mixture was heated at 90° C. for one hour. The cooled mixture was freed of volatile fractions. The residue was purified by chromatography (silica gel, eluent: methanol/dichloromethane). This resulted in the product with the molecular weight of 407.56 (C24H33N5O); MS (ESI): 408 (M+H+).
Reaction SMILES: IC.[CH2:3](N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+].[CH3:16][C:17]1[O:21][N:20]=[C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:18]=1[CH2:28][O:29][C:30]1[N:35]=[CH:34][C:33]([C:36]([NH:38][S:39]([CH:42]2[CH2:44][CH2:43]2)(=[O:41])=[O:40])=[O:37])=[CH:32][CH:31]=1>CN(C=O)C>[CH3:3][N:38]([C:36]([C:33]1[CH:34]=[N:35][C:30]([O:29][CH2:28][C:18]2[C:19]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[N:20][O:21][C:17]=2[CH3:16])=[CH:31][CH:32]=1)=[O:37])[S:39]([CH:42]1[CH2:44][CH2:43]1)(=[O:40])=[O:41]
Reactant: CCN(CC)CC
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NS(=O)(=O)C2CC2)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)N(C)S(=O)(=O)C2CC2)cn1
Temperature: 100 °C
Yield: 8.3 %

Procedure:
To a solution of mixture of iodomethane (120 μL, 1.91 mmol), triethylamine (245 μL, 1.75 mmol) and anhydrous sodium carbonate (36.9 mg, 0.35 mmol) in DMF (0.5 mL) was added cyclopropanesulfonic acid [6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine-3-carbonyl]-amide (44 mg, 0.11 mmol). The reaction mixture was then heated in the microwave for 40 min at 100° C. The mixture was then cooled and evaporated and the residue was purified by chromatography (SiO2, heptane:ethyl acetate 2:1 to 1:1) to give the title compound (3.9 mg, 9%) as a yellow solid. MS: m/e=486.3 [M+OAc]−.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]2[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:8]=2[F:15])=[N:5][N:6]=1.[CH3:16][NH:17][CH:18]1[CH2:23][C:22]([CH3:25])([CH3:24])[NH:21][C:20]([CH3:27])([CH3:26])[CH2:19]1>CN1C(=O)CCC1.C([O-])(O)=O.[Na+].O>[F:15][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]([O:13][CH3:14])[C:7]=1[C:4]1[S:3][C:2]([N:17]([CH3:16])[CH:18]2[CH2:19][C:20]([CH3:26])([CH3:27])[NH:21][C:22]([CH3:25])([CH3:24])[CH2:23]2)=[N:6][N:5]=1
Reactant: COc1cccc(F)c1-c1nnc(Br)s1
Reactant: CNC1CC(C)(C)NC(C)(C)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1cccc(F)c1-c1nnc(N(C)C2CC(C)(C)NC(C)(C)C2)s1
Yield: 27.6 %

Procedure:
A stirred solution of 2-bromo-5-(2-fluoro-6-methoxyphenyl)-1,3,4-thiadiazole (335 mg, 1.159 mmol) and N,2,2,6,6-pentamethylpiperidin-4-amine (197 mg, 1.159 mmol) in NMP (2.5 mL) was heated at 120° C. for ˜18 hours. The reaction mixture was diluted with saturated NaHCO3(aq) (30 mL), water (20 mL), and extracted with DCM (75 mL). The organic phase was separated, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo to afford the crude product as a brown oil/liquid. The crude material was purified by UV directed preparative HPLC under acidic conditions (0.1% TFA), collecting at 298 nm. The product containing fractions were combined and loaded onto a 5 g SCX cartridge (pre-wet with MeOH). The cartridge was washed with MeOH (30 mL) then flushed with 7M NH3 in MeOH (20 mL). The MeOH/NH3 was removed in vacuo to afford the title compound as an orange oil (121 mg, 28% yield). LC-MS: Rt 0.88 min; MS m/z 379.4 [M+H]+; [Method A]. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.49 (td, J=8.34, 6.57 Hz, 1H), 7.03 (d, J=8.59 Hz, 1H), 6.97 (t, J=9.09 Hz, 1H), 4.26-4.36 (m, 1H), 3.86 (s, 3H), 2.98 (s, 3H), 1.62 (dd, J=11.62, 2.53 Hz, 2H), 1.42 (t, J=12.13 Hz, 2H), 1.27 (br. s., 1H), 1.20 (s, 6H), 1.09 (s, 6H).
Reaction SMILES: [OH:1][C:2]1[C:7]2=[C:8]([CH3:20])[C:9]([O:11][CH2:12][CH2:13][CH2:14][NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.O=P(Cl)(Cl)Cl.[F:26][C:27]1[C:35](O)=[CH:34][CH:33]=[C:32]2[C:28]=1[CH:29]=[C:30]([CH3:37])[NH:31]2.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.ClCCl>[F:26][C:27]1[C:35]([O:1][C:2]2[C:7]3=[C:8]([CH3:20])[C:9]([O:11][CH2:12][CH2:13][CH2:14][NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:10][N:6]3[N:5]=[CH:4][N:3]=2)=[CH:34][CH:33]=[C:32]2[C:28]=1[CH:29]=[C:30]([CH3:37])[NH:31]2
Reactant: Cc1cc2c(F)c(O)ccc2[nH]1
Reactant: Cc1c(OCCCNS(C)(=O)=O)cn2ncnc(O)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1cc2c(F)c(Oc3ncnn4cc(OCCCNS(C)(=O)=O)c(C)c34)ccc2[nH]1
Temperature: 80 °C
Yield: 36.6 %

Procedure:
A mixture of N-[3-(4-hydroxy-5-methyl-pyrrolo[2,1-f][1,2,4]triazin-6yloxy)-propyl]-methanesulfonamide (530 mg, 1.77 mmol) and POCl3 was heated at 80° C. for 1.5 h. The volatiles were removed and the residue was diluted with dichloromethane, washed successively with cold NaHCO3 solution and brine, dried, and concentrated in vacuo to afford the crude chloroimidate intermediate (610 mg), which was heated with 4-fluoro-2-methyl-1H-indol-5-ol (495 mg, 3.0 mmol) and K2CO3 (3.0 g, 22 mmol) in DMF (8 mL) at 80-85° C. for 2 h. The mixture was diluted with dichloromethane and the solid was filtered. The filtrate was concentrated and the residue was purified by silica gel flash column chromatography eluting with 30% ethyl acetate/dichloromethane. The desired product was further purified by preparative HPLC to afford the title compound (290 mg, 34% yield) as a tan solid.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[N:6]([CH3:8])[CH3:7].[CH3:14][C:15]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:16]=1[S:17]([OH:20])(=[O:19])=[O:18].C1(C)C=CC(S(OC)(=O)=O)=CC=1>CCOCC>[S:17]([C:16]1[CH:21]=[CH:22][C:23]([CH3:25])=[CH:24][CH:15]=1)([O-:20])(=[O:19])=[O:18].[F:1][C:2]([F:12])([F:13])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[N+:6]([CH3:14])([CH3:8])[CH3:7]
Reactant: Cc1ccc(S(=O)(=O)O)c(C)c1
Reactant: CN(C)c1cccc(C(F)(F)F)c1
Agent: COS(=O)(=O)c1ccc(C)cc1
Solvent: CCOCC
Product: C[N+](C)(C)c1cccc(C(F)(F)F)c1
Product: Cc1ccc(S(=O)(=O)[O-])cc1

Procedure:
A mixture of 8.21 g (43.4 mmol) 3-(trifluoromethyl)-N,N-dimethylaniline and8.43 g (45.3 mmol) methyl p-toluenesulfonate (methyl tosylate) was mixed and heated to 80°±10° C. for 1.5 hr. The mixture was cooled and treated with ether, resulting in a suspension of fine powdery crystals. These were collected by filtration, washed with ether, and driedin a vacuum oven: 7.51 g (46.1%). The product was identified as 3-(trifluoromethyl)-N,N,N-trimethylanilinium tosylate by 1H NMR, IR,MS, and combustion analysis. Concentration of the filtrate yielded an additional 2.44 g (15.0%). The combined product was further purified by recrystallization from ethanol/toluene: mp 176.0°-178.2° C.; 1H NMR (CDCl3): δ 2.31 (s, 3H), 3.90 (s, 9H), 7.33 (aa`mm`, 4H), 7.59 (m 2H), 7.95 (m, 1H), and 8.40 ppm (m, 2H); IR (KBr): ν 1322, 1199, 1127, 812, and 689 cm-1 ; FDMS: m/e 204 amu (R4N+); anal. calcd. for C17H20F3NO3 (375.41): 3.7% N, 54.4% C, 5.4% H, and 15.2% F; found: 4.2, 4.6% N, 54.3, 54.4% C, 5.4, 5.7% H, and 15.3% F.
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10](=[O:16])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][C:31]([Cl:34])([Cl:33])[Cl:32])=[O:28].C1(N=C=NC2CCCCC2)CCCCC1.N1C=CC=CC=1>ClCCl>[C:1]([NH:8][CH2:9][C:10](=[O:16])[CH2:11][CH2:12][C:13]([O:15][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][C:31]([Cl:32])([Cl:33])[Cl:34])=[O:28])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)NCC(=O)CCC(=O)O
Reactant: O=C(CCCCCCCCCO)OCC(Cl)(Cl)Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)CCC(=O)OCCCCCCCCCC(=O)OCC(Cl)(Cl)Cl
Yield: 69.8 %

Procedure:
This compound was prepared from 5-(Boc-amino)-4-oxopentanoic acid (1.00 g; 4.3 mmol), the product from 12a (1.37 g; 4.3 mmol), N,N′-dicyclohexylcarbodiimide (DCC, 1.03 g; 5.0 mmol), and pyridine (2.0 mL) in dichloromethane (40 mL) using Procedure E. The crude product was purified on a 100×50 mm silica gel 60 column eluted with ethyl acetate-hexane (1:2), collecting 16×50 mL fractions. From evaporation of fractions 4-9 gave 1.6 g (71%) product was obtained (yellowish oil).
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([CH:11]1O[CH2:12]1)[Cl:10].[NH3:14]>>[C:2]1([CH:1]2[NH:14][CH2:12][CH:11]([CH2:9][Cl:10])[O:8]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: N
Reactant: ClCC1CO1
Product: ClCC1CNC(c2ccccc2)O1
Yield: 20 %

Procedure:
According to Carter and Blattacharye [J. Amer. Chem. Soc 75, 2503 (1953)], D,L-carnitine is obtained by reacting benzaldehyde, epichlorohydrin and ammonia in an organic solvent, the reaction product 2-phenyl-5-chloromethyloxazolidine is isolated and said compound is subsequently transformed into D,L-carnitine according to known techniques, with a yield of 20-25%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:40](Cl)([O:42]C(=O)OC(Cl)(Cl)Cl)Cl.[F:51][C:52]1[CH:60]=[CH:59][C:55]([CH:56]([OH:58])[CH3:57])=[CH:54][CH:53]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:40](=[O:42])[O:58][CH:56]([C:55]2[CH:59]=[CH:60][C:52]([F:51])=[CH:53][CH:54]=2)[CH3:57])=[C:18]([CH3:24])[CH:17]=1
Reactant: CC(O)c1ccc(F)cc1
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)OC(C)c4ccc(F)cc4)cc3C)c2cc1OC
Temperature: 25 °C
Yield: 63.9 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (90 mg) was added to toluene/triethylamine=10/1 (9 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (123 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 4-fluoro-α-methylbenzyl alcohol (58 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (87 mg, yield 64%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:27][C:28](Br)=[O:29].[NH2:31][CH:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:27][C:28]([NH:31][CH:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33]1)=[O:29]
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OC)cc32)cc1OC
Reactant: NC1CCc2ccccc21
Reactant: O=C(Br)CBr
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NC2CCc3ccccc32)cc1OC

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 1-amino-indane