Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([C:15]4[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=4)[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]=[CH2:30])=[CH:25][N:24]=1.[OH-].[K+]>CN1C(=O)CCC1>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:30][CH2:29][C:26]3[CH:25]=[N:24][C:23]([CH3:22])=[CH:28][CH:27]=3)[C:6]3[CH2:11][CH2:12][N:13]([C:15]4[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=4)[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: Cc1ccc(N2CCc3[nH]c4ccc(C)cc4c3C2)cc1
Reactant: C=Cc1ccc(C)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc(N2CCc3c(c4cc(C)ccc4n3CCc3ccc(C)nc3)C2)cc1

Procedure:
The title compound is prepared from a mixture of 2,3,4,5-tetrahydro-8-methyl-2-p-tolyl-1H-pyrido[4,3-b]indole, 2-methyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH2:27][CH2:28][CH2:29][N:30]4[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:43][C:44](=[O:46])[CH3:45].O>CN(C=O)C>[NH2:26][C:24]1[C:25]2=[C:17]([C:12]3[CH:13]=[CH:14][C:15]4[C:10]([CH:11]=3)=[N:9][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:16]=4)[CH:18]=[C:19]([CH2:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][N:33]([CH2:43][C:44](=[O:46])[CH3:45])[CH2:32][CH2:31]3)[N:20]2[N:21]=[CH:22][N:23]=1
Reactant: Nc1ncnn2c(CCCN3CCNCC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)CN1CCN(CCCc2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)CC1
Temperature: 50 °C
Yield: 12.9 %

Procedure:
5-(2-Benzyl-2H-indazol-6-yl)-7-(3-piperazin-1-yl-propyl)pyrrolo-[2,1-f][1,2,4]triazin-4-ylamine (75 mg, 0.16 mmol) was dissolved in anhydrous DMF (3.2 mL) and treated with K2CO3 (33 mg, 0.24 mmol) followed by the addition of chloroacetone (15 μL, 0.19 mmol). The mixture was heated to 50° C. for 18 h, cooled to rt and poured into water. The aqueous layer was extracted with 3×10 mL of EtOAc and the combined organic phases were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude was purified via preparative HPLC. The product containing fractions were collected, and the TFA from the eluent was removed via filtration through an acidic resin followed by washing with acetonitrile. The product was then eluted with 2M NH3 in MeOH. The filtrate was concentrated and the residue was crystallized from DCM-ether to provide the title compound (10.8 mg, 13%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.54 (s, 1H), 7.87 (s, 1H), 7.79 (d, 1H), 7.57 (s, 1H), 7.36 to 7.29 (m, 5H), 7.13 (d, 1H), 6.59 (s, 1H), 5.64 (s, 2H), 3.27 to 3.24 (m, 1H), 3.09 (s, 2H), 2.87 (t, 2H), 2.36 to 2.23 (m, 9H), 2.04 (s, 3H), 1.88 to 1.79 (m, 2H); ES-MS m/z 523.2 [M+H]+, RT (min) 2.08.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([F:19])[CH:17]=2)[N:12]=[C:11]([CH2:20]O)[C:10]=1[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:25])=O>C1COCC1.C1(C)C=CC=CC=1.N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([F:19])[CH:17]=2)[N:12]=[C:11]([CH2:20][Cl:25])[C:10]=1[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1c(CO)nc2ccc(F)cc2c1OCc1ccccc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: Cc1c(CCl)nc2ccc(F)cc2c1OCc1ccccc1
Reaction time: 1 h

Procedure:
[4-(Benzyloxy)-6-fluoro-3-methylquinolin-2-yl]methanol (4.02 g) was dissolved in THF (50 mL) and toluene (50 mL), and 10 drops of pyridine were added thereto. Thionyl chloride (1.50 mL) was gradually added dropwise thereto under ice-cooling, and the reaction mixture was stirred at the same temperature for 1 hour, and further stirred at room temperature for 1 hour. After the precipitated solid was collected by filtration, ethyl acetate and a saturated aqueous sodium hydrogen carbonate solution were gradually added with stirring to the filtrate under ice-cooling. After the foaming became stable, the organic layer was separated, washed sequentially with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated. The residue was purified by silica gel column chromatography (eluent: chloroform) to obtain 4-(benzyloxy)-2-(chloromethyl)-6-fluoro-3-methylquinoline (3.85 g).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([I:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].CCN(C(C)C)C(C)C.[C:22]([CH2:26][CH2:27][C:28](Cl)=[O:29])([O:24][CH3:25])=[O:23].O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[I:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([NH:1][C:28](=[O:29])[CH2:27][CH2:26][C:22]([O:24][CH3:25])=[O:23])[CH:11]=1
Reactant: COC(=O)CCC(=O)Cl
Reactant: COC(=O)c1ccc(I)cc1N
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)CCC(=O)Nc1cc(I)ccc1C(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.6 %

Procedure:
To a solution of methyl 2-amino-4-iodobenzoate (17 g, 61.3 mmol) in DCM (200 mL), was added DIEA (10.6 mL, 64.4 mmol) and DMAP (37.5 mg, 0.31 mmol). To this solution was added 3-(carbomethoxy)propionyl chloride (8.3 mL, 67.4 mmol) dropwise, and the reaction mixture was allowed to stir at rt for 2 h. To the reaction mixture was then added H2O (80 mL) and the mixture was allowed to stir for 30 min. The organic solution was separated and the aqueous solution was extracted with DCM (2×100 mL). The organic solutions were combined, washed with H2O (2×100 mL) and brine (1×100 mL), dried over Na2SO4, filtered and concentrated to give methyl 4-iodo-2-[(4-methoxy-4-oxobutanoyl)amino]benzoate (24.6 g, 99%).
Reaction SMILES: [S:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].[Cl:16][C:17]1[CH:22]=[C:21]([CH:23]2[CH2:28][CH2:27][C:26]([CH3:30])([CH3:29])[CH2:25][CH2:24]2)[CH:20]=[CH:19][C:18]=1O>N1C=CC=CC=1.C1(C)C=CC=CC=1>[F:5][C:4]([F:7])([F:6])[S:1]([O:8][C:18]1[CH:19]=[CH:20][C:21]([CH:23]2[CH2:24][CH2:25][C:26]([CH3:29])([CH3:30])[CH2:27][CH2:28]2)=[CH:22][C:17]=1[Cl:16])(=[O:3])=[O:2]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CC1(C)CCC(c2ccc(O)c(Cl)c2)CC1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC1(C)CCC(c2ccc(OS(=O)(=O)C(F)(F)F)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
8.2 ml of triflic anhydride are added at 5° C. to 9.7 g of 2-chloro-4-(4,4-dimethylcyclohexyl)phenol (compound IX.1) in 60 ml of pyridine, the reaction mixture is left to stand for 30 minutes at 0° C., and then the reaction mixture is stirred at room temperature for 12 hours. The reaction mixture is hydrolysed and then extracted with dichloromethane. The organic phase is dried over magnesium sulphate and the solvents are evaporated off under reduced pressure. The residue obtained is taken up in toluene, and then the solvents are evaporated off under reduced pressure. The residue obtained is purified by chromatography on a column of silica gel, eluting with a cyclohexane/ethyl acetate mixture which varies from 100/0 to 99/1 (v/v). 15 g of the compound are obtained.
Reaction SMILES: Br[C:2]1[C:3]2[NH:7][C:6]([C:8]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[C:9]3[N:31]=[C:12]([CH:13]=[C:14]4[NH:30][C:17](=[C:18]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[C:19]5[CH:20]=[CH:21][C:22]=1[N:23]=5)[CH:16]=[CH:15]4)[CH:11]=[CH:10]3)=[CH:5][CH:4]=2.[CH3:38][C@@:39]12[C:55](=[O:56])[CH2:54][CH2:53][C@H:52]1[C@H:51]1[C@@H:42]([C:43]3[CH:44]=[CH:45][C:46]([OH:57])=[CH:47][C:48]=3[CH2:49][CH2:50]1)[CH2:41][CH2:40]2.C1C=CC(P(C2C(OC3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=CC=3)=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(Cl)Cl>[C:24]1([C:18]2[C:19]3[CH:20]=[CH:21][C:22]([N:23]=3)=[C:2]([O:57][C:46]3[CH:45]=[CH:44][C:43]4[CH:42]5[CH:51]([CH2:50][CH2:49][C:48]=4[CH:47]=3)[CH:52]3[C:39]([CH3:38])([C:55](=[O:56])[CH2:54][CH2:53]3)[CH2:40][CH2:41]5)[C:3]3[NH:7][C:6]([C:8]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[C:9]4[N:31]=[C:12]([CH:13]=[C:14]5[NH:30][C:17]=2[CH:16]=[CH:15]5)[CH:11]=[CH:10]4)=[CH:5][CH:4]=3)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Reactant: Brc1c2nc(c(-c3ccccc3)c3ccc(cc4nc(c(-c5ccccc5)c5ccc1[nH]5)C=C4)[nH]3)C=C2
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC12CCC3c4ccc(Oc5c6nc(c(-c7ccccc7)c7ccc(cc8nc(c(-c9ccccc9)c9ccc5[nH]9)C=C8)[nH]7)C=C6)cc4CCC3C1CCC2=O

Procedure:
The general procedure was used to couple 5-bromo-10,20-diphenylporphin (27.1 mg, 0.05 mmol) with estrone (27 mg, 0.1 mmol), using Pd2(dba)3 (2.3 mg, 0.0025 mmol) and DPEphos (5.38 mg, 0.01 mmol) in the presence of Cs2CO3 (37.6 mg, 0.1 mmol). The reaction was conducted in THF at 100° C. for 24 h. The title compound was isolated by flash chromatography (silica gel, methylene chloride: hexanes (v/v)=8:2) as a purple-red solid (20 mg, 55%). 1H NMR (300 MHz, CDCl3) δ 10.13 (s, 1H), 9.39 (d, J=4.8 Hz, 2H), 9.29 (d, J=4.8 Hz, 4H), 8.98 (d, J=4.8 Hz, 4H), 8.86 (d, J=4.8 Hz, 4H), 8.22 (m, 4H), 7.75 (m, 6H), 7.14 (d, J=9.0 Hz, 1H), 6.88 (d, J=8.4 Hz, 1H), 6.64 (d, J=1.8 Hz, 1H), 1.86-2.62 (m, H from estrone), 1.26-1.52 (m, H from estrone), 0.85 (s, 3H), −2.77 (s, 2H). 13C NMR (75 MHz, CDCl3): δ 141.2, 138.1, 134.7, 133.0, 131.5, 130.8, 127.9, 127.8, 126.9, 126.5, 120.2, 119.7, 116.6, 114.1, 104.6, 50.3, 47.9, 44.0, 38.1, 35.8, 31.5, 29.4, 26.3, 25.8, 21.5, 13.8. UV-vis (CH2Cl2, Amax, nm): 413, 510, 544, 585, 641. HRMS-EI ([M]+): calcd for C50H42N4O2, 730.3308, found 730.3294.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH:9]=[O:10])[C:4]=1[NH:11][C:12](=[O:28])[CH2:13][CH:14]1[C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:21][C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH3:2].[CH2:29]([Mg]Br)[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH:9]([OH:10])[CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:4]=1[NH:11][C:12](=[O:28])[CH2:13][CH:14]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=2[O:21][C:22]2[C:27]1=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH3:2]
Reactant: Br[Mg]CCc1ccccc1
Reactant: CCc1cccc(C=O)c1NC(=O)CC1c2ccccc2Oc2ccccc21
Product: CCc1cccc(C(O)CCc2ccccc2)c1NC(=O)CC1c2ccccc2Oc2ccccc21

Procedure:
Following a procedure similar to that described in Example 14, but using N-(2-ethyl-6-formylphenyl)-2-(9H-xanthen-9-yl)acetamide (prepared by a procedure similar to that described in Preparation 29) and phenethylmagnesium bromide as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as crystals, melting at 128°-129° C. (after recrystallization from a mixture of ethyl acetate and hexane).
Reaction SMILES: O[C:2]1[C:7]([CH2:8][C:9]2[CH:22]=[CH:21][C:12]([CH:13]=[C:14]([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:23][C:24]1[C:30]([CH3:31])=[C:29]([OH:32])[C:28]([CH3:33])=[CH:27][C:25]=1[OH:26].S(=O)(=O)(O)O.C(=O)([O-])O.[Na+]>ClC(Cl)C>[CH3:33][C:28]1[C:29](=[O:32])[C:30]([CH3:31])=[C:24]([CH3:23])[C:25](=[O:26])[C:27]=1[CH:8]([C:7]1[CH:2]=[N:3][CH:4]=[CH:5][CH:6]=1)[C:9]1[CH:22]=[CH:21][C:12]([CH:13]=[C:14]([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:10]=1
Reactant: CCOC(=O)C(C)=Cc1ccc(Cc2cccnc2O)cc1
Reactant: Cc1cc(O)c(C)c(C)c1O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCOC(=O)C(C)=Cc1ccc(C(C2=C(C)C(=O)C(C)=C(C)C2=O)c2cccnc2)cc1
Yield: 83.2 %

Procedure:
To a solution of 1.0 g (3.36 mmol) of ethyl 4-[hydroxy-(3-pyridyl)]methyl-α-methylcinnamate in 10 ml of dichloroethane, 514 mg (3.38 mmol) of 2,3,5-trimethylhydroquinone and 0.28 ml (5.26 mmol) of concentrated sulfuric acid were added and refluxed by heating for 2 hours. The reaction mixture was made weakly alkaline with a saturated solution of sodium hydrogen carbonate, and the organic phase was separated while the aqueous phase was extracted with chloroform and the extract was combined with the organic phase. The organic phase was oxidized with ferric chloride, washed with water, dried, and concentrated. The residue was purified with silica gel column chromatography (isopropyl ether-acetic ester (1:1)), to give 1.2 g (yield 82.7%) of ethyl 4-[3,5,6-trimethyl-1,4-benzoquinon -2-yl(3-pyridyl)methyl]-α-methylcinnamate. The physical data are shown in Table 1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][CH2:21][CH2:22]Br)=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:24]([NH:26][CH2:27][CH3:28])[CH3:25]>>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][N:26]([CH2:27][CH3:28])[CH2:24][CH3:25])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCNCC
Reactant: CC(C)(C)OC(=O)N1CCCc2cc(OCCCCBr)ccc21
Product: CCN(CC)CCCCOc1ccc2c(c1)CCCN2C(=O)OC(C)(C)C

Procedure:
In analogy to example 2.9, 6-(4-Bromo-butoxy)-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester and diethylamine were converted to yield 6-(4-Diethylamino-butoxy)-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester as colorless oil.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])[CH3:3].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:47]([N:50]1[C:59]2[C:54](=[CH:55][C:56]([C:60]([NH:62]O)=[NH:61])=[CH:57][CH:58]=2)[C@H:53]([NH:64][C:65](=[O:70])[O:66][CH:67]([CH3:69])[CH3:68])[CH2:52][C@@H:51]1[CH3:71])(=[O:49])[CH3:48]>CN(C)C=O>[CH3:69][CH:67]([O:66][C:65](=[O:70])[NH:64][C@H:53]1[C:54]2[C:59](=[CH:58][CH:57]=[C:56]([C:60]3[N:62]=[C:11]([CH2:10][CH2:9][NH:8][C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[O:13][N:61]=3)[CH:55]=2)[N:50]([C:47](=[O:49])[CH3:48])[C@@H:51]([CH3:71])[CH2:52]1)[CH3:68]
Reactant: CC(=O)N1c2ccc(C(=N)NO)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)N1c2ccc(-c3noc(CCNC(=O)OC(C)(C)C)n3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 51.8 %

Procedure:
A flask was charged with N-{[(1,1-dimethylethyl)oxy]carbonyl}-β-alanine (227 mg, 1.200 mmol) and HATU (494 mg, 1.300 mmol) then filled with N,N-dimethylformamide (DMF) (5 mL). DIPEA (0.524 mL, 3.00 mmol) was added and the resulting pale yellow solution was stirred for 5 min. 1-Methylethyl {(2S,4R)-1-acetyl-6-[(hydroxyamino)(imino)methyl]-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl}carbamate (for a preparation, see Intermediate 56) (348 mg, 1 mmol) in N,N-dimethylformamide (DMF) (5 mL) was then added via syringe. The resulting mixture was stirred at room temperature for 30 min, at 110° C. for 5 h then cooled to room temperature and partitioned between AcOEt and water/brine (1/1). The layers were separated and the aqueous phase was extracted with AcOEt. The combined organic phases were washed with water/brine (1/1) (3×) then dried over MgSO4 and concentrated in vacuo. Purification of the residue by SP4 using 25 G silica cartridge (gradient: 23 to 73% AcOEt in Hexanes), gave 1-methylethyl((2S,4R)-1-acetyl-6-{5-[2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)ethyl]-1,2,4-oxadiazol-3-yl}-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl)carbamate (260 mg, 0.518 mmol, 51.8% yield) as a pale orange foam. LCMS (method G): Retention time 1.04 min, [M+H]+=502.0
Reaction SMILES: [CH3:1][C:2]1[N:11](OC(=O)C(C)(C)C)[C:10](=[O:19])[C:9]2[C:4](=[CH:5][C:6]3[CH2:23][CH2:22][CH:21]([N:24]([C:28]4[CH:29]=[CH:30][C:31]([C:34]([O:36]C)=[O:35])=[N:32][CH:33]=4)[CH2:25][C:26]#[CH:27])[C:7]=3[C:8]=2C)[N:3]=1.[OH-].[Na+].O>CO>[CH3:1][C:2]1[NH:11][C:10](=[O:19])[C:9]2[C:4](=[CH:5][C:6]3[CH2:23][CH2:22][CH:21]([N:24]([C:28]4[CH:29]=[CH:30][C:31]([C:34]([OH:36])=[O:35])=[N:32][CH:33]=4)[CH2:25][C:26]#[CH:27])[C:7]=3[CH:8]=2)[N:3]=1
Reactant: C#CCN(c1ccc(C(=O)OC)nc1)C1CCc2cc3nc(C)n(OC(=O)C(C)(C)C)c(=O)c3c(C)c21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C#CCN(c1ccc(C(=O)O)nc1)C1CCc2cc3nc(C)[nH]c(=O)c3cc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of methyl 5-[N-((6RS)-2-methyl-4-oxo-3-pivaloyloxy-methyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)-N-(prop-2-ynyl)amino]pyridine-2-carboxylate (1 g), sodium hydroxide (0.32 g), water (10 ml) and methanol (30 ml) was stirred at ambient temperature for 24 hours. The mixture was evaporated. Water (60 ml) was added and the mixture was acidified to pH 5 by the addition of 2N aqueous hydrochloric acid. The precipitate was isolated, washed with water and dried under vacuum. There was thus obtained 5-[N-((6RS)-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)-N-(prop-2-ynyl)amino]pyridine-2-carboxylic acid (0.68 g);
Reaction SMILES: Cl[CH2:2][C@H:3]([OH:10])[CH2:4][C:5]([O:7]CC)=[O:6].[CH3:11][N:12]([CH3:14])[CH3:13]>O>[OH:10][C@H:3]([CH2:4][C:5](=[O:6])[O-:7])[CH2:2][N+:12]([CH3:14])([CH3:13])[CH3:11]
Reactant: CN(C)C
Reactant: CCOC(=O)C[C@@H](O)CCl
Solvent: O
Product: C[N+](C)(C)C[C@H](O)CC(=O)[O-]
Temperature: 80 °C
Reaction time: 15 h
Yield: 75 %

Procedure:
400 g of crude ethyl (+) (R)-4-chloro-3-hydroxybutyrate, prepared according to Example 8, and 1 l of 45% trimethylamine in H2O are placed in a 2-liter reactor. The reaction mixture is heated to 80° C. and kept at this temperature for 15 h. After cooling and removing the excess of trimethylamine under nitrogen flow, the aqueous solution is extracted with 1.9 l of methylene chloride and analyzed with HPLC. L-carnitine is obtained with 75% yield.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][Br:19])=[CH:16][CH:17]=2)=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: BrCCCCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1ccc(-c2ccc(OCCCCCCCCCCCCCCCCBr)cc2)cc1
Yield: 70.1 %

Procedure:
An acetone solution of 90 m moles (21.8 g) of 4'-hydroxybiphenyl-4-carboxylic acid ethyl ester obtained in Example 24, 0.15 mole (57.6 g) of 1,16-dibromohexadecane, and 0.4 mole (55.3 g) of potassium carbonate was refluxed for four hours. The reaction solution was filtered. The filtrate was concentrated, and then purified by column chromatography to obtain 34.4 g of 4'-(16-bromohexadecyloxy)biphenyl-4-carboxylic acid ethyl ester. (yield: 70%)
Reaction SMILES: [Si]([O:18][C@@H:19]1[CH2:24][CH2:23][CH2:22][C@H:21]([CH2:25][CH2:26][C:27]([CH3:36])([CH3:35])[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:20]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:18][C@@H:19]1[CH2:24][CH2:23][CH2:22][C@H:21]([CH2:25][CH2:26][C:27]([CH3:36])([CH3:35])[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:20]1
Reactant: CC(C)(C)OC(=O)C(C)(C)CC[C@H]1CCC[C@@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(C)(C)CC[C@H]1CCC[C@@H](O)C1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
2 g of tert-butyl 4-[cis-3-(tert-butyl-diphenylsilanyloxy)cyclohexyl]-2,2-dimethylbutyrate are dissolved in 10 ml of tetrahydrofuran, and 8 ml of a 1 M solution of tetrabutylammonium fluoride and tetrahydrofuran are added. The mixture is stirred at 60° C. for 2 hours. The reaction mixture is concentrated under reduced pressure and purified on silica gel using the mobile phase n-heptane:ethyl acetate=20:1=>1:1. This gives 730 mg of tert-butyl 4-[cis-3-hydroxycyclohexyl)-2,2-dimethylbutyrate as an oil. C16H30O3 (270.42), Rf(n-heptane:ethyl acetate=5:1)=0.22.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]([NH:9][C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[C:29]5[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=5)[NH:23][N:22]=4)[N:19]=3)[N:14]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:13]=2)=[O:11])[CH3:8])=[CH:3][CH:2]=1.[H-].[Na+].Cl.Br[CH2:43][CH2:44][N:45]1[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1>CN(C=O)C>[N:1]1[CH:2]=[CH:3][C:4]([CH:7]([NH:9][C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[C:29]5[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=5)[N:23]([CH2:43][CH2:44][N:45]5[CH2:50][CH2:49][O:48][CH2:47][CH2:46]5)[N:22]=4)[N:19]=3)[N:14]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:37])([CH3:36])[CH3:38])[CH:13]=2)=[O:11])[CH3:8])=[CH:5][CH:6]=1
Reactant: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4cc(F)ccc34)nc12)c1ccncc1
Reactant: BrCCN1CCOCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CCN4CCOCC4)c4cc(F)ccc34)nc12)c1ccncc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 57.1 %

Procedure:
2-(6-Fluoro-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-pyridin-4-yl-ethyl)-amide (100 mg, 0.19 mmol) was combined with DMF (2 mL) at 0° C. to give a yellow solution. Sodium hydride (60% in mineral oil, 23 mg, 0.56 mmol) was added and the reaction was stirred at 0° C. for 10 min. 4-(2-Bromoethyl)morpholine hydrochloride (55 mg, 0.28 mmol) was added and the reaction was stirred at 0° C. for 30 min then warmed to room temperature. The reaction mixture was stirred for 2 h at room temperature then quenched with 5 mL of brine and 10 mL of water and extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with water and brine then dried with MgSO4, filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography (0-10% methanol in dichloromethane) to give 70 mg (58%) of 2-[6-fluoro-1-(2-morpholin-4-yl-ethyl)-1H-indazol-3-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-pyridin-4-yl-ethyl)-amide as a foaming solid. MS: (M+H)+=645.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[N:9]/[CH:10]([CH3:18])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:4][CH:3]=1.Br[CH2:20][CH:21]1[CH2:23][CH2:22]1.[OH-].[K+].C(=O)([O-])[O-].[K+].[K+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[N:9]/[C:10]([CH3:18])([CH2:20][CH:21]2[CH2:23][CH2:22]2)[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:6][CH:7]=1
Reactant: CC(/N=C/c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Reactant: BrCC1CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C(C)(CC1CC1)/N=C/c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 108.3 %

Procedure:
To a round-bottomed flask (100 ml) under an argon atmosphere was added tert-butyl 2-[(E)-(4-chlorophenyl)methyleneamino]propanoate (CAN 208927-33-7, 1.6 g, 5.97 mmole), 1-bromomethyl cyclopropane (CAN 7051-34-5, 4.5 ml, 51.43 mmole), and tetrabutyl ammonium chloride (0.166 g, 0.6 mmole). A mixture of potassium hydroxide (1.67 g, 29.85 mmole)/potassium carbonate (4.12 g, 29.85 mmole) was finely grained using a mortar and was added to the reaction mixture. The resulting mixture was stirred vigorously at room temperature for 24 h. Dichloromethane was added and the reaction mixture was filtered to remove insolubles. The solids were washed twice with 40 ml dichloromethane and the filtrate was evaporated to dryness on a rotary evaporator. The residue was taken up in ether (80 ml) and the organic solution was washed twice with 80 ml water. The organic phase was dried over sodium sulfate and evaporated in vacuo to yield the title compound (2.08 g) as a crude yellow oil which was used without any purification; MS (ESI, m/z): 322.3 (M+H+).