Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:6]=[CH:7][C:8]2[O:14][CH2:13][CH:12]3[CH2:15][CH2:16][CH2:17][CH2:18][N:11]3[CH2:10][C:9]=2[CH:19]=1)([O-])=O>CO>[ClH:1].[NH2:2][C:5]1[CH:6]=[CH:7][C:8]2[O:14][CH2:13][CH:12]3[CH2:15][CH2:16][CH2:17][CH2:18][N:11]3[CH2:10][C:9]=2[CH:19]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)CN1CCCCC1CO2
Agent: Cl
Solvent: CO
Product: Nc1ccc2c(c1)CN1CCCCC1CO2
Reaction time: 1 h
Yield: 103.6 %

Procedure:
2-Nitro-6,6a,7,8,9,10-hexahydro-12H-pyrido[2,1-c][1,4]benzoxazepine hydrochloride (2.46 g) dissolved in methanol (50 ml) was treated with 10% Pd--C (0.25 g), and hydrogenated on a Parr Hydrogenator for one hour, filtered and evaporated to yield a tacky solid (2.28 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1.[Br-].[O:16]1CCO[CH:17]1[CH2:21][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOCCN(CCOCCOC)CCOCCOC>ClCCl.C([O-])([O-])=O.[K+].[K+]>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:14]=[CH:13][C:10](/[CH:11]=[CH:21]/[CH:17]=[O:16])=[CH:9][CH:8]=1
Reactant: O=Cc1ccc(-c2ccccn2)cc1
Reactant: c1ccc([P+](CC2OCCO2)(c2ccccc2)c2ccccc2)cc1
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: ClCCl
Product: O=C/C=C/c1ccc(-c2ccccn2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.3 %

Procedure:
A mixture of 4-(2-pyridinyl)-benzaldehyde (1.76 g, 9.58 mmol), (1,3-dioxolan-2-ylmethyl)triphenylphosphonium bromide (6.45 g, 15.02 mmol), and TDA-1 (Tris(3,6-dioxaheptyl)amine, 3.20 mL, 10.00 mmol) in dichloromethane (50 mL) and sat. aq. K2CO3 (50 mL) was heated to reflux for 20 h. The layers were separated and the aqueous layer was extracted with dichloromethane (2×25 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried (MgSO4), and concentrated. THF (25 mL) and 10% HCl (25 mL) were added and the mixture was stirred for 1 h at rt. The reaction mixture was cooled to 0° C., made basic with 10% NaOH, and extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried (MgSO4), and concentrated. Purification by chromatography (SiO2, 3:1 hexane/ethyl acetate) provided 1.69 g (89%) of the title compound as a yellow solid. MS 210 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].[N+:10]([O-])([OH:12])=[O:11].O.C(Cl)Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClC(Cl)C>[F:8][C:7]1[C:2]([F:1])=[CH:3][C:4]([OH:9])=[C:5]([N+:10]([O-:12])=[O:11])[CH:6]=1
Reactant: Oc1ccc(F)c(F)c1
Reactant: O=[N+]([O-])O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: ClCCl
Solvent: CC(Cl)Cl
Solvent: O
Product: O=[N+]([O-])c1cc(F)c(F)cc1O
Temperature: 25 °C
Reaction time: 14 h
Yield: 29.7 %

Procedure:
A solution of 3,4-difluorophenol (5.0 g, 38.4 mmol) and tetrabutylammonium bromide (1.239 g, 3.8 mmol) in dichloroethane (30 mL) were added into a 250 mL round-bottomed flask. The mixture was stirred for 45 min before nitric acid (86 g, 96.09 mmol) (7%) was added. The reaction was stirred at RT for 14 h. Water (100 mL) and DCM (50 mL) was added. After stirring for another 10 min, the mixture was partitioned, and the aqueous layer was extracted with DCM (1×20 mL). The combined organic layer was dried (Na2SO4), and concentrated to give the crude product. The crude product was purified by chromatography on silica gel using EtOAc/hexance (0-50%, 30 min). Collected fractions were concentrated to give the title product (2.0 g, 30% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:16]2[C@@H:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:10][C@H:9]1[C:17](O)=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)OCC(C)C.[NH2:28][C:29]1[CH:33]=[C:32]([Br:34])[S:31][C:30]=1[C:35]([NH2:37])=[O:36].C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C.C(N(CC)CC)C>[Br:34][C:32]1[S:31][C:30]([C:35](=[O:36])[NH2:37])=[C:29]([NH:28][C:17]([C@@H:9]2[CH2:10][C@H:11]3[C@H:16]([CH2:15][CH2:14][CH2:13][CH2:12]3)[N:8]2[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[O:18])[CH:33]=1
Reactant: CC(C)(C)OC(=O)N1[C@H](C(=O)O)C[C@@H]2CCCC[C@@H]21
Reactant: NC(=O)c1sc(Br)cc1N
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1[C@H](C(=O)Nc2cc(Br)sc2C(N)=O)C[C@@H]2CCCC[C@@H]21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.6 %

Procedure:
To a solution of (2S,3aS,7aS)-1-(tert-butoxycarbonyl) octahydro-1H-indole-2-carboxylic acid (638 mg) and triethylamine (0.392 mL) in tetrahydrofuran (5 mL) was added 2-methylpropyl chlorocarbonate (0.324 mL) at 0° C., and the mixture was stirred at room temperature for 30 min. Thereafter, to the reaction system was added a solution of 3-amino-5-bromothiophene-2-carboxamide (250 mg) produced in Example 1, step D, in tetrahydrofuran (5 mL), and the mixture was stirred at 60° C. for 26 hr. Ethyl acetate (20 mL) and aqueous sodium hydrogen carbonate (10 mL) were added to the reaction mixture, and the separated aqueous layer was extracted with ethyl acetate (5 mL). The combined organic layers were washed with brine (5 mL) and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the object fraction was concentrated under reduced pressure to give the title compound (345 mg) as a pale-yellow amorphous solid.
Reaction SMILES: [H-].[Na+].F[C:4]1[N:12]=[C:11]2[C:7]([N:8]=[CH:9][N:10]2[CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)=[C:6]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([P:33](=[O:36])([OH:35])[OH:34])([OH:32])[PH2:30]=[O:31])=[CH:25][CH:24]=2)[N:5]=1.[CH2:37]([OH:39])[CH3:38]>>[CH2:37]([O:39][C:4]1[N:12]=[C:11]2[C:7]([N:8]=[CH:9][N:10]2[CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)=[C:6]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([P:33](=[O:36])([OH:35])[OH:34])([OH:32])[PH2:30]=[O:31])=[CH:25][CH:24]=2)[N:5]=1)[CH3:38]
Reactant: CCO
Reactant: O=[PH2]C(O)(c1ccc(Nc2nc(F)nc3c2ncn3CCc2cccc(O)c2)cc1)P(=O)(O)O
Agent: [H-]
Agent: [Na+]
Product: CCOc1nc(Nc2ccc(C(O)([PH2]=O)P(=O)(O)O)cc2)c2ncn(CCc3cccc(O)c3)c2n1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a cooled flask (0° C.) under an atmosphere of N2 containing 0.096 g (4.02 mmol) of sodium hydride was added 2.0 mL of absolute ethanol. After the effervescence had ceased, the solution was transferred via pipette to a cooled (0° C.) pressure flask, under an atmosphere of N2, containing a mixture of [(4-{2-Fluoro-9-[2-(3-hydroxy-phenyl)-ethyl]-9H -purin-6-ylamino}-phenyl)-hydroxy-phosphinoylmethyl]-phosphonic acid (0.199 g, 0.39 mmol) in 2.0 mL of absolute ethanol. Upon sealing the reaction vessel, the resulting mixture was stirred at ambient temperature for ˜10 min, then heated at 80° C. overnight. Ethanol was removed via N2 flow (slight heat) and the resulting thick suspension was dissolved in 25 mL of H2O (adjusted to pH ˜8 with 10% NaOH), filtered (0.2 μm, PTFE filter), and purified by RP-HPLC (CH3CN/H2O). Lyophilization provided a white solid (0.105 g): m/z 532 (M−H).
Reaction SMILES: SCC(C(CS)O)O.[CH3:9][O:10][CH2:11][CH2:12][C:13]([NH:15][C:16]1[S:17][C:18]2[CH:24]=[C:23]([S:25][C:26]#[N:27])[CH:22]=[CH:21][C:19]=2[N:20]=1)=[O:14].ClC1N2[N:34]=[C:35]([O:38][CH2:39][CH3:40])[CH:36]=[CH:37][C:32]2=[N:31][N:30]=1>O.C(O)C.O1CCCC1.P([O-])(O)(O)=O.[K+]>[CH2:39]([O:38][C:35]1[CH:36]=[CH:37][C:32]2[N:27]([C:26]([S:25][C:23]3[CH:22]=[CH:21][C:19]4[N:20]=[C:16]([NH:15][C:13](=[O:14])[CH2:12][CH2:11][O:10][CH3:9])[S:17][C:18]=4[CH:24]=3)=[N:30][N:31]=2)[N:34]=1)[CH3:40]
Reactant: CCOc1ccc2nnc(Cl)n2n1
Reactant: COCCC(=O)Nc1nc2ccc(SC#N)cc2s1
Agent: O=P([O-])(O)O
Agent: OC(CS)C(O)CS
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1ccc2nnc(Sc3ccc4nc(NC(=O)CCOC)sc4c3)n2n1
Temperature: 80 °C
Yield: 41.2 %

Procedure:
7 mg of potassium dihydrogen phosphate in 0.2 cm3 of water and 699 mg of DL-dithiothreitol are added to a degassed solution of 443 mg of 2-[(3-methoxypropanoyl)amino]-1,3-benzothiazol-6-yl thiocyanate in 10 cm3 of ethanol and 10 cm3 of tetrahydrofuran. The reaction is heated at 80° C. for 15 min and then 301 mg of 3-chloro-6-ethoxy[1,2,4]triazolo[4,3-b]pyridazine are added and the reaction is heated for a further 24 h. The reaction medium is then evaporated to dryness under reduced pressure. The residue is taken up in 20 cm3 of ethanol and 57 mg of sodium borohydride are added and the mixture is then brought to reflux for 18 h. The reaction medium is concentrated under reduced pressure. The residue is chromatographed by solid deposit on Biotage Quad 12/25 (KP-SIL, 60 A; 32-63 μm), elution being carried out with a gradient of 100% dichloromethane to 97/3 dichloromethane/methanol. 268 mg of N-{6-[(6-ethoxy[1,2,4]triazolo[4,3-b]pyridazin-3-yl)sulphanyl]-1,3-benzothiazol-2-yl}-3-methoxypropanamide are thus obtained in the form of a white powder, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[C:5]([NH:20][C:21](=O)[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=2)[CH:4]=1.N1C=CC=CC=1.Cl>[OH-].[Na+]>[CH2:13]([O:12][C:11]1[CH:10]=[C:6]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[N:20]=[C:21]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=1)[NH:9][C:7]2=[O:8])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1cc(NC(=O)c2cccc([N+](=O)[O-])c2)c(C(N)=O)cc1OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: COc1cc2nc(-c3cccc([N+](=O)[O-])c3)[nH]c(=O)c2cc1OCc1ccccc1
Temperature: 25 °C
Yield: 47 %

Procedure:
A suspension of 4-methoxy-5-benzyloxy-2-(3-nitrobenzoylamino) benzamide (8.00 g, possesses some pyridine.HCl) in 4N NaOH (200 mL) was heated at 100±5° C. for 10 h. The reaction mixture was allowed to cool to room temperature and pH was adjusted to 7-7.5 with 6 N HCl. A solid separated out, which was collected by filtration, washed with water (100 mL) and dried under vacuum to give 6-(benzyloxy)-7-methoxy-2-(3-nitrophenyl)quinazolin-4(3H)-one (3.22 g, 7.99 mmol, 47% over two steps). MS 404 (M+1) HPLC retention time 8.026 min.
Reaction SMILES: [BrH:1].C(O)(=O)C.[Cl:6][C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[C:14](=O)[CH2:15][S:16][C:17]#[N:18].O>C(O)(=O)C>[Br:1][C:17]1[S:16][CH:15]=[C:14]([C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([Cl:13])[C:7]=2[Cl:6])[N:18]=1
Reactant: Br
Reactant: N#CSCC(=O)c1cccc(Cl)c1Cl
Solvent: CC(=O)O
Solvent: O
Product: Clc1cccc(-c2csc(Br)n2)c1Cl
Temperature: 130 °C
Reaction time: 2 h
Yield: 94.6 %

Procedure:
A 25% hydrogen bromide/acetic acid (30 ml) solution was added to a solution of 2-(2,3-dichlorophenyl)-2-oxoethyl thiocyanate (3.10 g, 12.6 mmol) in acetic acid (30 ml), and the mixture was stirred at 130° C. for 2 hours. Water (60 ml) was poured to the reaction mixture, and crystals were collected by filtration and washed with water to give 3.68 g (94.6%) of the desired product as a solid.
Reaction SMILES: [CH3:1][C:2]([NH:5][S:6]([C:9]1[CH:13]=[CH:12][N:11]([CH3:14])[CH:10]=1)(=[O:8])=[O:7])([CH3:4])[CH3:3].C([Li])CCC.Cl[C:21]([O:23][CH3:24])=[O:22].Cl>C1COCC1.[Au]>[CH3:4][C:2]([NH:5][S:6]([C:9]1[CH:13]=[CH:12][N:11]([CH3:14])[C:10]=1[C:21]([O:23][CH3:24])=[O:22])(=[O:8])=[O:7])([CH3:1])[CH3:3]
Reactant: COC(=O)Cl
Reactant: Cn1ccc(S(=O)(=O)NC(C)(C)C)c1
Agent: [Au]
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)c1c(S(=O)(=O)NC(C)(C)C)ccn1C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of I g (4.62 mol) of N-(1,1-dimethylethyl)-1-methyl-1H-pyrrole-3-sulfonamide in 150 mL THF under a nitrogen atmosphere cooled to -78° C. was added dropwise at such a rate as to keep the temperature below -65° C. 4.1 mL (9.48 mmol) 2.32M n-butyllithium in hexanes. The resulting amber turbid solution was stirred at -78° C. for ca. 30 minutes. Methyl chloroformate (0.37 mL, 4.86 mmol) was added in one portion and the resulting gold reaction mixture was allowed to warm to room temperature and stirred for ca. 1.5 hours. The gold reaction mixture was cooled to 0° C. and acidified with 1N HCl. The THF phase was separated washed with brine, dried (MgSO4) and concentrated to an ember oil. The NMR of the crude reaction product was consistent with the title compound, additionally the NMR indicated that a trace of the starting material was also present. The crude material was combined with the product from a similar reaction run on the scale described below and chromatographed to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=1>>[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH:20][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=2)=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: NCc1ccc(Br)cc1
Product: O=C(NCc1ccc(Br)cc1)c1ccc(Cl)c([N+](=O)[O-])c1

Procedure:
A mixture of 4-chloro-3-nitrobenzoyl chloride was reacted with 4-Bromo-benzylamine to produce N-(4-Bromo-benzyl)-4-chloro-3-nitro-benzamide according to the procedure of Example 10A, which was treated sequentially using the procedures from Examples 22A and 22B to provide the title product.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[C:11]([C:18]([OH:20])=O)[CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[N:6][CH:7]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:54]1[CH2:59][CH2:58][N:57]([CH2:60][C:61]2[N:66]=[C:65]([NH2:67])[CH:64]=[CH:63][CH:62]=2)[CH2:56][CH2:55]1>CN(C=O)C.O>[CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[C:11]([C:18]([NH:67][C:65]4[CH:64]=[CH:63][CH:62]=[C:61]([CH2:60][N:57]5[CH2:56][CH2:55][O:54][CH2:59][CH2:58]5)[N:66]=4)=[O:20])[CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: Nc1cccc(CN2CCOCC2)n1
Reactant: Cc1cncc(-c2ccc3cccc(C(=O)O)c3n2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cncc(-c2ccc3cccc(C(=O)Nc4cccc(CN5CCOCC5)n4)c3n2)c1
Reaction time: 18 h
Yield: 22 %

Procedure:
2-(5-methylpyridin-3-yl)quinoline-8-carboxylic acid (0.135 g, 0.51 mmol) was combined with DIPEA (0.140 mL, 0.811 mmol) and HATU (0.200 g, 0.51 mmol) in DMF (5 mL). The mixture was stirred at room temperature for ten minutes, at which time 6-(morpholinomethyl)pyridin-2-amine (0.090 g, 0.466 mmol) was added. The mixture was stirred 18 hours, and then water (10 mL) was added. The resulting precipitate was collected by filtration, and the solids were triturated in methanol to obtain 2-(5-methylpyridin-3-yl)-N-(6-(morpholinomethyl)pyridin-2-yl)quinoline-8-carboxamide as a tan solid (0.045 g, 22% yield. MS (ESI) calcd for C26H25N5O2 (m/z): 439.20. found: 440 [M+1].
Reaction SMILES: C[Mg]I.[Br:4][C:5]1[CH:12]=[CH:11][C:8](C#N)=[C:7]([Cl:13])[CH:6]=1.Cl.C([O:17][CH2:18][CH3:19])C>>[Br:4][C:5]1[CH:12]=[CH:11][C:8]([C:18](=[O:17])[CH3:19])=[C:7]([Cl:13])[CH:6]=1
Reactant: CCOCC
Reactant: N#Cc1ccc(Br)cc1Cl
Agent: C[Mg]I
Agent: Cl
Product: CC(=O)c1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 72 %

Procedure:
To a stirred solution of methylmagnesium iodide (0.82 M solution in diethylether; 113 ml, 92.4 mmol) was added a solution of 4-bromo-2-chlorobenzonitrile (10 g, 46.2 mmol) in diethylether (92 ml) dropwise, and the mixture was heated at reflux temperature for 16 hours. The mixture was cooled down to room temperature, added concentrated hydrochloric acid (50 ml), and the mixture was stirred for 5 hours. The whole was extracted with diethylether. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate-hexane (1:10) to give title compound (7.77 g, 72% yield).
Reaction SMILES: [ClH:1].[CH:2]([S:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([OH:25])[CH:13]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:14][CH3:15])=[CH:8][CH:7]=1)([CH3:4])[CH3:3].[C:26](OC(=O)C)(=[O:28])[CH3:27]>C(#N)C>[ClH:1].[C:26]([O:25][CH:12]([C:9]1[CH:10]=[CH:11][C:6]([S:5][CH:2]([CH3:4])[CH3:3])=[CH:7][CH:8]=1)[CH:13]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:14][CH3:15])(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCCCNC(CC)C(O)c1ccc(SC(C)C)cc1
Agent: Cl
Solvent: CC#N
Product: CCCCCCCCNC(CC)C(OC(C)=O)c1ccc(SC(C)C)cc1

Procedure:
To 20 ml of acetonitrile, 5 gr (13 mmol) of 1-(4-isopropylthiophenyl)-2-n-octylamino-1-butanol hydrochloride and 5.3 g (52 mmol) of acetic anhydride are added successively. The mixture is refluxed for 2.5 hours. When cooling, it abandons a white solid. The latter is filtered off and twice recrystallised from acetonitrile.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].C([SiH2][O:24][C:25](C)(C)[C:26]1[CH:27]=[C:28]([CH:34]=[CH:35][C:36]=1[Cl:37])[CH2:29][NH:30][C:31](=[O:33])[CH3:32])(C)(C)C.CCOC(C)=O>C1COCC1>[Cl:37][C:36]1[CH:35]=[CH:34][C:28]([CH2:29][NH:30][C:31](=[O:33])[CH3:32])=[CH:27][C:26]=1[CH2:25][OH:24]
Reactant: CC(=O)NCc1ccc(Cl)c(C(C)(C)O[SiH2]C(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)NCc1ccc(Cl)c(CO)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.5 %

Procedure:
TBAF (1M in THF, 12.0 mL, 12.0 mmol) was added to a sol. of N-[3-(tert-butyl-dimethyl-silanyloxymethyl)-4-chloro-benzyl]-acetamide (2.05 g, 6.00 mmol) in THF (60 mL) at 0° C. The mixture was stirred for 2 h while warming up to rt. EtOAc (100 mL) was added, and the mixture was washed with aq. sat. NH4Cl (1×) and water (4×1). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (CH2Cl2/MeOH 90:10) yielded the title compound (750 mg, 59%). LC-MS: tR=0.63 min; ES+: 237.09.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[NH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:10]1.[CH2:23](Cl)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCCC1>[C:24]1([CH2:23][CH:18]([C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:9][CH:10]=2)[C:19]([O:21][CH3:22])=[O:20])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: ClCc1ccccc1
Reactant: COC(=O)Cc1c[nH]c2ccccc12
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(Cc1ccccc1)c1c[nH]c2ccccc12
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 89.5 %

Procedure:
To a 2-liter three necked round bottom flask equipped with an addition funnel was added, under nitrogen, 300 mL of dry tetrahydrofuran (THF) and 68.75 mL of lithium diisopropylamide (1.92M in cyclohexane/THF, 132 mmol). The mixture was cooled to -78° C., and a solution of indole-3-acetic acid, methyl ester (11.36 g, 60 mmol) in 300 mL of dry tetrahydrofuran was added dropwise. The mixture was then allowed to sit at -78° C. for 15 minutes, and then a solution of benzyl chloride (7.59 g, 60 mmol) in 300 mL of tetrahydrofuran was added dropwise. The reaction mixture must be stirred vigorously so that the precipitated dianion of indole-3-acetic acid, methyl ester reacts completely with the benzyl chloride. After 3 hours, TLC analysis indicated complete consumption of starting material, and 200 mL of aqueous saturated ammonium chloride was added. The aqueous layer was separated and washed with ether (2×100 mL). The combined ether extracts were added to the organic layer which was dried over magnesium sulfate, filtered and concentrated to 15.0 g (quantitative yield) of red-brown oil. This material was reduced to the corresponding tryptophol without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[S:23][C:22]([C:24]3[CH2:29][CH2:28][CH:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:26][CH:25]=3)=[N:21][CH:20]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1>C(O)C>[CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[S:23][C:22]([CH:24]3[CH2:29][CH2:28][CH:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:26][CH2:25]3)=[N:21][CH:20]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1
Reactant: CCOC(=O)C1CC=C(c2ncc(-c3cc(C)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC1
Solvent: CCO
Product: CCOC(=O)C1CCC(c2ncc(-c3cc(C)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC1
Reaction time: 72 h
Yield: 480 %

Procedure:
To ethyl 4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]-cyclohex-3-ene-1-carboxylate (0.15 g, 0.31 mmol) was added ethanol (2 mL) and argon was bubbled through the solution for 5 minutes. The flask was then purged/filled with argon three times. 10% Palladium on carbon (0.33 mg) was added to the flask and the flask was purged/filled with argon three times. A hydrogen balloon was added to the top of the flask and the reaction was purged/filled with argon three times. The reaction was stirred for 72 hours. Upon completion, the reaction was filtered carefully through celite and the celite pad was washed with methanol (70 mL). The filtrate was concentrated under reduced pressure and the solid was purified by silica gel chromatography to yield ethyl 4-[5-(3-methyl-5-{[4-(trifluoromethyl)-pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylate (0.73 g, 49% yield). MS ESI: [M+H]+ m/z 491.1. 1H NMR (500 MHz, CDCl3) δ 8.63 (d, J=5.3, 1H), 7.96-7.73 (m, 2H), 7.64 (s, 1H), 7.25 (s, 1H), 7.13-6.92 (m, 2H), 4.24-3.99 (m, 2H), 3.23-3.02 (m, 1H), 2.73-2.57 (m, 1H), 2.49 (s, 3H) 2.32-2.21 (m, 1H), 2.23-2.07 (m, 2H), 2.02-1.81 (m, 3H), 1.79-1.64 (m, 1H), 1.64-1.52 (m, 1H), 1.39-1.08 (m, 3H). rhSYK activity=++
Reaction SMILES: [F:1][C:2]([F:50])([F:49])[C:3]1[CH:4]=[C:5]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:6][N:7]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=1[N:31]([CH2:40][CH3:41])[C:32]1[O:33][CH2:34][C@@H:35]([C:37]([OH:39])=[O:38])[N:36]=1)[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][N:9]=1.[OH-].[Na+:52]>C(O)C>[Na+:52].[F:48][C:45]([F:46])([F:47])[C:43]1[CH:42]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:49])[F:50])[CH:44]=1)[CH2:6][N:7]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:29])([F:30])[F:28])[CH:24]=[CH:23][C:22]=1[N:31]([CH2:40][CH3:41])[C:32]1[O:33][CH2:34][C@@H:35]([C:37]([O-:39])=[O:38])[N:36]=1)[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)=[CH:10][N:9]=1
Reactant: CCN(C1=N[C@H](C(=O)O)CO1)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCN(C1=N[C@H](C(=O)[O-])CO1)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1

Procedure:
Methyl (S)-2-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethyl-amino]-4,5-dihydro-oxazole-4-carboxylate (190 mg) is dissolved in methanol (4 ml) and thereto is added a 1N-aqueous sodium hydroxide solution (1 ml), and the mixture is stirred at room temperature for 1 hour. To the reaction solution are added a 1N-hydrochloric acid and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform:methanol=1:0→4:1) to give (S)-2-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethyl-amino]-4,5-dihydro-oxazole-4-carboxylic acid (130 mg). The resulting (S)-2-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethyl-amino]-4,5-dihydro-oxazole-4-carboxylic acid (130 mg) is dissolved in ethanol (1 ml), and thereto is added 1N-aqueous sodium hydroxide solution (180 μl) and concentrated under reduced pressure to give (S)-2-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethyl-amino]-4,5-dihydro-oxazole-4-carboxylic acid sodium salt (120 mg). MS (m/z): 729 [M−Na]−