Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[C:5]([CH3:12])[C:3]=1[NH2:4].[N:13]([O-])=O.[Na+]>C(O)(=O)C.O>[Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[C:5]2[C:3]=1[NH:4][N:13]=[CH:12]2
Reactant: O=N[O-]
Reactant: Cc1cc([N+](=O)[O-])cc(Cl)c1N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(Cl)c2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-chloro-6-methyl-4-nitroaniline (5.49 g, 29.4 mmole) in acetic acid (150 mL) was added sodium nitrite (2.03 g, 29.4 mmole) pre-dissolved in water (5 mL). The resulting brown slurry was stirred overnight at room temperature, then at 60° C. for a further 4 hours. The bulk of the solvent was removed by evaporation in-vacuo and the resulting black residue re-dissolved in EtOAc (100 mL) and washed in brine (2×70 mL). The organic layer was dried (MgSO4), filtered and concentrated to give a mixture of starting material and product 91 mg(1.49 g). The crude mixture was taken through to the next step; 1H NMR (400 MHz, DMSO) δ 8.25(1H, s), 8.50(1H, s), 8.85(1H, s), 14.30(1H, br s).MS (ES+): m/e=198 (minus Boc).
Reaction SMILES: [CH:1]#[C:2][CH:3]([OH:9])[CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH3:8].[C:10]1([C:16](Br)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([C:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:9][CH:3]([CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH3:8])[C:2]#[CH:1])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: BrC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C#CC(O)C/C=C\CC
Product: C#CC(C/C=C\CC)OC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
Treatment of 22 g. of cis-oct-5-en-1-yne-3-ol, prepared according to the procedure of J. Fried, C. H. Lin, J. C. Sih, P. Dalven, G. F. Cooper, J. Amer. Chem. Soc., 94, 4342 (1972), with 58 g. of triphenylmethyl bromide in 100 ml. of pyridine and purification of Florisil®, all as described in Example 728 gives the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1.O.C(OCC)(=O)C.[ClH:33].[CH3:34][CH:35]1[O:40][CH:39]([CH3:41])[CH2:38][NH:37][CH2:36]1>>[ClH:33].[CH3:41][CH:39]1[O:40][CH:35]([CH3:34])[CH2:36][N:37]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)[CH2:38]1
Reactant: CC1CNCC(C)O1
Reactant: O=C(O)c1ccc(-c2ccc(OCCCCCCCCBr)cc2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Product: CC1CN(CCCCCCCCOc2ccc(-c3ccc(C(=O)O)cc3)cc2)CC(C)O1

Procedure:
A suspension of 4-[4-(8-bromooctyloxy)phenyl]benzoic acid (1 g) in 2,6-dimethylmorpholine (3.06 ml) was refluxed for 30 minutes. The reaction mixture was added to a mixture of water and ethyl acetate and adjusted to pH 2.0 with conc. HCl. The organic layer was taken and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give 4-[4-[8-(2,6-dimethylmorpholin-4-yl)octyloxy]phenyl]benzoic acid hydrochloride (0.95 g).
Reaction SMILES: Cl[C:2]1[N:3]([CH2:10][C@@:11]([CH3:31])([OH:30])[CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([O:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[H-].[Na+].O>CN(C=O)C>[CH3:31][C@@:11]1([CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([O:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)[O:30][C:2]2=[N:6][C:5]([N+:7]([O-:9])=[O:8])=[CH:4][N:3]2[CH2:10]1
Reactant: C[C@](O)(CN1CCC(Oc2ccc(C(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@]1(CN2CCC(Oc3ccc(C(F)(F)F)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.9 %

Procedure:
(S)-1-(2-Chloro-4-nitroimidazol-1-yl)-2-methyl-3-[4-(4-trifluoromethylphenoxy)piperidin-1-yl]propan-2-ol prepared in Example 253 (1.06 g, 2.3 mmol) was dissolved in DMF (15 ml). To the solution, sodium hydride (110 mg, 2.76 mmol) was added with cooling on ice-bath followed by stirring at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=5/1) and crystallized from methylene chloride-diisopropyl ether to afford (S)-2-methyl-6-nitro-2-[4-(4-trifluoromethylphenoxy)piperidin-1-ylmethyl]-2,3-dihydroimidazo[2,1-b]oxazole (431 mg, yield 44%) as a white powder.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2].[CH:16]1([NH2:19])[CH2:18][CH2:17]1>>[CH:16]1([NH:19][CH:12]2[CH2:13][CH2:14][N:9]([C:6]3[N:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][N:7]=3)[CH2:10][CH2:11]2)[CH2:18][CH2:17]1
Reactant: NC1CC1
Reactant: CCc1cnc(N2CCC(=O)CC2)nc1
Product: CCc1cnc(N2CCC(NC3CC3)CC2)nc1

Procedure:
The title compound is prepared from 1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-one and cyclopropylamine following a procedure analogous to that described in Intermediate 4. LC (method 12): tR=2.53 min; Mass spectrum (ESI+): m/z=247 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH3:12])[N:9]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:16]([OH:18])=[O:17])[C:8](=[O:23])[CH:7]=1.C1C(=O)N([Cl:36])C(=O)C1>ClC(Cl)C(O)=O.ClC(Cl)C>[Cl:36][C:7]1[C:8](=[O:23])[N:9]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:16]([OH:18])=[O:17])[C:10]([CH3:12])=[CH:11][C:6]=1[O:5][CH2:4][C:3]1[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:2]=1[F:1]
Reactant: Cc1ccc(C(=O)O)cc1-n1c(C)cc(OCc2ccc(F)cc2F)cc1=O
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C(O)C(Cl)Cl
Solvent: CC(Cl)Cl
Product: Cc1ccc(C(=O)O)cc1-n1c(C)cc(OCc2ccc(F)cc2F)c(Cl)c1=O
Yield: 51.6 %

Procedure:
3-[4-[(2,4-Difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoic acid (from above) (7.5 g, 19.4 mmol) and NCS (2.6 g, 19.4 mmol) were taken up in 65° C. dichloroethane (100 ml). A catalytic amount of dichloroacetic acid (2 drops) was added. After two hours the solvent was removed in vacuo and the residue was taken up in diethyl ether. The precipitate was collected on a filter pad and then taken up in 50% ethyl acetate/hexanes to remove residual succinimide. The precipitate was collected on a filter pad and then dried in vacuo to produce a white powder (4.2 g, 52%). 1H NMR (300 MHz, CD3OD) δ 8.10 (dd, J=7.85) 1.81 Hz, 1H), 7.83 (d, J=8.26, 1.81 Hz, 1H), 7.40 (app q, J=8.26 Hz, 1H), 7.58 (d, J=7.85 Hz, 1H), 7.13-7.06 (m, 2H), 6.74 (s, 1H), 5.40 (s, 2H), 2.14 (s, 3H), 2.04 (s, 3H); ES-MS m/z 420 (M+H). ES-HRMS m/z 420.0786 (M+H calcd for C21H17ClF2NO4 requires 420.0809).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11][CH2:12][C:13]([OH:15])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.[F:35][C:36]1[C:41](O)=[C:40]([F:43])[C:39]([F:44])=[C:38]([F:45])[C:37]=1[F:46]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11][CH2:12][C:13]([O:15][C:41]2[C:40]([F:43])=[C:39]([F:44])[C:38]([F:45])=[C:37]([F:46])[C:36]=2[F:35])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: COc1ccc(SCC(=O)O)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COc1ccc(SCC(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1OC
Yield: 99.8 %

Procedure:
A solution of 2-(3,4-dimethoxyphenylmercapto)ethanoic acid (1.71 g, 7.5 mmol), N-methylmorpholine (0.99 ml, 9.0 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.87 g, 9.7 mmol) and pentafluorophenol (2.76 g, 15.0 mmol) in DCM (100 ml) was stirred at room temperature overnight. The solution was washed with 2M hydrochloric acid, saturated aqueous sodium hydrogen carbonate and brine, dried, filtered and concentrated to give crude pentafluorophenyl 2-(3,4-dimethoxyphenylmercapto)ethanoate (2.95 g, 99%) as pink oil which was used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].[CH3:20][O:21][C:22]1[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=1[C:24](=[O:27])[CH2:25]Br.C([O-])([O-])=O.[K+].[K+]>>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH2:25][C:24]([C:23]1[CH:28]=[CH:29][CH:30]=[CH:31][C:22]=1[O:21][CH3:20])=[O:27])[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: COc1ccccc1C(=O)CBr
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccccc1C(=O)CN1C(=O)C(C)(C)c2cc(N)c([N+](=O)[O-])cc21
Yield: 605.8 %

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (1 g) is alkylated using 2-methoxyphenacyl bromide (9.6 g; 41.9 mmol) and K2CO3 (14.2 g; 102.7 mmol) at RT for 3 days. After filtration and evaporation of the solvent the crude material is de-acetylated under reflux in 2-propanol (150 ml) and hydrochloric acid (6 N; 100 ml). Pure 5-amino-1-[2-(2-methoxy-phenyl)-2-oxo-ethyl]-3,3-dimethyl-6-nitro-1,3-dihydro-indol-2-one (8.5 g) is obtained by aqueous work-up and re-crystallization.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[O:24]1[CH2:28][CH2:27][CH:26]([NH:29][C:30]2[CH2:34][S:33][C:32](=[O:35])[N:31]=2)[CH2:25]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9](/[CH:12]=[C:34]2/[C:30]([NH:29][CH:26]3[CH2:27][CH2:28][O:24][CH2:25]3)=[N:31][C:32](=[O:35])[S:33]/2)[CH2:8][CH2:7]1
Reactant: O=C1N=C(NC2CCOC2)CS1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: O=C1N=C(NC2CCOC2)/C(=C/C2CCN(Cc3ccc(C(F)(F)F)cc3C(F)(F)F)CC2)S1
Temperature: 80 °C
Reaction time: 1 h
Yield: 71.4 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (2.5 g) in 2-propanol (20 mL) were added 4-(tetrahydrofuran-3-ylamino)-1,3-thiazol-2(5H)-one (2.06 g) and piperidinium acetate (1.07 g). The reaction mixture was stirred at 80° C. for 1 hr, and the solvent was evaporated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.67 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([OH:11])=O)=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.O.ON1C2C=CC=CC=2N=N1.[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[CH2:28][CH2:29][NH2:30].Cl.CN(C)CCCN=C=NCC>C(#N)C>[NH2:1][C:2]1[C:3]([C:9]([NH:30][CH2:29][CH2:28][C:24]2[S:23][CH:27]=[CH:26][CH:25]=2)=[O:11])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1
Reactant: Nc1ncc(Br)nc1C(=O)O
Reactant: NCCc1cccs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: Nc1ncc(Br)nc1C(=O)NCCc1cccs1
Temperature: 25 °C
Yield: 66.4 %

Procedure:
A solution of 3-amino-6-bromopyrazine-2-carboxylic acid (0.50 g, 2.3 mmol; described in: Ellingson, R. C.; Henry, R. L. J. Am. Chem. Soc. 1949, 2798-2800), 1-hydroxybenzotriazole hydrate (0.41 g, 2.7 mmol) in acetonitrile (5 mL) were added to a stirred solution of 2-thien-2-ylethanamine (0.32 g, 2.5 mmol) in acetonitrile (5 mL) followed by addition of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.52 g, 2.7 mmol) and acetonitrile (1.5 mL). The resulting mixture was stirred at room temperature over night and the solvent was evaporated. The residue was re-crystallized from acetonitrile and subsequently from methanol to give 0.5 g (66% yield) of the title compound: 1H NMR DMSO-d6, 400 MHz) δ 8.73 (t, J=6 Hz, 1H), 8.34 (s, 1H), 7.71 (br s, 2H), 7.34 (dd, J=5, 1 Hz, 1H), 6.95 (d, J=3 Hz, 1H), 6.91 (m, 1H), 3.50 (q, J=7 Hz, 2H), 3.05 (t, J=7 Hz, 2H); MS (ES) m/z 327 and 329 (M++1).
Reaction SMILES: [CH:1]1([Si:7]([CH3:10])([CH3:9])Cl)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CN=C1.[CH2:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][C:17]1=[O:25].O>CN(C=O)C>[CH:1]1([Si:7]([CH3:10])([CH3:9])[O:25][C:17]2[CH2:18][C:19]3[C:24]([CH:16]=2)=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1Cc2ccccc2C1
Reactant: C[Si](C)(Cl)C1CCCCC1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(OC1=Cc2ccccc2C1)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.8 %

Procedure:
A solution of cyclohexyldimethylchlorosilane (84.62 g, 478.7 mmol) and imidazole (32.59 g, 478.7 mmol) in DMF (300 mL) was reacted with 2-indanone (57.62 g, 436.0 mmol). The reaction mixture was stirred overnight at room temperature, treated with water (300 mL) and extracted with Et2O (3×200 mL). The combined organic phases were washed with water (3×300 mL) and dried over sodium sulfate. The solvents were removed to leave an orange oil. Distillation under reduced pressure gave 81.67 g (68.8%) of the title compound as a yellow oil (bp. 140-142° C./0.2 mbar). 1H NMR (CDCl3, δ): 7.25-7.11 (m, 3H); 7.01 (td, 3J=7.3 Hz, 4J=1.4 Hz, 1H); 5.76 (d, 4J=0.7 Hz, 1H); 3.29 (s, 2H) 1.77-1.74 (m, 5H); 1.27-1.13 (m, 5H); 0.90 (m, 1H); 0.24 (s, 6H). 13C NMR (CDCl3, δ): 162.44; 145.24; 136.60; 126.47; 123.07; 122.37; 118.91; 106.32; 39.52; 27.69; 26.77; 26.46; 26.33; −3.55.
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:5]=1[NH2:6].N1C=CC=NC=1>C(Cl)(Cl)Cl>[Br:1][C:9]1[CH:10]=[C:4]([F:3])[C:5]([NH2:6])=[C:7]([F:11])[CH:8]=1
Reactant: Nc1c(F)cccc1F
Reactant: BrBr
Solvent: c1cncnc1
Solvent: ClC(Cl)Cl
Product: Nc1c(F)cc(Br)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.6 %

Procedure:
328 g (2.05 mol) of bromine was dissolved in 390 cm3 of chloroform and added drop-wise, while stirring, to a solution of 252 g (1.95 mol) of 2,6-difluoroaniline and 170 g (2.15 mol) of anhydrous pyrimidine dissolved in 780 cm3 of chloroform, over 2 hours. The solution was stirred at room temperature for 2 hours and washed with water. The chloroform was distilled off and the residue was distilled under reduced pressure (110° C./30 mmHg). The crystals formed were recrystallized from hexane to yield 340 g (1.63 mol) of 4-bromo-2,6-difluoroaniline.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10]C)=O)[CH2:4][CH2:3]1.O.[NH2:13][NH2:14]>C(O)C>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]([NH:13][NH2:14])=[O:10])[CH2:4][CH2:3]1
Reactant: NN
Reactant: COC(=O)C1CCN(C)CC1
Solvent: O
Solvent: CCO
Product: CN1CCC(C(=O)NN)CC1
Temperature: 120 °C
Yield: 72.5 %

Procedure:
In a 25 mL sealed tube, methyl 1-methylpiperidine-4-carboxylate (0.2 g, 1.0 eq.) was dissolved in ethanol (5 mL) at RT. Hydrazine hydrate (0.127 g, 2 eq.) was introduced dropwise at RT and the reaction mixture was heated at 120° C. for 20 h. The reaction mixture was concentrated under reduced pressure (40° C., 20 mm Hg) to afford the crude 1-methylpiperidine-4-carbohydrazide (0.145 g) which was used without further purification in the following step.
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][CH2:13][O:14][C:15]1[CH:30]=[CH:29][C:18]([CH2:19][CH:20]([C:25]([O:27]C)=[O:26])[C:21]([O:23]C)=[O:22])=[CH:17][CH:16]=1.[OH-].[Na+]>CO.O1CCCC1>[CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][CH2:13][O:14][C:15]1[CH:30]=[CH:29][C:18]([CH2:19][CH:20]([C:25]([OH:27])=[O:26])[C:21]([OH:23])=[O:22])=[CH:17][CH:16]=1
Reactant: COC(=O)C(Cc1ccc(OCCOc2ccc3c(c2)CCCC3)cc1)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C(Cc1ccc(OCCOc2ccc3c(c2)CCCC3)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.8 %

Procedure:
To a solution of dimethyl 4-[2-(5,6,7,8-tetrahydro-2-naphthoxy)ethoxy]benzylmalonate (1.28 g, 3.21 mmol) in a mixture of methanol (12.9 ml) and tetrahydrofuran (6.4 ml) is added a 2 mol/L aqueous solution of sodium hydroxide (8.01 ml, 16.03 mmol). The mixture is stirred for 2 hours at room temperature, and then the solvent was removed under a vacuum. The residue is dissolved in water and washed with ethyl acetate (10 ml). The aqueous solution is acidified to pH 2–3 with dilute hydrochloric acid and extracted with ethyl acetate (3×15 ml). The combined extracts are washed with water (20 ml) and brine (20 ml), dried over sodium sulfate, and concentrated. The residue is crystallized from ethyl acetate to give the title compound (1.17 g, 95%). HRMS calcd for C22H24O6: 384.4290. Found: 384.4291. MA calcd for C22H24O6: C, 68.74%; H, 6.29%. Found: C, 68.69%; H, 6.31%.
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].[NH2:5][CH2:6][C:7]1([C:17]2[S:18][C:19]([C:22]3[CH:23]=[C:24]([NH:29][C:30]4[N:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][N:31]=4)[CH:25]=[C:26]([CH3:28])[CH:27]=3)=[CH:20][N:21]=2)[CH2:16][CH2:15][C:10]2(OCC[O:11]2)[CH2:9][CH2:8]1.CS(O)(=O)=O>C(Cl)(Cl)Cl>[NH2:5][CH2:6][C:7]1([C:17]2[S:18][C:19]([C:22]3[CH:23]=[C:24]([NH:29][C:30]4[N:35]=[C:34]([C:36]([F:38])([F:37])[F:39])[CH:33]=[CH:32][N:31]=4)[CH:25]=[C:26]([CH3:28])[CH:27]=3)=[CH:20][N:21]=2)[CH2:8][CH2:9][NH:1][C:10](=[O:11])[CH2:15][CH2:16]1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(CN)CCC4(CC3)OCCO4)s2)c1
Agent: CS(=O)(=O)O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(CN)CCNC(=O)CC3)s2)c1
Temperature: 65 °C
Reaction time: 1 h
Yield: 2.5 %

Procedure:
Sodium azide (20.45 mg, 0.315 mmol, 3.0 equiv) was added to a stirring solution of the product of Step 1 (53 mg, 0.11 mmol) in chloroform (5 ml). Methanesulfonic Acid (0.082 ml, 1.258 mmol, 12 equiv) was added and the reaction was capped and stirred at 65° C. for 1 h. The yellow mixture was partitioned between EtOAc (2×85 ml) and saturated aqueous NaHCO3 (90 ml), and the combined organic layers were dried over MgSO4 and concentrated. The residual colorless oil was purified via reverse-phase HPLC (Acetonitrile/Water gradient with 0.1% TFA present). The desired fractions were partitioned between EtOAc (2×55 ml) and saturated aqueous NaHCO3 (65 ml). The combined organic layers were dried over Na2SO4 and concentrated, providing the desired title compound (1.3 mg, 2.5%) as a colorless solid-oil. MS ESI: [M+H]+ m/z 477.21. 1H NMR (500 MHz, CD3OD) δ 8.72 (d, 1H, J=4.6 Hz), 8.19 (bs, 1H), 7.98 (s, 1H), 7.44 (s, 1H), 7.16 (s, 1H), 7.13 (d, 1H, J=4.6 Hz), 3.45 (s, 2H), 2.95 (m, 2H), 2.05 (s, 3H), 1.90-1.57 (m, 6H). rhSYK activity=+++
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]([CH3:27])[C:8](=[O:26])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12]([C:22](=O)[CH2:23]Br)=[N:11][CH:10]=1.[NH2:37][C:38]([NH2:40])=[S:39]>C(O)C>[NH2:40][C:38]1[S:39][CH:23]=[C:22]([C:12]2[CH:13]=[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[CH3:21])[C:9]([C:8]([N:7]([CH2:6][C:5]3[CH:28]=[C:29]([C:31]([F:34])([F:32])[F:33])[CH:30]=[C:3]([C:2]([F:36])([F:35])[F:1])[CH:4]=3)[CH3:27])=[O:26])=[CH:10][N:11]=2)[N:37]=1
Reactant: NC(N)=S
Reactant: Cc1ccccc1-c1cc(C(=O)CBr)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCO
Product: Cc1ccccc1-c1cc(-c2csc(N)n2)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 86.6 %

Procedure:
A mixture of 73 mg (0.13 mmol) N-(3,5-bis-trifluoromethyl-benzyl)-6-bromoacetyl-N-methyl-4-o-tolyl-nicotinamide and 12 mg (0.15 mmol) thiourea in 1 ml ethanol was heated at reflux for 30 min. After cooling to room temperature the solvent was evaporated in vacuo and the residue was dissolved in ethyl acetate. Washing with 1 M aqueous sodium hydroxide solution was followed by extraction of the aqueous layer with three portions of ethyl acetate. The combined organic layers were dried with sodium sulfate and concentrated. Column chromatography afforded 62 mg (88%) of the title compound as a light orange solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[O:13][S:14]([CH3:17])(=[O:16])=[O:15].[CH3:18][CH:19]1[CH2:28][CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[CH3:18][CH:19]1[CH2:28][CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]1[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[O:13][S:14]([CH3:17])(=[O:16])=[O:15]
Reactant: COC(=O)c1ccc(CBr)c(OS(C)(=O)=O)c1
Reactant: CC1CCc2ccccc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CN2c3ccccc3CCC2C)c(OS(C)(=O)=O)c1
Temperature: 70 °C
Reaction time: 23 h
Yield: 73.5 %

Procedure:
A mixture of methyl 4-(bromomethyl)-3-[(methylsulfonyl)oxy]benzoate (0.70 g, 2.2 mmol), 2-methyl-1,2,3,4-tetrahydroquinoline (0.39 g, 2.6 mmol), potassium carbonate (0.60 g, 4.3 mmol) and N,N-dimethylformamide (14 mL) was stirred at 70° C. for 23 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-2/1) to give the title compound (0.63 g, yield 75%) as a pale-yellow oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]3[C:17]([C:20]([O-])=[O:21])=[CH:18][N:19]=[C:13]3[CH:12]=2)[CH2:4][CH2:3]1.[Li+].ClC1C=C(Cl)C=C(Cl)C=1C(Cl)=O.[CH:36]1([C:39]2[C:47]3[C:46]([NH2:48])=[CH:45][CH:44]=[CH:43][C:42]=3[N:41]([CH2:49][C:50]3[S:51][C:52]([CH3:55])=[N:53][N:54]=3)[N:40]=2)[CH2:38][CH2:37]1>CN1CCCC1=O.O>[CH:36]1([C:39]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][C:46]=3[NH:48][C:20]([C:17]3[N:14]4[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][N:5]5[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]5)=[CH:12][C:13]4=[N:19][CH:18]=3)=[O:21])[N:41]([CH2:49][C:50]3[S:51][C:52]([CH3:55])=[N:53][N:54]=3)[N:40]=2)[CH2:37][CH2:38]1
Reactant: Cc1nnc(Cn2nc(C3CC3)c3c(N)cccc32)s1
Reactant: CN1CCN(CCOc2ccn3c(C(=O)[O-])cnc3c2)CC1
Agent: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Agent: [Li+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1nnc(Cn2nc(C3CC3)c3c(NC(=O)c4cnc5cc(OCCN6CCN(C)CC6)ccn45)cccc32)s1
Temperature: 88 °C
Reaction time: 1 h
Yield: 53.7 %

Procedure:
To lithium 7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate (Example 56, Step A; 70.5 mg, 0.23 mmol) was added N-Methylpyrrolidinone (1 mL). The suspension was heated in order to affect dissolution. The reaction mixture was cooled in an ice-water bath under nitrogen, and 2,4,6-trichlorobenzoyl chloride (35.5 μL, 0.23 mmol) was added dropwise. The cold bath was removed once the addition was complete and the reaction mixture was stirred for a further 1 hour. The reaction mixture became cloudy. A solution of 3-cyclopropyl-1-((5-methyl-1,3,4-thiadiazol-2-yl)methyl)-1H-indazol-4-amine (48 mg, 0.168 mmol) in anhydrous N-Methylpyrrolidinone (1 mL) was then added to the reaction mixture, and the mixture was heated to 88° C. for 13.5 hours. The reaction mixture was cooled, diluted with water, and extracted multiple times with dichloromethane. The combined dichloromethane extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was purified by preparative thin-layer chromatography (silica, eluting with 7N ammonia/MeOH:MeOH:DCM in a 3:7:90 ratio) to afford the product (51.6 mg) as a dark yellow solid. MS (ES+APCI) m/z=572 (M+H).