Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:16]1[CH2:21][CH2:20][CH:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][C:17]1=[O:27]>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:16]2[CH2:21][CH2:20][CH:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][C:17]2=[O:27])=[CH:4][CH:3]=1
Reactant: Sc1ccc(Br)cc1
Reactant: CCOC(=O)C1CCC(Br)C(=O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1CCC(Sc2ccc(Br)cc2)C(=O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.4 %

Procedure:
To a solution of 4-bromobenzenethiol (2.92 g, 15.45 mmol) in 20 mL acetone was added K2CO3 (2.2 g, 15.18 mmol) and a solution of ethyl 4-bromo-3-oxocyclohexanecarboxylate (3.73 g, 15 mmol) in acetone (10 mL). The resulting suspension was stirred at room temperature for 2 hour, and then was partitioned between water and hexane. The organic layer was washed with water, then brine, then was dried over MgSO4, filtered, and concentrated. Purification by chromatography on silica gel (15% EtOAc in hexane) afforded 3.4 g (61%) of the title compound as an oil: MS (ES) m/z=356 [M]+.
Reaction SMILES: Cl.Cl.Cl.[NH2:4][CH2:5][CH2:6][C:7]1[N:8]=[CH:9][N:10]([CH2:12][CH2:13][CH2:14][NH:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)([CH3:18])[CH3:17])[CH:11]=1.[C:26]1([S:32](Cl)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl.[OH-].[Na+]>ClCCl.C(N(CC)CC)C>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:16]([NH:15][CH2:14][CH2:13][CH2:12][N:10]2[CH:11]=[C:7]([CH2:6][CH2:5][NH:4][S:32]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:34])=[O:33])[N:8]=[CH:9]2)([CH3:18])[CH3:17])=[CH:20][CH:21]=1
Reactant: CC(C)(NCCCn1cnc(CCN)c1)c1ccc(Cl)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(NCCCn1cnc(CCNS(=O)(=O)c2ccccc2)c1)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Triethylamine (0.46 g) was added to a stirred suspension of 3-[4-(2-aminoethyl)imidazol-1-yl]-N-[1-(4-chlorophenyl)-1-methylethyl]propylamine trihydrochloride (0.65 g) in dichloromethane (20 ml). The solution was cooled to 0° C. and benzenesulphonyl chloride (0.27 g) in dichloromethane (10 ml) was added dropwise with stirring. The mixture was stirred at 0° C. for 30 minutes and then at ambient temperature for 3 hours. The mixture was washed with water, sodium bicarbonate solution and then dried, filtered and evaporated to give a yellow oil which was dissolved in alcohol and treated with ethereal hydrogen chloride. The resulting salt was hygroscopic and so was converted back to the free base by treatment with aqueous sodium hydroxide solution to give N-[2-(1-{3-[1-(4-chlorophenyl)-1-methylethylamino]-propyl}imidazol-4-yl)ethyl]benzenesulphonamide as an oil.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([SH:10])[S:9][C:5]=2[CH:4]=1)#[CH:2].[C:13]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[C:1]([C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([S:10][CH3:13])[S:9][C:5]=2[CH:4]=1)#[CH:2]
Reactant: C#Cc1ccc2nc(S)sc2c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: C#Cc1ccc2nc(SC)sc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 139.2 %

Procedure:
To a stirred solution of 6-ethynylbenzo[d]thiazole-2-thiol (4.0 g, 21 mmol) from Step 2 of this Example in 20 mL of DMF at 0° C. were added K2CO3 (7.25 g, 5.25 mmol), and MeI (5 mL). The mixture was stirred at rt for 2 h before it was partitioned between EtOAc and water, the organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 3:1 DCM/hexanes to afford 6-ethynyl-2-(methylthio)benzo[d]thiazole (1.5 g, 35%) as an off-white solid. LCMS (ESI) m/z 206 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])/[CH:4]=[CH:5]/[C:6]1[CH:14]=[CH:13][C:11]([OH:12])=[C:8]([O:9][CH3:10])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH3:1][O:2][C:3](=[O:15])/[CH:4]=[CH:5]/[C:6]1[CH:14]=[CH:13][C:11]([O:12][CH2:3][CH2:4][CH2:5][CH3:6])=[C:8]([O:9][CH3:10])[CH:7]=1
Reactant: COC(=O)/C=C/c1ccc(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCOc1ccc(/C=C/C(=O)OC)cc1OC
Yield: 183.5 %

Procedure:
4.16 g (20.0 mmol) ferulic acid methyl ester was dissolved in 115 ml 2-butanone. 2.09 ml (22.0 mmol) η-butyl bromide and 11.06 g (80 mmol) potassium carbonate were added. The reaction suspension was then heated at reflux temperature for 20 hours. The reaction mixture was filtered. The filtrate was concentrated by evaporation. The crude product was recrystallised from 42 ml isopropyl alcohol and yielded 4.85 g (92%) (E)-4-butyloxy-3-methoxycinnamic acid methyl ester as white crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH2:9][CH2:8][N:7]4[CH2:15][CH2:16][CH2:17][CH:6]4[C:5]=3[C:4]=2[CH:3]=1.[H-].[Na+].[CH3:20][C:21]1[N:26]=[CH:25][C:24]([CH2:27][CH2:28]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:23][CH:22]=1>CN(C=O)C>[CH3:1][C:2]1[CH:14]=[CH:13][C:12]2[N:11]([CH2:28][CH2:27][C:24]3[CH:25]=[N:26][C:21]([CH3:20])=[CH:22][CH:23]=3)[C:10]3[CH2:9][CH2:8][N:7]4[CH2:15][CH2:16][CH2:17][CH:6]4[C:5]=3[C:4]=2[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(C)nc2)cc1
Reactant: Cc1ccc2[nH]c3c(c2c1)C1CCCN1CC3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C)nc2)CCN2CCCC12
Reaction time: 0.08 h

Procedure:
To a solution of 9-methyl-2,3,4,5,6,10c-hexahydro-1H-3a,6-diaza-cyclopenta[c]fluorene (100 mg, 0.422 mmol) in DMF (1 mL) was added sodium hydride (53 mg, 1.326 mmol). After stirring for 5 min, a solution of toluene-4-sulfonic acid 2-(6-methyl-pyridin-3-yl)-ethyl ester (386 mg, 1.326 mmol) in DMF (1 mL) was added dropwise at 0° C. and the reaction mixture stirred at RT for 6 h. The progress of reaction was monitored by TLC and LCMS. The reaction mixture was poured into ice-cold water and extracted with EtOAc (3×25 mL). The combined organic layer was washed with water (5×20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase HPLC to yield 9-methyl-6-[2-(6-methyl-pyridin-3-yl)-ethyl]-2,3,4,5,6,10c-hexahydro-1H-3a,6-diaza-cyclopenta[c]fluorene. 1H NMR, (CDCl3, freebase) δ (ppm): 8.07 (s, 1H), 7.28 (m, 2H), 7.07 (d, 1H), 7.0 (s, 2H), 4.72 (m, 1H), 4.3 (m, 1H), 4.18 (m, 1H), 3.31 (m, 1H), 3.2 (m, 1H), 3.12 (m, 1H), 3.0 (m, 2H), 2.7 (m, 1H), 2.51 (m, 1H), 2.5 (s, 3H), 2.48 (s, 3H), 2.4 (d, 1H), 2.28 (m, 1H), 2.2 (m, 1H), 2.0 (m, 1H), 1.8 (m, 1H). Chiral HPLC provided enantiomers 197a and 197b.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.C(OC1C=CC(C(F)(F)F)=CC=1C1[S:29][C:28]([NH:30][C:31](=[O:40])[C:32]2[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:33]=2[F:39])=[N:27][C:26]=1[C:41]([O:43][CH3:44])=[O:42])C=C>>[F:39][C:33]1[CH:34]=[CH:35][CH:36]=[C:37]([F:38])[C:32]=1[C:31]([NH:30][C:28]1[S:29][C:6]([C:5]2[CH:8]=[CH:9][CH:10]=[C:3]([O:2][CH3:1])[CH:4]=2)=[C:26]([C:41]([O:43][CH3:44])=[O:42])[N:27]=1)=[O:40]
Reactant: COc1cccc(C=O)c1
Reactant: C=CCOc1ccc(C(F)(F)F)cc1-c1sc(NC(=O)c2c(F)cccc2F)nc1C(=O)OC
Product: COC(=O)c1nc(NC(=O)c2c(F)cccc2F)sc1-c1cccc(OC)c1

Procedure:
Compound 113 was prepared as from 3-methoxybenzaldehyde as described for the preparation of Compound 63.
Reaction SMILES: C([O:5][C:6](=[O:31])[CH2:7][O:8][C:9]1[CH:10]=[C:11]([CH:28]=[CH:29][CH:30]=1)[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:16][C:15]=1[F:27])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:25]([O:24][C:22](=[O:23])[CH2:21][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][CH2:12][C:11]2[CH:10]=[C:9]([CH:30]=[CH:29][CH:28]=2)[O:8][CH2:7][C:6]([OH:31])=[O:5])=[C:15]([F:27])[CH:16]=1)[CH3:26]
Reactant: CCOC(=O)CCc1ccc(OCc2cccc(OCC(=O)OC(C)(C)C)c2)c(F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CCc1ccc(OCc2cccc(OCC(=O)O)c2)c(F)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 69.5 %

Procedure:
To a solution of ethyl 3-(4-{[3-(2-tert-butoxy-2-oxoethoxy)benzyl]oxy}-3-fluorophenyl)propanoate (0.43 g, 0.98 mmoL) in dichloromethane (15 mL) was added trifluoroacetic acid (1.1 g, 9.80 mmoL), and the mixture was stirred at 50° C. for, 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified with silica gel column chromatography (hexane/ethyl acetate=9:1) to give the title compound (0.26 g, yield 72%) as white powders.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[N:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1.CON(C)[C:19](=[O:38])[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]2[CH:37]=[CH:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:29]=2)=[CH:22][CH:21]=1.C(O)(=O)C>O1CCCC1>[N:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:19]([C:20]2[CH:21]=[CH:22][C:23]([O:26][CH2:27][C:28]3[CH:37]=[CH:36][C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:29]=3)=[CH:24][CH:25]=2)=[O:38])=[CH:11][CH:10]=1
Reactant: CON(C)C(=O)c1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: Cc1ccncc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C(Cc1ccncc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 80 %

Procedure:
To a solution of Lithium diisopropyl amide (1.0M) in tetrahydrofuran was added 4-picoline dropwise (7.55 ml, 5 eq.) at 0° C. under N2. After 30 min the anion was cooled to −78° C. In a separate round bottom flask N-Methoxy-N-methyl-4-(quinolin-2-ylmethoxy)-benzamide (5.0, 15.5 mmole) was dissolved in tetrahydrofuran (77 ml, 0.2M) and cooled to −78° C. under N2. 1.2 eq. of the 4-picoline anion was added dropwise to the amide solution. After 45 min, 1 eq. more of the 4-picoline anion was added. After an addition 30 min, acetic acid (40 ml) was added dropwise and the reaction was slowly warmed to ambient temperature. The solid product (acetate salt) was filtered and partitioned between saturated sodium bicarbonate and dichloromethane. The layers were separated, dried magnesium sulfate filtered and concentrated to provide the title compound as a tan solid (4.41 g, 80%). 1H NMR (400 MHz, CDCl3) δ 8.52 (d, J=5.8 Hz, 2 H), 8.19 (d, J=8.7 Hz, 1 H), 8.07 (d, J=8.7 Hz, 1H), 7.93 (m, 2 H), 7.82 (d, J=8.3 Hz, 1 H), 7.75 (m, 1 H), 7.61 (d, J=8.3 Hz, 1 H), 7.54 (dt, J=7.9, 1.0 Hz, 1 H), 7.23 (m, 2 H) 7.07 (m, 2H), 5.42 (s, 2H), 4.19 (s, 2H); MS: (M+H m/z=355.2).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([C:13](=[O:17])[CH:14]([Br:16])[CH3:15])[CH:6]=[C:7](C(F)(F)F)[CH:8]=1.[F:20]C(F)(F)C1C=C(C(=O)CC)C=C(C(F)(F)F)C=1>>[Br:16][CH:14]([CH3:15])[C:13]([C:5]1[CH:4]=[C:3]([C:2]([F:19])([F:18])[F:1])[CH:8]=[C:7]([F:20])[CH:6]=1)=[O:17]
Reactant: CCC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(Br)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: CC(Br)C(=O)c1cc(F)cc(C(F)(F)F)c1
Yield: 86 %

Procedure:
1-[3,5-Bis(trifluoromethyl)phenyl]-2-bromopropan-1-one: A stirred suspension of 1 g (3.7 mmol) of 1-[3,5-bis(trifluoromethyl)phenyl]-propan-1-one (Lancaster, Windham, N.J., USA) treated in a manner similar to that for Example 127, step (a) to give 2-bromo-1-[3-fluoro-5-(trifluoromethyl)phenyl]propan-1-one (1.1 g, 86%). 1H-NMR (DMSO-d6; 300 MHz) δ 8.46 (m, 2H), 8.09 (m, 1), 5.26 (q, 1H, J=6.6Hz), 1.96 (d, 3H, J=6.5 Hz). Mass spectrum (MALDI-TOF, CHCA matrix, m/z): Calcd. for C11H7OBrF6, 349.0 (M+H), found 348.9.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:19]=[CH:18][C:13]([C:14](OC)=[O:15])=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1.O.[NH2:23][NH2:24]>CCO>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([NH:23][NH2:24])=[O:15])=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: NN
Reactant: COC(=O)c1ccc(CNC(=O)c2ccc(Cl)cc2)cc1
Solvent: CCO
Solvent: O
Product: NNC(=O)c1ccc(CNC(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 70 %

Procedure:
To a suspension of methyl 4-{[(4-chlorobenzoyl)amino]methyl}benzoate (303 mg, 1.0 mmol) in EtOH (6 mL) was added hydrazine hydrate (1.0 mL). After stirring for 15 h at reflux, the reaction mixture was cooled to rt and a white solid precipitated out. Filtration, washing with water (3×2 mL) and drying under vacuo at 60° C. for 2 hrs gave 213 mg of the title compound (70%) as a white solid in 96.5% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [C:1]([C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH:10]([CH3:16])[CH:11]2[O:14][CH3:15])=[C:7]([CH2:17][CH2:18]O)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1COCC1.C1C(=O)N([Br:51])C(=O)C1>>[Br:51][CH2:18][CH2:17][C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:13]=[C:12]2[C:8]=1[CH2:9][CH:10]([CH3:16])[CH:11]2[O:14][CH3:15]
Reactant: COC1c2cc(C(C)(C)C)cc(CCO)c2CC1C
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC1c2cc(C(C)(C)C)cc(CCBr)c2CC1C
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a mixture of 27.58 g (105 mmol) of 2-(6-tert-butyl-1-methoxy-2-methyl-2,3-dihydro-1H-inden-4-yl)ethanol and 27.58 g (105 mmol) PPh3 in 450 ml of THF 18.72 g (105 mmol) of NBS was added at vigorous stirring for 5 min at 0° C. This mixture was stirred for 2 h at room temperature and then evaporated to dryness. A solution of the residue in 500 ml of hexanes was filtered through glass frit (G3), and the precipitate was additionally washed by 3×300 ml hexanes. The combined organic extract was evaporated to dryness. The product was isolated from the residue using flash chromatography on Silica Gel 60 (40-63 um, d 80 mm, 1250 mm; eluent: hexanes/ether=20/1, vol.). Yield 25.48 g (74%) of ca. 1 to 2 mixture of diastereomers.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:21])[N:10]([CH2:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([CH2:19][OH:20])[CH2:15][CH2:14]1)[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(C)=O.C(N(CC)CC)C>ClCCl>[CH2:1]([O:8][C:9](=[O:21])[N:10]([CH2:12][C@H:13]1[CH2:14][CH2:15][C@H:16]([CH:19]=[O:20])[CH2:17][CH2:18]1)[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C[C@H]1CC[C@H](CO)CC1)C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CN(C[C@H]1CC[C@H](C=O)CC1)C(=O)OCc1ccccc1

Procedure:
In analogy to the method described in example 1.2, 1.65 g (5.66 mmol) of trans-(4-hydroxymethyl-cyclohexylmethyl)-methyl-carbamic acid benzyl ester were treated with dimethylsulfoxide/triethylamine in dichloromethane between −78° C. and room temperature to yield 1.6 g (97.6%) trans-(4-formyl-cyclohexylmethyl)-methyl-carbamic acid benzyl ester as colorless oil, MS: 289 (M).
Reaction SMILES: [CH2:1]=[C:2]([CH:10]([OH:15])[C:11]([Cl:14])([Cl:13])[Cl:12])[C:3]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:4].[C:16](OC(=O)C)(=[O:18])[CH3:17].C([O-])(=O)C.[Na+]>C([O-])(=O)C.[Na+].C(O)(=O)C>[CH2:1]=[C:2]([CH:10]([O:15][C:16](=[O:18])[CH3:17])[C:11]([Cl:14])([Cl:13])[Cl:12])[C:3]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:4]
Reactant: C=C(C(=O)OCCCC)C(O)C(Cl)(Cl)Cl
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: C=C(C(=O)OCCCC)C(OC(C)=O)C(Cl)(Cl)Cl
Temperature: 120 °C
Yield: 91.4 %

Procedure:
To 1173.0 g of butyl 2-methylene-3-hydroxy-4,4,4-trichlorobutyrate (91% pure) charged in a 2-liter, 3-neck round bottom flask equipped with a mechanical stirrer, thermometer, and a condenser were added 520.0 g of acetic anhydride and 7.0 g of sodium acetate. The reaction mixture was heated at 120° C. for three hours. Unreacted acetic anhydride and formed acetic acid were stripped off under vacuum at <80° C./0.6 mm Hg. After cooling to room temperature, the solid sodium acetate that had settled to the bottom of the flask was separated. 1236.1 g of acetylated product was obtained, 91.3% purity (GC analysis), 91.4% yield. The product structure was confirmed by NMR spectroscopy.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]1[CH2:11][CH2:10][CH2:9][C:5]21[CH2:8][NH:7][CH2:6]2.[Cl:12][C:13]1[C:14]([C:32]2[CH:33]=[N:34][N:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=23)=[N:15][C:16]([NH:19][C:20]2[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[C:23](F)=[CH:22][C:21]=2[O:30][CH3:31])=[N:17][CH:18]=1.CN1CCCC21CNC2.CCN(C(C)C)C(C)C>CO.O.CC(N(C)C)=O.CO>[Cl:12][C:13]1[C:14]([C:32]2[CH:33]=[N:34][N:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=23)=[N:15][C:16]([NH:19][C:20]2[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[C:23]([N:7]3[CH2:8][C:5]4([CH2:9][CH2:10][CH2:11][N:4]4[CH3:3])[CH2:6]3)=[CH:22][C:21]=2[O:30][CH3:31])=[N:17][CH:18]=1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Reactant: CN1CCCC12CNC2
Agent: Cl
Solvent: CO
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1cc(N2CC3(CCCN3C)C2)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Temperature: 140 °C
Yield: 85.4 %

Procedure:
A mixture of 5-methyl-2,5-diazaspiro[3.4]octane dihydrochloride salt (Intermediate 47, 400 mg) in CH3OH/water was absorbed onto an SCX column. The column was washed with CH3OH and eluted with methanolic ammonia. The fractions containing product were combined and concentrated (caution: product is volatile). A mixture of 5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine (Intermediate 20, 250 mg, 0.60 mmol), 5-methyl-2,5-diazaspiro[3.4]octane (91 mg, 0.72 mmol) and DIPEA (0.365 mL, 2.11 mmol) in DMA (3 mL) was heated at 140° C. for 0.5 h in a microwave. The mixture was then diluted with CH3OH and absorbed onto an SCX column. The column was washed with CH3OH and eluted with 1:1 methanolic ammonia in CH2Cl2. Fractions containing the product were combined and concentrated to provide a solid. This solid was suspended in CH3OH, filtered, washed with diethyl ether and dried to give the title compound (267 mg, 85%) as a red solid; 1H NMR: 1.63-1.78 (2H, m), 2-2.12 (2H, m), 2.41 (3H, s), 2.69 (2H, t), 3.77 (2H, d), 3.90 (3H, s), 4.13 (2H, d), 6.30 (1H, s), 7.14 (1H, td), 7.34 (1H, t), 8.12 (1H, s), 8.41-8.46 (2H, m), 8.74 (1H, s), 8.86 (1H, d), 8.96 (1H, s); m/z: ES+ MH+ 521.46.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([CH2:35][O:36][CH3:37])[O:5][C:6]1[CH:7]=[C:8]([O:24][C:25]2[CH:26]=[N:27][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:29][CH:30]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]1[S:16][CH:17]([CH2:20][C:21](O)=[O:22])[CH2:18][N:19]=1)=[CH:11]2.Cl.C([N:41]=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[OH-].[NH4+]>CN(C)C=O>[CH3:37][O:36][CH2:35][CH:4]([CH2:3][O:2][CH3:1])[O:5][C:6]1[CH:7]=[C:8]([O:24][C:25]2[CH:26]=[N:27][C:28]([S:31]([CH3:34])(=[O:32])=[O:33])=[CH:29][CH:30]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]1[S:16][CH:17]([CH2:20][C:21]([NH2:41])=[O:22])[CH2:18][N:19]=1)=[CH:11]2
Reactant: COCC(COC)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COCC(COC)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(N)=O)S3)[nH]c12
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 73.3 %

Procedure:
A mixture of [2-(7-[2-methoxy-1-(methoxymethyl)ethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetic acid (190 mg), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (133 mg), 1-hydroxybenzotriazole (93 mg) and N,N-dimethylformamide (5 mL) was stirred at 50° C. for 20 min. After cooling to room temperature, 10% aqueous ammonium hydroxide solution (0.5 mL) was added to the mixture and the mixture was stirred at room temperature for 14 h. The mixture was concentrated under reduced pressure. The residue was dissolved in water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. The residual oil was crystallized from ethyl acetate. The resulting crystals were washed with diethyl. ether. The crystals were recrystallized from acetonitrile to give the title compound (139 mg, 74%) as colorless crystals. MS 549 (MH+). mp 172-173° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([C:17]([O:19][CH3:20])=[O:18])([CH3:16])[CH3:15])[CH2:9]1)=O)(C)(C)C.[ClH:21]>O1CCOCC1>[ClH:21].[CH3:20][O:19][C:17](=[O:18])[C:14]([CH3:15])([C@H:10]1[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]1)[CH3:16]
Reactant: COC(=O)C(C)(C)[C@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)C(C)(C)[C@H]1CCCNC1
Reaction time: 1 h

Procedure:
1.030 g of (R)-3-(1-methoxycarbonyl-1-methyl-ethyl)-piperidine-1-carboxylic acid tert-butyl ester are taken up in 10 ml of 4M HCl in dioxane. The reaction solution is left to stand at room temperature for 1 hour and is then concentrated under reduced pressure to provide the title compound as colourless solid which can be used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19][CH3:20])=[O:10].[C:21]([CH2:23][C:24](O)=[O:25])#[N:22].C(OC(=O)C)(=O)C>C1(C)C=CC=CC=1>[NH2:22][C:21]1[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[C:9](=[O:10])[N:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[S:19][CH3:20])[C:24](=[O:25])[CH:23]=1
Reactant: N#CCC(=O)O
Reactant: CSc1ccccc1CNC(=O)Nc1ccccc1C
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: CSc1ccccc1Cn1c(=O)cc(N)n(-c2ccccc2C)c1=O
Reaction time: 16 h

Procedure:
1-(2-Methylphenyl)-3-[2-(methylthio)benzyl]urea (23.47 g) and cyanoacetic acid (7.66 g) were ground together and acetic anhydride (23 ml) was added. The mixture was stirred and heated at 75°-80° C. for 30 h. Toluene (20 ml) was then added and heating continued for a further 16 hours. The reaction was cooled and filtered. The filtrate was heated to boiling and treated with charcoal. The solid was removed by filtration and the filtrate evaporated in vacuo. The resulting oil was dissolved in dichloromethane (300 ml) and trietbylamine (8.15 g) added. The mixture was stirred for 5 hours at room temperature and the solvent removed in vacuo. The residue was purified by column chromatography on silica gel eluting with ethyl acetate and the product was recrystallised from ethyl acetate. Yield=2.60 g.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][NH:7][C:8]1[N:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[N:11]=[C:10]([NH:20][C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=2)[N:9]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O.O>[NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][NH:7][C:8]1[N:13]=[C:12]([O:14][CH2:15][C:16]([F:18])([F:19])[F:17])[N:11]=[C:10]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:29][CH:30]=2)[N:9]=1
Reactant: COC(=O)c1ccc(Nc2nc(NCCNCCN)nc(OCC(F)(F)F)n2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: NCCNCCNc1nc(Nc2ccc(C(=O)O)cc2)nc(OCC(F)(F)F)n1
Temperature: 25 °C
Yield: 41.4 %

Procedure:
To a suspension of methyl 4-(4-(2-(2-aminoethylamino)ethylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (0.1 g) in acetone (6 mL) was added potassium carbonate (0.080 g) in water (6.00 mL). The mixture was heated to reflux for 16 hours. After cooling to room temperature, the reaction solution was acidified with 1N HCl to pH=3. All solvents were removed under vacuum. The residue was purified by prep. HPLC to give 4-(4-(2-(2-aminoethylamino)ethylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid (40 mg).