Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:15])=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:14])[C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1.[CH2:16](O)[CH3:17]>OS(O)(=O)=O>[CH3:1][C:2]([CH3:15])=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:14])[C:11]([O:13][CH2:16][CH3:17])=[O:12])=[CH:6][CH:5]=1
Reactant: CC(C)=Cc1ccc(C(C)C(=O)O)cc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(C)c1ccc(C=C(C)C)cc1

Procedure:
A solution of 2-(4-dimethylvinylphenyl)propionic acid (11.5 g) in anhydrous ethanol (250 ml) and 2.5 ml of 98% H2SO4 was refluxed for 4 hours. After cooling the solvent was removed and the oily residue was treated with a saturated NaHCO3 solution, extracted with two 100 ml portions of ether and dried over Na2SO4. Evaporation of the solvent gave a white oil which was dried at 40° in a vacuum stove for 3 hours to yield the title ester (12.5 g) as an oily product. Found: C% 75.65 (Calc 75.44); H% 8.62 (8.42).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:25][N:26]1[C:30](=[O:31])[C:29]([CH3:33])([CH3:32])[NH:28][C:27]1=[O:34]>>[CH3:25][N:26]1[C:30](=[O:31])[C:29]([CH3:33])([CH3:32])[N:28]([C:2]2[CH:3]=[CH:4][C:5]([C:8]([N:10]3[CH2:15][CH2:14][N:13]([C:16]4[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[N:17]=4)[CH2:12][CH2:11]3)=[O:9])=[CH:6][N:7]=2)[C:27]1=[O:34]
Reactant: CN1C(=O)NC(C)(C)C1=O
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(Br)nc3)CC2)nc1C
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4C(=O)N(C)C(=O)C4(C)C)nc3)CC2)nc1C
Yield: 63.1 %

Procedure:
Using (6-bromopyridin-3-yl)[4-(3,5,6-trimethylpyridin-2-yl)piperazin-1-yl]methanone (156 mg) described in Preparation Example 205 and 3,5,5-trimethylimidazolidine-2,4-dione (63 mg) described in Preparation Example 218 and by the reaction and treatment in the same manner as in Example 536, the title compound (114 mg) was obtained.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[N:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]=O)[CH:5]=1>>[CH2:1]([NH:3][CH2:10][C:6]1[CH:5]=[N:4][CH:9]=[CH:8][CH:7]=1)[CH3:2]
Reactant: CCN
Reactant: O=Cc1cccnc1
Product: CCNCc1cccnc1

Procedure:
prepared by reaction of ethylamine with pyridine-3-carbaldehyde
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[C:9]([F:28])[C:10]([CH3:27])=[C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH2:22][C:23]([O:25]C)=O)[N:17]=[CH:16]4)[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.[CH2:29]([NH2:32])[CH2:30][CH3:31]>>[CH:1]1([NH:4][C:5](=[O:6])[C:7]2[CH:12]=[C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH2:22][C:23](=[O:25])[NH:32][CH2:29][CH2:30][CH3:31])[N:17]=[CH:16]4)[C:10]([CH3:27])=[C:9]([F:28])[CH:8]=2)[CH2:3][CH2:2]1
Reactant: CCCN
Reactant: COC(=O)Cn1ncc2cc(-c3cc(C(=O)NC4CC4)cc(F)c3C)ccc21
Product: CCCNC(=O)Cn1ncc2cc(-c3cc(C(=O)NC4CC4)cc(F)c3C)ccc21

Procedure:
Example 136 was prepared by General Method D using methyl (5-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-1H-indazol-1-yl)acetate (Example 123) and 1-propylamine to give the title compound (0.005 g).
Reaction SMILES: [CH3:1][C:2]1([CH2:22][OH:23])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH2:3]1.[H-].[Na+].Cl[CH2:27][CH2:28][N:29]([CH3:31])[CH3:30]>CN(C=O)C>[CH3:30][N:29]([CH3:31])[CH2:28][CH2:27][O:21][C:18]1[CH:17]=[CH:16][C:15]([C:4]2[CH2:3][C:2]([CH2:22][OH:23])([CH3:1])[CH2:7][CH2:6][C:5]=2[C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:20][CH:19]=1
Reactant: CC1(CO)CCC(c2ccc(O)cc2)=C(c2ccc(O)cc2)C1
Reactant: CN(C)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCOc1ccc(C2=C(c3ccc(O)cc3)CCC(C)(CO)C2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (1-methyl-3,4-di(4-hydroxy-phenyl)-cyclohex-3-enyl)-methanol (30 mg, 1 eq.) in DMF (1 mL) was added NaH (10 mg, 1 eq.), and the reaction mixture was then stirred for 2 h at 25° C. To the reaction mixture was then added (2-chloro-ethyl)-dimethyl-amine (12 mg, 1 eq) and the mixture stirred for 16 hours. The reaction mixture was then partitioned between H2O/ethyl acetate (5 mL/5 mL). The organic layer was separated, dried over MgSO4, concentrated and purified HPLC (20%˜80% CH3CN/H2O with 0.1% TFA) to yield 4-{2-[4-(2-dimethylamino-ethoxy)-phenyl]-4-hydroxymethyl-4-methyl-cyclohex-1-enyl}-phenol.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([S:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([C@:22]([OH:28])([CH3:27])[C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.CCCN(C(NC(C1C=C(OC)C(OC)=C(OC)C=1)=O)=S)CCC>>[NH2:1][C:2]1[S:6][C:5]([S:7]([N:10]2[CH2:11][CH2:12][N:13]([C:16]3[CH:17]=[CH:18][C:19]([C@@:22]([OH:28])([CH3:27])[C:23]([F:26])([F:25])[F:24])=[CH:20][CH:21]=3)[CH2:14][CH2:15]2)(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: C[C@@](O)(c1ccc(N2CCN(S(=O)(=O)c3ccc(N)s3)CC2)cc1)C(F)(F)F
Agent: CCCN(CCC)C(=S)NC(=O)c1cc(OC)c(OC)c(OC)c1
Product: C[C@](O)(c1ccc(N2CCN(S(=O)(=O)c3ccc(N)s3)CC2)cc1)C(F)(F)F

Procedure:
(2R)-2-(4-(4-((5-amino-2-thiophenyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol. 1H NMR (400 MHz, CD3OD) δ=7.48 (d, J=8.8 Hz, 2H), 7.23 (d, J=4.1 Hz, 1H), 7.03-6.91 (m, 2H), 6.08 (d, J=4.1 Hz, 1H), 3.32-3.27 (m, 4H), 3.21-3.15 (m, 4H), 1.70 (s, 3H). m/z (ESI, +ve ion) 436.0 (M+H)+. GK-GKRP IC50 (Binding)=0.448 μM; GK-GKRP EC50 (LC MS/MS-2)=0.836 μM.
Reaction SMILES: C(OC([NH:8][C:9]1([C:42](O)=[O:43])[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[C:29]4[C:24](=[CH:25][N:26]=[C:27]([C:30]5[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=5)[CH:28]=4)[N:23](C4CCCCO4)[N:22]=3)[N:16]=2)[CH2:11][CH2:10]1)=O)(C)(C)C.[CH3:45][NH2:46]>>[NH2:8][C:9]1([C:42]([NH:46][CH3:45])=[O:43])[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[C:29]4[C:24](=[CH:25][N:26]=[C:27]([C:30]5[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=5)[CH:28]=4)[NH:23][N:22]=3)[N:16]=2)[CH2:11][CH2:10]1
Reactant: CN
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2cccc(-c3nn(C4CCCCO4)c4cnc(-c5cccnc5)cc34)n2)CC1
Product: CNC(=O)C1(N)CCN(c2cccc(-c3n[nH]c4cnc(-c5cccnc5)cc34)n2)CC1
Yield: 24 %

Procedure:
Following the procedures of Example 229, and starting with 4-(tert-butoxycarbonylamino)-1-(6-(5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)piperidine-4-carboxylic acid and methylamine, were reacted and purified via reverse phase HPLC using a gradient of MeCN in water with 0.1% HCOOH to afford 19 mg (24%) of 236 over two steps. ESI MS m/z 429.2 (M+1). 1H NMR (400 MHz, DMSO): 13.95 (s, 1H), 9.22 (d, J=8.4 Hz, 2H), 8.92 (s, 1H), 8.61 (s, 1H), 8.41 (d, J=7.6 Hz, 1H), 8.28 (s, 1H), 8.13 (s, 1H), 7.72 (t, J=7.9 Hz, 1H), 7.52 (d, J=7.6 Hz, 2H), 6.96 (d, J=8.3 Hz, 1H), 6.49 (s, 1H), 4.27 (d, J=13.0 Hz, 2H), 3.53 (t, J=12.5 Hz, 2H), 2.67 (s, 3H), 2.29 (m, 2H), 1.87-1.73 (m, 2H).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[C@H:20]([CH3:25])[CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].[F:28][C:29]([F:46])([F:45])[C@H:30]([OH:44])[CH2:31][CH2:32]OS(C1C=CC(C)=CC=1)(=O)=O.FC(F)(F)[C@H](O)CCO.FF>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[C@H:20]([CH3:25])[CH2:21][N:22]([CH2:32][CH2:31][C@@H:30]([OH:44])[C:29]([F:46])([F:45])[F:28])[C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)OCC[C@@H](O)C(F)(F)F)cc1
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](C)CNC2=O)CC1
Agent: FF
Agent: OCC[C@@H](O)C(F)(F)F
Agent: [H-]
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](C)CN(CC[C@@H](O)C(F)(F)F)C2=O)CC1
Yield: 5 %

Procedure:
The title compound was synthesized in analogy to example 17, from (R)-8-(1-isopropyl-piperidin-4-yloxy)-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 8), sodium hydride and (R)-toluene-4-sulfonic acid 4,4,4-trifluoro-3-hydroxy-butyl ester (prepared from commercially available (R)-4,4,4-trifluoro-butane-1,3-diol in analogy to M. Tordeux et. al, J. Fluorine Chem. 20, 301 (1982) and U.S. Pat. No. 5,405,967) to give the desired product as a light yellow oil (5%).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=O.CS(C)=O.[Si:11]([N:18]1[C@@H:21](CO)[CH2:20][C:19]1=[O:24])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].CCN(C(C)C)C(C)C.C[Mg+].[Br-].[NH4+].[Cl-]>C(Cl)Cl.O>[Si:11]([N:18]1[C@@H:21]([CH:1]([OH:5])[CH3:2])[CH2:20][C:19]1=[O:24])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)C[C@@H]1CO
Reactant: O=C(Cl)C(=O)Cl
Agent: C[Mg+]
Agent: [Br-]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(O)[C@H]1CC(=O)N1[Si](C)(C)C(C)(C)C
Reaction time: 0.25 h
Yield: 77.8 %

Procedure:
To a solution of oxalyl chloride (0.31 mL, 3.58 mmol) in CH2Cl2 (22 mL) at −78° was added dropwise a solution of DMSO (0.48 mL, 6.83 mmol) in CH2Cl2 (1.4 mL). After 15 min, a solution of 1-(tert-butyldimethylsilyl)-4(R)-(hydroxymethyl)azetidin-2-one (700 mg, 3.25 mmol) in CH2Cl2 (3.3 mL) was added and the reaction was stirred an extra 45 min. Finally, DIEA (2.8 mL, 16.25 mmol) was added and the reaction was stirred at room temperature for 2 h. The resulting mixture was diluted with H2O and extracted with CH2Cl2. The organic phase was washed with aqueous HCl (10%), saturated NaHCO3 and brine, dried (MgSO4), filtered and concentrated. The crude aldehyde was immediately used in the next step. To the crude aldehyde dissolved in THF (29 mL) was added dropwise MeMgBr (3M/Et2O, 2.7 mL, 8.18 mmol) The reaction mixture was stirred 1 h at 0° and 1 h at room temperature, followed by the addition of aqueous saturated NH4Cl solution. After extraction with EtOAc, the organic phase was washed with HCl (10%), saturated aqueous NaHCO3 and brine, dried (MgSO4), filtered and evaporated. The resulting mixture was purified by flash chromatography (SiO2, 40% EtOAc-hexane) to give 1-(tert-butyldimethylsilyl)-4(R)-(1-hydroxyethyl)azetidin-2-one (580 mg, 77% yield for two steps) as a mixture of isomers. 1H NMR (400 MHz, CDCl3) δ 4.02-3.96 (m, 1H), 3.81 (q, J=6.5 Hz, 1H), 4.33-4.27 (m, 1H), 3.50-3.43 (m,2H), 3.01 (dd, J=15.6, 5.6 Hz, 1H), 2.95 (dd, J=15.3, 2.9 Hz, 1H), 2.84 (dd, J=15.1, 5.6 Hz, 1H), 2.58 (dd, J=15.6, 2.9 Hz, 1H), 1.14 (d, J=6.4 Hz, 3H), 1.07 (d, J=6.7 Hz, 3H), 0.92-0,91 (m, 18H), 0.22-0.11 (m, 6H)
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][CH:7]([CH2:13][CH3:14])[C:8]2=[O:12])=[CH:4][C:3]=1[OH:15].C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH2:24][CH2:25][C:26]([O:28]CC)=[O:27].[OH-].[K+]>CN(C)C=O.CO.O>[O:12]=[C:8]1[C:9]2[C:5](=[CH:4][C:3]([O:15][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[C:2]([Cl:1])[C:10]=2[Cl:11])[CH2:6][CH:7]1[CH2:13][CH3:14]
Reactant: CCOC(=O)CCCBr
Reactant: CCC1Cc2cc(O)c(Cl)c(Cl)c2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: CCC1Cc2cc(OCCCC(=O)O)c(Cl)c(Cl)c2C1=O

Procedure:
6,7-Dichloro-2-ethyl-5-hydroxy-1-indanone (24.5 g., 0.1 mole) and anhydrous potassium carbonate (15.2 g., 0.11 mole) is stirred in dimethylformamide (100 ml.) while ethyl 4-bromobutyrate (21.4 g., 0.1 mole) is added dropwise. The mixture is stirred and heated at 55°-60° C. for two hours. Potassium hydroxide (7.92 g., 0.141 mole) in methanol (60 ml.) is then added. The solid mass that forms is broken up and the mixture is stirred at 80°-85° C. for 11/2 hours and poured into water (500 ml.). The aqueous mixture is heated to boiling, filtered and acidified (6N HCl). The solid that separates is collected, washed with water, air-dried and recrystallized from ethylacetate to obtain 25.6 g. of 4-(1(1-oxo-2-ethyl-6,7-dichloro-5-indanyloxy)butyric acid, m.p. 146°-148° C.
Reaction SMILES: C([CH:4]1[C:9](=O)[CH2:8][C:7](=[O:11])[O:6][C:5]1=[O:12])(=O)C.[Br:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17]>C(O)(=O)C>[Br:13][C:14]1[CH:15]=[C:16]2[C:18]([C:9]([CH2:4][C:5]([OH:12])=[O:6])=[CH:8][C:7](=[O:11])[NH:17]2)=[CH:19][CH:20]=1
Reactant: Nc1cccc(Br)c1
Reactant: CC(=O)C1C(=O)CC(=O)OC1=O
Solvent: CC(=O)O
Product: O=C(O)Cc1cc(=O)[nH]c2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
To a suspension of 3-acetyl-tetrahydropyran-2,4,6-trione (25 g, 0.147 mol) and acetic acid (50 ml) was added a solution of m-bromoaniline (25.3 g, 0.147 mol) in acetic acid (30 ml) at room temperature. The reaction was continuted under the same conditions for 30 minutes. The reaction mixture was poured into ice-water (1 L) and then the separated solid was filtered off by aspiration. The residue was washed with water and dried. The obtained solid (54 g) was added in small portions to concentrated sulfuric acid (250 ml) and stirred at room temperature for 16 hours. The reaction mixture was poured into ice-water and then the separated solid was filtered off by aspiration. The residue was washed with methanol and acetone and then dried to give 7-bromo-l,2-dihydro-2-oxo-4-quinolineacetic acid (19.5 g) as a white solid. The solid (19.5 g) was suspended in methanol 500 ml. Thionyl chloride 15.1 ml (207 mmol) was added dropwise thereto at room temperature and the mixture was refluxed for 0.5 hour. The reaction mixture was poured into ice-water (1 L) and then the separated solid was filtered off by aspiration. The residue was washed with water and recrystallized from methanol to give the entitled compound as white crystals (mp 208°-210 ° C. (from methanol), 13.6 g, yield 31.2 %).
Reaction SMILES: [C:1]([O:5][C:6](=[O:46])[NH:7][CH2:8][CH:9]([C:30]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][C:31]=1[CH3:45])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][O:20][C:21]2[C:26]([Cl:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=2[Cl:29])=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:48]1[CH:58]=[CH:57][CH:56]=[CH:55][C:49]=1[CH2:50][NH:51][C:52](=[O:54])[CH3:53]>>[C:52]([NH:51][CH2:50][C:49]1[CH:55]=[CH:56][CH:57]=[CH:58][C:48]=1[C:33]1[CH:34]=[CH:35][C:30]([CH:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][O:20][C:21]3[C:22]([Cl:29])=[CH:23][C:24]([CH3:28])=[CH:25][C:26]=3[Cl:27])=[CH:13][CH:12]=2)[CH2:8][NH:7][C:6](=[O:46])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[C:31]([CH3:45])[CH:32]=1)(=[O:54])[CH3:53]
Reactant: CC(=O)NCc1ccccc1Br
Reactant: Cc1cc(Cl)c(OCCOc2ccc(CC(CNC(=O)OC(C)(C)C)c3ccc(B4OC(C)(C)C(C)(C)O4)cc3C)cc2)c(Cl)c1
Product: CC(=O)NCc1ccccc1-c1ccc(C(CNC(=O)OC(C)(C)C)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)c(C)c1

Procedure:
Prepared according to the procedure described in EXAMPLE 7, step 2 using tert-butyl{3-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}-2-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propyl}carbamate from EXAMPLE 9, step 1 and N-(2-bromobenzyl)acetamide (V.13) as starting materials. Purification by column chromatography on silica gel (Combi-Flash by ISCO), eluting with Hex/EtOAc (10 to 100% in 15 min) afforded the desired compound as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][N:8]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:7]2)([O-])=O.O.O.Cl[Sn]Cl.C([O-])(O)=O.[Na+]>CN(C=O)C>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][N:8]([C:13]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:14])[CH2:7]2
Reactant: O=C(OCc1ccccc1)N1Cc2ccc([N+](=O)[O-])cc2C1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc2c(c1)CN(C(=O)OCc1ccccc1)C2
Reaction time: 8 h

Procedure:
To a solution of benzyl 5-nitro-1,3-dihydro-2H-isoindole-2-carboxylate (1.34 g, 4.49 mmol) in DMF (30 mL) was added SnCl2.2H2O (5.1 g, 22.5 mmol) as a powder. The mixture was stirred overnight. The reaction mixture was adjusted to basic pH with sat. aq. NaHCO3. The white precipitate formed was extracted with EtOAc (3×150 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel to provide benzyl 5-amino-1,3-dihydro-2H-isoindole-2-carboxylate. LCMS calc.=269.1; found=268.9 (M+H)+. 1H NMR (500 MHz, CDCl3): δ 7.46-7.34 (m, 5H); 7.12-6.93 (2 d, J=8.1, 1H); 6.66-6.53 (m, 2H); 5.25 (s, 2H); 4.69 (t, J=9.8 Hz, 4H); 3.71 (br s, 2H).
Reaction SMILES: [CH3:1][C@H:2]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[NH:5][C:4](=[O:13])[C@H:3]1[NH:14]C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:14][C@@H:3]1[C:4](=[O:13])[NH:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[O:8][C@@H:2]1[CH3:1]
Reactant: C[C@H]1Oc2ccccc2NC(=O)[C@H]1NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1Oc2ccccc2NC(=O)[C@H]1N
Yield: 98.4 %

Procedure:
To a solution of tert-butyl (2R,3S)-2-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylcarbamate (0.65 g, 2.22 mmol, Eq: 1.00) in DCM (11.2 mL) at 0° C. was added TFA (12.7 g, 8.26 mL, 111 mmol, Eq: 50.00). After 1 h the mixture was concentrated, the residue dissolved in 50 mL DCM and washed with sat. NaHCO3. The NaHCO3 mixture was extracted with DCM and the combined extracts dried over Na2SO4, filtered and concentrated to afford the title compound (0.42 g, 96%) as a yellow foam which was used without purification.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2([C:22]#N)[CH2:21][CH2:20][CH2:19]2)=[CH:14][CH:13]=1.Cl.CC[O:27]CC>CCCCCC>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2([CH:22]=[O:27])[CH2:21][CH2:20][CH2:19]2)=[CH:14][CH:13]=1
Reactant: N#CC1(c2ccc(Cl)cc2)CCC1
Reactant: CCOCC
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CCCCCC
Product: O=CC1(c2ccc(Cl)cc2)CCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A 1M solution of diisobutylaluminium hydride in hexane (100 ml) was added dropwise to a stirred solution of 1-(4-chlorophenyl)cyclobutanecarbonitrile (19.1 g) in dry ether (50 ml) at -30° C. under nitrogen. The mixture was allowed to warm to 0° C. and was kept at that temperature for 30 minutes. The mixture was cooled to -30° C. and 5N hydrochloric acid (100 ml) was added dropwise with stirring. The mixture was filtered to separate a solid and the filtrate was extracted with ether. The solid was added to the ether extracts which were washed with water and dried. Removal of the solvent gave 1-(4-chlorophenyl)cyclobutanecarbaldehyde as a yellow oil.
Reaction SMILES: [CH2:1]([N:4]([CH3:30])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([C:22]2[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=2)(O)[CH:19]=[CH2:20])=[C:14]([NH2:29])[CH:13]=1)[CH:2]=[CH2:3].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.O.[OH-].[Na+]>C(Cl)Cl>[CH2:1]([N:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]2[C:15]([C:18]([C:22]3[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=3)=[CH:19][CH:20]=[N:29]2)=[CH:16][CH:17]=1)[CH3:30])[CH:2]=[CH2:3]
Reactant: C=CCN(C)CCCCCCOc1ccc(C(O)(C=C)c2ccc(Br)cc2)c(N)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: C=CCN(C)CCCCCCOc1ccc2c(-c3ccc(Br)cc3)ccnc2c1
Reaction time: 1.5 h
Yield: 16.7 %

Procedure:
A solution of 0.5 g of (RS)-1-[4-[6-(allyl-methyl-amino)-hexyloxy]-2-amino-phenyl]-1-(4-bromo-phenyl)-prop-2-en-1-ol is added dropwise at 0° C. within 10 min. to a suspension of 0.25 g of pyridinium chlorochromate in methylene chloride. After 1.5 hr. at room temperature water is added, the mixture is adjusted to pH 12 with 2M sodium hydroxide and extracted with methylene chloride. The organic phase is dried, concentrated and the residue is purified over silica gel with methylene chloride/methanol 95:5 as the eluent. 80 mg of the title compound are obtained. 53 mg thereof are dissolved in methylene chloride/ethyl acetate and stirred with 26 mg of fumaric acid. After filtration there is obtained allyl-[6-[4-(4-bromo-phenyl)-quinolin-7-yloxy]-hexyl]-methyl-amine.fumarate (1:3), m.p 70° C., MS: m/e 453 (M+H+, 1 Br).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.[CH3:13][O:14][C:15](=[O:21])[CH2:16][S:17](Cl)(=[O:19])=[O:18]>N1C=CC=CC=1.ClCCl>[CH3:13][O:14][C:15](=[O:21])[CH2:16][S:17](=[O:19])(=[O:18])[NH:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[CH:3][C:4]=1[C:9]([F:10])([F:11])[F:12]
Reactant: Nc1ccc(F)cc1C(F)(F)F
Reactant: COC(=O)CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)CS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 6 h

Procedure:
5 g (27.64 mmol) of 4-fluoro-2-(trifluoromethyl)aniline is dissolved in 25 ml of dry pyridine, and the solution is cooled to 0° C. While maintaining the temperature, a solution of 4.82 g (27.4 mmol) of chlorosulfonylacetic acid methyl ester in 20 ml of dichloromethane is added dropwise to the cooled solution during the course of about 10 minutes. Then the mixture is stirred for 6 hours at room temperature. The reaction solution is then diluted with 100 ml of dichloromethane, the pyridine is extracted by shaking with 2N hydrochloride acid, the organic phase is dried over magnesium sulfate, filtered, and evaporated to dryness. The residue is crystallized from diethyl ether/hexane 1:1, thus obtaining 7.35 g (23.32 mmol)=84.35% of theory of a crystallized product, mp 84°14 86° C.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[NH2:6][C:7]1[CH:12]=[C:11]([NH:13][C:14]2[N:19]=[C:18]([C:20]3[CH:21]=[N:22][N:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=34)[C:17]([Cl:29])=[CH:16][N:15]=2)[C:10]([O:30][CH3:31])=[CH:9][C:8]=1[N:32]1[CH2:37][CH2:36][N:35]([C:38](=[O:49])[C@@H:39]([NH:41]C(=O)OC(C)(C)C)[CH3:40])[CH2:34][CH2:33]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[NH2:41][C@@H:39]([CH3:40])[C:38]([N:35]1[CH2:36][CH2:37][N:32]([C:8]2[CH:9]=[C:10]([O:30][CH3:31])[C:11]([NH:13][C:14]3[N:19]=[C:18]([C:20]4[CH:21]=[N:22][N:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=45)[C:17]([Cl:29])=[CH:16][N:15]=3)=[CH:12][C:7]=2[NH:6][C:1](=[O:4])[CH:2]=[CH2:3])[CH2:33][CH2:34]1)=[O:49]
Reactant: C=CC(=O)Cl
Reactant: COc1cc(N2CCN(C(=O)[C@H](C)NC(=O)OC(C)(C)C)CC2)c(N)cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1cc(Nc2ncc(Cl)c(-c3cnn4ccccc34)n2)c(OC)cc1N1CCN(C(=O)[C@H](C)N)CC1
Reaction time: 0.75 h
Yield: 28.2 %

Procedure:
A solution of acryloyl chloride (10.2 μL, 0.13 mmol) in CH2Cl2 (3 mL) was added dropwise to a stirred solution of (S)-tert-butyl N-[1-(4-{2-amino-4-[(5-chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)amino]-5-methoxyphenyl}piperazin-1-yl)-1-oxopropan-2-yl]carbamate (Intermediate 59, 65 mg) and DIPEA (0.75 mL) in CH2Cl2 (10 mL), which was cooled in an ice/water bath. The mixture was stirred for 0.75 h. then quenched with water (10 mL) and 2M Na2CO3 (5 mL). The phases were separated and the organic solution was dried (MgSO4) and concentrated in vacuo. The resulting residue was dissolved in CH2Cl2 (3 mL) and was then treated with TFA (0.1 mL). After standing for 0.25 h a second portion of TFA (0.2 mL) was added. After a further 0.25 h the solution was concentrated in vacuo and purified by preparative HPLC (Waters SunFire column, 5μ silica, 19 mm diameter, 100 mm length), eluting with decreasingly polar mixtures of water (containing 0.1% formic acid) and CH3CN. Fractions containing the desired compound were concentrated in vacuo to give the title compound (17 mg, 6% from 5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine) as a white solid; 1H NMR: 1.25 (3H, s), 2.83-2.96 (4H, m), 3.65-3.82 (7H, m), 4.14-4.23 (1H, m), 5.73 (1H, d), 61.9 (1H, d), 6.64-6.70 (1H, m), 6.69 (1H, s), 7.08-7.12 (1H, m) 7.30-7.37 (1H, m), 8.20-8.28 (2H, m), 8.35-8.41 (2H, m), 8.68 (1H, s), 8.80-8.84 (1H, m), 8.95 (1H, s), 9.11-9.15 (1H, m); m/z: ES+ MH+ 576.60.