Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH3:12])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:13]([O-])=O.[NH2:16][C:17](N)=[S:18].O>S1(CCCC1)(=O)=O>[NH2:16][C:17]1[S:18][C:2]2[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH3:12])(=[O:10])=[O:9])=[CH:4][C:3]=2[N:13]=1
Reactant: NC(N)=S
Reactant: CCS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: CCS(=O)(=O)c1ccc2sc(N)nc2c1
Temperature: 120 °C
Yield: 85.3 %

Procedure:
A suspension of 12.8 g of ethyl 4-chloro-3-nitrophenyl sulphone and 15.2 g of thiourea in 50 ml of sulpholane is heated to 120° C. and this temperature is maintained for 1.5 hours. The mixture is discharged into 600 ml of water, and the solid is filtered off with suction and washed with water. 10.6 g of colourless 2-amino-5-ethanesulphonylbenzothiazole are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH3:9][S:10](Cl)=[O:11]>>[Cl:8][C:5]1[N:6]=[CH:7][C:2]([NH:1][S:10]([CH3:9])=[O:11])=[CH:3][CH:4]=1
Reactant: CS(=O)Cl
Reactant: Nc1ccc(Cl)nc1
Product: CS(=O)Nc1ccc(Cl)nc1

Procedure:
The title compound is prepared from 5-amino-2-chloropyridine and methanesulfinyl chloride following a procedure analogous to that described for Intermediate 3 (Step 1). LC (method 1): tR=0.82 min; Mass spectrum (ESI+): m/z=191 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]2[C:15]3[CH:16]=[CH:17][C:18]([O:20][C:21]4[CH:26]=[CH:25][N:24]=[C:23](Cl)[N:22]=4)=[CH:19][C:14]=3[O:13][CH2:12]2)=[O:10])=[CH:4][C:3]=1[C:28]([F:31])([F:30])[F:29].[CH3:32][NH2:33].CCCCCC.CCOC(C)=O>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]2[C:15]3[CH:16]=[CH:17][C:18]([O:20][C:21]4[CH:26]=[CH:25][N:24]=[C:23]([NH:33][CH3:32])[N:22]=4)=[CH:19][C:14]=3[O:13][CH2:12]2)=[O:10])=[CH:4][C:3]=1[C:28]([F:31])([F:30])[F:29]
Reactant: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)N1COc2cc(Oc3ccnc(Cl)n3)ccc21
Reactant: CN
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNc1nccc(Oc2ccc3c(c2)OCN3C(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)n1

Procedure:
A solution of 50 mg (0.106 mMol) 6-(2-chloropyrimidin-4-yloxy)-benzooxazole-3-carboxylic acid (4-chloro-3-trifluoromethyl-phenyl)-amide in 1.5 ml THF and 107 μl MeNH2 (2 M in THF; 0.214 mMol) is stirred in a sealed vessel for 24 h at rt. Concentration of the reaction mixture and chromatography (Combi Flash; hexane/EtOAc 4:1-1:1) gives the title compound: MS: [M+1]+=466; HPLC: tRet=13.8; TLC(hexane/EtOAc 1:1): Rf=0.09.
Reaction SMILES: [CH2:1]=[C:2]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].Cl.[CH2:21]([N:23]([CH2:27][CH3:28])[CH2:24][CH2:25][SH:26])[CH3:22].N1CCCCC1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1>CO>[CH2:21]([N:23]([CH2:27][CH3:28])[CH2:24][CH2:25][S:26][CH2:1][CH:2]([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:3]([O:5][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:4])[CH3:22]
Reactant: CCN(CC)CCS
Reactant: C=C(Cc1ccccc1)C(=O)OCc1ccccc1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: Cl
Agent: [OH-]
Solvent: CO
Solvent: C1CCNCC1
Product: CCN(CC)CCSCC(Cc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The oil prepared in Step 10 (1.5 g, 5.95 mmol) is dissolved under argon in methanol (22 mL). To this solution is added 2-diethylaminoethanethiol hydrochloride (1 g, 5.95 mmol), piperidine (0.78 mL, 7.85 mmol) and benzyltrimethylammonium hydroxide (0.25 mL, 0.6 mmol), and the mixture is stirred at room temperature for 16 hours. The solvent is removed on a rotary evaporator and then the residue is purified by flash chromotography on silica gel to give the pure title compound.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[N:5]=[CH:4][N:3]=1.[H][H]>[Pd].C(O)C>[C:12]1([CH3:17])[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:6]1[C:7]([NH2:8])=[CH:2][N:3]=[CH:4][N:5]=1
Reactant: [H][H]
Reactant: Cc1ccccc1-c1ncnc(Cl)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Cc1ccccc1-c1ncncc1N
Yield: 786.4 %

Procedure:
4-Chloro-5-nitro-6-o-tolyl-pyrimidine (580 mg, 0.23 mmol) and 10% palladium on carbon (125 mg, 0.116 mmol) in ethanol were stirred under 1 atmosphere of hydrogen pressure for 16 hours. Filtration followed by removal of volatiles gave the desired compound as a yellow solid (335 mg, 78%) which was used in the next step without further purification.
Reaction SMILES: [Mg].[CH3:2][C:3]1[CH2:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2Br.BrCCBr.[Cl:17][Si:18](Cl)([CH3:20])[CH3:19]>C1COCC1>[Cl:17][Si:18]([CH3:20])([CH3:19])[C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH2:4][C:3]([CH3:2])=[CH:11]2
Reactant: CC1=Cc2cccc(Br)c2C1
Reactant: C[Si](C)(Cl)Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: CC1=Cc2cccc([Si](C)(C)Cl)c2C1

Procedure:
To 11.9 g (0.496 mol) of magnesium turnings in 80 mL of dry THF a solution of 50.0 g (0.239 mol) of 2-methyl-7-bromo-1H-indene and 45.0 g (0.239 mol) of 1,2-dibromoethane in 620 mL of THF was added dropwise by vigorous stirring in such rate that the mixture is refluxed. Then, this mixture was additionally refluxed for 30 minutes. Further on, to a solution of 110 g (0.853 mol) of dichlorodimethylsilane in 100 mL of THF the above-obtained solution of the Grignard reagent was added dropwise with vigorous stirring at room temperature using water bath to cool the reaction mixture. The resulting mixture was additionally stirred for 12 hours at ambient temperature, evaporated to dryness, and then 200 mL of dry ether was added. The obtained suspension was stirred for 20 minutes at room temperature and then filtered through glass frit (G3). The precipitate was additionally washed with 2×200 mL of ether. The combined filtrate was evaporated to dryness, and the residue was rectificated in vacuum, b.p. 105° C.-110° C./1 mm Hg. Yield 42.5 g (80%) of the title product. 1H NMR (CD2Cl2): δ 7.37-7.41 (m, 2H, 4,6-H), 7.30 (m, 1H, 5-H), 6.57 (m, 1H, 3-H), 3.51 (m, 2H, 1,1′-H), 2.23 (m, 3H, 2-Me), 0.81 (s, 6H, SiMe2). Anal. Calc. for C12H15ClSi: C, 64.69; H, 6.79%. Found: C, 64.56; H, 6.85%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.Br[C:18]([CH3:23])([CH3:22])[C:19]([OH:21])=[O:20].C(=O)([O-])[O-].[K+].[K+].S(=O)(=O)(O)O.[CH:35](O)([CH3:37])[CH3:36]>>[CH3:36][CH:35]([O:21][C:19]([C:18]([O:16][C:13]1[CH:12]=[CH:11][C:10]([C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[O:9])=[CH:15][CH:14]=1)([CH3:23])[CH3:22])=[O:20])[CH3:37]
Reactant: CC(C)O
Reactant: CC(C)(Br)C(=O)O
Reactant: O=C(c1ccc(O)cc1)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC(C)OC(=O)C(C)(C)Oc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Temperature: 120 °C
Yield: 83.9 %

Procedure:
465 g (2 mol) of (4-chlorophenyl)(4-hydroxyphenyl)methanone and 815 g (3.9 mol) of the 1-methylethyl ester of 2-bromo-2-methylpropanoic acid (alternative nomenclature: isopropyl 2-bromo-2-methylpropanoate) are introduced into a 4 liter reactor equipped with a stirrer and a condenser. The medium is heated to 120° C. and 265 g (1.92 mol) of potassium carbonate are then added with the aid of a funnel for solids. The reaction medium is subsequently heated for 5 hours at 140°-145° C. and then cooled to about 100° C. It is subsequently diluted with aqueous isopropyl alcohol and then acidified with sulfuric acid. The reaction medium is then cooled to 18°-20° C. in order to crystallize the product, which is filtered off and washed with sodium hydroxide solution and then water. The product is recrystallized from isopropanol to give 605 g of fenofibrate (yield=83.9%) with a purity greater than 99.5% (determination by high pressure liquid chromatography, abbreviated to HPLC).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].Br[C:14]([C:16]([F:19])([F:18])[F:17])=[CH2:15].C([O-])([O-])=O.[K+].[K+]>C1COCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:14]([C:16]([F:19])([F:18])[F:17])=[CH2:15])[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8]
Reactant: OB(O)c1cc(Cl)c(Cl)c(Cl)c1
Reactant: C=C(Br)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=C(c1cc(Cl)c(Cl)c(Cl)c1)C(F)(F)F
Temperature: 80 °C
Yield: 89.5 %

Procedure:
A mixture of 3,4,5-trichlorophenylboronic acid (3.376 g, 15 mmol), 2-bromo-3,3,3-trifluoroprop-1-ene (4.02 g, 23 mmol), K2CO3 (4.15 g, 30 mmol) and Pd(PPh3)2Cl2 (4.15 g, 30 mmol) in THF (16 mL) and H2O (8 mL) was heated at 80° C. in a sealed tube for 4 h. The mixture was cooled to rt and partitioned between EA (50 mL) and H2O (50 mL). The aqueous layer was extracted with EA (50 mL) and the combined organic layers were dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by column chromatography on silica gel to give the crude desired product (3.7 g; 90% yield) as a pale yellow solid.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([CH3:10])[CH3:9].[CH3:13][N:14]([CH3:16])[CH3:15].[CH2:17]1[O:20][CH:18]1[CH3:19]>>[C:1]([O-:12])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([CH3:9])[CH3:10].[CH3:13][N+:14]([CH3:16])([CH3:15])[CH2:17][CH:18]([OH:20])[CH3:19]
Reactant: CC(C)CCCCCCC(=O)O
Reactant: CC1CO1
Reactant: CN(C)C
Product: CC(C)CCCCCCC(=O)[O-]
Product: CC(O)C[N+](C)(C)C

Procedure:
Following the procedure set out in Example 7 above, isodecanoic acid was reacted with equal molar quantities each of trimethylamine and propylene oxide to obtain trimethyl-N-2-hydroxypropyl ammonium isodecanoate which structure was confirmed by NMR analysis as reported in Table 2. ##STR5##
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](/[CH:8]=[CH:9]/[CH:10]=O)[CH:5]=[CH:4][CH:3]=1.[CH3:12][N:13]1[C:17](=[O:18])[CH:16]=[CH:15][C:14]1=[O:19].[OH:20][C@@H:21]1[CH2:25][NH:24][C@H:23](C(O)=O)[CH2:22]1>>[OH:20][CH:21]1[CH2:22][CH:23]2[N:24]([CH:10](/[CH:9]=[CH:8]/[C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=3)[CH:16]3[C:17](=[O:18])[N:13]([CH3:12])[C:14](=[O:19])[CH:15]32)[CH2:25]1
Reactant: CN1C(=O)C=CC1=O
Reactant: Cc1cccc(/C=C/C=O)n1
Reactant: O=C(O)[C@@H]1C[C@H](O)CN1
Product: Cc1cccc(/C=C/C2C3C(=O)N(C)C(=O)C3C3CC(O)CN23)n1

Procedure:
The title compound is prepared analogously from 100 mg of (E)-3-(6-methylpyridin-2-yl)propenal, 75 mg of N-methylmaleimide and 100 mg of cis-4-hydroxy-L-proline.
Reaction SMILES: CN(C)C=O.[NH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][C:7]1=[O:16].[H-].[Na+].Br[CH2:20][CH:21]1[O:25][CH2:24][CH2:23][O:22]1>C(OCC)(=O)C.O>[O:22]1[CH2:23][CH2:24][O:25][CH:21]1[CH2:20][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][C:7]1=[O:16]
Reactant: O=c1ccc2ccccc2[nH]1
Reactant: BrCC1OCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=c1ccc2ccccc2n1CC1OCCO1
Temperature: 52.5 °C
Reaction time: 0.33 h

Procedure:
To 11.5 mL of an N,N-dimethylformamide solution containing 1.15 g of quinolin-2(1H)-one, 0.35 g of 60% sodium hydride was added, and the mixture was stirred at 50 to 55° C. for 20 minutes. Thereto was added 0.90 mL of 2-bromomethyl-1,3-dioxolane, and the reaction mixture was stirred at 85 to 95° C. for 30 minutes. The reaction mixture was further added with 0.35 g of 60% sodium hydride and 0.90 mL of 2-bromomethyl-1,3-dioxolane, and stirred for 1 hour. The mixture was further added with 0.35 g of 60% sodium hydride and 0.90 mL of 2-bromomethyl-1,3-dioxolane, and stirred for 1 hour and 30 minutes. The reaction mixture was cooled to room temperature, and then water and ethyl acetate were added thereto. The organic layer was separated, and the aqueous layer was extracted twice with ethyl acetate. The organic layer and the extract were combined, the resultant solution was washed with a saturated sodium chloride solution and dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure, and the residue thus obtained was purified by silica gel column chromatography [eluent; hexane:ethyl acetate 2:1] to obtain 0.89 g of a yellow oily substance, 1-(1,3-dioxolan-2-ylmethyl)quinolin-2(1H)-one.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][Cl:8].[C:9]1([P:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CN(C=O)C>[Cl-:8].[C:22]1([P+:15]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: ClCc1ccccn1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: [Cl-]
Product: c1ccc([P+](Cc2ccccn2)(c2ccccc2)c2ccccc2)cc1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A mixture of 60 parts by volume of DMF, 6.4 parts of 2-picolyl chloride and 13.2 parts of triphenylphosphine is stirred at 100° C. under nitrogen for 4 hours. The crystals which have precipitated are filtered off with suction, washed with petroleum ether and dried. 12 parts=59% of theory of triphenyl-2-picolylphosphonium chloride are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[C:14]([O:16][CH2:17][CH:18]2[O:20][CH2:19]2)[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[CH2:21]([NH:25][CH:26]1[CH2:31][C:30]([CH3:33])([CH3:32])[N:29]([O:34][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)[C:28]([CH3:42])([CH3:41])[CH2:27]1)[CH2:22][CH2:23][CH3:24]>C(O)C>[OH:1][C:2]1[CH:15]=[C:14]([O:16][CH2:17][CH:18]([OH:20])[CH2:19][N:25]([CH2:21][CH2:22][CH2:23][CH3:24])[CH:26]2[CH2:31][C:30]([CH3:32])([CH3:33])[N:29]([O:34][CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)[C:28]([CH3:42])([CH3:41])[CH2:27]2)[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:5]
Reactant: CCCCNC1CC(C)(C)N(OC2CCCCC2)C(C)(C)C1
Reactant: O=C(c1ccccc1)c1ccc(OCC2CO2)cc1O
Solvent: CCO
Product: CCCCN(CC(O)COc1ccc(C(=O)c2ccccc2)c(O)c1)C1CC(C)(C)N(OC2CCCCC2)C(C)(C)C1
Yield: 91.9 %

Procedure:
A mixture of 4.0 g (14.8 g mmol) of 2-hydroxy-4-(2,3-epoxypropoxy)benzophenone, 6.9 g (22.2 mmol) of 4-butylamino-1-cyclohexyloxy-2,2,6,6-tetramethylpiperidine, and 40 ml of ethanol is heated at reflux for 4 hours. Ethanol is evaporated, and the residue is purified by flash chromatography on silica gel (4:1 heptane: ethyl acetate) to afford 7.9 g (92% yield) of the title compound, a yellow oil.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3](=[O:10])[NH:2]1.[CH2:11]([N:17]=[C:18]=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>>[CH2:11]([NH:17][C:18]([N:2]1[C:3](=[O:10])[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1]1)=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: O=c1[nH]sc2ccccc12
Reactant: CCCCCCN=C=O
Product: CCCCCCNC(=O)n1sc2ccccc2c1=O

Procedure:
Following the synthetic procedure of 6a as described in Example 1, compound 6e (82% yield) was synthesized from benzo[d]isothiazol-3-one and n-hexyl isocyanate as a white solid. mp 52-53° C.; IR(CHCl3) 3290, 1711, 1662, 1540 cm−1; 1H-NMR (CDCl3) δ0.80-0.87 (m, 3H), 1.21-1.35 (m, 6H), 1.53-1.61 (m, 2H), 3.34-3.40 (m, 2H), 7.36 (t, J=7.6 Hz, 1H), 7.51 (d, J=7.6 Hz, 1H), 7.63 (t, J=7.6 Hz, 1H), 7.95 (d, J=6.9 Hz, 1H), 8.81 (br s, 1H); ESIMS m/e 279 (M++1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[CH2:10][C@@H:9]2[CH2:11][OH:12])=[N:6][CH:7]=1.[H-].[Na+].[Br:15][C:16]1[C:17](Cl)=[N:18][C:19]([CH3:22])=[N:20][CH:21]=1.C(=O)(O)[O-].[Na+]>C1COCC1>[Br:15][C:16]1[C:17]([O:12][CH2:11][C@H:9]2[CH2:10][C@@H:8]2[C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=2)=[N:18][C:19]([CH3:22])=[N:20][CH:21]=1
Reactant: Cc1ccc([C@H]2C[C@@H]2CO)nc1
Reactant: Cc1ncc(Br)c(Cl)n1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc([C@H]2C[C@@H]2COc2nc(C)ncc2Br)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.3 %

Procedure:
To a solution ((1S,2S)-2-(5-methylpyridin-2-yl)cyclopropyl)methanol (1.58 g, 9.7 mmol) in THF (25 mL) was added sodium hydride (466 mg, 11.6 mmol). The reaction mixture stirred at ambient temperature for 30 minutes. Next, a solution of 5-bromo-4-chloro-2-methylpyrimidine (2.0 g, 9.7 mmol) in THF (10 mL) was added and the reaction mixture was stirred at ambient temperature for two hours. Aqueous sodium bicarbonate (20 mL) was carefully added and the mixture was extracted with EtOAc (2×50 mL). The combined organics were dried over MgSO4, filtered and concentrated to the resulting residue, which was purified by column chromatography on silica gel (10% to 50% EtOAc in hexanes) to afford the title compound (2.7 g, 84.5%) as a yellow solid: LC/MS m/z=334.1 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]2([C:16]3=[CH:17][C:18]4[O:22][CH2:21][O:20][C:19]=4[CH:23]=[C:15]3[O:14][CH2:13]2)[C:5]1=[O:24].Br[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]Br.C(N(CC)CC)C>C1COCC1>[N:1]1([CH2:2][CH2:3][N:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]3([C:16]4=[CH:17][C:18]5[O:22][CH2:21][O:20][C:19]=5[CH:23]=[C:15]4[O:14][CH2:13]3)[C:5]2=[O:24])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: BrCCCCCBr
Reactant: NCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1N(CCN2CCCCC2)c2ccccc2C12COc1cc3c(cc12)OCO3

Procedure:
A mixture of 1′-(2-aminoethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.20 g, 0.62 mmol), 1,5-dibromopentane (0.08 mL, 0.62 mmol) and triethyl amine (0.17 mL, 1.23 mmol) in THF (10.0 mL) was refluxed for 15 hrs and concentrated in vacuo to dryness. The residue was subjected to flash chromatography eluting with 10% methanol in ethyl acetate to give 1′-(2-piperidin-1-ylethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, which was treated with 4.0 M HCl in dioxane to give the title compound (28%): mp>240° C.; 1H NMR (300 MHz, CD3OD) δ 7.40 (t, 1H), 7.27-7.11 (m, 3H), 6.51 (s, 1H), 6.17 (s, 1H), 5.86 (s, 2H), 4.91 (d, 1H), 4.71 (d, 1H), 4.40-4.13 (m, 2H), 3.95-3.84 (m, 1H), 3.66-3.37 (m, 3H), 3.14-2.96 (m, 2H), 2.06-1.45 (m, 6H); 13C NMR (75 MHz, CD3OD) δ 180.4, 157.5, 150.5, 143.8, 142.5, 133.9, 130.3, 125.3, 125.1, 120.6, 110.2, 103.9, 102.9, 94.2, 81.4, 59.7, 55.4, 54.9, 53.9, 36.4, 24.2, 22.6; MS (ES+) m/z 393 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7](=[O:17])[N:8]([CH:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])[CH:9]=[C:10]([Br:11])[C:5]=2[NH:4][N:3]=1>CCCCCC.C(O)C>[NH2:1][C:2]1[C:6]2[C:7](=[O:17])[N:8]([C@@H:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])[CH:9]=[C:10]([Br:11])[C:5]=2[NH:4][N:3]=1
Reactant: CC(C)C(C)n1cc(Br)c2[nH]nc(N)c2c1=O
Solvent: CCO
Solvent: CCCCCC
Product: CC(C)[C@@H](C)n1cc(Br)c2[nH]nc(N)c2c1=O
Yield: 44.1 %

Procedure:
Racemic 3-amino-7-bromo-5-(3-methylbutan-2-yl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one obtained in Step G of Example 13 (7.89 g) was resolved by HPLC (column: CHIRALPAK AD, 50 mmID×500 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane/ethanol=600/400(v/v)) to give the title compound (3.479 g) having a longer retention time.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:9][C:8]=2[Cl:19])[N:5]=[C:4]([C:20]#[N:21])[C:3]=1[C:22]#[C:23][Si](C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl.O1CCCC1>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([O:14][C:15]([F:16])([F:18])[F:17])=[CH:9][C:8]=2[Cl:19])[N:5]=[C:4]([C:20]#[N:21])[C:3]=1[C:22]#[CH:23]
Reactant: C[Si](C)(C)C#Cc1c(C#N)nn(-c2c(Cl)cc(OC(F)(F)F)cc2Cl)c1N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: C#Cc1c(C#N)nn(-c2c(Cl)cc(OC(F)(F)F)cc2Cl)c1N

Procedure:
To a stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethoxyphenyl)-4-trimethylsilylethynylpyrazole (0.4657 g) in dichloromethane (5 ml) cooled in an ice-water bath was slowly added tetra-n-butylammonium fluoride (1.07 ml of a 1M solution in tetrahydrofuran). After five minutes the ice-water bath was removed. Stirring was continued for ten minutes then the reaction mixture was washed with water. The aqueous layer was washed with dichloromethane. The combined organic layers were washed with brine, dried (Na2SO4) and evaporated to provide the title compound as an oily solid which upon drying in an oven crystallised to a white solid m.p. 175.7-176.1° C.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@H:3]([OH:6])[CH2:2]1.O[C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]=1[O:18][CH3:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:19][O:18][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][C:8]=1[O:6][C@@H:3]1[CH2:4][CH2:5][O:1][CH2:2]1)[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1ccc(O)c(OC)c1
Reactant: O[C@H]1CCOC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(O[C@@H]2CCOC2)c(OC)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.1 %

Procedure:
To a stirred solution of (3S)-tetrahydrofuran-3-ol (403 mg, 4.57 mmol), methyl 4-hydroxy-3-methoxy-benzoate (1.00 g, 5.49 mmol) and triphenylphosphane (1.44 g, 1.27 mL, 5.49 mmol) in THF (13 mL) at 0° C. was added DIAD (1.11 g, 1.06 mL, 5.49 mmol). The ice bath was removed and the reaction mixture was stirred at room temperature for 16 h, then at 55° C. for 4 h. The mixture was diluted with EtOAc and was washed with sat. aq. NaHCO3 (×2) and brine (×2). The organic layer was dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (0-30% ethyl acetate in hexane) to yield (R)-methyl 3-methoxy-4-(tetrahydrofuran-3-yloxy)benzoate (0.97 g, 84%) as a viscous liquid. ESI-MS m/z calc. 252.1, found 253.3 (M+1)+; Retention time: 1.72 minutes (3 min run).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([OH:31])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:54]1[CH:59]=[CH:58][C:57]([NH:60][CH2:61][CH2:62]O)=[CH:56][CH:55]=1>C(Cl)Cl.C(OCC)(=O)C>[ClH:13].[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:31][CH2:62][CH2:61][NH:60][C:57]4[CH:58]=[CH:59][N:54]=[CH:55][CH:56]=4)=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Reactant: OCCNc1ccncc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCNc1ccncc1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.8 %

Procedure:
Diethyl azodicarboxylate (261 mg, 1.5 mmol) was added dropwise to a suspension of of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (160 mg, 0.5 mmol), (prepared as described for the starting material in Example 24), triphenylphosphine (393 mg, 1.5 mmol) and 2-(N-(4-pyridyl)amino)ethanol (97 mg, 0.7 mmol) in methylene chloride (8 ml) and the mixture stirred for 2 hours at ambient temperature. The mixture was diluted with ethyl acetate (5 ml), the solid product was collected by filtration and purified by chromatography on an aluminium oxide column eluting with methylene chloride/acetonitrile/methanol (60/35/5). The purified solid was triturated with ether and collected by filtration. The solid was dissolved in a mixture of methylene chloride/methanol and 3M ethereal hydrogen chloride (0.5 ml) was added. The volatiles were removed by evaporation, the solid residue was suspended in ether, collected by filtration, washed with ether and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(N-(4-pyridyl)amino)ethoxy)quinazoline hydrochloride (95 mg, 37%).