Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[N:7]([CH3:8])[N:6]=[N:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)#[CH:2].Br[C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][N:18]=1.C(N(CC)CC)C>CN(C=O)C.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>[CH3:24][O:23][C:21](=[O:22])[C:20]1[CH:25]=[CH:26][C:17]([C:2]#[C:1][C:3]2[N:7]([CH3:8])[N:6]=[N:5][C:4]=2[C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[N:18][CH:19]=1
Reactant: C#Cc1c(-c2ccc(F)cc2)nnn1C
Reactant: COC(=O)c1ccc(Br)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C#Cc2c(-c3ccc(F)cc3)nnn2C)nc1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 79.1 %

Procedure:
A mixture of 5-ethynyl-4-(4-fluoro-phenyl)-1-methyl-1H-[1,2,3]triazole (101 mg, 0.5 mmol), methyl 6-bromonicotinate (130 mg, 0.6 mmol), triethylamine (174 μL, 1.25 mmol) and PdCl2(PPh3)2 (11 mg, 0.3 mol %) in DMF (1 mL) was evaporated and flushed with Ar five times. Then CuI (2 mg, 0.2 mol %) was added and the reaction mixture was stirred at 90° C. for 30 min and DMF (1 mL) was added. The mixture was then poured into sodium hydroxide solution (1 M) and extracted with ethyl acetate and the combined organic extracts washed with brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 0 to 50% ethyl acetate in heptane) afforded the title compound (133 mg, 79%) as a light yellow solid. MS: m/e=337.1 [M]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]3)[CH2:9][N:8]([C:22]([O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])=[O:23])[C:5]2=[CH:6][CH:7]=1.[CH2:31]([Sn](CCCC)(CCCC)C=C)[CH2:32]CC.[Cl-].[Li+]>O1CCCC1>[CH:31]([C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]3)[CH2:9][N:8]([C:22]([O:24][CH2:25][CH2:26][Si:27]([CH3:29])([CH3:28])[CH3:30])=[O:23])[C:5]2=[CH:6][CH:7]=1)=[CH2:32]
Reactant: CC(C)(C)OC(=O)N1CCC2(C1)CN(C(=O)OCC[Si](C)(C)C)c1ccc(Br)cc12
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=Cc1ccc2c(c1)C1(CCN(C(=O)OC(C)(C)C)C1)CN2C(=O)OCC[Si](C)(C)C
Reaction time: 21 h
Yield: 80.9 %

Procedure:
The 1-(2-(trimethylsilyl)ethyl) 1′-tert-butyl 5-bromospiro[indoline-3,3′-pyrrolidine]-1,1′-dicarboxylate (1.00 g, 2.01 mmol) obtained in Step 2 of Example 383 was dissolved in tetrahydrofuran (20 mL). Thereafter, tributyl(vinyl)tin (1.40 mL, 4.79 mmol), tetrakistriphenylphosphine palladium (240 mg, 0.21 mmol), and lithium chloride (260 mg, 6.13 mmol) were added to the above obtained solution at room temperature, and the thus obtained mixture was then stirred for 21 hours while heating under reflux. Thereafter, the reaction solution was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain 1-(2-(trimethylsilyl)ethyl) 1′-tert-butyl 5-vinylspiro[indoline-3,3′-pyrrolidine]-1,1′-dicarboxylate (723 mg, 81%) in the form of a light yellow solid.
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][OH:9])(=[O:5])[C:2]([CH3:4])=[CH2:3].C(N(CC)CC)C.[C:17](Cl)(=[O:20])[CH:18]=[CH2:19]>ClCCl>[C:1]([O:6][CH2:7][CH2:8][O:9][C:17](=[O:20])[CH:18]=[CH2:19])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=CC(=O)Cl
Reactant: C=C(C)C(=O)OCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)OCCOC(=O)C(=C)C
Reaction time: 0.17 h
Yield: 90 %

Procedure:
5.0 g of hydroxyethyl methacrylate was weighed into a 250 ml r.b. flask fitted with stirrer, thermometer and nitrogen blanket. 3.88 g of triethylamine was then added followed by 80 ml of dichloromethane. The mixture was cooled and 4.15 g of acryloylchloride was added dropwise. The reaction mixture turned yellow and after 10 min a precipitate formed. Stirring was continued for 90 minutes. The precipitated material (TMEDA.HCl) was then filtered off and the organic solution extracted with sodium bicarbonate solution. The solution was then dried over anhydrous magnesium sulphate and after filtration the solvent evaporated to give a pale yellow oil (yield˜90%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[C:16]([CH:18]([Br:20])[Br:19])[C:15]([Cl:21])=[CH:14][C:13]=2[Cl:22])=[N:4][N:5]([CH3:11])[C:6]=1[O:7][CH:8]([F:10])[F:9].[Br:23]N1C(=O)CCC1=O>ClC(Cl)(Cl)Cl>[Br:23][CH2:11][N:5]1[C:6]([O:7][CH:8]([F:9])[F:10])=[C:2]([Cl:1])[C:3]([C:12]2[CH:17]=[C:16]([CH:18]([Br:20])[Br:19])[C:15]([Cl:21])=[CH:14][C:13]=2[Cl:22])=[N:4]1
Reactant: Cn1nc(-c2cc(C(Br)Br)c(Cl)cc2Cl)c(Cl)c1OC(F)F
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)Oc1c(Cl)c(-c2cc(C(Br)Br)c(Cl)cc2Cl)nn1CBr
Yield: 28.8 %

Procedure:
A solution of 6 g (12 mmol) of 4-chloro-3-(2,4-dichloro-5-(di-bromomethyl)phenyl)-5-difluoromethoxy-1-methyl-1H-pyrazole and 6.4 g (36 mmol) of N-bromosuccinimide in 800 ml of tetrachloromethane was irradiated for 2 hours with a 150 W high-pressure mercury lamp and a UV lamp. The solids were then removed by filtration, and the filtrate was concentrated. Silica gel chromatography of the residue (eluent: hexane/ethyl acetate=4:1) gave 2 g of the target product. 1H-NMR (250 MHz, in CDCl3): δ [ppm]=5.87(s,2H); 6.82(t,1H); 7.03(s,1H); 7.52(s,1H); 8.08(s,1H).
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[CH2:7][CH2:8][N:9]1[CH:17]=[N:16][C:15]2[C:10]1=[N:11][C:12]([NH2:19])=[N:13][C:14]=2Cl)(=[O:3])[CH3:2].C([O-])=O.[NH4+]>CO.[Pd]>[C:1]([O:4][CH2:5][CH:6]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[CH2:7][CH2:8][N:9]1[CH:17]=[N:16][C:15]2[C:10]1=[N:11][C:12]([NH2:19])=[N:13][CH:14]=2)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(CCn1cnc2c(Cl)nc(N)nc21)COC(C)=O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(=O)OCC(CCn1cnc2cnc(N)nc21)COC(C)=O
Yield: 90.2 %

Procedure:
A suspension of 9-(4-acetoxy-3-acetoxymethylbut-1-yl)-2-amino-6-chloropurine (0.36 g, 1.0 mmol) and 10% palladium-on-charcoal (30 mg) in methanol containing ammonium formate (400 mM, 10 ml) was heated under reflux for 30 minutes. The mixture was allowed to cool, filtered and the solvent removed. The residue was taken up in water and the solution extracted twice with chloroform. The organic layers were combined, dried (magnesium sulphate) and the solvent removed to afford 9-(4-acetoxy-3-acetoxymethylbut-1-yl)-2-aminopurine (0.29 g, 90%). Recrystallisation from ethyl acetate-hexane gave white shiny plates (0.25 g, 78%) m.p. 102°-104° C.; λmax (MeOH) 222 (27,500), 244 (4,890), and 309 (7,160) nm; νmax (KBr) 3340, 3170, 1745, 1730, 1660, 1615 and 1580 cm-1 ; δH (CDCl3) 1.90-2.05 (3H, m, 2'-H and 3' -H), 2.07 (6H, s, 2×CH3), 4.15 (4H, d, J 5.2 Hz, 2×4'-H), 4.21 (2H, t, J 7.2 Hz, 1'-H), 5.16 (2H, br s, 2-NH2), 7.79 (1H, s, 8-H), and 8.70 (1H, s, 6-H); (Found: C, 52.10; H, 6.00; N, 21.49%. C14H19N5O4 requires C, 52.33; H, 5.96; N, 21.79%).
Reaction SMILES: [O:1]([CH:8]1[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:20]>ClCCl.O1CCOCC1>[ClH:20].[O:1]([CH:8]1[CH2:12][CH2:11][NH:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccccc2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: c1ccc(OC2CCNC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cooled solution of tert-butyl 3-phenoxypyrrolidine-1-carboxylate (172 mg, 0.65 mmol; which may be prepared as described in Step 2) in dichloromethane (4.3 mL) was added dropwise HCl 4N in dioxane (3.2 mL). The solution was warmed to room temperature and stirred for 1 h. The solvent was evaporated under reduced pressure to give the title compound (135 mg, quantitative) as an orange oil.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[N:11]=[C:10]([CH2:12]O)[CH:9]=[CH:8][CH:7]=1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Cl:5][C:6]1[N:11]=[C:10]([CH2:12][Cl:3])[CH:9]=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cccc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: ClCc1cccc(Cl)n1
Temperature: 25 °C

Procedure:
Thionyl chloride (12.6 mL; 173 mmol) in 100 mL chloroform was added dropwise to a solution of 6-chloro-2-hydroxymethylpyridine (13.0 g; 90.5 mmol), prepared as in step 3, in 100 mL chloroform. Upon complete addition the reaction mixture was heated at reflux for 2 hours. The reaction mixture was cooled to ambient temperature and carefully poured into 250 mL saturated aqueous sodium bicarbonate. The layers were separated and the aqueous was extracted with dichloromethane. The extracts were dried over magnesium sulfate and concentrated. 6-chloro-2-chloromethylpyridine was isolated as a pale yellow solid by flash chromatography (20% diethyl ether in hexane).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C:9]1([CH3:22])[CH3:21])=O)(C)(C)C.Cl>CO>[CH2:14]([N:11]1[CH2:12][CH2:13][NH:8][C:9]([CH3:22])([CH3:21])[CH2:10]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)CC1(C)C
Agent: Cl
Solvent: CO
Product: CC1(C)CN(Cc2ccccc2)CCN1
Yield: 108.4 %

Procedure:
3.30 g 4-Benzyl-2,2-dimethyl-piperazine-1-carboxylic acid tert-butyl ester were dissolved in 50 ml methanol, and 25 ml of 1N aqueous hydrochloric acid were added. After stirring overnight 5 ml of concentrated aqueous hydrochloric acid were added. After 2 h the volatiles were removed in vacuo and 2.40 g (97%) of the title compound were obtained as hydrochloride salt, which could be use without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10][C@@H:9]2[C:20]([O:22]C)=[O:21])=[CH:4][CH:3]=1.Cl.C(O)(=O)C>>[C:16]([O:15][C:13]([N:11]1[CH2:12][C@@H:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C@@H:9]([C:20]([OH:22])=[O:21])[CH2:10]1)=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: COC(=O)[C@H]1CN(C(=O)OC(C)(C)C)C[C@H]1c1ccc(F)cc1
Agent: Cl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1C[C@H](C(=O)O)[C@H](c2ccc(F)cc2)C1
Temperature: 95 °C
Reaction time: 3 h
Yield: 58.1 %

Procedure:
A mixture of the compound (2.7 g) obtained in step 3 and concentrated hydrochloric acid/acetic acid (4.2/4.2 mL) was stirred at 90 to 100° C. for 3 hr, and concentrated under reduced pressure. The residue was dissolved in DMAc (8.0 mL), Boc2O (2.8 g) and triethylamine (3.0 mL) were added at 0° C. and the mixture was stirred for 30 min. The mixture was poured into saturated aqueous ammonium chloride solution, and extracted twice with ethyl acetate. The extract was washed twice with water and with saturated brine, dried and concentrated under reduced pressure to give (3R*,4R*)-1-(tert-butoxycarbonyl)-4-(4-fluorophenyl)pyrrolidine-3-carboxylic acid (1.5 g, 56%) as a white powder.
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH:4]=[CH2:5].[CH2:8]([Mg]Br)[CH2:9][CH:10]=[CH2:11]>C1COCC1>[CH2:5]=[CH:4][CH2:3][CH2:2][C:1](=[O:6])[CH2:11][CH2:10][CH:9]=[CH2:8]
Reactant: C=CCCC(=O)Cl
Reactant: C=CCC[Mg]Br
Solvent: C1CCOC1
Product: C=CCCC(=O)CCC=C
Temperature: -78 °C

Procedure:
In an oven-dried 500 mL round-bottomed flask (t=g) was added 4-Pentenoyl chloride (6.04 mL, 54.7 mmol) in THF (80 mL) to give a tan solution. After cooling to −78° C., 3-Butenylmagnesium bromide (115 mL, 57.5 mmol) was added via syringe over 90 min. After warming to room temperature for 3 hours, the reaction was quenched with saturated NH4Cl solution. THF was stripped off and the remaining was extracted with EtOAc. The organic layer was washed with brine, dried with Na2SO4, and concentrated to a slightly yellow oil. Purification (two batches) by FCC up to 40% Et2O/hexane afforded the product as a colorless oil: (5.13 g, 68%). 1H NMR (400 MHz, CDCl3) δ 5.84-5.68 (m, 2H), 5.05-4.90 (m, 4H), 2.49 (t, J=7.4 Hz, 4H), 2.35-2.20 (m, 4H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=O)[CH:6]=[CH:5]2.[CH3:15][O:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([N:20]1[CH2:21][CH2:22][CH:17]([O:16][CH3:15])[CH2:18][CH2:19]1)=[O:14])[CH:6]=[CH:5]2
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Reactant: COC1CCNCC1
Product: COC1CCN(C(=O)c2ccc3cc(O)ccc3c2)CC1

Procedure:
The title compound was synthesised from 6-hydroxy-2-naphtoic acid (commercially available) and 4-methoxy-piperidine (commercially available) according to the procedure described for Example A. MS (m/e): 284.0 (MH−, 100%)
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5])#[CH:2].C(N(CC)CC)C.[Cl:17][CH:18]([Cl:22])[C:19](Cl)=[O:20]>ClCCl>[Cl:17][CH:18]([Cl:22])[C:19]([NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[CH:9][C:3]=1[C:1]#[CH:2])=[O:20]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: C#Cc1ccccc1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#Cc1ccccc1NC(=O)C(Cl)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Ethynylaniline (1.0 g, 8.53 mmol) was dissolved in anhydrous dichloromethane (20 mL) with triethylamine (1.6 mL, 11.0 mmol). The mixture was cooled in an ice-bath under nitrogen, then a solution of dichloroacetyl chloride (0.875 mL, 8.53 mmol) in anhydrous dichloromethane (20 mL) was added dropwise. After the addition was completed the ice-bath was removed and the mixture was stirred at room temperature for 2 h. The reaction mixture was then washed successively with water, 10% hydrochloric acid and saturated sodium bicarbonate solution. The organic solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound as a beige solid.
Reaction SMILES: [CH:1]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=[C:3]([I:10])[CH:2]=1.[CH3:11][Si](C=[N+]=[N-])(C)C.CCCCCC>CO>[CH3:11][O:8][C:7](=[O:9])[C:6]1[CH:5]=[CH:4][C:3]([I:10])=[CH:2][CH:1]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1ccc(I)cc1
Solvent: CO
Solvent: CCCCCC
Product: COC(=O)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
p-iodobenzoic acid (500 mg, 2.02 mmol) was dissolved in methanol (30 ml), to which was added 2M trimethylsilyl diazomethane/hexane solution (13 ml) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to yield a crude product (500 mg) of the title compound. This was used as a raw material in the subsequent reaction without purification.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:21]=[CH:22][CH:23]=1)[CH2:7][O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[C:14]([CH2:19][OH:20])[CH:15]=[N:16]2)=[CH:11][CH:10]=1.[CH3:24]I>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[C:6]([CH:21]=[CH:22][CH:23]=1)[CH2:7][O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[C:14]([CH2:19][O:20][CH3:24])[CH:15]=[N:16]2)=[CH:11][CH:10]=1
Reactant: OCc1cnc2cc(OCc3cccc(Cl)c3)ccc2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCc1cnc2cc(OCc3cccc(Cl)c3)ccc2c1
Reaction time: 0.17 h
Yield: 60.6 %

Procedure:
To a cooled solution of NaH (60% in mineral oil, 12 mg, 0.3 mmol) in DMF (0.5 mL) under an atmosphere of nitrogen, was added a solution of (7-((3-chlorobenzyl)oxy)quinolin-3-yl)methanol (Example 35, 30 mg, 0.10 mmol) in DMF (0.5 mL). The reaction was stirred for 10 minutes. Methyl iodide (0.019 mL, 0.3 mmol) was added and the reaction was stirred for an additional 25 minutes at 0° C. before being quenched with a sat. NH4Cl (aq.) solution. The aqueous layer was extracted with EtOAc. The organic layers were combined and concentrated onto silica. Purification (FCC, SiO2, 0-60%, EtOAc/hexanes) afforded the title compound as a white solid (19 mg, 61%). 1H NMR (400 MHz, CDCl3) δ 8.81 (d, J=2.0 Hz, 1H), 8.05 (d, J=1.6 Hz, 1H), 7.73 (d, J=8.6 Hz, 1H), 7.50 (s, 1H), 7.46 (d, J=2.7 Hz, 1H), 7.39-7.27 (m, 4H), 5.19 (s, 2H), 4.62 (s, 2H), 3.45 (s, 3H). [M+H]=314.2.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]3[CH:14]=[N:13][NH:12][C:10]3=2)[N:5]=[C:4]([CH3:15])[CH:3]=1.[CH:16]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[CH:16]1([NH:22][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]4[CH:14]=[N:13][NH:12][C:10]4=3)[N:5]=[C:4]([CH3:15])[CH:3]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: NC1CCCCC1
Reactant: Cc1cc(Cl)c2c(ccc3cn[nH]c32)n1
Product: Cc1cc(NC2CCCCC2)c2c(ccc3cn[nH]c32)n1
Yield: 67.8 %

Procedure:
9-Chloro-7-methyl-1H-pyrazolo[3,4-f]quinoline (0.44 g, 2.0 mmol) and cyclohexylamine (0.79 g, 8.0 mmol) were placed in a sealable reaction vessel which was flushed with nitrogen and then sealed. The reaction was placed in a ° C. bath and heated overnight. The excess cyclohexylamine was removed by rotary evaporation and the residue dissolved in methanol and treated with decolorizing carbon. After filtration through diatomaceous earth (Celite™), the methanol was removed by rotary evaporation and the residue partitioned between ethyl acetate and aqueous potassium hydroxide (KOH). The organic layer was washed with water and dried over sodium sulfate (Na2SO4), and the solvent was removed by rotary evaporation to give a white solid. The solid was washed with ether giving 9-(cyclohexylamino)-7-methyl-1H-pyrazolo[3,4-f]quinoline as white needles (0.38 g, 68%). The free base was converted to the corresponding hydrochloride salt by treatment with anhydrous hydrogen chloride (HCl)/ether.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.Br[CH2:19][CH2:20][N:21](C)[C:22](=O)OC(C)(C)C.FC(F)(F)C(O)=O>>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([O:17][CH2:19][CH2:20][NH:21][CH3:22])=[CH:15][CH:16]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CN(CCBr)C(=O)OC(C)(C)C
Reactant: Oc1ccc(-c2nc3cc(Br)cnc3[nH]2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CNCCOc1ccc(-c2nc3cc(Br)cnc3[nH]2)cc1

Procedure:
The title compound was prepared from 4-(6-bromo-3H-imidazo[4,5-b]pyridin-2-yl)phenol and tert-butyl 2-bromoethyl(methyl)carbamate using the method described in Example 41, followed by deprotection using trifluoroacetic acid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[CH:5]=[C:4]([C:13]#[N:14])[N:3]=1.[NH2:15][C@H:16]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17]1.CCN(CC)CC>CN1C(=O)CCC1>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6]([CH:5]=[C:4]([C:13]#[N:14])[N:3]=[C:2]2[NH:15][C@H:16]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17]2)=[CH:7][CH:8]=1
Reactant: N#Cc1cc2ccc(Cl)cc2c(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(C#N)cc3ccc(Cl)cc23)C1
Temperature: 160 °C
Yield: 79 %

Procedure:
To a solution of 1,7-dichloroisoquinoline-3-carbonitrile (500 mg, 2.24 mmol) in NMP (5 mL) was added (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate (460 mg, 2.46 mmol) and Et3N (453 mg, 4.48 mmol). The solution was heated to 160° C. for 30 minutes in a microwave reactor. The reaction was quenched with H2O (20 mL) and extracted with EtOAc (3×10 mL). The organic layers were combined and concentrated in vacuo. The crude product was purified by column chromatography eluting with ethyl acetate and petroleum ether (EtOAc/PE=1:10 to 1:5 gradient) to give the title compound (660 mg, 79%). ESI-MS m/z [M+H-tert-butyl]+ 317.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:27][CH2:28][C:29]#[CH:30])[C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([O:25][CH3:26])[CH:19]=2)=[O:10])=[CH:4][CH:3]=1.C[O-].[Na+].[CH2:34](Cl)[C:35]#[C:36][CH2:37][CH3:38].C(OCC)(=O)C>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([O:27][CH2:28][C:29]#[CH:30])[C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:34][C:35]#[C:36][CH2:37][CH3:38])=[C:20]([O:25][CH3:26])[CH:19]=2)=[O:10])=[CH:6][CH:7]=1
Reactant: C#CCOC(C(=O)Nc1ccccc1-c1ccc(O)c(OC)c1)c1ccc(Cl)cc1
Reactant: CCC#CCCl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: C#CCOC(C(=O)Nc1ccccc1-c1ccc(OCC#CCC)c(OC)c1)c1ccc(Cl)cc1

Procedure:
A solution of 1.3 g (3.1 mmol) 2-(4-chloro-phenyl)-N-(4′-hydroxy-3′-methoxy-biphenyl-2-yl)-2-prop-2-ynyloxy-acetamide, 6.0 ml (6.0 mmol) of a 1 M solution of sodium methoxide in methanol and 0.5 g (4.7 mmol) 2-pentynyl chloride in 50 ml of methanol is heated to reflux for 3 hours. After cooling, the reaction mixture is poured into ethyl acetate. The organic layer is washed with brine, dried over sodium sulfate and evaporated. The remaining product is subjected to flash-chromatography (ethyl acetate/hexane 4:6) to yield 2-(4-chlorophenyl)-N-(3′-methoxy-4′-pent-2-ynyloxy-biphenyl-2-yl)-2-prop-2-ynyloxy-acetamide as yellow oil.
Reaction SMILES: [OH-].[K+:2].[OH:3][C:4]1[CH:5]=[CH:6][C:7]2[CH:8]([C:19]3[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=3[C:21]([OH:23])=[O:22])[C:9]3[C:14]([O:15][C:16]=2[CH:17]=1)=[CH:13][C:12]([OH:18])=[CH:11][CH:10]=3>C(O)C>[OH:18][C:12]1[CH:11]=[CH:10][C:9]2[CH:8]([C:19]3[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=3[C:21]([O-:23])=[O:22])[C:7]3[C:16]([O:15][C:14]=2[CH:13]=1)=[CH:17][C:4]([OH:3])=[CH:5][CH:6]=3.[K+:2]
Reactant: O=C(O)c1ccccc1C1c2ccc(O)cc2Oc2cc(O)ccc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C([O-])c1ccccc1C1c2ccc(O)cc2Oc2cc(O)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.4 %

Procedure:
Aqueous potassium hydroxide (1 mL of 0.1 N, 0.1 mmol) was added to a solution of 2-(3,6-dihydroxy-9H-xanthen-9-yl)-benzoic acid [33 mg, 0.1 mmol, Cui, Y. et al., Yaoxue Tongbao, 1982, 17(9), 528] in 5 mL of ethanol and the mixture was stirred for additional 2 h at room temperature. The mixture was evaporated to dryness under reduced pressure to give 37 mg (100% yield) of the desired compound as a orange solid, mp>300° C. 1H NMR (D2O, 300 MHz): δ5.76 [s, H, —CH], 6.94-6.99 [m, 1H, Ar—H], 7.09-7.13 [m, 2H, Ar—H], 7.26-7.31 [m, 6H, Ar—H], 7.49-7.54 [m, 1H, Ar—H].
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:18])[CH:10]([Br:17])P(OC)(OC)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:29][O:30][C:31](=[O:40])[C:32]1[CH:37]=[CH:36][C:35]([CH:38]=O)=[CH:34][CH:33]=1>C1COCC1>[CH3:29][O:30][C:31](=[O:40])[C:32]1[CH:37]=[CH:36][C:35]([CH:38]=[C:10]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:18])[Br:17])=[CH:34][CH:33]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: COP(=O)(OC)C(Br)C(=O)OCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C=C(Br)C(=O)OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
To a cooled (−78° C.) solution of bromo-(dimethoxy-phosphoryl)-acetic acid benzyl ester (500 mg, 1.5 mmol) in THF (10 mL) was added LHMDS (1.2 mL of a 1M solution in THF, 1.2 mmol). The reaction was warmed to 0° C. and stirred for 30 minutes, then recooled to −78° C. 4-Formyl-benzoic acid methyl ester (163 mg, 1.0 mmol) in THF (2 mL) was added dropwise, and the reaction was allowed to warm to room temperature and stirred for 18 hours. The reaction was evaporated to dryness by rotary evaporator and purified by column chromatography on silica gel eluting with 50% ethyl acetate in hexanes to yield 4-(2-Benzyloxycarbonyl-2-bromo-vinyl)-benzoic acid methyl ester (358 mg, 64%) as a mixture of E and Z isomers. 1H NMR (300 MHz, CDCl3): δ 8.33 (s, 1H), 8.05 (d, J=7.5 Hz, 1H), 7.88 (m, 2H), 7.4-7.2 (m, 7H), 5.33 (s, 1H), 5.16 (s, 2H), 3.93-3.91 (s, 3H). LC-MS m/z=376 [C18H15BrO4+H]+.