Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C([O:12][CH:13]([CH3:26])[CH2:14][CH2:15][C:16]1[CH:21]=[C:20](Cl)[N:19]2[N:23]=[CH:24][CH:25]=[C:18]2[N:17]=1)(=O)C.[H-].[Na+]>CN(C=O)C>[OH:12][CH:13]([CH3:26])[CH2:14][CH2:15][C:16]1[CH:21]=[C:20]([O:1][CH2:2][C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[N:19]2[N:23]=[CH:24][CH:25]=[C:18]2[N:17]=1
Reactant: OCc1ccncc1
Reactant: CC(=O)OC(C)CCc1cc(Cl)n2nccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(O)CCc1cc(OCc2ccncc2)n2nccc2n1

Procedure:
The procedure of Example 1 was followed except using 340 mg of 4-(hydroxymethyl)pyridine, 280 mg of 5-(3-acetoxybutyl)-7-chloropyrazolo[1,5-a]pyrimidine and 105 mg of 60% sodium hydride and using DMF as a solvent. The title compound was obtained as colorless crystals (50 mg). The structure and melting point of the compound obtained are shown in Table 1.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[CH3:24][N:25]([CH3:31])[CH2:26][CH2:27][C:28](O)=[O:29]>>[CH3:1][O:2][C:3]([N:5]1[C@H:13]2[C@H:8]([C@:9]([O:23][C:28](=[O:29])[CH2:27][CH2:26][N:25]([CH3:31])[CH3:24])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Reactant: CN(C)CCC(=O)O
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC(=O)CCN(C)C

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and 3-dimethylamino propionic acid to yield (3aR,4S,7aR)-4-(3-dimethylamino-propionyloxy)-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester. MS [M+H] 413; RT 4.968 min; LC-MS Method ii
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:11][C:12]=2[CH3:13])=[CH:4][CH:3]=1.[Br:25]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:25][CH2:13][C:12]1[O:11][C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:9]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: CCOC(=O)c1c(-c2ccccc2)oc(C)c1-c1ccc(F)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1c(-c2ccccc2)oc(CBr)c1-c1ccc(F)cc1
Temperature: 25 °C

Procedure:
A solution of ethyl 4-(4-fluorophenyl)-5-methyl-2-phenylfuran-3-carboxylate (19.06 g, 58.76 mmol), N-bromosuccinimide (10.5 g, 58.8 mmol) and 2,2′-azobis(isobutyronitrile) (50 mg) in carbon tetrachloride (50 ml) was heated under reflux for 0.5 hr. After cooling the reaction solution to room temperature, white precipitate was removed by filtration, and the precipitate was washed with diethyl ether. The solvent of the collected filtrate was evaporated under reduced pressure to give a crude product of ethyl 5-(bromomethyl)-4-(4-fluorophenyl)-2-phenylfuran-3-carboxylate as a yellow liquid. The obtained liquid was dissolved in N,N-dimethylformamide (40 ml) and sodium acetate (9.64 g, 118 mmol) was added. The mixture was stirred overnight at room temperature. The reaction solution was diluted with water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane/ethyl acetate=6/1) to give the objective substance.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][C:7]3[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.Br[CH2:14][C:15]1[CH:34]=[CH:33][C:18]2/[C:19](=[C:29](/[CH3:32])\[C:30]#[N:31])/[C:20]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:21]=3[O:22][CH2:23][C:17]=2[CH:16]=1>>[CH:1]1([C:4]2[N:5]([CH2:14][C:15]3[CH:34]=[CH:33][C:18]4/[C:19](=[C:29](/[CH3:32])\[C:30]#[N:31])/[C:20]5[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:21]=5[O:22][CH2:23][C:17]=4[CH:16]=3)[C:6]3[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=3[N:8]=2)[CH2:3][CH2:2]1
Reactant: C/C(C#N)=C1/c2ccc(CBr)cc2COc2cc(F)ccc21
Reactant: c1ccc2[nH]c(C3CC3)nc2c1
Product: C/C(C#N)=C1/c2ccc(Cn3c(C4CC4)nc4ccccc43)cc2COc2cc(F)ccc21
Yield: 96.3 %

Procedure:
Using 2-cyclopropyl-1H-benzo[d]imidazole (Europeane Journal of Organic Chemistry, 2000, p 1229, 69 mg, 0.434 mmol) and (E)-2-[8-(bromomethyl)-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene]propanenitrile (160 mg, 0.447 mmol) obtained in Reference Example 1, and in the same manner as in Reference Example 1A, the title compound (182 mg, 95%) was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][CH:14]([O:17][CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])[CH2:13][CH2:12]2)=[CH:6][C:5]=1[C:26]([F:29])([F:28])[F:27])([O-:3])=[O:2].FC(F)(F)C(O)=O>ClCCl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][CH:14]([O:17][CH2:18][C:19]([OH:21])=[O:20])[CH2:13][CH2:12]2)=[CH:6][C:5]=1[C:26]([F:27])([F:28])[F:29])([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
To a solution of tert-butyl 2-(4-(4-nitro-3-(trifluoromethyl)phenylamino)cyclohexyloxy)acetate (1 g, 2.39 mmol) in dichloromethane (30 ml) was added trifluoroacetic acid (5 ml). The resulting solution was stirred for 2 hours at room temperature and then concentrated under vacuum. The resulting solution was diluted with dichloromethane (200 ml), washed with water (100 ml), dried over anhydrous sodium sulfate, filtered, and then concentrated under vacuum to afford 800 mg (92%) of 2-(4-(4-nitro-3-(trifluoromethyl)phenylamino)cyclohexyloxy)acetic acid as yellow oil. 1H NMR (300 MHz, DMSO): δ 12.5 (broad s, 1H), 8.07 (d, J=9.3 Hz, 1H), 7.45 (d, J=7.8 Hz, 1H), 7.07 (s, 1H), 6.87 (dd, J=2.4 Hz, 9.3 Hz, 1H), 4.03 (s, 2H), 3.32-3.46 (m, 2H), 1.91-2.03 (m, 4H), 1.17-1.41 (m, 4H).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:23][CH:24]=4)[N:19]([CH3:30])[N:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.C(N)CN.O>ClCCl.C(OCC)(=O)C>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([S:26]([CH3:29])(=[O:27])=[O:28])=[CH:23][CH:24]=4)[N:19]([CH3:30])[N:18]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)c2ccc(S(C)(=O)=O)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)C)c3n2)c2ccc(S(C)(=O)=O)cc21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 66.7 %

Procedure:
In a round-bottomed flask, 2-(6-methanesulfonyl-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (76 mg, 0.137 mmol) was dissolved in dichloromethane (0.7 ml) and trifluoroacetic acid (0.42 ml, 5.45 mmol) was added. The reaction mixture was stirred at room temperature for 2.5 h then concentrated. The residue was dissolved in dichloromethane (0.7 ml) and ethylenediamine (0.55 ml, 8.14 mmol) was added. The reaction was stirred at room temperature for 1 h then water and ethyl acetate were added. The resulting suspension was filtered and washed with hot water and ethyl acetate. The product collected was dried under high vacuum to provide 39 mg (67%) of 2-(6-methanesulfonyl-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide as a light yellow powder. MS: (2M+Na)+=875; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 12.89 (br. s, 1H), 9.13 (s, 1H), 8.71 (d, J=8.3 Hz, 1H), 8.46 (s, 1H), 8.42 (s, 1H), 7.92 (s, 1H), 7.76 (d, J=8.7 Hz, 1H), 4.31 (s, 3H), 3.35 (s, 3H), 1.55 (s, 9H).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([CH2:13][C:14]1[C:15]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[N:16][O:17][C:18]=1[C:19](OCC)=[O:20])[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].CC(C)([O-])C.[K+].S(Cl)(Cl)=O>C1COCC1.C(Cl)Cl>[F:30][C:27]1[CH:28]=[CH:29][C:24]([C:15]2[C:14]3[CH:13]=[N:6][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:19]([OH:20])[C:18]=3[O:17][N:16]=2)=[CH:25][CH:26]=1
Reactant: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1c(-c2ccc(F)cc2)noc1C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)c1ncc2c(-c3ccc(F)cc3)noc2c1O
Temperature: -78 °C
Reaction time: 14 h
Yield: 69 %

Procedure:
Ethyl 4-(((2,4-dimethoxybenzyl)(2-ethoxy-2-oxoethyl)amino)methyl)-3-(4-fluorophenyl)isoxazole-5-carboxylate (8.7 g, 17.4 mmol) was dissolved in 150 mL of THF and cooled to −78° C. Potassium tert-butoxide solution (34.8 mL, 34.8 mmol, 1M in THF) was added dropwise, and the mixture was stirred for 14 hours, the cold bath allowed to evaporate spontaneously. The reaction mixture was quenched with 30 mL of 1M HCl and 200 mL of saturated ammonium chloride solution. The product was extracted with EtOAc and the organic layer was dried over MgSO4 and concentrated to give 7.54 g of crude oil. The crude intermediate was dissolved in 100 mL of CH2Cl2. Thionyl chloride (1.8 mL, 24.9 mmol) was added and within minutes a precipitate began to form. The reaction mixture was stirred for another hour and the mixture was filtered through a medium porosity funnel. The solid was rinsed twice with cold CH2Cl2 and dried under vacuum to give 3.63 g of the title compound. MS: (+) m/z 303.37 (M+1).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([OH:13])[CH2:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[C:25]1([CH3:47])[CH:30]=[CH:29][C:28]([S:31]([O:34]C(CC)COCC2C=CC=CC=2)(=[O:33])=[O:32])=[CH:27][CH:26]=1>N1C=CC=CC=1>[CH2:1]([O:8][CH2:9][CH:10]([OH:13])[CH2:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:47][C:25]1[CH:30]=[CH:29][C:28]([S:31]([OH:34])(=[O:33])=[O:32])=[CH:27][CH:26]=1
Reactant: CCC(COCc1ccccc1)OS(=O)(=O)c1ccc(C)cc1
Agent: CCC(O)COCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1,000 g. (5.45 mole) of 1-benzyloxy-2-butanol in 2,000 ml. of pyridine, 1,170 g. (6.04 mole) of p-toluenesulfonyl chloride is added in small portions for a period of about 30 minutes at room temperature. During the addition the temperature raises, but it is kept at the room values by cooling the reaction mixture by an external circulation of ice-water; then the solution is vigorously stirred always at room temperature for about 16-20 hours. After cooling to 0°C, the solution is poured into ice-water and an oil precipitates, which is separated from the aqueous phase by decantation. The remaining water portion is twice extracted with benzene; then the oily and the benzene phases are combined together and the resulting benzene solution is cooled to about 10°C. Said organic solution is subsequently washed with concentrated hydrochloric acid, then with a saturated solution of sodium bicarbonate and finally with water, and dried over sodium sulfate. After distillation of the solvent a residue is obtained which is 1-benzyloxy-2-butanol p-toluenesulfonate which decomposes upon distillation. Yield of this step: 100%.
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[O:19][C:20]([CH3:30])=[C:21]([C:23]([O:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:24])[N:22]=2)[CH2:14][C@H:13]1[O:31][CH3:32])=O)C1C=CC=CC=1>[Pd].C(OCC)(=O)C>[NH2:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[O:19][C:20]([CH3:30])=[C:21]([C:23]([O:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:24])[N:22]=2)[CH2:14][C@H:13]1[O:31][CH3:32]
Reactant: CCCCOC(=O)c1nc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)oc1C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCOC(=O)c1nc(N2CC[C@H](N)[C@H](OC)C2)oc1C
Yield: 113.5 %

Procedure:
The same operation as in Example (95b) was performed using butyl cis(±)-2-(4-{[(benzyloxy)carbonyl]amino}-3-methoxypiperidin-1-yl)-5-methyl-1,3-oxazole-4-carboxylate obtained in Example (106b) (0.82 g, 1.84 mmol), 10% Pd/C (0.25 g) and ethyl acetate (15 mL), to obtain 0.65 g of the title compound as a yellow amorphous solid (100%).
Reaction SMILES: OS(O)(=O)=O.[Br:6][C:7]1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2.C1C(=O)N([Br:24])C(=O)C1>C(Cl)Cl>[Br:6][C:7]1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[C:14]([Br:24])[CH:13]=[CH:12][CH:11]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: Brc1cnc2ccccc2c1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: Brc1cnc2cccc(Br)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
To concentrated H2SO4 (130 ml) was added dropwise at 0° C., over 80 min, 3-bromoquinoline (50 g) at a rate allowing the internal temperature to be maintained between 0° and 10° C. After the addition was complete, NBS (48 g) was added portionwise and the reaction mixture was stirred at rt overnight. The reaction mixture was poured onto ice (2 l) and the resulting solid was dissolved in DCM (600 ml). The aq. layer was further extracted with DCM (600 ml) and the combined extracts were washed with 1M NaOH (300 ml) and concentrated in vacuo. The residue was adsorbed on SiO2 and the resulting dispersal was loaded on the top of a column and eluted with a DCM-Hex (1-1, 3 l) then DCM (3 l) and finally DCM-ether (1-1, 2 l). The title compound was recovered from the last fraction after evaporation to yield 40 g of a white solid.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Cl[C:13]1[CH:14]=[C:15]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[N:25]=1)[C:16]([O:18]C(C)(C)C)=[O:17].[H-].[Na+]>O1CCCC1>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([O:11][C:13]3[CH:14]=[C:15]([CH:23]=[C:24]([C:26]([F:29])([F:27])[F:28])[N:25]=3)[C:16]([OH:18])=[O:17])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)nc(C(F)(F)F)c1
Reactant: OC1CCC2(CC1)OCCO2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)c1cc(OC2CCC3(CC2)OCCO3)nc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a vial, 1,4-dioxaspiro[4.5]decan-8-ol (0.400 g, 2.53 mmol) was dissolved in tetrahydrofuran (8.44 mL) with tert-butyl 2-chloro-6-(trifluoromethyl)isonicotinate (0.510 g, 1.81 mmol) and cooled to 0° C. and a 60% mixture of sodium hydride in mineral oil (123 mg, 3.08 mmol) was added and the mixture was stirred for 30 minutes at 0° C. and at 25° C. for 30 minutes at which time TLC analysis showed most of the ester was consumed and a new spot with lower Rf was formed. The reaction was continued for 16 hours. LCMS analysis showed that it consisted mainly of the acid. TLC analysis showed the original product was not present. The reaction was quenched with water and extracted with EtOAc. The crude product was used in the next reaction without further purification. MS (ES): 348 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[CH:10][NH:11][CH:12]=1.[C:13](Cl)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[CH:10][N:11]([C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:12]=1
Reactant: Brc1ccccc1-c1c[nH]cn1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Brc1ccccc1-c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 14 h
Yield: 73.1 %

Procedure:
To a solution of 4-(2-bromophenyl)-1H-imidazole (880 mg, 3.94 mmol) in 10 mL DMF, were added TEA (0.605 mL, 4.34 mmol) and trityl chloride (1.21 g, 4.34 mmol). The mixture was stirred at rt for 14 h, then diluted with EtOAc. The organic phase was washed with H2O (2×) and brine, dried (Na2SO4), filtered through a 1″ pad of silica gel and concentrated. The crude product was purified by flash chromatography (0 to 40% EtOAc/hexanes gradient) to afford 1.34 g of Intermediate 217.1 as an off-white solid. LCMS (50 to 100% B, 4 min gradient, A 95% H2O/5% CH3CN/0.1% TFA, B=5% H2O/95% CH3CN/0.1% TFA) RT=0.77 min, 465.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[O:11][C:7]1([CH2:10][CH2:9][CH2:8]1)[CH2:6]/[C:5]/2=[CH:15]\[C:16](OCC)=[O:17].[CH:21]1([O:26][C:27]2[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=2[NH2:29])[CH2:25][CH2:24][CH2:23][CH2:22]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[O:11][C:7]1([CH2:10][CH2:9][CH2:8]1)[CH2:6]/[C:5]/2=[CH:15]\[C:16]([NH:29][C:28]1[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=1[O:26][CH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:17]
Reactant: Nc1ccccc1OC1CCCC1
Reactant: CCOC(=O)/C=C1\CC2(CCC2)Oc2ccc(Cl)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(/C=C1\CC2(CCC2)Oc2ccc(Cl)cc21)Nc1ccccc1OC1CCCC1

Procedure:
The title compound was prepared by the coupling ethyl (2E)-(6-chlorospiro[chromene-2,1′-cyclobutan]-4(3H)-ylidene)acetate (Step 2 of Intermediate 1) with 2-(cyclopentyloxy)aniline (120 mg, 0.681 mmol) (150 mg, 0.565 mmol) in presence of EDCI.HCl (163 mg, 0.851 mmol), HOBt (130 mg, 0.851 mmol) and triethylamine (157 μl, 1.134 mmol) in dichloromethane (5 ml) as described in Method A to give 95 mg of the product as a white solid; 1H NMR (300 MHz, CDCl3) δ 1.53-1.65 (m, 8H), 1.74-1.90 (m, 4H), 2.22-2.30 (m, 2H), 2.47-2.57 (m, 2H), 3.50 (s, 2H), 4.67 (br s, 1H), 6.75 (d, J=8.1 Hz, 2H), 6.85-6.96 (m, 2H), 7.04-7.10 (m, 2H), 8.32 (d, J=7.8 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:10]([B:11]2[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]2)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:22])=O>CN(C=O)C.C(Cl)(Cl)Cl>[CH3:1][C:2]1[C:10]([B:11]2[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]2)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:22])=[O:5]
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cccc1C(=O)O
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1c(B2OC(C)(C)C(C)(C)O2)cccc1C(=O)Cl
Reaction time: 3 h
Yield: 70.5 %

Procedure:
2-Methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid (1.2 g, 46.0 mmol) was placed into 40 ml scintillation vial equipped with a small stir bar. 10.0 ml of anhydrous chloroform was added following by 1.8 ml of thionyl chloride and 2 drops of anhydrous DMF. After 3 hours, the solvent and excess thionyl chloride were evaporated under vacuum. The brown residue was treated with 40 ml of hexane, filtered, and concentrated to give 985 mg (Yield=70.5%) of the product as a greenish oil. 1H NMR (CDCl3, 400 MHz) δ 8.15 (d, 1H), 7.95 (d, 1H), 7.3 (t, 1H), 2.75 (s, 3H), 1.4 (s, 12H). The reaction was run several times and the yield was ranging from 60 to 99%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-])=O.Br[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1.BrCC1C=CC=C(F)C=1>>[CH3:20][O:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[CH2:12][O:10][C:6]1[CH:5]=[C:4]([NH2:1])[CH:9]=[CH:8][CH:7]=1
Reactant: COc1cccc(CBr)c1
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: Fc1cccc(CBr)c1
Product: COc1cccc(COc2cccc(N)c2)c1

Procedure:
3-Nitro-phenol was reacted with 1-Bromomethyl-3-methoxy-benzene according to the procedure from Example 199A substituting 1-Bromomethyl-3-methoxy-benzene for 1-bromomethyl-3-fluoro-benzene then reduced according to the procedure from Example 199B to provide the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]2[O:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([CH3:22])[CH2:19][C:20]#C)[N:15]=2)[CH:8]=[C:7]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:6]=1[OH:27])([CH3:4])([CH3:3])[CH3:2].C[NH:29]CC#N.CNCC#C>>[C:23]([C:7]1[CH:8]=[C:9]([C:11]2[O:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([CH2:19][C:20]#[N:29])[CH3:22])[N:15]=2)[CH:10]=[C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[C:6]=1[OH:27])([CH3:26])([CH3:24])[CH3:25]
Reactant: CNCC#N
Reactant: C#CCN(C)CCc1coc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)n1
Agent: C#CCNC
Product: CN(CC#N)CCc1coc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)n1
Yield: 36 %

Procedure:
The experimental protocol used is identical to that described for the compound of Example 26, methylaminoacetonitrile being used as starting product in place of the N-methylpropargylamine. A white solid is obtained with a yield of 36%. Melting point: 165-167.8° C.
Reaction SMILES: [CH:1]([NH2:3])=O.[NH2:4][C:5]1[C:13]([I:14])=[CH:12][C:11]([Cl:15])=[CH:10][C:6]=1[C:7](O)=[O:8]>>[Cl:15][C:11]1[CH:10]=[C:6]2[C:5](=[C:13]([I:14])[CH:12]=1)[N:4]=[CH:1][NH:3][C:7]2=[O:8]
Reactant: NC=O
Reactant: Nc1c(I)cc(Cl)cc1C(=O)O
Product: O=c1[nH]cnc2c(I)cc(Cl)cc12
Temperature: 130 °C
Reaction time: 72 h
Yield: 84.5 %

Procedure:
To a round bottom flask was added formamide (4 equiv., 13.5 mmol, 605 mg) and 2-amino-5-chloro-3-iodo-benzoic acid (1000 mg, 3.4 mmol). The reaction was capped and shaken at 130° C. for 72 h. The reaction was cooled to room temperature, then the precipitate was collected by filtration and washed 3× with water. The precipitate was dried under vacuum, yielding 881 mg of 6-chloro-8-iodo-3H-quinazolin-4-one as a purple solid. 1H NMR (400 MHz, DMSO) δ 12.66-12.49 (s, 1H), 8.40-8.37 (d, J=2.4 Hz, 1H), 8.24-8.21 (s, 1H), 8.09-8.05 (d, J=2.4 Hz, 1H). LCMS M/Z (M+H)=307.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][CH2:6][CH:5]([O:8]/[N:9]=[C:10](/[C:16]2[N:17]=[C:18]([NH:21]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[S:19][CH:20]=2)\[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:4][CH2:3]1.[K+].[Br-]>C(O)=O>[CH2:1]=[C:2]1[CH2:7][CH2:6][CH:5]([O:8]/[N:9]=[C:10](/[C:16]2[N:17]=[C:18]([NH2:21])[S:19][CH:20]=2)\[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:4][CH2:3]1
Reactant: C=C1CCC(O/N=C(\C(=O)OCC)c2csc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)CC1
Agent: [Br-]
Agent: [K+]
Solvent: O=CO
Product: C=C1CCC(O/N=C(\C(=O)OCC)c2csc(N)n2)CC1

Procedure:
Ethyl (Z)-2-(4-methylenecyclohexyloxyimino)-2-(2-tritylaminothiazol-4-yl)acetate (171 mg) was subjected to formic acid deprotection as in Example 1a, but with a reaction time of 1 h. After chromatography, the title compound was obtained as a white solid (74 mg) (Found M+, 309.1135. C14H19N3O3S requires M, 309.1146)-, νmax (KBr) 1724, 1650 (sh), 1624, 1540, 1461, and 1444 cm-1 ; δH (CDCl3) 1.36 (3H, t, J 7 Hz), 1.83, 2.09 and 2.32 (8H, 3m), 4.40 (2H, q, J 7 Hz), 4.48 (1H, m), 4.64 (2H, s), 5.19 (2H, br s, D2O exch.), and 6.73 (1H, s).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7]CC)=[O:6].[CH2:13](Br)[CH2:14][CH3:15].C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>CC(=O)CC.CCO>[CH2:13]([O:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([OH:7])=[O:6])[CH2:14][CH3:15]
Reactant: CCOC(=O)c1cccc(O)c1
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Solvent: CCC(C)=O
Product: CCCOc1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under N2, the mixture of ethyl 3-hydroxybenzoate (4.16 g, 25 mmol), propyl bromide (4.31 g, 3.2 ml, 35 mmol) and potassium carbonate (4.15 g, 30 mmol) in dry 2-butanone (100 ml) was heated to reflux for 48 h. After the reaction mixture cooled down to 25° C., the suspended inorganic salt was removed by filtration. The concentration of the resulting solution by rotary evaporation yielded pale yellowish syrup, which was then mixed with 2N NaOH (18 ml, 36 mmol) and EtOH (30 ml). After this mixture was stirred for 2 h at 50° C., ethanol was removed at reduced pressure. The aqueous solution was acidified by 6N HCl to pH 2 at 5° C. to generate white precipitate, which was then collected by filtration. The recrystallization of this crude product from hexane/ether yielded pure 3-Propoxy-benzoic acid as colorless crystal (3.77 g, 83.7%). 1H-NMR (400 MHz, d6-DMSO): 7.43 (m, 1 arom. H); 7.34 (m, 2 arom. H); 7.08 (m, 1 arom. H); 3.88 (t, CH3CH2CH2O); 1.65 (m, CH3CH2CH2O); 0.88 (t, CH3CH2CH2O). 13C-NMR (100 MHz, d6-DMSO): 167.12 (—C═O); 158.63; 132.12; 129.68; 121.41; 119.33; 114.41; 69.09; 21.95; 10.32.