Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:54]=[CH:53][C:6]([C:7]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([CH:25]=[CH:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[NH:33][C:34](=[O:52])[C:35]3[CH:40]=[CH:39][C:38]([S:41][CH3:42])=[C:37]([S:43]([N:46]4[CH2:51][CH2:50][O:49][CH2:48][CH2:47]4)(=[O:45])=[O:44])[CH:36]=3)=[C:14]([S:16]([O:19]CC(C)(C)C)(=[O:18])=[O:17])[CH:15]=2)=[O:8])=[CH:5][C:4]=1[S:55]([N:58]1[CH2:63][CH2:62][O:61][CH2:60][CH2:59]1)(=[O:57])=[O:56]>CN(C)C=O.[Cl-].C[N+](C)(C)C>[CH3:1][S:2][C:3]1[CH:54]=[CH:53][C:6]([C:7]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([CH:25]=[CH:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[NH:33][C:34](=[O:52])[C:35]3[CH:40]=[CH:39][C:38]([S:41][CH3:42])=[C:37]([S:43]([N:46]4[CH2:51][CH2:50][O:49][CH2:48][CH2:47]4)(=[O:45])=[O:44])[CH:36]=3)=[C:14]([S:16]([OH:19])(=[O:18])=[O:17])[CH:15]=2)=[O:8])=[CH:5][C:4]=1[S:55]([N:58]1[CH2:63][CH2:62][O:61][CH2:60][CH2:59]1)(=[O:57])=[O:56]
Reactant: CSc1ccc(C(=O)Nc2ccc(C=Cc3ccccc3NC(=O)c3ccc(SC)c(S(=O)(=O)N4CCOCC4)c3)c(S(=O)(=O)OCC(C)(C)C)c2)cc1S(=O)(=O)N1CCOCC1
Agent: C[N+](C)(C)C
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CSc1ccc(C(=O)Nc2ccc(C=Cc3ccccc3NC(=O)c3ccc(SC)c(S(=O)(=O)N4CCOCC4)c3)c(S(=O)(=O)O)c2)cc1S(=O)(=O)N1CCOCC1
Temperature: 100 °C
Reaction time: 48 h
Yield: 43.2 %

Procedure:
To a solution of 5-[4-methylsulfanyl-3-(morpholine-4-sulfonyl)-benzoylamino]-2-(2-{[4-methylsulfanyl-3-(morpholine-4-sulfonyl)-benzoylamino]-phenyl}-vinyl)-benzenesulfonic acid, 2,2-dimethylpropyl ester (Example 58, 0.30 g, 0.31 mimol) in 10 mL of anhydrous dimethylformamide was added tetramethylammonium chloride (0.069 g, 0.62 mmol) and the solution purged with nitrogen. The mixture was then heated to 100° C. and its progress followed by analytical reverse phase HPLC. After two days no starting material remained and the reaction was cooled to room temperature. After filtering to remove excess tetramethylammonium chloride the mixture was concentrated to dryness and the purified using reverse phase HPLC (70% THF/water) as the eluant. Freeze drying overnight afforded 120 mg of the title compound as a yellow solid.(43%): 1HNMR (DMSO-d6) δ10.59 (s, 1H), 10.54 (s, 1H), 8.41 (dd, J=7 Hz, 2 Hz, 2H), 8.27 (m, 2H), 8.19 (d, J=16 Hz, 1H), 8.13 (d, J=2 Hz, 1H), 7.99 (dd, J=9 Hz, 2 Hz, 1H), 7.82 (d, J=8.5 Hz, 2), 7.79 (d J=7 Hz, 1H), 7.65 (dd, J=9 Hz, 2 Hz, 2H), 7.51 (d, J=8.5 Hz, 2H), 7.08 (d, J=16 Hz, 1H), 3.61 (m, 8H), 3.15 (m, 8H), 2.60 (s, 6H); MS (ES-NEG): [M−H]− 887; Anal. Calc. for C38H40N4O11S5-2.2H2O: C, 49.14; H, 4.82; N, 6.03. Found: C, 49.17; H, 5.07; N, 5.04. Analytical reverse phase HPLC shows compound is >90% pure.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=2)[CH2:9]1)=O)(C)(C)C.[ClH:31]>O1CCOCC1>[ClH:31].[CH3:30][O:29][C:25]1[CH:24]=[C:23]([CH2:22][CH2:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][CH:10]2[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]2)[CH:28]=[CH:27][CH:26]=1
Reactant: COc1cccc(CCc2ccccc2OC2CCCN(C(=O)OC(C)(C)C)C2)c1
Agent: Cl
Solvent: C1COCCO1
Product: COc1cccc(CCc2ccccc2OC2CCCNC2)c1
Reaction time: 2 h
Yield: 44 %

Procedure:
800 mg of 1-t-butoxycarbonyl-3-{2-[2-(3-methoxyphenyl) ethyl]phenoxy}piperidine [prepared as described in step (a) above] were dissolved in 8 ml of a 4N solution of hydrogen chloride in dioxane, and the solution was allowed to stand at room temperature for 2 hours. At the end of this time, the solution was concentrated by evaporation under reduced pressure, the resulting residue was dissolved in ethyl acetate, and the resulting solution was allowed to stand at room temperature. The crystals which precipitated were collected by filtration, to give 300 mg (yield 44%) of the title compound as colorless crystals, melting at 130°-132° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([OH:10])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.O[CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>O1CCCC1>[O:15]1[CH2:16][CH2:17][CH:12]([O:10][C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[NH:1][N:2]=[CH:3]3)[CH2:13][CH2:14]1
Reactant: Oc1ccc2[nH]ncc2c1
Reactant: OC1CCOCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: c1cc2[nH]ncc2cc1OC1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 4.7 %

Procedure:
To a solution of the 1H-indazol-5-ol (150 mg, 1.12 mmol) obtained in Reference Example 4 in tetrahydrofuran (6 ml) were added 4-hydroxytetrahydropyran (0.107 ml, 1.12 mmol), triphenylphosphine (293 mg, 1.12 mmol) and a 40%-diethyl azodicarboxylate-toluene solution (0.517 ml, 1.14 mmol) at 0° C. After 30 minutes, the mixture thus obtained was heated to room temperature. After stirring overnight, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by a silica gel column chromatography (eluent: chloroform/methanol) to obtain 5-(tetrahydro-2H-pyran-4-yloxy)-1H-indazole (11.4 mg, 47%).
Reaction SMILES: I[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[O:10][CH3:11].[Li]CCCC.[C:17]([S:21]([N:23]=[CH:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:22])([CH3:20])([CH3:19])[CH3:18].[NH4+].[Cl-]>C1COCC1.CCOCC.O>[CH3:11][O:10][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([O:8][CH3:9])[C:2]=1[CH:24]([NH:23][S:21]([C:17]([CH3:18])([CH3:20])[CH3:19])=[O:22])[C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: COc1cccc(OC)c1I
Reactant: CCOC(=O)C=NS(=O)C(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(NS(=O)C(C)(C)C)c1c(OC)cccc1OC
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A cooled (−78° C.) solution of 2-iodo-1,3-dimethoxybenzene (4.119 g; 15.13 mmol) in anh. THF (40 ml) was treated dropwise with a solution of 1.6 M n-BuLi in hexanes (10.40 ml; 16.64 mmol), and the resulting mixture was stirred at −78° C., under nitrogen, for 10 min. A solution of ethyl 2-((tert-butylsulfinyl)imino)acetate (3.106 g; 15.13 mmol) in anh. THF (20 ml) was added dropwise, and stirring at −78° C. was then continued for 25 min. The reaction mixture was treated with aq. sat. NH4Cl (30 ml), water (40 ml), and Et2O (60 ml). The separated aq. layer was extracted with Et2O (2×50 ml), and the mixed organic layers were washed with brine (40 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=20/1) afforded ethyl 2-(2,6-dimethoxyphenyl)-2-(1,1-dimethylethylsulfinamido)acetate as a yellow oil. LC-MS (conditions D): tR=0.91 min.; [M+H]+: 344.45 g/mol.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5](Cl)[C:4]=1[N+:11]([O-:13])=[O:12].[CH3:14][O:15][CH2:16][CH2:17][NH2:18]>>[CH3:1][NH:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5]([NH:18][CH2:17][CH2:16][O:15][CH3:14])[C:4]=1[N+:11]([O-:13])=[O:12]
Reactant: CNc1cc(Cl)cc(Cl)c1[N+](=O)[O-]
Reactant: COCCN
Product: CNc1cc(Cl)cc(NCCOC)c1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
0.09 mole (20 g of 2-methylamino-4,6-dichloro nitrobenzene was added portionwise to 80 ml of 2-methoxyethyl amine preheated to 80° C. After 2 hours' heating, the reaction medium was diluted with 100 ml of ice water and the desired product precipitated out. After filtering, water washing then vacuum drying in the presence of P2O5, it was recrystallized from 96° ethanol. It melted at 93° C.
Reaction SMILES: CS(Cl)(=O)=O.[Cl:6][C:7]1[CH:22]=[C:21]2[C:10]([CH2:11][C:12]3[CH:16]=[CH:15][N:14]([CH2:17][CH:18](O)[CH3:19])[C:13]=32)=[CH:9][CH:8]=1.C(N(CC)CC)C.[N-:30]=[N+:31]=[N-:32].[Na+]>ClCCl.C(OCC)C.CN(C)C=O.O>[N:30]([CH:18]([CH3:19])[CH2:17][N:14]1[CH:15]=[CH:16][C:12]2[CH2:11][C:10]3[C:21]([C:13]1=2)=[CH:22][C:7]([Cl:6])=[CH:8][CH:9]=3)=[N+:31]=[N-:32]
Reactant: CC(O)Cn1ccc2c1-c1cc(Cl)ccc1C2
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(Cn1ccc2c1-c1cc(Cl)ccc1C2)N=[N+]=[N-]
Yield: 59.8 %

Procedure:
0.95 ml of methanesulfonyl chloride was added dropwise while stirring to a solution, cooled to 0° C., of 1.52 g of (RS)-1-(7-chloro-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol and 3.4 ml of triethylamine in 40 ml of dichoromethane and the mixture was stirred at this temperature for an additional 1.5 hours. The reaction mixture was subsequently diluted with 280 ml of diethyl ether, washed twice with 70 ml of saturated sodium hydrogen carbonate solution each time and the combined aqueous phases were washed once with 70 ml of diethyl ether. The combined organic phases were washed with 70 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated in a vacuum. The brown oil obtained was dissolved in 30 ml of anhydrous dimethylformamide, treated with 718 mg of sodium azide and the reaction mixture was heated to 60° for 17 hours while stirring. After cooling the solution was poured into 140 ml of water and extracted twice with 140 ml of diethyl ether each time and once with 140 ml of ethyl acetate. The combined organic phases were washed once with 140 ml of water and once with 140 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. The brown oil obtained was purified by column chromatography on silica gel (toluene). 1.0 g (60%) of (RS)-1-(2-azido-propyl)-7-chloro-1,4-dihydro-indeno[1,2-b]-pyrrole was obtained as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[C:6](Br)[CH:7]=1.OC1C=CC=C2C=1N=CC=C2.[NH:24]1[CH:28]=[CH:27][N:26]=[CH:25]1.C(=O)([O-])[O-].[K+].[K+].[OH-].[NH4+]>CS(C)=O.CCOC(C)=O.O>[N:24]1([C:6]2[CH:7]=[C:2]([CH:3]=[C:4]([C:9]([F:10])([F:12])[F:11])[CH:5]=2)[NH2:1])[CH:28]=[CH:27][N:26]=[CH:25]1
Reactant: c1c[nH]cn1
Reactant: Nc1cc(Br)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1cc(-n2ccnc2)cc(C(F)(F)F)c1
Temperature: 120 °C
Reaction time: 1 h
Yield: 66.2 %

Procedure:
A mixture of 3-Amino-5-bromobenzotrifluoride (4.0 g, 0.0167 mol), 8-hydroxy quinoline (0.362 g, 0.0025 mol), Cul (0.476 g, 0.025 mol), imidazole (1.36 g, 0.0199 mol), and potassium carbonate (2.52 g, 0.0183 mol) in 17 mL of DMSO (degassed with argon for ˜10 min) was heated at 120° C. under an atmosphere of argon for 15 h; the HPLC indicated no starting material. A 14% aqueous solution of ammonium hydroxide was added to the cooled mixture and this was stirred for 1 h at ambient temperature. Water (50 mL) and EtOAc (200 mL) were added and the aqueous layer was extracted with EtOAc (3×30 mL). The combined organic layers were dried over Na2SO4 and concentrated. The crude product was purified by silica gel flash chromatography (eluted with EtOAc/hexanes) to provide 2.51 g of product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([C:11]2(O)[C:15]3=[N:16][CH:17]=[CH:18][C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:14]3[C:13](=[O:26])[O:12]2)[N:4]=1.B.[Na]>C(O)C>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([CH:11]2[C:15]3=[N:16][CH:17]=[CH:18][C:19]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[C:14]3[C:13](=[O:26])[O:12]2)[N:6]=1
Reactant: COc1cc(OC)nc(C2(O)OC(=O)c3c(-c4ccccc4)ccnc32)n1
Agent: B
Agent: [Na]
Solvent: CCO
Product: COc1cc(OC)nc(C2OC(=O)c3c(-c4ccccc4)ccnc32)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 73.2 %

Procedure:
1 g of 7-(4,6-dimethoxypyrimidin-2-yl)-7-hydroxy-4-phenylfuro[3,4-b]pyridin-5(7H)one was dissolved in 30 ml of ethanol, and 0.1 g of sodium boron hydride was added thereto at room temperature. The mixture was stirred at room temperature for 6 hours, and the ethanol was distilled off. Ice water was added to the residue, and the mixture was adjusted to pH 2-3 with dilute hydrochloric acid and then extracted with ethyl acetate. The extract was sufficiently washed with water and dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The resulting crude product was purified by silica gel column chromatography to obtain 0.7 g (yield 73%) of the desired compound. m.p.: 151°-153.5° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8](/[CH:14]=[CH:15]/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:22](Br)[CH:23]=[CH2:24]>>[OH:1][C:2]1[C:11]([CH2:24][CH:23]=[CH2:22])=[C:10]([O:12][CH3:13])[CH:9]=[C:8](/[CH:14]=[CH:15]/[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: C=CCBr
Reactant: COC(=O)c1c(O)cc(OC)cc1/C=C/c1ccccc1
Product: C=CCc1c(OC)cc(/C=C/c2ccccc2)c(C(=O)OC)c1O
Yield: 58 %

Procedure:
Use Compound 7 and allyl bromide as materials, and follow the method described in Example 7 to obtain a white solid as the product (58%). 1H NMR (400 MHz, DMSO-d6): 3.22 (d, J=7.6 Hz, 2H), 3.75 (s, 3H), 3.89 (s, 3H), 4.93 (dd, J1=16.0 Hz, J2=12.0 Hz, 1H), 4.96 (dd, J1=6.4 Hz, J2=12.0 Hz, 1H), 6.30 (m, 1H), 6.70 (s, 1H), 6.82 (d, J=16.0 Hz, 1H), 7.30 (m, 2H), 7.42 (d, J=7.6 Hz, 2H), 7.48 (t, J=7.6 Hz, 2H), 9.83 (s, 1H).
Reaction SMILES: O.[C:2]([OH:6])(=[O:5])[CH:3]=O.[NH2:7][CH2:8][CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1.Cl.[OH-].[K+]>O>[CH:3]1([C:2]([OH:6])=[O:5])[C:11]2[NH:12][C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:10]=2[CH2:9][CH2:8][NH:7]1
Reactant: O=CC(=O)O
Reactant: NCCc1c[nH]c2ccccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C1NCCc2c1[nH]c1ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
A solution of glyoxylic acid monohydrate (1.51 g, 16.4 mmol) in water (10 ml) was added dropwise to a stirred solution of tryptamine.HCl (3.0 g, 15.3 mmol) in water (200 ml). KOH (0.827 g, 14.7 mmol) in water (10 ml) was added. The reaction mixture was stirred at room temperature for 1 h after which time precipitation occurred. Following filtration under reduced pressure the white precipitate was collected and washed with water to furnish 2,3,4,9-tetrahydro-1H-beta-carboline-1-carboxylic acid Yield 1.9 g (58%); m/z 217 [M++H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[C:10](O)(=[O:14])[CH:11]([CH3:13])[CH3:12]>C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[C:10]([O:6][CH2:5][C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([CH3:1])[CH:3]=1)(=[O:14])[CH:11]([CH3:13])[CH3:12]
Reactant: Cc1cccc(CO)c1
Reactant: CC(C)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: Cc1cccc(COC(=O)C(C)C)c1
Yield: 59.8 %

Procedure:
25 g (0.2 mol) of 3-methylbenzyl alcohol (Aldrich), 18 g (0.2 mol) of isobutyric acid and 0.6 g of p-toluenesulfonic acid are heated in a 500 ml three-necked flask apparatus with a water separator until the water is completely separated. Washing is then firstly performed with diluted sodium hydrogencarbonate solution and thereafter with water. After removing the toluene by distillation, the residue is distilled using a bulb tube distillation oven. 23 g of product (60% of theoretical) is obtained.
Reaction SMILES: C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(NC(C)C)(C)C.Br[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]([F:33])[CH2:29][CH2:30][CH2:31][F:32])[CH:23]=1.[F:34][CH:35]([F:45])[O:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]#[CH:44])=[CH:39][CH:38]=1>O1CCOCC1.C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl.[Cu]I.CCOC(C)=O>[F:34][CH:35]([F:45])[O:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]#[C:44][C:22]2[CH:23]=[C:24]([CH:28]([F:33])[CH2:29][CH2:30][CH2:31][F:32])[CH:25]=[CH:26][CH:27]=2)=[CH:39][CH:38]=1
Reactant: FCCCC(F)c1cccc(Br)c1
Reactant: C#Cc1ccc(OC(F)F)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: N#Cc1ccccc1
Solvent: CC(C)NC(C)C
Solvent: C1COCCO1
Product: FCCCC(F)c1cccc(C#Cc2ccc(OC(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82 %

Procedure:
To a degassed solution of 13 mg (0.034 mmol) of bis(benzonitrile)dichloropalladium (II) in dioxane was added 0.145 gm (0.072 mmol) of a 10% (wt/wt) tri-t-butylphosphine in hexanes. The reaction mixture was stirred for 15 minutes at room temperature, treated with 4.3 mg of copper(I) iodide followed by 0.21 mL of diisopropylamine, stirred for 10 min, treated with 0.28 gm (1.14 mmol) of 1-bromo-3-(1,4-difluoro-butyl)benzene and 0.25 gm (1.48 mmol) of 1-difluoromethoxy-4-ethynylbenzene dissolved in 2 mL of dioxane. The reaction mixture was heated to 35° C. for 0.5 h, allowed to cool to room temperature, stirred at room temperature for 3 h, poured into EtOAc. The organic phase was separated, washed sequentially with water and brine, dried over Na2SO4 and concentrated under reduced pressure. Chromatography of the concentrate on silica gel with a gradient of 0% to 25% EtOAc-hexanes afforded 1-(3-{[4-(difluoromethoxy)phenyl]ethynyl}phenyl)-1,4-difluorobutane as an oil, 0.314 gm (82% yield); 1H NMR (400 MHz, CDCl3) δ: 1.77-2.07 (m, 4H), 4.51 (m, 2H), 5.48 (dq, 1H, J=4.4, 47.6 Hz), 6.51 (t, 1H, J=73.5 Hz), 7.08 (d, 1H, J=8.6 Hz), 7.22-7.36 (m, 3H), 7.45-7.52 (m, 3H).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[S:44][C:22]3=[CH:23][CH:24]=[C:25]4[C:30]([N:29]=[C:28]([NH:31][C:32]5[CH:37]=[CH:36][CH:35]=[C:34]([N:38]6[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]6)[CH:33]=5)[N:27]=[CH:26]4)=[C:21]3[CH:20]=2)=[O:18])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.Br.CO>C(Cl)Cl>[N:14]1([C:17]([C:19]2[S:44][C:22]3=[CH:23][CH:24]=[C:25]4[C:30]([N:29]=[C:28]([NH:31][C:32]5[CH:37]=[CH:36][CH:35]=[C:34]([N:38]6[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]6)[CH:33]=5)[N:27]=[CH:26]4)=[C:21]3[CH:20]=2)=[O:18])[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]1
Reactant: O=C(OCc1ccccc1)N1CCN(C(=O)c2cc3c(ccc4cnc(Nc5cccc(N6CCCCC6)c5)nc43)s2)CC1
Agent: Br
Solvent: CO
Solvent: ClCCl
Product: O=C(c1cc2c(ccc3cnc(Nc4cccc(N5CCCCC5)c4)nc32)s1)N1CCNCC1
Yield: 60 %

Procedure:
4-[2-(3-Piperidin-1-yl-phenylamino)-thieno[2,3-h]quinazoline-8-carbonyl]-piperazine-1-carboxylic acid benzyl ester (205 mg, 0.34 mmol) was dissolved in dry DCM (4 mL) and HBr (2 mL, 33 wt % solution in AcOH) added. The resultant mixture was stirred at room temperature for 0.5 hours and concentrated under reduced pressure. The yellow gum obtained was partitioned between Et2O and dilute HCl. The aqueous layer was extracted with Et2O (1×10 mL). The aqueous layer was then basified with saturated Na2CO3 and extracted with DCM (3×10 mL). The DCM organics were dried over Na2SO4, filtered and concentrated under reduced pressure. The brown gum obtained was redissolved in DCM, silica (˜5 mL) added and concentrated under reduced pressure. The solid obtained was subjected to column chromatography (10% MeOH in DCM, ˜100 mL silica) to give a bright yellow solid. This solid was triturated with Et2O, filtered and washed with Et2O (3×5 mL) and pentane (3×5 mL) to give a yellow powder (96.4 mg, 60% yield). MS (ES+) 473, (ES−) 472. δH (CDCl3) 1.5-1.9 (6H, m), 2.9-3.1 (4H, m), 3.2-3.3 (4H, m), 3.8-3.9 (4H, m), 6.7 (1H, m), 7.2-7.3 (3H, m), 7.4 (1H, s), 7.6-7.7 (3H, m), 8.2-8.3 (1H, s), 9.1 (1H, s)
Reaction SMILES: CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC.[CH3:16][O:17][C:18](=[O:35])[C@H:19]([C@@H:32]([CH3:34])[OH:33])[NH:20][C:21](=O)[C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1>C1COCC1>[CH3:34][CH:32]1[O:33][C:21]([C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)=[N:20][CH:19]1[C:18]([O:17][CH3:16])=[O:35]
Reactant: COC(=O)[C@@H](NC(=O)c1ccc([N+](=O)[O-])cc1)[C@@H](C)O
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Product: COC(=O)C1N=C(c2ccc([N+](=O)[O-])cc2)OC1C
Temperature: 60 °C
Reaction time: 2 h
Yield: 133.7 %

Procedure:
The Burgess reagent (0.60 g, 2.5 mmol) was added to a solution of N-(4-nitrobenzoyl)threonine methyl ester obtained in Example (97a) (0.57 g, 3 mmol) in THF (20 mL), and the mixture was stirred at 60° C. for two hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/4, 1/2, 1/1, 1/2) to obtain 1.06 g of the title compound as a colorless solid (100%).
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[NH2:5][C:6]1[C:15]2[N:16]=[C:17]([CH2:28][O:29][CH2:30][CH3:31])[N:18]([CH2:19][C:20]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])([CH3:22])[CH3:21])[C:14]=2[C:13]2[CH:12]=[CH:11][C:10]([OH:32])=[CH:9][C:8]=2[N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C.ClCCl>[NH2:5][C:6]1[C:15]2[N:16]=[C:17]([CH2:28][O:29][CH2:30][CH3:31])[N:18]([CH2:19][C:20]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])([CH3:22])[CH3:21])[C:14]=2[C:13]2[CH:12]=[CH:11][C:10]([O:32][CH2:3][C:2]#[CH:1])=[CH:9][C:8]=2[N:7]=1
Reactant: C#CCBr
Reactant: CCOCc1nc2c(N)nc3cc(O)ccc3c2n1CC(C)(C)NS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C#CCOc1ccc2c(c1)nc(N)c1nc(COCC)n(CC(C)(C)NS(C)(=O)=O)c12
Reaction time: 8 h
Yield: 24.7 %

Procedure:
Propargyl bromide (1.30 g, 9.19 mmol) was added to a mixture of N-[2-(4-amino-2-ethoxymethyl-7-hydroxy-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]methanesulfonamide (2.5 g, 6.13 mmol) and cesium carbonate (5.00 g, 12.3 mmol) in DMF. The mixture was stirred overnight and then was poured into water (600 mL). The mixture was stirred overnight and a gummy solid was isolated by filtration. The solid was dissolved in dichloromethane and the resulting solution was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, gradient elution with 0-30% of a 1:5 methanol/dichloromethane solution in dichloromethane) to provide 675 mg of N-{2-[4-amino-2-(ethoxymethyl)-7-(prop-2-ynyloxy)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}methanesulfonamide as an off-white solid. A small portion was recrystallized from methanol to yield an off-white solid, mp 175.0-176.0° C.
Reaction SMILES: C[C:2]1[CH:3]=[CH:4][C:5]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:16]C1C=CC=C(I)C=1C(O)=O.N1C=CN=N1>>[F:16][C:10]1[CH:2]=[CH:3][CH:4]=[C:5]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)[C:6]=1[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1c(F)cccc1I
Reactant: Cc1ccc(-n2nccn2)c(C(=O)O)c1
Agent: c1c[nH]nn1
Product: O=C(O)c1c(F)cccc1-n1nccn1

Procedure:
The title compound was prepared following the same general protocol as described for 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid in Example A11 using 2-fluoro-6-iodobenzoic acid and 1,2,3-triazole. ESI-MS (m/z): 208 [M+1]+.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([N:13]([CH3:15])[CH3:14])[N:5]=[C:4]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=2)[N:3]=1.C([O-])(=O)C.[K+]>CO.[Pd]>[NH2:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][C:4]2[N:5]=[C:6]([N:13]([CH3:15])[CH3:14])[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:2][N:3]=2)=[CH:22][CH:21]=1
Reactant: COC(=O)Cc1c(Cl)nc(Cc2ccc([N+](=O)[O-])cc2)nc1N(C)C
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)Cc1cnc(Cc2ccc(N)cc2)nc1N(C)C
Reaction time: 15 h
Yield: 97.2 %

Procedure:
A suspension of methyl [4-chloro-6-(dimethylamino)-2-(4-nitrobenzyl)pyrimidin-5-yl]acetate (3.00 g, 8.22 mmol) and potassium acetate (2.42 g, 24.7 mmol) in methanol (30 mL) was treated with 10% Pd/C (1.00 g). The resulting black suspension was stirred under an atmosphere of hydrogen for 15 hours and then filtered over Celite. The residue was rinsed with methanol and the filtrate concentrated to dryness before partitioning between EtOAc and water. The separated organic layer was sequentially washed with saturated NaHCO3 and brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. Chromatographic purification (silica gel, 1% MeOH in CHCl3) of the thus obtained crude product then yielded methyl [2-(4-aminobenzyl)-4-(dimethylamino)pyrimidin-5-yl]acetate (2.40 g, 97% yield) as a brown oil.