Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:22])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=2)[N:10]([C:18](=[O:20])[CH3:19])[C@@H:9]([CH3:21])[CH2:8]1)[CH3:3].[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:18]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:13][CH:12]=2)[C@H:7]([NH:6][C:5](=[O:22])[O:4][CH:2]([CH3:3])[CH3:1])[CH2:8][C@@H:9]1[CH3:21])(=[O:20])[CH3:19]
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(=O)N1c2ccc(-c3ccccc3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 100 °C
Yield: 92 %

Procedure:
A mixture of 1-methylethyl[(2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see example 4) (78.6 mg, 0.213 mmol), phenyl boronic acid (31.1 mg, 0.255 mmol), potassium carbonate (73.5 mg, 0.532 mmol) and tetrakis(triphenylphosphine)palladium(0) (12.30 mg, 10.64 μmol) in ethanol (2.5 mL) and toluene (2.5 mL) was degassed under house vacuum and quenched several times with nitrogen, and then was heated at 100° C. for 30 min before being cooled to room temperature. The mixture was filtered through celite and the insoluble washed with EtOH. Most of the solvent was concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient: 25 to 55% AcOEt in hexanes) gave 1-methylethyl [(2S,4R)-1-acetyl-2-methyl-6-phenyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (71.6 mg, 0.195 mmol, 92%) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH2:11])[CH:5]=1)([O-:3])=[O:2].O.O.[C:14](O)(=[O:18])[C:15](O)=[O:16].Cl>>[OH:16][C:15]1[C:14]([OH:18])=[N:11][C:6]2[C:7](=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:10]=1
Reactant: O=C(O)C(=O)O
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Agent: Cl
Solvent: O
Product: O=[N+]([O-])c1ccc2nc(O)c(O)nc2c1
Yield: 74.6 %

Procedure:
A mixture of 225 g (1.47 moles) of 4-nitro-o-phenylenediamine, 375 g. (2.97 moles) of oxalic acid dihydrate and 2250 ml. of 6 N hydrochloric acid is combined in a 3 necked 5 liter round bottom flask which is fitted with a reflux condenser and a teflon paddle stirrer. The suspension is heated at reflux temperature for one hour and allowed to stand at room temperature over night. The material is filtered and the dark brown solid collected is washed with five 300 ml. portions of hot distilled water. The solid is slurried in two equal portions each in 40 ml. of 2 N sodium hydroxide. Each mixture is heated to near boiling with stirring and filtered hot. The red-brown hot filtrate is treated with about two liters of 4 N hydrochloric acid for each batch and the slightly acidic mixtures are filtered while still hot. The brown solid collected is washed with water several times, air dried and finally dried in vacuo over phosphorous pentoxide at 78° C. to give 227.2 g of 2,3-dihydroxy-6-nitroquinoxaline. The reference for the above compound is H. I. X. Mager and W. Berends, Rec. Trav. Chim. 78, 5-21 (1959). An additional reference is F. H. S. Curd, D. G. Davey, and G. J. Stacy, Journ. Chem. Soc. 275, 1271-1277 (1949).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH:24]3[CH2:26][CH2:25]3)[CH2:22]O)[C:11](=[O:27])[C@:10]([CH2:29][C:30]([O:32][CH3:33])=[O:31])([CH3:28])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C(C=P(CCCC)(CCCC)CCCC)#N.[S:50]1[CH:54]=[CH:53][CH:52]=[C:51]1[S:55]([NH2:58])(=[O:57])=[O:56]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH:24]3[CH2:25][CH2:26]3)[CH2:22][NH:58][S:55]([C:51]3[S:50][CH:54]=[CH:53][CH:52]=3)(=[O:57])=[O:56])[C:11](=[O:27])[C@:10]([CH2:29][C:30]([O:32][CH3:33])=[O:31])([CH3:28])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CO)C2CC2)C1=O
Reactant: NS(=O)(=O)c1cccs1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: COC(=O)C[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CNS(=O)(=O)c2cccs2)C2CC2)C1=O
Temperature: 35 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-hydroxyethyl)-3-methyl-2-oxopiperidin-3-yl)acetate (100 mg, 0.184 mmol; Example 263, Step C) and cyanomethylenetributylphosphorane (177 μL, 0.734 mmol) in toluene (0.92 mL) was added thiophene-2-sulfonamide (90 mg, 0.55 mmol) and the resulting solution was stirred at 35° C. overnight. The reaction was quenched (sat. NH4Cl), extracted (2×EtOAc), and washed (brine). The combined organic layers were dried (Na2SO4) and concentrated under the reduced pressure. Purification of the residue by chromatography on silica gel (24 g SiO2, 35% EtOAc/Hex) provided the title compound as a pale yellow foam.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23].[C:25](Cl)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:18]([O:19][CH2:20][CH:21]([CH2:22][O:23][C:25]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[OH:24])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCCCCCCCCCCCCCCCOCC(O)CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCOCC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 93.7 %

Procedure:
51.69 Grams (150 mmol) of batylalcohol and 62.73 g (225 mmol) freshly recrystallized tritylchloride are dissolved at 35° C. in 350 ml methylene chloride. (Note: It is recommended that the tritylchloride be freshly recrystallized from halpasol, tradename for a petroleum ether fraction, b.p. 100°-120° C.). During 15 minutes, 22.77 g (225 mmol; 31.38 ml) triethylamine is added dropwise to the stirred solution at 30°-35° C. (cooling with a water bath). The reaction is continued for six hours at ambient temperature. (Note: It is recommended that a control TLC be done to make sure that the reaction is complete). The solution is then washed with 300 ml of a NaHCO3 solution (1%), dried over anhydrous sodium sulfate, filtered and evaporated under vacuum. The oily residue (155 g) is dissolved in 660 ml acetonitrile by warming up to 70° C. with stirring. After cooling to room temperature the title product crystallizes (preferentially after adding a few seed crystals). Crystallization is completed by standing overnight at ambient temperature. The crystallizate is filtered off to yield 82.5 g (93.7%) of crude product (m.p. 53°-55° C.) which can be used for the following step without purification. Recrystallization from halpasol (310 ml) yields 71 g (80%) of pure tritylbatylalcohol.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:5]([C:6]([OH:8])=O)[C:4]=1[C:12]([OH:14])=O.Cl.[NH2:16][C@@H:17]1[CH2:22][NH:21][C:20](=[O:23])[CH2:19][CH2:18]1.C(N(CC)CC)C>CN(C=O)C>[NH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:5]2[C:4]=1[C:12](=[O:14])[N:16]([C@H:17]1[CH2:18][CH2:19][C:20](=[O:23])[NH:21][CH2:22]1)[C:6]2=[O:8]
Reactant: Nc1cccc(C(=O)O)c1C(=O)O
Reactant: N[C@H]1CCC(=O)NC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1cccc2c1C(=O)N([C@H]1CCC(=O)NC1)C2=O
Temperature: 80 °C
Yield: 46.5 %

Procedure:
To a mixture of 3-amino phthalic acid hydrochloride (0.144 g, 0.664 mmol) and (S)-5-aminopiperidin-2-one hydrochloride (0.100 g, 0.664 mmol) in dry DMF (2.2 mL) was added triethylamine (0.933 mL, 6.64 mmol) and the reaction mixture was heated at 80° C. over 18 h. The crude mixture was quenched by the addition of a saturated aqueous NaHCO3 solution (30 mL) and extracted using DCM (3×20 mL). Combined organic phases were dried over MgSO4, filtered and concentrated. The crude residue was purified by preparative reverse phase HPLC to give the desired product 30 (0.08 g, 47%) as an off-white powder. 1H NMR (400 MHz, DMSO) δ 7.56 (s, 1H), 7.42 (dd, J=7.7, 7.7 Hz, 1H), 6.94 (m, 2H), 6.48 (br s, 2H), 4.32 (m, 1H), 3.60 (app t, J=11.3 Hz, 1H), 3.23-3.02 (m, 1H), 2.62-2.42 (obsc m, 1H), 2.42-2.21 (m, 2H), 1.86 (m, 1H). MS (ESI) m/z calcd for C13H14N3O3 [M+H]+ 260.3, found: 260.7.
Reaction SMILES: [CH3:1][N:2]([CH3:49])[CH2:3][CH2:4][NH:5][CH2:6][C@:7]12[CH2:45][CH2:44][C@@H:43]([C:46]([CH3:48])=[CH2:47])[C@@H:8]1[C@@H:9]1[C@@:22]([CH3:25])([CH2:23][CH2:24]2)[C@@:21]2([CH3:26])[C@@H:12]([C@:13]3([CH3:42])[C@@H:18]([CH2:19][CH2:20]2)[C:17]([CH3:28])([CH3:27])[C:16]([C:29]2[CH:41]=[CH:40][C:32]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[CH:31][CH:30]=2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1.CCN(C(C)C)C(C)C.[C:59]([CH2:64][CH2:65][C:66](Cl)=[O:67])([O:61][CH2:62]C)=[O:60]>ClCCCl.CN(C1C=CN=CC=1)C>[CH3:49][N:2]([CH3:1])[CH2:3][CH2:4][N:5]([CH2:6][C@:7]12[CH2:45][CH2:44][C@@H:43]([C:46]([CH3:48])=[CH2:47])[C@@H:8]1[C@@H:9]1[C@@:22]([CH3:25])([CH2:23][CH2:24]2)[C@@:21]2([CH3:26])[C@@H:12]([C@:13]3([CH3:42])[C@@H:18]([CH2:19][CH2:20]2)[C:17]([CH3:28])([CH3:27])[C:16]([C:29]2[CH:41]=[CH:40][C:32]([C:33]([O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:34])=[CH:31][CH:30]=2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[C:66](=[O:67])[CH2:65][CH2:64][C:59]([O:61][CH3:62])=[O:60]
Reactant: C=C(C)[C@@H]1CC[C@]2(CNCCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CCOC(=O)CCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=C(C)[C@@H]1CC[C@]2(CN(CCN(C)C)C(=O)CCC(=O)OC)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 5 h
Yield: 70.8 %

Procedure:
To a solution of tert-butyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(dimethylamino)ethylamino)methyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (48 mg, 0.072 mmol) in DCE (2 ml) was added Hunig's base (0.037 ml, 0.215 mmol), 3-carboethoxypropionyl chloride (21.54 mg, 0.143 mmol), and DMAP (1 mg, 8.19 mmol). The mixture was stirred at rt for 5 h then was loaded directly onto a silica gel column and was purified using a 0-5% MeOH in dichloromethane gradient to afford tert-butyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((N-(2-(dimethylamino)ethyl)-4-methoxy-4-oxobutanamido)methyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate as a white foam (53.8 mg, 0.051 mmol, 71.8% yield). LCMS: m/e 785.6 (M+H)+, 3.21 min (method 6).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:19]=[CH:18][C:17](=[O:20])[NH:16][C:10]=2[N:11]=[C:12]([S:14][CH3:15])[N:13]=1.I[CH2:22][CH3:23]>>[CH2:22]([N:16]1[C:10]2[N:11]=[C:12]([S:14][CH3:15])[N:13]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[C:9]=2[CH:19]=[CH:18][C:17]1=[O:20])[CH3:23]
Reactant: CSc1nc(-c2ccccc2F)c2ccc(=O)[nH]c2n1
Reactant: CCI
Product: CCn1c(=O)ccc2c(-c3ccccc3F)nc(SC)nc21

Procedure:
Prepared as described above in Example 108 starting from 4-(2-fluoro-phenyl)-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one and iodoethane to afford the title compound 8-ethyl-4-(2-fluoro-phenyl)-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one. LC MS (m/e)=316 (MH+). Rt=2.29 min
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([N:18]=[CH:19][CH:20]=2)[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:27].[Na+]>CO>[Cl:1][C:2]1[C:3]2[N:4]([N:18]=[CH:19][CH:20]=2)[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[C:6]([CH:8]([NH2:27])[CH3:9])[CH:7]=1
Reactant: [BH3-]C#N
Reactant: CC(=O)c1cc(Cl)c2ccnn2c1-c1cccc(F)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC(N)c1cc(Cl)c2ccnn2c1-c1cccc(F)c1
Temperature: 65 °C
Reaction time: 18 h
Yield: 88.8 %

Procedure:
The mixture of 1-[4-chloro-7-(3-fluorophenyl)pyrazolo[1,5-a]pyridin-6-yl]ethanone (0.2 g, 0.7 mmol) in methanol (7.0 mL) and the ammonium acetate (0.5340 g, 6.928 mmol) was heated at 65° C. for 1 hour, all solids dissolved. The sodium cyanoborohydride (0.1306 g, 2.078 mmol) was added and the solution was heated at 65° C. overnight. The reaction was incomplete, additional ammonium acetate and sodium cyanoborohydride were added and the reaction was stirred for another 18 hours. This was allowed to cool to room temperature, concentrated in vacuo, taken up in ethyl acetate and washed with a small amount of water, brine, dried over magnesium sulfate and concentrated to give 1-[4-chloro-7-(3-fluorophenyl)pyrazolo[1,5-a]pyridin-6-yl]ethanamine (0.18 g, 90%) as a viscous oil. LCMS calculated for C15H14ClFN3 (M+H)+: m/z=290.1. found: 289.9.
Reaction SMILES: [F:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([CH:9]=[CH:10][C:11]=1[F:12])[NH:5][CH2:6][CH2:7][F:8].C([O:17][CH:18]=[C:19]([C:25](OCC)=O)[C:20]([O:22][CH2:23][CH3:24])=[O:21])C.C(OC(=O)C)(=O)C.S(=O)(=O)(O)O>>[F:12][C:11]1[CH:10]=[C:9]2[C:4](=[C:3]([O:13][CH3:14])[C:2]=1[F:1])[N:5]([CH2:6][CH2:7][F:8])[CH:25]=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:18]2=[O:17]
Reactant: COc1c(NCCF)ccc(F)c1F
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1cn(CCF)c2c(OC)c(F)c(F)cc2c1=O
Temperature: 25 °C
Yield: 24.8 %

Procedure:
A mixture of the whole (0.0022 mole) of the 3,4-difluoro-N-(2-fluoroethyl)-2-methoxyaniline prepared as described in step (C3) and 0.57 g (0.0026 mole) of diethyl ethoxymethylenemalonate was heated at 140°-150° C. for 6 hours, after which it was allowed to cool to room temperature. 2 ml of acetic anhydride and 1 ml of concentrated sulfuric acid were added in that order to the mixture, and it was then allowed to stand at room temperature. The reaction mixture was then poured into ice-water to precipitate crystals, which were collected by filtration to give 0.18 g of ethyl 6,7-difluoro-1-(2-fluoroethyl)-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylate (X, R9' =2-fluoroethyl) as colorless crystals.
Reaction SMILES: [Si]([O:18][CH2:19][CH2:20]/[CH:21]=[CH:22]/[C@@H:23]([NH:28][P:29]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:30])[CH2:24][CH:25]([CH3:27])[CH3:26])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:18][CH2:19][CH2:20]/[CH:21]=[CH:22]/[C@@H:23]([NH:28][P:29]([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:30])[CH2:24][CH:25]([CH3:26])[CH3:27]
Reactant: CC(C)C[C@@H](/C=C/CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)NP(=O)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)C[C@@H](/C=C/CCO)NP(=O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of the TBDPS-protected alcohol 8c (700 mg, 0.983 mmol, crude) in dry THF (8 mL) at 0° C. was added TBAF (1.0M/THF, 1.23 mL, 1.23 mmol), and the reaction mixture was allowed to warm to rt while stirring under argon. As completion was not reached after 4 h, 0.75 eq of TBAF (0.75 mL) was added at 0° C. The reaction mixture was stirred further at rt for 3 h, then quenched with sat. aq. NH4Cl and diluted with EtOAc. The aqueous phase was separated and extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. Flash chromatography (SiO2, 95:5, EtOAc/MeOH) afforded 272 mg (77%, 2 steps) of the title compound as a white solid. mp 124.0-124.2° C.; [α]D23 −12.1 (c 1.0, DCM); 1H NMR (300 MHz, CDCl3) δ 8.00-7.83 (m, 4H), 758-7.35 (m, 6H), 5.52 (dd, 1H, J=15.3, 9.0 Hz), 5.24 (m, 1H), 4.58 (bs, 1H), 3.78-3.47 (m, 3H), 2.80 (appdd, 1H, J=9.2, 3.8 Hz), 2.16 (m, 2H), 1.68 (bs, 1H), 1.55-1.43 (m, 1H), 1.43-1.31 (m, 1H), 0.87 (dd, 6H, J=8.6, 6.4 Hz); HRMS (ESI) m/z calcd for C21H28H2PNa 380.1755, found 380.1725.
Reaction SMILES: [CH3:1][S-:2].[Na+].[Na+].Cl[C:6]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:7]=1[C:8]([O-:10])=[O:9]>CN1CCCC1=O>[CH3:1][S:2][C:6]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: C[S-]
Reactant: O=C([O-])c1ccc(C(F)(F)F)cc1Cl
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CSc1cc(C(F)(F)F)ccc1C(=O)O
Temperature: 90 °C
Yield: 100.1 %

Procedure:
A mixture of anhydrous sodium thiomethoxide (0.39 g, 0.00525M), 2-chloro-4-trifluoromethylbenzoic acid sodium salt (1.23 g, 0.005M) and anhydrous N-methylpyrrolidinone (10 ml, containing less than 0.01% of water) was heated at 90° C. for 2 hours. The mixture was cooled to 20° C., acidified and extracted (t-butyl methyl ether). The extract was washed (water) and evaporated to give 2-methylthio-4-trifluoromethylbenzoic acid (1.18 g, 100% yield). 1H-nmr 2.40(s,3H). 7.30(1H), 7.38(1H), 8.07(1H). The purity of the product was greater than 95%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[F:10].[Al+3].[Cl-].[Cl-].[Cl-].[C:15](Cl)(=[O:17])[CH3:16].O>C[N+]([O-])=O>[Cl:1][C:2]1[C:3]([F:10])=[CH:4][C:5]([O:8][CH3:9])=[C:6]([C:15](=[O:17])[CH3:16])[CH:7]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc(Cl)c(F)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: C[N+](=O)[O-]
Product: COc1cc(F)c(Cl)cc1C(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
To a stirred solution of DMF (10 mL) and 4-chloro-3-fluorophenol (1 g, 6.84 mmol) at RT, K2CO3 (1.4 g, 10.3 mmol) was added and solution was allowed to stir at room temperature for additional 15 min. Methyl iodide (1.16 g, 8.21 mmol) was added to the mixture and mixture was allowed to stir for overnight at RT. After the completion of reaction 10 mL of water was added and was extracted with ethyl acetate (3×15 mL) and the resulting organic layer was washed with water, brine and dried. 1-chloro-2-fluoro-4-methoxybenzene was obtained via column chromatography (10/1 Hexanes/Ethyl acetate). To a stirred solution of 1-chloro-2-fluoro-4-methoxybenzene (1.09 g, 6.82 mmol) and AlCl3 (1.36 g, 10.23 mmol) in CH3NO2 at 0° C., acetyl chloride (0.80 g, 10.23 mmol) was added and solution was allowed to warm up to room temperature and stir for overnight. After the completion of reaction 10 mL of water was added and was extracted with ethyl acetate (3×15 mL) and the resulting organic layer was washed with water, brine and dried. The solvent was removed in vacuo. The crude was purified by flash column chromatography using 10/1 Hexanes/Ethyl acetate to afford product (46%). 1H NMR: 2.59 (s, 3H), 3.91 (s, 3H), 6.78 (d, 1H, J=10.5 Hz), 7.85 (d, 1H, J=8.7 Hz).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][CH:14]([C:17]([O:19][CH3:20])=[O:18])[CH2:13][CH2:12]1.C([O-])([O-])=O.[K+].[K+].O>C(#N)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]([O:19][CH3:20])=[O:18])[CH2:13][CH2:12]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: COC(=O)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COC(=O)C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Yield: 58.6 %

Procedure:
A solution of 1-fluoro-4-nitrobenzene (3.5 g, 24.81 mmol), methyl piperidine-4-carboxylate (4.26 g, 29.77 mmol) and K2CO3 in 40 mL of ACN, was stirred at reflux overnight. The mixture was added to 150 mL of water, extracted with EA, dried over Na2SO4. The volatiles were removed in vacuo, and the residue was purified by chromatography with PE/EA (10:1˜2:1) to give 3.84 g of methyl 1-(4-nitrophenyl)piperidine-4-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([O:12][CH2:13][CH3:14])[N:6]=2.CCN(C(C)C)C(C)C.Cl[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>C(Cl)Cl>[CH2:33]([O:32][C:30]([NH:1][C:2]1[C:3]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([O:12][CH2:13][CH3:14])[N:6]=2)=[O:31])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CCOC(=O)c1nc2nc(OCC)ccc2cc1N
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1nc2nc(OCC)ccc2cc1NC(=O)OCc1ccccc1
Temperature: 65 °C
Reaction time: 16 h

Procedure:
To a solution of ethyl 3-amino-7-ethoxy-1,8-naphthyridine-2-carboxylate (51 mg, 0.20 mmol) and DIPEA (100 μL, 0.58 mmol) in DCM (0.7 mL), benzyl chloroformate (84 μL, 0.58 mmol) was added and the reaction mixture was heated at 65° C. with stirring in a sealed vial for 16 h. The crude reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (24 g silica gel column, eluting with 0-40% EtOAc/hexanes) to afford the sub-title compound. LCMS (ESI) calc. for C21H22N3O5 [M+H]+: m/z=396.2. found: 396.1.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH2:19][CH2:20][O:21][CH3:22].[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH2:19][CH2:20][O:21][CH3:22])[N:5]([CH2:4][CH2:3][CH2:2][NH:1][S:29]([C:26]3[CH:27]=[CH:28][C:23]([CH3:33])=[CH:24][CH:25]=3)(=[O:31])=[O:30])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCN
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCNS(=O)(=O)c1ccc(C)cc1
Yield: 32.4 %

Procedure:
Using the general method of Example 242, 1-(3-aminopropyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.53 g, 5.11 mmol) was reacted with p-toluenesulfonyl chloride (1.07 g, 5.62 mmol) to provide 750 mg of N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}-4-methylbenzenesulfonamide as a solid, m.p. 189-191° C. Analysis: Calculated for C23H27N5O3S.0.50 H2O: %C, 59.72; %H, 6.10; %N, 15.14; Found: %C, 59.73; %H, 5.95; %N, 15.08.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:15]COCC>>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCOCC
Reactant: CC(C)(C)[Si](C)(C)OCCCC(=O)O
Product: COC(=O)CCCO[Si](C)(C)C(C)(C)C
Reaction time: 8 h
Yield: 95 %

Procedure:
CH2N2 (1.04 g, 248.1 mmol) in ether (10 mL) was added to 4-[tert-butyl(dimethyl)silyl]oxybutanoic acid (5.41 g, 24.81 mmol) in a flask. The mixture was stirred overnight, concentrated to give the title compound (5.44 g, 95%). 1H NMR (400 MHz, CDCl3): δ 0.03 (6H, s), 0.88 (9H, s), 1.81-184 (2H, m), 2.39 (2H, t, J=7.2 Hz), 3.63 (2H, d, J=6.4 Hz), 3.66 (3H, s). [M+H] Calc'd for C11H24O3Si, 233. Found, 233.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:9][C@H:10]1[CH2:15][NH:14][CH2:13][CH2:12][NH:11]1>>[Br:1][C:2]1[C:3]([N:14]2[CH2:13][CH2:12][NH:11][C@@H:10]([CH3:9])[CH2:15]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H]1CNCCN1
Reactant: Clc1ncccc1Br
Product: C[C@H]1CN(c2ncccc2Br)CCN1

Procedure:
A mixture of 3-bromo-2-chloropyridine (0.76 g, 4 mmol, Aldrich) and (S)-(+)-2-methylpiperazine (0.6 g. 6 mmol, Aldrich) reacted under the conditions of Example 3c to give the title compound as a light-brown solid. MS (ESI, pos. ion) m/z: 256 (M+1).