Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11].[CH:12](O)(C)[CH3:13].[OH-].[Na+]>C1OCCOCCOCCOCCOCCOC1.O>[CH2:12]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11])[CH3:13]
Reactant: COc1cc(C=O)ccc1O
Reactant: CC(C)O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOc1ccc(C=O)cc1OC
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 92 %

Procedure:
76 grams of 4-hydroxy-3-methoxybenzaldehyde (0.5 mol) and 500 mL of isopropanol are added into a four-necked flask and then stirred for 20 minutes, a constant pressure dropping funnel is used for slowly dropping 150 milliliters of aqueous solution of 6.5 grams of 18-crown-6 ether and 133 grams of sodium hydroxide, and stirring is performed for 30 minutes, the reaction system is heated to 60° C., at which 85 grams of bromethyl is dropped for reacting for 5 to 6 hours while TLC tracking is implemented, after the reaction ends, the reaction system is cooled (to 15° C.) and is added with 500 mL of water for stopped reaction, the product is extracted by ether (3×300 mL), organic phase is washed with water to be neutral, anhydrous MgSO4 is dried, ether is partially distilled, a large amount of petroleum ether is added to precipitate crude product, the crude product is subjected to recrystallization by ether/petroleum ether to obtain 83 grams of 4-ethoxy-3-methoxybenzaldehyde:, and the yield is 92%.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C:8]2[S:9][CH:10]=[C:11]([C:13]([OH:15])=[O:14])[N:12]=2)[CH:7]=1.F[C:18]1C=C(C)C=CC=1C#N>>[F:16][C:5]1[CH:4]=[C:3]([CH3:18])[CH:2]=[CH:7][C:6]=1[C:8]1[S:9][CH:10]=[C:11]([C:13]([OH:15])=[O:14])[N:12]=1
Reactant: O=C(O)c1csc(-c2cc(Br)ccc2F)n1
Reactant: Cc1ccc(C#N)c(F)c1
Product: Cc1ccc(-c2nc(C(=O)O)cs2)c(F)c1

Procedure:
Following the procedure of Intermediate 129, replacing 5-bromo-2-fluoro-benzonitrile with 2-fluoro-4-methylbenzonitrile gave the title compound.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:31])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]=2[NH2:30])=[CH:10][CH:9]=1)[CH:2]=[CH2:3].N1C=CC=CC=1.[C:38]1([CH2:51][O:52][C:53](Cl)=[O:54])[C:50]2[CH2:49][C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:42]=2[CH:41]=[CH:40][CH:39]=1>C(Cl)Cl>[CH2:1]([O:4][C:5](=[O:31])[CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]=2[NH:30][C:53]([O:52][CH2:51][C:38]2[C:50]3[CH2:49][C:48]4[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=4)[C:42]=3[CH:41]=[CH:40][CH:39]=2)=[O:54])=[CH:12][CH:13]=1)[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)COc1ccc(COc2cccc(C(=O)c3ccccc3)c2N)cc1
Reactant: O=C(Cl)OCc1cccc2c1Cc1ccccc1-2
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CCOC(=O)COc1ccc(COc2cccc(C(=O)c3ccccc3)c2NC(=O)OCc2cccc3c2Cc2ccccc2-3)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 65.2 %

Procedure:
4-(2-Amino-3-benzoylphenoxymethyl)-phenoxyacetic acid allyl ester (9.03 g, 20.8 mmol) and freshly distilled pyridine (1.97 g, 25.0 mmol, 1.2 equiv) were dissolved in 100 mL of CH2Cl2. The resulting yellow solution was cooled to 0° C., and fluorenylmethoxycarbonyl chloride (4.83 g, 21.8 mmol, 1.05 equiv) was added. The resulting solution was stirred at 0° C. for 15 min and then at ambient temperature for 1 h. The solution was diluted with CH2Cl2 (150 mL), extracted twice with 1 N aqueous sodium bisulfate (100 mL), once with dilute aqueous sodium chloride (100 mL), and then concentrated to give a yellow foam. Silica gel chromatography with CH2Cl2 afforded 8.68 g (65% yield) of purified material as a white solid that was homogeneous by 1H NMR. The carboxylic acid (3-[3-Benzoyl-2-fluorenylmethoxycarbonylaminobenzoyloxymethyl]-phenoxyacetic acid) was full characterized after removal of the allyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[NH:14][C:13]4[N:21]=[CH:22][CH:23]=[CH:24][C:12]=4[N:11]3[C:25]=2[C:26]2[CH:31]=[CH:30][C:29]([C:32]3([NH:36]C(=O)OC(C)(C)C)[CH2:35][CH2:34][CH2:33]3)=[CH:28][CH:27]=2)=[CH:4][CH:3]=1.[ClH:44].O1CCOCC1>C(Cl)Cl>[ClH:44].[ClH:44].[ClH:44].[ClH:44].[NH2:36][C:32]1([C:29]2[CH:28]=[CH:27][C:26]([C:25]3[N:11]4[C:12]5[CH:24]=[CH:23][CH:22]=[N:21][C:13]=5[NH:14][C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=5[C:10]4=[N:9][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([NH2:1])=[CH:7][CH:6]=3)=[CH:31][CH:30]=2)[CH2:33][CH2:34][CH2:35]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccc(N)cc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Nc1ccc(-c2nc3n(c2-c2ccc(C4(N)CCC4)cc2)-c2cccnc2Nc2ccccc2-3)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 82.3 %

Procedure:
tert-Butyl (1-{4-[2-(4-aminophenyl)-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl]phenyl}cyclobutyl)carbamate (32.0 mg, 0.0561 mmol) was dissolved in DCM (1 mL). 4M HCl/dioxane (1 mL) was added to the mixture and stirred at room temperature for 6 hours. The mixture was concentrated and solidified with ether. The precipitated solids were collected by filtration and washed with ether to afford desired product (28.4 mg, 82.3%) as a pale red solid. 1HNMR (DMSO-d6) 400 MHz δ: 8.78 (br s, 3H), 8.66 (br s, 1H), 8.12 (dd, J=4.8, 1.6 Hz, 1H), 7.95 (dd, J=7.8, 1.4 Hz, 1H), 7.59-7.53 (m, 2H), 7.52-7.46 (m, 2H), 7.43-7.36 (m, 1H), 7.35-7.28 (m, 3H), 7.22-7.09 (m, 3H), 6.90 (dd, J=8.0, 1.6 Hz, 1H), 6.76 (dd, J=8.0, 4.8 Hz, 1H), 2.61-2.53 (m, 4H), 2.27-2.13 (m, 1H), 1.89-1.75 (m, 1H); LCMS: 471 [M+H].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.[CH:11]1([CH2:14][C:15](=[O:18])[CH:16]=[CH2:17])[CH2:13][CH2:12]1>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH:11]2[CH2:13][CH2:12]2)[CH3:9])=[CH:4][CH:3]=1
Reactant: C=CC(=O)CC1CC1
Reactant: C[C@H](N)c1ccc(Br)cc1
Solvent: CO
Product: C[C@H](NCCC(=O)CC1CC1)c1ccc(Br)cc1
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
(S)-1-(4-Bromophenyl)ethanamine (3.33 g) was added to a solution of 1-cyclopropylbut-3-en-2-one (3.07 g) in methanol (10 mL). The mixture was heated to 80° C. and stirred at this temperature for 10 min. After cooling to room temperature, the mixture was concentrated to give the crude title compound which was used without further purification. Yield: 5.20 g (crude).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:23][C:6]2[N:7]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[C:8]3[CH:9]=[CH:10][C:11]([C:14]#[N:15])=[CH:12][C:13]=3[C:5]=2[CH2:4]1.ClCCl.Cl[C:28]([O:30][CH:31]([CH3:33])[CH3:32])=[O:29]>N1C=CC=CC=1>[CH:31]([O:30][C:28](=[O:29])[NH:2][CH:3]1[CH2:23][C:6]2[N:7]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[C:8]3[CH:9]=[CH:10][C:11]([C:14]#[N:15])=[CH:12][C:13]=3[C:5]=2[CH2:4]1)([CH3:33])[CH3:32]
Reactant: N#Cc1ccc2c(c1)c1c(n2Cc2ccccn2)CC(N)C1
Reactant: CC(C)OC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)OC(=O)NC1Cc2c(n(Cc3ccccn3)c3ccc(C#N)cc23)C1
Temperature: 5 °C
Yield: 56.9 %

Procedure:
Add (±)-2-amino-4-pyridin-2-ylmethyl-1,2,3,4-tetrahydro-cyclopenta[b]indole-7-carbonitrile hydrochloride (35 g, 108 mmol) to a mixture of dichloromethane (350 mL) and pyridine (70 mL). Stir the mixture under nitrogen and cool to 5° C. Add isopropyl chloroformate (1M solution in toluene, 162 mL, 162 mmol). Remove the ice bath and stir the mixture at 22° C. After 16 h evaporate the solvent. Add the resulting residue to water (350 mL) and stir 2 h. Filter and dry the collected solid under vacuum at 45° C. Add the solid to ethyl acetate (400 mL) and heat the mixture to reflux. Then cool to 22° C. and filter the solid. Add the wet solid to ethyl acetate (200 mL) and heat to reflux for 30 min. Cool the mixture to 22° C. over one hour and then cool to 0-5° C. during 5 min. Filter the mixture and dry the isolated solid under vacuum to constant weight to provide 23 g (62%) of the title compound. MS (m/z): 374 (M+1).
Reaction SMILES: [OH-].[K+].[CH2:3]([C:10]1[NH:14][C:13]2[CH:15]=[CH:16][C:17]([Br:19])=[CH:18][C:12]=2[N:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:20]I>CC(C)=O.C(Cl)Cl>[CH2:3]([C:10]1[N:14]([CH3:20])[C:13]2[CH:15]=[CH:16][C:17]([Br:19])=[CH:18][C:12]=2[N:11]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Brc1ccc2[nH]c(Cc3ccccc3)nc2c1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: ClCCl
Product: Cn1c(Cc2ccccc2)nc2cc(Br)ccc21
Reaction time: 1 h
Yield: 36.8 %

Procedure:
Powdered KOH (5.25 g, 93.50 mmol) was added to a stirred solution of 2-benzyl-5-bromo-1H-benzimidazole (5.37 g, 18.70 mmol) in acetone (100 mL), after 10 min, methyl iodide (1.28 mL, 20.57 mmol) was added and the mixture was stirred for 1 h and diluted with DCM. The mixture was washed with water and brine, then dried over Na2SO4 and concentrated. The residue was taken up in DCM and hexanes and the resulting suspension filtered. The filter cake was washed with hexanes and dried on a high vacuum pump to give an off-white solid (2.07 g, 37%). LC-MS [M+H]+=302.1, RT=2.47 min
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([C:26]2([OH:32])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:14][CH2:13]2)=O)[CH:5]=[CH:6][C:7]=1[Cl:8].B>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([C:26]2([OH:32])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)[CH2:10][N:12]2[CH2:17][CH2:16][CH:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:22])[CH3:23])[CH2:14][CH2:13]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=O)C(c2ccc(Cl)c(Cl)c2)C2(O)CCCCC2)CC1
Agent: B
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCN(CC(c2ccc(Cl)c(Cl)c2)C2(O)CCCCC2)CC1
Temperature: 74 °C
Yield: 52.9 %

Procedure:
A solution of tert-butyl {1-[(3,4-dichlorophenyl)(1-hydroxycyclohexyl)acetyl]piperidin-4-yl}carbamate (364 mg, 0.75 mmol) in dry tetrahydrofuran (1 mL), under nitrogen, was treated with a solution of borane (1.0 M in tetrahydrofuran, 2.62 mL, 2.62 mmol). The reaction was heated at 74° C. for 2 h, after which time the reaction was cooled and quenched by the addition of methanol (4 mL). The solvents were removed in vacuo, and the products were purified via Biotage Horizon (FLASH 25 M, silica, gradient from 10% EtOAc/hexane to 90% EtOAc/hexane) to yield 187 mg (53%) tert-butyl {1-[2-(3,4-dichlorophenyl)-2-(1-hydroxycyclohexyl)ethyl]piperidin-4-yl}carbamate as a white foam which eluted first and 88 mg (31%) 1-{1-(3,4-dichlorophenyl)-2-[4-(methylamino)piperidin-1-yl]ethyl}cyclohexanol as a colorless oil which eluted second. tert-butyl {1-[2-(3,4-dichlorophenyl)-2-(1-hydroxycyclohexyl)ethyl]piperidin-4-yl}carbamate: MS (ES) m/z 471.3 ([M+H]+); HRMS: calcd for C24H36Cl2N2O3, 470.2103; found (ESI), 471.2165. 1-{1-(3,4-dichlorophenyl)-2-[4-(methylamino)piperidin-1-yl]ethyl}cyclohexanol: MS m/z 385/387/389 ([M+H]+). 1-{1-(3,4-dichlorophenyl)-2-[4-(methylamino)piperidin-1-yl]ethyl}cyclohexanol was converted to the dihydrochloride salt with a methanolic solution of hydrochloric acid and diethyl ether to yield 45 mg (41%) 1-[1-(3,4-dichlorophenyl)-2-[4-(methylamino)piperidin-1-yl]ethyl}cyclohexanol dihydrochloride as a white solid. HRMS: calcd for C20H30Cl2N2O.2.00 HCl, 456.1269; found (ESI), 385.183.
Reaction SMILES: [F:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][C:5]2[C:6]([CH3:9])=[N:7][S:8][C:4]=2[CH:3]=1.C(O)(=O)C>[Fe].C(OCC)(=O)C>[NH2:12][C:11]1[C:2]([F:1])=[CH:3][C:4]2[S:8][N:7]=[C:6]([CH3:9])[C:5]=2[CH:10]=1
Reactant: Cc1nsc2cc(F)c([N+](=O)[O-])cc12
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1nsc2cc(F)c(N)cc12
Temperature: 65 °C
Reaction time: 1 h
Yield: 95.6 %

Procedure:
A solution of 6-fluoro-3-methyl-5-nitro-1,2-benzisothiazole (0.740 g, 3.50 mmol), 5% acetic acid (25.0 mL) and ethyl acetate is heated to 65° C., treated with iron powder (0.980 g, 17.5 mmol), stirred at 65° C. for one hour, cooled to room temperature, and filtered to remove solids. The organic phase is separated, washed sequentially with water, saturated sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the title product as an orange solid (0.610 g) which is identified by NMR spectral analyses.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1C1C=NN(C)C=1)=[O:11].[F:25][C:26]1[CH:27]=[CH:28][C:29](C2C=CC(C)=CC=2C(O)=O)=[N:30][CH:31]=1>>[NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:29]1[CH:28]=[CH:27][C:26]([F:25])=[CH:31][N:30]=1)=[O:11]
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: Cc1ccc(-c2ccc(F)cn2)c(C(=O)O)c1
Product: Cc1ccc(-c2ccc(F)cn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1

Procedure:
The title compound was prepared following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1 using 2-(5-fluoropyridin-2-yl)-5-methylbenzoic acid. MS (ESI) 342 (M+H).
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[C:10]=2[CH:9]=[CH:8]1)C>C1COCC1.O>[F:27][C:24]([F:25])([F:26])[O:23][C:20]1[CH:19]=[CH:18][C:17]([NH:16][C:15]2[C:10]3[CH:9]=[CH:8][N:7]([CH2:6][CH2:5][C:4]([OH:28])=[O:3])[C:11]=3[N:12]=[CH:13][N:14]=2)=[CH:22][CH:21]=1
Reactant: CCOC(=O)CCn1ccc2c(Nc3ccc(OC(F)(F)F)cc3)ncnc21
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCn1ccc2c(Nc3ccc(OC(F)(F)F)cc3)ncnc21
Temperature: 80 °C
Reaction time: 2 h
Yield: 76.2 %

Procedure:
To a solution of 3-[4-(4-Trifluoromethoxy-phenylamino)-pyrrolo[2,3-d]pyrimidin-7-yl]-propionic acid ethyl ester (100 mg, 0.24 mmol) in 5 mL of THF:H2O (3:1)) was added CsCO3 (78 mg, 0.40 mmol). The mixture was heated at 80° C. and stirred for 2 h. The reaction mixture was concentrated and neutralized with acetic acid. The solid was filtered and dried to yield the tile compound as brown solid (67 mg, 77%). MS m/z 367.1 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH:12]=[C:11](Br)[C:10]3[CH:20]=[CH:21][CH:22]=[CH:23][C:9]2=3)[CH2:4][CH2:3]1.CCOCC.[CH3:29][C:30]1[O:31][CH:32]=[CH:33][CH:34]=1.CC(C)([O-])C.[K+]>O>[CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]3[CH:32]4[O:31][C:30]([CH3:29])([C:11]=3[C:10]3[CH:20]=[CH:21][CH:22]=[CH:23][C:9]2=3)[CH:34]=[CH:33]4)[CH2:4][CH2:3]1
Reactant: CN1CCC(=C2c3ccccc3C=C(Br)c3ccccc32)CC1
Reactant: Cc1ccco1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: CN1CCC(=C2c3ccccc3C3=C(c4ccccc42)C2(C)C=CC3O2)CC1

Procedure:
To a solution of 10.0 g. (0.0273 mole) of 1-methyl-4-(10-bromo-5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine in 50 ml. of dry ether is added 25 ml. of 2-methylfuran and 3.4 g. of potassium t-butoxide. The mixture is stirred and refluxed for 10 days. After the addition of water (1.0 1.), the mixture is extracted with an ether-benzene mixture (4:1). This organic phase is removed, washed with water, dried over magnesium sulfate, filtered, and the solvent is removed on a rotary evaporator. The residue that remains crystallizes readily to give 4.0 g. of product. The material is recrystallized from acetonitrile to give pure 1-methyl-4-(1-methyl-1,4-dihydro-1,4-epoxy-9H-tribenzo[a,c,e]cyclohepten-9-ylidene)piperidine, m.p. 175°-177°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]4([C:28]([O:30][CH3:31])=[O:29])[CH2:27][CH2:26][CH2:25]4)[CH2:14][C:13](=O)[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:43]>C1COCC1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]4([C:28]([O:30][CH3:31])=[O:29])[CH2:27][CH2:26][CH2:25]4)[CH2:14][C:13](=[S:43])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: COC(=O)C1(Oc2ccc(Cl)cc2C2CC(=O)NC(c3cc(F)ccc3C)C23C(=O)Nc2cc(Cl)ccc23)CCC1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)C1(Oc2ccc(Cl)cc2C2CC(=S)NC(c3cc(F)ccc3C)C23C(=O)Nc2cc(Cl)ccc23)CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.1 %

Procedure:
A mixture of racemic (2′S, 3S, 4′R)-6-chloro-4′-[5-chloro-2-(1-methoxycarbonyl-cyclobutoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (30 mg, 0.05 mmol) and P2S5 (44 mg, 0.2 mmol) in THF (1 mL) was stirred at room temperature overnight, and then diluted with toluene (10 mL). The mixture was concentrated in vacuo and the residue was washed with DCM twice. The DCM solution was collected and purified by flash chromatography to give the title compound as white solid (12 mg).
Reaction SMILES: N12CCCN=C1CCCCC2.CO[C:14](=[O:30])[C:15]1[C:16](=[C:21]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[CH:22]=[CH:23][CH:24]=1)[C:17]([O:19]C)=O.Cl.[NH2:32][CH:33]1[CH2:39][CH2:38][C:37](=[O:40])[NH:36][C:34]1=[O:35]>CN(C=O)C>[O:35]=[C:34]1[CH:33]([N:32]2[C:17](=[O:19])[C:16]3[C:15](=[CH:24][CH:23]=[CH:22][C:21]=3[CH2:25][NH:26][C:27](=[O:29])[CH3:28])[C:14]2=[O:30])[CH2:39][CH2:38][C:37](=[O:40])[NH:36]1
Reactant: COC(=O)c1cccc(CNC(C)=O)c1C(=O)OC
Reactant: NC1CCC(=O)NC1=O
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Temperature: 120 °C
Yield: 22.8 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.93 g, 6 mmol) was added dropwise to a stirred suspension of 3-(acetylamino-methyl)-phthalic acid dimethyl ester (1.61 g, 6.0 mmol) and aminoglutarimide hydrochloride (1.0 g, 6.0 mmol) in DMF (15 ml). The mixture was then heated to 120° C. for 24 hours. The cooled mixture was concentrated in vacuo and the residue was stirred with water (25 ml) and dichloromethane (20 ml). The resulting slurry was filtered to give 0.45 g (22%) of the product as a gray solid. Recrystallization from methanol gave a white solid: mp 177-179° C.; 1H NMR (DMSO-d6) 6 (11.02 (s, 1H), 8.36 (t, J=5.8 Hz, 1H), 7.74-7.55 (m, 3H), 5.05-4.98 (dd, J=5.3 and 12.5 Hz, 1H), 4.57 9D, j=5.9 Hz, 2H), 2.84-2.70 (m, 1H), 2.51-2.34 (m, 2H), 1.95-1.91 (m, 1H), 1.79 (s, 3H); 13C NMR (DMSO-d6) 6 (172.85, 169.89, 169.81, 167.56, 167.05, 139.37, 134.83, 133.35, 131.58, 127.14, 121.94, 48.91, 37.84, 30.98, 22.54, 22.05; Anal. Calcd. For C16H15N3O5+0.96 water: C, 55.45; H, 4.92; N, 12.12. Found: C, 55.27; H, 4.82; N, 12.00.
Reaction SMILES: [OH:1][C:2]1[C:7]2=[N:8][C:9]3[CH2:15][CH2:14][CH2:13][C:10]=3[C:11](=[O:12])[N:6]2[CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CC(CC)=O>[C:22]1([CH2:21][O:1][C:2]2[C:7]3=[N:8][C:9]4[CH2:15][CH2:14][CH2:13][C:10]=4[C:11](=[O:12])[N:6]3[CH:5]=[CH:4][CH:3]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=c1c2c(nc3c(O)cccn13)CCC2
Reactant: BrCc1ccccc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCC(C)=O
Product: O=c1c2c(nc3c(OCc4ccccc4)cccn13)CCC2
Reaction time: 18 h

Procedure:
A suspension of 2,3-dihydro-5-hydroxycyclopenta[d]pyrido[1,2-a]pyrimidin-10(1H)-one prepared as described in Example 1, (6.1 g), 9.9 g of anhydrous potassium bicarbonate, 6.2 g of benzyl bromide, and 300 ml of ethyl methyl ketone is stirred and slowly heated to reflux. Stirring and heating under reflux is continued for 18 hours. The hot solution is filtered to remove inorganic salts and the ethyl methyl ketone filtrate is concentrated in vacuo to give 10.0 g of crude product; this, when recrystallized from 1000 ml of cyclohexane, and the crystalline solid dried at 78° for 2 hours, gives 6.0 g of product, mp 150°-152°.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([CH2:10][N:11]3[C:19]4[C:14](=[C:15]([NH:20][C:21]([C:23]5[N:27]6[CH:28]=[CH:29][C:30](F)=[CH:31][C:26]6=[N:25][CH:24]=5)=[O:22])[CH:16]=[CH:17][CH:18]=4)[C:13]([CH3:33])=[N:12]3)[CH:7]=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.[CH3:34][C@@H:35]1[N:40]([CH3:41])[CH2:39][CH2:38][N:37]([CH2:42][CH2:43][OH:44])[CH2:36]1.CC(C)([O-])C.[K+]>C(O)(C)(C)C.O>[CH:1]1([C:4]2[N:9]=[C:8]([CH2:10][N:11]3[C:19]4[C:14](=[C:15]([NH:20][C:21]([C:23]5[N:27]6[CH:28]=[CH:29][C:30]([O:44][CH2:43][CH2:42][N:37]7[CH2:38][CH2:39][N:40]([CH3:41])[C@@H:35]([CH3:34])[CH2:36]7)=[CH:31][C:26]6=[N:25][CH:24]=5)=[O:22])[CH:16]=[CH:17][CH:18]=4)[C:13]([CH3:33])=[N:12]3)[CH:7]=[CH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: C[C@H]1CN(CCO)CCN1C
Reactant: Cc1nn(Cc2cccc(C3CC3)n2)c2cccc(NC(=O)c3cnc4cc(F)ccn34)c12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: Cc1nn(Cc2cccc(C3CC3)n2)c2cccc(NC(=O)c3cnc4cc(OCCN5CCN(C)[C@@H](C)C5)ccn34)c12
Temperature: 95 °C
Yield: 31 %

Procedure:
N-(1-((6-cyclopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-fluoroimidazo[1,2-a]pyridine-3-carboxamide (Example 16, Step G; 0.250 g, 0.568 mmol), (S)-2-(3,4-dimethylpiperazin-1-yl)ethanol (0.449 g, 2.84 mmol), and potassium t-butoxide (0.382 g, 3.41 mmol) were combined in t-butanol in a pressure tube. The tube was sealed and warmed to 95° C. for 16 hours, then allowed to cool to ambient temperature. The mixture was diluted with water and extracted with EtOAc. The combined organic extracts were washed with 10% aqueous potassium carbonate, dried over sodium sulfate and concentrated under reduced pressure. Column chromatography (10% MeOH/DCM/0.5% NH4OH) of the crude material followed by trituration with ether gave 102 mg (31%) of the title compound. MS (APCI), positive scan, m/z=579.1 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:20])([C:16]([F:19])([F:18])[F:17])[C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])[CH:5]=[C:4]([Cl:21])[C:3]=1[NH2:22].[F:23][C:24]1[C:32]([N+:33]([O-:35])=[O:34])=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](O)=[O:27].C(N(CC)CC)C.O=C1N([ClH]P([ClH]N2CCOC2=O)=O)CCO1>ClCCl>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:20])([C:16]([F:17])([F:18])[F:19])[C:9]([F:14])([F:15])[C:10]([F:11])([F:13])[F:12])[CH:5]=[C:4]([Cl:21])[C:3]=1[NH:22][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][CH:31]=[C:32]([N+:33]([O-:35])=[O:34])[C:24]=1[F:23]
Reactant: Nc1c(Cl)cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc1Br
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1c(Cl)cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc1Br)c1cccc([N+](=O)[O-])c1F
Temperature: 25 °C
Yield: 43.1 %

Procedure:
To a solution of 2-bromo-6-chloro-4-(1,2,2,3,3,3-hexafluoro-1-trifluoromethyl-propyl)phenylamine (Example I 8.1) (20 g, 47.1 mmol) and 2-fluoro-3-nitrobenzoic acid (17.4 g, 94.2 mmol) in dichloromethane (230 ml) was added triethylamine (19.7 ml, 141 mmol) and bis(2-oxo-3-oxazolidinyl)phosphonic chloride (“BOP-Cl”) (23.98 g, 94 mmol). The reaction mixture was heated to reflux for 6 hours. The reaction mixture was cooled to ambient temperature and quenched by the addition of aqueous hydrochloric acid (1N). The mixture was then extracted three times with dichloromethane. The combined organic extracts were washed with saturated aqueous sodium hydrogen carbonate, dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate 7:3) to give N-[2-bromo-6-chloro-4-(1,2,2,3,3,3-hexafluoro-1-trifluoromethylpropyl)phenyl]-2-fluoro-3-nitrobenzamide (12 g, 43% yield).