Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[Cl-].[Mg+2].[Cl-].N1C=CC=CC=1.ClC1[CH:28]=[CH:27][C:23]([C:24](Cl)=O)=[CH:22][CH:21]=1.Cl>ClCCl>[CH3:24][C:23]1[CH:27]=[CH:28][C:5]([C:3]([CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6])=[O:4])=[CH:21][CH:22]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)CC(=O)c1ccc(C)cc1
Reaction time: 0.25 h
Yield: 53.5 %

Procedure:
Ethyl acetoacetate (51.25 g, 390 mmol) was added dropwise to the stirred suspension of anhydrous magnesium chloride (37.54 g, 390 mmol) in dried dichloromethane (200 ml) over a period of 1 hour under argon atmosphere at 0° C. followed by pyridine (62.5 g, 788 mmol). After 15 minutes, 4-chlorobenzoylchloride (68.95 g, 394 mmol) was added dropwise and stirring was continued for 15 minutes at 0° C. and further stirred for 1.5 hours at 30° C. The resulting reaction mixture was neutralized with hydrochloric acid (6N, 235 ml) at 0-5° C., filtered and washed with water. The filtrate was extracted with diethylether (3×100 ml). The ether extract was washed with water, dried over anhydrous sodium sulphate and concentrated to dryness in vacuum. The obtained oil was taken in ammonium chloride (21 g in 200 ml water) solution containing ammonia (2 ml) and stirred at 30° C. for 20 minutes. The resulting solution was extracted with ethyl acetate (3×200 ml). Ethyl acetate extract was dried over anhydrous sodium sulphate, concentrated to yield the crude product, which was purified by column chromatography to yield the title compound as viscous oil (43 g, 48.2%). 1H-NMR (DMSO-d6): δ 1.15-1.18 (t, 3H), 4.08-4.13 (q, 2H), 4.20 (s, 2H), 7.61-7.64 (d, 2H), 7.94-7.97 (d, 2H). MS m/z: 227.1 (M+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:43])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2([NH:16][C:17]3[N:22]=[C:21]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])[N:20]=[C:19]([NH:29][C:30]4[CH:42]=[CH:41][C:33]([C:34]([O:36]C(C)(C)C)=[O:35])=[CH:32][CH:31]=4)[N:18]=3)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)[CH3:2].Cl.O1CCOCC1>>[CH2:1]([O:3][C:4](=[O:43])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2([NH:16][C:17]3[N:22]=[C:21]([O:23][CH2:24][C:25]([F:28])([F:26])[F:27])[N:20]=[C:19]([NH:29][C:30]4[CH:42]=[CH:41][C:33]([C:34]([OH:36])=[O:35])=[CH:32][CH:31]=4)[N:18]=3)[CH2:14][CH2:15]2)=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)COc1ccc(C2(Nc3nc(Nc4ccc(C(=O)OC(C)(C)C)cc4)nc(OCC(F)(F)F)n3)CC2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)COc1ccc(C2(Nc3nc(Nc4ccc(C(=O)O)cc4)nc(OCC(F)(F)F)n3)CC2)cc1
Yield: 103.9 %

Procedure:
tert-butyl 4-(4-(1-(4-(2-ethoxy-2-oxoethoxy)phenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (350 mg, 0.580 mmol) and 4 N HCl in Dioxane (2 mL, 8.00 mmol) were stirred for 1 h then concentrated under vacuum to give 4-(4-(1-(4-(2-ethoxy-2-oxoethoxy)phenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid (330 mg) which was used in the next step without purification. LC-MS (Condition A), MS m/z (M++H) 548.0.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:25][C:26]([CH3:35])([CH3:34])[CH2:27][CH:28]1[CH2:31][CH:30]([CH:32]=O)[CH2:29]1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl.C1(C)C=CC=CC=1>[Br:2][C:1]([Br:5])=[CH:32][CH:30]1[CH2:31][CH:28]([CH2:27][C:26]([CH3:35])([CH3:34])[CH3:25])[CH2:29]1
Reactant: CC(C)(C)CC1CC(C=O)C1
Reactant: BrC(Br)(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)(C)CC1CC(C=C(Br)Br)C1
Reaction time: 0.75 h

Procedure:
To a solution of carbon tetrabromide (205 g) in methylene chloride (600 mL) was added a solution of triphenylphosphine (325 g) in methylene chloride (350 mL) dropwise at ice temperature. After the mixture was stirred at ice temperature for 45 min, a solution of 3-(2,2-dimethylpropyl)cyclobutanecarbaldehyde in toluene was added to the reaction at ice temperature. The mixture was stirred at ice temperature for 1 hr and aqueous 10 w/v % sodium carbonate (660 mL) was added to the mixture dropwise at the same temperature. The resultant precipitate was filtered off and the filtrate was extracted with chloroform. The organic layer was washed with water and brine, then dried over sodium sulfate. After an addition of silica gel to the mixture, the mixture was stirred at RT. The sodium sulfate and silica gel were filtered off and the filtrate was concentrated in vacuo. The resultant residue was purified by silica gel column chromatography (Eluent: hexane) to give the title compound (120.33 g).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[S:3]([NH:6][S:7]([C:10]1[CH:15]=[C:14]([Br:16])[CH:13]=[CH:12][C:11]=1Br)(=[O:9])=[O:8])(=[O:5])=[O:4].[Na].CN(C=O)C.[Na][Na]>CO.[Cu]>[F:1][C:2]([F:19])([F:18])[S:3]([NH:6][S:7]([C:10]1[C:11]([C:11]2[C:10]([S:7]([NH:6][S:3]([C:2]([F:1])([F:18])[F:19])(=[O:4])=[O:5])(=[O:9])=[O:8])=[CH:15][C:14]([Br:16])=[CH:13][CH:12]=2)=[CH:12][CH:13]=[C:14]([Br:16])[CH:15]=1)(=[O:9])=[O:8])(=[O:5])=[O:4]
Reactant: O=S(=O)(NS(=O)(=O)C(F)(F)F)c1cc(Br)ccc1Br
Agent: [Cu]
Agent: [Na]
Agent: [Na][Na]
Solvent: CN(C)C=O
Solvent: CO
Product: O=S(=O)(NS(=O)(=O)C(F)(F)F)c1cc(Br)ccc1-c1ccc(Br)cc1S(=O)(=O)NS(=O)(=O)C(F)(F)F
Temperature: 120 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
Inside a glove box, a 250 mL round-bottom flask equipped with a stirring bar, reflux condenser, and a septum was charged with N-trifluoromethanesulfonyl-2,5-dibromo-benzene-sulfonamide, sodium salt (19.45 g, 50 mmoles), activated copper powder (40 g), and DMF (80 mL). The flask was heated to 120° C. under nitrogen and stirred overnight. The solution was cooled to room temperature, filtered, and the solids washed with DMF. The solvent was evaporated by distilling under high vacuum and the resulting solids were dried under vacuum. The dark solids were dissolved in water by heating to a reflux and adding hydrochloric acid to give pH of 1. Residual dark solids were filtered off then the solution was neutralized using aqueous sodium hydroxide, which gave a yellow-brown precipitate that was removed by filtration. The mixture was saturated with sodium chloride and concentrated at reflux to 400 mL. Upon cooling, magenta solids precipitated from solution. The solids were collected by vacuum filtration and dried under vacuum to give 13.2 g (68% crude yield). The solids were dissolved in methanol at a reflux, treated with decolorizing carbon, filtered, evaporated, and dried in a vacuum oven at 150° C. under nitrogen purge. The solids were recrystallized from dioxane (50 mL) inside the glove box after filtering off residual solids. The crystals were collected and washed with dioxane to remove much of the remaining magenta color. The recrystallization was repeated inside the glove box to give colorless crystals, which were dried in a vacuum oven at 150° C. under nitrogen purge and transferred to a glove box for storage and handling to give 10.78 g (55% yield) of N,N′-bis(trifluoromethanesulfonyl)-4,4′-dibromo-biphenyl-2,2′-disulfonamide, disodium salt. 19F NMR (DMSO-d6): −78.31 (s).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2.[CH2:13]([O:20][C:21]1[C:29]([Cl:30])=[CH:28][C:24]([C:25](O)=[O:26])=[C:23]([O:31][CH3:32])[CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:12][N:6]1[CH2:5][CH2:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][C:25](=[O:26])[C:24]2[CH:28]=[C:29]([Cl:30])[C:21]([O:20][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:22][C:23]=2[O:31][CH3:32])[CH2:7]1
Reactant: COc1cc(OCc2ccccc2)c(Cl)cc1C(=O)O
Reactant: CN1CCc2c(N)cccc2C1
Product: COc1cc(OCc2ccccc2)c(Cl)cc1C(=O)Nc1cccc2c1CCN(C)C2

Procedure:
The title compound was prepared in an analogous manner to Example 1 from 5-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline and 4-benzyloxy-5-chloro-2-methoxybenzoic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([OH:16])=O)[C:9]2=[O:17])=[CH:4][CH:3]=1.Br.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[CH2:26][NH:25][CH2:24]2.C(N=C=NCCCN(C)C)C>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][CH2:11][N:10]([CH2:13][C:14](=[O:16])[N:25]3[CH2:24][C:23]4[C:27](=[CH:28][CH:29]=[C:21]([C:20]([F:19])([F:31])[F:30])[CH:22]=4)[CH2:26]3)[C:9]2=[O:17])=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1ccc2c(c1)CNC2
Reactant: O=C(O)CN1CCC(c2ccc(F)cc2)C1=O
Agent: Br
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccc(F)cc2)C1=O)N1Cc2ccc(C(F)(F)F)cc2C1
Temperature: 25 °C

Procedure:
To a suspension of 2-(3-(4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid (0.102 g, 0.430 mmol; Example 216A) and 5-(trifluoromethyl)isoindoline hydrobromide (0.127 g, 0.473 mmol) in dichloromethane (0.75 mL) was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (0.114 mL, 0.645 mmol) and the reaction was stirred at room temperature. After stirring for 18 hours, the reaction was loaded onto a GraceResolv™ 4 g silica gel column (Grace Davison Discovery Sciences) and the product eluted with a gradient of 5% ethyl acetate/hexanes to 100% ethyl acetate/hexanes (Flow=20 mL/minute) over 30 minutes to give the title compound. 1H NMR (300 MHz, CDCl3) δ 7.58 (dd, J=8.5, 12.6, 2H), 7.42 (dd, J=8.1, 15.3, 1H), 7.36-7.21 (m, 2H), 7.12-6.93 (m, 2H), 4.91 (d, J=17.7, 4H), 4.29 (d, J=16.1, 1H), 4.17 (d, J=16.2, 1H), 3.85-3.54 (m, 3H), 2.72-2.50 (m, 1H), 2.19 (ddd, J=8.5, 12.9, 16.3, 1H); MS (ESI+) m/z 407.0 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH2:13][NH2:14])[CH2:7][CH2:6]1.[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[BH4-].[Na+].O>C(O)C>[CH2:15]([NH:14][CH2:13][CH2:12][CH2:11][N:8]1[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][CH2:2][NH:1][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCCCN1CCN(CCCN)CC1
Reactant: O=Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: c1ccc(CNCCCN2CCN(CCCNCc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 1,4-bis(3-aminopropyl)piperazine (0.513 mL, 2.49 mmol) and benzaldehyde (0.532 mL, 5.24 mmol) in absolute ethanol (20 mL) was added 3 Å molecular sieves (5 g). After stirring the mixture for 12 h at room temperature, sodium borohydride (1.9 g, 49.9 mmol) was added and the mixture was stirred for 12 h at room temperature. Then the reaction mixture was quentched by dropwise addition of water (20 mL) and ethanol was removed under reduced pressure. The aqueous residue was extracted with CH2Cl2 (3×30 mL) and the combined organic layers were extracted with HCl 1N (2×50 mL). The combined aqueous layers were neutralized with NaOH 1N (50 mL) and extracted with CH2Cl2 (3×30 mL). The combined organic layers were dried over MgSO4, evaporated to dryness and the oily residue purified by flash chromatography (neutral aluminium oxide, CH2Cl2/MeOH: 90/10).
Reaction SMILES: C[O:2][C:3](=[O:20])/[C:4](/[C:10]1[N:11]=[C:12]([NH:15][C:16](=[O:19])[CH2:17][Cl:18])[S:13][CH:14]=1)=[N:5]\[O:6][CH2:7][CH2:8][CH3:9].[OH-].[K+]>C(O)C.O>[Cl:18][CH2:17][C:16]([NH:15][C:12]1[S:13][CH:14]=[C:10](/[C:4](=[N:5]/[O:6][CH2:7][CH2:8][CH3:9])/[C:3]([OH:20])=[O:2])[N:11]=1)=[O:19]
Reactant: CCCO/N=C(\C(=O)OC)c1csc(NC(=O)CCl)n1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCO/N=C(\C(=O)O)c1csc(NC(=O)CCl)n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 3.2 g of 2-(2-chloroacetamido-4-thiazolyl)-(Z)-2-(n-propoxyimino)acetic acid methyl ester in 50 ml of ethanol is added under ice-cooling and stirring a solution of 2.23 g of potassium hydroxide (85%) in 20 ml of water, and the mixture is stirred for 5 hours at room temperature, followed by concentration under reduced pressure. The concentrate is dissolved in 30 ml of water, and washed twice with 30 ml each portion of ethyl acetate, followed by addition of activated charcoal. The charcoal is removed by filtration and the filtrate is then adjusted to pH 2 with 1N-HCl, and the resulting crystals are collected by filtration, washed with water, hexane and ether in this order to yield 2-(2-chloroacetamido-4-thiazolyl)-(Z)-2-(n-propoxyimino)acetic acid, m.p. 170°-171° C. (decomp.).
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[Br:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[C:14](Cl)[N:13]([CH2:18][CH3:19])[C:12]2=[O:20].C(Cl)Cl>O>[Br:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[C:14]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])[N:13]([CH2:18][CH3:19])[C:12]2=[O:20]
Reactant: CC(C)(C)N
Reactant: CCn1c(Cl)nc2c(Br)cccc2c1=O
Solvent: ClCCl
Solvent: O
Product: CCn1c(NC(C)(C)C)nc2c(Br)cccc2c1=O
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of tert-butylamine (1.1 mL, 10.43 mmol) and 8-bromo-2-chloro-3-ethylquinazolin-4(3H)-one (100 mg, 0.348 mmol, 481c) was sealed and set stirring for 3 h at 80° C. The reaction was cooled to RT, diluted with water, and extracted with DCM. The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure giving a pale yellow solid. The material was taken up DCM, adsorbed onto silica, and purified on 4 g SiO2 (eluent: 0-100% EtOAc/hexanes over 20 min, RediSep Gold). The product containing fractions were combined and concentrated under reduced pressure to a colorless residue (52 mg, 46%). m/z (ESI, +ve) 323.9 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]([NH2:17])=[O:16])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[N:14]=1.CC(C)([O-])C.[K+].Br[CH2:25][CH2:26][N:27]1[CH:31]=[CH:30][CH:29]=[CH:28]1.[I-].[K+]>CN(C=O)C>[NH2:1][C:2]1[C:3]([C:15]([NH2:17])=[O:16])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:25][CH2:26][N:27]3[CH:31]=[CH:30][CH:29]=[CH:28]3)[C:6]=2[N:14]=1
Reactant: NC(=O)c1cc2c(nc1N)[nH]c1ccccc12
Reactant: BrCCn1cccc1
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1cc2c3ccccc3n(CCn3cccc3)c2nc1N
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-amino-9H-pyrido[2,3-b]indole-3-carboxamide (5, 70 mg, 0.310 mmol) in DMF (2 mL) was added potassium tert-butoxide (84 mg, 0.749 mmol). The reaction mixture was stirred at room temperature for 10 min, then 1-(2-bromoethyl)-1H-pyrrole (162 mg, 0.930 mmol) and potassium iodide (164 mg, 0.930 mmol) were added and the mixture was stirred at room temperature overnight. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (150 mL). The layers were separated and the organic layer was washed with brine (100 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (0-3% methanol in methylene chloride gradient) to yield material which was subsequently triturated with ether to give pure 2-amino-9-[2-(1H-pyrrol-1-yl)ethyl]-9H-pyrido[2,3-b]indole-3-carboxamide as a white powder (20, 25 mg, 25%). NH4OAc standard conditions. DAD Retention time=6.79 min. M+H=320. 1H NMR (300 MHz, DMSO-d6): 8.71 (s, 1H), 7.97-7.89 (m, 1H), 7.79-7.69 (m, 1H), 7.67-7.50 (m, 2H), 7.24-7.04 (m, 4H), 6.62-6.59 (m, 2H), 5.88-5.82 (m, 2H), 4.57-4.47 (m, 2H), 4.34-4.24 (m, 2H).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][S:17][C:16]3=[O:21])[C:5]=12.[CH:22](=O)[CH2:23][CH2:24][CH3:25].N1CCCCC1>C(O)C>[CH:22](=[C:18]1[S:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][O:10][C:6]2[C:5]3[N:4]([CH:3]=[CH:2][N:1]=3)[CH:9]=[CH:8][CH:7]=2)[C:19]1=[O:20])[CH2:23][CH2:24][CH3:25]
Reactant: O=C1CSC(=O)N1CCCCOc1cccn2ccnc12
Reactant: CCCC=O
Solvent: CCO
Solvent: C1CCNCC1
Product: CCCC=C1SC(=O)N(CCCCOc2cccn3ccnc23)C1=O

Procedure:
To a solution of 1.22 g (4.0 mmol) of 3-[4-(imidazo-[1,2-a]pyridin-8-yloxy)butyl]thiazolidine-2,4-dione and 0.36 ml (4.0 mmol) of n-butyraldehyde in 20 ml of ethanol, 0.04 ml (0.4 mmol) of piperidine was added, followed by refluxing for 2 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=1/4) to yield 1.44 g (quant, yellow oily substance) of the desired product.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22]CC1C=CC=CC=1.C(O)(=O)C>[Pd].C(O)C>[F:1][C:2]([F:30])([F:31])[CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][OH:22]
Reactant: FC(F)(F)COCCOCCOCCOCCOCCOCCOCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: OCCOCCOCCOCCOCCOCCOCC(F)(F)F
Yield: 85.8 %

Procedure:
A stirred solution of the product of step (c) (16 g) and 10% palladium on carbon (1 g) in 1:1 acetic acid:ethanol (150 ml) was placed under an atmosphere of hydrogen at 20° C. for 24 hours. The reaction mixture was filtered through a pad of celite and the solvent removed in vacuo to give the title compound (11 g).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]2([CH2:15][CH2:14][CH2:13][CH2:12]2)[S:8][CH:7]1[CH3:16].[ClH:17].[S:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[C:20]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[N:19]1.C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>C(#N)C>[ClH:17].[S:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[C:20]([N:27]2[CH2:28][CH2:29][N:30]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:10](=[O:11])[C:9]4([CH2:15][CH2:14][CH2:13][CH2:12]4)[S:8][CH:7]3[CH3:16])[CH2:31][CH2:32]2)=[N:19]1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Reactant: CC1SC2(CCCC2)C(=O)N1CCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Product: CC1SC2(CCCC2)C(=O)N1CCCCN1CCN(c2nsc3ccccc23)CC1
Yield: 47.4 %

Procedure:
A mixture of 3-(4-bromobutyl)-2-methyl-1-thia-3-azaspiro[4.4]nonan-4-one (3.84 g), 1-(1,2-benzisothiazol-3-yl)piperazine hydrochloride (3.49 g), K2CO3 (5.90 g) and NaI (280 mg) in acetonitrile (215 ml) was heated at between 65°-80° C. for 16.5 hours and the product was processed in substantially the same manner as in Example 10 to afford 2.86 g of crystals, m.p. 210°-215° C.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[CH:3]([C:17]1[CH:21]=[CH:20][S:19][CH:18]=1)[C:4]([NH:6][C:7]1[CH:16]=[CH:15][C:10]([C:11](OC)=[O:12])=[CH:9][CH:8]=1)=[O:5].C([NH2:25])=O.C[O-].[Na+]>CN(C=O)C>[CH3:1][N:2]([CH3:22])[CH:3]([C:17]1[CH:21]=[CH:20][S:19][CH:18]=1)[C:4]([NH:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([NH2:25])=[O:12])=[CH:9][CH:8]=1)=[O:5]
Reactant: COC(=O)c1ccc(NC(=O)C(c2ccsc2)N(C)C)cc1
Reactant: NC=O
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)C(C(=O)Nc1ccc(C(N)=O)cc1)c1ccsc1
Temperature: 100 °C

Procedure:
Methyl 4-(2-(dimethylamino)-2-(thiophen-3-yl)acetamido)benzoate (E114) and formamide dissolved in DMF under Ar were heated to 100° C. The NaOMe was then added and the reaction heated for 2 hours. The reaction was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The extracts were dried (MgSO4), filtered and evaporated. Column chromatography (SiO2, 0-100% EtOAc/Hex) gave pure 4-(2-(dimethylamino)-2-(thiophen-3-yl)acetamido)benzamide (E115).
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][CH2:10][P:11](=[O:28])([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CCO>[OH:7][CH2:8][CH2:9][CH2:10][P:11](=[O:28])([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=P(CCCOC1CCCCO1)(OCc1ccccc1)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: O=P(CCCO)(OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C

Procedure:
A solution of dibenzyl [3-(tetrahydro-2H-pyran-2-yloxy)propyl]phosphonate (3.08 g, 7.62 mmol) and pyridiniurn p-toluenesulfonate (0.191 g, 0.762 mmol) in EtOH (76 mL) was stirred at 55° C. overnight. The reaction mixture was cooled to room temperature and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Biotage Horizon, 40M, Si, ˜30 mL/min, 100% hexanes for 360 mL, gradient to 100% EtOAc in hexanes over 3096 mL, 100% EtOAc for 3888 mL) to afford dibenzyl (3-hydroxypropyl)phosphonate. Rf=0.34 (EtOAc). LCMS calc.=321.13; found=321.04 (M+H)+. 1H NMR (500 MHz, CHCl3): δ 7.35-7.28 (m, 10 H); 5.02 (dd, J=11.9, 8.9 Hz, 2 H); 4.94 (dd, J=11.9, 8.0 Hz, 2 H); 3.60 (t, J=5.6 Hz, 2 H); 3.37 (s, 1 H); 1.90-1.75 (m, 4 H).
Reaction SMILES: NC1C2C[C:9](C)(C)[O:10]C=2C(C(OC)=O)=CC=1.N[C:18]1[C:23]2[CH2:24][C:25]([CH3:28])([CH3:27])[O:26][C:22]=2[C:21]([C:29]([OH:31])=[O:30])=[CH:20][C:19]=1[Cl:32]>>[Cl:32][C:19]1[CH:20]=[C:21]([C:29]([OH:31])=[O:30])[C:22]2[O:26][C:25]([CH3:28])([CH3:27])[CH2:24][C:23]=2[C:18]=1[O:10][CH3:9]
Reactant: COC(=O)c1ccc(N)c2c1OC(C)(C)C2
Reactant: CC1(C)Cc2c(N)c(Cl)cc(C(=O)O)c2O1
Product: COc1c(Cl)cc(C(=O)O)c2c1CC(C)(C)O2

Procedure:
Following the same procedure, 19.9 g of methyl 4-amino-2,2-dimethyl-2,3-dihydro-7-benzofurancarboxylate was transformed into 20.1 g of 4-amino-5-chloro-2,2-dimethyl-2,3-dihydro-7-benzofurancarboxylic acid, m.p. 176°-178° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:33])[NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(=O)([O-])[O-].[K+].[K+].O>C(Cl)Cl>[F:32][C:29]([F:30])([F:31])[C:26]1[CH:25]=[CH:24][C:23]([O:22][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[NH:15][C:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:33])=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccccc2Oc2ccc(C(F)(F)F)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccccc1Oc1ccc(C(F)(F)F)cc1)C1CCNCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-[2-(4-Trifluoromethyl-phenoxy)-phenylcarbamoyl]-piperidine-1-carboxylic acid tert-butyl ester (HVB01043, 0.2 g, 0.43 mmol) was dissolved in anhydrous DCM (5 ml), cooled to 0° C. and to this was added TFA (2.3 ml), and the reaction mixture was stirred under nitrogen for 1 h. The reaction mixture was poured onto solid potassium carbonate (6 g), and water (25 ml) added. Extracted with DCM and the organic layers dried over anhydrous magnesium sulphate, and evaporated in-vacuo, to afford an off white oil, 0.14 g, 89%. Rf: 0.47 (DCM), 1HNMR: (CDCl3, 270 MHz) δ 1.65 (2H, m, CHCH2), 1.79 (2H, m, CHCH2), 2.30 (1H, m, CH), 2.64 (2H, td, J=12.4, 2.7 Hz, NCH2), 3.10 (2H, m, NCH2), 6.97 (1H, dd, J=6.4, 30.5 Hz, Ar HD), 7.05 (2H, m, Ar HF), 7.06 (1H, m, Ar HB), 7.17 (1 h, t, J=7.2 Hz, Ar HC), 7.58, d, J=8.6 Hz, Ar HE), 8.39 (1H, d, J=7.9 Hz, Ar HA).