Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH:13](C([O-])=O)[C:14]([O:16]CC)=[O:15])[CH2:3][CH:4]([CH3:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].C(O)(=O)C.S(=O)(=O)(O)O>O>[CH3:1][CH:2]([CH2:3][CH:4]([CH3:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:13][C:14]([OH:16])=[O:15]
Reactant: CCCCCCCC(C)CC(C)C(C(=O)[O-])C(=O)OCC
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: CCCCCCCC(C)CC(C)CC(=O)O
Reaction time: 48 h
Yield: 88 %

Procedure:
In a nitrogen atmosphere, ethyl 2-(1,3-dimethyldecyl)malonate (4Et) (18.6 g, 0.0566 mol), acetic acid (40 g), water (20 g), and sulfuric acid (2 g) were placed in a reaction vessel and stirred for 48 hours under refluxing with heating while distilling off ethanol. The reaction mixture was diluted with tetrahydrofuran and water. The organic phase was washed with an aqueous saturated sodium chloride solution and concentrated under reduced pressure. The concentrate thus obtained was distilled under reduced pressure (bp: from 130° C. to 140° C./2 mmHg) to obtain 3,5-dimethyldodecanoic acid (5) (11.4 g, 0.0498 mol). A total yield of three steps from the 2-methylnonyl chloride (1Cl) was 59%.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH3:10][N+:11]([CH3:13])=[CH2:12].[I-]>C(#N)C>[CH3:10][N:11]([CH2:13][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)[CH3:12]
Reactant: C=[N+](C)C
Reactant: c1ccc2[nH]ccc2c1
Agent: [I-]
Solvent: CC#N
Product: CN(C)Cc1c[nH]c2ccccc12
Reaction time: 0.5 h

Procedure:
To a stirred solution of indole (5.6 g, 47.8 mmol) in acetonitrile (130 ml) is added Eschenmoser's salt (10 g, 54 mmol) under nitrogen atmosphere and the mixture is stirred for 30 min. The mixture is concentrated in vacuo and the residue is diluted with 1M sodium hydroxide solution and extracted with methylene chloride. The organic layer is dried over sodium carbonate and concentrated in vacuo to give 3-(dimethylaminomethyl)indole as a brown oil. To a solution of 3-(dimethylaminomethyl)indole in methylene chloride (200 ml) is dropped methyl iodide (5 ml, 80 mmol). The mixture is stirred at r.t. for 6 hrs. and concentrated in vacuo to give (3-indolylmethyl)trimethylammonium iodide as a brown foam. To a cooled (0° C.) suspension of sodium hydroxide (1.5 g, 37 mmol) in DMF (100 ml) is added trimethyl phosphonoacetate (6.7 ml, 41 mmol) and the mixture is stirred at 0° C. for 30 min. To the mixture is added (3-indolylmethyl)trimethylammonium iodide and the whole is stirred at r.t. overnight. The mixture is diluted with water and extracted with ethyl acetate. The organic layer is dried over magnesium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel with ethyl acetate to give methyl 3-(3-indolyl)-2-(dimethylphosphono)propionate a a brown oil.
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:53])[C@H:9]([CH2:49][CH:50]([CH3:52])[CH3:51])[N:10]([CH2:22][P@:23]([O:47][CH3:48])([CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30](=[O:46])[C@@H:31]2[CH2:35][CH2:34][CH2:33][N:32]2[C:36](OCC2C=CC=CC=2)=[O:37])=[O:24])[C:11](=[O:21])[CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1.CN1CCOCC1>CO.C(OCC)(=O)C.O.[Pd]>[C:1]1([NH:7][C:8](=[O:53])[C@H:9]([CH2:49][CH:50]([CH3:52])[CH3:51])[N:10]([CH2:22][P@:23]([O:47][CH3:48])([CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30](=[O:46])[C@@H:31]2[CH2:35][CH2:34][CH2:33][N:32]2[C:36](=[O:37])[C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)=[O:24])[C:11](=[O:21])[CH2:12][CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CO[P@](=O)(CCCCNC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1)CN(C(=O)CCCc1ccccc1)[C@@H](CC(C)C)C(=O)Nc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: CO[P@](=O)(CCCCNC(=O)[C@@H]1CCCN1C(=O)c1ccccc1)CN(C(=O)CCCc1ccccc1)[C@@H](CC(C)C)C(=O)Nc1ccccc1
Temperature: 0 °C

Procedure:
A solution of [[(R,S)-methoxy-[N-(N-(benzyloxycarbonyl)-L-prolyl)aminobutyl]phosphinyl]methyl]-4-phenylbutanoyl-L-leucine N-phenylamide (169 mg, 0.226 mmol) in methanol (2 mL) was stirred for 6 hours under an atmosphere of hydrogen in the presence of 20% palladium hydroxide-on-carbon (34 mg). The catalyst was removed by filtration through Celite, the filter washed with methanol, and the combined filtrate and washings evaporated. The resulting amine was dried under high vacuum, then dissolved in methylene chloride (2 mL), cooled to 0° C. and treated with benzoyl chloride (29 ml, 0.25 mmol) and N-methylmorpholine (27 μl, 0.25 mmol) at 0° C. for 90 min. The reaction mixture was diluted with ethyl acetate (25 mL), washed with 2N hydrochloric acid, saturated brine solution, dried (magnesium sulfate), and evaporated. Purification was achieved by flash chromatography on silica gel using initially 2% methanol in methylene chloride and subsequently 3% methanol in methylene chloride; yield 101 mg (62%); FAB MS: m/z 716 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:30]3[CH2:34][CH2:33][CH2:32][NH:31]3)=[N:9][C:10]=2[C:11]2[CH:29]=[CH:28][C:14]([C:15]([NH:17][C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[C:35](O)(=[O:39])[C:36]#[C:37][CH3:38]>>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:30]3[CH2:34][CH2:33][CH2:32][N:31]3[C:35](=[O:39])[C:36]#[C:37][CH3:38])=[N:9][C:10]=2[C:11]2[CH:29]=[CH:28][C:14]([C:15]([NH:17][C:18]3[CH:23]=[C:22]([C:24]([F:25])([F:27])[F:26])[CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1
Reactant: CC#CC(=O)O
Reactant: Nc1nccn2c([C@@H]3CCCN3)nc(-c3ccc(C(=O)Nc4cc(C(F)(F)F)ccn4)cc3)c12
Product: CC#CC(=O)N1CCC[C@H]1c1nc(-c2ccc(C(=O)Nc3cc(C(F)(F)F)ccn3)cc2)c2c(N)nccn12
Yield: 31.1 %

Procedure:
This compound was prepared, in an analogous manner as described in Example 2, from (S)-4-(8-amino-3-(pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide (intermediate 11) and 2-butynoic acid, to afford the title compound (7.1 mg, 31.1%). Data: UPLC (C) Rt: 2.63 min; m/z 534.2 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([CH:21]=[C:22]([CH3:24])[CH:23]=1)[O:16][CH2:17][CH2:18][CH2:19][OH:20])(=[O:11])=[O:10])#[N:2].C(N(CC)C(C)C)(C)C.CS(C)=O>ClCCl>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([CH:21]=[C:22]([CH3:24])[CH:23]=1)[O:16][CH2:17][CH2:18][CH:19]=[O:20])(=[O:11])=[O:10])#[N:2]
Reactant: Cc1cc(OCCCO)cc(OS(=O)(=O)c2ccccc2C#N)c1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(OCCC=O)cc(OS(=O)(=O)c2ccccc2C#N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.6 %

Procedure:
Sulfur trioxide pyridine complex (480 mg, 3.0 mmol) was added to a solution of 3-[3-(2-cyanophenylsulfonyloxy)-5-methylphenoxy]propanol (315 mg, 0.9 mmol), as prepared in the preceding step, N,N-diisopropylethylamine (0.5 mL, 3.9 mmol) and anhydrous dimethyl sulfoxide (0.2 mL, 2.8 mmol) in anhydrous dichloromethane (10 mL). The reaction mixture was stirred at ambient temperature for 1 hour and then quenched with 10% aqueous citric acid (30 mL). The mixture was extracted into dichloromethane (3×40 mL), and the dichloromethane solution was washed with 10% aqueous citric acid (30 mL) and dried over Na2SO4. After removing the solvent in vacuo, the residue was purified by flash column chromatography (dichloromethane) to give the title compound as a colorless oil (260 mg, 83%). 1H-NMR (300 MHz, CDCl3) δ 9.84 (s, 1H), 8.11 (m, 1H), 7.94 (m, 1H), 7.78-7.81 (m, 2H), 6.65 (s, 1H), 6.61 (s, 1H), 6.57 (s, 1H), 4.24 (t, J=6.0 Hz, 2H), 2.88 (t, J=6.0 Hz, 2H), 2.27 (s, 3H).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C[O:12][C:13]([C:15]1[CH:19]=[C:18]([C:20]2[CH2:24][C:23]([C:29]3[CH:34]=[C:33]([Cl:35])[C:32]([Cl:36])=[C:31]([Cl:37])[CH:30]=3)([C:25]([F:28])([F:27])[F:26])[O:22][N:21]=2)[O:17][C:16]=1[CH3:38])=O>C(OCC)C>[CH3:38][C:16]1[O:17][C:18]([C:20]2[CH2:24][C:23]([C:29]3[CH:34]=[C:33]([Cl:35])[C:32]([Cl:36])=[C:31]([Cl:37])[CH:30]=3)([C:25]([F:27])([F:26])[F:28])[O:22][N:21]=2)=[CH:19][C:15]=1[CH2:13][OH:12]
Reactant: COC(=O)c1cc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)oc1C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCOCC
Product: Cc1oc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)cc1CO
Reaction time: 20 h
Yield: 82.7 %

Procedure:
Diisobutylaluminium hydride (DIBAL-H, 21.9 ml, 1M in toluene) is added to a solution of 2-methyl-5-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-furan-3-carboxylic acid methyl ester (5.0 g) in diethyl ether (100 ml) under nitrogen at −5° C. After 15 it at −5° C., the cold bad is removed. After 20 hours at room temperature, the reaction mixture is diluted with ethyl acetate and is quenched with a saturated solution of NaHCO3. The organic phase is separated and washed with a saturated solution of NaHCO3 and with a saturated aqueous solution of NaCl, dried over Na2SO4 and concentrated in vacuo. The crude product is purified on a semi-preparative HPLC to yield {2-methyl-5-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-furan-3-yl}-methanol (3.88 g) as a white foam. MS (HPLC/MS): 428 (MH+).
Reaction SMILES: Br[C:2]1[C:7]([NH2:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:4][N:3]=1.[CH3:16][Si:17]([C:20]#[CH:21])([CH3:19])[CH3:18]>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:5]2[CH:6]=[C:7]([NH:8][C:21]#[C:20][Si:17]([CH3:19])([CH3:18])[CH3:16])[CH:2]=[N:3][CH:4]=2)=[CH:10][CH:11]=1
Reactant: Nc1cc(-c2ccc(Cl)cc2)cnc1Br
Reactant: C#C[Si](C)(C)C
Product: C[Si](C)(C)C#CNc1cncc(-c2ccc(Cl)cc2)c1

Procedure:
The product was obtained analogously to Example 7.1b starting from 2-bromo-5-(4-chlorophenyl)pyridin-3-ylamine (Example 16.1c) and trimethylsilylacetylene. Yield: 1.09 g (51% of theoretical); C16H17ClN2Si (M=300.858); calc.: molpeak (M+H)+: 301/303 (Cl); found: molpeak (M+H)+: 301/303 (Cl).
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([NH:8][CH3:9])=[N:5][C:4]=1[CH:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:14]([F:24])[CH:13]=1)[CH3:11])=[O:2].CC(C)=[O:27].OS(O)(=O)=O.O=[Cr](=O)=O.[Cr](O)(O)(=O)=O.CC(O)C>CC(C)=O.S(=O)(=O)(O)O.O>[F:24][C:14]1[CH:13]=[C:12]([CH:10]([C:4]2[N:5]=[C:6]([NH:8][CH3:9])[S:7][C:3]=2[C:1]([OH:27])=[O:2])[CH3:11])[CH:17]=[CH:16][C:15]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CNc1nc(C(C)c2ccc(-c3ccccc3)c(F)c2)c(C=O)s1
Reactant: CC(C)=O
Agent: O=[Cr](=O)(O)O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)O
Product: CNc1nc(C(C)c2ccc(-c3ccccc3)c(F)c2)c(C(=O)O)s1
Reaction time: 1 h
Yield: 20 %

Procedure:
5-Formyl-4-(1-(2-fluoro-4-biphenylyl)ethyl)-2-methylaminothiazole (1.00 g, 2.9 mmoles) was dissolved in acetone (20 ml). Jones reagent (chromic acid (VI) dissolved in a mixture of concentrated sulfuric acid and water) (2 ml) was added dropwise thereinto while cooling the system with ice, after which it was stirred for one hour. Then, an additional 2 ml of Jones reagent was added dropwise and the resulting mixture was stirred for one hour. A small quantity of 2-propyl alcohol was added to the reaction mixture, it was extracted with ether, and the ether layer was washed with water and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate to obtain the desired 4-(1-(2-fluoro-4-biphenylyl)ethyl)-2-methylamino-5-thiazolecarboxylic acid (205 mg, 0.58 mmole, yield 20%) as a white crystalline product.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[NH2:7][C:8]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:9]=1[C:10]([NH2:12])=[O:11].[OH-].[Na+].Cl>C(OCC)(=O)C.C1COCC1>[C:1]([NH:7][C:8]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:9]=1[C:10]([NH2:12])=[O:11])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)Cl
Reactant: NC(=O)c1cc(Cl)ccc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCC(=O)Nc1ccc(Cl)cc1C(N)=O
Yield: 92 %

Procedure:
Preparation D10, Step 1: Butyryl chloride (0.68 mL, 6.5 mmol, 1 eq) was slowly dripped into a mixture of 2-amino-5-chlorobenzamide (1.10 g, 6.5 mmol, 1 eq), 1.000N NaOH (6.50 mL, 6.5 mmol, 1 eq) and THF (enough to dissolve) at 0° C. More acid chloride and base were added to drive the reaction to completion. After 4 days ethyl acetate was added followed by 1N HCl. The layers were separated and the organic layer washed with 1N HCl (2×), saturated sodium bicarbonate (1×), and brine (1×). The organic layer was dried (MgSO4) and stripped to yield 2-butyramido-5-chlorobenzamide (1.44 g) as a white powder. Mass Spec (ESI) (M+H)+=241.0.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:8][CH2:9][C:10](Cl)=[O:11]>N1C=CC=CC=1.C(Cl)Cl>[Cl:8][CH2:9][C:10]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:11]
Reactant: Nc1ccccc1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(CCl)Nc1ccccc1
Yield: 91.1 %

Procedure:
To a solution of aniline (1 mL, 11 mmol) and CH2Cl2 (150 mL), pyridine (886 mL, 1 mmol) was added. Then 2-chloroacetyl chloride (872 mL, 11 mmol) was added dropwise over 10 min. After the addition was complete, the mixture was reacted at room temperature for 2 hours. The reaction was then quenched with water (100 mL), the layers were separated and the aqueous layer was extracted with CH2Cl2 (2×50 mL). The combined organic layer was washed water, brine, and dried over Na2SO4. The solvent was evaporated to give a colorless solid (1.7 g, 91% yield). The crude product was directly used for next step. 1H NMR (CDCl3, 400 MHz) δ 8.25 (br s., 1H), 7.57 (d, J=7.6 Hz, 2H), 7.39 (t, J=7.6 Hz, 2H), 7.20 (t, J=7.4 Hz, 1H), 4.22 (s, 2H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[S:9][C:8]([NH:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[N:7][CH:6]=1)=O.[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([O:28][CH3:29])=[C:22]([NH:24][C:25]([NH2:27])=[S:26])[CH:23]=1>CCO>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([O:28][CH3:29])=[C:22]([NH:24][C:25]2[S:26][CH:2]=[C:3]([C:5]3[S:9][C:8]([NH:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[N:7][CH:6]=3)[N:27]=2)[CH:23]=1
Reactant: CC(C)(C)C(=O)Nc1ncc(C(=O)CBr)s1
Reactant: COc1ccc(Cl)cc1NC(N)=S
Solvent: CCO
Product: COc1ccc(Cl)cc1Nc1nc(-c2cnc(NC(=O)C(C)(C)C)s2)cs1
Reaction time: 0.5 h
Yield: 41.1 %

Procedure:
A suspension of 21z (0.73 g, 2.3 mmol) and N-(5-chloro-2-methoxyphenyl)thiourea (0.73 g, 2.53 mmol) in EtOH (25 mL) was refuxed for 30 min. Upon cooling, the product was collected by filtration and washed with cold ethanol to yield 22z as a pale yellow solid (0.40 g, 84%). Mp decomposition at 216° C. 1H NMR (600 MHz, DMSO-d6): δ 11.86 (br s, 1H) 9.93 (br s, 1H), 8.64 (d, J=2.4 Hz, 1H), 7.83 (s, 1H), 7.18 (s, 1H), 7.02 (d, J=8.4 Hz, 1H), 6.98 (dd, J=8.4 Hz, 2.4 Hz, 1H), 3.86 (s, 3H), 1.25 (s, 9H). 13C NMR (150 MHz, DMSO-d6): δ 176.7, 162.1, 158.9, 146.6, 140.2, 136.4, 130.5, 124.7, 124.2, 121.3, 117.3, 112.1, 91.0, 56.1, 38.8, 26.6. HRMS m/z (ESI) calcd. for C18H19ClN4O2S2 (M+H)+ 423.0711. Found 423.0713.
Reaction SMILES: [I:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:12][CH:13]=O.[C:15]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:18]([O:17][C:15]([N:22]1[CH2:27][CH2:26][N:25]([CH2:13][CH2:12][C:3]2[CH:4]=[CH:5][C:6]3[C:7](=[O:11])[O:8][CH2:9][C:10]=3[C:2]=2[I:1])[CH2:24][CH2:23]1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: O=CCc1ccc2c(c1I)COC2=O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(CCc2ccc3c(c2I)COC3=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The crude (4-iodo-1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde (1.2 g) was dissolved in DCM (40 mL). Boc-piperazine (1.1 g, 5.9 mmol) was added into the solution, followed by addition of sodium triacetoxyborohydride (4.2 g, 20 mmol). The reaction was allowed to stir at RT overnight. The reaction was diluted with DCM, washed with sodium bicarbonate and brine, dried over MgSO4, and purified by silica gel chromatography to furnish tert-butyl-4-[2-(4-iodo-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazine-1-carboxylate. LC-MS (IE, m/z): 473 [M+1]+.
Reaction SMILES: [C:1]([O:5]O)([CH3:4])([CH3:3])C.[Cl-].[Na+].[Cl:9][C:10]1[N:15]=[C:14]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]2[CH2:26][C:25]([CH3:28])([CH3:27])[NH:24][C:23]([CH3:30])([CH3:29])[CH2:22]2)[N:13]=[C:12]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH:36]2[CH2:41][C:40]([CH3:43])([CH3:42])[NH:39][C:38]([CH3:45])([CH3:44])[CH2:37]2)[N:11]=1>[Mo](=O)(=O)=O.C1CCCCC1>[Cl:9][C:10]1[N:15]=[C:14]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]2[CH2:26][C:25]([CH3:28])([CH3:27])[N:24]([O:5][CH:1]3[CH2:4][CH2:19][CH2:18][CH2:17][CH2:3]3)[C:23]([CH3:30])([CH3:29])[CH2:22]2)[N:13]=[C:12]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH:36]2[CH2:41][C:40]([CH3:43])([CH3:42])[N:39]([O:5][CH:1]3[CH2:4][CH2:22][CH2:21][CH2:20][CH2:3]3)[C:38]([CH3:45])([CH3:44])[CH2:37]2)[N:11]=1
Reactant: CC(C)(C)OO
Reactant: CC1(C)CC(CCCCNc2nc(Cl)nc(NCCCCC3CC(C)(C)NC(C)(C)C3)n2)CC(C)(C)N1
Agent: O=[Mo](=O)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCCCC1
Product: CC1(C)CC(CCCCNc2nc(Cl)nc(NCCCCC3CC(C)(C)N(OC4CCCCC4)C(C)(C)C3)n2)CC(C)(C)N1OC1CCCCC1
Yield: 74 %

Procedure:
A mixture of 57.7 g (0.448 mol) of 70% aqueous tert-butylhydroperoxide, 250 ml of cyclohexane and 100 ml of saturated sodium chloride solution is agitated vigorously and the organic layer is then separated and dried over anhydrous magnesium sulfate. The drying agent is removed by filtration. The filtrate, 30.0 g (0.056 mol) of 2-chloro-4,6-bis[N-(2,2,6,6-tetramethylpiperidin-4-yl)butylamino]-s-triazine and 1.0 g of molybdenum trioxide are placed in a pressure bottle and heated at 130°-140° C. The reaction mixture quickly turns red and heating is continued till the red color is discharged. The reaction mixture is allowed to cool and solids are removed by filtration. The filtrate is concentrated under reduced pressure to give an oil which is purified by flash chromatography on silica gel to afford 30.3 g. (74% yield) of the title compound as a white glass.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3](=[O:10])[C:2]1=[N:11][OH:12].C(=O)([O-])[O-].[Na+].[Na+].[C:19]([O:22][CH2:23][CH2:24]Br)(=[O:21])[CH3:20].O>CN1CCCC1=O>[C:19]([O:22][CH2:23][CH2:24][O:12][N:11]=[C:2]1[C:3](=[O:10])[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:1]1)(=[O:21])[CH3:20]
Reactant: CC(=O)OCCBr
Reactant: O=C1C(=NO)Oc2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(=O)OCCON=C1Oc2ccccc2C1=O
Reaction time: 2 h
Yield: 63 %

Procedure:
g (0.01 mol) of benzofuran-2,3-dione 2-oxime (XI-1) in 5 ml of N-methyl-2-pyrrolidinone are stirred with 1.14 g (0.0108 mol) of sodium carbonate at 20° C. for 30 minutes. After the addition of 1.7 g (0.0102 mol) of 2-bromoethyl acetate, stirring is continued at 70° C. for 2 hours. The mixture is poured into 30 ml of water and the product is filtered off. The product is dried to afford 1.57 g (63% of theory) of crystalline 2-(3-oxo-3H-benzofuran-2-ylideneaminooxy)-ethyl acetate (XIV- 1).
Reaction SMILES: C[O:2][C:3](=[O:10])[C@@H:4]1[CH:8](O)[CH2:7][CH2:6][NH:5]1.CCN(S(F)(F)[F:17])CC>C(Cl)Cl>[F:17][CH:8]1[CH2:7][CH2:6][NH:5][C@@H:4]1[C:3]([OH:2])=[O:10]
Reactant: CCN(CC)S(F)(F)F
Reactant: COC(=O)[C@H]1NCCC1O
Solvent: ClCCl
Product: O=C(O)[C@H]1NCCC1F
Temperature: 25 °C

Procedure:
To a solution of the 3-hydroxyproline methyl ester in DCM at −78° C., DAST (4 eq.) was added dropwise with stirring. The reaction was slowly warmed to rt. It was stirred at rt for 16 h, then diluted with more DCM and washed with cold saturated sodium bicarbonate, dried over sodium sulfate, filtered, concentrated and purified by column chromatography (SiO2, 20-30% ethyl acetate/hexanes) to provide the desired 3-fluoroproline intermediate.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:15][C:16](=[O:18])[CH3:17])[CH:11]=2)[N:6]=1)[CH3:3].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[C:27](C(O)=O)=[CH:28]C=[CH:30][CH:31]=2)=[CH:22][CH:21]=1.CN(C1C=CC=CN=1)C.Cl.C(N=C=NCCCN(C)C)C.C(=O)([O-])[O-].[K+].[K+]>Cl.CN(C)C=O>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[CH:28][C:17]([C:16]([NH:15][C:10]3[CH:11]=[C:12]4[C:7](=[CH:8][CH:9]=3)[N:6]=[C:5]([CH2:4][N:2]([CH3:1])[CH3:3])[CH:14]=[CH:13]4)=[O:18])=[CH:30][CH:31]=2)=[CH:22][CH:21]=1
Reactant: O=C(O)c1ccccc1-c1ccc(Cl)cc1
Reactant: CC(=O)Nc1ccc2nc(CN(C)C)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CN(C)C=O
Product: CN(C)Cc1ccc2cc(NC(=O)c3ccc(-c4ccc(Cl)cc4)cc3)ccc2n1
Temperature: 110 °C
Reaction time: 2 h
Yield: 49.2 %

Procedure:
The N-[2-[(N,N-dimethylamino)methyl]-6-quinolinyl]acetamide (1.9 mg, 0.296 mmol) obtained in the above 1) was dissolved in concentrated hydrochloric acid (1.5 ml), and the solution was stirred at 110° C. for 2 hours. The solvent was distilled off under reduced pressure, an aqueous potassium carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue, 4′-chlorobiphenylcarboxylic acid (68.8 mg, 0.296 mmol) and dimethylaminopyridine (36.1 mg, 0.296 mmol) were dissolved in N,N-dimethylformamide (1.5 ml), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (56.6 mg, 0.296 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 16 hours. To the reaction solution was added an aqueous potassium carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by alumina column chromatography (developing solvent: ethyl acetate), and crystallized from ethyl acetate-diisopropyl ether (1:5) to obtain the titled compound (60.6 mg) as a white powder.
Reaction SMILES: [BH4-].[Na+].[Cl:3][CH2:4][CH2:5][CH2:6][CH:7]1[CH2:12][C:11](=[O:13])[C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=2[S:8]1(=[O:19])=[O:18]>C(O)C>[Cl:3][CH2:4][CH2:5][CH2:6][CH:7]1[CH2:12][CH:11]([OH:13])[C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=2[S:8]1(=[O:19])=[O:18]
Reactant: O=C1CC(CCCCl)S(=O)(=O)c2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=S1(=O)c2ccccc2C(O)CC1CCCCl
Yield: 90.9 %

Procedure:
200 mg (5.29 mmol) of sodium borohydride was added in portions to a solution of 620 mg (2.27 mmol) of the Compound 5 in 20 ml of ethanol while stirring under cooling with ice. After stirring for 17 hours at room temperature, the reaction mixture was concentrated under vacuum. A 0.1M phosphate buffer solution (pH 6.0) was added to the residue and the mixture was extracted with chloroform (three times). The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography using a 1:1 ethyl acetate-hexane solution as an eluent to obtain 567 mg (yield: 91%) of the title compound.