Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[C:6](Cl)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1COCC1>[C:6]([NH:1][CH2:2][CH2:3][CH2:4][OH:5])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: NCCCO
Solvent: C1CCOC1
Product: OCCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
3-(Tritylamino)-1-propanol was prepared according to the literature procedure (J.Heterocycl.Chem.; 1993, 30, 1197). To a solution of 3-amino-1-propanol (15.0 g/200 mmol) in THF (100 ml) was added a solution of tritylchloride (23.2 g/83.3 mmol) in THF (100 ml) dropwise at 0° C., and then the resulting solution was stirred at room temperature for 4 days. The solution was evaporated. The resulting residue was dissolved in water (100 ml) and dichloromethane (100 ml). The organic layer was separated. The aqueous layer was extracted with dichloromethane (100 ml×2). The combined organic layer was washed with brine (30 ml), dried over magnesium sulfate, filtered and concentrated. The residue was purified by recrystallization from toluene/hexane to afford a white crystal. (21.0 g/80%).
Reaction SMILES: [C:1](CC(N)=O)(=S)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.[NH2:15][CH:16]([CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[C:17]([NH:19][C:20]1([C:27]#[N:28])[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1)=[O:18]>>[C:17]([N:19]=[C:1]([NH:15][CH:16]([CH2:29][CH:30]1[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1)[C:17]([NH:19][C:20]1([C:27]#[N:28])[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]1)=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:18])[CH3:16]
Reactant: CN1CCC(C#N)(NC(=O)C(N)CC2CCCCC2)CC1
Reactant: NC(=O)CC(=S)c1ccccc1
Agent: Cl
Product: CC(=O)N=C(NC(CC1CCCCC1)C(=O)NC1(C#N)CCN(C)CC1)c1ccccc1

Procedure:
The title compound was prepared starting from thiobenzoyl acetamide and 2-amino-N-(4-cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-propionamide bis hydrochloride salt according to the procedure from Example 1, step b. MS, m/z 438=M+1.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][NH:12][CH:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10]2)[CH:6]=[CH:5][CH:4]=1.[C:22]([O:26][CH2:27][CH3:28])(=[O:25])[CH:23]=[CH2:24].C(N(CC)C(C)C)(C)C>C(O)C>[CH2:27]([O:26][C:22](=[O:25])[CH2:23][CH2:24][N:12]1[CH2:13][CH2:14][N:9]([C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:20])[F:21])[N:8]=2)[CH2:10][CH:11]1[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:28]
Reactant: CCOC(=O)C1CN(c2cccc(C(F)(F)F)n2)CCN1
Reactant: C=CC(=O)OCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOC(=O)CCN1CCN(c2cccc(C(F)(F)F)n2)CC1C(=O)OCC
Temperature: 80 °C
Reaction time: 96 h

Procedure:
To a solution of Example 94A (10 g, 33.0 mmol) and ethyl acrylate (14.29 mL, 132 mmol) in dry ethanol (30 mL) was added N,N-diisopropylethylamine (2.85 mL, 16.49 mmol). The mixture was heated to 80° C. and stirred for 4 days. Excess ethyl acrylate and ethanol were removed under vacuum. The residue was purified on a silica gel column (hexane:ethyl acetate=1:3) and then purified again via HPLC (Gilson®, Xbridge™ 50×100 mm column, eluted with pH=10 aqueous ammonium bicarbonate-ammonium hydroxide/acetonitrile, UV=220 nm) to give the title compound. 1H NMR (300 MHz, methanol-d4) δ ppm 1.20 (t, 3H, J=7 Hz) 1.26 (t, 3H, J=7 Hz), 2.52 (td, 2H, J=7, 3 Hz), 2.56-2.65 (m, 1 H), 2.83-3.07 (m, 2 H), 3.17 (ddd, 1H, J=12, 9, 3 Hz), 3.37 (ddd, 1H, J=12, 9, 3 Hz), 3.47-3.61 (m, 2 H), 3.86-3.95 (m, 1 H), 4.06-4.18 (m, 4 H), 4.29 (dd, 1H, J=13, 3 Hz), 6.92-7.01 (m, 2 H), 7.62-7.70 (m, 1 H); MS (DCI) m/z 404 (M+H)+.
Reaction SMILES: C(OC([N:11]1[CH2:19][C@@:18]2([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:13]([CH2:14][CH2:15][O:16][CH2:17]2)[CH2:12]1)=O)C1C=CC=CC=1.[H][H]>CO.[C].[Pd]>[C:24]([O:23][C:21]([NH:20][C@:18]12[CH2:19][NH:11][CH2:12][C@H:13]1[CH2:14][CH2:15][O:16][CH2:17]2)=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N[C@@]12COCC[C@@H]1CN(C(=O)OCc1ccccc1)C2
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@]12CNC[C@H]1CCOC2
Yield: 98.7 %

Procedure:
[(1S,6R)-1-tert-Butoxycarbonylamino-3-oxa-8-azabicyclo[4,3,0]nonan-8-yl]carboxylic acid benzyl ester (401 mg, 1.07 mmol) was dissolved in methanol (20 mL). 10% palladium-carbon (50% wet) (200 mg) was added, and the mixture was stirred in a hydrogen atmosphere for 2.5 hours. The catalyst was removed by filtration, and then the filtrate was concentrated under reduced pressure. A 1N sodium hydroxide solution was added, followed by extraction with chloroform. After drying over anhydrous sodium sulfate and filtration, the solvent was evaporated under reduced pressure to give 256 mg of the title compound as a colorless solid.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:25][CH2:24][C:6]2([CH2:14][C:13]3[C:8](=[CH:9][C:10]([C:15]4[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=4)[C:18]#[N:19])=[CH:11][CH:12]=3)[C:7]2=O)[CH2:5][CH2:4]1.C[Si]([N:30]=[C:31]=[N:32][Si](C)(C)C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[C:18]([C:17]1[CH:16]=[C:15]([C:10]2[CH:9]=[C:8]3[C:13](=[CH:12][CH:11]=2)[CH2:14][C:6]2([CH2:5][CH2:4][CH:3]([O:2][CH3:1])[CH2:25][CH2:24]2)/[C:7]/3=[N:32]\[C:31]#[N:30])[CH:22]=[CH:21][CH:20]=1)#[N:19]
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Reactant: COC1CCC2(CC1)Cc1ccc(-c3cccc(C#N)c3)cc1C2=O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COC1CCC2(CC1)Cc1ccc(-c3cccc(C#N)c3)cc1/C2=N/C#N
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 93.8 %

Procedure:
To a solution of 3-(4-methoxy-1′-oxo-1′,3′-dihydrospiro[cyclohexane-1,2′-indene]-6′-yl)benzonitrile (30 mg, 0.09 mmol) in CH2Cl2 (3 mL) was added TiCl4 (0.2 mL). It was stirred in microwave at 50° C. for 5 minutes. Then bis-trimethylsilylcarbodiimide (0.2 mL, 0.146 mmol) was added. The resulting mixture was stirred in microwave at 60° C. for 10 minutes. The reaction mixture was poured into ice-water, extracted with DCM. The combined organic phases were dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated to give (E)-N-(5′-(3-cyanophenyl)-4-methoxyspiro[cyclohexane-1,2′-indene]-3′(1′H)-ylidene)cyanamide (30 mg, crude).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[CH3:9][NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:9][N:10]([CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CNc1ccccc1
Reactant: ClCc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(Cc1ccccn1)c1ccccc1
Temperature: 120 °C
Reaction time: 4 h
Yield: 50.2 %

Procedure:
A mixture of 2-chloromethylpyridine (50 g), N-methylaniline (42 g), and potassium carbonate (120 g) in N,N-dimethylformamide (200 ml) was stirred for 4 hours at 120° C. The reaction mixture was cooled to room temperature, added to water (1 l), and extracted with ether. The ether extract was washed with water and then treated with activated carbon. After drying over magnesium sulfate, the ether extract was filtered and concentrated. The residue was crystallized from isopropyl alcohol to give N-methyl-N-(2-pyridylmethyl)aniline (39 g).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C(#N)C.[OH:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][CH:12]=1.Cl.Cl[CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>CN(C)C=O>[N:24]1([CH2:23][CH2:22][O:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][CH:12]=2)[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1
Reactant: NC(=O)c1ccc(O)cc1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: NC(=O)c1ccc(OCCN2CCOCC2)cc1
Reaction time: 0.5 h
Yield: 23.8 %

Procedure:
Potassium carbonate (15.1 g, 109 mmol, 3 eq.), acetonitrile (73 mL) and then 4-hydroxybenzamide (5 g, 36.5 mmol, 1 eq.) are placed in a 250 mL round-bottomed flask. The suspension is stirred for 30 minutes, followed by addition of 4-(2-chloroethyl)morpholine hydrochloride (8.82 g, 47 mmol, 1.3 eq.). 10 mL of dimethylformamide are added to this suspension, and the mixture is then stirred at a temperature in the region of 40° C. for 16 hours. The solvent is then evaporated off and the residue is diluted with water and extracted with dichloromethane. The aqueous phase is acidified with 5 N hydrochloric acid and reextracted with dichloromethane. The organic phases are combined, dried over magnesium sulfate and then concentrated to dryness under vacuum. 4-(2-Morpholin-4-ylethoxy)benzamide 2.17 g (23%) is thus obtained in the form of a white solid, which is used directly in the following step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[S:9](=[O:19])(=[O:18])[NH:8][CH2:7][C:6]=2[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][CH2:29][C@@H:30]1[O:32][CH2:31]1>CC(C)=O.C(OCC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[S:9](=[O:19])(=[O:18])[N:8]([CH2:28][CH2:29][C@H:30]3[CH2:31][O:32]3)[CH2:7][C:6]=2[CH:20]=1
Reactant: O=S1(=O)NCc2cc(F)ccc2N1c1ccccc1F
Reactant: BrCC[C@H]1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: O=S1(=O)N(CC[C@H]2CO2)Cc2cc(F)ccc2N1c1ccccc1F
Temperature: 45 °C
Reaction time: 14 h
Yield: 160 %

Procedure:
A solution 6-fluoro-1-(2-fluorophenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.13 g, 0.29 mmol) in acetone (3 mL) was treated with potassium carbonate (0.11 g, 0.81 mmol), (S)-(−)-4-Bromo-1,2-epoxybutane (0.14 mL, 1.41 mmol) and was heated to 45° C. for two h then at room temperature for 14 h. The reaction mixture was diluted with ethyl ether (40 mL) and washed with sat. sodium bicarbonate (2×20 mL), the organic layer was isolated, dried with MgSO4 and evaporated. The crude reaction product was purified by flash chromatography (SiO2, 3-50% ethyl acetate/heptane) to provided 6-fluoro-1-(2-fluorophenyl)-3-{2-[(2S)-oxiran-2-yl]ethyl}-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.17 g, 67%) as a white solid.
Reaction SMILES: [OH:1][CH:2]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:3][NH:4][C:5](=O)[CH2:6][CH2:7][CH2:8][CH2:9][C:10]([NH:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21]CC2C=CC=CC=2)=[C:17]([O:29]CC2C=CC=CC=2)[CH:16]=1)=O.B#B.CO>O1CCCC1>[OH:1][CH:2]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:3][NH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH:12][CH2:13][CH2:14][C:15]1[CH:16]=[C:17]([OH:29])[C:18]([OH:21])=[CH:19][CH:20]=1
Reactant: O=C(CCCCC(=O)NCC(O)c1ccccc1)NCCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Agent: B#B
Solvent: C1CCOC1
Solvent: CO
Product: Oc1ccc(CCNCCCCCCNCC(O)c2ccccc2)cc1O

Procedure:
A solution of N-(2-hydroxy-2-phenylethyl)-N'-[2-(3,4-bis(phenylmethoxy)phenyl)ethyl]hexane-1,6-diamide prepared in an analogous manner to that described in Example 12(a) above (3.48 g) in dry tetrahydrofuran (100 ml) was stirred under a nitrogen atmosphere whilst diborane in tetrahydrofuran (30 ml of 1M solution) was added and then the solution heated to reflux for 6 hours. Methanol (100 ml) was added to the cooled solution and the mixture evaporated to dryness. The residue was dissolved in methanolic HCl (100 ml) and heated to reflux for 18 hours. The solution was evaporated to dryness and the residue recrystallised from ethanol to give the title compound, as the dihydrochloride salt, colorless prisms (1.3 g) mp 188°-9°.
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]1[S:10][C:9]([C:11]([OH:13])=O)=[CH:8][CH:7]=1)(=[O:4])=[O:3].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:47][C@@H:48]([CH2:62][C:63]1[CH:68]=[C:67]([F:69])[CH:66]=[C:65]([F:70])[CH:64]=1)[C@H:49]([OH:61])[CH2:50][NH:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[C:55]([CH2:59][CH3:60])[CH:54]=1>C(Cl)Cl>[F:69][C:67]1[CH:68]=[C:63]([CH:64]=[C:65]([F:70])[CH:66]=1)[CH2:62][C@H:48]([NH:47][C:11]([C:9]1[S:10][C:6]([CH2:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:7][CH:8]=1)=[O:13])[C@H:49]([OH:61])[CH2:50][NH:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[C:55]([CH2:59][CH3:60])[CH:54]=1
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reactant: CS(=O)(=O)Cc1ccc(C(=O)O)s1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cccc(CNC[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2ccc(CS(C)(=O)=O)s2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 16.1 %

Procedure:
To a solution of acid from step 5 (115 mg, 0.52 mmol) and N,N-diisopropylethylamine (540 μL, 3.12 mmol) in methylene chloride (6.5 mL) was added HBTU (200 mg, 0.52 mmol) and the reaction mixture was stirred for 0.5 h. (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol (211 mg, 0.52 mmol) was added in one portion and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with methylene chloride and washed with saturated sodium bicarbonate, and saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash chromatography (silica, 1-5% methanol in chloroform) gave the title compound (45 mg): mp 128-131° C.; ESI MS m/z 537 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([CH2:9][N:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([CH3:19])[CH:17]=3)[C:12]([C:20]([OH:22])=O)=[CH:11]2)[C:4]=1[CH3:23].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.[NH2:49][CH2:50][C@H:51]([OH:53])[CH3:52]>C(Cl)Cl>[OH:53][C@H:51]([CH3:52])[CH2:50][NH:49][C:20]([C:12]1[C:13]2=[N:14][CH:15]=[C:16]([CH3:19])[CH:17]=[C:18]2[N:10]([CH2:9][C:5]2[C:4]([CH3:23])=[C:3]([O:2][CH3:1])[N:8]=[CH:7][N:6]=2)[CH:11]=1)=[O:22]
Reactant: COc1ncnc(Cn2cc(C(=O)O)c3ncc(C)cc32)c1C
Reactant: C[C@@H](O)CN
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ncnc(Cn2cc(C(=O)NC[C@@H](C)O)c3ncc(C)cc32)c1C
Temperature: 25 °C
Yield: 39.5 %

Procedure:
See FIG. 23(c). 1-((6-methoxy-5-methylpyrimidin-4-yl)methyl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (75 mg, 0.24 mmol) was taken in a thermal reactor. DCM (5 mL) was added to get a suspension. Added triethyl amine (0.067 mL, 0.48 mmol) followed by the addition of 1-Propanephosphonic acid cyclic anhydride (0.286 mL, 0.48 mmol). (R)-1-aminopropan-2-ol (36.1 mg, 0.48 mmol) was added and stirred at RT for ON. After completion of the reaction, reaction mixture was concentrated and dissolved in DCM:MeOH. This crude compound was subjected for reverse phase purification to obtain (R)—N-(2-hydroxypropyl)-1-((6-methoxy-5-methylpyrimidin-4-yl)methyl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (35.0 mg, 39.5%) as a off-white solid. ES+MS m/z: 370 (M+I). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.10 (d, J=5.84 Hz, 3 H ) 2.24 (s, 3 H ) 2.39 (s, 3 H ) 3.16-3.29 (m, 1 H ) 3.37-3.48 (m, 1 H ) 3.77 (br. s., 1H ) 3.93 (s, 3 H ) 4.85 (d, J=4.33 Hz, 1 H ) 5.63 (s, 2 H ) 7.74 (s, 1 H ) 8.12 (s, 1 H ) 8.33 (s, 1 H ) 8.41 (s, 1 H ) 8.82 (br. s., 1 H ).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]1[CH:19]=[CH:18][CH:17]=[CH:16][C:9]=1[O:10][CH2:11][CH2:12][C:13]([OH:15])=O.[Cl-].[Al+3].[Cl-].[Cl-]>CN(C=O)C.C(Cl)Cl>[F:7][C:8]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:9]=1[O:10][CH2:11][CH2:12][C:13]2=[O:15]
Reactant: O=C(O)CCOc1ccccc1F
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C1CCOc2c(F)cccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
Oxalyl chloride (8.79 mL) and one drop of DMF were added to an ice cold solution of 3-(2-fluorophenoxy)propanoic acid (9.27 g) in methylene chloride (50 mL). The solution was stirred at 0° C. for two hours, aluminum chloride (7.39 g, 55.42 mM) was added and the solution was stirred for 16 hours at room temperature. The mixture was poured onto ice water, and extracted three times with methylene chloride. The combined organics were washed with 0.5M NaOH and brine, dried, evaporated, and purified by column chromatography (eluting with 20% EtOAc/Hex) to give 8-fluorochroman-4-one (3) (8.20 g, 98%).
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1)\[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1.[C:22]([CH:24]([C:30]1[CH:35]=[CH:34][C:33](O)=[CH:32][CH:31]=1)[CH2:25][C:26]([O:28]C)=[O:27])#[N:23]>>[C:22]([CH:24]([C:30]1[CH:35]=[CH:34][C:33]([O:14][CH2:13][C:10]2[CH:9]=[CH:8][C:7]([O:6][CH2:5]/[C:4](/[C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=3)=[N:3]\[O:2][CH3:1])=[CH:12][CH:11]=2)=[CH:32][CH:31]=1)[CH2:25][C:26]([OH:28])=[O:27])#[N:23]
Reactant: CO/N=C(\COc1ccc(CO)cc1)c1cccc(F)c1
Reactant: COC(=O)CC(C#N)c1ccc(O)cc1
Product: CO/N=C(\COc1ccc(COc2ccc(C(C#N)CC(=O)O)cc2)cc1)c1cccc(F)c1
Yield: 18.73 %

Procedure:
Compound 35 was synthesized from (1Z)-1-(3-fluorophenyl)-2-[4-(hydroxymethyl)phenoxy]ethanone O-methyloxime (0.5 g, 1.8 mmol) and methyl 3-cyano-3-(4-hydroxyphenyl)propanoate (0.372 g, 1.8 mmol) by following the procedure described in scheme 18 (0.1 g, yield: 18.73%); Purity: 95.1%.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][N:7]2[C:12](=[O:19])[CH2:13][CH2:14][C:15](OC)=[O:16].[BH4-].[Na+].C(OCC)(=O)C>CO>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][N:7]2[C:12](=[O:19])[CH2:13][CH2:14][CH2:15][OH:16]
Reactant: COC(=O)CCC(=O)N1CCCc2c(Br)cccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(CCCO)N1CCCc2c(Br)cccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.9 %

Procedure:
To a solution of methyl 4-(5-bromo-3,4-dihydroquinolin-1(2H)-yl)-4-oxobutanoate (0.9 g, 2.76 mmol) in MeOH (30 mL) was added sodium borohydride (2.088 g, 55.2 mmol), and the resulting mixture was stirred at room temperature for 30 min. After this time, additional sodium borohydride (1.566 g, 41.4 mmol) was added slowly and the reaction was stirred for another 30 min. The reaction mixture was quenched with HCl and extracted with ethyl acetate. The combined organic layer was dried over anhydrous MgSO4, filtered, and concentrated. The resulting residue was purified by flash chromatography (0-100% ethyl acetate:hexanes then 10% CH3OH:ethyl acetate) to afford the title compound (0.6 g, 73% yield) as a colorless oil. LCMS, [M+H]+=298.0. 1H NMR (400 MHz, MeOD) δ 7.49 (d, J=8.1 Hz, 1H), 7.44 (br. s, 1H), 7.17 (t, J=8.1 Hz, 1H), 3.86-3.80 (m, 2H), 3.61 (t, J=6.2 Hz, 2H), 2.89 (t, J=6.9 Hz, 2H), 2.68 (t, J=7.4 Hz, 2H), 2.10-2.01 (m, 2H), 1.95-1.85 (m, 2H).
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([OH:13])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.Cl>O>[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20]([O:13][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCCCO
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCCCCCOS(=O)(=O)c1ccc(C)cc1
Yield: 95.3 %

Procedure:
20 ml of pyridine was added to 5.02 g (49.2 mM) of n-hexanol, followed by stirring below 0° C. To the mixture, 11.24 g (59.0 mM) of p-toluenesulfonyl chloride was added. The mixture was stirred for 6 hours below 0° C. After the reaction, the reaction mixture was poured into iced water and acidified with conc. HCl, followed by two times of extraction with dichloromethane, two times of washing with water, drying with sodium sulfate and distilling-off of the solvent to obtain 12.0 g (46.8 mM) of an objective product (yield: 95.0%).
Reaction SMILES: [Br:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[F:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][C:18]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.N1C=CC=CC=1.B(O)O>C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[C:15]1[CH:16]=[CH:17][C:18]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[C:13]([F:12])[CH:14]=1
Reactant: Fc1ccc2[nH]ncc2c1Br
Reactant: OB(O)c1ccc(OCc2ccccc2)c(F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: OBO
Solvent: c1ccncc1
Product: Fc1cc(-n2ncc3c(Br)c(F)ccc32)ccc1OCc1ccccc1
Reaction time: 24 h
Yield: 49.7 %

Procedure:
A mixture of 4-bromo-5-fluoro-1H-indazole (D15) (1.008 g, 4.69 mmol), {3-fluoro-4-[(phenylmethyl)oxy]phenyl}boronic acid 1.730 g, 7.03 mmol), copper(II) acetate (1.277 g, 7.03 mmol) and pyridine (0.758 mL, 0.742 g, 9.38 mmol) were stirred together vigorously under an air atmosphere with powdered 4A molecular sieves (5 g) at room temperature. After 6 days another 580 mg of boronic acid were added and stirring continued for a further 24 hrs. The mixture was filtered through celite, the celite was washed with dichloromethane and the combined filtrate was washed with water, dried over Na2SO4 and evaporated. Chromatography (silica gel, 0-100% dichloromethane in isohexane), followed by trituration of the product with diethyl ether gave the title compound (D16) (0.968 g) as a white solid.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.[H-].[Na+].Cl.Cl[CH2:16][C:17]1[N:18]([CH2:22][CH2:23][CH3:24])[CH:19]=[CH:20][N:21]=1.O>C1COCC1>[CH3:1][N:2]([CH2:16][C:17]1[N:18]([CH2:22][CH2:23][CH3:24])[CH:19]=[CH:20][N:21]=1)[C:3]1[CH:4]=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1
Reactant: CCCn1ccnc1CCl
Reactant: CNc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCn1ccnc1CN(C)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.1 %

Procedure:
N-methyl-4-nitroaniline (2.3 g) was dissolved in THF (92 ml), 60% sodium hydride (1.85 g) was added to the solution at 0° C., and the mixture was stirred for 1 hour at room temperature. 2-chloromethyl-1-propylimidazole hydrochloride (3.54 g) was added to the mixture at room temperature and the mixture was stirred for 240 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give N-methyl-4-nitro-N-[(1-propylimidazol-2-yl)methyl]aniline (2.7 g).
Reaction SMILES: C(OC([N:8]1[CH2:24][CH2:23][CH2:22][C@H:9]1[C:10]([NH:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:11])=O)(C)(C)C.C(OCC)(=O)C.[ClH:31]>>[ClH:31].[C:16]1([CH2:15][CH2:14][CH2:13][NH:12][C:10](=[O:11])[C@@H:9]2[CH2:22][CH2:23][CH2:24][NH:8]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NCCCc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(NCCCc1ccccc1)[C@@H]1CCCN1

Procedure:
A solution of 1-(tert-butyloxycarbonyl)-N-(3-phenylpropyl)-L-prolinamide (2.88 g.) in ethyl acetate-hydrogen chloride (3.9 N, 30 ml.) was stirred at room temperature for one half hour, then concentrated. A solution of the residue (2.80 g.) in ethyl acetate was concentrated, affording N-(3-phenylpropyl)-L-prolinamide hydrochloride as a syrup.
Reaction SMILES: [NH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])[NH2:2].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([C:22]2[C@H:31]3[C@H:26]([CH2:27][CH2:28][CH2:29][CH2:30]3)[C:25](=[O:32])N(CCO)N=2)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]>>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([C:22]2[C@H:31]3[C@H:26]([CH2:27][CH:28]=[CH:29][CH2:30]3)[C:25](=[O:32])[N:1]([C:3]3[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=3)[C:6]([OH:8])=[O:7])[N:2]=2)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: NNc1cccc(C(=O)O)c1
Reactant: COc1ccc(C2=NN(CCO)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Product: COc1ccc(C2=NN(c3cccc(C(=O)O)c3)C(=O)[C@H]3CC=CC[C@@H]23)cc1OC

Procedure:
Prepared from compound C and 3-hydrazinobenzoic acid as described for compound 35. Crystallized from ethyl acetate/petroleum ether (60°-80° C.). M.p. 185°-186° C.