Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].N1CCCC1.N1CCCCC1.N1CC[O:25][CH2:24]C1>C1(C)C(C)=CC=CC=1.C1(C)C=CC=CC=1.ClC1C=CC=CC=1.C1C=CC=CC=1>[O:25]1[C:6]2[C:5](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3](=[O:4])[CH2:2][CH2:24]1
Reactant: C1COCCN1
Reactant: O=C(CO)c1ccccc1
Solvent: Clc1ccccc1
Solvent: c1ccccc1
Solvent: C1CCNCC1
Product: O=C1CCOc2ccccc21

Procedure:
2-Hydroxyacetophenon (compound 1, R1 is as defined above) and compound 2 wherein R2 and R3 are as defined above are refluxed under heating in a solvent such as benzene, chlorobenzene, toluene and xylene, in the presence of a secondary amine such as pyrrolidine, piperidine and morpholine, using a Dean-Stark apparatus, while removing liberated water to give 4-chromanon (compound 3 wherein R1, R2 and R3 are as defined above).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11].CS(C)=O.C(N(C(C)C)CC)(C)C>ClCCl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[O:11]
Reactant: OCCCCCCCCCBr
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=CCCCCCCCCBr
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
9-Bromononan-1-ol (3 g. 13.4 mmol) was dissolved in dichloromethane (70 mL, 0.2M) and to this solution were added dimethyl sulfoxide (2.9 mL, 40.3 mmol) and diisopropylethylamine (7.0 mL, 40.3 mmol). The flask was then sealed under nitrogen and cooled to −15° C. Pyridine sulfur trioxide complex (6.4 g, 40.3 mmol) was added in two equal portions over 2 minutes and the resulting mixture was stirred at temperature between −10° C. and −20° C. for 30 minutes. The reaction was then quenched by adding water and the layers were separated. The organic layer was washed with aqueous sodium bisulfate (1M×3) and brine (×1), and then dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound as an amber oil (2.4 g 81% yield). 1H NMR (CDCl3, δ): 9.78 (s, 1H), 3.40 (t, 2H), 2.43 (t, 2H), 1.85 (m, 2H), 1.63 (m, 2H), 1.5-1.25 (m, 8H).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C:17]3([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:10])(=[O:9])[N:8]=1.C(N(CC)CC)C.[C:30](O)(=[O:37])[C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C:17]3([NH:22][C:30](=[O:37])[C:31]4[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=4)[CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:10])(=[O:9])[N:8]=1
Reactant: NC1=NS(=O)(=O)Nc2cccc(OCC3(N)CCCC3)c21
Reactant: O=C(O)c1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC1=NS(=O)(=O)Nc2cccc(OCC3(NC(=O)c4ccncc4)CCCC3)c21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 72.2 %

Procedure:
To a stirred suspension of 4-amino-5-((1-aminocyclopentyl)methoxy)-1H-benzo[c][1,2,6]thiadiazine 2,2-dioxide hydrochloride (346.83 mg, 1 mmol) in DMF (6 mL) was added triethylamine (0.278 mL, 2 mmol). After being stirred at room temperature for 10 min., a mixture of isonicotinic acid (123.11 mg, 1.1 mmol), EDCI (211 mg, 1.1 mmol) and HOBt (149 mg, 1.1 mmol) in 4 ml of DMF was added and the reaction mixture was then stirred at room temperature overnight. The resulting solution was purified by reverse phase HPLC, and then the product was re-crystallized from ethanol/water, after dry to give the title compound as a white solid (300 mg) in 72% yield. M.p.: >250° C. 1H NMR (400 MHz, DMSO-d6) δ 1.65-1.67 (m, 2H), 1.75-1.78 (m, 2H), 1.83-1.88 (m, 2H), 2.19-2.24 (m, 2H), 4.43 (s, 2H), 6.59 (d, J=8.0 Hz, 1H), 6.79 (d, J=8.0 Hz, 1H), 7.43 (t, J=8.0 Hz, 1H), 7.66 (d, J=8.0 Hz, 2H), 7.85 (s, 1H), 8.43 (s, 1H), 8.56 (s, 1H), 8.66 (d, J=8 Hz, 2H), 10.96 (s, 1H). MS 416 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.O=S(Cl)Cl.Cl.[NH:17]1[CH2:20][CH2:19][CH2:18]1.C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[N:17]1([C:5]([C:4]2[CH:8]=[CH:9][C:10]([F:11])=[C:2]([F:1])[CH:3]=2)=[O:7])[CH2:20][CH2:19][CH2:18]1
Reactant: O=C(O)c1ccc(F)c(F)c1
Reactant: C1CNC1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: O=C(c1ccc(F)c(F)c1)N1CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.1 %

Procedure:
3,4-Difluorobenzoic acid (1.03 g, 6.51 mmol) in CH2Cl2 (10 ml) was added SOCl2 (600 uL, 8.26 mmol) and DMF (3 drop). The reaction mixture was heated to reflux for 3 hr. The mixture was evaporated under vacuum and dried. The oil/solid mixture was taken into CH2Cl2 (20 mL) and added azetidine hydrochloride (731 mg, 7.82 mmol) and triethylamine (2.75 mL, 19.7 mmol). The reaction mixture was stirred at room temperature for 2 hr, quenched with 1 N HCl (60 mL) and extracted with EtOAc. The organic layers were dried over MgSO4 and concentrated to give pale yellow oil which was purified by flash column chromatography eluting with 30% EtOAc in hexanes to give a white solid (553 mg, 48% yield). 1H NMR (400 MHz, CDCl3) δ 7.50 (m, 1 H) 7.40 (m, 1 H) 7.16-7.25 (m, 1 H) 4.32 (d, J=6.82 Hz, 2 H) 4.24 (d, J=7.07 Hz, 2H) 2.33-2.42 (m, 2 H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>ClC(Cl)C.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:18][C:17]2[CH:20]=[CH:21][CH:22]=[C:15]([Cl:14])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=Cc1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccc(Cl)c2)CC1
Yield: 87.4 %

Procedure:
To a solution of piperazine-1-carboxylic acid tert-butyl ester (4.00 g, 21.5 mmol) in dry dichloroethane (70 mL) are added 3-chlorobenzaldehyde (2.49 mL, 3.08 g, 21.9 mmol), HOAc (2.58 mL, 2.71 g, 45.1 mmol) and NaBH(OAc)3 (5.46 g, 25.8 mmol) at ambient temperature. After stirring at ambient temperature for 3d, 2N NaOH (40 mL) is added, the layers are separated, and the aqueous layer is extracted with CH2Cl2 (4×50 mL). The combined organic extracts are washed with water (3×50 mL) and brine (80 mL) and dried over MgSO4. The crude material is purified by chromatography on silica gel, eluting with hexane:EtOAc mixtures, yielding 5.83 g (18.8 mmol, 87%) of the title compound as yellow oil. MS (ES): m/z 311.0/313.0 (50/18) [MH+]. tR (method A)=5.0 min.
Reaction SMILES: C1C2C(=CC=CC=2)C=CC=1.[Na].C1(C)C(S([N:21]2[C:30]([CH3:32])([CH3:31])[CH2:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22]2)(=O)=O)=CC=CC=1>C(COC)OC.COCOC>[CH3:31][C:30]1([CH3:32])[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][NH:21]1
Reactant: Cc1ccccc1S(=O)(=O)N1Cc2ccccc2CC1(C)C
Agent: [Na]
Solvent: COCCOC
Solvent: COCOC
Solvent: c1ccc2ccccc2c1
Product: CC1(C)Cc2ccccc2CN1
Yield: 85.3 %

Procedure:
To a stirred solution of naphthalene (5.8 g, 0.045 mol) in dimethoxyethane (50 mL) was added sodium metal (1.09 g, 0.039 mol.). The mixture was allowed to stir for four (4) hours until a dark green color persisted. To this was added of N-toluenesulfonyl-3,3-dimethyl-1,2,3,4-tetrahydroisoquinoline (5.0 g, 0.016 mol.) in 20 mL of dimethoxymethane. The reaction was monitored by gas chromatography. When the reaction was complete (≈2 hours), the mixture was quenched with saturated sodium chloride (70 mL). The mixture was partitioned between ethyl acetate (250 mL) and 10% HCL (250 mL) and the organic layer was discarded. 10% Sodium hydroxide was added to the aqueous layer until a pH=7 was obtained. The aqueous layer was further extracted over methylene chloride (2×100 mL), dried over magnesium sulfate, filtered and concentrated (25° C./150 torr) to produce 2.2 g (86%) of 3,3-dimethyl-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: [C:1]1([C:7](=[O:16])[CH2:8][S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:17]Br>C(O)(=O)C>[Br:17][CH:8]([S:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:16]
Reactant: O=C(CSc1ccccc1)c1ccccc1
Reactant: BrBr
Solvent: CC(=O)O
Product: O=C(c1ccccc1)C(Br)Sc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 1-phenyl-2-(phenylthio)ethanone (2.1 g) in acetic acid (20 mL) was added bromine (0.5 mL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound as a yellow oil (yield 2.9 g, about 100%).
Reaction SMILES: [CH3:1][Mg]Br.[C:4]([C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][CH2:10][CH2:11]2)(=[O:6])[CH3:5]>C1(C)C=CC=CC=1.C1COCC1.C1COCC1.C(OCC)(=O)C>[OH:6][C:4]([C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][CH2:10][CH2:11]2)([CH3:1])[CH3:5]
Reactant: C[Mg]Br
Reactant: CC(=O)c1cccc2c1CCC2
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(O)c1cccc2c1CCC2
Reaction time: 0.5 h

Procedure:
10 ml (14 mmol) of a 1.4 M methylmagnesium bromide solution in toluene-THF (3:1) is added in drops at 0° C. to a solution of 1.6 g (10 mmol) of 4-acetylindan (F. Dallacker, J. Van Wersch, Chem. Ber. 1972, 105, 2565) in 40 ml of THF. After 30 minutes at 0° C. and 1.5 hours at room temperature, the batch is diluted with 200 ml of ethyl acetate, washed with 1 M hydrochloric acid and saturated NaCl, dried (Na2SO4) and concentrated by evaporation in a vacuum. Column chromatography of the residue on silica gel with hexane-ethyl acetate yields 0.64 g of product.
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.CC([O-])(C)C.[K+].[Br:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1F>C1COCC1>[Br:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1[O:5][CH2:4][CH:1]1[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1
Reactant: OCC1CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(OCC2CC2)c(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.4 %

Procedure:
A 0.2 M solution of cyclopropyl methanol (441 uL, 5.5 mmol) in THF stirred at 0° C. under an atmosphere of nitrogen was treated with 2 equal portions of KOtBu (579 mg, 5.2 mmol). After 5 min the ice bath was removed; the mixture was stirred for 30 min at rt before resubmerging in the ice bath and cooling to 0° C. A solution of 2-bromo-1-fluoro-4-nitrobenzene (1 g, 4.5 mmol) in THF (3 mL) was added dropwise. After 20 min, the ice bath was removed and the mixture was stirred overnight. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (3×50 ml). The combined organic layers were washed brine (30 mL), dried over Na2SO4, filtered and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography using a gradient of EtOAc (5 to 50%) in hexanes to afford the title compound (1.07 g, 88%) as a yellow solid.
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7]([NH2:14])=[N:8][NH:9]2.CC(N(CC1C=CC(CN2C3C(=C(OC)C=CC=3)C(NS(C3SC(Cl)=CC=3)(=O)=O)=N2)=CC=1)C(=O)[O-])(C)C.Cl[CH2:53][C:54]1[CH:59]=[CH:58][C:57]([O:60][CH3:61])=[C:56]([O:62][CH3:63])[CH:55]=1>CS(C)=O.O>[CH3:63][O:62][C:56]1[CH:55]=[C:54]([CH2:53][N:9]2[C:10]3[C:6](=[C:5]([O:4][CH3:3])[CH:13]=[CH:12][CH:11]=3)[C:7]([NH2:14])=[N:8]2)[CH:59]=[CH:58][C:57]=1[O:60][CH3:61]
Reactant: COc1ccc(CCl)cc1OC
Reactant: COc1cccc2[nH]nc(N)c12
Agent: COc1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1ccc(CN(C(=O)[O-])C(C)(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(Cn2nc(N)c3c(OC)cccc32)cc1OC
Reaction time: 0.25 h
Yield: 84 %

Procedure:
Powdered KOH (0.494 g, 8.80 mmol) was dissolved in DMSO (20 mL) under nitrogen and 4-(methyloxy)-1H-indazol-3-amine (for a preparation see Intermediate 1) (0.653 g, 4 mmol) was added. The mixture was stirred for 15 min to give a deep red solution. 4-(Chloromethyl)-1,2-bis(methyloxy)benzene (0.896 g, 4.80 mmol) was added in one portion and the mixture was stirred for 2 h. The mixture was added to water (150 mL) and extracted with dichloromethane (3×50 mL). The dried (Na2SO4) extract was evaporated and the residue was triturated with diethyl ether (3×3 mL) to give the title compound (1.05 g, 84%) as an orange solid. LCMS (System B) RT=2.22 min, ES+ve m/z 314 (M+H)+.
Reaction SMILES: C(OC(C(N(C1C=CN=CC=1)[C@H](C(O)=O)C)C1CC2C(=CC=CC=2)C1)=O)C.C(OC(=O)CN)C1C=CC=CC=1.C([O:47][C:48](=[O:77])[CH2:49][NH:50][C:51](=[O:76])[C@H:52]([CH3:75])[N:53]([C:69]1[CH:74]=[CH:73][N:72]=[CH:71][CH:70]=1)[CH:54]([C:64]([O:66][CH2:67][CH3:68])=[O:65])[CH:55]1[CH2:63][C:62]2[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=2)[CH2:56]1)C1C=CC=CC=1.[H][H]>[Pd]>[CH2:67]([O:66][C:64]([CH:54]([N:53]([C:69]1[CH:70]=[CH:71][N:72]=[CH:73][CH:74]=1)[C@H:52]([C:51]([NH:50][CH2:49][C:48]([OH:77])=[O:47])=[O:76])[CH3:75])[CH:55]1[CH2:56][C:57]2[C:62](=[CH:61][CH:60]=[CH:59][CH:58]=2)[CH2:63]1)=[O:65])[CH3:68]
Reactant: CCOC(=O)C(C1Cc2ccccc2C1)N(c1ccncc1)[C@@H](C)C(=O)NCC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: CCOC(=O)C(C1Cc2ccccc2C1)N(c1ccncc1)[C@@H](C)C(=O)O
Agent: NCC(=O)OCc1ccccc1
Product: CCOC(=O)C(C1Cc2ccccc2C1)N(c1ccncc1)[C@@H](C)C(=O)NCC(=O)O

Procedure:
Using examples given above, N-[1-Ethoxycarbonyl-1-(2,3-dihydro-1H-inden-2-yl)-methyl]-(4-pyridyl)-alanine and glycine benzyl ester are reacted and the resulting N-[1-Ethoxycarbonyl-1-(2,3-dihydro-1H-inden-2-yl)-methyl]-(4-pyridyl)-alanyl-glycine benzyl ester treated with hydrogen in the presence of palladium on carbon to give the title compound.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:18])([F:17])[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[NH:12][O:13][C:14](=[O:16])[N:15]=2)[CH:6]=1.[Cl:19][C:20]1[CH:30]=[CH:29][CH:28]=[CH:27][C:21]=1[C:22]([O:24][CH2:25]Cl)=[O:23].[Cl-].[NH4+]>CN(C)C=O>[Cl:19][C:20]1[CH:30]=[CH:29][CH:28]=[CH:27][C:21]=1[C:22]([O:24][CH2:25][N:15]1[C:14](=[O:16])[O:13][N:12]=[C:11]1[C:7]1[CH:6]=[C:5]([C:4]([F:3])([F:17])[F:18])[CH:10]=[CH:9][N:8]=1)=[O:23]
Reactant: O=c1nc(-c2cc(C(F)(F)F)ccn2)[nH]o1
Reactant: O=C(OCCl)c1ccccc1Cl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=C(OCn1c(-c2cc(C(F)(F)F)ccn2)noc1=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 13.5 %

Procedure:
Into 2 ml of N,N-dimethylformamide was suspended 0.07 g of sodium hydride (60% oily), and 0.3 g of 3-(4-trifluoromethylpyridin-2-yl)-1,2,4-oxadiazol-5-one was added at room temperature. After stirring for 10 minutes, 0.5 g of chloromethyl 2-chlorobenzoate, and the mixture was stirred at 60° C. for 4 hours. The reaction solution was allowed to cool to room temperature, and poured into an aqueous saturated ammonium chloride solution, followed by extraction with ethyl acetate three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.07 g of [3-(4-trifluoromethylpyridin-2-yl)-1,2,4-oxadiazol-5-on-4-yl]methyl 2-chlorobenzoate (present compound (31)).
Reaction SMILES: [N:1]1([C:5](=[O:25])[CH2:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][C:21]=3[Cl:22])[NH:18][CH:17]=[C:16]4[CH:23]=[O:24])=[CH:9][CH:8]=2)[CH2:4][CH2:3][CH2:2]1.CC(=CC)C.Cl([O-])=[O:32].[Na+].O.O.OP([O-])(O)=O.[Na+]>C(#N)C.C(O)(C)(C)C.O>[N:1]1([C:5](=[O:25])[CH2:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][C:21]=3[Cl:22])[NH:18][CH:17]=[C:16]4[C:23]([OH:32])=[O:24])=[CH:9][CH:8]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1c[nH]c2cc(Cl)c(-c3ccc(CC(=O)N4CCC4)cc3)cc12
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: CC#N
Solvent: O
Product: O=C(O)c1c[nH]c2cc(Cl)c(-c3ccc(CC(=O)N4CCC4)cc3)cc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 15 %

Procedure:
To a solution of 5-{4-[2-(azetidin-1-yl)-2-oxoethyl]phenyl}-6-chloro-1H-indole-3-carbaldehyde (0.16 g, 0.453 mmol) in acetonitrile (8 mL) and tert-butanol (8 mL) was added 2-methyl-2-butene (8 mL). The reaction mixture was cooled to 0° C. and treated with a solution of sodium chlorite (456 mg, 5 mmol) and sodium phosphate monobasic dihydrate (1.06 g, 6.8 mmol) in water (6 mL). The reaction mixture was stirred for 2 hours at room temperature, and treated with additional sodium chlorite (607 mg, 6.67 mmol), sodium phosphate monobasic dihydrate (1.41 g, 9.04 mmol) and 2-methyl-2-butene (1 mL). The resulting mixture was stirred at room temperature overnight. The reaction mixture was partially evaporated in vacuo and extracted with EtOAc (30 mL×3). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified via prep-HPLC to give 5-{4-[2-(azetidin-1-yl)-2-oxoethyl]phenyl}-6-chloro-1H-indole-3-carboxylic acid (25 mg) as a yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([C:13]3([CH2:26][C:27]#[N:28])[CH2:18][CH2:17][N:16]([C:19]([C:21]4[O:25][N:24]=[CH:23][CH:22]=4)=[O:20])[CH2:15][CH2:14]3)[CH:12]=2)[CH:5]=[CH:4][N:3]=1.[N:29]1([C:34]2[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=2)[CH:33]=[CH:32][CH:31]=[N:30]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1.C(#N)C.O>[O:25]1[C:21]([C:19]([N:16]2[CH2:17][CH2:18][C:13]([CH2:26][C:27]#[N:28])([N:11]3[CH:12]=[C:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([NH:38][C:37]5[CH:36]=[CH:35][C:34]([N:29]6[CH:33]=[CH:32][CH:31]=[N:30]6)=[CH:40][CH:39]=5)[N:7]=4)[CH:9]=[N:10]3)[CH2:14][CH2:15]2)=[O:20])=[CH:22][CH:23]=[N:24]1
Reactant: N#CCC1(n2cc(-c3ccnc(Cl)n3)cn2)CCN(C(=O)c2ccno2)CC1
Reactant: Nc1ccc(-n2cccn2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: O
Solvent: C1COCCO1
Product: N#CCC1(n2cc(-c3ccnc(Nc4ccc(-n5cccn5)cc4)n3)cn2)CCN(C(=O)c2ccno2)CC1

Procedure:
A mixture of (4-(4-(2-chloropyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(isoxazol-5-ylcarbonyl)piperidin-4-yl)acetonitrile (30 mg, 0.08 mmol), 4-(1H-pyrazol-1-yl)aniline (18.9 mg, 0.119 mmol), and p-toluenesulfonic acid (12 mg, 0.067 mmol) in dry 1,4-dioxane (0.6 mL) was refluxed overnight. The mixture was diluted with acetonitrile and water, purified on RP-HPLC to give the desired product as a racemic mixture (22 mg, 52%). LCMS (M+H) 521.1.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:8]=2[C:9](O)=[O:10])=[CH:4][CH:3]=1.O1CCCC1.[OH-].[Na+]>C1C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:8]=2[CH2:9][OH:10])=[CH:17][CH:18]=1
Reactant: Cc1ccc(Oc2ccc(C)cc2C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: Cc1ccc(Oc2ccc(C)cc2CO)cc1

Procedure:
A solution of 121 g. of 2-(4-methyl-phenoxy)-5-methyl-benzoic acid in 600 ml. of tetrahydrofuran is slowly added dropwise, with cooling in an icebath, to 420 ml. of a 70% solution of sodium dihydro-bis(1-methoxyethoxy)aluminate in benzene and stirred for an additional hour at room temperature. To the obtained clear solution, 800 ml. of 20% aqueous sodium hydroxide solution are carefully added dropwise. Then, the organic phase is separated. The aqueous phase is extracted three additional times with ether. The organic extracts are washed with saturated sodium chloride solution and the latter dried over sodium sulfate. After evaporation of the ether, there is obtained 2-(4-methylphenoxy)-5-methyl-benzyl alcohol as an oil.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].CN(C)C=O.Cl.CN(C)CCCN=C=NCC.[Br:36][C:37]1[CH:38]=[C:39]([NH2:44])[C:40]([NH2:43])=[CH:41][CH:42]=1>C(OCC)(=O)C.N1C=CC=CC=1>[Br:36][C:37]1[CH:42]=[CH:41][C:40]2[NH:43][C:15]([CH2:14][C:9]3[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[N:8]=3)=[N:44][C:39]=2[CH:38]=1
Reactant: Nc1ccc(Br)cc1N
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1cc(N2CCOCC2)nc(Cc2nc3cc(Br)ccc3[nH]2)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.8 %

Procedure:
In a round-bottomed flask, 1.3 g of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate are introduced into 10 ml of dimethylformamide and then 10 ml of pyridine, 1.44 g of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride and 1.87 g of 4-bromobenzene-1,2-diamine are added. The reaction mixture is stirred at ambient temperature overnight and is then concentrated to dryness under reduced pressure. The residue is taken up in 40 ml of acetic acid and brought to reflux for 4 hours, then concentrated under reduced pressure. 100 ml of water are then added and a saturated aqueous solution of sodium bicarbonate is added until a pH in the region of 7 is obtained. 200 ml of ethyl acetate are then added and the resulting mixture is stirred for 1 hour. The precipitate formed is filtered then purified by silica gel column chromatography, elution being carried out with a gradient of the eluent CH2Cl2/MeOH: 80/20 in dichloromethane of 0% to 100% in 25 minutes. 560 mg of 2-[(5-bromo-1H-benzimidazol-2-yl)methyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of an off-white solid, the characteristics of which are the following:
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[N:8][C:9](I)=[C:10]([Cl:13])[CH:11]=2)[N:6]=[C:5]1[O:15][C@@H:16]1[CH2:20][O:19][C@@H:18]2[C@H:21]([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH2:22][O:23][C@H:17]12)[CH:2]=[CH2:3].CC1(C)C(C)(C)OB([C:40]2[CH:45]=[CH:44][C:43]([N:46]3[CH2:50][CH2:49][CH2:48][CH2:47]3)=[CH:42][CH:41]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C(Cl)Cl>[CH2:1]([N:4]1[C:12]2[C:7](=[N:8][C:9]([C:40]3[CH:41]=[CH:42][C:43]([N:46]4[CH2:47][CH2:48][CH2:49][CH2:50]4)=[CH:44][CH:45]=3)=[C:10]([Cl:13])[CH:11]=2)[N:6]=[C:5]1[O:15][C@@H:16]1[CH2:20][O:19][C@@H:18]2[C@H:21]([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH2:22][O:23][C@H:17]12)[CH:2]=[CH2:3]
Reactant: C=CCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O[Si](C)(C)C(C)(C)C)nc2nc(I)c(Cl)cc21
Reactant: CC1(C)OB(c2ccc(N3CCCC3)cc2)OC1(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: C=CCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O[Si](C)(C)C(C)(C)C)nc2nc(-c3ccc(N4CCCC4)cc3)c(Cl)cc21
Temperature: 80 °C
Reaction time: 15 h

Procedure:
1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichlormethane complex (17.1 mg, 0.021 mmol) was added to a stirred suspension of [(3R,3aR,6R,6aS)-3-(1-allyl-6-chloro-5-iodo-imidazo[4,5-b]pyridin-2-yl)oxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy-tert-butyl-dimethyl-silane (99.8 mg, 0.173 mmol), 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidine (59.6 mg, 0.218 mmol), and tripotassium phosphate (225.0 mg, 1.060 mmol) in dioxane (1.38 ml) and water (0.35 ml). The reaction mixture was degassed (3×) and placed under nitrogen before being heated to 80° C. After 15 hours, the reaction mixture was cooled to room temperature. The reaction mixture was partitioned between EtOAc (40 ml) and water (40 ml). The aqueous layer was extracted with EtOAc (2×20 ml). The organic layers were combined, washed with brine, dried over MgSO4, filtered, and evaporated under reduced pressure to give an amber residue. This residue was dissolved in DCM, loaded onto a 5 g silica solid load cartridge and purified using an ISCO Rf and a 4 g silica column (CV=4.8 ml). The column was eluted as follows: 100% hexane (5 CV), 0-30% EtOAc/hexane gradient (70 CV), 30% EtOAc/hexane (21 CV) at 18 ml/min. The product fractions were combined and evaporated under reduced pressure to give the title compound as a yellow residue. LC-MS: calculated for C31H41ClN4O4Si 596.26 observed m/e: 597.39 (M+H)+ (Rt 1.34/2 min).