Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.[OH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][N:15]=2)[N:10]=[CH:9][C:8]=1[C:17]([OH:19])=[O:18].O[N:21]1[C:25](=[O:26])[CH2:24][CH2:23][C:22]1=[O:27].S(Cl)(Cl)=O>N1C=CC=CC=1>[OH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][N:15]=2)[N:10]=[CH:9][C:8]=1[C:17]([O:19][N:21]1[C:25](=[O:26])[CH2:24][CH2:23][C:22]1=[O:27])=[O:18]
Reactant: O=C(O)c1cnc2cccnc2c1O
Reactant: O=C1CCC(=O)N1O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: O=C(ON1C(=O)CCC1=O)c1cnc2cccnc2c1O
Temperature: 25 °C
Reaction time: 5 h
Yield: 101.7 %

Procedure:
To a solution of dimethylformamide (47.5 kg) containing pyridine (4.7 kg), there were added 4-hydroxy-1,5-naphthyridine-3-carboxylic acid (2.8 kg) and N-hydroxy-succinimide (2.2 kg). To the mixture, there was dropwise added thionyl chloride (2.1 kg) while stirring at room temperature, and stirring was continued for 5 hours at the same temperature. The precipitated crystals were collected by filtration, washed with acetone and dried under reduced pressure to give 4.3 kg of N-(4-hydroxy-1,5-naphthyridine-3-carbonyloxy)succinimide. Purity, 97%
Reaction SMILES: [C:1]([C:4]1[O:5][CH:6]=[CH:7][C:8]=1Br)(=[O:3])[CH3:2].[C:10](=[S:12])=[S:11].[H-].[Na+].[CH3:15]O.CI>CN(C)C=O.O>[CH3:15][S:11][C:10]1[S:12][C:8]2[CH:7]=[CH:6][O:5][C:4]=2[C:1](=[O:3])[CH:2]=1
Reactant: CO
Reactant: CC(=O)c1occc1Br
Reactant: S=C=S
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: CSc1cc(=O)c2occc2s1
Temperature: 25 °C
Yield: 111.9 %

Procedure:
In accordance with the process disclosed in Tetrahedron, 35, 551 (1979), 2-acetyl-3-bromofuran (10.0 g, 53.2 mmol) and carbon disulfide (7.0 g, 93.2 mmol) were dissolved in anhydrous dimethylformamide (70 ml) and the solution was added with 55% sodium hydride (4.0 g, 93.2 mmol) over about 1.5 hours while it was stirred and inner temperature was maintained below 10° C. under ice cooling. After further stirring for 0.5 hour at the temperature, the solution was added with methanol (1.1 ml, 26.6 mmol) and further stirred at room teperature for 40 minutes. Then, the solution was heated and stirred in the boiling water bath for 1 hour and allowed to cool to room temperature. Under water cooling, the solution was added dropwise with methyl iodide (22.6 g, 159.6 mmol) and stirred at room temperature for 24 hours. The solution was injected into ice water, extracted with dichloromethane (300 ml×2 times), washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was recrystallized from ethanol using active carbon to obtain 5.9 g (yield: 56%) of 5-methylthio-7-oxo-7H-thiopyrano[3,2-b]furan as colorless needles.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][OH:10].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.CCOCC>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]=[O:10]
Reactant: OCCc1ccccc1Br
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: O=CCc1ccccc1Br
Reaction time: 15 h

Procedure:
A solution of 9.11 grams (0.045 mole) of 2-(2-bromophenyl)ethanol in 35 milliliters of methylene chloride was added to a stirred suspension of 14.62 grams (0.063 mole) of pyridinium chlorochromate in 75 milliliters of methylene chloride at ambient temperature whereupon a slightly exothermic reaction took place with the formation of a black reaction mixture. Stirring was continued for 15 hours at ambient temperature; then 150 milliliters of ether was added and the mixture filtered through silica gel on a pad of celite. The insoluble residue was washed with 100 milliliters of ether, filtered, the ether solutions combined and the solvents evaporated on a rotary evaporator to recover as residue, 8.0 grams (90 percent) of the desired 2-(2-bromophenyl)acetaldehyde intermediate as an oil. The oil had an Rf of 0.6 on silica gel when eluted with one percent methanol in chloroform.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[N:8]([C:22]3[CH:27]=[CH:26][C:25]([O:28]C)=[CH:24][CH:23]=3)[C:9]3[C:14]([C:15]=2[C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:5]([CH3:30])[O:4][N:3]=1.B(Br)(Br)Br.O.O1CCOCC1>C(Cl)Cl>[CH3:1][C:2]1[C:6]([C:7]2[N:8]([C:22]3[CH:23]=[CH:24][C:25]([OH:28])=[CH:26][CH:27]=3)[C:9]3[C:14]([C:15]=2[C:16](=[O:21])[C:17]([F:20])([F:18])[F:19])=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:5]([CH3:30])[O:4][N:3]=1
Reactant: COc1ccc(-n2c(-c3c(C)noc3C)c(C(=O)C(F)(F)F)c3ccccc32)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1noc(C)c1-c1c(C(=O)C(F)(F)F)c2ccccc2n1-c1ccc(O)cc1
Temperature: 25 °C

Procedure:
1-(2-(3,5-dimethylisoxazol-4-yl)-1-(4-methoxyphenyl)-1H-indol-3-yl)-2,2,2-trifluoroethanone was dissolved in dry DCM and the mixture was cooled on an ice-bath under an atmosphere of nitrogen. BBr3 (17 μl, 0.1 mmol) was added and the temperature was allowed to warm to RT and the mixture was stirred over night. Water, DCM and some dioxane were added, the phases were separated and the solvents were evaporated. The residue was passed through a short plug of silica with EtOAc as eluent. The residue was purified by preparative HPLC to provide the title compound 1-(2-(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-1H-indol-3-yl)-2,2,2-trifluoroethanone in 46% yield. ES/MS m/z: 401.1 (M+H), 399.1 (M−H); 1H NMR (methanol-d4, 500 MHz): 8.26 (m, 1H), 7.41-7.34 (m, 2H), 7.18 (m, 1H), 7.11 (m, 2H), 6.89 (m, 2H), 2.19 (s, 3H) and 2.01 (s, 3H).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].[Na].[C:10](#[N:13])[CH:11]=[CH2:12].O>C(O)C>[NH2:13][C:10]1[CH2:11][CH2:12][N:1]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=2)[N:2]=1
Reactant: NNc1ccccn1
Reactant: C=CC#N
Agent: [Na]
Solvent: CCO
Solvent: O
Product: NC1=NN(c2ccccn2)CC1

Procedure:
2-Hydrazinopyridine (0.545 g) was added to a solution of sodium (50 mg; 0.43 atoms) in dry absolute ethanol (2 ml) in a nitrogen atmosphere. Acrylonitrile (0.265 g; 0.32 ml; 1 mol) was added dropwise and the resulting solution heated for 4 hours on the steam bath. The reaction mixture was cooled, giving some crystals, and treated with water (10 ml) to give a suspension of a solid. The solid was collected and washed with water. Recrystallisation from ethanol (ca. 5 ml) gave the title compound m.p. 168°-169.5°. Thin Layer Chromatography: On Al2O3 in CHCl3 gave a single spot Rf 0.18.
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]([O:13][CH3:14])[NH:8][CH:9]=[C:10]([C:11]#[N:12])[C:5]=2[N:4]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:3]=1.CC1(C)C(C)(C)OB([C:28]2[CH:29]=[C:30]([C:33]([NH2:35])=[O:34])[S:31][CH:32]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O>[C:11]([C:10]1[C:5]2[N:4]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[CH:3]=[C:2]([C:28]3[CH:29]=[C:30]([C:33]([NH2:35])=[O:34])[S:31][CH:32]=3)[C:6]=2[C:7]([O:13][CH3:14])=[N:8][CH:9]=1)#[N:12]
Reactant: COC1NC=C(C#N)c2c1c(Br)cn2C1CCCC1
Reactant: CC1(C)OB(c2csc(C(N)=O)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1ncc(C#N)c2c1c(-c1csc(C(N)=O)c1)cn2C1CCCC1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 68.1 %

Procedure:
A mixture of 3-bromo-1-cyclopentyl-4-methoxy-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-7-carbonitrile (400 mg), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxamide (553 mg) obtained in Step B of Example 33, (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (102 mg), 2M aqueous sodium carbonate solution (1.24 mL) and DME (3.5 mL) was stirred under microwave irradiation at 120° C. for 1 hr 30 min. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (310 mg).
Reaction SMILES: [NH2:1][C:2]1[NH:3][CH2:4][CH2:5][CH:6]=1.C([O:9][CH:10]=[C:11]([C:17](OCC)=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])C>C(O)C>[O:9]=[C:10]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:17][N:3]2[CH2:4][CH2:5][CH2:6][C:2]2=[N:1]1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: NC1=CCCN1
Solvent: CCO
Product: CCOC(=O)c1cn2c(nc1=O)CCC2
Temperature: 0 °C
Reaction time: 1 h
Yield: 48.4 %

Procedure:
42 g. of 2-amino-pyrroline are dissolved in 400 ml. of ethanol and at 0°-7° C. a solution of 108 g. of diethyl ethoxy-methylene-malonate in 200 ml. ethanol is added dropwise. After the addition is completed the mixture is stirred for 1 hour at 0° C., and allowed to stand for 12 hours at -5° C. The precipitated crystals are filtered. After evaporation of the alcohol the residue is boiled with 200 ml. of benzene. After cooling the insoluble crystals are filtered off. The filtered crystals are combined and recrystallized from ethanol. 50.3 g. (48.4%) ethyl 2-oxo-2,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidine-3-carboxylate are obtained, melting at 193° C.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][SH:10].[Cl:11][C:12]1[CH:13]=[C:14]([S:19]([NH2:22])(=[O:21])=[O:20])[CH:15]=[CH:16][C:17]=1F.O>O1CCCC1>[Cl:11][C:12]1[CH:13]=[C:14]([S:19]([NH2:22])(=[O:20])=[O:21])[CH:15]=[CH:16][C:17]=1[S:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH3:3]
Reactant: NS(=O)(=O)c1ccc(F)c(Cl)c1
Reactant: COCCOCCS
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCCOCCSc1ccc(S(N)(=O)=O)cc1Cl
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
In a 25 ml, microwave tube was added sodium hydride (0.6 g) in tetrahydrofuran (10 mL) to give a suspension. 2-(2-Methoxyethoxy)ethanethiol (1 g) was added slowly. After stirring for 30 minutes, 3-chloro-4-fluorobenzenesulfonamide (1.54 g) dissolved in 10 mL tetrahydrofuran was added slowly. The mixture was heated at 110° C. for 30 minutes in a Biotage Initiator microwave reactor. Water was added, the product was extracted with ether (20 mL×3), dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography on silica eluting with 0-25% ethyl acetate in hexane.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].O=[C:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:14][CH2:13]1.N1CCCC1>CO>[C:18]([N:15]1[CH2:16][CH2:17][C:12]2([CH2:9][C:8](=[O:10])[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[O:1]2)[CH2:13][CH2:14]1)([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CC(=O)c1ccccc1O
Solvent: CO
Solvent: C1CCNC1
Product: O=C1CC2(CCN(C(=O)OCc3ccccc3)CC2)Oc2ccccc21

Procedure:
The synthesis of compound 19A-19D is outlined in Scheme 19. The 2′-hydroxyacetophenone 1.1a was condensed with benzyl 4-oxopiperidine-1-carboxylate (19.1) in refluxing methanol in the presence of pyrrolidine to provide N-Cbz-spiro[2H-1-benzopyran-2,4′-piperidine]-4(3H)-one (19.2). Conversion of the ketone 19.2 to the enol triflate derivative 19.3 was achieved using N-phenylbis(trifluoromethanesulphonimide) 1.4 as triflating reagent. Conversion of the enol triflate 19.3 to the corresponding boron derivative 19.4 was achieved using 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane 1.14 and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct, abbreviated as [Pd(dppf)Cl2.CH2Cl2]. Suzuki type coupling of the boronate derivative 19.4 with tert-butyl 4-bromophenylcarbamate 19.5 in ethylene glycol dimethyl ether in the presence of tetrakis triphenylphosphine palladium(0), lithium chloride, and an aqueous solution of sodium carbonate afforded the tert-butyloxycarbonyl (Boc) protected aniline derivative 19.6. Acidic hydrolysis of 19.6 provided the aniline derivative 19.7 which reacted with acyl chlorides 19.8a, 19.8b, isopropylsulfonyl chloride (6.5b) or ethyl isocyanate (19.11) to give the corresponding amide derivatives 19.9, sulfonamide derivative 19.10 or urea derivative 19.12, respectively. The derivatives 19.9, 19.10 and 19.12 were converted to compounds 19A-19D by treatment with iodotrimethylsilane.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.CCN(CC)CC.[Cl:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([S:33](Cl)(=[O:35])=[O:34])[CH:31]=2)[C:26]([Cl:37])=[CH:25][N:24]=1>C(Cl)Cl>[Cl:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([S:33]([NH:1][C@@H:2]3[CH2:3][CH2:4][C@H:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]3)(=[O:35])=[O:34])[CH:31]=2)[C:26]([Cl:37])=[CH:25][N:24]=1
Reactant: O=S(=O)(Cl)c1ccc2c(Cl)cnc(Cl)c2c1
Reactant: CC(C)(C)OC(=O)[C@H]1CC[C@@H](N)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)[C@H]1CC[C@@H](NS(=O)(=O)c2ccc3c(Cl)cnc(Cl)c3c2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of t-butyl cis-4-aminocyclohexanecarboxylate (282 mg, 1.20 mmol), NEt3 (0.33 mL, 2.37 mmol) and 1,4-dichloro-7-isoquinolinesulphonyl chloride (296 mg, 1.00 mmol) in CH2Cl2 (10 mL) was stirred at 0° C. for 1 h. The mixture was diluted with CH2Cl2 (150 mL), was washed with dilute HCl (30 mL, 1 M), water, dried (MgSO4) and evaporated in vacuo. The residue was purified by column chromatography upon silica gel using pentane-EtOAc (100:0 to 75:25) to give t-butyl cis-4-{[(1,4-dichloro-7-isoquinolinyl)sulphonyl]amino}cyclohexanecarboxylate (360 mg, 0.78 mmol) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([SH:9])[C:5]([SH:8])=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:17]1[C:18](=[O:25])[N:19]([CH3:24])[C:20](=[O:23])[C:21]=1Cl.O>CN(C=O)C>[CH3:24][N:19]1[C:20](=[O:23])[C:21]2[S:9][C:4]3[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][C:5]=3[S:8][C:17]=2[C:18]1=[O:25]
Reactant: CN1C(=O)C(Cl)=C(Cl)C1=O
Reactant: Cc1ccc(S)c(S)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2sc3c(=O)n(C)c(=O)c=3sc2c1
Temperature: 80 °C
Reaction time: 7 h

Procedure:
A stirred solution of 4-methylbenzene-1,2-dithiol (0.5 g) in anhydrous DMF (50 ml) was treated with K2CO3 and 3,4-dichloro-1-methyl-pyrrole-2,5-dione (0.73 g) and stirred for about 7 hours at 80° C. The reaction mixture was poured into water and extracted with MTBE. The combined organic phases were washed once with water and after removal of the solvent under reduced pressure the crude product (0.85 g) was purified by flash column chromatography on silica gel (cyclohexane/ethyl acetate 9:1) to yield the compound ex. I-2 (0.25 g); m.p.: 171-176° C.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH:2]1[CH:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18]O)[CH2:13][CH2:12]1.CCN(S(F)(F)[F:26])CC.O>ClCCl>[O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH:2]1[CH:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][F:26])[CH2:13][CH2:12]1
Reactant: OCCC1CCC(C2COC3(CCCCC3)O2)CC1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Solvent: O
Product: FCCC1CCC(C2COC3(CCCCC3)O2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The above 2-(4-(1,4-dioxaspiro[4.5]decyl)cyclohexyl)ethanol (20 g, 70.8 mmol) was dissolved in dichloromethane (70 ml), followed by dropwise adding to the solution, DAST (13 g, 80.7 mmol), stirring at 0° C. for one hour, adding water to the reaction solution, washing the resulting organic layer successively with a saturated aqueous solution of sodium bicarbonate and water, distilling off the solvent, purifying the residue according to column chromatography using heptane/ethyl acetate as a developing solvent, on silica gel, to obtain 1-(4-(1,4-dioxaspiro[4,5]decyl)cyclohexyl)-2-fluoroethane, adding thereto formic acid (80 ml), refluxing the mixture for 2 hours, extracting the resulting product with toluene, washing the extraction solution successively with a saturated aqueous solution of sodium bicarbonate, distilling off the solvent, to isolate 4-(4-(2-fluoroethyl)cyclohexyl)cyclohexanone (8.0 g, 35.3 mmol). The yield of this product from 2-(4-(1,4-dioxaspiro[4,5]decyl)cyclohexyl)ethanol was 49.9%.
Reaction SMILES: [Br-:1].[CH3:2][N+:3]([CH3:23])([CH2:20][CH2:21]O)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].P(Br)(Br)[Br:25]>C1C=CC=CC=1>[Br-:25].[CH3:2][N+:3]([CH3:23])([CH2:20][CH2:21][Br:1])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCCCCCCCC[N+](C)(C)CCO
Reactant: BrP(Br)Br
Agent: [Br-]
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCCCC[N+](C)(C)CCBr
Reaction time: 24 h
Yield: 213.3 %

Procedure:
A total of 3.95g (0.010 mole) of dimethyl-(2-hydroxy)ethyl-hexadecyl ammonium bromide and 0.9910g (0.00366 mol phosphorous tribromide was slurried in 20 ml of benzene and allowed to react at room temperature (about 25° C.) with stirring for 24 hours under nitrogen. The solvent was removed in vacuo and the residue washed several times with anhydrous ether. The resulting amorphous solid was recrystallized from ethyl acetate, filtered and dried to yield 3.57g (77%) of the desired product. Calc. % C 52.51, % H 9.49, %N 3.06, %Br 34.93; Found % C 51.80, H 10.06, %N 3.06, % Br 34.18; m.p. 185°-190° C. The 1H NMR and IR agree with the proposed structure.
Reaction SMILES: [CH2:1]([N:3](CC)[CH2:4]C)[CH3:2].C(N=C=S)C.[NH2:13][C:14]1[C:15]([Cl:30])=[N:16][C:17]2[C:22]([C:23]=1[NH:24][CH2:25][C:26]([CH3:29])([OH:28])[CH3:27])=[CH:21][CH:20]=[CH:19][CH:18]=2>N1C=CC=CC=1>[Cl:30][C:15]1[C:14]2[N:13]=[C:4]([NH:3][CH2:1][CH3:2])[N:24]([CH2:25][C:26]([CH3:27])([OH:28])[CH3:29])[C:23]=2[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:16]=1
Reactant: CC(C)(O)CNc1c(N)c(Cl)nc2ccccc12
Reactant: CCN(CC)CC
Solvent: CCN=C=S
Solvent: c1ccncc1
Product: CCNc1nc2c(Cl)nc3ccccc3c2n1CC(C)(C)O
Temperature: 80 °C
Yield: 77.2 %

Procedure:
Triethylamine (3.15 mL, 22.6 mmol) and ethyl isothiocyanate (1.19 mL, 13.6 mmol) were sequentially added to a solution of 1-[(3-amino-2-chloro-4-quinolinyl)amino]-2-methyl-2-propanol (3.00 g, 11.3 mmol) in pyridine (50 mL), and the reaction was heated for five minutes at 80° C. 1,(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.60 g, 13.6 mmol) was added slowly, and the reaction was heated overnight at 80° C., allowed to cool to ambient temperature, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (300 mL), and the resulting solution was washed with brine (3×) and water (1×), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting with 2-3% methanol in dichloromethane) to provide 2.78 g of 1-[4-chloro-2-(ethylamino)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]3([CH2:14][CH2:13]3)[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH2:64]([N:66]1[CH2:72][CH2:71][CH2:70][N:69]([CH:73]2[CH2:78][CH2:77][CH:76]([NH2:79])[CH2:75][CH2:74]2)[CH2:68][CH2:67]1)[CH3:65]>CN(C=O)C>[CH:1]1([N:6]2[CH2:12][C:11]3([CH2:14][CH2:13]3)[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:79][CH:76]5[CH2:75][CH2:74][CH:73]([N:69]6[CH2:70][CH2:71][CH2:72][N:66]([CH2:64][CH3:65])[CH2:67][CH2:68]6)[CH2:78][CH2:77]5)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCN1CCCN(C2CCC(N)CC2)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CC1)C(=O)N2C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN1CCCN(C2CCC(NC(=O)c3ccc(Nc4ncc5c(n4)N(C4CCCC4)CC4(CC4)C(=O)N5C)c(OC)c3)CC2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-(9′-Cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-3-methoxybenzoic acid (Intermediate 5) (44 mg, 0.1 mmol, 1 eq), DIPEA (35 μl, 0.2 mmol, 2 eq) and TBTU (36 mg, 0.12 mmol, 1.2 eq) were added to 1 mL DMF and the resulting solution was stirred at rt for 20 min before the addition of 4-(4-ethyl-1,4-diazepan-1-yl)cyclohexanamine (Intermediate 15) as the trihydrochloride salt (32 mg, 0.1 mmol, 1 eq) and DIPEA (53 μL, 0.3 mmol, 3 eq). The RM was then stirred at rt for 2 hours before purifying by preparative RP-HPLC-MS (Preparative—2) to provide 4-(9′-cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-N-(4-(4-ethyl-1,4-diazepan-1-yl)cyclohexyl)-3-methoxybenzamide as a mixture cis and trans isomers (white solid, 10 mg, 16%).
Reaction SMILES: [CH2:1]([O:8][C@H:9]([CH3:13])[C@@H:10]([OH:12])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:16](I)[CH2:17][CH2:18][CH3:19].O>CN(C)C=O>[CH2:1]([O:8][C@@H:9]([C@@H:10]([O:12][CH2:16][CH2:17][CH2:18][CH3:19])[CH3:11])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCI
Reactant: C[C@H](O)[C@@H](C)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCO[C@@H](C)[C@@H](C)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.3 %

Procedure:
1.90 g of (2S,3R)-3-benzyloxy-2-butanol was dissolved in 50 ml of dry N,N-dimethylformamide. Thereto was added in small portions 2.53 g of about 60% oily sodium hydride. The mixture was stirred for 1 hour at room temperature. 11.63 g of butyl iodide was dropped with ice cooling. The mixture was stirred overnight at room temperature. The reaction mixture was poured into water. The resulting mixture was extracted with ether three times. The extract was washed with water three times, dried and concentrated. The residue was subjected to Kugel-rohr distillation (1 mmHg) to obtain 2.05 g of (2R,3S)-2-benzyloxy-3butoxybutane.
Reaction SMILES: [NH:1]1[C:9]2[CH2:8][CH2:7][CH2:6][C:5](=[N:10]O)[C:4]=2[CH:3]=[CH:2]1.CC(C[AlH]CC(C)C)C.[F-].[Na+].O>C(Cl)Cl>[NH:1]1[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][NH:10][C:4]=2[CH:3]=[CH:2]1
Reactant: ON=C1CCCc2[nH]ccc21
Agent: CC(C)C[AlH]CC(C)C
Agent: [F-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: c1cc2c([nH]1)CCCCN2
Reaction time: 2 h
Yield: 33.4 %

Procedure:
To a stirred solution of 1,5,6,7-tetrahydro-indol-4-one oxime (1.2 g, 7.7 mmol) in DCM (anhydrous, 250 mL) was added DIBAL-H (1M solution in DCM, 35 mL) at 0° C. under nitrogen. After 2 hours, NaF (7 g) was added followed by water (2.24 g). After 20 mins, the reaction was filtered through celite and the solvent was removed to give 350 mg of 1,4,5,6,7,8-hexahydro-pyrrolo[3,2-b]azepine as a brown oil
Reaction SMILES: [F:1][C:2]1([F:37])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[C:24](C(C)(C)C)=[C:25]([CH:29]=[CH:30][CH:31]=5)[C:26]([O-:28])=[O:27])[C:20]([CH3:36])=[CH:19][CH:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.O.Cl>CC#N>[F:37][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=5)[C:26]([OH:28])=[O:27])[C:20]([CH3:36])=[CH:19][CH:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1cccc(C(=O)[O-])c1C(C)(C)C
Agent: Cl
Solvent: O
Solvent: CC#N
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1cccc(C(=O)O)c1
Temperature: 45 °C
Reaction time: 36 h

Procedure:
To a slurry of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate (1.0 eq) in MeCN (3.0 vol) is added water (0.83 vol) followed by concentrated aqueous HCl (0.83 vol). The mixture is heated to 45±5° C. After stirring for 24 to 48 hours the reaction is complete and the mixture is allowed to cool to ambient. Water (1.33 vol) is added and the mixture stirred. The solid is collected by filtration, washed with water (2×0.3 vol), and partially dried on the filter under vacuum. The solid is dried to constant weight (<1% difference) in a vacuum oven at 60° C. with a slight N2 bleed to afford 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid.HCl as an off-white solid.