Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9]([OH:11])=[O:10])=[N:4][CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[CH3:13]O>>[Br:1][C:2]1[C:3]([C:9]([O:11][CH3:13])=[O:10])=[N:4][CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CO
Reactant: O=C(O)c1nccc(Cl)c1Br
Agent: Cl
Product: COC(=O)c1nccc(Cl)c1Br
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-bromo-4-chloropyridine-2-carboxylic acid (1.75 g, 7.4 mmol) in MeOH was added anhydrous HCl. The resulting mixture was stirred at room temperature for 18 hr. The reaction mixture was concentrated to give a solid, which was partitioned between Et2O and saturated NaHCO3. Organic layer was dried over MgSO4, filtered and concentrated to give a brown residue. This material was purified via flash column chromatography to yield 1.35 g of product as a pale yellow oil.
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[C:13]1([CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C[Si](C)(C)Cl.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:41])(=O)=O)=CC=1>C1COCC1.C(Cl)Cl>[CH3:25][O:24][C:22](=[O:23])[CH:21]([F:41])[CH2:20][CH2:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)CCCc1ccccc1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: COC(=O)C(F)CCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 62.9 %

Procedure:
nBuLi (13.8 ml, 22 mmol, 1.6 M in hexane) was added dropwise into a 0° C. solution of diisopropylamine (3.39 ml,24 mmol) in THF (34 ml). The reaction mixture was stirred at 0° C. for 15 minutes then cooled to −75 ° C. and treated slowly with a solution of methyl 4-phenylbutyrate (3.56 g, 20 mmol) in THF (10 ml). After 30 minutes stirring at −75° C., trimethylchlorosilane ( 5.06 ml, 40 mmol) was added dropwise and the reaction mixture was allowed to warm up to room temperature. After 30 minutes, reaction mixture was concentrated, the residue was taken up in CH2Cl2 (100 ml), the resulting precipitate was filtered, filtrate was cooled to 13° C. and subsequently treated slowly with a solution of N-fluorodibenzenesulfonimide (6.3 g, 20 mmol) in CH2Cl2 (50 ml). After 3 hours stirring at room temperature, the reaction mixture was washed with H2O (2 times). The aqueous phase was extracted with CH2Cl2, the combined organic phases were dried over Na2SO4 and concentrated. The residue was chromatographed over silica gel (hexane-ethylacetate 99:1 then 98:2) to provide (RS)-2-fluoro-4-phenyl-butyric acid methyl ester (2.47 g, 63%) as a colorless oil, MS: m/e=196.1 (M+).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH2:11]([C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])(C)(C)C.[K+]>CS(C)=O>[CH2:11]([C:18]1[CH:19]=[CH:20][C:21]([NH:22][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])=[CH:23][CH:24]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: Nc1ccc(Cc2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccccc1Nc1ccc(Cc2ccccc2)cc1

Procedure:
The product (621 mg) is obtained according to the method of stage 1 of Example 4, by using 958 μL of 2-fluoro-nitrobenzene and 2 g of 4-benzylaniline in the presence of 1.63 of potassium tert-butanolate in 30 mL of DMSO.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][N:17]=3)[C:12](=[O:19])[C:11]3[CH2:20][CH2:21][O:22][C:10]2=3)=[CH:5][CH:4]=1.[I-].[Na+]>CC(N(C)C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:18]3[N:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:12]3[O:19][CH2:21][CH2:20][C:11]=3[C:10]2=[O:22])=[CH:5][CH:4]=1
Reactant: COc1ccc(-n2c3c(c(=O)c4cccnc42)CCO3)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1ccc(-n2c(=O)c3c(c4cccnc42)OCC3)cc1
Temperature: 0 °C

Procedure:
A solution of 3,9-dihydro-9-(4-methoxyphenyl)-furo[2,3-b][1,8]naphthyridin-4(2H)-one (1 g.) and sodium iodide (1 g.) in dry dimethylacetamide (10 ml.) was heated to 70° C. for 4 hr in a nitrogen atmosphere. The product was cooled, poured over ice-water, filtered, dried and recrystallized from CH2Cl2 to yield the desired product, m.p. 282°-284° C.
Reaction SMILES: C([O:9][CH2:10][CH2:11][N:12]1[C:24]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[C:16]([Cl:25])[C:15]=2[N:14]=[CH:13]1)(=O)C1C=CC=CC=1.N>CO>[Cl:25][C:16]1[C:15]2[N:14]=[CH:13][N:12]([CH2:11][CH2:10][OH:9])[C:24]=2[C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:17]=1
Reactant: O=C(OCCn1cnc2c(Cl)nc3ccccc3c21)c1ccccc1
Agent: N
Solvent: CO
Product: OCCn1cnc2c(Cl)nc3ccccc3c21
Temperature: 20 °C
Reaction time: 72 h

Procedure:
A mixture of 25.3 g (0.072 mole) of 1-(2-benzoyloxyethyl)-4-chloro-1H-imidazo[4,5-c]quinoline (from Example 120) and 500 ml of 10% ammonia in methanol was stirred at about 20° C. for three days, and was filtered and then evaporated to low volume. The slurry was mixed with diethyl ether, and the solid was separated by filtration, washed with ether and recrystallized from methanol to provide white crystals of 4-chloro-1-(2-hydroxyethyl)-1H-imidazo[4,5-c]quinoline, m.p. 185°-187° C. Analysis: Calculated for C12H10ClN3O: %C, 58.2; %H, 4.1; %N, 17.0; Found: %C, 58.0; %H, 4.0; %N, 17.3.
Reaction SMILES: Br[CH:2]1[C:20](=[O:21])[C:6]2=[CH:7][CH:8]=[C:9]3[C:14]([O:13][CH2:12][C:11]4[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:10]3=4)=[C:5]2[CH2:4][CH2:3]1.[N:22]1([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:29][CH2:28][CH2:27][C@H:23]1[C:24]([OH:26])=[O:25].C(N(C(C)C)CC)(C)C>C(#N)C.C(OCC)(=O)C>[N:22]1([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:29][CH2:28][CH2:27][CH:23]1[C:24]([O:26][C@@H:2]1[C:20](=[O:21])[C:6]2=[CH:7][CH:8]=[C:9]3[C:14]([O:13][CH2:12][C:11]4[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:10]3=4)=[C:5]2[CH2:4][CH2:3]1)=[O:25]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: O=C1c2ccc3c(c2CCC1Br)OCc1cc(Cl)ccc1-3
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)O[C@H]1CCc2c(ccc3c2OCc2cc(Cl)ccc2-3)C1=O
Temperature: 50 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
To a solution of 2-bromo-8-chloro-2,3,4,6-tetrahydro-1H-dibenzo[c,h]chromen-1-one (1.05 g, 2.9 mmol) and Boc-Pro-OH (1.75 g, 8.1 mmol) in acetonitrile (9.0 mL) was added diisopropylethylamine (1.5 mL, 8.7 mmol). The solution was stirred under argon at 50° C. for two hours. Extra Boc-Pro-OH (620 mg, 2.9 mmol) and diisopropylethylamine (0.5 mL, 2.9 mmol) were added and the reaction was stirred at 50° C. for 16 hours. The reaction was cooled to room temperature and diluted with ethyl acetate. The organics were washed with water and brine, dried with magnesium sulfate and concentrated. The crude material was purified by flash column chromatography and the product (2S)-1-tert-butyl 2-(8-chloro-1-oxo-2,3,4,6-tetrahydro-1H-dibenzo[c,h]chromen-2-yl) pyrrolidine-1,2-dicarboxylate was isolated as a mixture of diastereomers (0.99 g, 69% yield).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH:9]12[CH2:15][CH:12]([CH:13]=[CH:14]1)[CH:11]=[CH:10]2>C1(C)C=CC=CC=1>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([S:1][CH:10]2[CH2:11][CH:12]3[CH2:15][CH:9]2[CH:14]([S:1][C:2]2[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=2)[CH2:13]3)=[CH:3][CH:4]=1
Reactant: Oc1ccc(S)cc1
Reactant: C1=CC2C=CC1C2
Solvent: Cc1ccccc1
Product: Oc1ccc(SC2CC3CC(Sc4ccc(O)cc4)C2C3)cc1
Temperature: 25 °C

Procedure:
To the reactor of Example 1 was added 66 grams of 4-mercaptophenol, 100 ml. toluene and 24.1 grams of 2,5-norbornadiene. The mixture was reacted for 2.5 hours at 70° C. The mixture was cooled to ambient temperature and after 16 hours the white solid was filtered and washed with benzene. The product contained 17.9% sulfur and had a melting point of 142°-146° C.
Reaction SMILES: [CH:1]1([CH2:6][N:7]2[C:12](=[O:13])[C:11]([C:14]([O:16]CC)=O)=[CH:10][C:9]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[N:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1(C)C(C)=CC=CC=1>[CH2:27]([NH:34][C:14]([C:11]1[C:12](=[O:13])[N:7]([CH2:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[N:8]=[C:9]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[CH:10]=1)=[O:16])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(=O)c1cc(-c2ccc(OC)cc2)nn(CC2CCCC2)c1=O
Reactant: NCc1ccccc1
Solvent: Cc1ccccc1C
Product: COc1ccc(-c2cc(C(=O)NCc3ccccc3)c(=O)n(CC3CCCC3)n2)cc1
Yield: 78.5 %

Procedure:
In xylene, 2-cyclopentylmethyl-4-ethoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one and benzylamine were reacted at 140° C. for 2 hours. Post-treatments were conducted as in Example 68, whereby the title compound was obtained in a yield of 78.5%.
Reaction SMILES: C(OC(=O)[N:7]([C:16]1[N:17]([CH2:21][C:22]2[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[CH:23]=2)[CH:18]=[CH:19][N:20]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:29][C:24]1[CH:23]=[C:22]([CH:27]=[C:26]([Cl:28])[CH:25]=1)[CH2:21][N:17]1[CH:18]=[CH:19][N:20]=[C:16]1[NH:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(F)cc1)c1nccn1Cc1cc(Cl)cc(Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1ccc(CNc2nccn2Cc2cc(Cl)cc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 63 %

Procedure:
To a solution of [1-(3,5-dichloro-benzyl)-1H-imidazol-2-yl]-(4-fluoro-benzyl)-carbamic acid tert-butyl ester in CH2Cl2 was added trifluoroacetic acid. The reaction solution was stirred at room temperature for 3 h. When all the starting material was consumed, the mixture was diluted with CH2Cl2 and washed with water. The organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel preparative TLC using CH2Cl2:MeOH 95:5 as an eluent to afford the title compound (24 mg, 63%); LCMS m/z 350 [C17H14Cl2FN3+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.C(=O)(O)[O-].[Na+]>O1CCCC1>[N:14]1([C:11](=[O:13])[CH2:10][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: C1COCCN1
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Cc1ccc([N+](=O)[O-])cc1)N1CCOCC1
Temperature: 35 °C
Reaction time: 1 h

Procedure:
A room temperature solution of 1.8839 gms. (4-Nitro-phenyl)-acetic acid in tetrahydrofuran (5 mL) is treated with 1.8069 gms. 1′,1′-carbonyl-diimidizole. The reaction mixture is stirred for 1 h. The reaction mixture is then treated with 1.0 mL morpholine. The reaction is heated overnight at 35° C. The reaction is then allowed to cool to room temperature, and is made basic with the addition of saturated aqueous sodium bicarbonate. The resulting mixture is extracted with ethyl acetate. The aqueous layer is re-extracted four more times with ethyl acetate. The combined organics are evaporated to dryness in vacuo. The crude product residue is then chromatographed by flash silica gel chromatography using 60% ethyl acetate in hexanes as the eluant. Following evaporation of solvent, 1-morpholin-4-yl-2-(4-nitro-phenyl)-ethanone is isolated as a white solid in the amount of 1.4009 gms.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][N:8]([C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:27])[NH:23][CH2:24][CH2:25][CH3:26])=[CH:18][CH:17]=1)=[O:14])[CH2:7]2)([O-])=O.[H][H]>CN(C)C=O.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][N:8]([C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:27])[NH:23][CH2:24][CH2:25][CH3:26])=[CH:18][CH:17]=1)=[O:14])[CH2:7]2
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc([N+](=O)[O-])cc3C2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Product: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(N)cc3C2)cc1

Procedure:
A solution of 5-nitro-N-[4-(propylcarbamoyl)phenyl]-1,3-dihydro-2H-isoindole-2-carboxamide (37 mg, 0.1 mmol) in 1 ml dimethylformamide in the presence of 11 mg of 10% Pd on carbon was treated with a hydrogen balloon overnight at room temperature. The suspension was filtered through diatomaceous earth and purified by reverse-phase HPLC to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.51 (s, 1H), 8.24 (t, J=5.6 Hz, 1H), 7.74-7.78 (m, 2H), 7.62-7.66 (m, 2H), 7.19 (d, J=7.9 Hz, 1H), 6.78-6.89 (m, 2H), 4.67-4.71 (m, 4H), 3.15-3.26 (m, 2H), 1.46-1.59 (m, 2H), 0.89 (t, J=7.4 Hz, 3H); MS (ESI(+)) m/e 339 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH:9]=[CH:10]OCC)=[CH:4][N:3]=1.Cl>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH:9]=[CH:10][NH:8][C:6]=2[N:7]=1
Reactant: CCOC=Cc1cnc(Cl)nc1N
Agent: Cl
Product: Clc1ncc2cc[nH]c2n1

Procedure:
To a solution of 2-Chloro-5-(2-ethoxy-vinyl)-pyrimidin-4-ylamine (38.0 g, 0.19 mol) in ETOH (1000 ml) is added concentrated aqueous HCl (37%, 100 g, 1.00 mol) at rt. The reaction mixture is heated to reflux for 3 h and then evaporated to dryness under reduced pressure. Aqueous sodium carbonate solution (5%, 500 mL) is added to the residue, and the mixture is extracted with EtOAc (3×). The combined organic layers are dried over MgSO4, filtered, and concentrated under reduced pressure. The residue is recrystallized from hexane/ether (4/1, 250 ml) to give the title compound as an off-white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].[H-].[Na+].Br[CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>CN(C=O)C>[C:27]([O:26][C:24]([CH2:23][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C(OCc1ccccc1)c1cc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cn1c(C(=O)OCc2ccccc2)cc2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
50.25 g of benzyl 2-indolecarboxylate (Preparation 2.1, step A) are dissolved in 140 ml of anhydrous DMF, followed by addition over 30 minutes, under a stream of dry nitrogen, of a solution of 6.6 g of NaH at 80% in oil, in 100 ml of DMF. The reaction medium is stirred for 90 minutes at RT and is then cooled on an ice bath and 42.91 ml of tert-butyl bromoacetate are added dropwise. After stirring at RT overnight, the DMF is evaporated off and the residue is taken up in DCM and then in water. After stirring, the phases are separated by settling and the aqueous phase is then extracted twice-with DCM; the combined organic phases are washed with saturated NaCl solution and then dried over MgSO4. After filtration and evaporation, the residue is taken up in a mixture of 100 ml of ethyl ether and 100 ml of heptane. After stirring for 2 hours, the crystals formed are filtered off and then washed with 50 ml of a heptane/ethyl ether mixture (70/30; v/v) and dried in an oven. 58 g of the expected product are obtained: m.p. 95-96° C.
Reaction SMILES: C([O:5][C:6]([CH2:8][N:9]1[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([NH:40][CH2:41][C:42]([O:44]C(C)(C)C)=[O:43])[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28]3[C:33]4=[N:34][O:35][N:36]=[C:32]4[C:31]([N+:37]([O-:39])=[O:38])=[CH:30][CH:29]=3)=[CH:23][CH:22]=2)[CH2:14][CH2:13][N:12]([CH2:49][C:50]([O:52]C(C)(C)C)=[O:51])[CH2:11][CH2:10]1)=[O:7])(C)(C)C.Cl.CCOCC>O1CCOCC1>[C:50]([CH2:49][N:12]1[CH2:13][CH2:14][N:15]([CH2:18][CH:19]([NH:40][CH2:41][C:42]([OH:44])=[O:43])[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28]3[C:33]4=[N:34][O:35][N:36]=[C:32]4[C:31]([N+:37]([O-:39])=[O:38])=[CH:30][CH:29]=3)=[CH:23][CH:22]=2)[CH2:16][CH2:17][N:9]([CH2:8][C:6]([OH:7])=[O:5])[CH2:10][CH2:11]1)([OH:52])=[O:51]
Reactant: CC(C)(C)OC(=O)CNC(Cc1ccc(Nc2ccc([N+](=O)[O-])c3nonc23)cc1)CN1CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: O=C(O)CNC(Cc1ccc(Nc2ccc([N+](=O)[O-])c3nonc23)cc1)CN1CCN(CC(=O)O)CCN(CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100.9 %

Procedure:
To a solution of Compound 16 (15.7 mg, 0.02 mmol) in 1,4-dioxane (1 mL) at 0-5° C. was added 4M HCl(g) in 1,4-dioxane (1 mL) dropwise over ˜15 min. The resulting mixture was allowed to warm to room temperature. Ether (˜15 mL) was added to the reaction mixture and stirred for 10 min. The resulting mixture was placed in the freezer for 1 h. The solid residue was filtered and washed with ether and quickly dissolved in 18μΩ deionized water. Evaporation of the aqueous solution gave pure Compound 17 (12.4 mg, 90%) as an orange solid. 1H NMR (CD3OD) δ 2.82-3.48 (m, 13H), 3.78-4.08 (m, 10H), 6.76 (d, 1H), 7.40-7.55 (m, 4H), 8.51 (d, 1H). HRMS (Positive ion FAB) Calcd for C27H34N8O9 [M+H]+ m/z 615.2527. Found: [M+H]+ m/z 615.2520. Analytical HPLC (tR=3.6 min, Method 2).
Reaction SMILES: CN(C=O)C.[C:6]1([C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:18]([CH2:21][NH:22][C:23]4[CH:24]=[CH:25][N:26]=[C:27]5[C:32]=4[N:31]=[CH:30][C:29]([OH:33])=[CH:28]5)=[N:19][N:20]=3)[N:17]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl[C:35]([F:40])([F:39])C([O-])=O.[Na+].C(=O)([O-])[O-].[Cs+].[Cs+]>O>[F:39][CH:35]([F:40])[O:33][C:29]1[CH:28]=[C:27]2[C:32]([C:23]([NH:22][CH2:21][C:18]3[N:16]4[N:17]=[C:12]([C:6]5[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=5)[CH:13]=[CH:14][C:15]4=[N:20][N:19]=3)=[CH:24][CH:25]=[N:26]2)=[N:31][CH:30]=1
Reactant: Oc1cnc2c(NCc3nnc4ccc(-c5ccccc5)nn34)ccnc2c1
Reactant: O=C([O-])C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)Oc1cnc2c(NCc3nnc4ccc(-c5ccccc5)nn34)ccnc2c1
Temperature: 100 °C
Reaction time: 18 h
Yield: 17.7 %

Procedure:
DMF (0.5 mL) and water (0.1 mL) were added to a pressure vessel containing 8-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylamino)-1,5-naphthyridin-3-ol (50 mg, 135 μmol), sodium 2-chloro-2,2-difluoroacetate (47 mg, 311 μmol), cesium carbonate (62 mg, 190 μmol). The reaction mixture was stirred at 100° C. for 18 h, cooled to RT and concentrated in vacuo. Purification by MPLC (DCM/MeOH+1% NH4OH: 100/0 to 90/10) afforded the title compound (10 mg, 17% yield). MS m/z=420.1 [M+H]+. Calc'd for C21H15F2N7O: 419.40.
Reaction SMILES: C(OC([NH:8][C:9]1([CH2:14][OH:15])[CH2:13][CH2:12][O:11][CH2:10]1)=O)(C)(C)C.[ClH:16].O1CCOCC1>>[ClH:16].[NH2:8][C:9]1([CH2:14][OH:15])[CH2:13][CH2:12][O:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)NC1(CO)CCOC1
Agent: Cl
Solvent: C1COCCO1
Product: NC1(CO)CCOC1

Procedure:
A solution of [3-(tert-butoxycarbonylamino)oxolan-3-yl]methanol (2.50 g, 11.5 mmol) in 4M HCl-dioxane (30 mL) was stirred at room temperature for 2 h. The mixture was concentrated in vacuo and dried to give (3-aminooxolan-3-yl)methanol hydrochloride as a pale brown oil (2.17 g, quant.). 1H-NMR (400 MHz, DMSO-d6) δ 1.89-2.01 (2H, m), 3.51-3.58 (2H, m), 3.66 (2H, s), 3.71-3.76 (1H, m), 3.86-3.92 (1H, m), 8.33 (3H, brs).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][O:13][CH2:14][CH2:15][CH2:16][NH2:17]>>[Br:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([NH:17][CH2:16][CH2:15][CH2:14][O:13][CH3:12])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1Br
Reactant: COCCCN
Product: COCCCNc1cc(Br)ccc1[N+](=O)[O-]
Reaction time: 48 h

Procedure:
A solution of 26.49 g of 2,4-dibromo-1-nitrobenzene [51686-78-3] and 70 ml of 3-methoxypropylamine is stirred at room temperature for 4 hours and subsequently left to stand at 3° C. for 2 days. The reaction mixture is concentrated by evaporation. The title compound is obtained as a yellow oil from the residue by means of flash chromatography (SiO2 60F). Rf=(1:3 EtOAc-heptane). Rt=4.99 (gradient I).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][N:25]([CH2:37][CH3:38])[C:26](=[N:34][C:35]#[N:36])OC2C=CC=CC=2)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[CH2:40]([NH2:43])[CH2:41][CH3:42]>>[CH2:1]([O:3][C:4](=[O:39])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:16][C:15]=2[CH2:24][N:25]([CH2:37][CH3:38])[C:26]([NH:43][CH2:40][CH2:41][CH3:42])=[N:34][C:35]#[N:36])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=NC#N)Oc2ccccc2)c1
Reactant: CCCN
Product: CCCNC(=NC#N)N(CC)Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OCC)ccc1OC

Procedure:
Prepared according to the procedure described in Example 33, Step 6, using the following starting materials: [2′-(3-cyano-1-ethyl-2-phenyl-isoureidomethyl)-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid ethyl ester and propylamine.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:11]=[C:12]=S)=[N:7][NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.Cl.[NH2:23][CH2:24][C@@:25]1([OH:33])[CH:30]2[CH2:31][CH2:32][N:27]([CH2:28][CH2:29]2)[CH2:26]1.C(N=C=NC(C)C)(C)C>CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([NH:11][C:12]3[O:33][C@:25]4([CH2:24][N:23]=3)[CH:30]3[CH2:31][CH2:32][N:27]([CH2:28][CH2:29]3)[CH2:26]4)=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: NC[C@]1(O)CN2CCC1CC2
Reactant: Fc1ccc2c(N=C=S)n[nH]c2c1
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Fc1ccc2c(NC3=NC[C@@]4(CN5CCC4CC5)O3)n[nH]c2c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 63.5 %

Procedure:
To 6-fluoro-3-isothiocyanato-1H-indazole (0.20 g, 1.04 mmol) in DMF (15 mL) was added triethylamine (0.43 mL, 3.11 mmol) and (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (0.26 g, 1.14 mmol) at room temperature. The reaction was stirred at 70° C. for 2 hours. The reaction was cooled to room temperature and treated with N,N′-diisopropylcarbodiimide (0.48 mL, 3.11 mmol). The reaction was then heated to 70° C. for 2 hours. The reaction was cooled to ambient temperature and concentrated. The crude product was purified by column chromatography (85% chloroform, 14% methanol, 1% ammonium hydroxide) to afford (R)—N-(6-fluoro-1H-indazol-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (0.22 g, 0.66 mmol, 64% yield) as a white powder. 1H NMR (500 MHz, DMSO-D6) δ ppm 12.16 (s, 1H), 8.00 (s, 1H), 7.59-7.67 (m, 1H), 7.09 (dd, J=9.77, 2.14 Hz, 1H), 6.81-6.88 (m, 1H), 3.81 (d, J=9.16 Hz, 1H), 3.56 (d, J=8.85 Hz, 1H), 3.00 (s, 2H), 2.78 (s, 2H), 2.67 (t, J=7.32 Hz, 2H), 2.01 (d, J=2.44 Hz, 1H), 1.92 (s, 1H), 1.59 (d, J=5.80 Hz, 2H), 1.46 (s, 1H). MS (LC/MS) R.T.=1.44; [M+H]+=316.16.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@@H:21](/[CH:31]=[CH:32]/[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39](=[O:47])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[C@@:22]([OH:30])([CH2:26][CH2:27][O:28][CH3:29])[C:23]([OH:25])=[O:24])=[O:20])[C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[BH4-].[Na+].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO.C(OCC)(=O)C>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@@H:21](/[CH:31]=[CH:32]/[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH:39]([OH:47])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[C@@:22]([OH:30])([CH2:26][CH2:27][O:28][CH3:29])[C:23]([OH:25])=[O:24])=[O:20])[C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:11]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CCOC)C(=O)O)C(=O)OC)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(O)CCCCCCC)[C@@](O)(CCOC)C(=O)O)C(=O)OC)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 57 %

Procedure:
No. 5233427 (14.4 mg, 0.022 mmol) was dissolved in methanol (1.0 mL), and the solution was cooled to 0° C. in an ice bath. Sodium tetrahydroborate (5 mg, 0.13 mmol) was added, and the mixture was stirred for 3 hours. The progress of the reaction was stopped by adding water, and the mixture was diluted in ethyl acetate. An aqueous solution of 0.5 M citric acid was added and the mixture was separated. The separated organic layer was washed with water and a saturated brine in order, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated. The residue was purified by diol thin layer chromatography (dichloromethane:methanol=50 50) to obtain the target compound at a yield of 57%.