Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1CCC(CNC(C2C3OCCOC=3C=CC=2)=O)CC1.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31](S(CCCCl)(=O)=O)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].[I-].[Na+].C(N(CC)CC)C>CN(C)C=O>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)CCCCl)CC1
Agent: O=C(NCC1CCNCC1)c1cccc2c1OCCO2
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCNCC1
Temperature: 90 °C
Reaction time: 4 h
Yield: 193.6 %

Procedure:
A mixture of 2,3-dihydrobenzo[1,4]dioxine-5-carboxylic acid(piperidin-4-ylmethyl)amide (28.6 g, 104 mmol), 4-(3-chloropropane-1-sulfonyl)piperazine-1-carboxylic acid tert-butyl ester (33.9 g, 104 mmol), sodium iodide (7.8 g, 52 mmol), and triethylamine (29 mL, 209 mmol) in N,N-dimethylformamide (70 mL) was stirred at 90° C. for 4 hours. The cooled reaction mixture was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with water (three times) and brine, dried (Na2SO4) and the solvents evaporated in vacuo. The crude product was purified by silica gel chromatography (5% methanol-dichloromethane) and crystallization from ethyl acetate-hexane to give 4-[3-(4-{[2,3-dihydrobenzo[1,4]dioxin-5-carbonyl)amino]-methyl}piperidin-1-yl)propane-1-sulfonyl]piperazine-1-carboxylic acid tert-butyl ester (37.5 g, 64%); m.p. 130-132° C. Analysis for C27H43N4O7 S: Calcd.: C, 57.12; H, 7.63; N, 9.87. Found: C, 57.01; H, 7.40; N, 9.94.
Reaction SMILES: [H-].[Na+].Cl.[CH2:4]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:13](=O)[CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH:23]1[CH:28]=[CH:27][C:26](N(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O)=[CH:25][CH:24]=1>CN(C=O)C>[CH2:4]([N:11]1[CH2:12][C:13]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:15][CH2:16]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1=O
Reactant: O=S(=O)(N(c1ccccc1)S(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=C(c2ccccc2)CN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 49.7 %

Procedure:
To a solution of sodium hydride (60% in oil, 6.36 g) in DMF (100 mL) was added ethyl 1-benzyl-3-oxopiperidine-4-carboxylate monohydrochloride (19.0 g) at 0° C., and the mixture was stirred for 5 min. N-phenylbis(trifluoromethanesulfonimide) (25.0 g) was added, and the mixture was stirred at 0° C. for 1 hr. The reaction mixture was poured into ice water, and the resultant product was extracted with ethyl acetate. The organic layer was washed with water and brine and dried, and the solvent was evaporated under reduced pressure. To a mixture of the obtained residue in toluene (125 mL) and water (7.5 mL) were added dihydroxyphenylborane (5.82 g), potassium carbonate (4.40 g) and tetrakis(triphenylphosphine)palladium(0) (3.67 g), and the mixture was stirred under an argon atmosphere at 100° C. for 14 hr. The reaction mixture was poured into water, and the resultant product was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 10→20% ethyl acetate/hexane) to give ethyl 1-benzyl-5-phenyl-1,2,3,6-tetrahydropyridine-4-carboxylate (10.2 g) as a pale yellow oil.
Reaction SMILES: Cl[CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][C:7]([N:13]3[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]3=[O:25])=[C:8]([F:12])[CH:9]=2)[NH:4][C:3]1=[O:26].C(N(CC)CC)C>O1CCCC1.C(Cl)Cl>[F:12][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N:13]1[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:22])([F:23])[F:21])[N:15]([CH3:24])[C:14]1=[O:25])[NH:4][C:3](=[O:26])[CH:2]=[CH:11]2
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc3c(cc2F)CC(Cl)C(=O)N3)c1=O
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc3[nH]c(=O)ccc3cc2F)c1=O
Yield: 97.4 %

Procedure:
A stirred solution of 5.2 grams (0.013 mole) of 3-(3-chloro-6-fluoro-3,4-dihydroquinolin-2-on-7-yl)-1-methyl-6-trifluoromethyluracil and 6.2 grams (0.061 mole) of triethylamine in 200 mL of tetrahydrofuran was concentrated under reduced pressure to a residue. The residue was dissolved in methylene chloride and washed with water. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 4.5 grams of 3-(6-fluoroquinolin-2-on-7-yl)-1-methyl-6-trifluoromethyluracil, mp 179° C., dec. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C(Cl)(=O)C.[NH:5]1[CH2:10][CH2:9][CH:8]=[C:7]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)[CH2:6]1>[OH-].[OH-].[Pd+2].CO>[NH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)[CH2:6]1
Reactant: C1=C(c2c[nH]c3ncccc23)CNCC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)Cl
Solvent: CO
Product: c1cnc2[nH]cc(C3CCCNC3)c2c1
Reaction time: 0.25 h
Yield: 56 %

Procedure:
10 ml acetylchloride was slowly added to 200 ml of MeOH (−10° C.). After 15 minutes, this solution was added to compound 5 (1.43 g, 7.18 mmol) and 20% Pd(OH)2/C (130 mg). The mixture was hydrogenated at 50 psi for 1 hour. The mixture was filtered and concentrated. A subsequent filtration over SCX-2, followed by flash chromatography (MeOH/triethylamine (97/3) afforded compound 6 (0.81 g, 4.02 mmol, 55%) which was reacted with 1 equivalent of fumaric acid in EtOH and concentrated. Recrystallization from EtOH/ethylacetate afforded a solid (free base/fumaric acid (2:1)), mp>225° C. (decomposition). 1H-NMR (400 MHz, D2O): δ 8.04 (bd, J=5 Hz, 1H), 7.93 (bd, J=8 Hz, 1H), 7.13 (bs, 1H), 7.01 (dd, J=8 Hz, 5 Hz, 1H), 6.36 (s, 1H), 3.46-3.40 (m, 1H), 3.37-3.31 (m, 1H), 3.14-3.04 (m, 1H), 2.92-2.82 (m, 2H), 2.0-1.87 (m, 2H), 1.8-1.54 (m, 2H).
Reaction SMILES: C1(C[N:5]2[C:11]3[CH:12]=[CH:13][C:14](C4C=CC(OCCOCCC)=CC=4)=[CH:15][C:10]=3[CH:9]=[C:8]([C:29]([OH:31])=O)[CH2:7][CH2:6]2)CC1.C(Cl)(=O)C([Cl:35])=O.C[N:39](C=O)C>C1COCC1>[ClH:35].[ClH:35].[NH:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:9]=[C:8]([C:29]([NH2:39])=[O:31])[CH2:7][CH2:6]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3CC2CC2)cc1
Reactant: CN(C)C=O
Solvent: C1CCOC1
Product: Cl
Product: NC(=O)C1=Cc2ccccc2NCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In THF (5 ml) was dissolved 1-cyclopropylmethyl-7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.25 g). Under ice-cooling, to the solution were added oxalyl chloride (0.11 ml) and DMF (catalytic amount). The mixture was stirred at room temperature for 1 hour, and the solvent was evaporated under reduced pressure. In THF (25 ml) was dissolved the residue, and the solution was added dropwise to a solution of 4-[N-methyl-N-(tetrahydro-2H-pyran-4-yl)aminomethyl]aniline (0.14 g) and triethylamine (0.41 ml) in THF (5 ml), under ice-cooling. The mixture was stirred at room temperature overnight under nitrogen atmosphere and the solvent was evaporated under reduced pressure. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/methanol/triethylamine), which was dissolved in ethyl acetate. To the solution was added 4N hydrochloric acid-ethyl acetate, and the solvent was evaporated to give 1-cyclopropylmethyl-7-[4-(2-propoxyethoxy)phenyl]-N-[4-[[N-methyl-N-tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide dihydrochloride (Compound 36) (0.32 g) as pale yellow amorphous.
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:4])[CH2:2][OH:3].C(N(C(C)C)CC)(C)C.[Si:22](OS(C(F)(F)F)(=O)=O)([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24].O>C(Cl)Cl>[CH2:6]([O:5][C:1](=[O:4])[CH2:2][O:3][Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(CO)OCc1ccccc1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)[Si](OCC(=O)OCc1ccccc1)(C(C)C)C(C)C
Temperature: 25 °C
Yield: 78.7 %

Procedure:
To a solution of benzyl glycolate (46.91 g, 0.282 mol) and diisopropylethylamine (74 mLs, 0.423 mol) in CH2Cl2, cooled via water bath, was added a solution of TIPSOTf (95 g, 0.31 mol) in CH2Cl2. The resulting mixture was allowed to warm to ambient temperature then poured into water, washed twice with 10% aqueous NaHSO4, dried over Na2SO4 and concentrated in vacuo. Flash chromatography (SiO2, 0 to 5% EtOAc in hexanes) afforded 71.6 g of 663.
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11](=[O:20])[N:12]([CH3:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:6][CH:5]=1.[SH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1>>[S:21]=[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]1[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11](=[O:20])[N:12]([CH3:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:6][CH:5]=1
Reactant: CN(C(=O)Oc1ccc(CCO)cc1)c1ccccc1
Reactant: Sc1ccccn1
Product: CN(C(=O)Oc1ccc(CCn2ccccc2=S)cc1)c1ccccc1
Yield: 25 %

Procedure:
The title compound was prepared in 25% yield as an oil using methyl-phenyl-carbamic acid 4-(2-hydroxy-ethyl)-phenyl ester and 2-mercaptopyridine. HPLC-MS: m/z=365.2 (M+1); Rt=4.08 min.
Reaction SMILES: Cl.[CH3:2]NOC.C(N(CC)CC)C.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=1[CH2:23][C:24](Cl)=O.C[Mg]Br.CCOCC.BrC1C=C(C2[S:46][C:45]([NH:47][C:48](=[O:57])[C:49]3[C:54]([F:55])=[CH:53][CH:52]=[CH:51][C:50]=3[F:56])=[N:44]C=2C)C=CN=1>C(Cl)Cl>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=1[C:23]1[S:46][C:45]([NH:47][C:48](=[O:57])[C:49]2[C:54]([F:55])=[CH:53][CH:52]=[CH:51][C:50]=2[F:56])=[N:44][C:24]=1[CH3:2]
Reactant: COc1ccc(OC)c(CC(=O)Cl)c1
Reactant: CNOC
Reactant: Cc1nc(NC(=O)c2c(F)cccc2F)sc1-c1ccnc(Br)c1
Agent: C[Mg]Br
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(OC)c(-c2sc(NC(=O)c3c(F)cccc3F)nc2C)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Into a slurry of N,O-dimethylhydroxylamine hydrochloride (732 mg, 7.5 mmol) in CH2Cl2 (10.0 mL) at room temperature was added triethylamine (1.52 g, 15.0 mmol). The mixture was stirred at room temperature for 10 minutes, cooled to −78° C. Into the reaction mixture a solution of 2-(2,5-dimethoxyphenyl)acetyl chloride (1.08 g, 5.0 mmol) in CH2Cl2 (5.0 mL) was added dropwise. The mixture was gradually warm to room temperature. After 30 minutes at room temperature, the reaction mixture was quenched by slow addition of a solution of saturated NaHCO3, extracted with CH2Cl2. The extract was dried (Na2SO4), filtered and concentrated to the crude 32a (950 mg). The crude amide was taken up in THF (10.0 mL). Into the resulting solution at 0° C. was added dropwise a solution of 3M methylmagnesium bromide in ether (2.00 mL, 6.00 mmol). The mixture was stirred at room temperature for 3 hours, cooled to 0° C., quenched with ice. The mixture was acidified with 6N HCl. After 1 hour at room temperature, the mixture was neutralized with a solution of saturated NaHCO3, extracted with CH2Cl2. The extract was dried (Na2SO4), filtered and concentrated. The resulting methyl ketone was used directly without purification to prepare Compound 55 in the similar manner as described for the preparation of Compound 27.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8](=O)[CH2:9][CH3:10])=[CH:6][N:5]2[N:12]=[C:13]([NH:15][C:16](=[O:18])[CH3:17])[N:14]=[C:4]2[C:3]=1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=1.[NH:29]([C:31]1[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=1)[NH2:30].[C:39](Cl)(=O)C.BrC1C(C)=C(C2C=CC=C(C(F)(F)F)C=2)C2N(N=C(NC(=O)C)N=2)C=1>>[C:35]([C:34]1[CH:37]=[CH:38][C:31]([N:29]2[C:8]([C:7]3[C:2]([CH3:1])=[C:3]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[CH:20]=4)[C:4]4[N:5]([N:12]=[C:13]([NH:15][C:16](=[O:18])[CH3:17])[N:14]=4)[CH:6]=3)=[C:9]([CH3:10])[CH:39]=[N:30]2)=[CH:32][CH:33]=1)#[N:36]
Reactant: CCC(=O)c1cn2nc(NC(C)=O)nc2c(-c2cccc(C(F)(F)F)c2)c1C
Reactant: N#Cc1ccc(NN)cc1
Reactant: CC(=O)Cl
Agent: CC(=O)Nc1nc2c(-c3cccc(C(F)(F)F)c3)c(C)c(Br)cn2n1
Product: CC(=O)Nc1nc2c(-c3cccc(C(F)(F)F)c3)c(C)c(-c3c(C)cnn3-c3ccc(C#N)cc3)cn2n1

Procedure:
The title compound was prepared from N-[7-methyl-6-propionyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-acetamide (Int. 26, 11 mg, 0.023 mmol) and 4-hydrazino-benzonitrile (7 μL, 0.051 mmol) using similar methods to those employed in Example 40, Steps 3 and 4. During step 4 the acetyl group was lost, which was re-introduced by reaction with acetyl chloride using a similar method to that used for Intermediate 18 to give the title compound as a cream solid (3 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:19][N:18]=[N:17][N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20]CN(C(C)C)C(C)C.CI>CN1C(=O)CCC1.O>[CH3:20][N:18]1[N:17]=[N:16][C:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:10][CH:11]=2)=[N:19]1
Reactant: CCN(C(C)C)C(C)C
Reactant: c1ccc(COc2ccc(-c3nnn[nH]3)cc2)cc1
Solvent: CI
Solvent: O
Solvent: CN1CCCC1=O
Product: Cn1nnc(-c2ccc(OCc3ccccc3)cc2)n1
Temperature: 18 °C

Procedure:
To a stirred solution containing 337 g of the tetrazole and 362 mL of DIPEA in 1 L of NMP cooled to 18° C. under N2 was added dropwise over 1.5 hrs 200 g of methyl iodide in 170 mL NMP. After stirring an additional hour at room temperature, the reaction mixture was diluted with 340 mL of water and the reaction mixture was diluted with 340 mL of water and cooled to 18° C. The resulting solid was collected, washed with water, recrystallized from ethanol and dried in vacuo at 50° C. to give 232.3 g of 2-methyl-5-(4-benzyloxyphenyl)-2H-tetrazole.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C@H:7]2[CH2:11][CH2:10][CH2:9][C@H:8]2[NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])=[CH:4][CH:3]=1.Br[C:22]1C=CC(O[C@@H]2CCCC[C@@H]2N)=CC=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C@@H:7]2[CH2:11][CH2:10][CH2:9][CH2:22][C@@H:8]2[NH:12][S:13]([CH:16]([CH3:17])[CH3:18])(=[O:14])=[O:15])=[CH:19][CH:20]=1
Reactant: CC(C)S(=O)(=O)N[C@@H]1CCC[C@@H]1Oc1ccc(Br)cc1
Reactant: N[C@H]1CCCC[C@H]1Oc1ccc(Br)cc1
Product: CC(C)S(=O)(=O)N[C@H]1CCCC[C@H]1Oc1ccc(Br)cc1

Procedure:
The title compound of Step 7 was prepared according to the general procedure for the synthesis of cis-N-[2-(4-bromophenoxy)cyclopentyl]propane-2-sulfonamide in Example 5, except that (1S,2R)-2-(4-bromophenoxy)cyclohexanamine was used in place of cis-2-(4-bromophenoxy)cyclopentan-amine, and the product purification was carried out using a gradient of 0% to 1% methanol in dichloromethane. N-[(1S,2R)-2-(4-bromophenoxy)cyclohexyl]propane-2-sulfonamide was obtained as a white foam. Yield: 1.67 g, 4.44 mmol, 75%. 1H NMR (400 MHz, CDCl3) δ 1.36 (d, J=6.9 Hz, 3H), 1.37 (d, J=6.9 Hz, 3H), 1.37-1.48 (m, 4H), 1.77-1.88 (m, 3H), 2.06 (m, 1H), 3.12 (septet, J=6.8 Hz, 1H), 3.54 (m, 1H), 4.48 (d, J=9.5 Hz, 1H), 4.54 (m, 1H), 6.84 (d, J=9.0 Hz, 2H), 7.39 (d, J=9.0 Hz, 2H). The enantiomer of N-[(1S,2R)-2-(4-bromophenoxy)cyclohexyl]propane-2-sulfonamide was prepared using similar chemistry to that described above in this Step 7, but employing (1S,2S)-2-(4-bromophenoxy)cyclohexanol as starting material instead of (1R,2R)-2-(4-bromophenoxy)cyclohexanol. The absolute stereochemistry of the enantiomer of N-(1S,2R)-2-(4-bromophenoxy)cyclohexyl]propane-2-sulfonamide was established via X-ray crystallography.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][OH:11].[H-].[Na+].[CH3:14]I.O>O1CCCC1.C(O)(=O)C>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][O:11][CH3:14]
Reactant: Cc1cccc(CCO)c1Br
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: COCCc1cccc(C)c1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.5 %

Procedure:
To a stirred solution of 2-(2-bromo-3-methylphenyl)ethanol (1.6 g, 7.4 mmol) in tetrahydrofuran (20 ml) was added sodium hydride (50% in oil) (0.46 g, 9.6 mmol). After stirring the mixture for 15 min methyl iodide (1.6 g, 11.3 mmol) was added and the reaction mixture was stirred for 3 h. at room temperature. Water (0.2 g) was added and then acetic acid (0.2 g). The solvents were evaporated under reduced pressure and purification of the residue by column chromatography on silica gel using methylene chloride as eluent gave 1.5 g (89%) of the desired product as an oil.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:23]O>>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([CH2:14][C:15]([O:17][CH3:23])=[O:16])=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Oc2ccccc2)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(Oc2ccccc2)cc1

Procedure:
To a solution of 4-phenoxyphenylacetic acid (1.0 g, 4.38 mmoles) in methanol (5.0 ml) was added concentrated sulfuric acid (0.05 ml, 0.88 mmoles) and the mixture was heated to reflux for about 5 hours. The mixture was cooled and concentrated under reduced pressure. To the residue was added a saturated aqueous solution of sodium bicarbonate (20.0 ml) and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over MgSO4, filtered and evaporated to dryness to afford the title compound.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]([CH3:13])[N:6]=1)([CH3:3])[CH3:2].C1COCC1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O>CCOCC>[CH:1]([O:4][C:5]1[C:10]([CH2:11][NH2:12])=[CH:9][CH:8]=[C:7]([CH3:13])[N:6]=1)([CH3:3])[CH3:2]
Reactant: Cc1ccc(C#N)c(OC(C)C)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccc(CN)c(OC(C)C)n1
Temperature: 0 °C
Yield: 89.2 %

Procedure:
The nitrile 32a (1.25 g, 7.12 mmol) solubilized in Et2O (20 mL) and THF (10 mL) was added in small portion to a mixture of LiAlH4 (0.54 g, 2 mol eq) in Et2O (50 mL) stirred at 0° C. Then the mixture was stirred at room temperature overnight. The excess of LiAlH4 was decomposed by water addition at 0° C., the solid formed was filtered, washed with Et2O and the filtrate was separated. The organic phase was anhydrified over Na2SO4 and evaporated to dryness to obtain 33a as yellow oil (1.14 g, 6.35 mmol, 89% Yield) used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.[Br:10][CH2:11][C:12]([C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1)=O>C(O)C>[BrH:10].[C:8]([C:6]1[CH:5]=[CH:4][N:3]2[CH:11]=[C:12]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=3)[N:1]=[C:2]2[CH:7]=1)#[N:9]
Reactant: O=C(O)c1ccc(C(=O)CBr)cc1
Reactant: N#Cc1ccnc(N)c1
Solvent: CCO
Product: Br
Product: N#Cc1ccn2cc(-c3ccc(C(=O)O)cc3)nc2c1

Procedure:
8.5 g of 2-amino-4-cyanopyridine and 27.5 g of 4-bromoacetylbenzoic acid are boiled in 260 ml of ethanol for 20 h. After cooling, the precipitate is filtered off with suction and subjected to the customary working-up. 4-(7-Cyanoimidazo[1,2-a]pyridin-2-yl)benzoic acid hydrobromide is obtained, m.p. >310°.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:38][CH3:39])=[CH:4][C:5](OC2C=CC(F)=CC=2F)=[C:6](C2C3C=CN(S(C4C=CC(C)=CC=4)(=O)=O)C=3C(=O)N(C)C=2)[CH:7]=1.C([O-])([O-])OCC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1.C(OCC)(=O)C>[N:1]1[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[NH:38][CH:39]=1
Reactant: CNc1cc(Oc2ccc(F)cc2F)c(-c2cn(C)c(=O)c3c2ccn3S(=O)(=O)c2ccc(C)cc2)cc1N
Agent: CCOC([O-])[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: c1ccc2[nH]cnc2c1

Procedure:
A suspension of 4-[5-amino-2-(2,4-difluorophenoxy)-4-(methylamino)phenyl]-6-methyl-1-[(4-methylphenyl)sulfonyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (0.045 g, 0.082 mmol) in tetrahydrofuran (0.80 mL) was treated with ethyl orthoformate (0.041 mL, 0.245 mmol) and p-toluenesulfonic acid monohydrate (1.6 mg, 8.2 μmol) and at 50° C. for 1 h. The reaction mixture was concentrated to give a residue. This residue was diluted with ethyl acetate (30 mL), washed with saturated sodium bicarbonate solution (20 mL), dried with sodium sulfate, filtered, and concentrated to give the intermediate benzimidazole which was used immediately without further purification. The intermediate benzimidazole was dissolved in ethanol (1.00 mL), treated with 1.0 M sodium hydroxide in water (0.327 mL, 0.327 mmol), and heated at 80° C. for 1 h. The reaction mixture was purified via preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (19.5 mg, 59%). 1H NMR (300 MHz, DMSO-d6) δ 11.97 (br s, 1H), 8.19 (s, 1H), 7.68 (s, 1H), 7.40-7.28 (m, 1H), 7.26-7.21 (m, 2H), 7.17 (s, 1H), 7.08-6.88 (m, 2H), 6.24-6.10 (m, 1H), 3.77 (s, 3H), 3.52 (s, 3H); LCMS calculated for C22H17F2N4O2 (M+H)+: m/z=407.1. found: 407.1.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:21]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:20]=3[O:19][CH2:18]1)[C:5](=[O:17])[N:6]2[CH2:11][C:12]([O:14]CC)=[O:13].O=C1C2(C3=CC4OCOC=4C=C3OC2)C2C(=CC=CC=2)N1CC(OCC)=O>>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:21]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:20]=3[O:19][CH2:18]1)[C:5](=[O:17])[N:6]2[CH2:11][C:12]([OH:14])=[O:13]
Reactant: CCOC(=O)CN1C(=O)C2(COc3cc(F)c(F)cc32)c2c(Br)cccc21
Agent: CCOC(=O)CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21
Product: O=C(O)CN1C(=O)C2(COc3cc(F)c(F)cc32)c2c(Br)cccc21
Yield: 100 %

Procedure:
Following the procedure as described in EXAMPLE 2, and making non-critical variations using ethyl (4′-bromo-5,6-difluoro-2′-oxospiro[1-benzofuran-3,3′-indol]-1′(2′ H)-yl)acetate to replace ethyl (2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetate, the title compound was obtained in 100% yield. The product was used directly in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](Cl)=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[N:4][CH:3]=1.[NH2:16][CH2:17][C:18]([CH3:21])([OH:20])[CH3:19]>ClCCl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:16][CH2:17][C:18]([CH3:21])([OH:20])[CH3:19])=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[N:4][CH:3]=1
Reactant: O=[N+]([O-])c1cnc2cc(Br)cnc2c1Cl
Reactant: CC(C)(O)CN
Solvent: ClCCl
Product: CC(C)(O)CNc1c([N+](=O)[O-])cnc2cc(Br)cnc12
Temperature: 10 °C
Reaction time: 8 h

Procedure:
A mixture of 7-bromo-4-chloro-3-nitro[1,5]naphthyridine (92.5 g, 321 mmol) and dichloromethane (1.5 L) was cooled to 10° C. 1-Amino-2-methylpropan-2-ol (63.01 g, 707 mmol) was added dropwise over a period of 30 minutes; during the addition, the reaction temperature did not rise above 13° C. The reaction mixture was allowed to slowly warm to room temperature and stirred overnight. The solvent was removed under reduced pressure, and the solid residue was mixed with water (200 mL). The solid was isolated by filtration, washed with water (2×200 mL), and dried in a vacuum oven overnight at 35° C. to provide 1-[(7-bromo-3-nitro[1,5]naphthyridin-4-yl)amino]-2-methylpropan-2-ol.