Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[CH:14][C:10]=2[C:11](O)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH3:38][C:39]1[CH:44]=[CH:43][N:42]=[CH:41][C:40]=1[NH2:45]>CN(C)C=O.O.CC#N>[CH3:38][C:39]1[CH:44]=[CH:43][N:42]=[CH:41][C:40]=1[NH:45][C:11](=[O:12])[C:10]1[CH:14]=[C:15]([C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)[CH:16]=[CH:17][C:9]=1[O:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccncc1N
Reactant: O=C(O)c1cc(-c2ccncc2)ccc1OCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: O
Product: Cc1ccncc1NC(=O)c1cc(-c2ccncc2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-[(phenylmethyl)oxy]-5-(4-pyridinyl)benzoic acid (may be prepared as described in Description 79; 110 mg, 0.33 mmol), EDC (126 mg, 0.66 mmol) and HOBT (101 mg, 0.66 mmol) in dimethylformamide (2 ml) stirred in air at room temperature for 1 h. 4-Methylpyridin-3-amine (35.6 mg, 0.33 mmol) was then added in one charge. The reaction mixture was stirred at 25° C. overnight. The reaction mixture was diluted with water (25 ml), and then extracted with ethyl acetate (60 ml×3). The organic phases were combined, washed with brine (50 ml×3), dried over anhydrous MgSO4 and concentrated. The residue was purified by Prep-HPLC (instrument: Gilson GX-281, Column: Shimadzu 15 μm, 250×20 mm×2, Mobile Phase: A=10 mmol NH4HCO3/water B=CH3CN, Flow rate: 30.0 ml/L method: B=55%-65%, 0.0-7.2 min; B=65%-95%, 7.2-7.5 min; B=95%-95%, 7.5 min-11.5 min, the RT=10.0 min) to yield the title compound as a pink solid. 94 mg.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]([OH:24])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][CH2:26][C:27]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:28]=1[O:29][CH2:30][C:31]([N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)=[O:32]>>[F:43][C:40]1[CH:41]=[CH:42][C:27]([CH2:26][NH:25][C:22]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:19])[C:9]=2[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:21])[CH3:20])=[O:24])=[C:28]([O:29][CH2:30][C:31]([N:33]2[CH2:34][CH2:35][O:36][CH2:37][CH2:38]2)=[O:32])[CH:39]=1
Reactant: NCc1ccc(F)cc1OCC(=O)N1CCOCC1
Reactant: CC1(C)OCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Product: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1OCC(=O)N1CCOCC1)c(OCc1ccccc1)c2=O

Procedure:
The title compound can be prepared from intermediate 27, 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylic acid and intermediate 131, 2-(2-(aminomethyl)-5-fluorophenoxy)-1-morpholinoethanone. 1H NMR (CDCl3, 500 MHz) δ ppm: 1.59 (6H, s, gem-Me), 3.38, 3.54 (4H, br, NCH2), 3.62 (4H, m, OCH2), 3.96 (2H, m, NCH2), 4.01 (2H, m, OCH2), 4.55 (2H, s, OCH2), 4.55 (2H, d, J=4.3 Hz, NCH2), 5.17 (2H, s, OCH2), 6.53 (1H, dd, J=10, 2.1 Hz, Ar—H), 6.63 (1H, dt, J=2.5, 8 Hz, Ar—H), 7.23–7.26 (1H, m, Ar—H), 7.28–7.30 (3H, m, Ar—Hs), 7.42–7.44 (2H, m, Ar—Hs), 8.00 (1H, t, J=5.5 Hz, NH); 13C NMR (CDCl3, 125.77 Hz) δ ppm: 27.74, 38.76, 42.30, 42.98, 45.38, 58.06, 66.55, 66.78, 66.91, 74.72, 76.27, 100.40, 100.61, 108.07, 108.23, 122.56, 128.37, 128.49, 128.84, 130.88, 130.96, 139.69, 141.36, 141.98, 156.70, 157.02, 157.10, 159.58, 162.04, 163.99, 162.86, 165.79. HRMS (ESI) calcd for C30H34N4O7F (M+H) 581.2412. found 581.2393.
Reaction SMILES: [Br:1][C:2]1[C:3]2[CH2:4][C@@H:5]3[CH2:14][NH:13][CH2:12][CH2:11][N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1.Br[CH2:16][C:17]([O:19][CH3:20])=[O:18].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:20][O:19][C:17](=[O:18])[CH2:16][N:13]1[CH2:12][CH2:11][N:6]2[C:7]3[CH:8]=[CH:9][CH:10]=[C:2]([Br:1])[C:3]=3[CH2:4][C@@H:5]2[CH2:14]1
Reactant: Brc1cccc2c1C[C@@H]1CNCCN21
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)CN1CCN2c3cccc(Br)c3C[C@@H]2C1
Reaction time: 15 h
Yield: 64.9 %

Procedure:
(10aR)-9-Bromo-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole (0.07 g, 0.27 mmol) and methyl bromoacetate (43 mg, 0.27 mmol) were dissolved in acetonitrile (2 mL). Potassium carbonate (44 mg, 0.32 mmol) was added and the solution was boiled with stirring for 15 h. The solvent was removed and the residue was partitioned between dichloromethane and brine. Organic phases were pooled, dried with MgSO4 and the solvent was evaporated. Chromatography on silica gel (dichloromethane/methanol 98:2) gave (10aR)-(9-bromo-3,4,10,10a-tetrahydro-1H-pyrazino[1,2-a]indol-2-yl)-acetic acid methyl ester (57 mg, 63%), MS: m/e=325.2 (M+H+).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([NH:12][CH2:13][C:14]1[O:15][C:16]([CH3:19])=[CH:17][CH:18]=1)=[N:7]2.[CH:20]([Sn](CCCC)(CCCC)CCCC)=[CH2:21]>>[CH3:19][C:16]1[O:15][C:14]([CH2:13][NH:12][C:6]2[CH:5]=[CH:4][C:3]3[C:8](=[CH:9][CH:10]=[CH:11][C:2]=3[CH:20]=[CH2:21])[N:7]=2)=[CH:18][CH:17]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1ccc(CNc2ccc3c(Br)cccc3n2)o1
Product: C=Cc1cccc2nc(NCc3ccc(C)o3)ccc12

Procedure:
The title compound, MS: m/e=265.3 (M+H+), was prepared in accordance with the general method of example 22 from (5-bromo-quinolin-2-yl)-(5-methyl-furan-2-ylmethyl)-amine and vinyltributyltin.
Reaction SMILES: [F:1][C:2]1[C:26](/[N:27]=[CH:28]\[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][C:5]1[C:6](=[O:22])[O:7][C:8]2[CH:15]=[C:14]([O:16][C:17]3[S:18][CH:19]=[CH:20][N:21]=3)[CH:13]=[CH:12][C:9]=2[C:10]=1[CH3:11].[Br:35]N1C(=O)CCC1=O.O>C1COCC1>[Br:35][CH2:11][C:10]1[C:9]2[CH:12]=[CH:13][C:14]([O:16][C:17]3[S:18][CH:19]=[CH:20][N:21]=3)=[CH:15][C:8]=2[O:7][C:6](=[O:22])[C:5]=1[CH2:4][C:3]1[CH:23]=[CH:24][CH:25]=[C:26](/[N:27]=[CH:28]\[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(Cc2cccc(/N=C\c3ccccc3)c2F)c(=O)oc2cc(Oc3nccs3)ccc12
Solvent: O
Solvent: C1CCOC1
Product: O=c1oc2cc(Oc3nccs3)ccc2c(CBr)c1Cc1cccc(/N=C\c2ccccc2)c1F
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
THF (4.5 mL) was added to 3-(2-fluoro-3-{[1-phenyl-meth-(Z)-ylidene]-amino}-benzyl)-4-methyl-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran (compound 6a-3-4-1P) (226 mg), and the mixed solution was stirred at −78° C. for 20 minutes, and further stirred at 0° C. for 1 hour to yield a dark brown solution. This solution was added over 10 minutes to a solution of N-bromosuccinimide (178 mg) in THF (3.0 mL) (which had been prepared in advance in a separate container), and the mixture was further stirred at 0° C. for 1 hour. The reaction solution was added to water (5 mL) to complete the reaction, and the solution was extracted with ethyl acetate. The resultant organic layer extraction liquid was washed with saturated saline, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was then distilled away under reduced pressure, and a residue (320 mg) containing the title compound was obtained.
Reaction SMILES: [CH:1]1([C:7]2[N:12]3[N:13]=[CH:14][C:15]([C:16]#[N:17])=[C:11]3[N:10]=[CH:9][C:8]=2[C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:31][C:32]([F:42])([F:41])[C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH2:36]Br>CN(C)C=O.O>[CH:1]1([C:7]2[N:12]3[N:13]=[CH:14][C:15]([C:16]#[N:17])=[C:11]3[N:10]=[CH:9][C:8]=2[C:18]2[CH:19]=[CH:20][C:21]([O:24][CH2:36][C:35]3[CH:38]=[CH:39][CH:40]=[C:33]([C:32]([F:31])([F:41])[F:42])[CH:34]=3)=[CH:22][CH:23]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: N#Cc1cnn2c(C3CCCCC3)c(-c3ccc(O)cc3)cnc12
Reactant: FC(F)(F)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cnn2c(C3CCCCC3)c(-c3ccc(OCc4cccc(C(F)(F)F)c4)cc3)cnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.2 %

Procedure:
To a solution of 53 mg (0.17 mmol) of 7-cyclohexyl-6-(4-hydroxy-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carbonitrile in 3 mL of dimethylformamide (DMF) was added 72 mg (0.22 mmol) of cesium carbonate (Cs2CO3), followed by 0.034 mL (0.22 mmol) of 3-(trifluoromethyl)-benzyl bromide, and the resulting heterogeneous mixture was stirred at rt overnight. The reaction mixture was diluted with water and extracted with ethyl acetate, and the combined organic extracts were concentrated to give a residue which was chromatographed on silica gel (Biotage; DCM) to afford 65 mg (80% yield) of desired 7-cyclohexyl-6-[4-(3-trifluoromethyl-benzyloxy)-phenyl]-pyrazolo[1,5-a]pyrimidine-3-carbonitrile as indicated by 1H NMR; LC-MS—calcd for C27H23F3N4O [M++H]+: 477.18, found: 477.1.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]#[C:17][CH2:18][N:19]2[CH2:24][CH2:23][O:22][CH2:21][C:20]2([CH3:26])[CH3:25])[CH2:11][C@H:10]1[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[C:30]([CH3:35])[CH:29]=1)=O)(C)(C)C>C(OCC)(=O)C.C(O)C>[ClH:1].[ClH:1].[ClH:1].[CH3:35][C:30]1[CH:29]=[C:28]([CH:33]=[CH:32][C:31]=1[CH3:34])[CH2:27][C@H:10]1[NH:9][CH2:14][CH2:13][N:12]([CH2:15][C:16]#[C:17][CH2:18][N:19]2[CH2:24][CH2:23][O:22][CH2:21][C:20]2([CH3:26])[CH3:25])[CH2:11]1
Reactant: Cc1ccc(C[C@@H]2CN(CC#CCN3CCOCC3(C)C)CCN2C(=O)OC(C)(C)C)cc1C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1ccc(C[C@@H]2CN(CC#CCN3CCOCC3(C)C)CCN2)cc1C
Reaction time: 12 h

Procedure:
A solution of 4N hydrogen chloride in ethyl acetate was added to a solution of (2R)-1-tert-butoxycarbonyl-2-(3,4-dimethylbenzyl)-4-[4-(3,3-dimethylmorpholino)-2-butynyl]piperazine (40.0 g) in ethanol (120 ml) at room temperature and the whole was stirred for 12 hours. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate (500 ml) and potassium carbonate solution. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (300 ml). The combined extract was dried over sodium sulfate and evaporated under reduced pressure, and the residue was purified by column chromatography on silica gel using a mixed solvent of n-hexane and ethyl acetate (3:1). The fractions containing the objective compound were collected and evaporated under reduced pressure, and treated with 4N hydrogen chloride in ethyl acetate to give (3R)-3-(3,4-dimethylbenzyl)-1-[4-(3,3-dimethylmorpholino)-2-butynyl]piperazine trihydrochloride (37.7 g).
Reaction SMILES: CC(C[AlH]CC(C)C)C.[C:10]([C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[CH2:14][CH2:13]1)#N.O.S(=O)(=O)(O)[OH:37]>CCCCCC.CCCCC>[CH:10]([C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[CH2:14][CH2:13]1)=[O:37]
Reactant: CCCCCc1ccc(-c2ccc([C@H]3CC[C@H](C#N)CC3)cc2)cc1
Reactant: O=S(=O)(O)O
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCCCC
Solvent: CCCCCC
Solvent: O
Product: CCCCCc1ccc(-c2ccc([C@H]3CC[C@H](C=O)CC3)cc2)cc1
Reaction time: 18 h

Procedure:
112 ml of a 20% solution of DIBALH in hexane are added dropwise to a solution of 33.2 g of 4-(trans-4-cyanocyclohexyl)-4'-pentylbiphenyl in 1 l of pentane, and the mixture is stirred for 18 hours. Water is then added dropwise until the evolution of gas subsides and then 200 ml of 25% sulfuric acid are added dropwise. The organic phase is separated off, dried over Na2SO4 and evaporated. Colourless deliquescent crystals are obtained.
Reaction SMILES: [SH:1][CH:2]1[N:5]([C:6](=[C:15]([OH:17])[CH3:16])[C:7]([O:9][CH2:10][C:11]([Cl:14])([Cl:13])[Cl:12])=[O:8])[C:4](=[O:18])[CH:3]1[NH:19][C:20](=[O:29])[CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl[C:31]([O:33][CH2:34][CH:35]1[CH2:37][CH2:36]1)=[O:32]>[Ag].C(N(CC)CC)C>[CH:35]1([CH2:34][O:33][C:31]([S:1][CH:2]2[N:5]([C:6](=[C:15]([O:17][C:31]([O:33][CH2:34][CH:35]3[CH2:37][CH2:36]3)=[O:32])[CH3:16])[C:7]([O:9][CH2:10][C:11]([Cl:14])([Cl:12])[Cl:13])=[O:8])[C:4](=[O:18])[CH:3]2[NH:19][C:20](=[O:29])[CH2:21][O:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:32])[CH2:37][CH2:36]1
Reactant: CC(O)=C(C(=O)OCC(Cl)(Cl)Cl)N1C(=O)C(NC(=O)COc2ccccc2)C1S
Reactant: O=C(Cl)OCC1CC1
Agent: [Ag]
Solvent: CCN(CC)CC
Product: CC(OC(=O)OCC1CC1)=C(C(=O)OCC(Cl)(Cl)Cl)N1C(=O)C(NC(=O)COc2ccccc2)C1SC(=O)OCC1CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 66.5 %

Procedure:
To a solution of silver salt of 2,2,2-trichloroethyl α-[4-mercapto-3-phenoxyacetamido-2-oxoazetidin-1-yl]-α-(1-hydroxyethylidene)acetate (695 mg) in hexamethyl phoshorotriamide (8 ml) is added a mixture of cyclopropylmethyl chloroformate (480 mg) and triethylamine (180 mg), and the mixture is stirred for 1 hour. The reaction mixture is poured into ice water, and is extracted with benzene. The extract solution is washed with water, dried, and evaporated in leave residue. Purification of the residue by chromatography over silica gel to give 2,2,2-trichloroethyl α-[4-cyclopropylmethoxycarbonylthio-3-phenoxyacetamido-2-oxoazetidin-1-yl]-α-(1-cyclopropylmethoxycarbonyloxyethylidene)acetate (650 mg). Yield: 64.4%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)[CH3:2].[Br:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[F:22])[CH:17]=O>C(O)C>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:17][C:16]2[CH:19]=[CH:20][C:21]([F:22])=[C:14]([Br:13])[CH:15]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: O=Cc1ccc(F)c(Br)c1
Solvent: CCO
Product: CCOC(=O)c1ccc(N=Cc2ccc(F)c(Br)c2)cc1
Temperature: 25 °C
Yield: 45.7 %

Procedure:
A mixture of 4-amino-benzoic acid ethyl ester (1.65 g, 10 mmol) and 3-bromo-4-fluoro-benzaldehyde (2.03 g, 10 mmol) in ethanol (100 mL) was heated to reflux for 2 hours. Then the reaction mixture cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 4-{[1-(3-bromo-4-fluoro-phenyl)-methylidene]-amino}-benzoic acid ethyl ester (1.6 g, 46%) as a white solid: LC/MS m/e calcd for C16H13BrCFNO2 M+: 350.2, observed: 350.2, 352.2.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[C:9]([CH:11]([Cl:16])[C:12](Cl)([Cl:14])[Cl:13])[CH:8]=[C:7]([CH:17]([Cl:22])[C:18](Cl)([Cl:20])[Cl:19])[CH:6]=1>CO>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([C:17]([Cl:22])=[C:18]([Cl:19])[Cl:20])[CH:8]=[C:9]([C:11]([Cl:16])=[C:12]([Cl:13])[Cl:14])[CH:10]=1
Reactant: COc1cc(C(Cl)C(Cl)(Cl)Cl)cc(C(Cl)C(Cl)(Cl)Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(C(Cl)=C(Cl)Cl)cc(C(Cl)=C(Cl)Cl)c1
Reaction time: 8 h

Procedure:
To a magnetically stirred solution of 30 mg (0.73 mmol) of sodium hydroxide in 0.2 mL methanol was slowly added a solution of 0.122 g (0.28 mmol) of the product of Step B in 0.1 mL methanol. A white precipitate was deposited and the reaction mixture was then stirred overnight. The reaction mixture was then evaporated in vacuo and the residue was purified on a silica gel flash chromatography column eluted with hexane. Evaporation of the purified fractions afforded the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C@@H:5]1[NH:10][CH2:9][CH2:8][N:7]([C:11]2[C:20]3[N:19]=[C:18]([C:21]([F:24])([F:23])[F:22])[S:17][C:16]=3[NH:15][C:14]3[CH:25]=[CH:26][CH:27]=[CH:28][C:13]=3[N:12]=2)[CH2:6]1.Br[CH2:30][CH2:31][CH2:32][OH:33]>>[CH3:1][O:2][CH2:3][CH2:4][C@H:5]1[CH2:6][N:7]([C:11]2[C:20]3[N:19]=[C:18]([C:21]([F:23])([F:24])[F:22])[S:17][C:16]=3[NH:15][C:14]3[CH:25]=[CH:26][CH:27]=[CH:28][C:13]=3[N:12]=2)[CH2:8][CH2:9][N:10]1[CH2:30][CH2:31][CH2:32][OH:33]
Reactant: OCCCBr
Reactant: COCC[C@H]1CN(C2=Nc3ccccc3Nc3sc(C(F)(F)F)nc32)CCN1
Product: COCC[C@H]1CN(C2=Nc3ccccc3Nc3sc(C(F)(F)F)nc32)CCN1CCCO

Procedure:
Using the method of Example 351, using (S)-10-[3-(2-methoxy-ethyl)-piperazin-1-yl]-2-trifluoromethyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene and 3-bromo-propan-1-ol, 15 hours at reflux after the addition of alcohol, and two purifications by flash chromatography: the first, eluting with a gradient of a 3% solution of methanol in ethyl acetate (0-100%), and then with a gradient of methanol: ethyl acetate (3%-5% methanol in ethyl acetate); and the second, eluting with a gradient of solutions of 2M ammonia in methanol, in ethyl acetate (4%-5% over 40 minutes), gives the title compound: mass spectrum (APCI, m/e): 470 (M+1); NMR (1H, 300 MHz, DMSO-d6): δ 8.47 (s, 1H), 6.96-6.81 (m, 3H), 6.70 (m, 1H), 4.42 (m, 1H), 3.54-3.37 (m, 6H), 3.37-3.18 (m, 2H), 3.15 (s, 3H), 2.68 (m, 2H), 2.58-2.45 (m, 1H), 2.35 (m, 2H), 1.68 (m, 2H), 1.55 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[NH:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[N:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[H-].[Na+].Cl[CH2:25][C:26]1[O:30][C:29]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:28][CH:27]=1.C(OCC)(=O)C>CN(C)C=O>[CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[N:14]([CH2:25][C:26]3[O:30][C:29]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:28][CH:27]=3)[C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCCN(c2nc3ccccc3[nH]2)CC1
Reactant: CCOC(=O)c1ccc(CCl)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(Cn2c(N3CCCN(C(=O)OCC)CC3)nc3ccccc32)o1
Reaction time: 72 h

Procedure:
Combine 1-ethoxycarbonyl-4-(1H-benzimidazol-2-yl)[1,4]diazepane (10 mmol) and sodium hydride (10 mmol) in dimethylformamide (20 mL). After gas evolution ceases, add ethyl 5-chloromethyl-2-furoate (10 mmol) and stir. After 3 days, evaporate in vacuo to give a residue. Combine the residue and ethyl acetate. Extract with water and brine. Dry the the organic layer over Na2SO4, filter, and evaporate in vacuo to give 1-ethoxycarbonyl-4-(1-(5-(ethoxycarbonyl)fur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepane.
Reaction SMILES: Br[CH:2]([C:8]([C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[O:17][CH3:18])=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH2:19][C:20]([NH2:22])=[S:21]>C(O)C>[NH2:22][C:20]1[S:21][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:8]([C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])[N:19]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)C(Br)C(=O)c1cc(Cl)ccc1OC
Solvent: CCO
Product: CCOC(=O)c1sc(N)nc1-c1cc(Cl)ccc1OC
Temperature: 25 °C
Yield: 31.5 %

Procedure:
A mixture of ethyl 2-bromo-3-(5-chloro-2-methoxyphenyl)-3-oxopropanoate (assumed to be 13.2 mmol) and thiourea (1.01 g, 13.3 mmol) in ethanol (25 mL) were heated to reflux for 3 hours, then cooled to room temperature for 18 hours. The resultant solid was removed by filtration and the filtrate evaporated under vacuum. DCM was added to the residue, the organics washed with sodium hydrogen carbonate (sat.aq.), water and brine, and evaporated to dryness. The residue was triturated (DCM) to give ethyl 2-amino-4-(5-chloro-2-methoxyphenyl)thiazole-5-carboxylate (1.30 g, 31%) as a yellow solid. LCMS (method 1) [M+H]+=313.2, RT=3.15 min. 1H NMR (400 MHz, DMSO-d6): δ (ppm) 7.77 (s, br, 2H), 7.39 (dd, 1H), 7.22 (d, 1H), 7.05 (d, 1H), 4.00 (q, 2H), 3.70 (s, 3H), 1.04 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([NH:18][C:19]([C:26]3[S:30][C:29]([CH3:31])=[N:28][CH:27]=3)([CH3:25])[C:20](OCC)=[O:21])=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.[BH4-].[Na+].O>C(O)C.O1CCCC1>[F:36][C:32]1[CH:33]=[CH:34][CH:35]=[C:2]([F:1])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([NH:18][C:19]([C:26]3[S:30][C:29]([CH3:31])=[N:28][CH:27]=3)([CH3:25])[CH2:20][OH:21])=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)C(C)(NC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cccn12)c1cnc(C)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: Cc1ncc(C(C)(CO)NC(=O)c2c(C)nc3c(OCc4c(F)cccc4F)cccn23)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.2 %

Procedure:
To a solution of 110 mg of ethyl 2-[({8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridin-3-yl}carbonyl)amino]-2-(2-methyl-1,3-thiazol-5-yl)propanoate in 3.3 ml of ethanol and 0.66 ml of tetrahydrofuran were added 40 mg of sodium borohydride at 0° C., followed by stirring at room temperature for 16 hours. To the reaction mixture was added water, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and the solvent was then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 80 mg of 8-[(2,6-difluorobenzyl)oxy]-N-[1-hydroxy-2-(2-methyl-1,3-thiazol-5-yl)propan-2-yl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13](I)=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:20]=1.[CH3:21][C:22]([OH:39])([CH3:38])[CH2:23][N:24]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[N:25]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([C:27]4[CH:26]=[N:25][N:24]([CH2:23][C:22]([OH:39])([CH3:38])[CH3:21])[CH:28]=4)=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:20]=1
Reactant: NC(=O)c1nc2n(c1I)C1CC(C1)c1ccc(Br)cc1-2
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CC(C)(O)Cn1cc(-c2c(C(N)=O)nc3n2C2CC(C2)c2ccc(Br)cc2-3)cn1

Procedure:
10-bromo-3-iodo-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carb oxamide was reacted with 2-methyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]propan-2-ol similarly to as described in Example 4 to produce crude 10-bromo-3-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide. This intermediate was reacted with (2R)-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol via General Procedure E to afford 39 mg (24%) of 10-[(3R)-3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-ynyl]-3-[1-(2-hydroxy-2-methyl-propyl)pyrazol-4-yl]-5,6,7,12-tetrahydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide. M+1=527.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@H:14]3[CH2:16][C@H:15]3[CH2:17][CH2:18][NH2:19])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:27]1[N:32]=[C:31]([CH3:33])[N:30]=[C:29]([C:34]#[N:35])[CH:28]=1.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@H:14]3[CH2:16][C@H:15]3[CH2:17][CH2:18][NH:19][C:27]3[N:32]=[C:31]([CH3:33])[N:30]=[C:29]([C:34]#[N:35])[CH:28]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: Cc1nc(Cl)cc(C#N)n1
Reactant: NCC[C@@H]1C[C@@H]1C1CCN(c2ncc(Cl)cn2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(C#N)cc(NCC[C@@H]2C[C@@H]2C2CCN(c3ncc(Cl)cn3)CC2)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2-{(1S,2S)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethanamine (29 mg, 0.10 mmol) from step 3 of this example was dissolved in DMF (0.4 mL), cesium carbonate (168 mg, 0.52 mmol) was added, stirred at room temperature for 10 minutes, then cooled down to 0° C. 6-chloro-2-methylpyrimidine-4-carbonitrile (17.5 mg, 0.114 mmol; from step 4 of this example) was added in DMF (0.1 mL) via syringe. Reaction was kept at 0° C. for 30 minutes, then warmed up to room temperature for 1 hour. Water (50 mL) was added, extracted with EtOAc (50 mL×2), second wash with Brine (20 mL). The combined organic phase was dried by magnesium sulfate, filter, concentrated and purified by column chromatography through a 40 gram RediSep Rf™ silica gel cartridge eluting with 17% acetone/hexanes to give the title compound as a pale yellow solid.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl-].[Li+].[C:7]1([CH3:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:14](Cl)(=[O:16])[CH3:15]>ClC(Cl)C>[CH3:13][C:7]1[CH:12]=[CH:11][C:10]([C:14]([CH3:15])=[O:16])=[CH:9][CH:8]=1
Reactant: CC(=O)Cl
Reactant: Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Li+]
Solvent: CC(Cl)Cl
Product: CC(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an agitated mixture of aluminium chloride (20 g., 0.15 mole) and lithium chloride (3.18 g., 0.075 mole) and dichloroethane (20 ml) at -15° C. was slowly added toluene (4.6 g., 0.05 mole) and acetyl chloride (3.93 g., 0.05 mole) in dichloroethane (10 ml). The reaction mixture was left at -15° C. for one hour then allowed to warm up to room temperature overnight. After working up as described in Example 1, the 4-methylacetophenone obtained (7.17 g.), had a 1H NMR estimated purity of about 95%. 1H NMR showed less than 2% ortho isomers.