Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.C(OC(=O)[NH:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[C:51]([CH2:58][N:59]5[CH2:62][CH:61]([F:63])[CH2:60]5)[CH:52]=[CH:53][CH:54]=4)[O:49][C:48]=3[C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1)(C)(C)C.C(O)(C(F)(F)F)=O.CO>C(Cl)Cl>[NH2:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[C:51]([CH2:58][N:59]5[CH2:62][CH:61]([F:63])[CH2:60]5)[CH:52]=[CH:53][CH:54]=4)[O:49][C:48]=3[C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)=[CH:43][CH:42]=2)[CH2:38][CH2:39][CH2:40]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(CN5CC(F)C5)cccc4c3=O)cc2)CCC1
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: NC1(c2ccc(-c3c(-c4ccccc4)oc4c(CN5CC(F)C5)cccc4c3=O)cc2)CCC1
Yield: 57 %

Procedure:
Following the procedure of 3-[4-(1-amino-cyclobutyl)-phenyl]-6-fluoro-2-phenyl-chromen-4-one, (1-{4-[8-(3-fluoro-azetidin-1-ylmethyl)-4-oxo-2-phenyl-4H-chromen-3-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester was treated with TFA. The resultant free base was subjected to flash chromatography (SiO2, gradient 0 to 15% MeOH in DCM) to afford the title compound as a white solid (13 mg, 57%). 1H NMR (400 MHz, DMSO-d6): δ 7.97 (dd, J=8.0 and 1.7 Hz, 1H), 7.74 (dd, J=7.1 and 1.4 Hz, 1H), 7.47-7.28 (m, 8H), 7.08 (d, J=8.2 Hz, 2H), 5.27-5.06 (m, 1H), 3.94 (s, 2H), 3.65-3.56 (m, 2H), 3.29-3.16 (m, 2H), 2.36-2.27 (m, 2H), 2.11-1.87 (m, 5H), 1.65-1.54 (m, 1H). LCMS (Method E): RT=2.31 min, [M+H]+=455.
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.S(=O)(=O)(O)O.[OH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]1[C:28](=[O:32])[CH2:29][CH2:30][CH:31]=1>O.CC(C)=O.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.[O-2].[O-2].[O-2].[Cr+6].[Cr]>[O:32]=[C:28]1[C:27]([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][C:20]([OH:3])=[O:19])=[CH:31][CH2:30][CH2:29]1
Reactant: CC(C)=O
Reactant: O=C1CCC=C1CCCCCCCO
Agent: O=[Cr](=O)=O
Agent: [Cr+6]
Agent: [Cr]
Solvent: O
Product: O=C(O)CCCCCCC1=CCCC1=O
Reaction time: 1.5 h

Procedure:
8N Jones reagent [90 ml; prepared by dissolving chromium trioxide (24.0 g) in a small volume of water, treating carefully with concentrated sulphuric acid (20.7 ml) and diluting with water to 90 ml with cooling] was added to a stirred solution of 2-(7-hydroxyheptyl)cyclopent-2-enone (39.2 g) in acetone (400 ml) at 10°-22° C. at a rate such that the deep red colouration caused by the addition of one drop of the Jones reagent had changed to green before addition of the next drop. The resulting mixture was then stirred at 15°-20° C. for 90 minutes. The reaction mixture was diluted with sufficient water to dissolve the precipitated chromium salts and was then extracted four times with diethyl ether. The combined ether extracts were washed with water, and then extracted three times with aqueous 2N sodium carbonate solution. The combined aqueous solutions were then acidified to pH 1 by the dropwise addition of concentrated hydrochloric acid and extracted twice with diethyl ether. The combined ethereal extracts were dried over magnesium sulphate and evaporated in vacuo to give an oil which crystallised on standing. Recrystallisation from a mixture of petroleum ether (b.p. 40°-60° C.) and diethyl ether gave 7-(5-oxocyclopent-1-enyl)heptanoic acid (28 g), m.p. 41°-43° C.
Reaction SMILES: [Br:1][C:2]1[S:12][C:5]2[N:6]=[C:7]([CH3:11])[CH:8]=[C:9]([NH2:10])[C:4]=2[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=1.CC(C)([O-])C.[Na+].[C:26]1([S:32](Cl)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1.CN(C=O)C>[Br:1][C:2]1[S:12][C:5]2=[N:6][C:7]([CH3:11])=[CH:8][C:9]([NH:10][S:32]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:34])=[O:33])=[C:4]2[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1cc(N)c2c(-c3cccc(Br)c3)c(Br)sc2n1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cc(NS(=O)(=O)c2ccccc2)c2c(-c3cccc(Br)c3)c(Br)sc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.9 %

Procedure:
To a stirred solution of 2-bromo-3-(3-bromophenyl)-6-methylthieno[2,3-b]pyridin-4-amine (Description 49) (1 g, 2.51 mmol) in THF (10 mL) and DMF (5 mL) was added sodium tert-butoxide (0.603 g, 6.28 mmol) and benzenesulfonyl chloride (0.648 mL, 5.02 mmol). The reaction mixture stirred at RT under nitrogen for ca. 30 min. The reaction mixture was quenched with saturated ammonium chloride solution (ca. 30 mL) and extracted with DCM (25 mL×4). The combined organics were dried and concentrated. The residue was purified via normal phase chromatography eluted with a gradient of 0-50% ethyl acetate in DCM, to afford the title compound (1.12 g). LCMS (A) m/z: 539 [M+1]+, Rt 1.45 min (acidic).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18](O)=[O:19])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[N:23]1([C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:3]=[N:2][NH:1][CH:5]=5)[CH:22]=[CH:21][C:9]=4[C:10]=3[N:11]=2)=[O:19])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Reactant: C1CCNCC1
Product: O=C(c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2)N1CCCCC1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with piperidine (1.2 equiv) to give 161 (17.9 mg, M+1 381.2)
Reaction SMILES: Br[CH2:2][C:3]1[N:4]=[C:5]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[S:6][C:7]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[NH:20][C:19](=[O:21])[O:18][N:17]=2)=[C:12]([F:22])[CH:11]=1.[N-:33]=[N+:34]=[N-:35].[Na+]>CN(C)C=O>[N:33]([CH2:2][C:3]1[N:4]=[C:5]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[S:6][C:7]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[NH:20][C:19](=[O:21])[O:18][N:17]=2)=[C:12]([F:22])[CH:11]=1)=[N+:34]=[N-:35]
Reactant: O=c1[nH]c(-c2ccc(OCc3sc(-c4ccc(C(F)(F)F)cc4)nc3CBr)cc2F)no1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(-c2noc(=O)[nH]2)c(F)c1
Reaction time: 5 h
Yield: 100.9 %

Procedure:
To a solution of 126 mg of 3-{4-[4-bromomethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-fluoro-phenyl}-4H-[1,2,4]oxadiazol-5-one in 1.3 mL of dimethylformamide was added 43.5 mg of sodium azide. The resulting solution was stirred for 5 h and then concentrated under reduced pressure to give 118 mg of 3-{4-[4-azidomethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-fluoro-phenyl}-4H-1,2,4-oxadiazol-5-one which was used in the next step without further purification.
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:15](=[NH:16])[N:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]3=[N:12][C:11]=2SC)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23][OH:24].O>CO>[C:1]1([S:7]([C:10]2[C:15](=[NH:16])[N:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]3=[N:12][C:11]=2[O:24][CH3:23])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CO
Reactant: CSc1nc2ccccn2c(=N)c1S(=O)(=O)c1ccccc1
Solvent: O
Product: COc1nc2ccccn2c(=N)c1S(=O)(=O)c1ccccc1
Temperature: 90 °C

Procedure:
3-Benzenesulfonyl-2-methylsulfanyl-pyrido[1,2-a]pyrimidin-4-ylideneamine (50 mg, 0.15 mmol) was dissolved in methanol (2 ml) and heated at 90° C. for 4 days. When the conversion reached about 50% the product was isolated from the starting material by preparative HPLC (XTerra™ MS C18 5.0 mM, MeOH/H2O as the eluent) to yield 21 mg of bright yellow product.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:8][C:7]=1[CH2:25]Br)=[O:5])[CH3:2].[CH2:27]([O:29][C:30](=[O:44])[CH2:31][NH:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][C:35]=1[O:42][CH3:43])[CH3:28].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:8][C:7]=1[CH2:25][N:32]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][C:35]=1[O:42][CH3:43])[CH2:31][C:30]([O:29][CH2:27][CH3:28])=[O:44])=[O:5])[CH3:2]
Reactant: CCOC(=O)CNCc1ccc(OC)cc1OC
Reactant: CCOC(=O)c1sc(N(C(=O)OC(C)(C)C)c2ccccc2)nc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1nc(N(C(=O)OC(C)(C)C)c2ccccc2)sc1C(=O)OCC
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.8 %

Procedure:
A mixture of 4-bromomethyl-2-(tert-butoxycarbonyl-phenyl-amino)-thiazole-5-carboxylic acid ethyl ester (451 mg, 1.02 mmol), (2,4-dimethoxy-benzylamino)-acetic acid ethyl ester (260 mg, 1.02 mmol) and potassium carbonate (213 g, 1.54 mmol) in anhydrous dimethylformamide (4 mL) was stirred at room temperature for 18 h before it was quenched with water, extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and hexanes to give the title compound as a white solid (562 mg): MS: (+) m/z 614.13 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]([C:31]([N:33]2[CH2:36][CH:35]([O:37]C3CCCCO3)[CH2:34]2)=[O:32])[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([C:17]2[NH:21][C:20]([C:22]3[S:23][CH:24]=[CH:25][N:26]=3)=[CH:19][CH:18]=2)[CH:8]=[C:9]([O:11][C@@H:12]([CH3:16])[CH2:13][O:14][CH3:15])[CH:10]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(N(CC)CC)C>CO>[F:1][C:2]1[CH:30]=[C:29]([CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([C:17]2[NH:21][C:20]([C:22]3[S:23][CH:24]=[CH:25][N:26]=3)=[CH:19][CH:18]=2)[CH:8]=[C:9]([O:11][C@@H:12]([CH3:16])[CH2:13][O:14][CH3:15])[CH:10]=1)[C:31]([N:33]1[CH2:34][CH:35]([OH:37])[CH2:36]1)=[O:32]
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)N3CC(OC4CCCCO4)C3)cc2F)cc(-c2ccc(-c3nccs3)[nH]2)c1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CO
Solvent: CCN(CC)CC
Product: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)N3CC(O)C3)cc2F)cc(-c2ccc(-c3nccs3)[nH]2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.4 %

Procedure:
2-(5-{3-(2-Fluoro-4-{[3-(tetrahydro-2H-pyran-2-yloxy)azetidin-1-yl]carbonyl}phenoxy)-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-1H-pyrrol-2-yl)-1,3-thiazole (110 mg, 0.181 mmol) synthesized in Example (42b) was dissolved in methanol (10 mL), and 10-camphorsulfonic acid (20 mg, 0.086 mmol) was added, followed by stirring at room temperature overnight under nitrogen atmosphere. To the reaction solution, triethylamine (0.1 mL) was added, and the solvent was distilled off under reduced pressure. The resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=90%-100%) to afford the desired compound (62 mg, yield 65%) as a yellow solid.
Reaction SMILES: [H-].[Na+].[OH:3][N:4]=[C:5]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:6]([NH:8][CH3:9])=[O:7].[CH2:16]([O:20][C:21](=[O:31])[NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29]Cl)[N:24]=1)[CH2:17][C:18]#[CH:19].O>CN(C=O)C.CCOC(C)=O>[CH3:9][NH:8][C:6](=[O:7])[C:5](=[N:4][O:3][CH2:29][C:25]1[N:24]=[C:23]([NH:22][C:21](=[O:31])[O:20][CH2:16][CH2:17][C:18]#[CH:19])[CH:28]=[CH:27][CH:26]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C#CCCOC(=O)Nc1cccc(CCl)n1
Reactant: CNC(=O)C(=NO)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C#CCCOC(=O)Nc1cccc(CON=C(C(=O)NC)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
49 mg (1.22 mmol) of sodium hydride were added to a solution of 200 mg (1.12 mmol) of 2-(hydroxyimino)-N-methyl-2-phenylacetamide (only Z diastereoisomer in 5 ml of DMF, and the suspension was stirred for 30 minutes at room temperature. Then, a solution of 268 mg (1.12 mmol) of but-3-in-1-yl[6-(chloromethyl)pyridin-2-yl]carbamate in 5 ml was added. The mixture was stirred for 3.5 hours at room temperature and then poured into 70 ml of water and admixed with 50 ml of AcOEt. The organic phase was separated off and dried over MgSO4. After removing the solvent, this gave 388 mg (95% purity, 88:12 mixture of Z and E diastereoisomers) of but-3-yn-1-yl{6-[({[2-(methylamino)-2-oxo-1-phenylethylidene]amino}oxy)methyl]pyridin-2-yl}-carbamate.
Reaction SMILES: FC1C=CC([CH2:6][NH:7][C:8](=[O:27])[CH2:9][N:10]2[CH2:14][CH2:13][N:12]([C:15]3[S:16][C:17]([C:21]([O:23]CC)=[O:22])=[C:18]([CH3:20])[N:19]=3)[C:11]2=[O:26])=CC=1.CC1N=C(N2CCN(CC(NC)=O)C2=O)SC=1C(OCC)=O>>[CH3:20][C:18]1[N:19]=[C:15]([N:12]2[CH2:13][CH2:14][N:10]([CH2:9][C:8]([NH:7][CH3:6])=[O:27])[C:11]2=[O:26])[S:16][C:17]=1[C:21]([OH:23])=[O:22]
Reactant: CCOC(=O)c1sc(N2CCN(CC(=O)NCc3ccc(F)cc3)C2=O)nc1C
Agent: CCOC(=O)c1sc(N2CCN(CC(=O)NC)C2=O)nc1C
Product: CNC(=O)CN1CCN(c2nc(C)c(C(=O)O)s2)C1=O

Procedure:
Following the procedure as described in Preparation 9, making variations as required to replace ethyl 2-(3-(2-(4-fluorobenzylamino)-2-oxoethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylate with ethyl 4-methyl-2-(3-(2-(methylamino)-2-oxoethyl)-2-oxoimidazolidin-1-yl)thiazole-5-carboxylate, the crude title compound was obtained.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([NH:10][CH2:11][C:12]3[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:19])=[CH:8][C:7]([C:20](OCC)=[O:21])=[CH:6][N:5]2[C:25]=1[CH3:26].O.[OH-].[Na+]>O1CCCC1>[CH3:1][C:2]1[N:3]=[C:4]2[C:9]([NH:10][CH2:11][C:12]3[C:13]([CH3:19])=[CH:14][CH:15]=[CH:16][C:17]=3[CH3:18])=[CH:8][C:7]([CH2:20][OH:21])=[CH:6][N:5]2[C:25]=1[CH3:26]
Reactant: CCOC(=O)c1cc(NCc2c(C)cccc2C)c2nc(C)c(C)n2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc(C)c1CNc1cc(CO)cn2c(C)c(C)nc12
Yield: 66.5 %

Procedure:
To a stirred solution of ethyl 2,3-dimethyl-8-(2,6-dimethylbenzylamino)-imidazo[1,2-a]pyridine-6-carboxylate (1.2 g, 3.4 mmol) in tetrahydrofuran (30 ml) was added LiALH4 (0.7 g, 18.5 mmol) during 20 min. at 5° C. 0.7 ml of water was added dropwise, followed by 0.7 ml of 15% sodium hydroxide and then 2.1 ml of water. The solids were removed by filtration and washed thoroughly with methylene chloride: methanol (1:1). The filtrate and washings were combined and the solvents were removed under reduced pressure. The residue was purified by column chromatography on silica gel using methylene chloride:methanol (10:1) as eluent. Treating the residue with diethyl ether and filtration gave 0.7 g (67%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[C:5]2[CH:18]=[C:19]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:20]=[C:21]([C:22]([NH2:24])=O)[C:4]=2[N:3]=1.O=P(Cl)(Cl)Cl>ClCCl.CN(C=O)C>[CH3:1][C:2]1[N:6]([CH2:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[C:5]2[CH:18]=[C:19]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:20]=[C:21]([C:22]#[N:24])[C:4]=2[N:3]=1
Reactant: Cc1nc2c(C(N)=O)cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nc2c(C#N)cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
To the mixture of 2-methyl-6-(4-morpholinyl)-1-(1-naphthalenylmethyl)-1H-benzimidazole-4-carboxamide, prepared as described in Example 33 (0.4 g, 0.999 mmol) in Dichloromethane (DCM) (50 mL) was added in POCl3 (0.931 mL, 9.99 mmol) and followed by the addition of ten drops of DMF. The reaction was stirred at rt for 1 h. The mixture was quenched with aqueous sodium bicarbonate solution. The aqueous phase was extracted with DCM (100 mL). The combined organic phase was washed with Brine then dried (MgSO4), filtered and the solvent removed in-vacuo. The crude was purified on silica (20˜50% EtOAc/Hexane) to give the product (0.246 g, 64%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.45 (s, 3H), 2.96-3.15 (m, 4H), 3.62-3.72 (m, 4H), 6.05 (s, 2H), 6.32 (d, J=7.07 Hz, 1H), 7.29-7.44 (m, 3H), 7.57-7.74 (m, 2H), 7.86 (d, J=8.08 Hz, 1H), 8.02 (d, J=7.83 Hz, 1H) 8.22 (d, 1H), MS (ES+) m/z 383.2 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14].ClCCl>N1C=CC=CC=1>[C:13]([O:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1)(=[O:15])[CH3:14]
Reactant: O=Cc1ccc(OCCO)cc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OCCOc1ccc(C=O)cc1
Temperature: 0 °C

Procedure:
A mixture of the crude 4-(2-hydroxyethoxy)benzaldehyde (30 g, 0.18 mol) and acetic anhydride (40 g, 0.40 mol) was dissolved in 125 mL of dry pyridine and heated at reflux for 3 hr, after which time the reaction mixture was poured onto ca. 200 g of crushed ice. The crude oil was taken up into 150 mL of dichloromethane and washed twice with 5% HCl (2×75 mL) and once with brine (1×75 mL). The organic layer was then dried with sodium sulfate and the solvent was removed under reduced pressure. The crude residue was distilled at 148° C. (1×10-3 mm) to give 12.9 g (25% overall yield) of a slightly cloudy liquid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15](S(C)(=O)=O)[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[NH2:28][C:29]1[N:30]=[CH:31][C:32](B2OC(C)(C)C(C)(C)O2)=[N:33][CH:34]=1>>[O:25]1[CH2:26][CH2:27][N:22]([C:4]2[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=[C:2]([C:32]3[N:33]=[CH:34][C:29]([NH2:28])=[N:30][CH:31]=3)[N:3]=2)[CH2:23][CH2:24]1
Reactant: CC1(C)OB(c2cnc(N)cn2)OC1(C)C
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: Nc1cnc(-c2nc(N3CCOCC3)c3sc(CN4CCNCC4)cc3n2)cn1

Procedure:
2-Chloro-6-((4-methanesulfonylpiperazin-1-yl)methyl)-4-morpholinothieno[3,2-d]pyrimidine (75 mg) was reacted with 5-aminopyrazine-2-boronic acid pinacol ester following General Procedure A to give 20 mg of 187 following reversed phase HPLC purification. MS (Q1) 491 (M)+
Reaction SMILES: [NH2:1][NH2:2].[Br:3][C:4]1[CH:5]=[N:6][C:7](OC)=[C:8]([CH:11]=1)[C:9]#[N:10]>>[Br:3][C:4]1[CH:11]=[C:8]2[C:9]([NH2:10])=[N:2][NH:1][C:7]2=[N:6][CH:5]=1
Reactant: COc1ncc(Br)cc1C#N
Reactant: NN
Product: Nc1n[nH]c2ncc(Br)cc12
Reaction time: 3 h
Yield: 72 %

Procedure:
35 ml (23.47 mmol) of hydrazine is added at room temperature to 5 g (23.47 mmol) of 5-bromo-2-methoxynicotinonitrile. The reaction medium is carried at 100° C. for 3 hours. After returning to room temperature, the precipitate obtained is filtered, rinsed with water and then dried at 50° C. to yield 3.6 g (72%) of 5-bromo-1H-pyrazolo[3,4-b]pyridine-3-amine in the form of a yellow solid.
Reaction SMILES: C(S([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)=[C:17]3[C:13]=2[C:14]2[CH:33]=[C:32]([CH3:34])[CH:31]=[N:30][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=O)=O)C.[C:35](O)([C:37](F)(F)F)=[O:36]>>[CH2:35]([O:36][C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)=[C:17]3[C:13]=2[C:14]2[CH:33]=[C:32]([CH3:34])[CH:31]=[N:30][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)[CH3:37]
Reactant: CCS(=O)(=O)c1cccc(-c2ccc(OCC3CCN(C)CC3)c3[nH]c4ncc(C)cc4c23)c1
Reactant: O=C(O)C(F)(F)F
Product: CCOc1cccc(-c2ccc(OCC3CCN(C)CC3)c3[nH]c4ncc(C)cc4c23)c1

Procedure:
The title compound was synthesized using an analogous procedure to that outlined in the preparation of Compound 176. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.35 (t, J=6.95 Hz, 3H) 1.44-1.56 (m, 2H) 2.10-2.18 (m, 1H) 2.25 (br. s., 5H) 2.80 (d, J=4.80 Hz, 3H) 2.97-3.07 (m, 2H) 3.52 (d, J=11.62 Hz, 2H) 4.06-4.09 (m, 4H) 6.98-7.14 (m, 5H) 7.44 (t, J=7.71 Hz, 1H) 7.64 (s, 1H) 8.25 (s, 1H) 9.28 (br. s., 1H) 11.87 (s, 1H); [M+H] calc'd for C27H32N3O2, 430.2; found, 430.5; [M+H+TFA] calc'd for C29H33N3O4F3, 544.2; found, 544.4.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([C:13]3[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=3)=[CH:10][C:9]=2[CH:21]=1)[CH:2]([CH3:4])[CH3:3].C(O)(=O)C.[NH:26]1[CH2:31][CH2:30][CH:29]([C:32]([OH:34])=[O:33])[CH2:28][CH2:27]1.C([BH3-])#N.[Na+]>C(Cl)Cl.CO.CS(C)=O>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([C:13]3[CH:14]=[CH:15][C:16]([CH2:17][N:26]4[CH2:31][CH2:30][CH:29]([C:32]([OH:34])=[O:33])[CH2:28][CH2:27]4)=[CH:19][CH:20]=3)=[CH:10][C:9]=2[CH:21]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: O=C(O)C1CCNCC1
Reactant: CC(C)Cc1ccc2oc(-c3ccc(C=O)cc3)cc2c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)Cc1ccc2oc(-c3ccc(CN4CCC(C(=O)O)CC4)cc3)cc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22 %

Procedure:
A mixture of 4-(5-isobutylbenzofuran-2-yl)benzaldehyde (22 mg, 0.08 mmol), acetic acid (7 μL, 0.12 mmol) and piperidine-4-carboxylic acid (15 mg, 0.12 mmol) in DCM/MeOH (1:1, 1.4 mL) was stirred at room temperature for 1 h. Sodium cyanoborohydride (2.5 mg, 0.04 mmol) was added and the reaction mixture was stirred for 4 h at room temperature. After concentration of solvent under reduced pressure, the resulting residue was dissolved in an aliquot of DMSO and purified by reverse phase preparative HPLC (Phenomenex reverse phase Luna 5μ C18(2) column, 60×21.2 mm ID) to yield the desired final product (1 6.9 mg, 55%): >95% purity by LCMS, ESI-MS: 392.0 (M+H)+, 1H NMR (400 MHz, CD3OD) δ 8.01 (d, 2H), 7.59 (d, 2H), 7.43 (d, 1H), 7.39 (s, 1H), 7.26 (s, 1H), 7.13 (dd, 1H), 4.36 (s, 2H), 3.58(m, 2H), 3.10 (m, 2H), 2.65(m, 1H), 2.57 (d, 2H), 1.90 (m, 1H), 0.92 (d, 6H).
Reaction SMILES: [N:1]1[NH:2][N:3]=[N:4][C:5]=1[NH2:6].Cl[CH2:8][C:9]1[C:10]([CH3:15])=[N:11][O:12][C:13]=1[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.ClCCl>[CH3:15][C:10]1[C:9]([CH2:8][N:2]2[N:3]=[N:4][C:5]([NH2:6])=[N:1]2)=[C:13]([CH3:14])[O:12][N:11]=1
Reactant: Cc1noc(C)c1CCl
Reactant: Nc1nn[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1noc(C)c1Cn1nnc(N)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 40 %

Procedure:
2H-tetrazol-5-amine (1.29 g, 12.5 mmol), 4-(chloromethyl)-3,5-dimethylisoxazole (1.56 mL, 12.5 mmol) and potassium carbonate (1.73 g, 15.5 mmol) in DMF (20 mL) were heated to 80° C. with stirring for 16 hours. The reaction was cooled to room temperature, diluted with dichloromethane (100 mL) and washed consecutively with brine and water. The organics were dried over sodium sulfate and concentrated with rotary evaporation. The crude product was purified by silica gel chromatography (0-10% gradient ethyl acetate/dichloromethane) affording 2-((3,5-dimethylisoxazol-4-yl)methyl)-2H-tetrazol-5-amine as a white crystalline solid (970 mg, 40% yield) MS M+H calculated 195.1, found 195.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH2:9][O:10][CH3:11])=[C:6]([CH3:12])[N:5]=[C:4]([NH2:13])[N:3]=1.[CH2:14]([NH2:19])[CH2:15][CH2:16][CH2:17][CH3:18]>O1CCOCC1>[NH2:13][C:4]1[N:3]=[C:2]([NH:19][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:7]([CH2:8][CH2:9][O:10][CH3:11])=[C:6]([CH3:12])[N:5]=1
Reactant: COCCc1c(C)nc(N)nc1Cl
Reactant: CCCCCN
Solvent: C1COCCO1
Product: CCCCCNc1nc(N)nc(C)c1CCOC
Reaction time: 7 h
Yield: 57.5 %

Procedure:
A mixture of 4-chloro-5-(2-methoxyethyl)-6-methylpyrimidine-2-ylamine (150 mg, 0.74 mmol), amylamine (0.86 ml) and dioxane (1.5 ml) was kept at 90° C. for 7 hours. The reaction mixture was concentrated in vacuo, and the residue was extracted with chloroform and a saturated aqueous NaHCO3 solution. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (4%MeOH: CHCl3) to give the object compound (108 mg, 57.5%).