Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:28][C@H:29]1[CH2:34][C:33]2[C:35]([N:39]3[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]3)=[CH:36][CH:37]=[CH:38][C:32]=2[O:31][CH2:30]1>CN(C)C=O>[CH3:45][N:42]1[CH2:43][CH2:44][N:39]([C:35]2[C:33]3[CH2:34][C@H:29]([NH:28][C:11](=[O:13])[C:10]4[CH:9]=[CH:8][C:7]([N:4]5[CH2:3][CH2:2][O:1][CH2:6][CH2:5]5)=[CH:15][CH:14]=4)[CH2:30][O:31][C:32]=3[CH:38]=[CH:37][CH:36]=2)[CH2:40][CH2:41]1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CO3)CC1
Reactant: O=C(O)c1ccc(N2CCOCC2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(N4CCOCC4)cc2)CO3)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 68 %

Procedure:
A solution of 4-morpholinobenzoic acid (380 mg, 1.83 mmol; described in: Degutis, J.; Rasteikiene, L.; Degutiene, A. Zh. Org. Khim. 1978, 14(10), 2060–2064) and 1,1′-carbonyldiimidazole (310 mg, 1.92 mmol) in anhydrous N,N-dimethylformamide (12 mL) was stirred at 75° C. for 30 min. The mixture was allowed to cool after which a solution of (S)-3-amino-5-(4-methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran (430 mg, 1.74 mmol) in N,N-dimethylformamide (8 mL) was added. The reaction mixture was stirred at room temperature for 3 days. Another portion of 1,1′-carbonyldiimidazole (57 mg, 0.35 mmol) was added, and the mixture was stirred for an additional 3.5 h. The solvent was removed in vacuo, and the residue was purified by column chromatography on silica (eluent: chloroform/ethanol; 93:7+0.5% NH3) affording 513 mg (68% yield) of the title compound as a white solid: mp 210–212° C.; [α]22D−145° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 436 (65, M+).
Reaction SMILES: [OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:33][S:34][CH3:35])[N:8]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[NH:32][N:31]=[N:30][N:29]=3)=[CH:18][CH:17]=2)[C:9]=1[C:10]([O:12]CC)=[O:11])([CH3:4])[CH3:3].[OH-].[Na+]>>[OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:33][S:34][CH3:35])[N:8]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[NH:32][N:31]=[N:30][N:29]=3)=[CH:18][CH:17]=2)[C:9]=1[C:10]([OH:12])=[O:11])([CH3:4])[CH3:3]
Reactant: CCOC(=O)c1c(C(C)(C)O)nc(CSC)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: [Na+]
Agent: [OH-]
Product: CSCc1nc(C(C)(C)O)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.7 %

Procedure:
A mixture of 217 mg of ethyl 4-(1-hydroxy-1-methylethyl)-2-methylthiomethyl-1-{4-[2-(tetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate [prepared as described in Example 102(e)] and 3.2 ml of a 0.5N aqueous solution of sodium hydroxide was stirred at room temperature for 1 hour. At the end of this time, the insoluble matter was filtered off, and the filtrate was mixed with 1.6 ml of a 1N aqueous solution of hydrochloric acid. The amorphous powder which had precipitated was collected by filtration, to give 155 mg of the title compound, melting at 172°-181° C. (with softening).
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:11])=[C:4]([NH2:10])[CH:5]=[C:6]([F:9])[C:7]=1[F:8].[C:12](O)(=[O:16])[C:13](O)=[O:14]>Cl>[F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[C:4]2[C:3]=1[NH:11][C:12](=[O:16])[C:13](=[O:14])[NH:10]2
Reactant: Nc1cc(F)c(F)c(F)c1N
Reactant: O=C(O)C(=O)O
Agent: Cl
Product: O=c1[nH]c2cc(F)c(F)c(F)c2[nH]c1=O
Reaction time: 8 h
Yield: 36.8 %

Procedure:
To a brown solution of 3,4,5-trifluoro-1,2-phenylenediamine (285 mg, 1.75 mmol) in aqueous 2N HCl (10 mL) is added oxalic acid (221 mg, 1,75 mmol). The brown mixture is brought to reflux and stirred under N2 overnight. The mixture is filtered to yield 139 mg (37%) of crude title compound. An analytical sample is prepared by dissolving 42 mg of this brown powder in 2.5 mL-boiling ethanol. Upon cooling, brown, rod-like, crystals are formed, which are filtered and dried in vacuo to-yield 15 mg (36%) of pure title compound: 1H NMR (DMSO-d6), 6.91 (m, 1H), 12.02 (s, 1H), 12.19 (s, 1H); analysis calculated for C8H3F3N2O2 : C, 44.46; H, 1.40; N, 12.96. Found: C, 44.42; H, 1.16; N, 12.76.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:45][CH3:46])=[C:10]([CH2:19][N:20]([CH2:29][C:30]3[CH:31]=[C:32]([C:37]4[CH:42]=[CH:41][CH:40]=[C:39]([CH:43]=O)[CH:38]=4)[C:33]([CH3:36])=[CH:34][CH:35]=3)[C:21]([C:23]3([C:26]([NH2:28])=[O:27])[CH2:25][CH2:24]3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].C([N:54]1[CH2:59][CH2:58][NH:57][CH2:56][C@@H:55]1[CH3:60])(OC(C)(C)C)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:45][CH3:46])=[C:10]([CH2:19][N:20]([CH2:29][C:30]3[CH:31]=[C:32]([C:37]4[CH:42]=[CH:41][CH:40]=[C:39]([CH2:43][N:57]5[CH2:58][CH2:59][NH:54][C@H:55]([CH3:60])[CH2:56]5)[CH:38]=4)[C:33]([CH3:36])=[CH:34][CH:35]=3)[C:21]([C:23]3([C:26]([NH2:28])=[O:27])[CH2:24][CH2:25]3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN(Cc1ccc(C)c(-c2cccc(C=O)c2)c1)C(=O)C1(C(N)=O)CC1
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN(Cc1ccc(C)c(-c2cccc(CN3CCN[C@H](C)C3)c2)c1)C(=O)C1(C(N)=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.3 %

Procedure:
A mixture of N1-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N1-[(3′-formyl-6-methyl-3-biphenylyl)methyl]-1,1-cyclopropanedicarboxamide (55 mg, 0.088 mmol), (S)—N1-Boc-2-methyl-piperazine (17.69 mg, 0.088 mmol), sodium triacetoxyborohydride (37.4 mg, 0.177 mmol) and acetic acid (6.07 μL, 0.106 mmol) in DCM (2 mL) was stirred at room temperature overnight. The reaction mixture was quenched with saturated NaHCO3 and extracted with DCM twice. The combined organic layers were concentrated under vacuum to give the crude residue. It was re-dissolved in 25% TFA in DCM (2 mL) and stirred at room temperature for 2 h. Solvent was evaporated under a stream of nitrogen and then purified with a Gilson HPLC (with 0.1% TFA in the solvents), eluting with 10 to 60% CH3CN in water at a flow rate of 20 mL/min. The product fractions were combined, washed with saturated NaHCO3 and extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and then concentrated under vacuum to give N1-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N1-[(6-methyl-3′-{[(3R)-3-methyl-1-piperazinyl]methyl}-3-biphenylyl)methyl]-1,1-cyclopropanedicarboxamide as a solid (35 mg, 56.1%). LC-MS m/z 707 (M+H)+, 0.74 min (ret time).
Reaction SMILES: Cl[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH3:23][C:24]1([CH3:30])[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]1.CS(C)=O>O>[CH3:23][C:24]1([CH3:30])[CH2:29][CH2:28][CH2:27][N:26]([C:2]2[C:3]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=3)[CH2:25]1
Reactant: CC1(C)CCCNC1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(Cl)nc2c1
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCCC(C)(C)C3)nc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 10-mL sealed tube, was placed methyl 3-chloro-2-(4-fluorophenyl)quinoxaline-6-carboxylate (150 mg, 0.47 mmol, 1.00 equiv), 3,3-dimethylpiperidine (107 mg, 0.95 mmol, 2.00 equiv), DMSO (2 mL). The resulting solution was stirred overnight at 100° C. in an oil bath. The resulting solution was diluted with 20 mL of H2O. The resulting solids were collected by filtration. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:40). This resulted in 120 mg (64%) of methyl 3-(3,3-dimethylpiperidin-1-yl)-2-(4-fluorophenyl)quinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: CCCCCC.[H-].[Na+].[C:9]([CH2:11]P(=O)(OCC)OCC)#[N:10].[O:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22](=O)[CH2:21]1>C1COCC1.O>[O:20]1[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:22]([CH2:11][C:9]#[N:10])=[CH:21]1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: O=C1COc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: N#CCc1coc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101 %

Procedure:
To a stirred mixture of hexane washed sodium hydride (2.21 g, 0.046 mol, 50%/mineral oil) in THF (125 mL), was added diethyl cyanomethylphosphonate (8.15 g, 0.046 mol) dropwise. The reaction was stirred at room temperature for 1/2 hour, 3-coumaranone (sublimed) (5.6 g, 0.042 mol) in THF (100 mL) was added dropwise at 0° C., and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with water (300 mL), and extracted with ether (800 mL). The extracts were washed with brine (2×100 mL), dried (MgSO4), and concentrated to yield 6.67 g (100%) of the product as an off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2[O:12][C:11](C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][S:32]([NH:35][CH2:36][CH3:37])(=[O:34])=[O:33]>>[CH:11]([OH:12])=[O:33].[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[CH2:31][S:32]([NH:35][CH2:36][CH3:37])(=[O:33])=[O:34])=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: CCNS(=O)(=O)Cc1ccccc1Br
Product: CCNS(=O)(=O)Cc1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1
Product: O=CO

Procedure:
The title compound was prepared using analogous conditions to those described in Example 1 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine and 1-(2-bromophenyl)-N-ethylmethanesulfonamide. MS (ESI): mass calcd. for C19H19FN4O2S, 386.12; m/z found, 387.0 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.39 (s, 1H), 8.08 (d, J=1.4, 1H), 7.93 (m, 1H), 7.71-7.61 (m, 1H), 7.49-7.27 (m, 5H), 4.36 (s, 2H), 2.85 (q, J=7.2, 2H), 1.06 (t, J=7.2, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[CH:7]=[CH:6][C:5]=1[NH2:15])([O-])=O.Cl.C(O[C:20](=N)[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])C>CCO.[Pd]>[S:11]1[CH:12]=[CH:13][CH:14]=[C:10]1[C:8]1[CH:7]=[CH:6][C:5]2[N:15]=[C:20]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[NH:1][C:4]=2[CH:9]=1
Reactant: Nc1ccc(-c2cccs2)cc1[N+](=O)[O-]
Reactant: CCOC(=N)CC(=O)OCC
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)Cc1nc2ccc(-c3cccs3)cc2[nH]1
Reaction time: 3 h

Procedure:
2-Nitro-4-(2-thienyl)phenylamine (1.0 equivalent) and 10% Pd/C (0.1 equivalents) were suspended in anhydrous EtOH at room temperature. The reaction flask was evacuated and subsequently filled with H2. The resulting mixture was allowed to stir under a hydrogen atmosphere for 3 hours. Ethyl 3-ethoxy-3-iminopropanoate hydrochloride (2.0 equivalents) was then added and the resulting mixture was heated at reflux for 12 hours. After this time, the solution was filtered through a plug of Celite, concentrated, dissolved in 50 mL of 2 N HCl and washed with CH2Cl2. The aqueous layer was brought to pH 12 with concentrated NH4OH(aq) and extracted with CH2Cl2. The combined organic layers were dried with MgSO4 and concentrated to yield a brown oil which was purified by silica gel chromatography (5:95 MeOH:CH2Cl2) to provide a yellow solid. LC/MS m/z 287.1 (MH+), Rt 1.98 minutes.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([Cl:15])=[CH:10][C:9]=2[CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[O:5])C.O[Li].O.Cl>C1COCC1.CCO.O>[Cl:15][C:11]1[CH:12]=[C:13]2[C:8](=[C:9]([CH2:16][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:10]=1)[NH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:14]2
Reactant: CCOC(=O)c1cc2cc(Cl)cc(CN3CCOCC3)c2[nH]1
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc2cc(Cl)cc(CN3CCOCC3)c2[nH]1
Temperature: 45 °C
Reaction time: 1 h
Yield: 25.4 %

Procedure:
To a solution of 53 mg (0.16 mmol) of 5-chloro-7-morpholin-4-ylmethyl-1H-indole-2-carboxylic acid ethyl ester in THF/EtOH/H2O (2.5 ml) at RT was added 21 mg of LiOH.H2O. The reaction mixture was stirred at 45° C. for one hour and then acidified with aqueous HCl 1M. The product was extracted with EtOAc and concentrated under vacuo to afford 12 mg (25%) of 5-chloro-7-morpholin-4-ylmethyl-1H-indole-2-carboxylic acid as a white solid. ES-MS m/e (%): 293.1(M−H+).
Reaction SMILES: COP([CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])(OC)=O.[O:15]=[C:16]1[C:25](=O)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH:18]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[NH:17]1>C1(C)C=CC=CC=1.C1COCC1>[C:11]([O:10][C:8]([CH:7]=[C:25]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH:18]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[NH:17][C:16]1=[O:15])=[O:9])([CH3:12])([CH3:13])[CH3:14]
Reactant: COP(=O)(CC(=O)OC(C)(C)C)OC
Reactant: CCOC(=O)C1CCCCCCC(=O)C(=O)N1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCCCCCC(=CC(=O)OC(C)(C)C)C(=O)N1
Reaction time: 0.42 h

Procedure:
Potassium hexamethyldisilylamide (40.5 mL of a 0.58M solution in toluene, 23.5 mmol) is added to THF (60 mL), and then cooled to 0° C. t-Butyl dimethylphosphonoacetate (4.6 mL, 23.5 mmol) is added dropwise, and the reaction is warned to room temperature and stirred for 25 minutes. Ethyl 2,3-di-oxo-1-azacyclodecane-10-carboxylate (2.83 g, 11.74 mmol) is added in THF (15 mL), and the reaction is stirred at room temperature for 2.5 hours. The reaction is quenched with saturated ammonium chloride, and then extracted several times with ethyl acetate. The combined organic layers are dried (MgSO4), and the solvent is evaporated. The product is purified by silica gel chromatography (30% ethyl acetate/hexane) to give ethyl 3-t-butoxycarbonylmethylidene-2-oxo-1-azacyclodecane-10-carboxylate.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:28][CH3:29])=[C:10]([CH2:19][NH:20][C:21](=[O:27])[CH2:22][CH2:23][C:24]([OH:26])=O)[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[CH3:30][N:31]1[CH2:36][CH2:35][CH:34]([CH2:37][C:38]2[CH:39]=[C:40]([C:44]3[CH:49]=[CH:48][CH:47]=[C:46]([CH2:50][NH2:51])[CH:45]=3)[CH:41]=[CH:42][CH:43]=2)[CH2:33][CH2:32]1.C(N(CC)CC)C.ClCCl>CCOC(C)=O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:28][CH3:29])=[C:10]([CH2:19][NH:20][C:21](=[O:27])[CH2:22][CH2:23][C:24]([NH:51][CH2:50][C:46]3[CH:45]=[C:44]([C:40]4[CH:41]=[CH:42][CH:43]=[C:38]([CH2:37][CH:34]5[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]5)[CH:39]=4)[CH:49]=[CH:48][CH:47]=3)=[O:26])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CCC(=O)O
Reactant: CN1CCC(Cc2cccc(-c3cccc(CN)c3)c2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CCC(=O)NCc1cccc(-c2cccc(CC3CCN(C)CC3)c2)c1

Procedure:
A mixture of 4-({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)-4-oxobutanoic acid (0.080 g, 0.198 mmol), (({3′-[(1-methyl-4-piperidinyl)methyl]-3-biphenylyl}methyl)amine, triethylamine (0.080 mL, 0.575 mmol) and dichloromethane (DCM) (3 mL) was stirred at room temperature overnight. The LC-MS suggested that the reaction was complete. The reaction was diluted with EtOAc and washed in turn with sat. aq. NaHCO3, then saturated aqueous NaCl. The organic phase was dried (Na2SO4) and evaporated to give a residue (175 mg). This residue was purified on a Gilson HPLC on RP column CH3CN—H2O (0.1% TFA) gradient [10-80%]. Fractions containing the desired product were combined and evaporated to a small volume, then treated with saturated aqueous NaHCO3. The mixture was extracted with EtOAc (2×) and the combined extracts were washed with saturated aqueous NaCl and dried (Na2SO4), then evaporated to a glassy solid (52.2 mg). LC-MS m/z 680.7 (M+H)+, 0.76 min (ret time).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[O:23]1[CH2:26][C:25](=O)[CH2:24]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:12]=[CH:13][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([CH:25]4[CH2:26][O:23][CH2:24]4)[CH2:19][CH2:18]3)=[CH:15][CH:16]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1
Reactant: Cn1nc(Cl)cc(Nc2ccc(C3CCNCC3)cn2)c1=O
Reactant: O=C1COC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cn1nc(Cl)cc(Nc2ccc(C3CCN(C4COC4)CC3)cn2)c1=O
Temperature: 55 °C
Reaction time: 1 h
Yield: 60.3 %

Procedure:
To a solution of 6-chloro-2-methyl-4-(5-(piperidin-4-yl)pyridin-2-ylamino)pyridazin-3(2H)-one (639 mg, 2.00 mmol, Eq: 1.00) and oxetan-3-one (288 mg, 4.00 mmol, Eq: 2.0) in THF (10 ml) was added acetic acid (360 mg, 343 μl, 5.99 mmol, Eq: 3.0). The reaction mixture stirred under N2, at 55° C. for 1 h. Then sodium triacetoxyborohydride (847 mg, 4.00 mmol, Eq: 2.0) was added and the mixture was stirred at 65° C. for 2 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was partitioned between DCM and saturated NaHCO3. The layers were separated and the organic layer was washed with water. The organic layer was then dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 24 g, 0% to 40% (60:10:1 DCM:MeOH:NH4OH)/DCM) gradient) to give 6-chloro-2-methyl-4-(1′-oxetan-3-yl-1′,2′,3′,4′,5′,6′-hexahydro-[3,4′]bipyridinyl-6-ylamino)-2H-pyridazin-3-one (453 mg, 60%). LC/MS-ESI observed [M+H]+ 376. 1H NMR in CDCl3 is consistent with desired product.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:32][CH:33]=[C:34]([CH3:36])[CH3:35])[CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C@@H:17]([NH:22][C:23]([N:25]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:24])[CH2:18][CH:19]([CH3:21])[CH3:20])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:44]([C:46]1([OH:52])[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1)#[CH:45].C#C>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:52][C:46]1([C:44]#[C:45][C:2]2[CH:7]=[CH:6][C:5]([N:8]([CH2:32][CH:33]=[C:34]([CH3:36])[CH3:35])[CH:9]3[CH2:14][CH2:13][N:12]([C:15]([C@@H:17]([NH:22][C:23]([N:25]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)=[O:24])[CH2:18][CH:19]([CH3:20])[CH3:21])=[O:16])[CH2:11][CH2:10]3)=[CH:4][CH:3]=2)[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1
Reactant: C#CC1(O)CCCCC1
Reactant: CC(C)=CCN(c1ccc(I)cc1)C1CCN(C(=O)[C@H](CC(C)C)NC(=O)N2CCCCCC2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C#C
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)=CCN(c1ccc(C#CC2(O)CCCCC2)cc1)C1CCN(C(=O)[C@H](CC(C)C)NC(=O)N2CCCCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.1 %

Procedure:
(S)-Azepane-1-carboxylic acid (1-{4-[(4-iodo-phenyl)-(3-methyl-but-2-enyl)-amino]-piperidine-1-carbonyl}-3-methyl-butyl)-amide (0.50 g, 0.49 mmol) was dissolved in THF (4 mL), treated with triethylamine (0.34 mL, 2.45 mmol), 1-ethynyl-1-cyclohexanol (94 RL, 0.74 mmol), Pd(Ph3P)2Cl2 (34 mg, 0.049 mmol), and cuprous iodide (4.8 mg, 0.028 mmol). The reaction was stirred overnight at room temperature, then heated to 40° C. overnight. Another 1.5 equivalents of the acetylene, 0.1 equivalents of Pd(Ph3P)2Cl2, and 0.05 equivalents of cuprous iodide were added and the reaction was heated to 40° C. overnight. The reaction was then concentrated in vacuo and chromatographed on silica gel eluting with 4:3 hexane/EtOAc to give 116 mg (39%) of the desired product.
Reaction SMILES: C1COC2C=CC(NC3C(F)=CN=C(NC4C=CC=C(O)C=4)N=3)=CC=2O1.[NH2:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[C:31]#[N:32].[Cl:36][C:37]1[N:42]=[C:41](Cl)[C:40]([F:44])=[CH:39][N:38]=1>>[Cl:36][C:37]1[N:42]=[C:41]([NH:27][C:28]2[CH:35]=[CH:34][CH:33]=[C:30]([C:31]#[N:32])[CH:29]=2)[C:40]([F:44])=[CH:39][N:38]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: N#Cc1cccc(N)c1
Agent: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Product: N#Cc1cccc(Nc2nc(Cl)ncc2F)c1
Yield: 85.8 %

Procedure:
In a manner analogous to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 3-aminobenzonitrile (142 mg, 1.2 mmol) and 2,4-dichloro-5-fluoropyrimidine (100 mg, 0.6 mmol) gave 2-chloro-N4-(3-cyanophenyl)-5-fluoro-4-pyrimidineamine (128 mg, 86%) as a white solid. The reaction of 2-chloro-N4-(3-cyanophenyl)-5-fluoro-4-pyrimidineamine (50 mg, 0.2 mmol) and 3-aminophenol (66 mg, 0.6 mmol) gave N4-(3-cyanophenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine (40 mg, 62%). 1H NMR (acetone-d6): δ 6.48 (ddd, J=0.9, 2.4 and 7.8 Hz, 1H), 7.10 (t, J=8.1 Hz, 1H), 7.18 (ddd, J=1.2, 2.1 and 8.1 Hz, 1H), 7.33 (t, J=2.1 Hz, 1H), 7.45 (dt, J=1.2 and 7.8 Hz, 1H), 7.54 (t, J=8.1 Hz, 1H), 8.08 (d, J=3.3 Hz, 1H), 8.14 (ddd, J=1.5, 2.7 and 8.4 Hz, 1H), 8.39 (t, J=2.1 Hz, 1H), 8.58 (s, 1H, NH), 8.84 (s, 1H, NH); 19F NMR (282 MHz, acetone-d6): δ −167.41; LCMS: ret. time: 17.75 min.; purity: 92.39%; MS (m/e): 322.59 (MH+).
Reaction SMILES: [CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[C:10](=[NH:14])OCC.[NH2:15][NH:16][C:17]([NH2:19])=[S:18]>OS(O)(=O)=O.CO>[CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[C:10]([NH:15][NH:16][C:17]([NH2:19])=[S:18])=[NH:14]
Reactant: CCOC(=N)c1ncc([N+](=O)[O-])n1C
Reactant: NNC(N)=S
Agent: O=S(=O)(O)O
Solvent: CO
Product: Cn1c([N+](=O)[O-])cnc1C(=N)NNC(N)=S
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
To a stirred mixture of ethyl 1-methyl-5-nitro-2-imidazolecarboximidate (0.198 g., 0.001 mole) and thiosemicarbazide (0.091 g., 0.001 mole) in 5 ml. of methanol is added 1 drop of conc. H2SO4 and the mixture is stirred at room temperature for 50 minutes. The solid is filtered and washed with methanol, yielding 0.149 g. of the title compound, melting point 200°-201° C. dec.
Reaction SMILES: Cl.[F:2][C:3]([F:14])([F:13])[C:4]1([C:9]([O:11][CH3:12])=[O:10])[CH2:8][CH2:7][NH:6][CH2:5]1.CCN(C(C)C)C(C)C.[Br:24][C:25]1[CH:26]=[N:27][C:28](Cl)=[N:29][CH:30]=1.CCCCCC>CCO>[Br:24][C:25]1[CH:26]=[N:27][C:28]([N:6]2[CH2:7][CH2:8][C:4]([C:3]([F:2])([F:13])[F:14])([C:9]([O:11][CH3:12])=[O:10])[CH2:5]2)=[N:29][CH:30]=1
Reactant: COC(=O)C1(C(F)(F)F)CCNC1
Reactant: Clc1ncc(Br)cn1
Agent: Cl
Solvent: CCCCCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: COC(=O)C1(C(F)(F)F)CCN(c2ncc(Br)cn2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 62.3 %

Procedure:
To a solution of methyl 3-(trifluoromethyl)pyrrolidine-3-carboxylate hydrochloride (0.32 g, 1.36 mmol) in EtOH (10.0 mL) was added DIPEA (1.1 mL, 6.79 mmol) at rt and the mixture stirred at rt for 10 min followed by addition of 5-bromo-2-chloropyrimidine (0.26 g, 1.36 mmol). The reaction was heated up to 70° C. for 1 h. After reaction completion (by TLC), the solvent was evaporated and the crude residue purified over 60-120 M silica-gel using 10.0% EtOAc:hexane to obtain the desired product as a yellow solid (0.30 g, 63% yield). MS: 354.02 [M+H]+.