Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[CH:16]=[C:15]([NH:17][CH:18]([CH3:20])[CH3:19])[C:14]([C:21]4[O:22][C:23]([NH:26][CH2:27][CH2:28][CH2:29][O:30][Si](C(C)(C)C)(C)C)=[N:24][N:25]=4)=[CH:13][N:12]=3)[CH:8]=[CH:9][C:4]=2N=C1.CCC[CH2:41][N+:42](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:30][CH2:29][CH2:28][CH2:27][NH:26][C:23]1[O:22][C:21]([C:14]2[C:15]([NH:17][CH:18]([CH3:20])[CH3:19])=[CH:16][C:11]([NH:10][C:7]3[CH:6]=[CH:5][C:4]([C:41]#[N:42])=[CH:9][CH:8]=3)=[N:12][CH:13]=2)=[N:25][N:24]=1
Reactant: CC(C)Nc1cc(Nc2ccc3ncsc3c2)ncc1-c1nnc(NCCCO[Si](C)(C)C(C)(C)C)o1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)Nc1cc(Nc2ccc(C#N)cc2)ncc1-c1nnc(NCCCO)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N2-(benzo[d]thiazol-6-yl)-5-(5-((3-((tert-butyldimethylsilyl)oxy)propyl)amino)-1,3,4-oxadiazol-2-yl)-N4-isopropylpyridine-2,4-diamine (52a) (150 mg, 0.2 mmol) in THF (10 mL) was cooled to 0° C. Added TBAF (1M in THF) (2 equiv.) to the reaction mixture. Reaction mixture was warmed to room temperature and stirred for 1 h. Reaction mixture was quenched by using 10% NaHCO3 solution. The aqueous layer was extracted with EtOAc (twice). The organic layers were collected together, dried over Na2SO4, filtered and concentrated. The crude material was purified by column chromatography through silica gel and MeOH: DCM as eluent. The material obtained was further purified by prep HPLC to provide the desired compound, 4-((5-(5-((3-hydroxypropyl)amino)-1,3,4-oxadiazol-2-yl)-4-(isopropylamino)pyridin-2-yl)amino)benzonitrile. 1H NMR: 400 MHz, CD3OD: δ 1.35 (d, J=6.40 Hz, 6H), 1.89-1.96 (m, 2H), 3.46 (t, J=6.80 Hz, 2H), 3.71 (t, J=6.00 Hz, 2H), 3.79-3.83 (m, 1H), 6.21 (s, 1H), 7.58-7.65 (m, 3H), 7.73-7.76 (m, 2H), 8.37 (s, 1H). LC/MS: XBridge Phe 8, 4.6×30 mm, 3.5 μm; Solvent A=2% ACN: 98% H2O: 10 mM NH4COOH; Solvent B=98% ACN: 2% H2O: 10 mM NH4COOH; gradient 0-100% B over 1.5 min (3.2 min run time); retention time: 1.486 min; LCMS (ES-API), m/z 394.0 (M+H). HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95% H2O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H2O: 0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23 min run time); Flow rate: 1.0 μL/min; Retention time: 5.812 min; Purity: 99.4%.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH2:7]([N:14]1[CH2:28][CH:17]2[C:18]3[CH:19]=[C:20]([O:26][CH3:27])[CH:21]=[CH:22][C:23]=3[C:24](=O)[CH:16]2[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOCC>[CH2:7]([N:14]1[CH2:15][CH:16]2[C:24](=[CH2:1])[C:23]3[CH:22]=[CH:21][C:20]([O:26][CH3:27])=[CH:19][C:18]=3[CH:17]2[CH2:28]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)[O-]
Reactant: COc1ccc2c(c1)C1CN(Cc3ccccc3)CC1C2=O
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CCOCC
Product: C=C1c2ccc(OC)cc2C2CN(Cc3ccccc3)CC12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyltriphenylphosphonium bromide (18.1 g, 50.7 mmol) and potassium tert-butoxide (5.7 g, 50.7) were added to a solution of 2-benzyl-5-methoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one (9.9 g, 33.8 mmol) in anhydrous ether (68 mL). The reaction mixture was stirred for 1 hour at room temperature then filtered through celite. The celite was washed with ether (200 mL), and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2) using a 0-35% ethyl acetate-hexanes gradient to afford 8.1 g (82%—two steps) of the subtitle compound. MS calculated for C20H21NO+H: 292, observed: 292.
Reaction SMILES: BrCC1C(C2C=CC=CC=2Cl)=NC2C(N=1)=C(Cl)C=CC=2.Br[CH2:22][C:23]1[C:32]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[Cl:39])=[N:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][C:29]=2[Cl:40])[N:24]=1.CN(C=O)C.[N-:46]=[N+:47]=[N-:48].[Na+]>>[N:46]([CH2:22][C:23]1[C:32]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[Cl:39])=[N:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][C:29]=2[Cl:40])[N:24]=1)=[N+:47]=[N-:48]
Reactant: Clc1ccccc1-c1nc2c(Cl)cccc2nc1CBr
Reactant: [N-]=[N+]=[N-]
Agent: Clc1ccccc1-c1nc2cccc(Cl)c2nc1CBr
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1nc2cccc(Cl)c2nc1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a stirring solution of a mixture of 3-(bromomethyl)-5-chloro-2-(2-chlorophenyl)quinoxaline and 2-(bromomethyl)-5-chloro-3-(2-chlorophenyl)-quinoxaline (8.5418 g, 23.21 mmol) in DMF (100.0 mL, 23.21 mmol) was added sodium azide (3.017 g, 46.42 mmol) at room temperature and the mixture was stirred at room temperature. After 40 min, the mixture was partitioned between EtOAc (200 mL) and H2O (100 mL). The organic layer was washed with brine (100 mL×1), dried over Na2SO4, filtered, and concentrated under reduced pressure to give 2-(azidomethyl)-5-chloro-3-(2-chlorophenyl)quinoxaline as a brown liquid: LC-MS (ESD major peak of m/z 330.1 [M+H]+. The crude product was carried on crude without purification for the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([I:11])=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[N:12]1[CH:17]=[CH:16]C=[CH:14][CH:13]=1.O1CCCC1.C(NCC)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([I:11])=[C:6]([CH:10]=1)[C:7]([N:12]([CH2:17][CH3:16])[CH2:13][CH3:14])=[O:8]
Reactant: c1ccncc1
Reactant: O=C(Cl)c1cc(Cl)ccc1I
Solvent: C1CCOC1
Solvent: CCNCC
Product: CCN(CC)C(=O)c1cc(Cl)ccc1I
Temperature: 25 °C
Reaction time: 3 h
Yield: 61 %

Procedure:
In a 100 mL round bottomed flask was placed the 5-chloro-2-iodobenzoyl chloride prepared above. Pyridine (50 mL, 600 mmol) and tetrahydrofuran (10 mL, 100 mmol) were then added. To the reaction mixture was added diethylamine (3 mL, 30 mmol) and the mixture was stirred for 3 hr at rt. The mixture was stirred for an additional 3 hr at 50° C. The mixture was allowed to cool to rt and then concentrated under reduced pressure. The residue was dissolved in EtOAc (100 mL) and then washed with 1N HCl (50 mL×2), 1N NaOH (50 mL), brine (50 mL), and dried over anhydrous MgSO4. Insoluble materials were removed by filtration and the filtrate was concentrated under reduced pressure to obtain the title compound (1.96 g, 61%) as a light yellow syrup. LCMS: (FA) ES+ 338, 340; 1H NMR (300 MHz, d6-DMSO) δ ppm 7.86 (d, 1H), 7.38 (d, 1H), 7.21 (dd, 1H), 3.61-3.68 (m, 1H), 2.91-3.29 (m, 3H), 1.17 (t, 3H), 1.01 (t, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH:4](/[CH:5]=[CH:6]\[C:7](=[O:13])[O:8][CH2:9][CH:10]([F:12])[F:11])[CH:3]1[C:14]([OH:16])=[O:15].[CH2:18]([N:21]1[CH2:25][C:24](=[O:26])[N:23]([CH2:27]O)[C:22]1=[O:29])[C:19]#[CH:20]>C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:17])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:13])[O:8][CH2:9][CH:10]([F:11])[F:12])[C@H:3]1[C:14]([O:16][CH2:27][N:23]1[C:24](=[O:26])[CH2:25][N:21]([CH2:18][C:19]#[CH:20])[C:22]1=[O:29])=[O:15]
Reactant: CC1(C)C(/C=C\C(=O)OCC(F)F)C1C(=O)O
Reactant: C#CCN1CC(=O)N(CO)C1=O
Solvent: ClC(Cl)Cl
Product: C#CCN1CC(=O)N(COC(=O)[C@@H]2[C@H](/C=C\C(=O)OCC(F)F)C2(C)C)C1=O

Procedure:
Using the procedure of Step F of Example 9, (1R, cis) 2,2-dimethyl-3-[(Z) 3-oxo-3-(2,2-difluoroethoxy)-1-propenyl]-cyclopropane-carboxylic acid and [3-propargyl-2,5-dioxo-imidazolidinyl]-methanol were reacted to obtain [3-propargyl-2,5-dioxo-imidazolidinyl]-methyl (1R,cis) 2,2-dimethyl-3-[(Z) 3-oxo-3-(2,2-difluoroethoxy-1-propenyl]-cyclopropane-carboxylate with a specific rotation of [α]D20 =+18°±2° (c=1% in CHCl3).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.[C:18]([C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)(=[O:20])[CH3:19].C(=O)([O-])[O-].[Na+].[Na+].C(#N)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[N:10]=[C:5]3[CH:4]=[CH:3][C:2]([C:25]4[CH:26]=[C:21]([C:18](=[O:20])[CH3:19])[CH:22]=[CH:23][CH:24]=4)=[CH:7][N:6]3[CH:8]=2)=[CH:12][CH:13]=1
Reactant: CC(=O)c1cccc(B(O)O)c1
Reactant: Clc1ccc(-c2cn3cc(Br)ccc3n2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC#N
Product: CC(=O)c1cccc(-c2ccc3nc(-c4ccc(Cl)cc4)cn3c2)c1
Yield: 95.2 %

Procedure:
This compound was prepared according to a process similar to that described in stage 6.3, by reacting 5 g (16.26 mmol) of 6-bromo-2-(4-chlorophenyl)imidazo[1,2-a]pyridine, prepared according to the protocol described in stage 6.1, with 3.46 g (21.13 mmol) of 3-acetylphenylboronic acid, in the presence of a 2M aqueous solution of sodium carbonate (90 ml) and of 0.94 g (0.81 mmol) of tetrakis(triphenylphosphine)palladium in 180 ml of a mixture of acetonitrile and toluene (v/v). 5.37 g of expected product are obtained
Reaction SMILES: [C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:19][C:20]1[CH:31]=[CH:30][C:23]([C:24]([CH2:26][CH2:27][CH2:28]I)=[O:25])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(C(C)=O)C>[F:19][C:20]1[CH:21]=[CH:22][C:23]([C:24]([CH2:26][CH2:27][CH2:28][N:10]2[CH2:9][CH2:8][C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:12][CH2:11]2)=[O:25])=[CH:30][CH:31]=1
Reactant: O=C(CCCI)c1ccc(F)cc1
Reactant: c1ccc(C2(c3ccccc3)CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: O=C(CCCN1CCC(c2ccccc2)(c2ccccc2)CC1)c1ccc(F)cc1

Procedure:
6.1 g. of 4,4 -diphenylpiperidine are heated to boiling with 6.2 g. of 3-(p-fluorobenzoyl)propyl iodide and 5.3 g of anhydrous sodium carbonate in 30 cc. of methyl ethyl ketone for 8 hours while stirring. After cooling, the precipitated salt is filtered off and the filtrate is evaporated to dryness. The residue is dissolved in water and the aqueous solution is rendered alkaline by the addition of sodium hydroxide solution. The resulting base is recovered by repeated extraction with ether. The combined ether extracts are dried over potassium carbonate, the ether is distilled off, and the residue is recrystallized from ethanol with the addition of activated charcoal. Thereby, 9 g. of 1-[3-(p-fluorobenzoyl)-propyl]-4,4-diphenylpiperidine of the melting point 107° to 108° C. are obtained. On adding fumaric acid to its solution in ether, the fumarate of the melting point 195° to 197° C. is obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH2:10][CH2:11][CH3:12])=[CH:4][C:3]=1[N:13]=[C:14]=[O:15].C1(C)C=CC=CC=1.C[O:24][C:25]([NH:27][NH2:28])=O>C1C=CC=CC=1>[Cl:8][C:6]1[C:5]([O:9][CH2:10][CH2:11][CH3:12])=[CH:4][C:3]([N:13]2[C:25](=[O:24])[NH:27][NH:28][C:14]2=[O:15])=[C:2]([F:1])[CH:7]=1
Reactant: COC(=O)NN
Reactant: CCCOc1cc(N=C=O)c(F)cc1Cl
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Product: CCCOc1cc(-n2c(=O)[nH][nH]c2=O)c(F)cc1Cl
Reaction time: 8 h
Yield: 115.3 %

Procedure:
A solution of 2-fluoro-4-chloro-5-n-propoxyphenyl isocyanate (1.8 g) in benzene (10 ml) was added to a toluene solution containing methoxycarbonylhydrazine (0.71 g), and the resultant mixture was allowed to stand overnight. The precipitated crystals were collected by filtration and dissolved in a 4M aqueous sodium hydroxide solution (10 ml) under heating. To the resulting solution, conc. hydrochloric acid was added, and the precipitated crystals were collected by filtration to give 2.6 g of 4-(4-chloro-2-fluoro-5-n-propoxyphenyl)urazol. M.P., 181°-182° C. IR νmax (cm-1): 3150, 1710, 1680. NMR δ (ppm): 1.1 (3H, t), 4.0 (3H, q), 7.0 (1H, d), 7.3 (1H, d)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:27])[C:12]=1[C:13]1[N:14]=[CH:15][N:16]([C:18]2[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][N:19]=2)[CH:17]=1.C1N=C[N:30](C(N2C=NC=C2)=O)C=1.[OH-].[NH4+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:27])[C:12]=1[C:13]1[N:14]=[CH:15][N:16]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([NH2:30])=[O:23])=[CH:20][N:19]=2)[CH:17]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cn1nnc(-c2ccccc2F)c1-c1cn(-c2ccc(C(=O)O)cn2)cn1
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cn1nnc(-c2ccccc2F)c1-c1cn(-c2ccc(C(N)=O)cn2)cn1
Temperature: 60 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
To a solution of 6-(4-(4-(2-fluorophenyl)-1-methyl-1H-1,2,3-triazol-5-yl)-1H-imidazol-1-yl)nicotinic acid (69 mg, 0.189 mmol) in DMF (3 mL) was added CDI (37 mg, 0.227 mmol) and the resulting mixture stirred at 60° C. for 1 h. After cooling to room temperature ammonium hydroxide (300 μL, 1.9 mmol) was added and reaction mixture was stirred for 1 h and then evaporated. Purification by chromatography (reverse phase HPLC) afforded the title compound (56 mg, 81%) as a white foam. MS: m/e=364.1 [M+H]+.
Reaction SMILES: [CH:1]1([NH:7][CH2:8][CH:9]([OH:12])[CH2:10][CH3:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH2:15](Br)[CH3:16].O>O1CCCC1>[CH:1]1([NH:7][CH2:8][CH:9]([O:12][CH2:15][CH3:16])[CH2:10][CH3:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCC(O)CNC1CCCCC1
Reactant: CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(CC)CNC1CCCCC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 45.8 %

Procedure:
N-Cyclohexyl-N-(2-hydroxybutyl)amine (3 g) is dissolved in tetrahydrofuran (50 ml), and thereto is added with stirring sodium hydride (60% oily dispersion, 2.1 g) under ice-cooling, and the mixture is heated with stirring at 60° C. for one hour. To the reaction mixture is added dropwise with stirring ethyl bromide (2.1 g) under ice-cooling, and the mixture is stirred at room temperature for 4 hours. Water is added to the reaction mixture, and the mixture is extracted with ethyl acetate. The extract is concentrated under reduced pressure to remove the solvent, and the residue is purified by silica gel column chromatography (solvent; methylene chloride:methanol:aqueous ammonia=100:10:1) to give N-cyclohexyl-N-(2-ethoxybutyl)amine(1.6 g) as a colorless oil.
Reaction SMILES: Cl[CH:2]([CH2:5][C:6]1[CH:16]=[CH:15][C:9]2[N:10]=[C:11]([S:13][CH3:14])[S:12][C:8]=2[CH:7]=1)[CH:3]=O.[NH2:17][C:18]1[N:23]=[N:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=1.O>C(O)CCC>[CH3:14][S:13][C:11]1[S:12][C:8]2[CH:7]=[C:6]([CH2:5][C:2]3[N:23]4[N:22]=[C:21]([C:24]#[N:25])[CH:20]=[CH:19][C:18]4=[N:17][CH:3]=3)[CH:16]=[CH:15][C:9]=2[N:10]=1
Reactant: CSc1nc2ccc(CC(Cl)C=O)cc2s1
Reactant: N#Cc1ccc(N)nn1
Solvent: O
Solvent: CCCCO
Product: CSc1nc2ccc(Cc3cnc4ccc(C#N)nn34)cc2s1
Temperature: 25 °C
Yield: 43.2 %

Procedure:
A stirred mixture of 2-chloro-3-(2-(methylthio)benzo[d]thiazol-6-yl)propanal from Step 4 of Example 117 (1.3 g, 4.8 mmol) and 6-aminopyridazine-3-carbonitrile (0.8 g, 7.2 mmol) in 1-butanol (48 mL) was heated at reflux overnight. The mixture was cooled to rt and water (100 mL) was added. The mixture was extracted with EtOAc (3×60 mL, and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 50:1 to 20:1 DCM/MeOH to afford 3-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-b]pyridazine-6-carbonitrile as a yellow solid (0.7 g, 44%). 1H NMR (300 MHz, CDCl3) δ 8.09 (d, J=9.0 Hz, 1H), 7.83-7.78 (m, 2H), 7.69 (s, 1H), 7.36 (d, J=8.4 Hz, 1H), 7.29 (d, J=9.3 Hz, 1H), 4.46 (s, 2H), 2.78 (s, 3H). LCMS (ESI) m/z 338 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:14][CH2:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:15])[CH:10]=3)[NH:5][C:4]=2[CH:3]1[C:16]1C=CC=C[CH:17]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:45]#[C:46][C:47]1[CH:52]=[CH:51][C:50]([Cl:53])=[CH:49][CH:48]=1>C1(C)C=CC=CC=1>[Cl:53][C:50]1[CH:51]=[CH:52][C:47]([C:46]#[C:45][N:5]2[C:6]3[C:11](=[CH:10][C:9]([CH3:15])=[CH:8][CH:7]=3)[C:12]3[CH2:13][CH2:14][N:2]([CH3:1])[CH:3]([CH2:16][CH3:17])[C:4]2=3)=[CH:48][CH:49]=1
Reactant: Clc1ccc(C#CBr)cc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CCN(C)C3c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: Cc1ccccc1
Product: CCC1c2c(c3cc(C)ccc3n2C#Cc2ccc(Cl)cc2)CCN1C
Temperature: 80 °C

Procedure:
2,6-dimethyl-1-phenyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (276 mg, μmol) was mixed with CuSO4.5H2O (50 mg, 0.2 mmol), 1,10-phenanthroline (72 mg, 0.4 mmol), K3PO4 (425 mg, 2 mmol) and 1-(bromoethynyl)-4-chlorobenzene (237 mg, 1.1 mmol) in toluene (8-10 ml). The reaction mixture was flushed with nitrogen and heated at 80° C. for 16 h. The reaction mixture was filtered through Celite, and the Celite bed was rinsed with dichloromethane. Combined organic layer was concentrated under reduced pressure and the residue was purified by silica gel chromatography (100-200 mesh) eluting with 60-80% ethyl acetate in hexane to obtain 9-((4-chlorophenyl)ethynyl)-1-ethyl-2,6-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole as brown semi solid (90 mg). The product was dissolved in 50% aqueous TFA:acetonitrile (1:1) and stirred at 50° C. to obtain the title compound as TFA salt (off white solid). 1H NMR (CD3OD) TFA SALT 7.65 (d, 1H), 7.45-7.3 (m, 4H), 7.2 (m, 3H), 7.05 (m, 2H), 6.7 (d, 2H), 6.25 (s, 1H), 4.25 (d, 1H), 4.15 (d, 1H), 3.4 (m, 2H), 3.2 (m, 2H), 2.9 (bs, 3), 2.4 (s, 3H).
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[Br:22][C:23]1[N:24]=[C:25]([CH2:28]O)[S:26][CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCCOC)=O)=NC(OCCOC)=O>C1COCC1.O>[Br:22][C:23]1[N:24]=[C:25]([CH2:28][O:20][C:17]2[CH:18]=[CH:19][N:14]([C:11]3[CH:12]=[CH:13][C:6]4[N:5]=[C:4]([CH:1]5[CH2:2][CH2:3]5)[N:8]([CH3:9])[C:7]=4[CH:10]=3)[C:15](=[O:21])[CH:16]=2)[S:26][CH:27]=1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cc21
Reactant: OCc1nc(Br)cs1
Agent: COCCOC(=O)N=NC(=O)OCCOC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4nc(Br)cs4)cc3=O)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 27.2 %

Procedure:
To a solution of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (289 mg), (4-bromo-1,3-thiazol-2-yl)methanol (399 mg) and triphenylphosphine (808 mg) in THF (8 ml) was added bis(2-methoxyethyl) azodicarboxylate (722 mg), and the mixture was stirred at room temperature for 3 h. The mixture was poured into water and extracted with EtOAc. The extract was washed with brine, dried over MgSO4, concentrated and purified by silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH) to give the title compound (128 mg) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:8])=[CH:4][CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:16][CH2:17][CH2:18][CH2:19]Br>CO.O>[C:3]1([CH3:8])[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:1]1[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: Cc1ccccc1N
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1ccccc1N1CCCC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 41.1 %

Procedure:
To a solution of o-toluidine (2.0 g; 18.7 mmol) in methanol (62 mL) was added sodium carbonate (4.95 g; 46.75 mmol) followed by 1,4-dibromobutane (4.85 g; 22.4 mmol). The resulting mixture was stirred at 50° C. under a nitrogen atmosphere overnight and then diluted with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by automated silica gel column chromatography (Biotage®) eluting with ethyl acetate/hexanes (0 to 40% v/v over 900 mL gradient elution) to yield the title product as a dark yellow-orange oil (1.24 g).
Reaction SMILES: O[CH2:2][CH2:3][C@H:4]1[C:9]2[CH:10]=[CH:11][C:12]([CH2:14][N:15]3[CH2:19][CH2:18][O:17][C:16]3=[O:20])=[CH:13][C:8]=2[CH2:7][CH2:6][O:5]1.CS(Cl)(=O)=O.CS(OCC[C@H]1C2C=CC(C(N)=O)=CC=2CCO1)(=O)=O.S([O-])(=O)(=O)C.[C:51]([C:53]1[CH:54]=[C:55]2[C:60](=[CH:61][CH:62]=1)[C:59]([N:63]1[CH2:68][CH2:67][NH:66][C@H:65]([CH3:69])[CH2:64]1)=[CH:58][CH:57]=[CH:56]2)#[N:52]>>[CH3:69][C@H:65]1[N:66]([CH2:2][CH2:3][C@H:4]2[C:9]3[CH:10]=[CH:11][C:12]([CH2:14][N:15]4[CH2:19][CH2:18][O:17][C:16]4=[O:20])=[CH:13][C:8]=3[CH2:7][CH2:6][O:5]2)[CH2:67][CH2:68][N:63]([C:59]2[CH:58]=[CH:57][CH:56]=[C:55]3[C:60]=2[CH:61]=[CH:62][C:53]([C:51]#[N:52])=[CH:54]3)[CH2:64]1
Reactant: O=C1OCCN1Cc1ccc2c(c1)CCO[C@H]2CCO
Reactant: C[C@@H]1CN(c2cccc3cc(C#N)ccc23)CCN1
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)OCC[C@@H]1OCCc2cc(C(N)=O)ccc21
Agent: CS(=O)(=O)[O-]
Product: C[C@@H]1CN(c2cccc3cc(C#N)ccc23)CCN1CC[C@@H]1OCCc2cc(CN3CCOC3=O)ccc21

Procedure:
3-{[(1S)-1-(2-Hydroxyethyl)-3,4-dihydro-1H-2-benzopyran-6-yl]methyl}-1,3-oxazolidin-2-one was reacted with methanesulfonyl chloride, as described for the preparation of 2-[(1S)-6-(aminocarbonyl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethyl methanesulfonate. The resultant crude mesylate was then condensed with (3R)-1-(6-cyano-1-naphthyl)-3-methylpiperazine, as described for Example 1b), to yield the title compound. M+H=511.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1[NH2:8].[CH2:10]([OH:15])[C:11]([F:14])([F:13])[F:12].O.[OH-].[Li+]>CS(C)=O.O>[Cl:9][C:5]1[N:4]=[N:3][C:2]([O:15][CH2:10][C:11]([F:14])([F:13])[F:12])=[C:7]([NH2:8])[CH:6]=1
Reactant: OCC(F)(F)F
Reactant: Nc1cc(Cl)nnc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Nc1cc(Cl)nnc1OCC(F)(F)F
Temperature: 80 °C
Reaction time: 2 h
Yield: 84.4 %

Procedure:
To a solution of 3.28 g 3,6-dichloro-pyridazin-4-ylamine in 30 mL dimethylsulfoxide and 4.0 g trifluoroethanol was added 1.84 g lithium hydroxide hydrate and 3 mL water and the mixture was heated to 80° C. for 18 h. The reaction mixture was diluted with 100 mL water and stirred at ambient temperature for 2 h. The resulting solid was collected by filtration washed with water and dried to constant weight under high vacuum to yield 3.84 g of the title compound as off white crystals, MS 228.1 and 230.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[S:9]([C@H:12]1[CH2:16][CH2:15][N:14]([C:17]2[N:22]=[C:21]([C:23]#[N:24])[CH:20]=[CH:19][N:18]=2)[CH2:13]1)(=[O:11])=[O:10].[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.CCN(C(C)C)C(C)C>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([N:29]2[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]2)[CH:5]=[CH:4][C:3]=1[S:9]([C@H:12]1[CH2:16][CH2:15][N:14]([C:17]2[N:22]=[C:21]([C:23]#[N:24])[CH:20]=[CH:19][N:18]=2)[CH2:13]1)(=[O:11])=[O:10]
Reactant: N#Cc1ccnc(N2CC[C@H](S(=O)(=O)c3ccc(F)cc3Cl)C2)n1
Reactant: CN1CCNCC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2ccc(S(=O)(=O)[C@H]3CCN(c4nccc(C#N)n4)C3)c(Cl)c2)CC1
Temperature: 60 °C
Reaction time: 20 h
Yield: 69.1 %

Procedure:
In a 10 mL round-bottomed flask, (S)-2-(3-(2-chloro-4-fluorophenylsulfonyl)pyrrolidin-1-yl)pyrimidine-4-carbonitrile (example 73) (50 mg, 136 μmol, 1 eq) was combined with acetonitrile (4 mL) to give a light yellow solution. 1-Methylpiperazine (20.7 mg, 22.9 μl, 204 μmol, 1.5 eq) and DIEA (35.2 mg, 47.6 μl, 273 μmol, 2 eq) were added. The reaction mixture was heated to 60° C. and stirred for 20 h. After that, 1-methylpiperazine (0.7 eq) and of DIEA (1 eq) were added. The reaction mixture was stirred at 60° C. for 5 h. After that, additional 1-methylpiperazine (1 eq) and DIEA (1.2 eq) were added. The reaction mixture was stirred at 60° C. for 16 h. The crude reaction mixture was concentrated in vacuo. The reaction mixture was poured into aqueous 5% Na2CO3 solution and extracted with EtOAc (3×10 mL). The organic layers were combined and washed with saturated aqueous NaCl solution (1×). The organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 10 g, CH2Cl2/MeOH 98/2) to yield a light yellow foam (42 mg, 69%). MS: m/z=447.1409 [M+H]+.