Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C([O:13][C:14](=O)/[CH:15]=[C:16](\[C:23]1[CH:28]=[CH:27][C:26]([C:29]#[C:30][CH2:31][N:32]([CH3:34])[CH3:33])=[CH:25][CH:24]=1)/[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)C.[Cl-].[NH4+].ClCCl>O1CCCC1>[CH3:34][N:32]([CH3:33])[CH2:31][C:30]#[C:29][C:26]1[CH:27]=[CH:28][C:23](/[C:16](/[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:15]\[CH2:14][OH:13])=[CH:24][CH:25]=1
Reactant: CCOC(=O)/C=C(/c1ccccc1)c1ccc(C#CCN(C)C)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)CC#Cc1ccc(/C(=C\CO)c2ccccc2)cc1
Reaction time: 3 h

Procedure:
A 1 M solution of diisobutylaluminum hydride in tetrahydrofuran (8 mL) was added drop wise to a cooled (0° C.) solution of the above ester (0.650 g; 1.80 mmol) in dry tetrahydrofuran (50 mL). The reaction stirred at the temperature for 3 hours and then added saturated ammonium chloride (30 ml). The resulting mixture was stirred for 30 min, and the mixture was then added dichloromethane (150 ml) and hyflo super cell medium (15 g). The resulting suspension was stirred at ambient temperature 2 hours. The mixture was filtered and subsequently evaporated in vacuo. The crude product were taken up in dichloromethane (150 ml) and washed with water (2×50 ml). The dichloromethane phase was dried with anhydrous magnesium sulfate and subsequently evaporated in vacuo giving (Z)-3-[4-(3-dimethylamino-prop-1-ynyl)-phenyl]-3-phenyl-prop-2-en-1-ol
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N:15]=[CH:16][C:17]([OH:35])([C:31]([F:34])([F:33])[F:32])[CH2:18][C:19]2([C:22]3[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=3[O:29][CH3:30])[CH2:21][CH2:20]2)[N:6]=1)=O.[BH4-].[Na+]>>[F:28][C:26]1[CH:25]=[CH:24][C:23]([O:29][CH3:30])=[C:22]([C:19]2([CH2:18][C:17]([C:31]([F:32])([F:33])[F:34])([OH:35])[CH2:16][NH:15][C:11]3[CH:10]=[CH:9][CH:8]=[C:7]4[C:12]=3[CH:13]=[CH:14][C:5]([CH2:3][OH:2])=[N:6]4)[CH2:21][CH2:20]2)[CH:27]=1
Reactant: COC(=O)c1ccc2c(N=CC(O)(CC3(c4cc(F)ccc4OC)CC3)C(F)(F)F)cccc2n1
Agent: [BH4-]
Agent: [Na+]
Product: COc1ccc(F)cc1C1(CC(O)(CNc2cccc3nc(CO)ccc23)C(F)(F)F)CC1

Procedure:
Analogously to Example 40, 200 mg (0.41 mmol) of 5-{3-[1-(5-fluoro-2-methoxyphenyl)cycloprop-1-yl]-2-hydroxy-2-(trifluoromethyl)propylidenamino}-quinoline-2-carboxylic acid methyl ester is reacted with 156 mg (4.1 mmol) of sodium borohydride. After working-up and purification on silica gel with hexane-ethyl acetate (0-75%), 119 mg (63% of theory) of the product is obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:7](=[O:8])[CH2:6][C:5](=[O:9])[C:4]([CH3:11])([CH3:10])[S:3]1.C(Cl)(Cl)Cl.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Br:29][C:30]1[CH:35]=[CH:34][C:33]([Pb+3])=[C:32]([CH2:37][CH3:38])[CH:31]=1.Cl>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[Br:29][C:30]1[CH:35]=[CH:34][C:33]([CH:6]2[C:7](=[O:8])[C:2]([CH3:12])([CH3:1])[S:3][C:4]([CH3:11])([CH3:10])[C:5]2=[O:9])=[C:32]([CH2:37][CH3:38])[CH:31]=1
Reactant: CCc1cc(Br)ccc1[Pb+3]
Reactant: CC1(C)SC(C)(C)C(=O)CC1=O
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCc1cc(Br)ccc1C1C(=O)C(C)(C)SC(C)(C)C1=O
Temperature: 80 °C
Yield: 40.9 %

Procedure:
2,2,6,6-Tetramethylthiopyran-3,5-dione (10 g, 0.053 mol) (described in Helvetica Chimica Acta, 1992, 75(7), 2265-69) and 4-dimethylaminopyridine (32 g, 0.26 mol) are added to a mixture of chloroform (200 ml) and toluene (50 ml). The reaction mixture is flushed with nitrogen for 15 minutes at ambient temperature. 4-Bromo-2-ethylphenyllead triacetate (34 g, 0.06 mol) is added in one portion and the reaction mixture is stirred and heated to 80° C. (pre-heated oil bath) under an atmosphere of nitrogen for 1 hour. The reaction mixture is cooled to room temperature, acidified to pH 1 with 2N aqueous hydrochloric acid, filtered through a plug of diatomaceous earth and the two phases are separated. The aqueous phase is extracted with dichloromethane (2×100 ml). The organic phases are combined, washed with water, and dried over anhydrous sodium sulfate. The mixture is filtered, and the filtrate is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give 4-(4-bromo-2-ethylphenyl)-2,2,6,6-tetramethylthiopyran-3,5-dione as a white solid (8 g).
Reaction SMILES: I[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[CH:7][C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][CH2:26][NH2:27]>>[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][CH2:26][NH:27][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[CH:7][C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1cc(N2CCCC2)c2ccc(I)cc2n1
Reactant: NCCc1ccccc1Cl
Product: Cc1cc(N2CCCC2)c2ccc(NCCc3ccccc3Cl)cc2n1

Procedure:
In analogy to example 1, on reaction of 7-iodo-2-methyl-4-pyrrolidin-1-yl-quinoline with 2-(2-chlorophenyl)-ethylamine there was obtained [2-(2-Chloro-phenyl)-ethyl]-(2-methyl-4-pyrrolidin-1-yl-quinolin-7-yl)-amine as light brown foam. ISP mass spectrum, m/e: 366.2 (M+1 calculated for C22H24ClN3: 366).
Reaction SMILES: [NH2:1]/[C:2](/[CH3:19])=[C:3](\[C:6]1[CH2:7][CH2:8][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10][CH:11]=1)/[C:4]#[N:5].[Cl-].N1(C=[N+](C)C)C2C=CC=C[C:24]=2N=N1.[OH-].[Na+]>ClCCl>[CH2:12]([N:9]1[CH2:8][C:7]2[CH:24]=[N:1][C:2]([CH3:19])=[C:3]([C:4]#[N:5])[C:6]=2[CH2:11][CH2:10]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: C/C(N)=C(\C#N)C1=CCN(Cc2ccccc2)CC1
Reactant: C[N+](C)=Cn1nnc2ccccc21
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1ncc2c(c1C#N)CCN(Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 24 h
Yield: 60.4 %

Procedure:
To a solution of (E)-3-amino-2-(1-benzyl-1,2,3,6-tetrahydro-pyridin-4-yl)-but-2-enenitrile (15 g, 0.056 mole) in dichloromethane (200 mL), freshly prepared benzotriazol-1-ylmethylene-dimethyl-ammonium chloride (12 g, 0.068 mole) was added in one portion. The mixture was stirred for 24 h at ambient temperature. NaOH (2N, 200 mL) was added, and the resulting mixture was stirred vigorously for 5 min. The phases were separated and the aqueous phase was extracted with dichloromethane (100 mL). The combined organic phases were dried over magnesium sulfate, and the solvent was removed in vacuo. The crude product was purified by column chromatography to give 7-benzyl-3-methyl-5,6,7,8-tetrahydro-2,7-naphthyridine-4-carbonitrile as a colorless oil (8.9 g, 53% yield).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:5]2[C:10]=1[CH:9]=[N:8][C:7](SC)=[N:6]2.CC1N=C(C2C=CC=CC=2)N2C=1C=NC(S(C)(=O)=O)=N2.Cl.[N:40]1([CH2:46][CH2:47][O:48][C:49]2[CH:54]=[CH:53][C:52]([NH2:55])=[CH:51][CH:50]=2)[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1.C(N(CC)CC)C>C(O)C>[CH3:1][C:2]1[N:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:5]2[C:10]=1[CH:9]=[N:8][C:7]([NH:55][C:52]1[CH:53]=[CH:54][C:49]([O:48][CH2:47][CH2:46][N:40]3[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]3)=[CH:50][CH:51]=1)=[N:6]2
Reactant: Nc1ccc(OCCN2CCCCC2)cc1
Reactant: CSc1ncc2c(C)nc(-c3ccccc3)n2n1
Agent: Cc1nc(-c2ccccc2)n2nc(S(C)(=O)=O)ncc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1nc(-c2ccccc2)n2nc(Nc3ccc(OCCN4CCCCC4)cc3)ncc12
Yield: 8.2 %

Procedure:
Applying the displacement procedure, using 5-methyl-2-(methylthio)-7-phenylimidazo[5,1-f][1,2,4]triazine (Intermediate 72) (50 mg, 0.17 mmol), (4-{[2-(1-piperidinyl)ethyl]oxy}phenyl)amine hydrochloride (45 mg, 0.17 mmol), triethylamine (0.024 mL, 0.17 mmol) and ethanol (2.5 mL) to afford 5-methyl-7-phenyl-N-(4-{[2-(1-piperidinyl)ethyl]oxy}phenyl)imidazo[5,1-f][1,2,4]triazin-2-amine (6 mg) as a yellow solid. MS m/z 429 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1S(C)=O.[CH2:17]([OH:26])/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1CCN2C(=NCCC2)CC1>O1CCOCC1>[Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1[O:26][CH2:17][CH:18]=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: OC/C=C/c1ccccc1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Br
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: Nc1nc(OCC=Cc2ccccc2)c(Br)c(-c2ccco2)n1

Procedure:
From 5-bromo-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl-amine, (E)-cinnamyl alcohol and DBU in dioxane. EI-MS m/e (%): 373 (M{81Br}+, 4), 371 (M{79Br}+, 4), 292 ([M—Br]+, 8),202 (14), 117(100), 115 (38),91 (17).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[CH:32]=[CH:31][C:14]([C:15]([NH:17][C@@H:18]3[CH2:26][C@:21]4([O:25][CH2:24][CH2:23][CH2:22]4)[CH2:20][C@@H:19]3[C:27]([O:29][CH3:30])=[O:28])=[O:16])=[CH:13][CH:12]=2)=[CH:3][CH2:2]1>CO>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([C:11]2[CH:12]=[CH:13][C:14]([C:15]([NH:17][C@@H:18]3[CH2:26][C@:21]4([O:25][CH2:24][CH2:23][CH2:22]4)[CH2:20][C@@H:19]3[C:27]([O:29][CH3:30])=[O:28])=[O:16])=[CH:31][CH:32]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)[C@H]1C[C@]2(CCCO2)C[C@H]1NC(=O)c1ccc(C2=CCOc3ccccc32)cc1
Solvent: CO
Product: COC(=O)[C@H]1C[C@]2(CCCO2)C[C@H]1NC(=O)c1ccc(C2CCOc3ccccc32)cc1
Reaction time: 6 h
Yield: 80 %

Procedure:
Methyl (5R,7S,8R)-8-{[4-(2H-chromen-4-yl)benzoyl]amino}-1-oxaspiro[4.4]nonane-7-carboxylate from reaction 34e (0.12 g, 0.29 mmol) was dissolved in methanol (30 mL), degassed with nitrogen, 5% Pd/C was added and the reaction was charged to 55 psi hydrogen. The reaction was shaken for 6 h. The catalyst was removed over Celite and the filtrate was concentrated to give methyl (5R,7S,8R)-8-{[4-(3,4-dihydro-2H-chromen-4-yl)benzoyl]amino}-1-oxaspiro[4.4]nonane-7-carboxylate (0.10 g, 80%) as a clear oil.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([NH:7][C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1Cl)=[N:15][CH:14]=[CH:13][CH:12]=2)=O.Cl.C([O:27][NH2:28])C1C=CC=CC=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(O)(C)C>[N:15]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:16]=1[C:17]1[N:28]3[O:27][CH2:2][CH2:3][CH2:4][C:5]3=[N:7][C:8]=1[CH:9]=[N:10]2
Reactant: NOCc1ccccc1
Reactant: O=C(CCCCl)Nc1cnc2cccnc2c1Cl
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: CC(C)O
Product: c1cnc2c(c1)ncc1nc3n(c12)OCCC3
Reaction time: 72 h
Yield: 5.2 %

Procedure:
A mixture of 4-chloro-N-(4-chloro[1,5]naphthyridin-3-yl)butanamide (3.1 g, 11 mmol) and O-benzylhydroxylamine hydrochloride (2.1 g, 13 mmol) in isopropanol (75 mL) was heated at reflux for 24 hours, then pyridinium p-toluenesulfonate (0.25 g, 1.0 mmol) was added and reflux continued for 48 more hours. The reaction mixture was then concentrated under reduced pressure and dichloromethane (50 mL) and saturated aqueous sodium carbonate (25 mL) were added and the mixture was stirred for 72 hours. The dichloromethane layer was then separated, concentrated under reduced pressure, and the residue purified by chromatography (silica gel eluted with 10% methanol in dichloromethane containing 5 mL of ammonium hydroxide solution per liter) to provide 0.13 g of 9,10-dihydro-8H-[1,2]oxazino[2′,3′:1,2]imidazo[4,5-c][1,5]naphthyridine.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29]O)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:50]C(Cl)(Cl)C(C(Cl)(Cl)Cl)=O>C(Cl)Cl>[Cl:50][CH2:29][CH2:28][O:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][O:21][CH2:20][CH2:19][O:18][Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(C(Cl)(Cl)Cl)C(Cl)(Cl)Cl
Reactant: CC(C)(C)[Si](OCCOCCOCCOCCO)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)[Si](OCCOCCOCCOCCCl)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Yield: 98.4 %

Procedure:
Compound 10 (813 mg, 1.88 mmol) and triphenylphosphine (995 mg, 3.76 mmol) were dissolved in CH2Cl2, and then at −78° C., hexachloroacetone (0.57 mL, 3.76 mmol) was added dropwise to the solution. The reaction temperature was raised to 0° C., and the progress of the reaction was monitored by TLC which indicated that it was over in 40 min Solvent was removed at room temperature and the crude product was chromatographed (SiO2, gradient, hexane/EtOAc 10:1 to 8:1) to give 834 mg (1.85 mmol, 98%) of 36 as a clear colorless oil. Rf 0.89 (hexane/EtOAc 1:1); 1H NMR (400 MHz, CDCl3) 7.68 (m, 4H, H-2 of phenyl), 7.45-7.35 (m, 6H, H-3 and H-4 of phenyl), 3.81 (t, 2H, J=5.4 Hz, CH2CH2OSi), 3.74 (t, 2H, J=6.0 Hz, CH2CH2Cl), 3.67-3.59 (m, 12H, ClCH2CH2(OCH2CH2)2OCH2CH2OSi), 1.05 (s, 9H, C(CH3)3); MS (ESI) Calcd for C24H35ClO4SiNa (M+Na+): 473.2. Found: 473.2.
Reaction SMILES: N#N.Br[C:4]1[CH:9]=[C:8]([S:10]([CH2:13][CH3:14])(=[O:12])=[O:11])[CH:7]=[CH:6][C:5]=1[O:15][CH3:16].[CH3:17][N:18]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:37]3[CH:38]=[N:39][N:40]([CH3:42])[CH:41]=3)[CH:24]=2)[C:19]1=[O:43].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:13]([S:10]([C:8]1[CH:7]=[CH:6][C:5]([O:15][CH3:16])=[C:4]([C:26]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:37]4[CH:38]=[N:39][N:40]([CH3:42])[CH:41]=4)[CH:24]=3)[C:19](=[O:43])[N:18]([CH3:17])[CH:27]=2)[CH:9]=1)(=[O:12])=[O:11])[CH3:14]
Reactant: Cn1cc(-c2ccc3c(=O)n(C)cc(B4OC(C)(C)C(C)(C)O4)c3c2)cn1
Reactant: CCS(=O)(=O)c1ccc(OC)c(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#N
Solvent: C1COCCO1
Solvent: O
Product: CCS(=O)(=O)c1ccc(OC)c(-c2cn(C)c(=O)c3ccc(-c4cnn(C)c4)cc23)c1
Yield: 55.7 %

Procedure:
For 5 min N2 was bubbled into a mixture of 2-bromo-4-ethylsulfonyl-1-methoxybenzene (300 mg, 1.07 mmol), the title compound of Example 46, step 2 (300 mg, 0.82 mmol), K3PO4 (435.6 mg, 2.05 mmol) and Pd(dppf)Cl2 (120.2 mg, 0.16 mmol) in dioxane (8 mL) and water (0.8 mL) which was then microwaved at 110° C. for 30 min. Purification by silica gel chromatography (DCM:MeOH=100:0 to 20:1) gave the title compound (200 mg, 55.7%) as a yellow solid. 1H NMR (CDCl3, 400 MHz) δ 8.51 (d, J=8.4 Hz, 1H), 8.03 (dd, J1=8.8 Hz, J2=2.8 Hz, 1H), 7.86 (d, J=2.4 Hz, 1H), 7.72 (s, 1H), 7.64 (s, 1H), 7.63-7.61 (m, 1H), 7.19 (d, J=8.8 Hz, 1H), 7.15 (d, J=1.2 Hz, 1H), 7.09 (s, 1H), 3.97 (s, 3H), 3.85 (s, 3H), 3.68 (s, 3H), 3.18 (q, J=7.6 Hz, 2H), 1.35 (t, J=7.6 Hz, 3H). LCMS: 438.1 (M+H)+
Reaction SMILES: [C:1]([O:4][CH:5]1[NH:8][C:7](=[O:9])[CH:6]1[CH2:10][CH2:11][CH2:12][NH:13][C:14]([NH:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])=[N:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])(=[O:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[C:47](Cl)(=[O:49])[CH3:48]>C1COCC1>[C:1]([O:4][CH:5]1[N:8]([C:47](=[O:49])[CH3:48])[C:7](=[O:9])[CH:6]1[CH2:10][CH2:11][CH2:12][NH:13][C:14]([NH:26][C:27]([O:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:28])=[N:15][C:16]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:17])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC(=O)OC1NC(=O)C1CCCNC(=NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)OC1C(CCCNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)C(=O)N1C(C)=O
Reaction time: 0.17 h
Yield: 67.2 %

Procedure:
To a -78° C. THF (20 mL) solution of compound 13 (trans:cis ratio, 2:1; 580 mg; 1.16 mmol) was added 1N THF solution of sodium bis(trimethylsilyl)amide (1.36 mL, 1.36 mmol), followed by 10 min stirring of the resultant solution. Acetyl chloride (96 mL, 1.36 mmol) was added, and the temperature of the resultant solution was raised to room temperature, stirred for 30 min, and concentrated. The residue was partitioned between ether and water. The organic phase was dried (Na2SO4) and concentrated. The residue was purified by silica gel chromatography (4:1/ether:hexane) to afford 420 mg (57%) of the product as a mixture of trans and cis (2:1) isomers.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[S:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[F:19].N1C=CC=CC=1.[Cl-:26].[Cl-].IC1C=CC=CC=1>O1CCCC1>[NH2:1][C:2]1[C:3]([S:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[F:19])=[CH:4][C:5]([C:8](=[O:10])[CH3:9])=[CH:6][C:7]=1[Cl:26]
Reactant: CC(=O)c1ccc(N)c(Sc2ccc(F)cc2F)c1
Reactant: [Cl-]
Solvent: c1ccncc1
Solvent: Ic1ccccc1
Solvent: C1CCOC1
Product: CC(=O)c1cc(Cl)c(N)c(Sc2ccc(F)cc2F)c1
Reaction time: 1.5 h
Yield: 75.7 %

Procedure:
A mixture of 4'-amino-3'-(2,4-difluorophenylthio)acetophenone (2 g), pyridine (0.623 g) and iodobenzene dichloride (2.7 g) in tetrahydrofuran (20 ml) was stirred for 1.5 hours at 0° to 5° C. The mixture was concentrated to dryness. The residue was dissolved in ethyl acetate, washed with water and an aqueous solution of sodium hydrogensulfite successively, dried, and evaporated. The solid residue was washed with a mixture of hexane and ethanol to give 4'-amino-3'-chloro-5'-(2,4-difluorophenylthio)acetophenone (1.7 g).
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].I[C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH:26]([CH3:28])[CH3:27])(=[O:25])=[O:24])=[CH:19][CH:18]=3)[N:15]=2)[N:10]([S:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH:9]=1.C(N(CC)CC)C>CN(C=O)C.[Cu]I.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>[CH:26]([S:23]([C:20]1[CH:19]=[CH:18][C:17]([C:14]2[N:15]=[C:16]3[C:8]([C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])=[CH:9][N:10]([S:29]([C:32]4[CH:33]=[CH:34][C:35]([CH3:38])=[CH:36][CH:37]=4)(=[O:30])=[O:31])[C:11]3=[N:12][CH:13]=2)=[CH:22][CH:21]=1)(=[O:24])=[O:25])([CH3:28])[CH3:27]
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3nc(-c4ccc(S(=O)(=O)C(C)C)cc4)cnc32)cc1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)n2cc(C#C[Si](C)(C)C)c3nc(-c4ccc(S(=O)(=O)C(C)C)cc4)cnc32)cc1
Temperature: 25 °C
Yield: 56.5 %

Procedure:
(Trimethylsilyl)acetylene (168.1 mg, 241.9 μL, 1.711 mmol) was added dropwise to a stirred solution of 7-iodo-2-(4-isopropylsulfonylphenyl)-5-(p-tolylsulfonyl)pyrrolo[2,3-b]pyrazine (765 mg, 1.316 mmol), triethylamine (665.8 mg, 917.1 μL, 6.580 mmol), copper(I) iodide (30.07 mg, 0.1579 mmol) and Pd(PPh3)4 (76.04 mg, 0.06580 mmol) in DMF (7 mL) at 0° C. and the resulting solution allowed to warm to ambient temperature over 64 hours. The solution was added dropwise to a mixture of EtOAc/ice water and the layers separated. The organic layer was washed with brine (×2), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion™, 40 g column, eluting with 2 to 20% EtOAc/DCM, loaded in DCM) to give the sub-title product as a beige solid (410.4 mg, 56% Yield). 1H NMR (400.0 MHz, DMSO) δ 0.17 (t, 9H), 1.07 (d, 6H), 2.38 (qn, 3H), 3.45-3.50 (m, 1H), 7.36 (d, 2H), 7.90 (d, 2H), 7.96 (d, 2H), 8.27 (d, 2H), 8.60 (s, 1H) and 9.08 (s, 1H) ppm; MS (ES+) 552.0.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[C:13]([CH:15]([NH:20][C:21]([CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[NH:29][C:30]([C:32]1[N:33]([CH2:42][CH2:43][CH2:44]Cl)[C:34]2[C:39]([CH:40]=1)=[CH:38][CH:37]=[C:36]([Cl:41])[CH:35]=2)=[O:31])=[O:22])[CH2:16][CH:17]([CH3:19])[CH3:18])#[N:14]>CN(C=O)C>[C:13]([CH:15]([NH:20][C:21]([CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[NH:29][C:30]([C:32]1[N:33]([CH2:42][CH2:43][CH2:44][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[C:34]2[C:39]([CH:40]=1)=[CH:38][CH:37]=[C:36]([Cl:41])[CH:35]=2)=[O:31])=[O:22])[CH2:16][CH:17]([CH3:19])[CH3:18])#[N:14]
Reactant: CC(C)CC(C#N)NC(=O)C1CCCCC1NC(=O)c1cc2ccc(Cl)cc2n1CCCCl
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)CC(C#N)NC(=O)C1CCCCC1NC(=O)c1cc2ccc(Cl)cc2n1CCCN1CCOCC1
Reaction time: 48 h
Yield: 27.1 %

Procedure:
To a stirred slurry of morpholine (0.05 ml, 0.51 mmol) and potassium carbonate (0.09 g, 0.68 mmol) in DMF (1.2 ml) was added 6-Chloro-1-(3-chloro-propyl)-1H-indole-2-carboxylic acid [2-(1-cyano-3-methyl-butylcarbamoyl)-cyclohexyl]-amide from Example 19 (0.17 g, 0.34 mmol) at room temperature. The reaction was stirred for 48 hours before being partitioned between ethyl acetate and 1N NaOH. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The resulting crude oil was chromatographed (5% MeOH/dichloromethane) to yield 6-chloro-1-(3-morpholin-4-yl-propyl)-1H-indole-2-carboxylic acid [2-(1-cyano-3-methyl-butylcarbamoyl)-cyclohexyl]-amide (0.05 g, 27%); [M+H=543].
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][C:9]([N+:12]([O-])=O)=[CH:10][CH:11]=[C:4]2[C:3]1=[O:15]>O>[NH2:12][C:9]1[CH:8]=[C:5]2[C:6](=[O:7])[N:2]([CH3:1])[C:3](=[O:15])[C:4]2=[CH:11][CH:10]=1
Reactant: CN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O
Solvent: O
Product: CN1C(=O)c2ccc(N)cc2C1=O
Reaction time: 2 h

Procedure:
To a solution of SnCl2 dihydrate (19.2 g, 85 mmol) in 8 ml water and 24 ml concentrated Hcl was added N-methyl-4-nitrophthalimide (4.5 g, 21.8 mmol). The mixture was stirred vigorously for 2 hours, and allowed to stand overnight. The mixture was then concentrated to ¾ original volume using rotavapor. The solid obtained was filtered and washed with water several times. The solid was dried to give 4-amino-N-methylphthalimide ((2.1 g (54.7%), Mp 247-248° C.).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]=[C:3](B2OC(C)(C)C(C)(C)O2)[CH2:2]1.[NH2:16][C:17]1[O:18][CH2:19][CH2:20][C@:21]2([C:35]3[C:30](=[N:31][CH:32]=[C:33](Br)[CH:34]=3)[O:29][C:28]3[C:23]2=[CH:24][C:25]([NH:37][C:38](=[O:46])[C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][N:40]=2)=[CH:26][CH:27]=3)[N:22]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>>[NH2:16][C:17]1[O:18][CH2:19][CH2:20][C@:21]2([C:35]3[C:30](=[N:31][CH:32]=[C:33]([C:3]4[CH2:2][O:1][CH2:6][CH2:5][CH:4]=4)[CH:34]=3)[O:29][C:28]3[C:23]2=[CH:24][C:25]([NH:37][C:38](=[O:46])[C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][N:40]=2)=[CH:26][CH:27]=3)[N:22]=1
Reactant: CC1(C)OB(C2=CCCOC2)OC1(C)C
Reactant: NC1=N[C@@]2(CCO1)c1cc(NC(=O)c3ccc(Cl)cn3)ccc1Oc1ncc(Br)cc12
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: NC1=N[C@@]2(CCO1)c1cc(NC(=O)c3ccc(Cl)cn3)ccc1Oc1ncc(C3=CCCOC3)cc12
Temperature: 85 °C
Yield: 21.7 %

Procedure:
A microwave vial was charged with 2-(5,6-dihydro-2H-pyran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (32.2 mg, 0.153 mmol), (S)—N-(2′-amino-3-bromo-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazin]-7-yl)-5-chloropicolinamide (64 mg, 0.128 mmol, Example 1), bis[di-tert-butyl(4 dimethylaminophenyl)phosphine]dichloropalladium(II) (4.53 mg, 6.39 μmol) and potassium phosphate (81 mg, 0.383 mmol). The vial was evacuated and backfilled with nitrogen (procedure was repeated twice). Dioxane (2 mL) and water (0.7 mL) were added and the reaction mixture was purged for 1 min with nitrogen. The vial was placed in a preheated oilbath and heated to 85° C. After 12 hours an additional portion of all reagents were added and the reaction mixture was heated for 4.5 hs to 100° C. The reaction mixture was cooled to room temperature and partitioned between EtOAc and water. The organic phase was separated and dried over MgSO4. The solvent was removed under reduced pressure. The residue was purified by preparative reversed-phase HPLC using a Phenomenex Gemini column, 10 micron, C18, 110 Å, 100×50 mm, 0.1% TFA in CH3CNH2O, gradient 10% to 100% over 20 min. The combined fractions were concentrated. The residue was dissolved in MeOH and loaded onto a Varian Bond Elut SCX column. The product was eluted with a 2M solution of NH3 in MeOH. 14 mg of (S)—N-(2′-amino-3-(5,6-dihydro-2H-pyran-3-yl)-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazin]-7-yl)-5-chloropicolinamide were obtained as a tan solid. MS m/z=503.7 [M]+. Calculated for C26H22ClN5O4: 503.94.