Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[S:4])([S-:3])[NH2:2].[NH4+].[Br-].[Br:7][CH2:8][C:9]([C:11]1[CH:16]=[CH:15][N+:14]([CH3:17])=[CH:13][CH:12]=1)=O>CO>[Br-:7].[CH3:17][N+:14]1[CH:15]=[CH:16][C:11]([C:9]2[N:2]=[C:1]([SH:3])[S:4][CH:8]=2)=[CH:12][CH:13]=1
Reactant: NC(=S)[S-]
Reactant: C[n+]1ccc(C(=O)CBr)cc1
Agent: [Br-]
Agent: [NH4+]
Solvent: CO
Product: C[n+]1ccc(-c2csc(S)n2)cc1
Temperature: 25 °C

Procedure:
0.69 g Ammonium dithiocarbamate were dissolved in 10 ml MeOH and 1.47 g 4-(2-bromoacetyl)-1-methylpyridinium bromide were added. After 2 h at ambient temperature the mixture was refluxed. After cooling the precipitate was filtered, washed with MeOH and dried.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]([OH:15])=O)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:25][CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[C:21]([CH:24]=1)[C:22]#[N:23].C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>O.CN(C)C=O>[C:22]([C:21]1[CH:24]=[C:17]([NH:16][C:13]([C:11]2[CH:10]=[N:9][N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH:12]=2)=[O:15])[CH:18]=[CH:19][C:20]=1[O:25][CH2:26][C:27]([CH3:29])([CH3:28])[CH3:30])#[N:23]
Reactant: O=C(O)c1cnn(-c2ccc(F)cc2)c1
Reactant: CC(C)(C)COc1ccc(N)cc1C#N
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)COc1ccc(NC(=O)c2cnn(-c3ccc(F)cc3)c2)cc1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.5 %

Procedure:
1-(4-Fluorophenyl)pyrazole-4-carboxylic acid (2 g), 5-amino-2-neopentyloxybenzonitrile (2.2 g), triethylamine (2 g) and diethyl cyanophosphate (1.6 g) were added to dimethylformamide (20 ml) and the mixture was stirred at room temperature for 1 h. The reaction mixture was added into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. n-Hexane was added to the residue to allow crystallization. The crystals were recrystallized from hydrous methanol to give the title compound (1.2 g), melting point: 196–197° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.CO[CH:20](OC)[N:21]([CH3:23])[CH3:22].C(C1C(N=CN(C)C)=NC(SCC)=NC=1)#N>>[CH2:11]([S:10][C:4]1[N:3]=[C:2]([N:1]=[CH:20][N:21]([CH3:23])[CH3:22])[C:7]([C:8]#[N:9])=[CH:6][N:5]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(OC)N(C)C
Reactant: N#Cc1cnc(SCc2ccccc2)nc1N
Agent: CCSc1ncc(C#N)c(N=CN(C)C)n1
Product: CN(C)C=Nc1nc(SCc2ccccc2)ncc1C#N

Procedure:
A solution of the product from Example 183B was reacted with N,N-dimethylformamide dimethyl acetal according to the procedure from Example 156B substituting the product from Example 183B for the product from Example 156B to provide the title compound.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][N:9]=[C:8]2[NH:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[C:20]([C:25]#[CH:26])[CH:19]=1)(=O)C.[OH-].[Na+].Cl>CO>[C:25]([C:20]1[CH:19]=[C:18]([NH:17][C:8]2[C:7]3[C:12](=[CH:13][C:14]([O:15][CH3:16])=[C:5]([OH:4])[CH:6]=3)[N:11]=[CH:10][N:9]=2)[CH:23]=[CH:22][C:21]=1[F:24])#[CH:26]
Reactant: C#Cc1cc(Nc2ncnc3cc(OC)c(OC(C)=O)cc23)ccc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C#Cc1cc(Nc2ncnc3cc(OC)c(O)cc23)ccc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.7 %

Procedure:
To a suspension of 4-((3-ethynyl-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl acetate (5.29 g) and methanol (30 mL) was added 5 mol/L NaOH (10.00 mL) at room temperature. The reaction mixture was stirred at room temperature for 4 h, and was adjusted to pH 7 with 0.1 N HCl (aq). The mixture was filtered to give the title compound as a white solid (3.90 g, 83.69%).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:11]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12].[CH3:26]I.O>C1COCC1>[C:11]([C:15]1[CH:16]=[CH:17][C:18]([CH:21]([CH3:26])[C:22]([O:24][CH3:25])=[O:23])=[CH:19][CH:20]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: COC(=O)Cc1ccc(C(C)(C)C)cc1
Reactant: CI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C(C)c1ccc(C(C)(C)C)cc1
Yield: 52.3 %

Procedure:
23.3 mL of lithium bis(trimethylsilyl)amide (1.0 M, 23 mmols) was added dropwise to 4.75 g (23 mmols) of methyl 4-tert-butylphenylacetate in 100 mL of dry THF at −78° C. while stirring under nitrogen. The mixture was stirred at this temperature for 45 minutes, then 1.5 mL (24 mmol) methyl iodide was added dropwise and the solution was stirred for an additional 1 hour at −78° C. The mixture was poured into 200 mL of H2O and the desired product was extracted with 500 mL diethyl ether. The organic layer was backwashed once with 500 mL H2O, dried over K2CO3, and concentrated under reduced pressure to yield 5.12 of a dark oil. The oil was purified via silica gel chromatography eluting with a solvent gradient of hexane to hexane/ethyl acetate 19:1. The fractions containing the desired product were combined and concentrated under reduced pressure to yield the title compound 2.65 g (53%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[OH-].[K+].Br[CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1>C(O)C>[I:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1
Reactant: Oc1cccc(I)c1
Reactant: BrCc1ccc2ccccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Ic1cccc(OCc2ccc3ccccc3c2)c1

Procedure:
To a solution of 3-iodophenol (4.0 g, 18 mmol) in ethanol (40 mL) is added potassium hydroxide (1.0 g, 18 mmol) and 2-(bromomethyl) naphthalene (4.0 g, 18 mmol) and this mixture is refluxed overnight. The hot reaction is filtered and the filtrate is chilled in ice. The ensuing precipitate is collected by filtration to give the title compound. 1H NMR (300 MHz, CDCl3) δ 7.84-7.89 (m, 4H), 7.48-7.53 (m, 3H), 7.40 (d, 1H), 7.29-7.32 (m, 1H), 6.95-7.04 (m, 2H), 5.20 (s, 2H); MS (EI) 360 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:12]=1[CH:13]=[O:14].C(=O)=O.CC(C)=O.[NH4+].[Cl-]>C1COCC1>[Cl:10][C:11]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:12]=1[CH:13]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[OH:14]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: Clc1ccc([Mg]Br)cc1
Agent: O=C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(Cl)c(C(O)c2ccc(Cl)cc2)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
To a solution of (4-chlorophenyl)magnesium bromide (1M in Et2O, 81 ml, 81 mmol) in THF (200 ml) was added drop wise a solution of 2-chloro-5-nitrobenzaldehyde (10 g, 53.9 mmol) in THF (100 ml) at −78° C. (dry ice/acetone bath). After the addition, the reaction mixture was further stirred at −78° C. for 1 h then 10 min at 0° C. (ice bath). A saturated aqueous NH4Cl solution (400 ml) was added and the resulting mixture was extracted with AcOEt (2×400 ml). The combined organic layers were washed with brine then dried over Na2SO4, filtered and evaporated to dryness. The resulting crude material was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, heptane/TBME 95:5→6:4) to yield the title compound (14.4 g, 48.4 mmol, 90%) as a beige solid. TLC: RF=0.80 (heptane/DCM/TBME 1:1:2); HPLC: AtRet=2.43 min; LC-MS: m/z not detected; 1H NMR (400 MHz, CDCl3): 6.20 (s, 1H), 7.36 (s, 4H), 7.53 (d, J=8.6, 1H), 8.13 (dd, J=8.8, 2.9, 1H), 8.66 (d, J=2.7, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:17]=[N:18][CH:19]=[C:20](Br)[CH:21]=1)[CH2:10][C:9]2([CH3:24])[CH3:23])=[O:5])[CH3:2].[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.Cl.CN(C)CC(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:17]=[N:18][CH:19]=[C:20]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:21]=1)[CH2:10][C:9]2([CH3:24])[CH3:23])=[O:5])[CH3:2]
Reactant: C1COCCN1
Reactant: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1cncc(Br)c1)N2
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1cncc(N3CCOCC3)c1)N2
Temperature: 120 °C
Yield: 50.6 %

Procedure:
A mixture of 2-(5-bromo-pyridin-3-yl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.39 g, 1.0 mmol), morpholine (0.35 g, 4 mmol), copper (I) iodide (114 mg, 0.6 mmol), N,N-dimethyl glycine hydrochloride (112 mg, 0.8 mmol) and potassium carbonate (0.42 g, 3 mmol) in dimethylsulfoxide (10 mL) was heated for 12 h at 120° C. After colling to room temperature, the mixture was treated with ethyl acetate (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. Purification on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company) (30% ethyl acetate/hexanes) to afford 4,4-dimethyl-2-(5-morpholin-4-yl-pyridin-3-yl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.20 g, 51%) as a white solid: MS (ESI) M+1=396.3.
Reaction SMILES: C1(=O)N(CC)C(=O)C2=CC=CC=C12.[CH3:14][NH:15][SH:16](=[O:18])=[O:17].[C:19]1(=[O:36])[N:23]([CH2:24][CH2:25][CH2:26]S(Cl)(=O)=O)[C:22](=[O:31])[C:21]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:20]12>>[C:22]1(=[O:31])[N:23]([CH2:24][CH2:25][CH3:26])[C:19](=[O:36])[C:20]2=[CH:35][CH:34]=[CH:33][CH:32]=[C:21]12.[CH3:14][NH:15][SH:16](=[O:18])=[O:17]
Reactant: O=C1c2ccccc2C(=O)N1CCCS(=O)(=O)Cl
Agent: CCN1C(=O)c2ccccc2C1=O
Agent: CN[SH](=O)=O
Product: CCCN1C(=O)c2ccccc2C1=O

Procedure:
Synthesised according to the method described for 2-phthalimidoethane-N-methylsulfonamide from 3-phthalimidopropanesulfonyl chloride (2.50 g). Yield: 854 mg (35%). 1H-NMR (CDCl3) δ (ppm) 7.82-7.76 (m, 2H), 7.72-7.64 (m, 2H), 4.13 (br s, 1H), 3.78 (t, J=6.8 Hz, 2H), 3.07-2.99 (m, 2H), 2.74 (d, J=5.2 Hz, 3H), 2.21-1.18 (m, 2H).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:8]=2[CH2:17][N:18]2[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[N:18]1([CH2:17][C:8]2[CH:9]=[CH:10][C:11]([C:13]([F:14])([F:15])[F:16])=[CH:12][C:7]=2[N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(C(F)(F)F)cc2N2CCOCC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1ccc(CN2CCNCC2)c(N2CCOCC2)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 80.2 %

Procedure:
A 100 mL round-bottom flask was charged with tert-butyl 4-[[2-(morpholin-4-yl)-4-(trifluoromethyl)phenyl]methyl]piperazine-1-carboxylate (1.30 g, 3.03 mmol, 1.00 equiv), dichloromethane (20 mL). The mixture was cooled to 0° C. Trifluoroacetic acid (3 mL) was added dropwise. The resulting solution was stirred overnight at room temperature and concentrated under pressure to yield 0.800 g (crude) of 4-[2-(piperazin-1-ylmethyl)-5-(trifluoromethyl)phenyl]morpholine as a light yellow solid. LCMS (ESI, m/z): 330 [M+H]+.
Reaction SMILES: [C:1]([Si:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:44]1[C:48](=[O:49])[C:47]2=[CH:50][CH:51]=[CH:52][CH:53]=[C:46]2[C:45]1=[O:54].N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:1]([Si:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[O:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][N:44]1[C:48](=[O:49])[C:47]2[C:46](=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:45]1=[O:54])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC(C)(C)[Si](OCCCCO)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OCCCCON1C(=O)c2ccccc2C1=O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.6 %

Procedure:
4-(tert-Butyl-diphenyl-silanyloxy)-butan-1-ol (10.0 g, 30.5 mmol), triphenylphosphine (8.0 g, 30 mmol), and N-hydroxyphthalimide (4.97 g, 30.5 mmol) were combined in anhydrous tetrahydrofuran (200 ml) att 0° C. and the resultant solution was stirred at 0° C. for 1 hour. Diethyl azodicarboxylate (5.31 g, 30.5 mmol) was added at 0° C., and the reaction mixture was allowed to gradually warm to room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in chloroform. Precipitation ensued, and the white solid was removed by filtration. The filtrate was concentrated and purified with column chromatography (hexane/ethyl acetate (3/1)) to afford 2-[4-(tert-butyl-diphenyl-silanyloxy)-butoxy]-isoindole-1,3-dione (11.06 g, 77% yield) as colorless crystals: 1H NMR (400 MHz, DMSO-d6) δ 7.84 (4H, s), 7.59 (4H, dd, J=7.6, 1.0 Hz), 7.39-7.43 (6H, m), 4.13 (2H, t, J=6.4 Hz), 3.68 (2H, t, J=5.8 Hz), 1.67-1.78 (4H, m), 0.95 (9H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[C:26]([C:28]([OH:31])([CH3:30])[CH3:29])[CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([CH:14]=[C:15]3[S:19][C:18](SCC)=[N:17][C:16]3=[O:23])=[CH:11][CH:12]=2)[CH:7]=[N:6]1.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][C@@H:40]1[CH2:45][OH:46])=[O:38])([CH3:35])([CH3:34])[CH3:33]>>[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][N:42]([C:18]2[S:19][C:15](=[CH:14][C:10]3[CH:9]=[C:8]4[C:13](=[CH:12][CH:11]=3)[N:5]([CH2:4][C:3]3[CH:24]=[CH:25][C:26]([C:28]([OH:31])([CH3:29])[CH3:30])=[CH:27][C:2]=3[Cl:1])[N:6]=[CH:7]4)[C:16](=[O:23])[N:17]=2)[CH2:41][C@@H:40]1[CH2:45][OH:46])=[O:38])([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)N1CCNC[C@@H]1CO
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(C)(C)O)cc3Cl)c2)S1
Product: CC(C)(C)OC(=O)N1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(C)(C)O)cc4Cl)c3)S2)C[C@@H]1CO

Procedure:
4-(5-{1-[2-Chloro-4-(1-hydroxy-1-methyl-ethyl)-benzyl]-1H-indazol-5-ylmethylene}-4-oxo-4,5-dihydro-thiazol-2-yl)-2-(R)-hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester was prepared from 5-{1-[2-Chloro-4-(1-hydroxy-1-methyl-ethyl)-benzyl]-1H-indazol-5-ylmethylene}-2-ethylsulfanyl-thiazol-4-one and 2-(R)—Hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester following General Procedure C.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[CH3:35][O:36][C:37]1[CH:38]=[C:39]([C:43]2[C:48]([NH2:49])=[CH:47][C:46]([N:50]3[CH2:55][CH2:54][O:53][CH2:52][CH2:51]3)=[CH:45][N:44]=2)[CH:40]=[N:41][CH:42]=1.Cl[C:57]1[C:66]2[C:61](=[C:62]([Cl:67])[CH:63]=[CH:64][CH:65]=2)[N:60]=[C:59]([C:68]2[CH:73]=[C:72]([CH3:74])[CH:71]=[CH:70][N:69]=2)[C:58]=1[CH3:75].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:67][C:62]1[CH:63]=[CH:64][CH:65]=[C:66]2[C:61]=1[N:60]=[C:59]([C:68]1[CH:73]=[C:72]([CH3:74])[CH:71]=[CH:70][N:69]=1)[C:58]([CH3:75])=[C:57]2[NH:49][C:48]1[C:43]([C:39]2[CH:40]=[N:41][CH:42]=[C:37]([O:36][CH3:35])[CH:38]=2)=[N:44][CH:45]=[C:46]([N:50]2[CH2:55][CH2:54][O:53][CH2:52][CH2:51]2)[CH:47]=1
Reactant: COc1cncc(-c2ncc(N3CCOCC3)cc2N)c1
Reactant: Cc1ccnc(-c2nc3c(Cl)cccc3c(Cl)c2C)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: COc1cncc(-c2ncc(N3CCOCC3)cc2Nc2c(C)c(-c3cc(C)ccn3)nc3c(Cl)cccc23)c1

Procedure:
The Buchwald coupled product was prepared according to Procedure H using dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.020 g, 0.042 mmol), 5′-methoxy-5-morpholino-2,3′-bipyridin-3-amine (0.091 g, 0.32 mmol), 4,8-dichloro-3-methyl-2-(4-methylpyridin-2-yl)quinoline (0.08 g, 0.26 mmol) and Pd2dba3 (0.010 g, 0.011 mmol) and sodium tert-butoxide (0.063 g, 0.66 mmol) in toluene (2.6 mL) at 100° C. for 48.3 h. The crude product was purified by column chromatography on alumina (0 to 50% EtOAc in hexanes) to give the desired product 8-chloro-N-(5′-methoxy-5-morpholino-2,3′-bipyridin-3-yl)-3-methyl-2-(4-methylpyridin-2-yl)quinolin-4-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.55 (1H, d, J=4.9 Hz), 8.35 (1H, s), 8.12 (2H, dd, J=4.6, 2.2 Hz), 7.89 (2H, dd, J=8.0, 2.3 Hz), 7.85 (1H, s), 7.66 (1H, s), 7.53 (1H, t, J=7.6 Hz), 7.34 (1H, m), 7.29 (1H, dd, J=2.7, 1.8 Hz), 5.70-5.72 (1H, m), 3.76 (3H, s), 3.60 (4H, t, J=4.8 Hz), 3.23 (4H, m), 2.46 (3H, s), 2.27 (3H, s). Mass Spectrum (ESI) m/e=553.3 (M+1).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[N:4]=1.[O:15]=[C:16]1[NH:25][C:24]2[N:23]=[C:22]([O:26][CH2:27][CH2:28][CH2:29][CH:30]=O)[CH:21]=[CH:20][C:19]=2[CH2:18][CH2:17]1>>[CH3:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[CH2:10][CH2:11][N:12]([CH2:30][CH2:29][CH2:28][CH2:27][O:26][C:22]3[N:23]=[C:24]4[C:19]([CH2:18][CH2:17][C:16](=[O:15])[NH:25]4)=[CH:20][CH:21]=3)[CH2:13][CH2:14]2)[N:4]=1
Reactant: O=CCCCOc1ccc2c(n1)NC(=O)CC2
Reactant: Cc1ccnc(N2CCNCC2)n1
Agent: Cl
Product: Cc1ccnc(N2CCN(CCCCOc3ccc4c(n3)NC(=O)CC4)CC2)n1

Procedure:
In a manner similar to that of other examples above, 4-methyl-2-piperazin-1-yl-pyrimidine hydrochloride (U.S. Pat. No. 6,303,603) was coupled by reductive amination to 4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde followed by typical workup and purification to give the title compound. MS: APCI: M+1: 397.2 (Exact Mass: 396.23).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[C:3]=1[CH3:9].[B:10](OC(C)C)([O:15]C(C)C)[O:11]C(C)C.[Li]CCCC>C1COCC1.C1(C)C=CC=CC=1>[CH3:8][C:4]1[C:3]([CH3:9])=[C:2]([B:10]([OH:15])[OH:11])[CH:7]=[CH:6][N:5]=1
Reactant: Cc1nccc(Br)c1C
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1nccc(B(O)O)c1C
Temperature: -20 °C
Reaction time: 2 h

Procedure:
A solution of 4-bromo-2,3-dimethyl-pyridine (1.38 g) and triisopropyl borate (2.05 mL) in 4 mL dry THF and 14 mL dry toluene was stirred on a dry ice-acetone bath to an internal temperature of −65° C. and 3.56 mL n-BuLi in hexanes was added dropwise over 0.5 h. Stirring continued at −65° C. for additional 2 h, then the bath was removed the mixture allowed to warm to −20° C. Reaction was quenched by addition of 10 mL 2M HCl, then allowed to warm to rt and diluted with more THF. 5M NaOH was added until the mixture reached pH 7, layers formed and the organic layer was collected. Several more extractions with THF were done and the combined organic extracts were dried with brine and Na2SO4 and concentrated under reduced pressure. The product crystallized and two crops were collected, for a total of 304 mg of 2,3-dimethylpyridine-4-boronic acid. LCMS (m/z) 153.
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:3]#[CH:4].C([Mg]Cl)#C.C(=O)C1C=CC=CC=1.Br[C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1/[C:26](=[CH:34]/[C:35]1[NH:36][CH:37]=[CH:38][C:39]=1[O:40][CH3:41])/[C:27](=[O:33])[NH:28]2>[Cu]I.CN(C=O)C.CCN(CC)CC>[OH:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:3]#[C:4][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1/[C:26](=[CH:34]/[C:35]1[NH:36][CH:37]=[CH:38][C:39]=1[O:40][CH3:41])/[C:27](=[O:33])[NH:28]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Reactant: C#CC(O)c1ccccc1
Agent: [Cu]I
Agent: C#C[Mg]Cl
Solvent: CCN(CC)CC
Solvent: O=Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CC(O)c3ccccc3)c21

Procedure:
Using Method D above, 3-hydroxy-3-phenyl-1-propyne (0.1 g, 0.78 mmol) (prepared by the addition of ethynylmagnesium chloride (Aldrich) to benzaldehyde (Aldrich) through Method A above) was coupled to (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (0.1 g, 0.31 mmol) (Starting Material 1) using DPPFPdCl2 (12.6 mg) (Aldrich) and CuI (3 mg) (Aldrich) as catalyst in DMF (5 mL) and Et3N (5 mL) as solvent at 85° C. for 18 h, yielding rac-(Z)-1,3-dihydro-4-(3-hydroxy-3-phenyl-1-propynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 42 mg, 38%).
Reaction SMILES: C([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([Si:25]([CH:32]([CH3:34])[CH3:33])([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27])[CH:17]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>[OH-].[Pd+2].[OH-].CO>[CH:32]([Si:25]([CH:26]([CH3:28])[CH3:27])([CH:29]([CH3:31])[CH3:30])[N:18]1[C:19]2=[N:20][CH:21]=[CH:22][CH:23]=[C:24]2[C:16]([CH2:15][C:12]2[CH:11]=[CH:10][C:9]([NH2:8])=[CH:14][CH:13]=2)=[CH:17]1)([CH3:33])[CH3:34]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(Cc2ccc(NCc3ccccc3)cc2)c2cccnc21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(Cc2ccc(N)cc2)c2cccnc21
Reaction time: 2 h

Procedure:
Benzyl-[4-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenyl]-amine (112, 210.0 mg, 0.447 mmol), methanol (15.0 mL) and palladium hydroxide (30.0 mg, 0.214 mmol) were combined. The reaction mixture was hydrogenated under an atmosphere of hydrogen (1 atm) at room temperature for 2 hours. Filtration and concentration gave the compound (113, 154 mg, 91%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH2:7][C@@H:8]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=O.C(OCC)(=O)C.[OH-].[Na+]>CCOCC.O1CCCC1>[CH2:18]([C@H:8]([NH2:7])[CH2:9][N:11]1[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH2:16]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CN1CCN(C(=O)[C@@H](N)Cc2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN1CCN(C[C@@H](N)Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.5 %

Procedure:
Lithium aluminum hydride (531 mg) was suspended in anhydrous ether (14 ml) with ice cooling in the nitrogen gas atmosphere and then a solution of 1-[(2S)-2-amino-3-phenylpropionyl]-4-methylpiperazine (1.48 g) in anhydrous tetrahydrofuran (7 ml) was dropwise added to the resulting suspension. The reaction system was stirred at room temperature for 4 hours. Ethyl acetate was gradually dropwise added to the reaction liquid with ice cooling till the reaction system did not undergo foaming any more. Then a 2N sodium hydroxide aqueous solution was added to the reaction system and the resulting mixture was extracted with chloroform. The resulting organic phase was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give the title compound (Reference Compound 1-1, 1.25 g).
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:13]=[CH:14][CH:15]=3)[N:10]=[CH:9][C:8]=2[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH2:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>CCO.[Pd]>[C:1]1([C:7]2[C:16]3[C:11](=[C:12]([C:17]([F:20])([F:18])[F:19])[CH:13]=[CH:14][CH:15]=3)[N:10]=[CH:9][C:8]=2[CH:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH3:22])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1ccccc1
Yield: 101.6 %

Procedure:
4-phenyl-3-(1-phenylvinyl)-8-(trifluoromethyl)quinoline (0.050 g, 0.133 mmol) and 5% Pd/C (0.010 g) in EtOH (7 mL) is hydrogenated on a Parr shaker (40 psi hydrogen) overnight. The reaction is filtered through Celite and concentrated. The product is chromatographed eluting with 2:98 ethyl acetate:hexanes to afford the title compound (0.051 g). MS (ESI) m/z 378; HRMS: calcd for C24H18F3N+H, 378.14696; found (ESI, [M+H]+), 378.1459.