Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][NH+:12]([CH2:14][CH2:15]Cl)[CH3:13])=[CH:10][C:5]=2[O:4][CH2:3]1.[N:17]1([C:22]2[N:26]=[C:25]([CH:27]3[CH2:31][CH2:30][CH2:29][NH:28]3)[S:24][N:23]=2)[CH:21]=[CH:20][N:19]=[CH:18]1.[I-].[K+].OP([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[O:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH2:14][CH2:15][N:28]3[CH2:29][CH2:30][CH2:31][CH:27]3[C:25]3[S:24][N:23]=[C:22]([N:17]4[CH:21]=[CH:20][N:19]=[CH:18]4)[N:26]=3)[CH3:13])=[CH:10][C:5]=2[O:4][CH2:3]1
Reactant: c1cn(-c2nsc(C3CCCN3)n2)cn1
Reactant: C[NH+](CCCl)Cc1ccc2c(c1)OCO2
Agent: Cl
Agent: O=P([O-])([O-])O
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(CCN1CCCC1c1nc(-n2ccnc2)ns1)Cc1ccc2c(c1)OCO2
Temperature: 25 °C
Yield: 4.9 %

Procedure:
A solution of benzo[1,3]dioxol-5-ylmethyl-(2-chloro-ethyl)-methyl-ammonium hydrochloride (130 mg, 492 μmol), 3-imidazol-1-yl-5-pyrrolidin-2-yl-[1,2,4]thiadiazole (110 mg, 497 μmol), potassium iodide (20 mg, 120 μmol), and TEA (200 μL, 1.44 mmol) in DMF (1.8 mL) was heated at 140 C for 7 min. The reaction mixture was cooled to r.t. and poured into 10 mL of 1N K2HPO4(aq)/EtOAc (1:1). The organic layer was isolated and concentrated to crude residue. Purification was achieved using reverse phase HPLC (5% to 100% Acetonitrile/H2O, 0.1% TFA) to afford 10 mg (4%) of benzo[1,3]dioxol-5-ylmethyl-{2-[2-(3-imidazol-1-yl-[1,2,4]thiadiazol-5-yl)-pyrrolidin-1-yl]-ethyl}-methyl-amine as the TFA salt. [M+H]+ 412.85; 1H NMR (400 MHz, CDCl3) δ 9.23 (s, 1H), 7.95 (s, 1H), 7.46 (s, 1H), 6.88 (s, 1H), 6.81 (m, 2H), 6.01 (s, 2H), 4.24 (m, 1H), 4.15 (m, 2H), 3.0-3.4 (m, 5H), 2.72 (s, 3H), 2.58 (m, 1H), 2.40 (m, 1H), 1.98 (m, 2H), 1.90 (m, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([CH3:9])=[CH:5][C:4]([C:10]([OH:12])=O)=[CH:3]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:46][C:47]1[CH:48]=[C:49]2[C:53](=[CH:54][C:55]=1[NH:56][C@@H:57]([CH3:61])[CH2:58][O:59][CH3:60])[N:52]([CH3:62])[C:51](=[O:63])[C:50]2([CH3:65])[CH3:64]>CN1C(=O)CCC1>[CH3:60][O:59][CH2:58][C@@H:57]([NH:56][C:55]1[CH:54]=[C:53]2[C:49]([C:50]([CH3:65])([CH3:64])[C:51](=[O:63])[N:52]2[CH3:62])=[CH:48][C:47]=1[NH:46][C:10]([C:4]1[CH:5]=[C:6]([CH3:9])[C:7](=[O:8])[N:2]([CH3:1])[CH:3]=1)=[O:12])[CH3:61]
Reactant: Cc1cc(C(=O)O)cn(C)c1=O
Reactant: COC[C@H](C)Nc1cc2c(cc1N)C(C)(C)C(=O)N2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@H](C)Nc1cc2c(cc1NC(=O)c1cc(C)c(=O)n(C)c1)C(C)(C)C(=O)N2C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1,5-dimethyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid D1 (47 mg; 0.28 mmol), is dissolved in NMP (500 μl) and DIPEA (135 μl; 0.85 mmol) and HATU (111 mg; 0.29 mmol) is added. The reaction mixture is stirred at ambient temperature for 15 min. 5-Amino-6-((S)-2-methoxy-1-methyl-ethylamino)-1,3,3-trimethyl-1,3-dihydro-indol-2-one E-1.1 (85 mg; 0.31 mmol) dissolved in NMP (500 μl) is added and stirring is continued for 12 h at ambient temperature. The reaction mixture is poured on water and extracted with DCM once. The organic phase is dried with MgSO4 and concentrated under reduced pressure.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:23]2[C:22]3[CH:21]=[CH:20][C:19]([Br:24])=[CH:18][C:17]=3[N:16]=[C:15]([NH2:25])[C:14]=2[N:13]=[C:12]1[CH2:26][O:27][CH2:28][CH3:29].C(N(CC)CC)C.[OH-].[Na+]>C(Cl)(Cl)Cl.O>[NH2:25][C:15]1[C:14]2[N:13]=[C:12]([CH2:26][O:27][CH2:28][CH3:29])[N:11]([CH2:10][CH2:9][CH2:8][CH2:7][NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[C:23]=2[C:22]2[CH:21]=[CH:20][C:19]([Br:24])=[CH:18][C:17]=2[N:16]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CCCCN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CCCCNS(C)(=O)=O
Reaction time: 4 h
Yield: 120.6 %

Procedure:
Methanesulfonyl chloride (0.44 mL, 5.7 mmol) was added to a suspension of 1-(4-aminobutyl)-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine (2.04 g, 5.2 mmol) and triethylamine (0.94 mL, 6.8 mmol) in chloroform (100 mL), and the reaction was stirred for four hours. Water was added; a precipitate formed. The aqueous layer was adjusted to pH 10 with the addition of 50% aqueous sodium hydroxide. The precipitate was isolated by filtration, washed with cold chloroform, and dried overnight on the filter funnel. Material from another run was added, and entire procedure was repeated to eliminate unreacted starting material. N-{4-[4-Amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl]butyl}methanesulfonamide (2.95 g) was obtained as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([NH2:15])=[O:14].O.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20](S(O)(=O)=O)=[CH:19][CH:18]=1.C(=O)C1C=CC=CC=1.C1(C)C=CC=CC=1>CC(O)=O>[C:17]1([CH:27]2[NH:1][C:2]3[CH:6]=[C:5]([C:7]4[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=4)[S:4][C:3]=3[C:13](=[O:14])[NH:15]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: NC(=O)c1sc(-c2ccncc2)cc1N
Solvent: O=Cc1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1NC(c2ccccc2)Nc2cc(-c3ccncc3)sc21
Yield: 28.3 %

Procedure:
A mixture of 3-amino-5-(pyridin-4-yl)thiophene-2-carboxamide (99.9 mg, 0.456 mmol), p-toluenesulfonic acid monohydrate (8.67 mg, 0.046 mmol), benzaldehyde (0.056 mL, 0.547 mmol) and toluene (5 mL) was refluxed for 2 h. The reaction didn't occur. After cooling, AcOH (3 mL) was added, and the mixture was refluxed for 3 h. The reaction mixture was concentrated in vacuo. The residue was suspended in DMSO (3 mL) and the insoluble materials were filtered off. The filtrate was purified by preparative HPLC (ODS column, 0.1% TFA, water-MeCN=95:5-0:100). The fractions containing the object were basified by sat. aqueous sodium hydrogen carbonate, and the organic materials were extracted with EtOAc. The organic layer was dried over magnesium sulfate and concentrated in vacuo to afford the title compound (4.0 mg, yield 2.86%) as a yellow solid:
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[O:24][CH2:23][C@@H:19]3[CH2:20][NH:21][CH2:22][C@H:18]3[C@@H:17]2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:34](OC(=O)C)(=[O:36])[CH3:35]>>[C:34]([N:21]1[CH2:22][C@H:18]2[C@H:17]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[CH3:31])[C@@H:16]([O:15][C@@H:13]([C:5]3[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=[C:3]([C:2]([F:1])([F:32])[F:33])[CH:4]=3)[CH3:14])[O:24][CH2:23][C@@H:19]2[CH2:20]1)(=[O:36])[CH3:35]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccccc1[C@@H]1[C@@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC[C@@H]2CNC[C@H]21
Product: CC(=O)N1C[C@H]2CO[C@H](O[C@H](C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](c3ccccc3C)[C@@H]2C1

Procedure:
The title compound was prepared from (3aS,6R,7R,7aR)-6-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-7-(2-methylphenyl)octahydropyrano[3,4-c]pyrrole and acetic anhydride according to the procedures used for example 19. MS: (MH)+516.
Reaction SMILES: C([Li])(CC)C.C1CCCCC1.[C:12]([O:16][C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=1[CH3:28])=[O:18])([CH3:15])([CH3:14])[CH3:13].CON(C)[C:32](=[O:35])[CH2:33][CH3:34]>C1COCC1>[C:12]([O:16][C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=1[CH2:28][C:32](=[O:35])[CH2:33][CH3:34])=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: COc1ccc(NC(=O)OC(C)(C)C)c(C)c1
Reactant: CCC(=O)N(C)OC
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CCC(=O)Cc1cc(OC)ccc1NC(=O)OC(C)(C)C
Temperature: -60 °C
Reaction time: 1 h
Yield: 74.3 %

Procedure:
A solution of 1.3M sec-butyl lithium/cyclohexane (81 mL, 0.105 mol) was added slowly to 11.85 g (0.05 mol) of N-tert-butoxycarbonyl-4-methoxy-2-methylaniline in 80 mL of THF while keeping the temperature below −40° C. with a dry ice-ethanol bath. The bath was removed and the temperature allowed to rise to −20° C. and then the bath was replaced. After the temperature had cooled to −60° C., 6.1 g (0.052 mol) of N-methoxy-N-methylpropanamide in an equal volume of THF was added dropwise. The reaction mixture was stirred 1 hour, the cooling bath removed and stirred an additional 1 hour. It was then poured into a mixture of 200 mL of ether and 200 mL of 1N HCl. The organic layer was separated, washed with water, dried over Na2SO4 and concentrated at reduced pressure to give 10.9 g (74% yield) of 1-(2-(tert-butoxycarbonylamino)-5-methoxyphenyl]-2-butanone, melting at 80-81° C., after chromatography on silica eluting with 5% EtOAc/toluene.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([OH:3])=[O:2].[C:12]1([S:18]([NH2:21])(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[N:21][S:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:20])=[O:19])=[CH:6][CH:5]=1)([OH:3])=[O:2]
Reactant: NS(=O)(=O)c1ccccc1
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=C(O)c1ccc(C=NS(=O)(=O)c2ccccc2)cc1

Procedure:
In a manner similar to Example 2, 1.00 g (6.6 mmol) of 4-carboxybenzaldehyde, 1.05 g (6.6 mmol) of benzenesulfonamide and 20 mg of TsOH in 120 mL of toluene were heated for 2.5 hours to afford 1.82 g (90%) of SULF-2 as a white powder; IR (Nujol) 3400-2400 (br), 1680, 1605, 1283, 1160, 1083 cm-1 ; 1H NMR (DMSO-d6, TMS ext std)δ9 .17 (s, 1), 8.1-7.3 (m, 9).
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][N:15]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)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>[Cl:13][C:14]1[N:15]=[CH:16][C:17]([C:2]2[S:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=2)=[CH:18][CH:19]=1
Reactant: OB(O)c1ccc(Cl)nc1
Reactant: CCOC(=O)c1sc(Br)nc1C
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: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)c1sc(-c2ccc(Cl)nc2)nc1C
Yield: 69.1 %

Procedure:
Ethyl 2-bromo-4-methyl-1,3-thiazole-5-carboxylate (1 g, 1.3 eq, 4 mmol) is added to a mixture of 2-chloro-5-pyridine boronic acid (0.48 g, 1 eq, 3.07 mmol), tetrakis(triphenylphosphine)palladium (0.18 g, 0.05 eq, 0.15 mmol) and an aqueous solution of 2 M potassium carbonate (3 ml, 2 eq, 6.14 mmol) in toluene/ethanol (18 ml, 2:1 v/v). The mixture is refluxed overnight and the solvent is evaporated, then taken up in ethyl acetate, and washed two times with an aqueous solution of sodium hydrogenocarbonate. The organic layer is dried over magnesium sulfate, filtered and concentrated under vacuum. Purification by chromatography over silicagel (eluent: dichloromethane 100%) affords 0.6 g of ethyl 2-(6-chloropyridin-3-yl)-4-methyl-1,3-thiazole-5-carboxylate i97.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH:10]#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>[C:10]([C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: O=Cc1ccccc1Br
Reactant: C#CCCCCCCCCCC
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCC#Cc1ccccc1C=O

Procedure:
A mixture of 2-bromobenzaldehyde (10.05 mmoles), 1-dodecyne (12.03 mmoles), cuprous iodide (0.11 mmoles) and bis(triphenylphosphine) palladium chloride (0.20 mmoles) in freshly distilled triethylamine (30 ml.) was heated for one hour at reflux producing a white precipitate. The reaction mixture was cooled and filtered. The filtrate was evaporated to dryness at reduced pressure and then dissolved in diethyl ether (50 ml) and washed with brine (50 ml). After treatment with anhydrous magnesium sulfate and charcoal, the solution was evaporated to afford a dark oil, which was purified by flash chromatography (2% Et2O/hexane) to yield the desired product.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[C:5]([O:9][C:10](=[O:28])[NH:11][C:12]1[CH:17]=[C:16]([O:18][C:19]2[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][N:20]=2)[C:15]([Cl:26])=[CH:14][C:13]=1[F:27])([CH3:8])([CH3:7])[CH3:6].BrBr>C(O)(=O)C>[C:5]([O:9][C:10](=[O:28])[NH:11][C:12]1[CH:17]=[C:16]([O:18][C:19]2[N:20]=[C:21]3[S:1][C:2]([NH2:3])=[N:25][C:22]3=[CH:23][CH:24]=2)[C:15]([Cl:26])=[CH:14][C:13]=1[F:27])([CH3:8])([CH3:6])[CH3:7]
Reactant: N#C[S-]
Reactant: CC(C)(C)OC(=O)Nc1cc(Oc2ccc(N)cn2)c(Cl)cc1F
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)Nc1cc(Oc2ccc3nc(N)sc3n2)c(Cl)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.6 %

Procedure:
Potassium thiocyanate (2.70 g, 27.8 mmol) was dissolved in acetic acid (190 mL), tert-butyl{5-[(5-aminopyridin-2-yl)oxy]-4-chloro-2-fluorophenyl}carbamate (2.40 g, 6.78 mmol) was added, and the mixture was stirred at room temperature for 30 min. To the solution was added dropwise a solution (20 mL) of bromine (1.13 g, 7.07 mmol) in acetic acid, and the mixture was stirred at room temperature for 13 hr. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (300 mL), washed with saturated aqueous sodium hydrogen carbonate solution (100 mL×2) and saturated brine (50 mL), and dried over anhydrous magnesium sulfate. The dried organic layer was purified by basic silica gel chromatography (ethyl acetate), and the eluted fraction was concentrated under reduced pressure to give the title compound (2.69 g, 97%) as a white powder.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[CH:20]=[C:19]([NH:21][CH:22]3[CH2:26][CH2:25][NH:24][CH2:23]3)[N:18]=[CH:17][N:16]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[C:36](Cl)(=[O:39])[CH:37]=[CH2:38]>C1COCC1>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15]2[N:16]=[CH:17][N:18]=[C:19]([NH:21][CH:22]3[CH2:26][CH2:25][N:24]([C:36](=[O:39])[CH:37]=[CH2:38])[CH2:23]3)[CH:20]=2)=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC(=O)Cl
Reactant: c1ccc(Oc2ccc(Nc3cc(NC4CCNC4)ncn3)cc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C=CC(=O)N1CCC(Nc2cc(Nc3ccc(Oc4ccccc4)cc3)ncn2)C1
Temperature: -60 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of N4-(4-phenoxyphenyl)-N6-(pyrrolidin-3-yl)pyrimidine-4,6-diamine (0.13 g, 0.3 mmol) in THF (1.5 mL) at −60° C. were added DIPEA (0.07 g, 0.5 mmol) and acryloyl chloride (I M solution in THF, 0.3 mL, 0.3 mmol), and the reaction mixture was stirred at −60° C. for 5 min. The reaction mixture was quenched by adding water and it was extracted with EtOAc (2×5 mL). The combined EtOAc extract was washed with brine (3 mL), was dried over Na2SO4 and was concentrated under reduced pressure. The residue obtained was purified by column chromatography (SiO2, 230-400, chloroform/methanol: 98/2) to give 1-(3-(6-(4-phenoxyphenylamino)pyrimidin-4-ylamino)pyrrolidin-1-yl)prop-2-en-1-one (I-85) as a light green solid. 1H NMR (DMSO-d6) 5 ppm: 1.83-1.86 & 1.90-1.94 (m, 1H), 2.07-3.0 & 2.16-2.20 (m, 1H), 3.38-3.86 (m, 4H), 4.2-4.75 & 4.35-4.5 (bs, 1H), 5.65 (dt, J=2 & 10 Hz, 1H), 5.78 (d, J=3.6 Hz, 1H), 6.11 & 6.15 (dd, J=2.4 & 7.0 Hz & dd, J=2.4 & 7.2 Hz, 1H), 6.51-6.64 (m, together 1H), 6.93-7.00 (m, 4H), 7.07-7.18 (m, 2H), 7.36 (t, J=8 Hz, 2H), 7.51 (d, J=8 Hz, 2H), 8.12 (s, 1H), 8.93 (s, 1H); LCMS: m/e 401.8 (M+1).
Reaction SMILES: CC([Si](C1C=CC=CC=1)(C1C=CC=CC=1)[O:6][C@H:7]([CH2:13][P:14]([C:18]#[C:19][C:20]1[C:21]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)=[N:22][C:23]2[C:28]([C:29]=1[CH:30]([CH3:32])[CH3:31])=[CH:27][CH:26]=[CH:25][CH:24]=2)([O:16][CH3:17])=[O:15])[CH2:8][C:9]([O:11][CH3:12])=[O:10])(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.CC(O)=O.[N+](=C)=[N-]>C1COCC1.CCOCC.CCOC(C)=O>[F:39][C:36]1[CH:37]=[CH:38][C:33]([C:21]2[C:20]([C:19]#[C:18][P:14]([O:16][CH3:17])([CH2:13][C@@H:7]([OH:6])[CH2:8][C:9]([O:11][CH3:12])=[O:10])=[O:15])=[C:29]([CH:30]([CH3:32])[CH3:31])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=2)=[CH:34][CH:35]=1
Reactant: COC(=O)C[C@@H](CP(=O)(C#Cc1c(-c2ccc(F)cc2)nc2ccccc2c1C(C)C)OC)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: C=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CC(=O)O
Product: COC(=O)C[C@H](O)CP(=O)(C#Cc1c(-c2ccc(F)cc2)nc2ccccc2c1C(C)C)OC
Temperature: 25 °C
Reaction time: 20 h
Yield: 72.4 %

Procedure:
A mixture of (S)-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-4-[[[2-(4-fluorophenyl)-4-(1-methylethyl)-3-quinolinyl]ethynyl]methoxyphosphinyl]butanoic acid, methyl ester (729 mg, 0.997 mmol), tetra-n-butylammonium fluoride (1.0M in THF, 3.0 ml, 3.0 mmol), and HOAc (304 mg, 5.06 mmol) in THF (12 ml) was stirred at room temperature for 20 hours. The solution was cooled to 0° C., quenched with 5% KHSO4, and extracted twice with EtOAc. The pooled EtOAc layers were washed twice with 5% KHSO4 and once with brine. The combined aqueous layers were back-extracted 3× with EtOAc and pooled with the initial EtOAc extracts. Drying (Na2SO4), followed by filtration and removal of the solvent afforded a yellow oil. The oil was dissolved in Et2O and EtOAc and treated with excess diazomethane for 30 minutes. The excess diazomethane was destroyed by the addition of HOAc and solvent was removed in vacuo. The residue was chromatographed (flash, Merck SiO2, 40% acetone in hexane) to afford (S)-4-[[[2-(4-fluorophenyl)-4-(1-methylethyl)- 3-quinolinyl]ethynyl]-methoxyphosphinyl]-3-hydroxybutanoic acid, methyl ester (349 mg, 72%) as a white oily foam.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]([C:11]3[C:20]4[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=4)[N:14]=[C:13]([C:22]4[C:23]([CH3:28])=[N:24][CH:25]=[CH:26][CH:27]=4)[C:12]=3[CH3:29])[CH2:9][C:8]([CH3:31])([CH3:30])[C:5]2=[N:6][CH:7]=1.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.CC(C)([O-])C.[Na+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>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]>[CH3:31][C:8]1([CH3:30])[C:5]2=[N:6][CH:7]=[C:2]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH:3]=[C:4]2[N:10]([C:11]2[C:20]3[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=3)[N:14]=[C:13]([C:22]3[C:23]([CH3:28])=[N:24][CH:25]=[CH:26][CH:27]=3)[C:12]=2[CH3:29])[CH2:9]1
Reactant: Cc1ncccc1-c1nc2cc(F)ccc2c(N2CC(C)(C)c3ncc(Br)cc32)c1C
Reactant: C1COCCN1
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: Cc1ncccc1-c1nc2cc(F)ccc2c(N2CC(C)(C)c3ncc(N4CCOCC4)cc32)c1C
Temperature: 120 °C

Procedure:
Prepared according to procedure N using 4-(6-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-7-fluoro-3-methyl-2-(2-methylpyridin-3-yl)-quinoline (41 mg, 0.086 mmol), Pd2dba3 (7.86 mg, 8.59 μmol), morpholine (8.23 μL, 0.094 mmol), sodium tert-butoxide (16.5 mg, 0.172 mmol) and XPhos (8.19 mg, 0.017 mmol) in toluene (1.5 mL) and heating in the microwave for 1 h at 120° C. After purification 4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-7-fluoro-3-methyl-2-(2-methyl-3-pyridinyl)quino line was obtained as a yellow film. 1H NMR (400 MHz, chloroform-d) δ ppm 8.66 (1H, dt, J=4.9, 1.7 Hz), 7.78-7.88 (2H, m), 7.67 (1H, d, J=7.6 Hz), 7.57-7.63 (1H, m), 7.30-7.40 (2H, m), 5.84 (1H, d, J=2.0 Hz), 3.70-3.92 (6H, m), 2.93-3.12 (4H, m), 2.42 (3H, s), 2.08 (3H, s), 1.66 (3H, m), 1.59 (3H, s). Mass Spectrum (ESI) m/e=484 (M+1).
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]1[CH2:15][CH2:14][C:13]([CH2:18][OH:19])([CH2:16][OH:17])[CH2:12][CH2:11]1)(C(C)(C)C)(C)C.CO[C:22](OC)([CH3:24])[CH3:23].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>CN(C)C=O>[CH3:23][C:22]1([CH3:24])[O:17][CH2:16][C:13]2([CH2:12][CH2:11][CH:10]([CH2:9][OH:8])[CH2:15][CH2:14]2)[CH2:18][O:19]1
Reactant: CC(C)(C)[Si](C)(C)OCC1CCC(CO)(CO)CC1
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)OCC2(CCC(CO)CC2)CO1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of EXAMPLE 391D (1 g) and 2,2-dimethoxypropane (1.276 mL) in N,N-dimethylformamide (6.93 mL) was added para-toluenesulfonic acid monohydrate (1.451 g). The reaction was stirred for 4 hours at room temperature, triethylamine was added and the solution was concentrated by rotary evaporation. The residue was placed under high vacuum overnight to remove N,N-dimethylformamide. The residue was purified by regular phase flash column chromatography (Analogix—0-100% hexanes/ethyl acetate).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[F:11][C:12]([F:22])([F:21])[C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.COC(OC)OC.[BH4-].[Na+]>CO>[F:11][C:12]([F:21])([F:22])[C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH:1][CH2:2][CH2:3][C:4]2[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=2)=[CH:15][CH:14]=1
Reactant: NCCc1ccc(O)cc1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: CO
Product: Oc1ccc(CCNCc2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.6 %

Procedure:
A suspension of tyramine (1 g; 7.29 mmol) in MeOH (8 ml) was treated with 4-trifluoromethyl benzaldehyde (1.27 g; 7.29 mmol) and trimethylorthoformate (5 ml). The reaction mixture was stirred at rt overnight and then treated with sodium borohydride (0.69 g; 18.23 mmol) in small portions. After stirring for 30 minutes, it was concentrated and partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated. Crystallization from ethyl ether-hexane provided the title compound as a white crystalline solid (1.67 g; 78% yield). 1H NMR (CDCl3) δ 7.54 (d, 2H, J=8.0), 7.37 (d, 2H, J=8.0), 7.00 (d, 2H, J=8.4), 6.68 (d, 2H, J=8.4), 4.50 (bs, 2H), 3.86 (s, 2H), 2.88 (t, 2H, J=6.9), 2.77 (t, 2H, J=6.9).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:18]=[C:17](F)[CH:16]=[CH:15][C:10]=2[C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=1[Cl:20].[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>CS(C)=O.C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[CH:16]=[CH:15][C:10]=2[C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=1[Cl:20]
Reactant: COC(=O)c1ccc(F)cc1Oc1cnc(N)c(Cl)c1
Reactant: C1CNCCN1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(N2CCNCC2)cc1Oc1cnc(N)c(Cl)c1
Reaction time: 3 h

Procedure:
A solution of EXAMPLE 324C (8.90 g) and piperazine (10.34 g) in dimethylsulfoxide (100 mL) was heated to 85° C. After stirring for 3 hours, the reaction was cooled, diluted with ethyl acetate (400 mL) and washed with water (2×250 mL), brine (250 mL), dried over magnesium sulfate, filtered, and concentrated to give the title compound.