Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]([F:44])=[C:14]([CH:43]=2)[C:15]([NH:17][C:18]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:19]=2[N:28]2[CH2:33][CH2:32][CH2:31][C@H:30]([N:34](C)[C:35](=O)OC(C)(C)C)[CH2:29]2)=[O:16])=[CH:4][N:3]=1.Cl.C(Cl)Cl.[OH-].[Na+]>O1CCOCC1.CCOC(C)=O.CO>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]([F:44])=[C:14]([CH:43]=2)[C:15]([NH:17][C:18]2[CH:23]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:21]=[CH:20][C:19]=2[N:28]2[CH2:33][CH2:32][CH2:31][C@H:30]([NH:34][CH3:35])[CH2:29]2)=[O:16])=[CH:6][N:7]=1
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CCCN(c2ccc(C(F)(F)F)cc2NC(=O)c2cc(C#Cc3cnc(N)nc3)ccc2F)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CO
Product: CN[C@H]1CCCN(c2ccc(C(F)(F)F)cc2NC(=O)c2cc(C#Cc3cnc(N)nc3)ccc2F)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a yellow solution of (S)-tert-butyl 1-(2-(5-(2-(2-aminopyrimidin-5-yl)ethynyl)-2-fluorobenzamido)-4-(trifluoromethyl)phenyl)piperidin-3-yl(methyl)carbamate (0.397 g, 0.65 mmol) in 3 mL dioxane at 0 deg. C. was added hydrogen chloride 4.0 M in dioxane (1.6 ml, 6.5 mmol). The reaction was allowed to warm to ambient temp, as the clump, which formed would not go into solution. 3 mL of CH2Cl2, was added followed by 5 mL MeOH to give a homogenous yellow solution. After 30 min, the solution was concentrated in vacuo to give a yellow solid, which was treated with 1N NaOH and EtOAc. The organic layer was washed twice with 1N NaOH, dried over anhyd. Na2SO4, filtered, and concentrated in vacuo to give (S)-5-(2-(2-aminopyrimidin-5-yl)ethynyl)-2-fluoro-N-(2-(3-(methylamino)piperidin-1-yl)-5-(trifluoromethyl)phenyl)benzamide as a light yellow solid. MS m/z=513 [M+H]+. Calc'd for C26H24F4N6O: 512.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[N:26]([CH2:27][C:28]4[CH:29]=[C:30]([CH:35]=[CH:36][CH:37]=4)[C:31]([O:33]C)=[O:32])[CH:25]=[CH:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.O1CCCC1.[OH-].[Na+].Cl>O.CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[N:26]([CH2:27][C:28]4[CH:29]=[C:30]([CH:35]=[CH:36][CH:37]=4)[C:31]([OH:33])=[O:32])[CH:25]=[CH:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: COC(=O)c1cccc(Cn2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c32)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cccc(Cn2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c32)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 78.4 %

Procedure:
To a solution of methyl 3-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]methyl}benzoate (800 mg) in a mixed solvent of tetrahydrofuran (4.0 mL) and methanol (4.0 mL) was added 1N aqueous sodium hydroxide solution (4.0 mL), and the mixture was stirred at room temperature for 12 hrs. 1N Hydrochloric acid (4.0 mL) and water (15 mL) were added to the reaction mixture, and the mixture was stirred at room temperature for 30 min. The resultant precipitate was collected by filtration, washed with water (10 mL×3) and diisopropyl ether (10 mL×3) and dried under reduced pressure (80° C.) to give the title compound (610 mg) as a white powder.
Reaction SMILES: [C:1]([O:4]O)(=O)[CH3:2].C([O-])(=O)C.[Na+].[CH:11]1([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:19][CH:18]=2)CC=[CH:13][CH2:12]1.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[C:20]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:19]=[CH:18][C:17]([CH2:16][CH:11]2[CH2:2][CH:1]3[CH:13]([O:4]3)[CH2:12]2)=[CH:22][CH:21]=1
Reactant: C1=CCC(Cc2ccc(-c3ccccc3)cc2)C1
Reactant: CC(=O)OO
Agent: CC(=O)[O-]
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: c1ccc(-c2ccc(CC3CC4OC4C3)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Peracetic acid in acetic acid (60 ml; 40%) was added over 5 min. to a cooled mixture of sodium acetate (8g) and 4-(3-cyclopenten-1-ylmethyl)-1,1'-biphenyl (20 g) in chloroform (150 ml). The mixture was stirred vigorously at room temperature for 4 h., then it was cooled and a solution of sodium metabisulphite was slowly added. The chloroform layer was washed with water, dilute sodium hydroxide solution, water and brine, dried and evaporated to give a 1:3 mixture (TLC) of two products (20 g). Crystallisation from methylene dichloride-ether gave two crops, rich in the slower running isomer (TLC). Recrystallisation from methylene dichloride/ether gave pure (±)-(1α,3α,5α)-3-([1,1'-biphenyl]-4-ylmethyl)-6-oxabicyclo[3.1.0]hexane (9.6 g), m.p. 130°-132° C.
Reaction SMILES: [Cl:1][C:2]1(Cl)[CH2:4][CH:3]1[O:5][N:6]=[C:7]([C:13]1([O:18][CH2:17][CH2:16][O:15]1)[CH3:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9].C([SnH](CCCC)CCCC)CCC.N(C(C)(C)C#N)=NC(C)(C)C#N>C1(C)C=CC=CC=1>[Cl:1][CH:2]1[CH2:4][CH:3]1[O:5][N:6]=[C:7]([C:13]1([O:15][CH2:16][CH2:17][O:18]1)[CH3:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C(=NOC1CC1(Cl)Cl)C1(C)OCCO1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=NOC1CC1Cl)C1(C)OCCO1
Yield: 33.9 %

Procedure:
A solution of ethyl 2-(2,2-dichlorocyclopropyloxyimino)-3,3-ethylenedioxybutyrate (syn isomer)(312 mg) and tri-n-butyltinhydride (0.55 ml) in toluene (2 ml) was refluxed under nitrogen atmosphere in the presence of catalytic amount of 2,2'-azobisisobutyronitrile for 2 hours. The reaction mixture was concentrated in vacuo. The residue was subjected to column chromatography on silica gel (24 g) and eluted with a mixture of diethyl ether and n-hexane (1:2 V/V). The fractions containing the compound, which had higher Rf-value on TLC [development solvent system: diethyl ether and n-hexane (2:1 V/V)], were collected and concentrated in vacuo to give ethyl 2-(2-chlorocyclopropyloxyimino)-3,3-ethylenedioxybutyrate (syn isomer)(94 mg).
Reaction SMILES: Br[CH2:2][C:3]1([CH3:16])[CH2:7][C:6]2[C:8]([CH3:15])=[C:9]([NH2:14])[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=2[O:4]1.[NH:17]1[CH2:27][CH2:26][CH:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:19][CH2:18]1>C1(C)C(C)=CC=CC=1>[NH2:14][C:9]1[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]2[O:4][C:3]([CH2:2][N:17]3[CH2:27][CH2:26][CH:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:19][CH2:18]3)([CH3:16])[CH2:7][C:6]=2[C:8]=1[CH3:15]
Reactant: CCOC(=O)C1CCNCC1
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(CBr)O2
Solvent: Cc1ccccc1C
Product: CCOC(=O)C1CCN(CC2(C)Cc3c(C)c(N)c(C)c(C)c3O2)CC1
Temperature: 180 °C
Reaction time: 15 h
Yield: 27.2 %

Procedure:
In an autoclave, a mixture of 2-bromomethyl-2,3-dihydro-2,4,6,7-tetramethyl-5-benzofuranamine (8.4 g), ethyl isonipecotate (14 g), and xylene (20 mL) was stirred under nitrogen gas at 180° C. for 15 hours. The supernatant was taken from the reaction mixture and washed with water, saturated aqueous NaHCO3, and saturated aqueous NaCl, dried over MgSO4, treated with activated carbon, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=5:1 to 2:1) and crystallized from hexane to provide 2.9 g of the title compound. Yield 27%.
Reaction SMILES: [N+]([O-])([O-])=O.[Ce+4].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.C([N:30]1[CH2:35][CH2:34][O:33][CH:32]([C:36]2[O:40][N:39]=[C:38]([CH3:41])[CH:37]=2)[CH2:31]1)C1C=CC=CC=1>C(#N)C.O>[CH3:41][C:38]1[CH:37]=[C:36]([CH:32]2[O:33][CH2:34][CH2:35][NH:30][CH2:31]2)[O:40][N:39]=1
Reactant: Cc1cc(C2CN(Cc3ccccc3)CCO2)on1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: Cc1cc(C2CNCCO2)on1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Ammonium cerium(IV) nitrate (442 mg, 0.806 mmol) was added to a solution of 4-benzyl-2-(3-methyl-1,2-oxazol-5-yl)morpholine (C37) (100 mg, 0.39 mmol) in acetonitrile/water (5:1 mixture, 6 mL). The reaction mixture was stirred at 25° C. for 4 hours, then concentrated in vacuo; preparative thin-layer chromatography on silica gel (Eluent: 10:1 dichloromethane/methanol) provided the product as a yellow oil. Yield: 40 mg, 0.24 mmol, 62%. 1H NMR (400 MHz, CDCl3) δ 6.11 (s, 1H), 4.79 (dd, J=10.0, 2.4 Hz, 1H), 4.01 (ddd, J=11.8, 2.5, 2.4 Hz, 1H), 3.81-3.89 (m, 1H), 3.35 (dd, J=12.7, 2.5 Hz, 1H), 2.99-3.07 (m, 3H), 2.30 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([O:27][CH3:28])[C:25]=1[OH:26])[O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:16][C:17](=[O:19])[NH2:18])[C:11]([NH2:20])=[C:10]2[C:21]#[N:22].[CH3:29]COCC>>[CH3:28][O:27][C:24]1[CH:23]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:25]=1[O:26][CH3:29])[O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:16][C:17](=[O:19])[NH2:18])[C:11]([NH2:20])=[C:10]2[C:21]#[N:22]
Reactant: COc1cc(Oc2ccc3c(c2)c(C#N)c(N)n3CC(N)=O)cc(OC)c1O
Reactant: CCOCC
Product: COc1cc(Oc2ccc3c(c2)c(C#N)c(N)n3CC(N)=O)cc(OC)c1OC

Procedure:
Using the general method of selective demethylation described for Example 31 5-(3,5-dimethoxy-4-hydroxyphenoxy)-2-amino-1-carbamoylmethyl-1H-indole-3-carbonitrile (95 mg) was obtained as a beige solid from 5-(3,4,5-trimethoxyphenoxy)-2-amino-1-carbamoylmethyl-1H-indole-3-carbonitrile (150 mg; 0.37 mmol) after trituration with Et2O.
Reaction SMILES: [N:1]1([C:51](OC(C)(C)C)=O)[CH2:50][CH2:49][CH2:48][C@H:2]1[C:3]([NH:5][C@H:6]([C:14]([NH:16][C@H:17]([C:25]([NH:27][CH2:28][C:29]([NH:31][C@H:32]([C:37]([NH:39][C@H:40]([C:45]([NH2:47])=[O:46])[CH2:41][CH2:42][S:43][CH3:44])=[O:38])[CH2:33][CH:34]([CH3:36])[CH3:35])=[O:30])=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].Cl>C(O)(=O)C>[NH:1]1[CH2:51][CH2:50][CH2:49][CH2:48][C@H:2]1[C:3]([NH:5][C@H:6]([C:14]([NH:16][C@H:17]([C:25]([NH:27][CH2:28][C:29]([NH:31][C@H:32]([C:37]([NH:39][C@H:40]([C:45]([NH2:47])=[O:46])[CH2:41][CH2:42][S:43][CH3:44])=[O:38])[CH2:33][CH:34]([CH3:36])[CH3:35])=[O:30])=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(N)=O
Agent: Cl
Solvent: CC(=O)O
Product: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCCN1)C(N)=O

Procedure:
Condensation of BocPro-Phe-DPheNHNH2 (2.44 g.) and HGly-Leu-MetNH2 hydrochloride salt (1.6 g.) by the acyl azide method (Yajima et al., Chem. Pharm. Bull., vol. 19, p. 1900, 1971) gave BocPro-Phe-Phe-Gly-Leu-MetNH2 in 79% yield. De-t-butoxycarbonylation of BocPro-Phe-Phe-Gly-Leu-MetNH2 using hydrogen chloride in acetic acid gave HPro-Phe-Phe-Gly-Leu-MetNH2, which was isolated as the amorphous white solid hydrochloride salt monohydrate in 31% yield.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)[CH3:2].[Li]CCCC.[F:15][C:16]1[C:17]([F:25])=[C:18](F)[C:19]([F:23])=[C:20]([F:22])[CH:21]=1.Cl>O1CCCC1>[F:15][C:16]1[C:17]([F:25])=[CH:18][C:19]([F:23])=[C:20]([F:22])[C:21]=1[NH:7][C:6]1[CH:8]=[CH:9][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=1
Reactant: Fc1cc(F)c(F)c(F)c1F
Reactant: CCc1ccc(N)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1ccc(Nc2c(F)c(F)cc(F)c2F)cc1
Reaction time: 1 h

Procedure:
The starting material is prepared as follows: 4-Ethylaniline (242.36 g; 2.00 mol) is dissolved in dry tetrahydrofuran (900 ml). A solution of n-BuLi (2.5 M in hexanes, 800 ml; 2.00 mol) is added under N2 with cooling maintaining the reaction temperature below 15°. After stirring for 1 hour at 10°, neat pentafluorobenzene (168.06 g; 1.00 mol) is added with cooling to the mixture, keeping the temperature at 10-200. The reaction is stirred at ambient temperature for 1.5 hours, then aqueous HCl (6 N; 500 ml) is added slowly with vigorous stirring and cooling, keeping the reaction temperature below 350°. The quenched reaction is stirred at ambient temperature for 0.5-18 hours. The aqueous layer is separated, and the organic phase is concentrated under reduced pressure (30-150 mm) to one-fourth volume. The concentrate is diluted with heptane (300 ml) and extracted with water (300 ml). The separated top organic layer is stirred over 230-400 mesh silica gel (50 g) and filtered. The filter cake is washed with heptane (4×50 ml). The combined filtrate and washings are concentrated under reduced pressure (20-30 mm) to give solid crude product. This material is recrystallized from hot heptane (200 ml) and collected at 0°. This solid is washed with cold heptane (100 ml) and dried under reduced pressure at 400 to give pure N-(2′,3′,5′,6′-tetrafluorophenyl)4-ethylaniline.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([N:17]([CH2:19][CH2:20][O:21][CH3:22])[CH3:18])=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([OH:15])=O)=[CH:4][CH:3]=1.Cl.[NH2:24][CH2:25][C@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]1[OH:32].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C)C(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([N:17]([CH2:19][CH2:20][O:21][CH3:22])[CH3:18])=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([NH:24][CH2:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]2[OH:32])=[O:15])=[CH:6][CH:7]=1
Reactant: NC[C@H]1CCCC[C@H]1O
Reactant: COCCN(C)c1ncc(C(=O)O)cc1-c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COCCN(C)c1ncc(C(=O)NCC2CCCCC2O)cc1-c1ccc(Cl)cc1

Procedure:
In analogy to example 1f, 5-(4-chloro-phenyl)-6-[(2-methoxy-ethyl)-methyl-amino]-nicotinic acid was coupled with cis-2-aminomethyl-1-cyclohexanol hydrochloride using TBTU and N,N-diisopropyl ethyl amine in N,N-dimethylacetamide to give racemic 5-(4-chloro-phenyl)-N-((1RS,2RS)-2-hydroxy-cyclohexylmethyl)-6-[(2-methoxy-ethyl)-methyl-amino]-nicotinamide as an off-white solid. MS (ISP) 432.4 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH2:9][CH3:10])=[O:7].[C:11](Cl)(=[O:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>>[C:11]([C:4]1[CH:3]=[C:2]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[NH:1][CH:5]=1)(=[O:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCOC(=O)c1ccc[nH]1
Reactant: CCCCCCC(=O)Cl
Product: CCCCCCC(=O)c1c[nH]c(C(=O)OCC)c1
Yield: 71.1 %

Procedure:
Starting with 2.0 g of ethyl pyrrole carboxylate (14 mmol) and 4.2 ml (26 mmol) of heptanoylchloride and following a procedure analogous to the one described above, 2.5 g (70% yield) of the desired product is obtained. 1H NMR (δ ppm, CDCl3): 10.07 (s, br, 1H, NH); 7.53 (dd, J=1.60, 3.35 Hz, 1H, α-pyrrolic); 7.27 (dd, J=1.60, 2.47; 1H; β-pyrrolic); 4.32 (q, 2H, J=7.14 Hz, CO2Et); 2.73 (t, 2H, J=7.50, α-CO CH2); 1.67 (m, 2H, β-CO CH2); 1.33 (t, 3H, J=7.14, CO2Et); 1.28 (m, 6H, γ,δ,ε CH2); 0.85 (m, 3H, end-CH3). 13C NMR (δ ppm, CDCl3): 196.32; 161.26; 127.07; 126.24; 124.01; 114.86; 60.99; 39.78; 31.62; 29.05; 24.59; 22.48; 14.30; 13.99. Exact mass calculated for C14H22NO3 (M+H)=252.159969, found=252.159072.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7](B3OC(C)(C)C(C)(C)O3)[C:8]=2[O:12][CH2:13][CH2:14][CH3:15])[N:3]1[C:25](=[O:27])[CH3:26].Br[C:29]1[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:31][N:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C1C=C(C(C)C)C(C2C=CC=C(P(C3CCCCC3)C3CCCCC3)C=2)=C(C(C)C)C=1)C.C1C=[C-]C(C2C(N)=CC=CC=2)=CC=1.Cl[Pd+].O1CCOCC1.O>[CH3:1][C@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:29]3[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:31][N:30]=3)[C:8]=2[O:12][CH2:13][CH2:14][CH3:15])[N:3]1[C:25](=[O:27])[CH3:26]
Reactant: CCCOc1c(B2OC(C)(C)C(C)(C)O2)ccc2c1CC[C@H](C)N2C(C)=O
Reactant: CS(=O)(=O)c1ccc(Br)nc1
Agent: Cl[Pd+]
Agent: CC(C)c1cc(C(C)C)c(-c2cccc(P(C3CCCCC3)C3CCCCC3)c2)c(C(C)C)c1
Agent: Nc1ccccc1-c1[c-]cccc1
Solvent: C1COCCO1
Solvent: O
Product: CCCOc1c(-c2ccc(S(C)(=O)=O)cn2)ccc2c1CC[C@H](C)N2C(C)=O
Temperature: 100 °C
Yield: 27 %

Procedure:
A mixture of (S)-1-(2-methyl-5-propoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-1 (2H)-yl)ethanone (0.055 g, 0.147 mmol), 2-bromo-5-(methylsulfonyl)pyridine (0.037 g, 0.155 mmol), XPhos Precatalyst 2nd Generation (0.012 g, 0.015 mmol), and cesium carbonate (0.144 g, 0.442 mmol) in 1,4-dioxane (2.0 mL) and water (0.40 mL) was heated in the microwave at 100° C. for 1.5 h. The reaction mixture was filtered through Celite and concentrated to afford an orange oil. This material was purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 25-100% ethyl acetate-hexane) to afford (S)-1-(2-methyl-6-(5-(methylsulfonyl)pyridin-2-yl)-5-propoxy-3,4-dihydroquinolin-1(2H)-yl)ethanone (0.016 g, 27%) as a tan solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.85 (t, J=7.33 Hz, 3H), 1.07 (d, J=6.45 Hz, 3H), 1.32-1.50 (m, 2H), 1.56 (dt, J=14.07, 7.04 Hz, 2H), 2.14 (s, 3H), 2.19-2.33 (m, 1H), 2.79-2.94 (m, 1H), 3.37 (s, 3H), 3.50 (td, J=6.30, 2.64 Hz, 2H), 4.51-4.75 (m, 1H), 7.33 (br d, J=8.50 Hz, 1H), 7.64 (d, J=8.50 Hz, 1H), 8.08-8.21 (m, 1H), 8.36 (dd, J=8.50, 2.35 Hz, 1H), 9.14 (d, J=2.05 Hz, 1H). MS (ESI, pos. ion) m/z 403 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8]([C:18](=[O:21])[NH:19][CH3:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[C:23]([CH3:33])=[CH:24][C:25]([O:31][CH3:32])=[C:26]([CH:30]=1)[C:27](O)=[O:28].Cl.[N:35]1[CH:40]=[CH:39][C:38]([C:41]2([NH2:44])[CH2:43][CH2:42]2)=[CH:37][N:36]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[F:1][C:2]1[C:7]2[C:8]([C:18]([NH:19][CH3:20])=[O:21])=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:30]=[C:26]([C:27](=[O:28])[NH:44][C:41]2([C:38]3[CH:39]=[CH:40][N:35]=[N:36][CH:37]=3)[CH2:43][CH2:42]2)[C:25]([O:31][CH3:32])=[CH:24][C:23]=1[CH3:33]
Reactant: NC1(c2ccnnc2)CC1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)c(F)c12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ccnnc5)CC4)c(OC)cc3C)c(F)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (0.080 g, 0.177 mmol, 1.0 eq), 1-(pyridazin-4-yl)cyclopropanamine HCl (0.024 g, 0.177 mmol, 1.0 eq) in DMF at 0° C. was added TEA (0.090 g, 0.89 mmol, 5.0 eq) and BOP reagent (0.117 g, 0.264 mmol, 1.5 eq). The reaction mixture was stirred at RT overnight. The reaction mixture was diluted with water, extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel (60-120) column chromatography using 4% MeOH/CHCl3 as eluent. Yield: 0.060 g (60.0%). 1H NMR (400 MHz, CD3OD): δ 9.08 (m, 1H), 9.05 (d, J=1.0, 5.8 Hz, 1H), 7.97-7.93 (m, 2H), 7.72 (s., 1H), 7.54 (m, 1H), 7.51 (d, J=8.4 Hz, 1H), 7.31-7.25 (m, 3H), 7.19 (s, 1H), 4.10 (s, 3H), 2.95 (s, 3H), 2.30 (s, 3H), 1.63 (s, 4H). 19F NMR (376.57 MHz, CD3OD): δ −112.33, −122.75. LCMS: (ES+) m/z=569.2 (M+H)+
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[C:10]([O:14][C:15]([NH:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>CO.O>[C:10]([O:14][C:15]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([NH:22][C:2]2[N:7]=[C:6]([NH:22][C:21]3[CH:20]=[CH:19][C:18]([NH:17][C:15]([O:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:16])=[CH:24][CH:23]=3)[C:5]([F:9])=[CH:4][N:3]=2)=[CH:23][CH:24]=1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1
Reactant: Fc1cnc(Cl)nc1Cl
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(Nc2ncc(F)c(Nc3ccc(NC(=O)OC(C)(C)C)cc3)n2)cc1
Temperature: 70 °C

Procedure:
2,4-Dichloro-5-fluoropyrimidine (75 mg, 0.45 mmol) was dissolved in a mixture of MeOH (2 ml) and H2O (0.2 ml). 4-tert-butoxycarbonylaminoaniline (374 mg, 1.8 mmol) was added and the mixture was refluxed for 24 hours (70° C. oil-bath temperature). The mixture was cooled to 22° C., concentrated to dryness under reduced pressure and subjected to column chromatography on silica gel (CHCl3 Acetone, 9:1) to give N2,N4-bis[4-(tert-butoxycarbonylamino)phenyl]-5-fluoro-2,4-pyrimidinediamine. 1H NMR (DMSO-d6+CD3OD): δ 7.96 (d, 1H, J=3.5 Hz), 7.63 (d, 2H, J=8.8 Hz), 7.49 (d, 2H, J=8.8 Hz), 7.37 (d, 2H, J=8.8 Hz), 7.24 (d, 2H, J=8.8 Hz), 1.45 (s, 9H), 1.43 (s, 9H); LCMS: purity: 97.9%; MS (m/e): 511.04 (M+, 100).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][NH2:12])=[CH:8][C:6]=2[N:7]=1.CCN(CC)CC.C([O:28][C:29](=O)[CH2:30][N:31]([CH3:33])[CH3:32])C>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)[C:5]2[S:10][C:9]([CH2:11][NH:12][C:29](=[O:28])[CH2:30][N:31]([CH3:33])[CH3:32])=[CH:8][C:6]=2[N:7]=1
Reactant: NCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CCOC(=O)CN(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)CC(=O)NCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: 25 °C
Reaction time: 33 h

Procedure:
To a solution of (2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methanamine 27 from Example 11 (50 mg, 0.2 mmol) in CH2Cl2 (4 mL) was added Et3N (84 μL, 0.6 mmol) and dimethylglycine ethyl ester (0.3 mmol). The reaction stirred 18-48 h at room temperature before being quenched with water. The aqueous layer was extracted with EtOAc. The combined organics were dried over Na2SO4 and concentrated in vacuo to give N-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-2-(dimethylamino)acetamide which was utilized in a Suzuki coupling according to General Procedure A. The crude material was purified by reversed phase HPLC to give 350 (10 mg). MS (Q1) 452 (M)+
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH:29]([OH:31])[CH3:30])[NH:5][C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([C:25]#[N:26])[CH:22]=[C:21]([Cl:27])[CH:20]=2)[C:12]=1[F:28])=[O:8]>O=[Mn]=O>[C:29]([C:4]1[NH:5][C:6]([C:7]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]3[CH:24]=[C:23]([C:25]#[N:26])[CH:22]=[C:21]([Cl:27])[CH:20]=3)[C:12]=2[F:28])=[O:8])=[C:2]([Br:1])[N:3]=1)(=[O:31])[CH3:30]
Reactant: CC(O)c1nc(Br)c(C(=O)NCc2ccc(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2F)[nH]1
Agent: O=[Mn]=O
Product: CC(=O)c1nc(Br)c(C(=O)NCc2ccc(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2F)[nH]1
Yield: 53 %

Procedure:
The title compound (0.055 g, 53%) was obtained as a white solid by MnO2 oxidation of 4-bromo-N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-2-(1-hydroxyethyl)-1H-imidazole-5-carboxamide using a similar process to that described herein. 1H NMR (400 MHz, DMSO-d6) δ ppm 14.51 (br. s., 1H), 8.72-8.79 (m, 1H), 7.83 (s, 1H), 7.45-7.56 (m, 3H), 7.31-7.41 (m, 1H), 4.51 (br. s., 2H), 2.55 (s, 3 H). ES-LCMS: m/z 524.8, 526.8, 528.7 (M+1).
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:7]=[C:8]([NH:12][C:13](=[O:20])[O:14][CH2:15][C:16]#CCO)[CH:9]=[CH:10][CH:11]=1>C(Cl)CCl>[CH:10]1[CH:11]=[C:6]([Cl:5])[CH:7]=[C:8]([NH:12][C:13]([O:14][C:15]#[C:16][Cl:3])=[O:20])[CH:9]=1
Reactant: O=C(Nc1cccc(Cl)c1)OCC#CCO
Reactant: O=S(Cl)Cl
Solvent: ClCCCl
Product: O=C(Nc1cccc(Cl)c1)OC#CCl
Reaction time: 17 h

Procedure:
In another procedure on the same scale, the thionyl chloride in 25 ml of EDC was stirred at 65° while a warm solution of 4-hydroxy-2-butynyl N-(3-chlorophenyl)carbamate in 75 ml of EDC was added dropwise over a period of 60 minutes. After 17 hours at 65°, the solvent was evaporated to afford 6.5 g of barban which was analyzed by HPLC: barban -- 97.5% (w/w), biscarbamate -- 1.0% (w/w); bisurea -- 1.6% (w/w).