Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10](Br)=[CH:9][N:8]=[C:7]([S:12][CH3:13])[N:6]=1)=[O:4].[Na+].[C:15]1([S:21]([O-:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CS(C)=O>[CH3:1][O:2][C:3]([C:5]1[C:10]([S:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:23])=[O:22])=[CH:9][N:8]=[C:7]([S:12][CH3:13])[N:6]=1)=[O:4]
Reactant: COC(=O)c1nc(SC)ncc1Br
Reactant: O=S([O-])c1ccccc1
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)c1nc(SC)ncc1S(=O)(=O)c1ccccc1
Temperature: 65 °C
Reaction time: 1.5 h
Yield: 63.5 %

Procedure:
A mixture of 5-bromo-2-methylsulfanylpyrimidine-4-carboxylic acid methyl ester (2.3 g), benzenesulfinic acid sodium salt (1.9 g) and dimethyl sulfoxide (35 mL) was treated with bis[copper(I)triflate]benzene complex (3.3 g), and the resulting mixture was stirred at 65° C. for 1.5 hours. The mixture was cooled to 40° C. and filtered through Celite. The filtrate was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and ethyl acetate (1:0 to 4:1 by volume) to afford the title compound as a pale yellow solid (1.8 g).
Reaction SMILES: [CH:1]1[C:6]([C:7]2[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=2)=[CH:5][CH:4]=[C:3](O)[CH:2]=1.C(Cl)(=O)C1C=CC=CC=1>>[OH:13][C:10]1[CH:9]=[CH:8][C:7]([C:6]2[CH:1]=[CH:2][CH:3]=[CH:4][CH:5]=2)=[CH:12][CH:11]=1
Reactant: Oc1ccc(-c2ccc(O)cc2)cc1
Solvent: O=C(Cl)c1ccccc1
Product: Oc1ccc(-c2ccccc2)cc1

Procedure:
reacting 4,4'-hydroxybiphenyl with the 4-(RO) benzoyl chloride from step (a) to form 4-(4-(RO) benzoyloxy) -4'-hydroxybiphenyl; and
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.O1CCCC1.[NH2:26][C:27]1[S:28][CH2:29][CH2:30][N:31]=1>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([NH:26][C:27]3[S:28][CH2:29][CH2:30][N:31]=3)=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Reactant: NC1=NCCS1
Solvent: C1CCOC1
Solvent: O
Product: O=C(Cn1c(-c2ccc(Cl)cc2)nc2cccnc21)NC1=NCCS1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 9.3 %

Procedure:
A suspension of 2-(4-chlorophenyl-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.0174 mole) 1,1'-carbonyldiimidazole (2.82 g, 0.0174 mole) and dry tetrahydrofuran (100 ml) was stirred at room temperature for 3.5 hours with a stream of nitrogen bubbling through it. Solid 2-amino-2-thiazoline (2.67 g, 0.0261 mole) was added to the reaction mixture. The resulting suspension was allowed to stir at room temperature overnight. The solvent was evaporated under reduced pressure to give a white solid. The solid was triturated in water (200 ml), filtered, and the filter cake was rinsed twice more with water. The resulting solid was heated in boiling isopropyl alcohol to dissolve most of it, filtered while hot, and cooled to room temperature. A white precipitate formed. Water was added, and the white solid was filtered and rinsed once with isopropyl alcohol and twice with isopropyl ether. A 1.0-g sample of the resulting 3.3 g of white solid was dried at high vacuum to give 0.6 g (29%) of title compound, mp. 227°-229° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[CH:9][N:8]([CH:24]([CH3:30])[C:25](OCC)=[O:26])[C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:31][N:32]([CH3:36])[CH2:33][CH2:34][NH2:35].C(=O)=O>CO>[CH3:31][N:32]([CH3:36])[CH2:33][CH2:34][NH:35][C:25](=[O:26])[CH:24]([N:8]1[C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=2[C:10]([C:11]2[CH:12]=[CH:13][C:14]([O:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:15][CH:16]=2)=[CH:9]1)[CH3:30]
Reactant: CCOC(=O)C(C)n1cc(-c2ccc(Oc3ccccc3)cc2)c2c(N)ncnc21
Reactant: CN(C)CCN
Agent: O=C=O
Solvent: CO
Product: CC(C(=O)NCCN(C)C)n1cc(-c2ccc(Oc3ccccc3)cc2)c2c(N)ncnc21
Reaction time: 18 h

Procedure:
A mixture of ethyl 2-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]propionate (425 mg), N,N-dimethylethylenediamine (2 ml) and methanol (20 ml) was boiled under reflux for 18 hours with the exclusion of carbon dioxide. The mixture was cooled and filtered, the filtrate was diluted with water (50 ml) and stirred with ether. The mixture was left standing for 18 hours and the solid which precipitated was collected by filtration, washed with water and then ether and dried to give N-(2-dimethylaminoethyl)-2-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)propionamide, m.p. 163-164° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][CH:8]=[C:9](Br)[CH:10]=1)=[O:4].C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>CN(C)C=O.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>[CH3:1][O:2][C:3](=[O:4])[C:5]1[CH:10]=[C:9]([C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=2)[CH:8]=[N:7][CH:6]=1
Reactant: COC(=O)c1cncc(Br)c1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cncc(-c2ccc(Cl)cc2)c1
Temperature: 80 °C
Yield: 79.4 %

Procedure:
81 mg (0.07 mmol)Pd(PPh3)4 was added under argon at room temperature to a solution of 1.0 g (4.63 mmol) methyl-5-bromo-pyridine-3-carboxylate in 23 ml N,N-dimethylformamide and the mixture was heated to 80° C. Then 2.26 g (6.94 mmol) cesium carbonate and 0.84 g (5.09 mmol) of 4-chlorophenyl boronic acid were added and the mixture was stirred at 80° C. over night. The reaction mixture was cooled to room temperature, filtered, and the filtrate evaporated. The residue was taken up with ethyl acetate, washed twice with water, dried over sodium sulphate and evaporated. Chromatography on silica (eluent: ethyl acetate/n-heptane 1:3) gave 0.91 g (69%) of 5-(4-Chloro-phenyl)-nicotinic acid methyl ester
Reaction SMILES: [N+](=[CH:3][Si](C)(C)C)=[N-].[OH:8][CH2:9][CH:10]([C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=1)[C:11]([O:13][CH3:14])=[O:12].F[B-](F)(F)F.[H+].O>ClCCl>[CH3:3][O:8][CH2:9][CH:10]([C:15]1[CH:16]=[C:17]([C:25]([F:26])([F:27])[F:28])[CH:18]=[C:19]([C:21]([F:23])([F:22])[F:24])[CH:20]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)C(CO)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: O
Solvent: ClCCl
Product: COCC(C(=O)OC)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 78.9 %

Procedure:
(Diazomethyl)trimethylsilane (1.6 mL, 3.2 mmol) was added dropwise to a stirred, cooled (0° C.) mixture of (RS)-methyl α-(hydroxymethyl)-3,5-bis(trifluoromethyl)benzeneacetate (Description 7, 1.0 g, 3.2 mmol) and aqueous fluoroboric acid (48%, 585 mg, 3.2 mmol) in dichloromethane (10 mL) and the mixture was stirred at room temperature for 20 minutes. Further (diazomethyl)trimethylsilane (0.8 mL, 1.6 mmol) was added and the mixture was stirred at room temperature for 20 minutes. Further (diazomethyl)trimethylsilane (0.4 mL, 0.8 mmol)) was added and the mixture was stirred at room temperature for 20 minutes. Further (diazomethyl)trimethylsilane (0.4 mL, 0.8 mmol)) was added and the mixture was stirred at room temperature for 30 minutes, poured into water (40 mL) and extracted with dichloromethane (2×40 mL). The combined organic fractions were dried (MgSO4), the solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel, eluting with isohexane/EtOAc (90:10), to give the title compound as a colorless oil (834 mg, 80%). 1H NMR (400 MHz, CDCl3) δ 3.36 (3H, s), 3.69–3.73 (1H, m), 3.74 (3H, s), 3.92–3.96 (1H, m), 3.99–4.03 (1H, m), and 7.80–7.81 (3H, m).
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:16]2[NH:20][N:19]=[C:18]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[F:52][C:53]1[CH:54]=[CH:55][C:56]([C:66]([F:69])([F:68])[F:67])=[C:57]([NH:59][CH:60]2[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]2)[CH:58]=1>CN(C=O)C.O>[F:52][C:53]1[CH:54]=[CH:55][C:56]([C:66]([F:69])([F:67])[F:68])=[C:57]([NH:59][CH:60]2[CH2:61][CH2:62][N:63]([C:25](=[O:27])[CH2:24][NH:23][C:21]([C:18]3[CH:17]=[C:16]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)[NH:20][N:19]=3)=[O:22])[CH2:64][CH2:65]2)[CH:58]=1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Reactant: Fc1ccc(C(F)(F)F)c(NC2CCNCC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCC(Nc2cc(F)ccc2C(F)(F)F)CC1)c1cc(-c2ccccc2)[nH]n1
Reaction time: 8 h
Yield: 44.4 %

Procedure:
DIPEA (232 mg, 1.8 mmol) was added to a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (148 mg, 0.6 mmol) in DMF (2 mL) followed by HOBt (95 mg, 0.7 mmol) and EDCI.HCl (137 mg, 0.7 mmol). After 2 minutes (5-fluoro-2-trifluoromethyl-phenyl)-piperidin-4-yl-amine dihydrochloride (prepared according to the method used for the synthesis of Intermediate 3) (150 mg, 0.6 mmol) was added to the reaction mixture and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with cold water, extracted with ethyl acetate and dried over sodium sulfate. The organic layer was concentrated under reduced pressure. Purification by column chromatography (using 60-120 silica gel and 5% MeoH in CHCl3 as eluent) afforded 129 mg (44.4% Yield) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(5-fluoro-2-trifluoromethyl-phenylamino)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 490.18, 95.08%. 1H NMR (300 MHz, DMSO-d6): δ13.8 (s, 1H), 8.0 (bs, 1H), 7.8 (d, 2H), 7.5 (t, 4H), 7.1 (bs, 1H), 6.8 (d, 1H), 6.5 (t, 1H), 5.0 (d, 1H), 4.4 (d, 1H), 4.3 (d, 2H), 3.8 (m, 2H), 3.7 (m, 2H), 3.2 (t, 1H), 2.8 (t, 1H), 2.0 (m, 2H), 1.5 (m, 2H).
Reaction SMILES: Br[C:2]1[C:7]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:6][C:5]([NH:13][C:14](=[O:34])[C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][N:24]([C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:23][C@H:22]3[CH3:33])=[N:17][CH:16]=2)=[C:4]([Cl:35])[CH:3]=1.O1CCCC1.[B:41](OC)([O:44]C)[O:42]C.Cl>O.C(O)C>[Cl:35][C:4]1[C:5]([NH:13][C:14](=[O:34])[C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][N:24]([C:27](=[O:32])[C:28]([CH3:30])([CH3:29])[CH3:31])[CH2:23][C@H:22]3[CH3:33])=[N:17][CH:16]=2)=[CH:6][C:7]([O:8][C:9]([F:11])([F:12])[F:10])=[C:2]([B:41]([OH:44])[OH:42])[CH:3]=1
Reactant: C[C@@H]1CN(C(=O)C(C)(C)C)CCN1c1ccc(C(=O)Nc2cc(OC(F)(F)F)c(Br)cc2Cl)cn1
Reactant: COB(OC)OC
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H]1CN(C(=O)C(C)(C)C)CCN1c1ccc(C(=O)Nc2cc(OC(F)(F)F)c(B(O)O)cc2Cl)cn1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 57 %

Procedure:
Under an atmosphere of nitrogen, a mixture of N-(4-bromo-2-chloro-5-trifluoromethoxy-phenyl)-6-[(R)-4-(2,2-dimethyl-propionyl)-2-methyl-piperazin-1-yl]-nicotinamide (20.0 g, 34.6 mmol) and tetrahydrofuran (200 mL) was cooled to 0° C. and then 1.3 M isopropylmagnesium chloride lithium chloride complex in tetrahydrofuran (79.9 mL, 104 mmol) was added dropwise at 0-10° C. After 2.5 h, boric acid, trimethyl ester (12.0 mL, 106 mmol) was added dropwise, and then 1 N HCl (105 mL) was added and the reaction mixture was stirred overnight. The reaction mixture was extracted with EtOAc (250 mL); the organic layer was washed with water, sat. aq. NaHCO3, dried over MgSO4, and evaporated to give crude product (22.8 g). To the crude product was added ethanol (230 mL) and then slowly water (57.5 mL). The resulting mixture was stirred for 10 days and filtered to give the title intermediate as a crystalline solid (10.7 g, 57% yield).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14](=[N:16]O)[CH3:15])[C@@H:10]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Ni]>[CH2:1]([N:8]1[CH2:13][CH2:12][C@H:11]([CH:14]([NH2:16])[CH3:15])[C@@H:10]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=NO)[C@H]1CCN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)cc1
Agent: [Ni]
Solvent: CO
Product: CC(N)[C@H]1CCN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)cc1

Procedure:
A solution of 1.6 g (4.7 mmol) 1-[(3S,4S)-1-Benzyl-3-(4-chloro-phenyl)-piperidin-4-yl]-ethanone oxime in 300 mL methanol was hydrogenated over Raney Nickel (3.5 bar, 30° C., 23 h). The mixture was filtered and evaporated to dryness. The residue was purified by column chromatography over silica eluting with a gradient formed from DCM, methanol and NH3aq. to yield after evaporation of the product containing fractions 0.7 g (45%) of the title compound as colorless viscous oil. MS (m/e): 329.4 [(M+H)+].
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([CH2:15][CH2:16][C:17]([OH:19])=O)=[O:14])=[CH:5][CH:4]=1.[NH:20]1[CH2:27][CH2:26][CH2:25][C@H:21]1[C:22]([OH:24])=[O:23]>>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([CH2:15][CH2:16][C:17]([N:20]2[CH2:27][CH2:26][CH2:25][C@H:21]2[C:22]([OH:24])=[O:23])=[O:19])=[O:14])=[CH:5][CH:4]=1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: COc1ccc(C(=O)CCC(=O)O)c2ccccc12
Product: COc1ccc(C(=O)CCC(=O)N2CCC[C@H]2C(=O)O)c2ccccc12

Procedure:
3-(4-Methoxy-1-naphthoyl)propionic acid is coupled to L-proline as described in Examples 15 and 16 to give 1-[3-(4-methoxy-1-naphthoyl)propionyl]-L-proline. The preciding compound is reacted with bromine in acetic acid as in Example 26 and the product reacted with potassium thioacetate in ethanol to give the product of the Example as a glass.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([OH:33])=[C:29]([NH2:34])[CH:28]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:35][O:36][C:37](=[O:39])[CH3:38])(=[O:3])[CH3:2].Cl[C:41](=[CH2:44])[C:42]#[N:43].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]4[O:33][CH:41]([C:42]#[N:43])[CH2:44][NH:34][C:29]=4[CH:28]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:35][O:36][C:37](=[O:39])[CH3:38])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(O)c(N)c3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: C=C(Cl)C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc4c(c3)NCC(C#N)O4)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 22.4 %

Procedure:
To a stirred solution of acetic acid (2R,3R,4R,5S,6S)-3,4,5-triacetoxy-6-[3-(3-amino-4-hydroxy-benzyl)-4-chloro-phenyl]-tetrahydro-pyran-2-ylmethyl ester (1.8 g, 3.2 mmol) in acetonitrile (15 mL) was added 2-chloroacrylonitrile (0.35 mL, 4.5 mmol) and potassium carbonate (882 mg, 6.4 mmol). After the reaction was refluxed overnight, the mixture was filtered through a celite bed. The filtrate was concentrated and purified by silica gel column chromatography to furnish acetic acid (2R,3R,4R,5S,6S)-3,4,5-triacetoxy-6-[4-chloro-3-(2-cyano-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-phenyl]-tetrahydro-pyran-2-ylmethyl ester (440 mg).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:6]=1[Cl:14].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH2:25][CH2:26][CH:27]2[C:36]3[C:31](=[CH:32][C:33]([O:39][CH3:40])=[C:34]([O:37][CH3:38])[CH:35]=3)[CH2:30][CH2:29][NH:28]2)[CH:20]=[CH:21][C:22]=1[O:23][CH3:24].N1C=CC=CC=1>C1COCC1>[Cl:14][C:6]1[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:5]=1[O:4][CH2:3][CH2:2][N:28]1[CH2:29][CH2:30][C:31]2[C:36](=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39][CH3:40])[CH:32]=2)[CH:27]1[CH2:26][CH2:25][C:19]1[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:17]([O:16][CH3:15])[CH:18]=1
Reactant: COc1ccc(CCC2NCCc3cc(OC)c(OC)cc32)cc1OC
Reactant: O=[N+]([O-])c1ccc(Cl)c(OCCBr)c1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1ccc(CCC2c3cc(OC)c(OC)cc3CCN2CCOc2cc([N+](=O)[O-])ccc2Cl)cc1OC
Yield: 32.6 %

Procedure:
To a solution of 15 (315 mg, 1.13 mmol) in anhydrous THF (3 mL) were sequentially added 1-(2-(3,4-dimethoxy-phenyl)-ethyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline (16, Morimoto et al, Heterocycles 1996 43:2557; Brossi et al, Helv Chim Acta 1960 43:1459; Meyers et al, Tetrahedron Lett 1981 22:5115; Meyers et al, J Am Chem Soc 1983 105:117) (404 mg, 1.13 mmol) and pyridine (0.3 mL). The reaction mixture was heated under reflux for 2 days before it was partitioned between EtOAc and water (20 mL each). The organic layer was separated, washed with water (15 mL), brine (15 mL), and dried over Na2SO4. The solids were filtered and the filtrate was purified by chromatography (silica gel) eluting with hexanes:EtOAc (1:1) to give 17 (205 mg)
Reaction SMILES: COC1C=CC(C[O:8][C@@H:9]([CH3:57])[C:10]([O:12][C@H:13]2[C@H:18]([NH:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][CH2:16][N:15]([C:24]3[CH:29]=[C:28]([C:30]#[N:31])[CH:27]=[C:26]([NH:32][C:33]4[N:38]=[C:37]([N:39](CC)[CH2:40][C:41]5C=CC(OC)=CC=5)[C:36]5=[N:51][CH:52]=[C:53]([C:54]#[N:55])[N:35]5[N:34]=4)[C:25]=3[Cl:56])[CH2:14]2)=[O:11])=CC=1.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>ClCCCl>[OH:8][C@@H:9]([CH3:57])[C:10]([O:12][C@H:13]1[C@H:18]([NH:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][CH2:16][N:15]([C:24]2[CH:29]=[C:28]([C:30]#[N:31])[CH:27]=[C:26]([NH:32][C:33]3[N:38]=[C:37]([NH:39][CH2:40][CH3:41])[C:36]4=[N:51][CH:52]=[C:53]([C:54]#[N:55])[N:35]4[N:34]=3)[C:25]=2[Cl:56])[CH2:14]1)=[O:11]
Reactant: CCN(Cc1ccc(OC)cc1)c1nc(Nc2cc(C#N)cc(N3CC[C@@H](NC(=O)OC)[C@H](OC(=O)[C@H](C)OCc4ccc(OC)cc4)C3)c2Cl)nn2c(C#N)cnc12
Solvent: ClCCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCNc1nc(Nc2cc(C#N)cc(N3CC[C@@H](NC(=O)OC)[C@H](OC(=O)[C@H](C)O)C3)c2Cl)nn2c(C#N)cnc12
Temperature: 35 °C
Reaction time: 8 h
Yield: 14.1 %

Procedure:
To a solution of (S)-(3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-4-((methoxycarbonyl)amino)piperidin-3-yl 2-((4-methoxybenzyl)oxy)propanoate (0.050 g, 0.061 mmol) in DCE (3 mL) was added anisole (0.027 ml, 0.243 mmol) followed by TFA (25% in DCE) (4.68 mL, 15.18 mmol) and stirred at 35° C. for overnight. The reaction mixture was concentrated at 30° C. and resultant residue was washed with diethylether to give solid and this was purified by reverse phase preparative HPLC and collected fractions were lyophilized to give (S)-(3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-4-((methoxycarbonyl)amino)piperidin-3-yl 2-hydroxypropanoate (0.005 g) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:11][C:12]([OH:14])=O.S(Cl)(Cl)=O.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1.[CH2:32]([NH:35][CH2:36][CH2:37][CH3:38])[CH2:33][CH3:34]>O>[CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:11][C:12]([N:35]([CH2:36][CH2:37][CH3:38])[CH2:32][CH2:33][CH3:34])=[O:14]
Reactant: CCCNCCC
Reactant: Cc1c(CC(=O)O)cccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: CCCN(CCC)C(=O)Cc1cccc([N+](=O)[O-])c1C
Reaction time: 0.5 h

Procedure:
A mixture of 22.0 g (0.105 mole) of 2-methyl-3-nitrophenylacetic acid and 25 cc of thionyl chloride was slowly heated to 75° and the copious evolution of gasses allowed to moderate. The temperature was raised and the solution was refluxed for 1 hour. The reaction was concentrated in vacuo. The residual straw-colored syrup was chased several times with dry toluene, diluted with 100 cc of dry toluene and added to a cool (10°) mixture of 13 g of sodium carbonate in 150 cc of water and 150 cc of toluene containing 14.5 cc (10.6 g, 0.12 mole) of di-n-propylamine with very slow stirring. After 30 minutes, the ice-bath was removed. Stirring was continued for one hour. An additional 0.5 g of solid sodium carbonate was added to the reaction. After 15 minutes, the organic phase was separated, washed with 5% aqueous sodium carbonate followed by 2N hydrochloric acid and, finally, water. The organic solution was dried over magnesium sulfate, concentrated in vacuo and pumped free of solvent to give 29.5 g of 2-methyl-3-nitrophenyl-N,N-di-n-propylacetamide as a straw-colored syrup.
Reaction SMILES: CS(O[CH2:6][C@H:7]([C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][C:18]=1[CH3:24])[CH2:8][O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC.[F-:42].C(OCC)C>CC(O)(C)C>[CH2:10]([O:9][CH2:8][C@@H:7]([C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][C:18]=1[CH3:24])[CH2:6][F:42])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1cc(Br)ccc1[C@H](COCc1ccccc1)COS(C)(=O)=O
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC(C)(C)O
Solvent: CCOCC
Product: Cc1cc(Br)ccc1[C@@H](CF)COCc1ccccc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 76.2 %

Procedure:
To 24A (0.74 g, 1.790 mmol) in tBuOH (10 mL) was added TBAF (1.0 M in THF, 5.37 mL, 5.37 mmol). The mixture was stirred at 80° C. for 2 h. Ethyl ether was added and the mixture was filtered. The filtrate was evaporated and the crude product was purified by flash chromatography (0-30% EtOAc/hexanes) to give 24B (0.46 g, 1.364 mmol, 76% yield) as colorless oil. 1H NMR (400 MHz, chloroform-d) δ ppm 7.27-7.43 (m, 7H) 7.13 (d, J=8.34 Hz, 1H) 4.74 (d, J=5.56 Hz, 1H) 4.62 (d, J=5.56 Hz, 1H) 4.47-4.59 (m, 2H) 3.71-3.81 (m, 1H) 3.60-3.70 (m, 1H) 3.37-3.57 (m, 1H) 2.33 (s, 3H); 19F NMR (376 MHz, chloroform-d) δ ppm −224.19 (s, 1F).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Cl[CH:12]([C:18]([CH3:20])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14]>C1(C)C=CC=CC=1>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:12]([C:18]([CH3:20])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:6][CH:5]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: CCOC(=O)C(Cl)C(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(Oc1ccc(Cl)cc1)C(C)=O
Temperature: 80 °C
Yield: 37 %

Procedure:
A 60% dispersion of sodium hydride in mineral oil (40 g, 1 mol) was washed with dry petroleum ether and suspended in dry toluene (700 ml). The suspension was stirred under argon and carefully treated with a solution of 4-chlorophenol (128.6 g, 1 mol) in dry toluene (300 ml) added dropwise. The resulting suspension was stirred for 1 hour, warmed to 80° C. and treated with ethyl 2-chloroacetoacetate (165 g, 1 mol) added dropwise to maintain the internal temperature between 80°-85° C. The resulting solution was stirred at 80° C. for 4 hours, cooled and carefully treated with ice. The organic phase was washed with water (3×200 ml), 10% sodium hydroxide (2×75 ml), 75 ml), water (20 ml) and brine (100 ml), dried with magnesium sulfate, filtered and concentrated. The resulting oil was distilled in vacuo [bp 126°-132° C. (0.1 mm)]to give 95 g (37%) of ethyl 2-(4-chlorophenoxy)-acetoacetate.