Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.C([Li])CCC.CON(C)[C:29](=[O:31])[CH3:30]>C1COCC1>[C:29]([C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][CH:3]=1)(=[O:31])[CH3:30]
Reactant: CON(C)C(C)=O
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Br)cc2)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)c1ccc(C2CN(C(=O)OC(C)(C)C)CCO2)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
tert-Butyl 2-(4-bromophenyl)morpholine-4-carboxylate (750 mg, 2.19 mmol, CAS 1131220-82-0) in THF (6 ml) was cooled to −78° C., treated dropwise with n-butyllithium (2.05 ml, 3.29 mmol, 1.6 M solution in hexane) and stirred 1 h at −78° C. N-Methoxy-N-methylacetamide (226 mg, 2.19 mmol) was added and the mixture was stirred for 1 h at −78° C., and then allowed to warm up to −5° C. The reaction mixture was quenched by addition of saturated ammonium chloride solution (4 ml) and water (4 ml) and the resulting mixture was partitioned between water and ethyl acetate.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]2[N:9]=[C:10]([CH2:16][CH2:17][CH3:18])[CH:11]=[C:12]([C:13]([OH:15])=O)[C:7]=2[CH:6]=[N:5]1)[CH3:3].[NH2:19][CH2:20][C:21]1[C:22](=[O:29])[NH:23][C:24]([CH3:28])=[CH:25][C:26]=1[CH3:27].CN1CCOCC1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CS(C)=O>[CH3:27][C:26]1[CH:25]=[C:24]([CH3:28])[NH:23][C:22](=[O:29])[C:21]=1[CH2:20][NH:19][C:13]([C:12]1[C:7]2[CH:6]=[N:5][N:4]([CH:2]([CH3:1])[CH3:3])[C:8]=2[N:9]=[C:10]([CH2:16][CH2:17][CH3:18])[CH:11]=1)=[O:15]
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: CCCc1cc(C(=O)O)c2cnn(C(C)C)c2n1
Agent: On1nnc2cccnc21
Solvent: CS(C)=O
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: CCCc1cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c2cnn(C(C)C)c2n1

Procedure:
The title compound was prepared in the same manner as described in example 109 using 1-(1-methylethyl)-6-propyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (70 mg, 0.283 mmol), DMSO(3 mL), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (80 mg, 0.425 mmol), N-methylmorpholine (0.124 mL, 1.132 mmol), 1-hydroxy-7-azabenzotriazole (77 mg, 0.566 mmol), and EDC (109 mg, 0.566 mmol). The collected solid was washed with water and methanol and dried under high vacuum to give 73 mg (68%) of product. LCMS E-S (M+H)=382.3 1H NMR (400 MHz, DMSO-d6) δ ppm 0.82-1.10 (m, 3 H), 1.48 (d, J=6.8 Hz, 6 H), 1.77 (m, 2 H), 2.13 (s, 3 H), 2.21 (s, 3 H), 2.85 (t, J=7.6 Hz, 2 H), 4.36 (d, J=4.8 Hz, 2 H), 5.20 (m, 1 H), 5.90 (s, 1 H), 7.38-7.58 (m, 1 H), 8.26 (s, 1 H), 8.73 (t, J=4.7 Hz, 1 H), 11.57 (br. s., 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[NH2:21][CH2:22][C@H:23]([OH:28])[C@@H:24]([OH:27])[CH2:25][OH:26]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[C:13]([NH:21][CH2:22][C@H:23]([OH:28])[C@@H:24]([OH:27])[CH2:25][OH:26])=[O:15])=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)O)cc1/C=C/c1ccc(Cl)cc1
Reactant: NC[C@H](O)[C@@H](O)CO
Product: COc1ccc(C(=O)NC[C@H](O)[C@@H](O)CO)cc1/C=C/c1ccc(Cl)cc1

Procedure:
The captioned compound was synthesized from 4-methoxy-3-[(E)-2-(4-chlorophenyl)vinyl]benzoic acid obtained in step B of Example 2-2-7 and (2S,3S)-4-amino-1,2,3-butanetriol (CAS registry number: 168113-19-7) in accordance with the same procedure as in the methods described in step C of Example 1-2-3.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][CH2:17][OH:18])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:19]([O:18][CH2:17][CH2:16][CH2:15][CH:12]1[CH2:13][CH2:14][N:10]([C:8]([O:7][C:3]([CH3:6])([CH3:5])[CH3:4])=[O:9])[CH2:11]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(CCCO)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [H-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CCCOCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
NaH (0.92 g, 38 mmol, 1.7 equiv.) was added to a solution of 3-[1-(tert-butoxycarbonyl)-3-pyrrolidinyl]-1-propanol (5.11 g, 22.3 mmol) in anhydrous THF (180 mL) at 0° C. under N2. The mixture was warmed to room temperature and stirred for about 2 h. Then benzyl bromide (3.2 mL, 26.9 mmol, 1.2 equiv.) and tetra-n-butylammonium bromide (0.72 g, 2.2 mmol, 0.10 equiv.) were added at room temperature. The solution was stirred for 20 h at room temperature, after which time period the reaction was completed as judged by TLC analysis (SiO2, EtOAc/petroleum ether 1:10). The reaction was then quenched by the addition of 20 mL of saturated aqueous NH4Cl solution. The product was extracted into EtOAc (3×60 mL), and the combined organic layers were washed with brine. After concentration in vacuo, the residue was applied onto a silica gel column, which was eluted with EtOAc/petroleum ether 1:20-1:10 to provide the product (6.20 g, 87%) as a colorless oil. 1H NMR (CDCl3, 300 MHz) δ 7.30-7.37 (m, 5H), 4.52 (s, 2H), 3.42-3.57 (m, 4H), 3.23-3.30 (m, 1H), 2.89 (dd, 1H, J=10.5, 8.7 Hz), 2.06-2.12 (m, 1H), 1.96-2.01 (m, 1H), 1.61-1.69 (m, 2H), 1.47-1.51 (m, 3H), 1.48 (s, 9H).
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][CH2:5][NH:6][C:7](=[O:30])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([S:22][C:23]2[CH:28]=[CH:27][C:26](Br)=[CH:25][CH:24]=2)[CH2:15][CH:16]([CH3:21])[CH2:17][CH2:18][CH2:19][CH3:20])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+].[F:38][C:39]([F:51])([F:50])[O:40][C:41]1[CH:42]=[C:43](B(O)O)[CH:44]=[CH:45][CH:46]=1>>[CH3:21][CH:16]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:15][CH:14]([C:11]1[CH:10]=[CH:9][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:31])=[O:2])=[O:30])=[CH:13][CH:12]=1)[S:22][C:23]1[CH:24]=[CH:25][C:26]([C:44]2[CH:43]=[CH:42][C:41]([O:40][C:39]([F:51])([F:50])[F:38])=[CH:46][CH:45]=2)=[CH:27][CH:28]=1
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Reactant: CCCCC(C)CC(Sc1ccc(Br)cc1)c1ccc(C(=O)NCCC(=O)OC)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCC(C)CC(Sc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1)c1ccc(C(=O)NCCC(=O)O)cc1
Yield: 50.6 %

Procedure:
3-{4-[1-(4-bromo-phenylsulfanyl)-3-methyl-heptyl]-benzoylamino}-propionic acid methyl ester (100 mg, 0.2 mmol), potassium carbonate (83 mg, 0.6 mmol), 3-trifluoromethoxyphenyl boronic acid (76 mg, 0.4 mmol) and tetrakis-(triphenylphosphine)palladium (23 mg, 0.02 mmol) are placed in a flask. After the reaction is purged with N2 for several times, THF/H2O (20 ml/5 ml) is added. The resulting solution is refluxed overnight, concentrated, diluted with ethyl acetate, acidified with 1 N HCl (0.6 mL), extracted with ethyl acetate. The organic layers are dried and purified with reverse phase HPLC to afford the title compound (58 mg). MS (ES): 544.1 [M+H]+.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.CC(C)([O-])C.[K+].[CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)=[CH2:17]>C(O)(=O)C>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:16][CH2:17][C:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]=1
Reactant: C=Cc1ccccn1
Reactant: C1=Cc2ccccc2C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: C1=C(CCc2ccccn2)c2ccccc2C1

Procedure:
This compound is prepared as described by Dressler and Kurland J.O.C. 29, 175 (1964). Under nitrogen gas, 500 g. indene plus 5 g. potassium t-butoxide are stirred and heated to 130°. 2-Vinyl pyridine (220 g., 2.0 M) is added dropwise over a period of 1 hour keeping the temperature at 135°-145° C. during addition and for 2 hours after addition is completed. The reaction mixture is cooled and 25 ml. acetic acid is added, followed by filtration. A flash distillation yields 395 g. (84%) crude product boiling 160°-175°/0.3 mm. This is redistilled to give 353 g. (75%) of oil (3-[2(pyridyl)ethyl]indene) boiling point 135°-140°/0.1 mm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[N:22][C:23]([N:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)=[CH:24][CH:25]=4)[CH:18]=3)[N:13]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH:12]=2)[CH:8]=[N:7]1.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=NC(N5CCN(C)CC5)=CC=4)C=3)NC=2)C=N1.[OH:80][CH2:81][C:82](O)=[O:83].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:31][CH2:30][N:29]([C:81](=[O:80])[CH2:82][OH:83])[CH2:28][CH2:27]5)=[N:22][CH:21]=4)[CH:18]=3)[N:13]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH:12]=2)[CH:8]=[N:7]1
Reactant: O=C(O)CO
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCNCC5)nc4)cnc32)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN1CCN(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccc(F)c6)c5)c4c3)cn2)CC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(C(=O)CO)CC5)nc4)cnc32)cc1

Procedure:
Using similar reaction conditions as described in step-ii of example-124, 3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-5-(6-(piperazin-1-yl)pyridin-3-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (step 1 compound of example 137) (75 mg, 0.123 mmol) was coupled with 2-hydroxyacetic acid (14 mg, 0.185 mmol) using HATU (71 mg, 0.185 mmol), HOBt (25 mg, 0.185 mmol) and DIPEA (86 μL, 0.493 mmol) in DMF (1 mL) to get 70 mg (85.3.0%) yield of the title compound after purification by column (Silica gel 60/120) chromatography using 5% methanol in dichloromethane as eluent. MS: m/z=666.5 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([NH:14]C(=O)C)([CH3:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].C1([SiH2]C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([NH2:14])([CH3:13])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)NC1(C)CCN(Cc2ccccc2)C1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: O=C([O-])O
Product: CC1(N)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Add titanium (IV) isopropoxide (2.8 mL, 9.46 mmol) dropwise to a stirred mixture of N-(1-benzyl-3-methylpyrrolidin-3-yl)-acetamide (2 g, 8.6 mmol) and diphenylsilane (10 mL). Stir overnight at room temperature under nitrogen. Pour into saturated aqueous sodium hydrogen carbonate and extract with chloroform. Combine the organic layers and wash with saturated aqueous sodium chloride, dry (magnesium sulfate) and concentrate. Add methanol and filter off the white precipitate. Add bulk Isolute sorbent SCX-2 silica (20 g) and stir for 2 h. Filter off the silica, wash with methanol and with 2 N ammonia in methanol. Concentrate to give 1-benzyl-3-methylpyrrolidin-3-ylamine which may be used in the next step without further purification (1.31 g, 86%). 1H NMR (300 MHz, CDCl3) δ 7.22-7.35 (5H, m), 3.59 (2H, d, J=2.26 Hz), 2.83 (1H, td, J=8.67, 5.27 Hz), 2.37-2.51 (2H, m), 2.30 (1H, d, J=9.04 Hz), 1.76-1.86 (1H, m), 1.66-1.74 (3H, m), 1.24 (3H, s), MS (ES): m/z=191 [M+H].
Reaction SMILES: [NH2:1][C:2]1[N:22]=[C:5]2[C:6]([C:10]3[CH:11]=[C:12]([N:16]([CH3:21])[S:17]([CH3:20])(=[O:19])=[O:18])[CH:13]=[CH:14][CH:15]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.Br[C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)=[CH:26][CH:25]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:21][N:16]([C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:1][C:24]4[CH:25]=[CH:26][C:27]([N:30]5[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]5)=[CH:28][CH:29]=4)[N:22]=3)[CH:9]=[CH:8][CH:7]=2)[CH:11]=1)[S:17]([CH3:20])(=[O:19])=[O:18]
Reactant: CN(c1cccc(-c2cccn3nc(N)nc23)c1)S(C)(=O)=O
Reactant: CN1CCN(c2ccc(Br)cc2)CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2ccc(Nc3nc4c(-c5cccc(N(C)S(C)(=O)=O)c5)cccn4n3)cc2)CC1

Procedure:
A round bottom flask was charged with potassium carbonate (0.56 g, 4.0 mmol) and acetone (20 mL). To the suspension was added N-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-methanesulfonamide (1.0 g, 3.4 mmol) followed by iodomethane (0.25 mL, 4.0 mmol). The mixture was stirred at room temperature for 18 hours. The mixture was diluted with dichloromethane (20 mL), filtered through a plug of diatomaceous earth, rinsed with dichloromethane and evaporated to a viscous oil. The material was subjected to high vacuum for 18 hours. N-Methyl-N-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-methanesulfonamide was isolated as pale yellow solid (1.03 g, 98%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.76-7.70 (m, 2H), 7.53 (d, J=7.9 Hz, 1H), 7.39 (t, J=7.5 Hz, 1H), 3.34 (s, 3H), 2.86 (s, 3H), 1.35 (s, 12H). MS=312 (MH)+. 127b) N-[3-(2-Amino-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-phenyl]-N-methyl-methanesulfonamide was prepared from 8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (500.0 mg, 2.347 mmol) and N-methyl-N-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-methanesulfonamide (800.0 mg, 2.571 mmol) in a manner analogous to Example 2c. Product isolated as a white foam (0.529 g, 71%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.57 (d, J=6.5 Hz, 1H), 8.13-8.10 (m, 1H), 8.07 (d, J=7.9 Hz, 1H), 7.75 (d, J=7.5 Hz, 1H), 7.53 (t, J=8.0 Hz, 1H), 7.45 (d, J=8.0 Hz, 1H), 6.99 (t, J=6.9 Hz, 1H), 6.12 (s, 2H), 3.31 (s, 3H), 3.01 (s, 3H). MS=318 (MH)+. 127c) N-Methyl-N-(3-{2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-yl}-phenyl)-methanesulfonamide was prepared from N-[3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-phenyl]-N-methyl-methanesulfonamide (75.0 mg, 0.236 mmol) and 1-(4-bromo-phenyl)-4-methyl-piperazine (67.0 mg, 0.262 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a yellow foam (0.033 g, 28%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.41 (d, J=6.6, 1H), 8.13 (s, 3H), 7.93 (d, J=7.9 Hz, 1H), 7.59 (d, J=7.4 Hz, 1H), 7.56-7.45 (m, 3H), 7.44 (dd, J=8.2, 1.2 Hz, 1H), 6.98-6.92 (m, 3H), 6.64 (s, 1H), 3.42 (s, 3H), 3.19-3.14 (m, 4H), 2.89 (s, 3H), 2.63-2.57 (m, 4H), 2.36 (s, 3H). MS=492 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([Cl:25])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10](Cl)=[O:11].B([O-])=O.[Na+].C(O)(=O)C>COCCOCCOC.O>[Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([Cl:25])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[CH2:10][OH:11]
Reactant: O=C(Cl)c1cc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Agent: O=B[O-]
Agent: [Na+]
Solvent: COCCOCCOC
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)cc1CO
Temperature: 25 °C
Reaction time: 15 h
Yield: 94.1 %

Procedure:
A solution of 41.5 g of 5-(2,6-dichloro-4-trifluoromethyl-phenoxy)-2-nitro-benzoic acid chloride in 100 ml of diglyme was added to a mixture of 4.2 g of sodium boranate and 60 ml of diglyme at -5° to -10° C. The reaction mixture was stirred for about 15 hours at room temperature, diluted with 1.2 liters of water and acidified with acetic acid, and the product was filtered off. 36 g (94% of theory) of 5-(2,6-dichloro-4-trifluoromethyl-phenoxy)-2-nitro-benzyl alcohol, of melting point 143° C., were obtained.
Reaction SMILES: [ClH:1].Cl.[F:3][C:4]1[CH:5]=[C:6]([NH:31][C:32]([NH:34][C:35](=[O:44])[CH2:36][C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=2)=S)[CH:7]=[CH:8][C:9]=1[O:10][C:11]1[C:16]2=[C:17]([CH3:30])[C:18]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)=[CH:19][N:15]2[N:14]=[CH:13][N:12]=1.FC1C=CC(CC(N=C=O)=[O:54])=CC=1>C1COCC1.Cl.FC1C=C(NC(=O)CC(NC2C=CC(F)=CC=2)=O)C=CC=1OC1C2=C(C)C(OCCN3CCOCC3)=CN2N=CN=1>[ClH:1].[ClH:1].[F:3][C:4]1[CH:5]=[C:6]([NH:31][C:32]([NH:34][C:35](=[O:44])[CH2:36][C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=2)=[O:54])[CH:7]=[CH:8][C:9]=1[O:10][C:11]1[C:16]2=[C:17]([CH3:30])[C:18]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)=[CH:19][N:15]2[N:14]=[CH:13][N:12]=1
Reactant: Cc1c(OCCN2CCN(C)CC2)cn2ncnc(Oc3ccc(NC(=S)NC(=O)Cc4ccc(F)cc4)cc3F)c12
Reactant: O=C=NC(=O)Cc1ccc(F)cc1
Agent: Cc1c(OCCN2CCOCC2)cn2ncnc(Oc3ccc(NC(=O)CC(=O)Nc4ccc(F)cc4)cc3F)c12
Agent: Cl
Solvent: C1CCOC1
Product: Cc1c(OCCN2CCN(C)CC2)cn2ncnc(Oc3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3F)c12
Reaction time: 8 h
Yield: 46 %

Procedure:
To a solution of 3-fluoro-4-(5-methyl-6-(2-(4-methylpiperazin-1-yl)ethoxy)pyrrolo[2,1-f][1,2,4]triazin-4-yloxy)benzenamine (20 mg, 0.05 mmol, Compound B of Example 45) in 1 mL of THF at room temperature was added a solution of 2-(4-fluorophenyl)acetyl isocyanate in toluene (0.36 M, 0.18 mL, Compound C of Example 4) and the solution was allowed to stir overnight. HPLC analysis and LC-MS analysis indicated the completion of the reaction and the organic solvent was thus removed under reduced pressure. The residue was purified on preparative HPLC. The title compound (15 mg, 46%) was finally obtained as a 2.HCl salt after a work-up similar to that described for Compound D of Example 36.
Reaction SMILES: C(OP([CH2:9][C:10]#[N:11])(=O)OCC)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:22]([O:24][C:25]1[CH:26]=[C:27]([C:33]([C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[C:37]([OH:43])[CH:36]=2)=O)[CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[CH3:23].O>C1COCC1>[CH2:22]([O:24][C:25]1[CH:26]=[C:27](/[C:33](/[C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[C:37]([OH:43])[CH:36]=2)=[CH:9]\[C:10]#[N:11])[CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[CH3:23]
Reactant: CCOc1cc(C(=O)c2ccc(OC)c(O)c2)ccc1OC
Reactant: CCOP(=O)(CC#N)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1cc(/C(=C\C#N)c2ccc(OC)c(O)c2)ccc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
To a solution of cyanomethylphosphonic acid diethyl ester (8.1 mL, 51.6 mmol) in anhydrous THF (50 mL) was added lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 51.6 mL, 51.6 mmol) at 0° C. and stirred for 30 min at room temperature followed by addition of (3-ethoxy-4-methoxy-phenyl)-(3-hydroxy-4-methoxy-phenyl)-methanone (5.20 g, 17.2 mmol) in THF (40 mL) and refluxed overnight. The reaction mixture was poured into water (50 mL), extracted with CH2Cl2 (2×60 mL). The combined organic phases were washed with brine (60 mL), dried over MgSO4, and purified via flash column chromatography (EtOAc/Hexane) to give E/Z-3-(3-ethoxy-4-methoxy-phenyl) -3-(3-hydroxy-4-methoxy-phenyl)-acrylonitrile as an off-white solid (5.26 g, 94% yield). The product was used in the next step without further purification.
Reaction SMILES: C([O:3][C:4](=[O:32])[C:5]([O:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)([CH3:23])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][NH:19][C:18](=[O:21])[N:17]2[CH3:22])=[CH:9][CH:8]=1)C.[H-].[Na+].[C:35]([C:39]1[CH:46]=[CH:45][C:42]([CH2:43]Br)=[CH:41][CH:40]=1)([CH3:38])([CH3:37])[CH3:36]>CN(C=O)C.CCOCC.Cl>[C:35]([C:39]1[CH:46]=[CH:45][C:42]([CH2:43][N:19]2[CH2:20][CH:16]([CH2:15][CH2:14][O:13][C:10]3[CH:11]=[CH:12][C:7]([CH2:6][C:5]([O:24][C:25]4[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=4)([CH3:23])[C:4]([OH:32])=[O:3])=[CH:8][CH:9]=3)[N:17]([CH3:22])[C:18]2=[O:21])=[CH:41][CH:40]=1)([CH3:38])([CH3:37])[CH3:36]
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCC2CNC(=O)N2C)cc1)Oc1ccc(F)cc1
Reactant: CC(C)(C)c1ccc(CBr)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CN1C(=O)N(Cc2ccc(C(C)(C)C)cc2)CC1CCOc1ccc(CC(C)(Oc2ccc(F)cc2)C(=O)O)cc1
Reaction time: 0.33 h
Yield: 45 %

Procedure:
To a mixture of 80 mg of 2-(4-Fluoro-phenoxy)-2-methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-propionic acid ethyl ester in 5 mL of dry DMF at 0° C. under an atmosphere of nitrogen, 18 mg of NaH (0.45 mmol) is added. The resulting solution is allowed to stand at r.t. for 20 min. Then 0.08 mL of 4-tert-butylbenzyl bromide is added and resulting mixture is allowed to stand at r.t. for overnight. Reaction mixture is diluted with Et2O and 1N HCl. Organic layer is then washed with 1N HCl (2×10 mL), brine (2×10 mL), dried over Na2SO4, filtered and concentrated under vacuum. The crude material is in 5 mL of EtOH and 0.4 mL of 5N NaOH. The mixture is heated to reflux for 1 h. The organic solvent is then removed under vacuum and residue is dissolved in CH2Cl2 and 1N HCl. Aqueous layer is washed with CH2Cl2 (2×10 mL). Combined organic layer is dried over Na2SO4, filtered and concentrated under vacuum. The crude material is purified by MS/LC to give 45 mg (45%) of the title product. 1H NMR (400 MHz, CDCl3): δ 7.33 (d, 2H, J=8.4 Hz), 7.18, 7.16 (ABq, 4H, J=8.6 Hz), 6.96-6.92 (m, 2H), 6.88-6.85 (m, 2H), 6.77 (d, 2H, J=8.8 Hz), 4.38, 4.29 (ABq, 2H, J=14.8 Hz), 3.98 (t, 2H, J=6.0 Hz), 3.69 (bs, 1H), 3.73-3.66 (m, 1H), 3.44 (t, 1H, J=8.6 Hz), 3.25, 3.11 (ABq, 2H, J=13.8 Hz), 3.06 (t, 1H, J=8.6 Hz), 2.86 (s, 3H), 2.28-2.19 (m, 1H), 1.97-1.89 (m, 1H), 1.38 (s, 3H), 1.30 (s, 9H). HRMS (ES+) m/z exact mass calcd for C33H40N2O5F (m+1) 563.2921, found 563.2917.
Reaction SMILES: [CH:1]([N:4]([CH:25]([CH3:27])[CH3:26])[C:5](=[O:24])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([CH:21]=[O:22])=[CH:16][C:15]=2[Cl:23])=[CH:10][CH:9]=1)([CH3:3])[CH3:2].[O:28]1CCCC1.O.Cl([O-])=O.[Na+].NS(O)(=O)=O>C(OCC)(=O)C.O>[CH:25]([N:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:24])[CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21]([OH:28])=[O:22])=[CH:16][C:15]=2[Cl:23])=[CH:12][CH:13]=1)([CH3:27])[CH3:26]
Reactant: CC(C)N(C(=O)COc1ccc(-c2c(Cl)cc(C=O)cc2Cl)cc1)C(C)C
Reactant: C1CCOC1
Agent: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)N(C(=O)COc1ccc(-c2c(Cl)cc(C(=O)O)cc2Cl)cc1)C(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
124 mg of the product of Stage E were mixed with 2 ml of tetrahydrofuran, 3.5 ml of water, 98 mg of sodium chlorite monohydrate and 87 mg of amidosulfonic acid and the mixture was stirred for 90 minutes at ambient temperature and evaporated under reduced pressure to obtain a residue which was obtained which is taken up in ethyl acetate. The organic phase was washed with IN sodium hydroxide, dried over magnesium sulfate and evaporated under reduced pressure to obtain 97.8 mg of the expected product with a Rf=0.26 (cyclohexane/ethyl acetate 8/2).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[C:6]([NH:8][CH:9]1[CH2:12][C:11]([F:14])([F:13])[CH2:10]1)=[O:7].[N:18]1([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(#N)C>[F:13][C:11]1([F:14])[CH2:12][CH:9]([NH:8][C:6]([C:5]2[CH:4]=[C:3]([CH:17]=[CH:16][CH:15]=2)[CH2:2][N:21]2[CH2:20][CH2:19][N:18]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:23][CH2:22]2)=[O:7])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(NC1CC(F)(F)C1)c1cccc(CCl)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccc(C(=O)NC3CC(F)(F)C3)c2)CC1
Yield: 98.7 %

Procedure:
3-(Chloromethyl)-N-(3,3-difluorocyclobutyl)benzamide (12.82 mmol, 3.33 g), tert-butyl piperazine-1-carboxylate (12.82 mmol, 2.388 g), potassium carbonate (38.5 mmol, 5.32 g) and sodium iodide (2.56 mmol, 0.384 g) were combined and heated at reflux in acetonitrile (50 ml) for 2 hours. The solvent was removed under reduced pressure and the residue taken up in dichloromethane, washed with water, dried over sodium sulfate and concentrated under vacuum to afford the title compound (5.179 g).