Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]([C:22]1[CH:27]=[CH:26][C:25]([O:28]C)=[CH:24][CH:23]=1)([C:14]1[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])#[N:2].B(Br)(Br)Br>ClCCl>[C:1]([C:3]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)([C:22]1[CH:23]=[CH:24][C:25]([OH:28])=[CH:26][CH:27]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])#[N:2]
Reactant: CCOC(=O)CCCCCC(C#N)(c1ccc(OC)cc1)c1ccc(OC)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)CCCCCC(C#N)(c1ccc(O)cc1)c1ccc(O)cc1
Temperature: -70 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
To a solution of ethyl 7-cyano-7,7-bis(4-methoxyphenyl)heptanoate (2.0 g, 5 mmol.) in dichloromethane (20 ml) was added dropwise a solution of boron tribromide (5.07 g, 20 mmol.) in dichloromethane (15 ml) while stirring at -70° C. The reaction mixture was warmed up to 5° C. taking 2 hours, to which was added ice-water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous saline solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to a silica gel column chromatography, eluting with hexane--ethyl acetate (2:1), to afford the title compound (1.7 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[CH:20]=[N:21][C:22]([NH:25][C:26]3([C:29](O)=[O:30])[CH2:28][CH2:27]3)=[N:23][CH:24]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1.[Cl-].[NH4+].C(Cl)CCl.C1C=CC2N(O)N=[N:44]C=2C=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl.CN(C=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[CH:24]=[N:23][C:22]([NH:25][C:26]3([C:29]([NH2:44])=[O:30])[CH2:28][CH2:27]3)=[N:21][CH:20]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:16])[F:17])[CH:12]=[CH:11][N:10]=2)[CH:7]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(NC3(C(=O)O)CC3)nc2)c1
Reactant: On1nnc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(NC3(C(N)=O)CC3)nc2)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
1-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]amino}cyclopropanecarboxylic acid (177 mg, 0.411 mmol, as prepared in Example 2.3), ammonium chloride (66 mg, 1.2 mmol), EDC (0.158 g, 0.823 mmol), HOBT (0.111 g, 0.823 mmol), N,N-diisopropylethylamine (0.359 mL, 2.06 mmol) and DMF (4 mL) were combined and stirred at rt for 14 hours. The reaction mixture was concentrated in vacuo, then diluted with water and extracted with EtOAc (2×). The combined organic portions were washed with saturated sodium bicarbonate, then brine. The organic portions were collected and dried with MgSO4, filtered, and concentrated in vacuo to afford a brown solid. The residue was diluted with 1:1 CH2Cl2:hexanes and stirred for 10 min, then filtered. The solid was washed with 1:1 CH2Cl2:hexanes, then methanol to afford 1-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]amino}cyclopropanecarboxamide. MS ESI calcd. for C20H19F3N2O [M+H]+ 430. found 430. 1H NMR (500 MHz, DMSO-d) δ 10.22 (s, 1H), 8.82 (d, J=4.8 Hz, 1H), 8.60-8.55 (m, 2H), 7.85 (s, 1H), 7.82 (s, 1H), 7.47 (s, 1H), 7.26 (d, J=4.9 Hz, 1H), 7.17 (s, 1H), 7.11 (s, 1H), 6.92 (s, 1H), 2.32 (s, 3H), 1.33 (d, J=3.3 Hz, 2H), 0.92 (d, J=3.2 Hz, 2H).
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:12][N:11](C(OCC2C=CC=CC=2)=O)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C(O)C.[C].[Pd]>[Si:1]([O:8][CH:9]1[CH2:12][NH:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC1CN(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OC1CNC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.9 %

Procedure:
Into a solution of benzyl 3-[(tert-butyldimethylsilyl)oxy]azetidine-1-carboxylate (4.2 g, 13.06 mmol, 1.00 equiv) in ethanol (15 mL) was added palladium carbon (1.3 g, 0.30 equiv) at 0° C. in water/ice bath. The resulting solution was stirred overnight at room temperature. The solids were filtered off. The resulting mixture was concentrated under vacuum to afford 2.2 g (90%) of 3-[(tert-butyldimethylsilyl)oxy]azetidine (50.4) as a light yellow liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[N:13][NH:12][C:11](=[O:23])[C:10]=2[C:24]#[N:25])=[CH:5][CH:4]=1.[CH2:26](Cl)[CH:27]([CH3:29])[CH3:28]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[N:13][N:12]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:11](=[O:23])[C:10]=2[C:24]#[N:25])=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2n[nH]c(=O)c(C#N)c2-c2ccc(OC)cc2)cc1
Reactant: CC(C)CCl
Product: COc1ccc(-c2nn(CC(C)C)c(=O)c(C#N)c2-c2ccc(OC)cc2)cc1
Yield: 71.8 %

Procedure:
Using 5,6-bis(4-methoxyphenyl)-4-cyano-2H-pyridazin-3-one and isobutyl chloride as starting materials, the procedures of Example 1 were repeated likewise, whereby the title compound was obtained in a yield of 71.8%.
Reaction SMILES: [NH:1]1[C:5]2[N:6]=[CH:7][CH:8]=[C:9]([C:10]#N)[C:4]=2[CH:3]=[CH:2]1.CC(C[Al]CC(C)C)C.CC(C[AlH]CC(C)C)C.Cl.C([O-])(O)=[O:32].[Na+]>C1COCC1>[NH:1]1[C:5]2[N:6]=[CH:7][CH:8]=[C:9]([CH:10]=[O:32])[C:4]=2[CH:3]=[CH:2]1
Reactant: O=C([O-])O
Reactant: N#Cc1ccnc2[nH]ccc12
Agent: CC(C)C[AlH]CC(C)C
Agent: CC(C)C[Al]CC(C)C
Agent: Cl
Solvent: C1CCOC1
Product: O=Cc1ccnc2[nH]ccc12
Temperature: -78 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
To a solution of (200 mg, 1.4 mmol) of 1H-Pyrrolo[2,3-b]pyridine-4-carbonitrile in THF (7 mL) at −78° C. under nitrogen was added Dibal-H (1.0 M in toluene, 3.07 mL, 3.07 mmol). The reaction mixture was stirred at −78° C. for 1 hr, warmed to 55° C. and stirred for additional 2 hr. One additional equivalent of DIBAL-H (1.4 mL, 1.4 mmol) was added and the mixture stirred at 55° C. for 2 hr. The mixture was cooled to 5° C., acidified with 2 M HCl and stirred for 15 min. The mixture was then neutralized with saturated NaHCO3 (aq), extracted with CH2Cl2 (5×25 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give 1H-Pyrrolo[2,3-b]pyridine-4-carboxaldehyde (107 mg, 52%). MS (ES+): 146 [MH+]. 1H NMR (DMSO-d6, 400 MHz): δ 7.22 (d, 1H, J=3.6 Hz), 7.57 (d, 1H, J=4.8 Hz), 7.67 (d, 1H, J=2.4 Hz), 8.61 (d, 1H, J=5.2 Hz), 10.42 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=2)[C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=2)=[CH:4][CH:3]=1.C([Li])CCC.C(O[B:38]1[O:42][C:41]([CH3:44])([CH3:43])[C:40]([CH3:46])([CH3:45])[O:39]1)(C)C.O>C1COCC1.C(Cl)(Cl)Cl>[CH:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:27]=[CH:28][C:19]=1[N:8]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)[C:5]1[CH:4]=[CH:3][C:2]([B:38]2[O:39][C:40]([CH3:45])([CH3:46])[C:41]([CH3:43])([CH3:44])[O:42]2)=[CH:7][CH:6]=1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: Brc1ccc(N(c2ccc3ccccc3c2)c2ccc3ccccc3c2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC1(C)OB(c2ccc(N(c3ccc4ccccc4c3)c3ccc4ccccc4c3)cc2)OC1(C)C
Temperature: -78 °C
Reaction time: 24 h
Yield: 77.4 %

Procedure:
8.5 g (20 mmol) of (4-bromophenyl)dinaphthalene-2-ylamine was dissolved in 100 ml of THF and was cooled to −78° C. 9.6 ml (24 mmol) of 2.5M n-butyllithium was added slowly to the THF solution and maintained at the same temperature as above for an hour to allow reaction. 4.4 g (24 mmol) of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was added to the reaction solution, and was maintained at the same temperature as above for an hour. The reaction solution was heated to room temperature (RT) and stirred for 24 hours. Water was added to end the reaction. 300 ml of chloroform was added to the solution and washed with 200 ml of water. The resulting organic layer was dried with anhydride magnesium sulfate. 7.3 g of dinaphthalen-2-yl-[4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolane-2-yl)phenyl]amine (intermediate B) was obtained through silica chromatography with a yield of 77%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]1[CH2:15][CH2:14][CH:13]([CH:16]=[CH:17][C:18](=[O:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[O:12]1>[Ni].CO>[CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]1[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][C:18](=[O:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[O:12]1
Reactant: CCCCCC(=O)C=CC1CCC(CCCCCCCC(=O)OC)O1
Agent: [Ni]
Solvent: CO
Product: CCCCCC(=O)CCC1CCC(CCCCCCCC(=O)OC)O1
Yield: 84.9 %

Procedure:
III (3.52 g, 0.0100 mole) methanol (50 ml), and Raney nickel (0.5 g) were stirred under hydrogen at a pressure of 1 atmosphere, until absorption stopped. After filtration, the solvent was removed from a water bath (60° C, 10 mm Hg). The residual light yellowish oil (3.60 g) was distilled under reduced pressure to give 3.01 g (85%) of VIII as a light yellowish oil, b0.03 165°-176° C, nD25 1.4608.
Reaction SMILES: Cl.[N:2]1[CH:3]=[CH:4][N:5]2[CH:10]=[CH:9][N:8]=[C:7]([N:11]3[CH2:15][CH2:14][C@H:13]([NH2:16])[CH2:12]3)[C:6]=12.[F:17][C:18]1[CH:19]=[C:20]([N:24]2[CH:28]=[N:27][C:26]([C:29](O)=[O:30])=[N:25]2)[CH:21]=[CH:22][CH:23]=1.C(N(CC)C(C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[F:17][C:18]1[CH:19]=[C:20]([N:24]2[CH:28]=[N:27][C:26]([C:29]([NH:16][C@H:13]3[CH2:14][CH2:15][N:11]([C:7]4[C:6]5[N:5]([CH:4]=[CH:3][N:2]=5)[CH:10]=[CH:9][N:8]=4)[CH2:12]3)=[O:30])=[N:25]2)[CH:21]=[CH:22][CH:23]=1
Reactant: N[C@H]1CCN(c2nccn3ccnc23)C1
Reactant: O=C(O)c1ncn(-c2cccc(F)c2)n1
Agent: CCN(CC)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CCN(c2nccn3ccnc23)C1)c1ncn(-c2cccc(F)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.8 %

Procedure:
To a suspension of (S)-1-(imidazo[1,2-a]pyrazin-8-yl)pyrrolidin-3-amine hydrochloride salt (84 mg, 0.3 mmol) and 1-(3-fluorophenyl)-1H-1,2,4-triazole-3-carboxylic acid (63 mg, 0.3 mmol) in DMF (5 mL) was added diethylisopropyl amine (650 mg, 5 mmol), followed by HATU (120 mg, 0.31 mmol). The resulting solution was stirred at room temperature for 1 h. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous solutions of KH2PO4 and NaHCO3, followed by brine. The organic layer was concentrated in vacuo and the residue purified by reverse phase HPLC (acetonitrile-H2O with 0.1% TFA as eluent) to give 88 mg of the title compound (75% yield) as a white solid.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][C:10]1[CH:23]=[CH:22][C:13]([O:14][CH:15]([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][CH:11]=1.OO.S(=O)(O)[O-:29].[Na+]>S(=O)(=O)(O)O.C(O)(=O)C>[F:25][C:2]([F:24])([F:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([C:10]1[CH:23]=[CH:22][C:13]([O:14][CH:15]([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][CH:11]=1)=[O:29]
Reactant: CCOC(=O)C(C)Oc1ccc(Sc2ccccc2C(F)(F)F)cc1
Reactant: O=S([O-])O
Agent: O=S(=O)(O)O
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)C(C)Oc1ccc(S(=O)c2ccccc2C(F)(F)F)cc1

Procedure:
To a stirred solution containing 7.4 g. (0.020 mole) of ethyl 2-[4-(2-trifluoromethylphenylthio)phenoxy]propionate and a catalytic amount of sulfuric acid (3 drops) in 50 ml of glacial acetic acid is added a solution containing 2.23 g. (0.021 mole) of 32% hydrogen peroxide in 10 ml. of glacial acetic acid over a period of several minutes at 25°. The resultant solution is stirred for 24 hours under ambient conditions, at which time the reaction is essentially complete. After the reaction mixture is treated with sodium bisulfite to destroy any excess peroxide the solvent is removed in vacuo at 40° and the residue taken-up in ether. The ethereal solution is washed with a 5% potassium carbonate solution until basic, water until neutral, a saturated sodium chloride solution, dried with magnesium sulfate, and concentrated in vacuo to give 6.85 g. of material. The last traces of solvent are removed by exposure to high vacuum (0.1 mm) at 70° to afford ethyl 2-[4-(2-trifluoromethylphenylsulfinyl)phenoxy]propionate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[C:9]([CH3:10])=[CH:8][C:7]([F:11])=[CH:6][C:5]=1[I:12].[Br:14]NC(=O)CCC(N)=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:13])[C:4]1[C:5]([I:12])=[CH:6][C:7]([F:11])=[CH:8][C:9]=1[CH2:10][Br:14]
Reactant: NC(=O)CCC(=O)NBr
Reactant: COC(=O)c1c(C)cc(F)cc1I
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1c(I)cc(F)cc1CBr

Procedure:
A mixture of 4-fluoro-2-iodo-6-methyl-benzoic acid methyl ester (1.14 g, 3.74 mmol), N-bromosuccinamide (0.796 g, 4.5 mmol), and benzoyl peroxide (0.024 g, 0.146 mmol) in carbon tetrachloride (50 mL) was heated at reflux until majority of ester was consumed (as analyzed by GC/MS). The resulting mixture was filtered, the filtrate was concentrated to afford 2-bromomethyl-4-fluoro-6-iodo-benzoic acid methyl ester. The material was used without further purification
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([C:6]1[CH:20]=[CH:19][C:9]2[N:10]=[C:11]([NH:13][C:14]([NH:16][CH2:17][CH3:18])=[O:15])[S:12][C:8]=2[CH:7]=1)=[O:5].C(N(CC)CC)C.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C=O)C>[CH2:17]([NH:16][C:14]([NH:13][C:11]1[S:12][C:8]2[CH:7]=[C:6]([C:4](=[O:5])[CH2:3][CH2:2][NH:1][C:28](=[O:35])[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:20]=[CH:19][C:9]=2[N:10]=1)=[O:15])[CH3:18]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCNC(=O)Nc1nc2ccc(C(=O)CCN)cc2s1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCNC(=O)Nc1nc2ccc(C(=O)CCNC(=O)c3ccccc3)cc2s1
Reaction time: 0.08 h
Yield: 27.7 %

Procedure:
A solution of 1-(6-(3-aminopropanoyl)-2-benzothiazolyl)-3-ethylurea (0.033 g, 0.10 mmol) in 1 mL anhydrous DMF was treated with triethylamine (0.028 mL, 0.20 mmol, 2.0 eq) at room temperature. It was stirred for about 5 min, followed by the addition of benzoyl chloride (0.014 mL, 0.12 mmol, 1.2 eq). It was stirred for about 2.5 hours, quenched with MeOH, filtered, concentrated, and purified by HPLC to give the desired compound 0.011 g (28%). LC/MS 396.7 (M+1); LC retention time 2.74 min.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[NH:7]1[CH:11]=[CH:10][C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:8]1.Br[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH3:26])=[CH:20][CH:19]=1>C(#N)C>[CH2:25]([O:24][C:21]1[CH:22]=[CH:23][C:18]([N:7]2[CH:11]=[CH:10][C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:8]2)=[CH:19][CH:20]=1)[CH3:26]
Reactant: CCOc1ccc(Br)cc1
Reactant: CCOC(=O)c1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)c1ccn(-c2ccc(OCC)cc2)n1
Temperature: 82 °C
Reaction time: 7 h

Procedure:
A 10 mL Schlenk tube was dried under vacuum, filled with nitrogen and consecutively charged with 19.4 mg (0.102 mmol, 0.2 eq) Cul, 332.3 mg (1.020 mmol, 2.0 eq) Cs2CO3, 100.0 mg (0.714 mmol, 1.4 eq) ethyl 1H-pyrazole-3-carboxylate (6), 102.4 mg (73.0 μL, 0.510 mmol, 1.0 eq) p-bromophenetol and 1 mL dry ACN. The light brown suspension was degassed by vaccum/N2 cycles and stirred first at 82° C. for 7 h and than after adding 0.5 mL dry DMF (solubility issue) at 120° C. for further 65 h. The GC-MS analysis showed full conversion. ACN and DMF were removed under high pressure and the brown residue was suspended in 10 mL EtOAc. After filtration of the brown suspension through a pad of silica and flushing with 150 mL EtOAc the colorless filtrate was concentrated under reduced pressure leading to 52.1 mg (39%) crude product as a green-brown oil. Final purification by column chromatography (CH/EtOAc 3:1, size: 15.5×2.0 cm, 20 g silica gel) yielded the pure title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=[C:4](I)[N:3]=1.C([Li])CCC.[CH:22](=[O:24])[CH3:23]>C1COCC1>[Cl:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=[C:4]([CH:22]([OH:24])[CH3:23])[N:3]=1
Reactant: Clc1nc(I)ccc1OCc1ccccc1
Reactant: CC=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(O)c1ccc(OCc2ccccc2)c(Cl)n1
Temperature: 22 °C
Reaction time: 1 h
Yield: 69.5 %

Procedure:
2-Chloro-3-benzyloxy-6-iodo-pyridine (416 mg, 1.2 mmol) in THF (4 mL) was cooled to -78° C. and treated with n-butyllithium (1.2 mL of 1.6M in hexanes, 1.92 mmol). After 60 minutes, acetaldehyde (237 mg, 5.4 mmol) was added and the reaction was allowed to warm to 22° C. over 2 hours. The reaction was quenched with water (5 mL) and concentrated in vacuo. The remaining solution was extracted several times with ethyl acetate, dried over MgSO4, and concentrated in vacuo to yield an oil. The oil was chromatographed 1:1 hexane/ethyl acetate to yield 220 mg (70%) of 2-chloro-3-benzyloxy-6-(1-hydroxyethyl)-pyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:11]3([CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)[CH2:10][N:9]2[CH:24]([CH3:26])[CH3:25])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:11]3([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[CH2:10][N:9]2[CH:24]([CH3:26])[CH3:25])=[CH:6][CH:7]=1
Reactant: CC(C)N1CC2(CCN(C(=O)OC(C)(C)C)CC2)C1c1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)N1CC2(CCNCC2)C1c1ccc(Cl)cc1
Yield: 285.7 %

Procedure:
Under a nitrogen atmosphere, treat 1,1-dimethylethyl 1-(4-chlorophenyl)-2-isopropyl-2,7-diazaspiro[3.5]nonane-7-carboxylate (2.74 g) in dry CH2Cl2 (10 mL) with trifluoroacetic acid (2×5 mL) at RT for 45 min. Concentrate the reaction mixture in vacuo. Add CH2Cl2 (10 mL) and concentrate in vacuo (three times) to give a viscous colorless oil (5.76 g). Partition this oil between CH2Cl2 and 1N NaOH. Concentrate the dried (MgSO4) CH2Cl2 solution in vacuo to give the title compound (1.37 g) as a viscous oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[S:24](=[O:26])(=[O:25])[N:23]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:22](=[O:31])[CH2:21]2)=[CH:16][CH:15]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[C:65]1([NH2:72])[C:66]([NH2:71])=[CH:67][CH:68]=[CH:69][CH:70]=1>CN(C)C=O>[NH2:71][C:66]1[CH:67]=[CH:68][CH:69]=[CH:70][C:65]=1[NH:72][C:10](=[O:12])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[S:24](=[O:26])(=[O:25])[N:23]([C:27]([CH3:29])([CH3:28])[CH3:30])[C:22](=[O:31])[CH2:21]2)=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C2CC(=O)N(C(C)(C)C)S2(=O)=O)cc1)C(=O)O
Reactant: Nc1ccccc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C2CC(=O)N(C(C)(C)C)S2(=O)=O)cc1)C(=O)Nc1ccccc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.2 %

Procedure:
To a solution of N,N-dimethylformamide (5.0 mL) was added (2S)-2-[(tert-butoxycarbonyl)amino]-3-[4-(2-tert-butyl-1,1-dioxido-3-oxoisothiazolidin-5-yl)phenyl]propanoic acid (709.6 mg, 1.561 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (712 mg, 1.87 mmol), and N,N-diisopropylethylamine (1.3 mL, 7.80 mmol) and premixed for 5 minutes and then 1,2-benzenediamine (253 mg, 2.34 mmol) was added and stirred at room temperature overnight. Product was concentrated and purified on preparative LCMS to give the product (690 mg, 67%). LCMS found for C27H37N4O6S (M+H)+: m/z=545.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][CH:17]=O)=[C:12]([O:19][CH:20]([CH3:22])[CH3:21])[CH:11]=2)[CH2:6][CH2:5]1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:34]3[N:35]=C(S(C)(=O)=O)[N:37]=[CH:38][C:33]=3[S:32][C:31]=2[C:43]([NH2:45])=[O:44])=[CH:26][CH:25]=1>CN(C)C=O.CO>[F:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[C:34]3[N:35]=[C:17]([NH:16][C:13]4[CH:14]=[CH:15][C:10]([N:7]5[CH2:8][CH2:9][N:4]([CH3:3])[CH2:5][CH2:6]5)=[CH:11][C:12]=4[O:19][CH:20]([CH3:22])[CH3:21])[N:37]=[CH:38][C:33]=3[S:32][C:31]=2[C:43]([NH2:45])=[O:44])=[CH:28][CH:29]=1
Reactant: CC(C)Oc1cc(N2CCN(C)CC2)ccc1NC=O
Reactant: CS(=O)(=O)c1ncc2sc(C(N)=O)c(-c3ccc(F)cc3)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)Oc1cc(N2CCN(C)CC2)ccc1Nc1ncc2sc(C(N)=O)c(-c3ccc(F)cc3)c2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
27 mg of sodium hydride (at 60%) are added to a solution of 126 mg of N-[4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]formamide in 2 ml of dimethylformamide. The suspension is stirred at ambient temperature for 30 min, and is then diluted with 1 ml of dimethylformamide, and a solution of 80 mg of 7-(4-fluorophenyl)-2-(methylsulfonyl)thieno[3,2-d]pyrimidine-6-carboxamide in 2 ml of dimethylformamide is added. The mixture is stirred at ambient temperature for 30 min, and then diluted with 50 ml of methanol. The mixture is stirred at ambient temperature for 1 h, and then concentrated under vacuum. The residue is purified on 40 g of silica, elution being carried out with 0-20% of methanol in dichloromethane, and then by high performance liquid chromatography (Macherey-Nagel 250×40 mm reverse phase C18 Nucleodur 10μ column. Eluent: MeCN containing 0.07% TFA and H2O containing 0.07% TFA. 10% MeCN hold: 3 min, gradient up to 95% MeCN in 37 min and then 95% MeCN hold of 8 min. Flow rate: 70 ml/min). The fractions containing the expected material are loaded on to a 2 g Varian Bond Elut SCX cartraige (preconditioned with MeOH). Washing the cartridge four times with methanol, followed by elution of the expected material with 2N ammonia in methanol gives, after drying, 10 mg of 7-(4-fluorophenyl)-2-{[4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxamide.
Reaction SMILES: [C:1]([C:3]([NH:20][C:21](=[O:33])[C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=1)([CH3:19])[CH2:4][N:5]1[C:13]([O:14][CH3:15])=[C:12]2[C:7]([CH:8]=[C:9]([N+:16]([O-])=O)[CH:10]=[CH:11]2)=[N:6]1)#[N:2]>[Pd].CO>[NH2:16][C:9]1[CH:10]=[CH:11][C:12]2[C:7]([CH:8]=1)=[N:6][N:5]([CH2:4][C:3]([NH:20][C:21](=[O:33])[C:22]1[CH:23]=[CH:24][C:25]([O:28][C:29]([F:32])([F:30])[F:31])=[CH:26][CH:27]=1)([C:1]#[N:2])[CH3:19])[C:13]=2[O:14][CH3:15]
Reactant: COc1c2ccc([N+](=O)[O-])cc2nn1CC(C)(C#N)NC(=O)c1ccc(OC(F)(F)F)cc1
Agent: [Pd]
Solvent: CO
Product: COc1c2ccc(N)cc2nn1CC(C)(C#N)NC(=O)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 64.2 %

Procedure:
A mixture of N-[1-cyano-2-(3-methoxy-6-nitro-2H-indazol-2-yl)-1-methylethyl]-4-trifluoromethoxybenzamide (30 mg) described in Example 139 and palladium on charcoal in methanol (2 mL) were stirred at room temperature under hydrogen for 2.5 hours. The reaction mixture was filtered through a plug of Celite® and concentrated under reduced pressure to yield a residue that was purified by chromatography (SiO2, heptane/EA) to afford the title compound as a white solid (18 mg, 64%). MS (ES): M/Z [M+H]=434. 1H NMR: (400 MHz, CHLOROFORM-d): 1.88 (s, 3H), 4.38 (s, 3H), 4.41 (d, 1H), 4.72 (d, J=14.2 Hz, 1H), 6.48 (dd, J=9.0, 1.8 Hz, 1H), 6.53 (d, J=1.2 Hz, 1H), 7.31 (d, J=8.3 Hz, 2H), 7.55 (d, J=9.0 Hz, 1H), 7.98 (d, J=8.8 Hz, 2H) and 9.43 (s, 1H). 19F NMR (376 MHz, CHLOROFORM-d): −58.0 (s, 3F).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][C:6]#[N:7].[CH3:11][C:12]([CH3:25])([CH2:19][C:20](OCC)=[O:21])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].[Na]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]([C:6]#[N:7])[C:20](=[O:21])[CH2:19][C:12]([CH3:25])([CH3:11])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)CC(C)(C)CC(=O)OCC
Reactant: N#CCc1cccc(Cl)c1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)CC(C)(C)CC(=O)C(C#N)c1cccc(Cl)c1
Yield: 67.9 %

Procedure:
Starting with 75.0 g (0.495 mol) of 3-chlorobenzyl cyanide, 160.58 g (0.743 mol) of diethyl 3,3-dimethylglutarate, 14.80 g (0.643 mol) of sodium, and 260 ml of dry ethanol a total of 108.08 g (71% yield) of the desired product was obtained using the procedure described in Example I, Part A.