Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:25]=[C:24]3[C:19]([C:20]([NH:26][C:27]4[C:35]5[O:34][CH:33]=[CH:32][C:31]=5[CH:30]=[CH:29][C:28]=4[Cl:36])=[N:21][CH:22]=[N:23]3)=[CH:18][C:17]=2[O:37][CH3:38])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:36][C:28]1[CH:29]=[CH:30][C:31]2[CH:32]=[CH:33][O:34][C:35]=2[C:27]=1[NH:26][C:20]1[C:19]2[C:24](=[CH:25][C:16]([O:15][CH2:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[C:17]([O:37][CH3:38])[CH:18]=2)[N:23]=[CH:22][N:21]=1
Reactant: COc1cc2c(Nc3c(Cl)ccc4ccoc34)ncnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc2c(Nc3c(Cl)ccc4ccoc34)ncnc2cc1OCC1CCNCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.9 %

Procedure:
A mixture of 7-(N-tert-butoxycarbonylpiperidin-4-ylmethoxy)-4-(6-chlorobenzofuran-7-ylamino)-6-methoxyquinazoline (0.4 g), trifluoroacetic acid (3 ml) and methylene chloride (12 ml) was stirred at ambient temperature for 3 hours. The mixture was evaporated and the residue was diluted with water. The mixture was basified to pH11 by the addition of 1 N aqueous sodium hydroxide solution and methylene chloride was added. The precipitate which was formed was collected by filtration, washed with water and dried under vacuum to give the title compound (0.195 g); NMR Spectrum: (DMSOd6 and CF3CO2D) 1.55 (m, 2H), 2.0 (m, 2H), 2.25 (m, 1H), 2.95 (m, 2H), 3.4 (m, 2H), 4.05 (s, 3H), 4.2 (d, 2H), 7.1 (d, 1H), 7.4 (s, 1H), 7.55 (d, 1H), 7.8 (d, 1H), 8.05 (d, 1H), 8.2 (s, 1H), 8.85 (s, 1H), Mass Spectrum: M−H− 437.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:9])[CH2:6][CH2:7][NH2:8])[CH3:3].[C:10]([O:14][C:15]([NH:17][CH2:18][C:19](O)=[O:20])=[O:16])([CH3:13])([CH3:12])[CH3:11].C1CCC(N=C=NC2CCCCC2)CC1.CN1CCOCC1>ClCCl>[C:10]([O:14][C:15]([NH:17][CH2:18][C:19]([NH:8][CH2:7][CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:9])=[O:20])=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CCOC(=O)CCN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCOC(=O)CCNC(=O)CNC(=O)OC(C)(C)C
Yield: 62 %

Procedure:
A solution of β-alanine ethyl ester hydrochloride salt (5) (3.07 g; 0.02 mmol), N-(tertbutoxycarbonyl)glycine (3.5 g; 0.02 mmol), DCCI (4.12 g; 0.02 mmol) and 4-methylmorpholine (2.2 ml) in dichloromethane (60 ml) was stirred overnight under argon atmosphere at ambient temperature. After filtration the residue was purified by flash chromatography eluting with dichloromethane/ethanol (96/4) to give ethyl 3-[(2-tertbutoxycarbonylaminoacetyl)amino]propanoate (6).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][Cl:19])=[CH:11][CH:10]=1)=O)C.O.[NH2:22][NH2:23]>C(O)(C)C>[Cl:19][CH2:18][CH2:17][CH2:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]2[CH2:6][CH2:5][C:4](=[O:3])[NH:22][N:23]=2)=[CH:10][CH:11]=1
Reactant: NN
Reactant: CCOC(=O)CCC(=O)c1ccc(OCCCCl)cc1
Solvent: O
Solvent: CC(C)O
Product: O=C1CCC(c2ccc(OCCCCl)cc2)=NN1

Procedure:
In a 500 mL round bottom flask, 4-[4-(3-chloro-propoxy)-phenyl]-4-oxo-butyric acid ethyl ester (7.85 g, 26.3 mmol), and hydrazine monohydrate (2.55 mL, 52.7 mmol), in isopropanol (200 mL) was heated to reflux 14 h. The reaction was cooled and the solvent concentrated under vacuum. Purification with silica gel chromatography eluting with methylene chloride/methanol (95:5) produced 5.2 g (74%). MS m/z 267 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)=[CH:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]([O:14][CH3:15])[CH:7]=1.[H-].[Na+].F[C:27]1[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[CH:29][CH:28]=1>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:23])[C:4]([C:16]1[CH:17]=[CH:18][C:19]([O:22][C:27]2[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[CH:29][CH:28]=2)=[CH:20][CH:21]=1)=[CH:5][C:6]1[CH:7]=[C:8]([O:14][CH3:15])[CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: COC(=O)C(=Cc1cc(OC)cc(OC)c1)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C(=Cc1cc(OC)cc(OC)c1)c1ccc(Oc2ccc(C=O)cc2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 77.6 %

Procedure:
Under argon, 8 (433.0 g, 1.37 mol) was dissolved in dry DMF (1.6 L) and to this sodium hydride (60.4 g, 1.51 mol) was added. To the resulting orange solution 4-fluorobenzaldehyde (185.0 mL, 1.71 mol) was added and heated at 80° C. for 18 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (3.0 L) and extracted with water (3×1.0 L), then brine (1×1.0 L). The organic layer was dried over anhydrous sodium sulfate, filtered and solvent was evaporated. The residue was suspended in methanol (3.0 L) and stirred overnight. Solid was filtered and dried under vacuum at 40° C. to yield 9 as pale yellow, solid (445 g, 77%): mp 108-110° C. 1HNMR (360 MHz, CDCl3) δ 9.94 (s, 1H), 7.86 (d, J=8.6 Hz, 2H), 7.80 (s, 1H), 7.28 (d, J=8.6 Hz, 2H), 7.11 (overlapped d, J=9.0 Hz, 2H), 7.08 (overlapped d, J=9.0 Hz, 2H), 6.36 (t, J=2.2 Hz, 1H), 6.25 (d, J=2.2 Hz, 2H), 3.83 (s, 3H), 3.63 (s, 6H); Anal. (C25H22O6) C, H.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([F:21])[CH:15]=3)[C:9]([C:11]([OH:13])=O)=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.[F:22][C:23]([F:27])([F:26])[CH2:24][NH2:25].N1C2C=CC=C(O[P+](N(C)C)(N(C)C)N(C)C)C=2N=N1.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[NH2:1][C:2]1[C:7]2=[C:8]([C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([F:21])[CH:15]=3)[C:9]([C:11]([NH:25][CH2:24][C:23]([F:27])([F:26])[F:22])=[O:13])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1
Reactant: Nc1ccc(-c2c(C(=O)O)cn3ncnc(N)c23)cc1F
Reactant: NCC(F)(F)F
Agent: CN(C)[P+](Oc1cccc2[nH]nnc12)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Nc1ccc(-c2c(C(=O)NCC(F)(F)F)cn3ncnc(N)c23)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.8 %

Procedure:
4-amino-5-(4-amino-3-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid (24.6 g, 85.6 mmol) was added to a mixture of 2,2,2-trifluoro-1-aminoethane (42.4 g, 428 mmol), benzotriazolyloxytris(dimethylamino)phosphonium PF6 (56.8 g, 128 mmol) and 4-methylmorpholine (43.3 g, 428 mmol) in DMF (500 mL). The reaction mixture was stirred at rt for 16 h. The resulting precipitate was isolated by filtration and then washed with acetone and diethyl ether to give the desired product (22 g, 70%); 1H NMR (300 MHz, DMSO-d6) δ 8.37 (dd, J=8.5, 8.5 Hz, 1H), 8.12 (s, 1H), 7.94 (s, 1H), 7.92-8.03 (br s, 1H), 7.89 (s, 1H), 6.99 (dd, J=12.2, 1.8 Hz, 1H), 6.85 (dd, J=12.2, 1.8 Hz, 1H), 6.74-6.6.82 (m, 1H), 5.35 (s, 2H), 5.13-3.22 (br s, 1H), 3.87-4.01 (m, 2H); ES-MS m/z 369.2 (MH)+; HPLC RT (Method B) 2.05 min.
Reaction SMILES: [CH3:1][C:2]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])[CH3:3].[CH3:9][C:10]1[N:11]=[CH:12][N:13]([C@@H:15]([CH3:18])[CH2:16][OH:17])[CH:14]=1>C(Cl)Cl>[Si:5]([O:17][CH2:16][C@@H:15]([N:13]1[CH:14]=[C:10]([CH3:9])[N:11]=[CH:12]1)[CH3:18])([C:2]([CH3:4])([CH3:3])[CH3:1])([CH3:7])[CH3:6]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1cn([C@@H](C)CO)cn1
Solvent: ClCCl
Product: Cc1cn([C@@H](C)CO[Si](C)(C)C(C)(C)C)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 2.6 %

Procedure:
In a 500-mL round-bottom flask, (S)-2-(4-methyl-1H-imidazol-1-yl)propan-1-ol (12.0 g) and TEA (12 mL) were dissolved in DCM at room temperature. To this solution, TBSCl (21.3 g, 0.141 mol) was added, and the resulting mixture was stirred at room temperature overnight. The mixture was washed with H2O, the organic phase was separated, and the aqueous was extracted with DCM. The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified on a silica gel column eluted with 1/30-1/9 MeOH/DCM, affording a sample (1.20 g), which was further purified by prep-HPLC, to afford the title compound (0.557 g). 1H NMR (CDCl3): δ 7.41 (d, 1H), 6.67-6.65 (m, 1H), 4.16-4.10 (m, 1H), 3.73-3.62 (m, 2H), 2.20 (d, 3H), 1.44 (d, 3H), 0.86 (s, 9H), −0.04 (s, 6H); LCMS: 255 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[C:15]([OH:17])[CH:14]=[C:13]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][OH:27])=[CH:20][CH:19]=3)[CH:12]=2)=[CH:7][CH:6]=1.[C:28]([OH:33])(=O)[C:29]([CH3:31])=[CH2:30]>>[CH3:30][C:29](=[CH2:31])[C:28]([O:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[C:15]([O:17][C:28](=[O:33])[C:29]([CH3:31])=[CH2:30])[CH:14]=[C:13]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][O:27][C:28](=[O:33])[C:29]([CH3:31])=[CH2:30])=[CH:20][CH:19]=3)[CH:12]=2)=[CH:9][CH:10]=1)=[O:33]
Reactant: OCCCc1ccc(-c2cc(O)cc(-c3ccc(CCCO)cc3)c2)cc1
Reactant: C=C(C)C(=O)O
Product: C=C(C)C(=O)OCCCc1ccc(-c2cc(OC(=O)C(=C)C)cc(-c3ccc(CCCOC(=O)C(=C)C)cc3)c2)cc1

Procedure:
In analogy to step 2 of example 1, 4,4″-bis-(3-hydroxy-propyl)-[1,1′;3′,1″]terphenyl-5′-ol and methacrylic acid are reacted to give 2-methyl-acrylic acid-4,4″-bis-[3-(2-methyl-acryloyloxy)-propyl]-[1,1′;3′,1″]terphenyl-5′-yl ester as colourless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:23])[CH2:11][N:10]([C:12]3[NH:13][C:14](=[O:22])[C:15]4[CH:20]=[CH:19][N:18]([CH3:21])[C:16]=4[N:17]=3)[CH2:9]2)=[CH:4][CH:3]=1.[H][H]>C(OCC)(=O)C.CO.[Pd]>[CH3:21][N:18]1[C:16]2[N:17]=[C:12]([N:10]3[CH2:9][C:8]([CH3:23])([C:5]4[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=4)[CH2:11]3)[NH:13][C:14](=[O:22])[C:15]=2[CH:20]=[CH:19]1
Reactant: [H][H]
Reactant: Cn1ccc2c(=O)[nH]c(N3CC(C)(c4ccc(Br)cc4)C3)nc21
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cn1ccc2c(=O)[nH]c(N3CC(C)(c4ccccc4)C3)nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.6 %

Procedure:
A mixture of 2-(3-(4-bromophenyl)-3-methylazetidin-1-yl)-7-methyl-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one (100.3 mg, 269 μmol) in ethyl acetate (2.7 mL) and methanol (2.8 mL) was treated with 10% palladium on carbon (9.2 mg, ˜10% weight of starting material used). The flask was capped with a rubber septum and a hydrogen balloon was attached. The reaction was stirred at room temperature overnight. At this time, the reaction was concentrated in vacuo onto Celite®. Flash chromatography (24 g silica gel column, 20-100% ethyl acetate/hexanes) afforded 7-methyl-2-(3-methyl-3-phenyl-azetidin-1-yl)-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one as an off-white solid (43.2 mg, 54.6%). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.61 (s, 3H) 3.53 (s, 3H) 4.10 (d, J=8.67 Hz, 2H) 4.24 (d, J=8.29 Hz, 2H) 6.23 (d, J=3.01 Hz, 1H) 6.73 (d, J=3.20 Hz, 1H) 7.13-7.50 (m, 5H) 10.90 (s, 1H). LC-MS calcd. for C17H19N4O [(M+H)+] 295, obsd. 295.1.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:14]=1[OH:15])[CH2:8][CH:9]1[CH2:11][O:10]1)([CH3:4])([CH3:3])[CH3:2].[CH3:20][C:21]1([CH3:28])[NH:25][C:24](=[O:26])[NH:23][C:22]1=[O:27]>[Cl-].[Li+]>[OH:10][CH:9]([CH2:8][C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:14]([OH:15])=[C:13]([C:16]([CH3:19])([CH3:17])[CH3:18])[CH:12]=1)[CH2:11][N:23]1[C:22](=[O:27])[C:21]([CH3:28])([CH3:20])[NH:25][C:24]1=[O:26]
Reactant: CC1(C)NC(=O)NC1=O
Reactant: CC(C)(C)c1cc(CC2CO2)cc(C(C)(C)C)c1O
Agent: [Cl-]
Agent: [Li+]
Product: CC1(C)NC(=O)N(CC(O)Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Reaction time: 1 h
Yield: 79.4 %

Procedure:
25 mg of lithium chloride are added to 5.25 g (0.02 mol) of 3,5-di-tert.-butyl-4-hydroxybenzyl-oxirane and 2.56 g (0.02 mol) of 5,5-dimethylhydantoin and the mixture is kept at a melt at 220°-230° C for 60 minutes whilst stirring in a nitrogen atmosphere. After cooling, a glassy residue is obtained, which when recrystallised from toluene/isopropanol gives 6.2 g (78% of theory) of 3-[2-hydroxy-3-(3,5-di-tert.-butyl-4-hydroxyphenyl)-propyl]-5,5-dimethylhydantoin of melting point 175°-76° C in the form of colourless crystals.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH2:11][CH2:12][Cl:13].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC.O>[Cl:13][CH2:12][CH2:11][CH2:10][O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1
Reactant: Oc1ccc(I)cc1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: ClCCCOc1ccc(I)cc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 105.4 %

Procedure:
To a solution of 4-iodophenol (20.0 g) and 1-bromo-3-chloropropane (18.6 g) in 2-butanone (200 mL), potassium carbonate (25.1 g) was added and stirred at 100° C. for 5 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure to give the titled compound (28.4 g) as an orange-colored oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:11])=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.Br[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.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>[Br:1][C:2]1[C:3]([CH3:11])=[C:4]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Brc1cccnc1
Reactant: Cc1c(Br)cccc1B(O)O
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: [Na+]
Solvent: Cc1ccccc1
Product: Cc1c(Br)cccc1-c1cccnc1
Temperature: 110 °C

Procedure:
(3-Bromo-2-methylphenyl)boronic acid (3 g, 13.96 mmol) and 3-bromopyridine (2.69 ml, 27.92 mmol) in toluene (24 ml) were stirred under argon, then Na2CO3 (5.18 g, 48.86 mmol) and Pd(PPh3)4 (161 mg, 0.14 mmol) were added and the reaction was heated to 110° C. for 48 h. The solvent was evaporated and after addition of ethyl acetate the organic layer was filtered through Celite, then washed with water and dried with Na2SO4, evaporated to dryness and the product was obtained and used without further purification in step 22.2. Yield: 3.01 g, 87
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH3:10])[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[C:23](O)(=[O:26])[CH2:24][OH:25].N1C=CN=C1>O1CCCC1.C(N(CC)CC)C>[C:1]([S:4][CH2:5][CH:6]([CH3:10])[C:7]([O:9][C:24](=[O:25])[CH2:23][OH:26])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)SCC(C)C(=O)O
Reactant: O=C(O)CO
Agent: O=C(n1ccnc1)n1ccnc1
Agent: c1c[nH]cn1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)SCC(C)C(=O)OC(=O)CO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-Acetylthio-2-methylpropanoic acid (6.48 g) is taken into 40 ml of dry tetrahydrofuran. To this 1,1'-carbonyldiimidazole (0.48 g) is added and stirred for 30 minutes at room temperature. Glycolic acid (6.08 g) and 11.2 ml of triethylamine in 60 ml of dry tetrahydrofuran are added. After several minutes, the imidazole salt of glycolic acid begins to come out of solution. The reaction is permitted to run overnight at room temperature. The crystalline salt is filtered and the filtrate concentrated to dryness in vacuo. The residue is taken up into ethyl acetate, washed with 1N hydrochloric acid and three times with water, dried over magnesium sulfate and concentrated to dryness in vacuo. This product is converted to its dicyclohexylamine salt by dissolving in ether/hexane and precipitating by the addition of dicyclohexylamine. The salt is recrystallized from ether, m.p. 120°-122°. This salt is then converted to the free acid, O-[3-(acetylthio)-2-methylpropanoyl]glycolic acid by adding to ethyl acetate, adding 10% potassium bisulfate solution, then crystallizing from ethyl/hexane, yield 2.96 g., m.p. 50°-51°.
Reaction SMILES: [CH2:1]([O:3][N:4]=[C:5]([C:11]1[N:12]=[C:13]([OH:16])[S:14][CH:15]=1)[C:6]([O:8]CC)=[O:7])[CH3:2].C(O)C.[OH-].[K+].Cl>O>[CH2:1]([O:3][N:4]=[C:5]([C:11]1[N:12]=[C:13]([OH:16])[S:14][CH:15]=1)[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCON=C(C(=O)OCC)c1csc(O)n1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCON=C(C(=O)O)c1csc(O)n1

Procedure:
To a solution of 10 g. of ethyl α-ethoxyimino-(2-hydroxythiazol-4-yl)acetate in 30 ml. of ethanol is added a solution of 11.47 g. of KOH in 50 ml. of water at room temperature and the mixture is stirred for 25 minutes. The reaction mixture is condensed under reduced pressure and is made acidic with 10% aq. HCl. Ethyl acetate extract of the reaction mixture is extracted with 10% aq.NaHCO3. The aqueous layer is then made acidic with 10% aq.HCl and extracted again with ethyl acetate. From the ethyl acetate extract, after being washed, dried and condensed is obtained a crystalline substance. Recrystallization from benzene-ethanol gives α-ethoxyimino-(2-hydroxythiazol-4-yl)acetic acid. 7.5 g. Melting point: 131.5° C. (dec.).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH:9]=[CH:10][CH:11]=[C:12]2[CH2:17][OH:18].O1C[CH2:22][CH2:21][CH2:20]1.[H-].[Na+].C(Br)C=C>O>[CH2:22]([O:18][CH2:17][C:12]1[C:13]2[C:8](=[C:7]([C:2]3[N:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH:16]=[CH:15][CH:14]=2)[CH:9]=[CH:10][CH:11]=1)[CH:21]=[CH2:20]
Reactant: C1CCOC1
Reactant: OCc1cccc2c(-c3ncccn3)cccc12
Agent: [H-]
Agent: [Na+]
Solvent: C=CCBr
Solvent: O
Product: C=CCOCc1cccc2c(-c3ncccn3)cccc12
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a 250 ml single neck round bottom flask equipped with a reflux condensor and an argon inlet is added 2.35 gm of the 5-pyrimidyl-1-naphthylcarbinol and 100 ml of anhydrous tetrahydrofuran. The system is cooled to 0° C. and after cooling 0.26 gm sodium hydride is added. The system is stirred for an additional 20 minutes and 1.1 ml of allyl bromide is added. The system is allowed to come to room temperature over 1/2-hour and is stirred there for an additional 2 hours. Afterwards, the system is heated at reflux for 17 hours. At this time, water is added to the system and the product extracted with methylene chloride. The methylene chloride is then washed with water and dried over sodium sulfate. The methylene chloride is removed by stripping to give the 5-pyrimidyl-1-naphthylcarbinol allylether.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[S:10][CH:9]=[C:8]([C:11]([OH:13])=O)[CH:7]=2)[CH:3]=[N:2]1.[NH:14]1[CH2:18][CH2:17][CH2:16][CH:15]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1.C(#N)C>S(Cl)(Cl)=O>[NH:2]1[CH:3]=[C:4]([C:6]2[S:10][CH:9]=[C:8]([C:11]([N:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)=[O:13])[CH:7]=2)[CH:5]=[N:1]1
Reactant: c1ccc(C2CCCN2)nc1
Reactant: O=C(O)c1csc(-c2cn[nH]c2)c1
Solvent: CC#N
Solvent: O=S(Cl)Cl
Product: O=C(c1csc(-c2cn[nH]c2)c1)N1CCCC1c1ccccn1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 19.8 %

Procedure:
5-(1H-Pyrazol-4-yl)-thiophene-3-carboxylic acid (0.075 g, 0.39 mmol) was suspended in thionyl chloride (1 mL) and the mixture heated at 60° C. for 1 hour. The mixture was cooled and concentrated by evaporation, azeotroping with toluene (×3). 2-Pyrrolidin-2-yl-pyridine (0.173 g, 1.17 mmol) and acetonitrile (1.5 mL) were added and the reaction mixture stirred for 30 minutes and then the solvent was removed by evaporation. The crude material was purified by HPLC, eluting with 5%-95% acetonitrile in water (0.1% formic acid) over 20 minutes. The fractions containing the desired product were evaporated, azeotroping with methanol (×3), to give the title compound as a foam (0.025 g). LCMS m/z 325.18 [M+H]+ R.T.=5.07 min (Analytical Method 2).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH:12](NC(C)C)(C)[CH3:13].[Li]CCCC.BrCCBr>O1CCCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3([CH2:13][CH2:12]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: CC(C)NC(C)C
Reactant: O=C1Cc2ccc(Br)cc2N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: BrCCBr
Product: O=C1Nc2cc(Br)ccc2C12CC2
Temperature: 0 °C
Reaction time: 20 h

Procedure:
A solution of 6-bromoindolin-2-one (2 g, 9.43 mmol) and diisopropylamine (2.00 g, 2.82 ml, 19.8 mmol) in tetrahydrofuran (16 ml) was cooled to −25° C. and a solution of nBuLi (1.6 M in hexane, 23.6 ml, 37.7 mmol) was added dropwise. The reaction mixture was warmed to 0° C. and a solution of 1,2-dibromoethane (5.32 g, 2.44 ml, 28.3 mmol) in tetrahydrofuran (2 ml) was added dropwise. The reaction mixture was warmed to room temperature, stirred for 20 hours and carefully quenched with brine (2 ml) and conc. HCl (2 ml, ice bath). The reaction mixture was diluted with tert-butyl methyl ether and water. The aqueous phase was extracted with tert-butyl methyl ether, the combined organic phases were washed with brine and dried over sodium sulfate. The solvent was evaporated and the residue purified by silica gel chromatography using ethyl acetate/heptane as eluent. The title compound was obtained as red crystals (1.11 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]3[CH:14]=[CH:13][C:12](Br)=[CH:11][C:9]=3[S:10][C:6]=2[C:5]([C:16]([NH2:18])=[O:17])=[CH:4][N:3]=1.B(O)(O)[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[NH2:1][C:2]1[C:7]2[C:8]3[CH:14]=[CH:13][C:12]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=4)=[CH:11][C:9]=3[S:10][C:6]=2[C:5]([C:16]([NH2:18])=[O:17])=[CH:4][N:3]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: NC(=O)c1cnc(N)c2c1sc1cc(Br)ccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC(=O)c1cnc(N)c2c1sc1cc(-c3cccc(C(F)(F)F)c3)ccc12
Temperature: 120 °C

Procedure:
A mixture of 1-amino7-bromo[1]benzothieno[3,2-c]pyridine-4-carboxamide (Example 12, Step 10), 3-trifluoromethylboronic acid (1.5 equiv), PdCl2dppf (0.1 equiv), Na2CO3 1 M (3.0 equiv) in DMF (0.15 M) was heated in the microwave reactor at 120° C. for 10 min. The reaction mixture was partitioned between EtOAc and H2O with the addition of DMSO. The organic phase was separated, dried over Na2SO4, filtered, evaporated and purified by flash chromatography (10% MeOH in CH2Cl2) to provide the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]([O:11][CH3:12])=[O:10])=[C:4]([NH:13][C:14]2[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=2)[N:3]=1.[CH2:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:22]#[CH:23].C(N(CC)CC)C>CC(N(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.[Cu]I>[C:27]([O:26][C:25]([NH:24][CH2:21][C:22]#[C:23][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]([O:11][CH3:12])=[O:10])=[C:4]([NH:13][C:14]2[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=2)[N:3]=1)=[O:31])([CH3:30])([CH3:29])[CH3:28]
Reactant: C#CCNC(=O)OC(C)(C)C
Reactant: COC(=O)c1c(C)nc(Cl)nc1Nc1cccc(C)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: COC(=O)c1c(C)nc(C#CCNC(=O)OC(C)(C)C)nc1Nc1cccc(C)c1
Temperature: 90 °C
Yield: 33.8 %

Procedure:
Methyl 2-chloro-4-methyl-6-(m-tolylamino)pyrimidine-5-carboxylate (0.4 g, 1.371 mmol), tert-butyl prop-2-ynylcarbamate (0.426 g, 2.74 mmol), tetrakis(triphenylphosphine)palladium (0.032 g, 0.027 mmol), and copper (I) iodide (0.026 g, 0.137 mmol) was dispersed in DMA (5 mL). Triethylamine (0.382 mL, 2.74 mmol) was added and the mixture was degassed with nitrogen for 5 min. The reaction mixture was placed in a sealed tube and heated at 90° C. for 4 h, after which it was filtered through a pad of Celite, which was rinsed with MeOH. The filtrate was purified via reverse phase preparative HPLC and the fractions were concentrated in vacuo to give the title compound as a brown oil (0.190 g, 34%). [M+H] calc'd for C22H26N4O4, 411. found, 411.