Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:13]1([C:19]#[C:20][C:21]2[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH:29](=O)[CH2:30][CH3:31]>>[F:12][C:5]1[CH:4]=[CH:3][C:2]([N:1]([CH2:25][C:24]2[CH:27]=[CH:28][C:21]([C:20]#[C:19][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:22][CH:23]=2)[CH2:29][CH2:30][CH3:31])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(N)ccc1F
Reactant: O=Cc1ccc(C#Cc2ccccc2)cc1
Reactant: CCC=O
Product: CCCN(Cc1ccc(C#Cc2ccccc2)cc1)c1ccc(F)c(C(=O)OC)c1

Procedure:
The title compound was prepared following the procedure described in Example 44 step a) using methyl 5-amino-2-fluorobenzoate (500 mg, 2.96 mmol), 4-(phenylethynyl)benzaldehyde (610 mg, 2.96 mmol) and propanal (Aldrich, 540 μL, 7.39 mmol). The title compound was obtained as a sticky colorless oil (628 mg, 53%). HPLC, Rt: 5.4 min (purity: 99.1%). LC/MS, M+(ESI): 402.2. 1H NMR (CDCl3) δ: 7.51-7.44 (m, 4H), 7.32 (m, 3H), 7.17 (m, 3H), 6.92 (dd, J=9.8, 9.6 Hz, 1H), 6.74 (m, 1H), 4.50 (s, 2H), 3.88 (s, 3H), 3.33 (t, J=7.3 Hz, 2H), 1.65 (m, 2H), 0.92 (t, J=7.5 Hz, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([CH3:11])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.Cl[C:19]([O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[O:20].O>O1CCCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:19](=[O:20])[O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])[N:7]([CH3:11])[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Cn1nc(C(C)(C)C)cc1N
Solvent: C1CCOC1
Solvent: O
Solvent: c1ccncc1
Product: Cn1nc(C(C)(C)C)cc1NC(=O)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.3 %

Procedure:
To a solution of 3-tert-butyl-1-methyl-1H-pyrazole-5-amine (500 g, 3.26 mmol) and pyridine (0.310 ml, 3.92 mmol) in tetrahydrofuran (11 ml) was added 2,2,2-trichloroethyl chloroformate (0.542 ml, 3.92 mmol) with ice-cooling, and the mixture was stirred at room temperature for 2 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give 925 mg (86.5%) of the desired product as an oil.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2([CH2:23][CH2:24][CH2:25][CH2:26]Br)[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])=[CH:4][CH:3]=1.[Cl:30][C:31]1[CH:40]=[CH:39][CH:38]=[C:37]2[C:32]=1[CH:33]=[CH:34][C:35]([N:41]1[CH2:46][C@H:45]([CH3:47])[NH:44][C@H:43]([CH3:48])[CH2:42]1)=[N:36]2>>[F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2([CH2:23][CH2:24][CH2:25][CH2:26][N:44]3[C@H:45]([CH3:47])[CH2:46][N:41]([C:35]4[CH:34]=[CH:33][C:32]5[C:37](=[CH:38][CH:39]=[CH:40][C:31]=5[Cl:30])[N:36]=4)[CH2:42][C@@H:43]3[CH3:48])[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(F)cc1)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: C[C@@H]1CN(c2ccc3c(Cl)cccc3n2)C[C@H](C)N1
Product: C[C@@H]1CN(c2ccc3c(Cl)cccc3n2)C[C@H](C)N1CCCCC1(C(=O)NCc2ccc(F)cc2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-4-fluoro-benzylamide and 5-chloro-2-(cis-3,5-dimethyl-piperazin-1-yl)-quinoline.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[NH2:26][C@H:27]1[CH2:31][NH:30][CH2:29][C@H:28]1[OH:32]>C(O)CCC>[NH2:26][C@H:27]1[CH2:31][N:30]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=[C:4]([N:13]3[CH2:19][C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]3)[CH:3]=2)[CH2:29][C@H:28]1[OH:32]
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: N[C@H]1CNC[C@H]1O
Solvent: CCCCO
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N3C[C@@H](O)[C@@H](N)C3)c2c1
Temperature: 180 °C

Procedure:
A mixture of 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (740 mg, 2.0 mmol, prepared in analogy to the one in Example 2-1) and cis-4-aminopyrrolidin-3-ol (600 mg, 6.0 mmol) in n-butanol (0.2 mL) was heated at 180° C. for 3 days. After being cooled to room temperature, the mixture was purified by preparative HPLC to afford the product as a solid. MS obsd. (ESI+) [(M+H)+] 439, 1H NMR (400 MHz, CD3OD) δ ppm 8.12 (dd, J=7.83, 1.26 Hz, 1 H), 8.02 (s, 1 H), 7.87 (d, J=7.07 Hz, 1 H), 7.82-7.71 (m, 2 H), 7.67-7.57 (m, 2 H), 5.93 (s, 1 H), 5.33 (s, 2 H), 4.66 (d, J=2.02 Hz, 1 H), 4.56 (brs, 2 H), 4.28-4.17 (m, 2 H), 4.13-3.99 (m, 2 H), 3.91 (s, 1 H), 3.76 (brs, 2 H), 3.37 (s, 3 H), 2.50 (s, 3 H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][C:13]1[CH:14]=[C:15]([N+:19]([O-])=O)[CH:16]=[CH:17][CH:18]=1.C(Cl)[Cl:23]>O.C(O)(=O)C.[Fe]>[ClH:23].[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=1)[NH2:19]
Reactant: O=[N+]([O-])c1cccc(COc2ccc3ccccc3c2)c1
Reactant: ClCCl
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: Cl
Product: Nc1cccc(COc2ccc3ccccc3c2)c1
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere, a stirred mixture of 4.5 grams (0.016 mole) 3-(naphth-2-yloxymethyl)nitrobenzene and 4.5 grams (0.081 mole) of iron powder in 10 mL of water and 50 mL of acetic acid was heated at reflux for about six hours. After this time the reaction mixture was cooled to ambient temperature, and 100 mL of methylene chloride was added. The mixture was filtered, and an additional 100 mL of methylene chloride was added to the filtrate. The methylene chloride layer was separated and washed with four portions of an aqueous solution saturated with sodium bicarbonate and then with two portions of an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to a residue. The residue was then dissolved in diethyl ether and treated with an excess of an ethereal solution of hydrogen chloride. The resultant precipitate was collected by filtration and recrystallized from ethyl acetate and diethyl ether, yielding 3.1 grams of 3-(naphth-2-yloxymethyl)aniline hydrochloride. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH:4]([CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)[NH:5]COC([Si](C)(C)C)C.[C:25](OCC)(=[O:27])C>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3](=[O:24])[C:4]([CH2:25][OH:27])([CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)[NH2:5]
Reactant: CCOC(C)=O
Reactant: COC(=O)C(Cc1c[nH]c2ccccc12)NCOC(C)[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C(N)(CO)Cc1c[nH]c2ccccc12

Procedure:
α-Trimethylsilylethoxymethyl-DL-tryptophan methyl ester (1.0 g, 2.8 mmol) was stirred for 48 hours at room temperature in trifluoroacetic acid (10 mL). After evaporation of the acid in vacuo, the oily residue was treated with aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried over Na2SO4 and evaporated to give an oil. Trituration with ethyl acetate gave 0.45 g (655) of α-hydroxymethyl-DL-tryptophan methyl ester, mp 148°-149° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:7]2[CH:8]=[C:9]([C:12]3[NH:16][C:15]([C:17]#[N:18])=[CH:14][CH:13]=3)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:19])[O:3]1.[CH2:21](Br)[C:22]#[CH:23]>>[CH3:1][C:2]1([CH3:20])[C:7]2[CH:8]=[C:9]([C:12]3[N:16]([CH2:23][C:22]#[CH:21])[C:15]([C:17]#[N:18])=[CH:14][CH:13]=3)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:19])[O:3]1
Reactant: C#CCBr
Reactant: CC1(C)OC(=O)Nc2ccc(-c3ccc(C#N)[nH]3)cc21
Product: C#CCn1c(C#N)ccc1-c1ccc2c(c1)C(C)(C)OC(=O)N2

Procedure:
5-(4,4-Dimethyl-2-oxo-1,4,dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrol-2-carbonitrile (0.74 g, 2.8 mmol) and propargylbromide (0.5 g, 4.2 mmol) were reacted, according to General Method A, to afford the title compound, m.p. 222–224° C. (0.13 g, 15%). 1H-NMR (DMSO-d6) δ 1.65 (s, 6H), 3.64 (t, J=2.3 Hz, 1H), 4.85 (d, J=2.3 Hz, 2H), 6.37 (d, J=4 Hz, 1H), 7.01 (d, J=8.2 Hz, 1H), 7.11 (d, J=4 Hz, 1H), 7.43 (m, 2H), 10.45 (s, 1H), MS (APCI (−)) m/z 304 (M−H)−
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[OH-:13].[Na+].Cl.[NH2:16][CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=1)=O>O.C(O)C>[NH2:16][C:17]1[C:18]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:22][CH:21]=2)=[N:7][C:8]2[C:4]([C:5]=1[C:6]([OH:11])=[O:13])=[CH:3][C:2]([F:1])=[CH:10][CH:9]=2
Reactant: O=C1Nc2ccc(F)cc2C1=O
Reactant: NCC(=O)c1ccc(C(F)(F)F)cc1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1c(-c2ccc(C(F)(F)F)cc2)nc2ccc(F)cc2c1C(=O)O
Yield: 68.9 %

Procedure:
To a stirred suspension of 4.13 g of 5-fluoroisatin in 36 ml of water was added a solution of 5.62 g of sodium hydroxide in 20 ml of water. The stirred solution was heated to 80°-90° C. and a solution of 8.42 g of 2-amino-1-[4-(trifluoromethyl)phenyl]ethanone, hydrochloride in 61 ml of ethanol and 61 ml of water was added dropwise over 1.5 hours. When addition was complete, the mixture was refluxed for 20 minutes, then the ethanol was distilled off. The mixture was cooled in an ice bath, then filtered through celite. The filtrate was acidified to pH 4 with acetic acid, the solid collected, washed with water and recrystallized from acetonitrile, giving 6.04 g of the desired product as a yellow solid, mp 260°-262° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:6](=[O:13])[NH:5][C:4](=[O:14])[CH:3]=1.C(O)(=O)C.[N:19]([O-])=[O:20].[Na+]>O>[NH2:1][C:2]1[N:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:6](=[O:13])[NH:5][C:4](=[O:14])[C:3]=1[N:19]=[O:20]
Reactant: CCCCCn1c(N)cc(=O)[nH]c1=O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCCCCn1c(N)c(N=O)c(=O)[nH]c1=O
Reaction time: 2 h

Procedure:
To a stirring mixture of 6-amino-1-pentylpyrimidine-2,4(1H,3H)-dione (4.0 g, 0.020 mol) and acetic acid (20 mL, 0.4 mol) in water (20 mL) was slowly added sodium nitrite (1.5 g, 0.022 mol). Stirring was continued at room temperature for 2 h at which time the reaction mixture became pink and precipitate formed. The reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in aqueous NaOH solution and extracted with methylene chloride to remove byproducts. The aqueous solution was neutralized with HCl and concentrated. The residue was treated with methanol and filtered. The filtrate was concentrated to give the desired product as pink solid. LCMS calculated for C9H15N4O3 (M+H): 227.1; found: 227.1 (M+H), 249.1 (M+Na).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:22])[C:8]=2[NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[N:3]=1.[CH3:23][NH:24][CH2:25][CH2:26][CH2:27][NH:28][CH3:29]>>[ClH:1].[ClH:1].[Cl:22][C:7]1[C:8]([NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:24]([CH3:23])[CH2:25][CH2:26][CH2:27][NH:28][CH3:29])[CH:11]=[CH:10]2
Reactant: CNCCCNC
Reactant: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(Cl)ccc12
Product: CNCCCN(C)c1ccc2c(NC(=O)CC3CCCCC3)c(Cl)ccc2n1
Product: Cl
Yield: 79.4 %

Procedure:
Prepared according to the method of example 2, using N-(2,6-dichloro-5-quinolinyl)-cyclohexaneacetamide (Example 1 (a)) (100 mg) and N,N′-dimethyl-1,3-propanediamine (300 mg). Further purification by HPLC (Symmetry—0.1% aqueous trifluoroacetic acid/acetonitrile) followed by conversion to its hydrochloride salt as described in example 2, afforded the title compound as a solid (56 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[CH:4][N:3]=1.[C-:10]#[N:11].[Na+]>CCO>[Br:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][C:10]#[N:11])=[CH:6][CH:7]=1
Reactant: BrCc1ccc(Br)nc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCO
Product: N#CCc1ccc(Br)nc1
Temperature: 25 °C
Yield: 61.1 %

Procedure:
A solution of 2-bromo-5-(bromomethyl)pyridine (example 40e) (6 g, 24 mmol) and NaCN (1.42 g, 29 mmol) in absolute EtOH (50 mL) was heated at 80° C. for 8 h. The mixture was then cooled to room temperature then evaporated. The residue was suspended in water and extracted with EtOAc. The organic phase was washed with brine, dried over MgSO4, filtered and evaporated. The residue was purified by chromatography on silica gel (5-30% EtOAc/hexanes) to give 2.89 g (63%) of 2-(6-Bromopyridin-3-yl)acetonitrile. 1H NMR (400 MHz, dMSO): δ 4.07 (s, 2H), 7.66-7.68 (d, 1H), 7.72-7.73 (dd, 1H), 8.36-8.37 (d, 1H).
Reaction SMILES: C(Cl)(=O)C.CC([Si](C1C=CC=CC=1)(C1C=CC=CC=1)[O:10][CH:11]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]([OH:51])[CH:29]1[O:33][CH:32]([CH:34]2[CH2:38][CH2:37][CH:36]([CH:39]([OH:50])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[O:35]2)[CH2:31][CH2:30]1)[CH2:12][C:13]1[C:14](=[O:19])[O:15][CH:16]([CH3:18])[CH:17]=1)(C)C.C(=O)(O)[O-].[Na+]>CO.C(OCC)C>[OH:10][CH:11]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]([OH:51])[CH:29]1[O:33][CH:32]([CH:34]2[CH2:38][CH2:37][CH:36]([CH:39]([OH:50])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[O:35]2)[CH2:31][CH2:30]1)[CH2:12][C:13]1[C:14](=[O:19])[O:15][CH:16]([CH3:18])[CH:17]=1
Reactant: CCCCCCCCCCC(O)C1CCC(C2CCC(C(O)CCCCCCCCC(CC3=CC(C)OC3=O)O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O2)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Solvent: CC(=O)Cl
Product: CCCCCCCCCCC(O)C1CCC(C2CCC(C(O)CCCCCCCCC(O)CC3=CC(C)OC3=O)O2)O1
Temperature: 25 °C
Reaction time: 24 h
Yield: 82 %

Procedure:
To a solution of acetyl chloride (20 μL) in 400 μL of methanol, a solution of 16a (6.8 mg, 8.2 μmol) in 400 μL of diethyl ether was added at room temperature. The solution was stirred at room temperature until TLC showed that no more starting material was left (about 24 h) . Solid sodium bicarbonate was slowly added until no more gas evolution was observed. The mixture was concentrated under reduced pressure. Diethyl ether (5 mL) was added, and the resulting solution was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. Purification by MPLC (1:3 hexane:ethyl actate) give 1a (4.0 mg, 82%) as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH2:13][C@@H:12]3[C@@H:9]([CH2:10][N:11]3C(OC(C)(C)C)=O)[CH2:8]2)[CH:2]=1.O.[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([OH:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1>C(O)C>[CH3:22][C:23]1[CH:24]=[CH:25][C:26]([S:29]([OH:32])(=[O:31])=[O:30])=[CH:27][CH:28]=1.[CH3:22][C:23]1[CH:24]=[CH:25][C:26]([S:29]([OH:32])(=[O:31])=[O:30])=[CH:27][CH:28]=1.[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH2:13][C@@H:12]3[C@@H:9]([CH2:10][NH:11]3)[CH2:8]2)[CH:2]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CN(c3cccnc3)C[C@H]21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Product: c1cncc(N2C[C@@H]3CN[C@@H]3C2)c1
Reaction time: 6 h
Yield: 74.8 %

Procedure:
The product of Example 38K (100 mg, 0.36 mmol) in ethanol (10 mL) was treated with 4-methylbenzenesulfonic acid monohydrate (144 mg, 0.76 mmol) at 80° C. and allowed to stir for 6 hours. The mixture was concentrated under reduced pressure and the residue was diluted with warm methyl tert-butyl ether (20 mL) and stirred at ambient temperature for 10 hours. The precipitate was isolated by filtration and dried under reduced pressure at 40-50° C. to provide the title compound (140 mg, 86% yield). 1H NMR (MeOH-d4, 300 MHz) δ2.40 (s, 6H), 3.28 (dd, J=10.9, 6.4 Hz, 1H), 3.40 (dd, J=12.9, 5.5 Hz, 1H), 3.60 (m, 1H), 3.78 (dd, J=11.1, 5.0 Hz, 1H), 4.04 (d, J=10.8 Hz, 1H), 4.28 (d, J=12.9 Hz, 1H), 4.30 (m, 1H), 5.14 (dd, J=7.1, 5.4 Hz, 1H), 7.24 (d, J=7.8 Hz, 4H), 7.68 (d, J=8.1 Hz, 4H), 7.88 (dd, J=8.8, 5.4 Hz, 1H), 8.02 (ddd, J=9.1, 2.7, 1.3 Hz, 1H), 8.20 (d, J=5.4 Hz, 1H), 8.34 (d, J=3.0 Hz, 1H); m/z 176 (M+H)+; Anal. calculated for C10H13N3.2.4 TsOH.H2O: C, 53.07; H, 5.68; N, 6.93. Found: C, 52.99; H, 5.23;
Reaction SMILES: S(O[CH2:6][CH:7]([O:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)[CH3:8])(=O)(=O)C.[NH2:24][C:25]([CH3:29])([CH3:28])[CH2:26][OH:27]>O>[ClH:23].[OH:27][CH2:26][C:25]([NH:24][CH2:6][CH:7]([O:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)=[CH:14][CH:15]=1)[CH3:8])([CH3:29])[CH3:28]
Reactant: CC(COS(C)(=O)=O)Oc1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: CC(C)(N)CO
Solvent: O
Product: CC(CNC(C)(C)CO)Oc1ccc(Oc2ccc(Cl)cc2)cc1
Product: Cl

Procedure:
A mixture of 13 g (0.0365 mol) of the mesylate of Example 34 and of 32.5 g (0.365 mol) of 2-amino-2-methyl-1-propanol is heated slowly to 170° C. The reaction mixture is allowed to return to ambient temperature and is taken up in water. The insoluble matter is extracted with diethyl ether and the organic phase obtained is washed with water and dried over dry sodium sulphate to give, after evaporation of the solvent, 12.7 g of a limpid pale yellow oil. After treating 12 g of this oil in a solution of hydrogen chloride in diethyl ether, and purifying the product by crystallisation from ethyl acetate, 11.2 g of a white powder which is soluble in water to the extent of 200 g/l are obtained.
Reaction SMILES: [CH2:1]([Li])CCC.[C:6]1([CH2:12][CH2:13][C:14](=O)[CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.CCCCCC>[C:6]1([CH2:12][CH2:13][C:14]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH2:1])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(CCc1ccccc1)CCc1ccccc1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=C(CCc1ccccc1)CCc1ccccc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 85.6 %

Procedure:
A suspension of 1.59 g (4.45 mmol) of methyltriphenylphosphonium bromide in 100 ml of tetrahydrofuran was cooled to -78° C., treated with 2.2 ml (4.5 mmol) of n-butyllithium, warmed to 0° C, was recooled to -78° C. The resulting solution was treated via cannula with a solution of 1.59 g (4.45 mmol) of 1,5diphenyl-3-pentanone in 20 ml of tetrahydrofuran. After being allowed to stir at ambient temperature for 2 h, the solution was diluted with hexane, washed sequentially with water and saturated brine, dried over MgSO4, and concentrated in vacuo. The mixture was purified by flash chromatography to give 0.90 g (86%) of the desired compound as a colorless oil. 1H NMR (CDCl3) δ 2.37 (t, J=8 Hz, 4H), 2.76 (t, J=8 Hz, 4H), 4.81 (s, 2H), 7.15-7.3 (m, 10H). Mass spectrum (M+NH4)+ =254.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH:4]([CH:5]=[C:6]([Cl:18])[C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=2)[CH:3]1[C:19](O)=[O:20].S(Cl)([Cl:25])=O>C(Cl)(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:22])[CH:4]([CH:5]=[C:6]([Cl:18])[C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=2)[CH:3]1[C:19]([Cl:25])=[O:20]
Reactant: CC1(C)C(C=C(Cl)c2ccc(OC(F)(F)F)cc2)C1C(=O)O
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)C(C=C(Cl)c2ccc(OC(F)(F)F)cc2)C1C(=O)Cl
Yield: 94.7 %

Procedure:
19.4 g (0.058 mol) of 2,2-dimethyl-3-(2-chloro-2-(4-trifluoromethoxy-phenyl)-vinyl)-cyclopropanecarboxylic acid were dissolved in 150 ml of carbon tetrachloride, and 15 g of thionyl chloride were slowly added dropwise at 25° C., while stirring. The mixture was then heated to the reflux temperature for 4 hours. After this reaction time, excess thionyl chloride and carbon tetrachloride were distilled off under a waterpump vacuum. Last residues of solvent were removed by brief incipient distillation under 2 mm Hg at a bath temperature of 60° C. 19.4 g (95% of theory) of 2,2-dimethyl-3-(2-chloro-2-(4-trifluoromethoxy-phenyl)-vinyl)-cyclopropanecarboxylic acid chloride were obtained as an oily liquid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[O:6][CH2:7][C:8](=[O:13])[N:9]([CH3:12])[C:10]=2[N:11]=1.CC1(C)C(C)(C)OB([C:28]2[CH:29]=[N:30][C:31]([NH2:34])=[N:32][CH:33]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:34][C:31]1[N:32]=[CH:33][C:28]([C:2]2[N:3]=[C:4]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:5]3[O:6][CH2:7][C:8](=[O:13])[N:9]([CH3:12])[C:10]=3[N:11]=2)=[CH:29][N:30]=1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: CN1C(=O)COc2c(N3CCOCC3)nc(Cl)nc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CN1C(=O)COc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Temperature: 120 °C
Yield: 71.6 %

Procedure:
A mixture of 2-chloro-8-methyl-4-morpholin-4-yl-8H-pyrimido[5,4-b][1,4]oxazin-7-one (100 mg, 0.35 mmol), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine (116 mg, 0.53 mmol), Pd(PPh3)2Cl2 (25 mg, 0.035 mmol) and sodium carbonate (1.0 mL, 1.0 mmol, 1M aqueous solution) in acetonitrile (4 mL) was degassed then heated at 120° C. for 30 minutes using microwave irradiation. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with methanol and the product eluted with 2M ammonia in methanol. The basic fractions were combined and concentrated in vacuo. The resulting residue was purified by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 0.1% HCO2H in water on a gradient of acetonitrile 5-98%) affording 120 as a white solid (86 mg, 71%). LCMS: RT=3.04 min, [M+H]+=344. 1H NMR (400 MHz, CDCl3): δ 9.14 (2H, s), 5.25 (2H, broad s), 4.62 (2H, s), 3.81 (8H, s), 3.49 (3H, s).
Reaction SMILES: [OH:1][C:2]1([C:41]2[CH:55]=[CH:54][CH:53]=[CH:52][C:42]=2[O:43][CH2:44][CH2:45][CH2:46][C:47]([O:49]CC)=[O:48])[CH2:7][CH2:6][N:5]([C:8]([C@:10]2([O:31][C:32]3[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[S:34][CH:33]=3)[CH2:15][CH2:14][CH2:13][N:12]([C:16](=[O:27])[C:17]3[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:20]=[N:19][CH:18]=3)[C@@H:11]2[CH2:28][CH2:29][CH3:30])=[O:9])[CH2:4][CH2:3]1.[OH-].[K+]>CO.CCOC(C)=O>[OH:1][C:2]1([C:41]2[CH:55]=[CH:54][CH:53]=[CH:52][C:42]=2[O:43][CH2:44][CH2:45][CH2:46][C:47]([OH:49])=[O:48])[CH2:3][CH2:4][N:5]([C:8]([C@:10]2([O:31][C:32]3[CH:36]=[C:35]([C:37]([F:40])([F:38])[F:39])[S:34][CH:33]=3)[CH2:15][CH2:14][CH2:13][N:12]([C:16](=[O:27])[C:17]3[C:22]([C:23]([F:24])([F:26])[F:25])=[CH:21][CH:20]=[N:19][CH:18]=3)[C@@H:11]2[CH2:28][CH2:29][CH3:30])=[O:9])[CH2:6][CH2:7]1
Reactant: CCC[C@H]1N(C(=O)c2cnccc2C(F)(F)F)CCC[C@@]1(Oc1csc(C(F)(F)F)c1)C(=O)N1CCC(O)(c2ccccc2OCCCC(=O)OCC)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCC[C@H]1N(C(=O)c2cnccc2C(F)(F)F)CCC[C@@]1(Oc1csc(C(F)(F)F)c1)C(=O)N1CCC(O)(c2ccccc2OCCCC(=O)O)CC1
Temperature: 23 °C
Reaction time: 1 h
Yield: 95.9 %

Procedure:
To 86 (40 mg, 0.05 mmol, 1 eq) in MeOH was added KOH (3.5N, 5 equiv). Reaction was brought to 65° C. for 1 hour then cooled down to 23° C. Reaction was diluted with EtOAc, washed with sat. NH4Cl and brine. The organic layer was dried over MgSO4, filtered and concentrated down. HPLC purification, C18, CH3CN/H2O, 70% to 100% CH3CN provided 37 mg (100% yield) of product A91.