Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10](=[O:21])/[CH:11]=[CH:12]/[C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([Cl:20])[CH:14]=2)[CH2:6][CH2:5]1.[O:22]=[C:23]1[NH:27][CH:26]=[C:25]([C:28](O)=[O:29])[O:24]1.CCN(C(C)C)C(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CN(C=O)C.CCOC(C)=O>[Cl:20][C:15]1[CH:14]=[C:13](/[CH:12]=[CH:11]/[C:10]([N:7]2[CH2:6][CH2:5][CH:4]([CH2:3][CH2:2][NH:1][C:28]([C:25]3[O:24][C:23](=[O:22])[NH:27][CH:26]=3)=[O:29])[CH2:9][CH2:8]2)=[O:21])[CH:18]=[C:17]([Cl:19])[CH:16]=1
Reactant: O=C(O)c1c[nH]c(=O)o1
Reactant: NCCC1CCN(C(=O)/C=C/c2cc(Cl)cc(Cl)c2)CC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C(NCCC1CCN(C(=O)/C=C/c2cc(Cl)cc(Cl)c2)CC1)c1c[nH]c(=O)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (E)-1-(4-(2-aminoethyl)piperidin-1-yl)-3-(3,5-dichlorophenyl)prop-2-en-1-one (Example 30, step 4) (110 mg, 0.336 mmol) and 2-oxo-2,3-dihydrooxazole-5-carboxylic acid (Example 21, step 1) (167 mg, 0.504 mmol) in DMF (2 ml) was added DIPEA (0.470 mL, 2.69 mmol) and T3P® (50% in EtOAc, 1.571 ml, 2.69 mmol). The reaction mixture was stirred at RT overnight.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[C:5]([O:9][C:10](=[O:26])[NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][NH2:25])=[CH:18][CH:17]=1)([CH3:8])([CH3:7])[CH3:6].C([BH3-])#N.[Na+].O1CC[CH2:33][CH2:32]1>O>[CH2:32]([O:3][C:1](=[O:4])[CH2:2][NH:25][CH2:24][CH2:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:10]([O:9][C:5]([CH3:8])([CH3:6])[CH3:7])=[O:26])=[CH:21][CH:20]=1)[CH3:33]
Reactant: CC(=O)O
Reactant: CC(C)(C)OC(=O)NCCCCc1ccc(OCCN)cc1
Reactant: C1CCOC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CNCCOc1ccc(CCCCNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38 %

Procedure:
Dimethylacetone dicarboxylate (1.43 mL, 9.69 mmol) and glacial acetic acid (0.56 mL, 9.70 mmol) were added sequentially to a solution of {4-[4-(2-aminoethoxy)phenyl]-butylcarbamic acid tert-butyl ester (1) (1.0 g, 3.24 mmol) in tetrahydrofuran (20 mL). The reaction was stirred for 2 hours at ambient temperature, then cooled to −30° C. Sodium cyanoborohydride (0.61 g, 9.70 mmol) was added in three portions and the reaction slowly warmed to room temperature over 12 hours. After this time, the reaction was quenched by the addition of water (5 mL). The volatiles was then removed under vacuum to give an oil. This oil was diluted with water (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organics were washed with water (3×10 mL) and then brine (3×10 mL), dried over anhydrous sodium sulfate and concentrated to give 2 (0.576 g, 38% yield) as a clear oil: 1H NMR (500 MHz, CDCl3) δ 1.44 (s, 9H), 1.46-1.52 (m, 2H), 1.55-1.64 (m, 2H), 2.56-2.58 (m, 4H), 2.64-2.65 (m, 2H), 2.72-2.79 (m, 2H), 2.88-2.93 (m, 2H), 3.74 (d, 6H), 3.88-3.93 (m, 1H), 4.44-4.49 (m, 2H), 6.40 (br, 1H), 6.85 (d, 2H), 7.09 (d, 2H); m/z (ESI) 467.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:13]([C:16]([CH2:27][CH2:28][CH3:29])(C(OCC)=O)[C:17]([O:19]CC)=[O:18])[CH2:14][CH3:15].C(O)C>O>[C:17]([OH:19])(=[O:18])[CH:16]([CH2:27][CH2:28][CH3:29])[CH2:13][CH2:14][CH3:15]
Reactant: CCCC(CCC)(C(=O)OCC)C(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: CCCC(CCC)C(=O)O
Temperature: 140 °C
Reaction time: 5 h
Yield: 87.4 %

Procedure:
A mixture of 70 g of p-toluenesulfonic acid monohydrate, 140 g of diethyl dipropylmalonate and 9 ml of water was heated to reflux in a flask equipped with a distillation column packed with Raschig rings. Ethanol was distilled as it formed and the pot temperature was maintained at 120°-155° C. by periodic addition of water to the pot. After 5 hours, 25 ml of water had been added and the evolution of ethanol had nearly stopped. The mixture was maintained at 140° C. for 18 hours and then was cooled and treated with 100 ml of water. The layers were separated to afford 72.2 g (87.8% yield) of valproic acid as a light brown liquid. The water layer was washed with 50 ml of toluene and the toluene was combined with the crude valproic acid layer. Vacuum distillation afforded a colorless valproic acid fraction (72 g, 87% yield) boiling at 132° C./28" Hg.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:20]=[C:19](I)[C:9]2[N:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:11]=[N:12][C:8]=2[CH:7]=1)=[O:5])[CH3:2].[NH2:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1.C(O)CCO.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.O.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>[NH2:22][C:23]1[CH:28]=[C:27]([C:19]2[C:9]3[N:10]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH:11]=[N:12][C:8]=3[CH:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:20]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: CCOC(=O)c1cc(I)c2c(c1)ncn2-c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Solvent: OCCCO
Product: CCOC(=O)c1cc(-c2cccc(N)c2)c2c(c1)ncn2-c1ccccc1

Procedure:
This was prepared analogously to the above product from 5-ethoxycarbonyl-7-iodo-1-phenylbenzimidazole (2.1 g, 5.36 mmol), 3-aminophenylboronic acid (1.1 g, 8.04 mmol), 1,3-propanediol (1.9 ml, 26.8 mmol), potassium carbonate (3.7 g, 26.8 mmol) and bis(triphenylphosphin)palladium dichloride (50 mg, 0.07 mmol) in a mixture of dimethoxyethane (10 ml) and water (5 ml). The title product was obtained as an off-white solid (1.30 g, 68%) m/z, 358.2 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([NH2:17])[C:10]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:7]=1.[OH:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+].ClCCl>CN(C=O)C>[NH2:17][C:9]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:5]2[N:4]=[CH:3][C:2]([C:22]3[CH:23]=[CH:24][C:19]([OH:18])=[CH:20][CH:21]=3)=[CH:7][N:6]2[N:8]=1
Reactant: Nc1nn2cc(Br)cnc2c1-c1ccccn1
Reactant: OB(O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Nc1nn2cc(-c3ccc(O)cc3)cnc2c1-c1ccccn1
Temperature: 120 °C
Yield: 67.9 %

Procedure:
6-Bromo-3-pyridin-2-yl-pyrazolo[1,5-a]pyrimidin-2-ylamine (50 mg, 0.17 mmol) and 4-hydroxyphenylboronic acid (48 mg, 0.35 mmol) were suspended in dry DMF (1.4 ml). Aqueous 2M Na2CO3 (0.346 mL, 0.69 mmol) was added and the reaction mixture was degassed. [1,1-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex in dichloromethane (1:1 ratio, 8 mg, 0.010 mmol) was added and the mixture was heated in a microwave at 120° C. for 20 minutes. After allowing the reaction to cool down to room temperature, the mixture was concentrated under reduced pressure. The resulting solid was purified by silica gel chromatography eluting with EtOAc to afford the title compound as a yellow solid (35 mg, 67% yield). MS (ES+) 304. δH (DMSO-d6) 6.8 (1H, d), 7.1 (3H, m), 7.2 (1H, d), 7.3 (1H, t), 7.9 (1H, t), 8.6 (2H, m), 8.8 (1H, s), 9.2 (1H, s), 9.7 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[C:14]([CH3:16])[C:5]([O:6][CH2:7][CH2:8][N:9]([CH2:12][CH3:13])[CH2:10][CH3:11])=[C:4]([CH3:17])[CH:3]=1.[CH3:18][S:19]([O:22]S(C)(=O)=O)(=[O:21])=[O:20]>C(#N)C>[CH3:18][S:19]([OH:22])(=[O:21])=[O:20].[CH2:10]([N:9]([CH2:12][CH3:13])[CH2:8][CH2:7][O:6][C:5]1[C:14]([CH3:16])=[CH:15][C:2]([NH:1][S:19]([CH3:18])(=[O:21])=[O:20])=[CH:3][C:4]=1[CH3:17])[CH3:11]
Reactant: CS(=O)(=O)OS(C)(=O)=O
Reactant: CCN(CC)CCOc1c(C)cc(N)cc1C
Solvent: CC#N
Product: CCN(CC)CCOc1c(C)cc(NS(C)(=O)=O)cc1C
Product: CS(=O)(=O)O

Procedure:
To 4.55 g (19.3 mmol) of 2-(4-amino-2,6-dimethylphenoxy)-N,N-diethylethanamine in 40 mL of acetonitrile add 3.40 g (19.5 mmol) of methanesulfonic anhydride. After the addition is complete, stir the reaction for 2 hours at 50° C. Remove the solvent in vacuo. Recrystallize the residue from acetone/ether to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([CH2:12][CH2:13][OH:14])=[CH:7][CH:8]=2)[N:3]=1.[O:15]1CCOCC1>O>[OH:14][CH2:13][CH2:12][C:6]1[CH:5]=[C:4]2[C:9]([CH:10]=[CH:11][C:2]([CH:1]=[O:15])=[N:3]2)=[CH:8][CH:7]=1
Reactant: C1COCCO1
Reactant: Cc1ccc2ccc(CCO)cc2n1
Solvent: O
Product: O=Cc1ccc2ccc(CCO)cc2n1
Temperature: 25 °C
Yield: 89 %

Procedure:
2-(2-methylquinolin-7-yl)ethanol (0.220 g, 1.17 mmol) was dissolved in dioxane (5 mL) and water (0.05 mL). The reaction was treated with SeO2 (0.156 g, 1.41 mmol) and the mixture was heated to reflux for 2 hours. After cooling to ambient temperature, the solid was removed by filtration and washed with DCM. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel (ethyl acetate/hexanes 5:1) to give 7-(2-hydroxyethyl)quinoline-2-carbaldehyde (0.21 g, 1.04 mmol, 89% yield) as a solid.
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][O:7][C:8](=[O:32])[N:9]([CH2:30][CH3:31])[CH2:10][C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:12]=2B2OC(C)(C)C(C)(C)O2)=[CH:4][CH:3]=1.[CH3:35][O:36][C:37](=[O:47])[CH2:38][C:39]1[CH:44]=[C:43]([Cl:45])[CH:42]=[C:41](Br)[CH:40]=1>>[CH3:35][O:36][C:37](=[O:47])[CH2:38][C:39]1[CH:40]=[C:41]([C:12]2[CH:13]=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[CH:16][C:11]=2[CH2:10][N:9]([CH2:30][CH3:31])[C:8]([O:7][CH2:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:34][CH:33]=2)=[O:32])[CH:42]=[C:43]([Cl:45])[CH:44]=1
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1)C(=O)OCc1ccc(F)cc1
Reactant: COC(=O)Cc1cc(Cl)cc(Br)c1
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(Cl)cc(CC(=O)OC)c1)C(=O)OCc1ccc(F)cc1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: ethyl-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-carbamic acid 4-fluoro-benzyl ester and (3-bromo-5-chloro-phenyl)-acetic acid methyl ester.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:25]([C:28]([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[CH:32]=2)=[O:29])=[CH:24][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[NH:15][CH:14]=[C:13]([C:16]([NH:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[O:17])[CH:12]=2)[CH:6]=1.[CH3:38]N(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl.COC(=O)CCN.Cl>CN(C=O)C.O>[F:1][C:2]1[CH:27]=[CH:26][C:25]([C:28]([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[CH:32]=2)=[O:29])=[CH:24][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[NH:15][CH:14]=[C:13]([C:16]([NH:18][CH2:19][CH2:20][C:21]([O:23][CH3:38])=[O:22])=[O:17])[CH:12]=2)[CH:6]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1cccc(NC(=O)c2ccc(F)c(Oc3ccnc(-c4cc(C(=O)NCCC(=O)O)c[nH]4)c3)c2)c1
Agent: COC(=O)CCN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)CCNC(=O)c1c[nH]c(-c2cc(Oc3cc(C(=O)Nc4cccc(C)c4)ccc3F)ccn2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 5-[4-(2-fluoro-5-{[(3-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxylic acid (Example 275) (100 mg, 0.23 mmol) in 10 ml of anhydrous DMF were added HATU (100 mg, 0.26 mmol) and N,N-diisopropylethylamine (85 mg, 0.66 mmol). The mixture was stirred at room temperature for 10 minutes, followed by addition of β-alanine methyl ester hydrochloride (46 mg, 0.33 mmol). The mixture was stirred for another minutes and poured into 100 ml of water. 2M HCl was added dropwise with vigorous stirring until pH=4. The precipitates were filtered, washed with water and dried in vacuo to give methyl 3-[({5-[4-(2-fluoro-5-{[(3-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]propanoate as white solid. Yield: 110 mg, 92%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=2[CH:21]=O)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[CH2:24]([NH2:26])[CH3:25]>>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=2[CH2:21][NH:26][CH2:24][CH3:25])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2cc(C)ccc2C=O)c1
Reactant: CCN
Product: CCNCc1ccc(C)cc1-c1cc(CC(=O)OCC)ccc1OC

Procedure:
Prepared according to the procedure described in Example 33, Step 4, using the following starting materials: (2′-formyl-6-methoxy-5′-methyl-biphenyl-3-yl)-acetic acid ethyl ester and ethylamine (2M in THF).
Reaction SMILES: [CH3:1][O:2][C:3]1(O)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.S([O-])(O)=[O:11].[Na+].S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:11]
Reactant: O=S([O-])O
Reactant: COC1(O)CCCCC1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CO[C@H]1CCCCC1=O

Procedure:
Reaction was carried out in the same manner as in Example 16. After the peak due to (S)-2)-methoxycyclohexanol had disappeared, the reaction solution was given 2 g of sodium hydrogensulfite with stirring so that the reaction solution did not change potassium iodide starch paper into purple any longer. The reaction solution was adjusted to pH 2 or below with 10% sulfuric acid, followed by stirring at 20-25° C. for 1 hour. The reaction solution was adjusted to pH 7.5-8 with an aqueous solution of sodium carbonate, followed by stirring at 20-25° C. for 1 hour. The reaction solution was adjusted again to pH 2 or below with 10% sulfuric acid, followed by stirring at 20-25° C. for 2 hours. The reaction solution was extracted three times with 100 g of toluene. The toluene layers were combined together and washed with a saturated aqueous solution of sodium chloride. After concentration and distillation in the same manner as in Example 1, there was obtained 10.3 g (80 mmol) of (S)-2-methoxycyclohexanone having a chemical purity of 99.3% and an optical purity of 99.6% ee. This product was heated at 60° C. for 48 hours in the same manner as in Example 16; it decreased in optical purity to 99.0% ee.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH:9][CH2:10][C:11]([CH3:14])([OH:13])[CH3:12])=[CH:4][N:3]=1.[O:15]1[CH:20]=[CH:19][CH2:18][CH2:17][CH2:16]1.O>ClCCl.CC1C=CC(S(O)(=O)=O)=CC=1.N1C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH:9][CH2:10][C:11]([CH3:14])([O:13][CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][O:15]2)[CH3:12])=[CH:4][N:3]=1
Reactant: C1=COCCC1
Reactant: CC(C)(O)CNc1cnc(Cl)nc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CC(C)(CNc1cnc(Cl)nc1Cl)OC1CCCCO1
Reaction time: 16 h
Yield: 90.1 %

Procedure:
To a mixture of 1-(2,4-dichloropyrimidin-5-ylamino)-2-methylpropan-2-ol (258 mg, 1.09 mmol) and 3,4-dihydro-2H-pyran (0.200 ml, 2.18 mmol) in dichloromethane (7 ml) was added pyridine 4-methylbenzenesulfonate (13.7 mg, 0.055 mmol) and the reaction mixture was stirred for 16 hours. The reaction mixture was poured into water and extracted with Et2O. The organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give a crude oil. The crude residue was purified by silica gel chromatography (hexane/ethyl acetate, 100:0 to 3:1) to afford 2,4-dichloro-N-(2-methyl-2-(tetrahydro-2H-pyran-2-yloxy)propyl)pyrimidin-5-amine (315 mg, 0.982 mmol, 90% yield) as a pale yellow oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.18 (s, 3H) 1.23 (s, 3H) 1.25-1.75 (m, 6H) 3.27-3.32 (m, 2H) 3.37-3.49 (m, 1H) 3.69-3.83 (m, 1H) 4.74-4.86 (m, 1H) 5.75 (t, J=6.32 Hz, 1H) 8.36 (s, 1H).
Reaction SMILES: Cl.[CH3:2][O:3][CH:4]1[CH2:7][NH:6][CH2:5]1.BrCCC[C:12]12[CH:22]=[CH:21][CH:20]=[CH:19][CH:13]1[C:14]([NH:16][C:17]2=[O:18])=[O:15].C([O-])([O-])=O.[K+].[K+].[CH2:29]1[CH2:33]OC[CH2:30]1>>[CH3:2][O:3][CH:4]1[CH2:7][N:6]([CH2:30][CH2:29][CH2:33][N:16]2[C:14](=[O:15])[C:13]3[C:12](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:17]2=[O:18])[CH2:5]1
Reactant: COC1CNC1
Reactant: O=C1NC(=O)C2(CCCBr)C=CC=CC12
Reactant: C1CCOC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC1CN(CCCN2C(=O)c3ccccc3C2=O)C1
Yield: 65 %

Procedure:
A suspension of 3-methoxyazetidine (275) (MacKenzie et al., PCT Int. Appl. WO 9605193, 1996) (1.6 g, 18.8 mmol), 2-(3-bromopropyl)phthalimide (4.8 g, 17.9 mmol) and K2CO3 (3.7 g, 26.9 mmol) in THF (150 mL) was stirred at reflux temperature for 18 h. The solution was cooled, the solvent evaporated and the residue partitioned between water (50 mL) and EtOAc (100 mL). The aqueous layer was extracted with EtOAc (2×150 mL), the combined organic fraction washed with water (2×100 mL) and brine (100 mL), dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-5%) of MeOH/DCM, to give phthalimide 300 (5.2 g, 65%) as a colourless oil: 1H NMR δ 7.84 (dd, J=5.4, 3.1 Hz, 2H, Harom), 7.70 (dd, J=5.4, 3.1 Hz, 2H, Harom), 3.95 (p, J=5.8 Hz, 1H, CHO), 3.73 (t, J=7.1 Hz, 2H, CH2N), 3.55-3.60 (m, 2H, CH2N), 3.22 (s, 3H, OCH3), 2.78-2.84 (m, 2H, CH2N), 2.51 (t, J=7.1 Hz, 2H, CH2N), 1.72 (p, J=7.1 Hz, 2H, CH2); MS (APCI) m/z 275 (MH+, 100%); HRMS (FAB+) calcd for C15H19N2O3 (MH+) m/z 275.1396, found 275.1391.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:12]([O:14]CC)=O)=[C:4]([NH:8][C:9]([NH2:11])=[S:10])[S:5][C:6]=1[CH3:7].[OH-].[Na+].CC(O)=O>CCO>[CH3:1][C:2]1[C:3]2[C:12](=[O:14])[NH:11][C:9](=[S:10])[NH:8][C:4]=2[S:5][C:6]=1[CH3:7]
Reactant: CCOC(=O)c1c(NC(N)=S)sc(C)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1sc2[nH]c(=S)[nH]c(=O)c2c1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 22.2 %

Procedure:
To a suspension of ethyl 4,5-dimethyl-2-thioureidothiophene-3-carboxylate (Example 50a) (37 mg, 0.17 mmol) in dry EtOH (10 mL) was added sodium hydroxide (21 mg, 0.52 mmol). The reaction mixture was then stirred at room temperature for 5 minutes and refluxed for 10 minutes. The reaction mixture was cooled to room temperature, neutralized with 10% AcOH and then concentrated to dryness. The residue was purified by chromatography on silica gel (Gradient 0-50% EtOAc in Hexanes) to give the title compound (8 mg) in 24% yield. 1H NMR (400 MHz, DMSO-d6) δ2.25 (s, 6H), 12.24 (s, 1H), 13.27 (s, 1H). MS 202 (MH+).
Reaction SMILES: [CH3:1][C:2](=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C(OCC)C.[BH4-].[Na+]>C1(C)C=CC=CC=1>[CH3:1][CH:2]([OH:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCCCCCCC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCCCCCCCCCCCCC(C)O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Pentadecanone (200 g) was added a 3-litre three-necked flask under nitrogen, to which diethyl ether (1000 ml) was slowly added from a dropping funnel. Sodium borohydride (63.54 g) was then slowly added and the mixture stirred for two days at room temperature under nitrogen. Toluene was added to the reaction vessel and the contents transferred to a separating funnel. The organic layer was washed with water and the aqueous layer was collected. The aqueous layer was washed with toluene, which was combined with the previous organic layer. The product was dried with magnesium sulphate and filtered under vacuum. The solvent was then stripped on a rotary evaporator at 100° C. to yield the title compound.
Reaction SMILES: [CH:1]1([C:5]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=3)=[C:7]([F:18])[C:6]=2[O:19][CH2:20][CH:21]2[CH2:23][O:22]2)[CH2:4][CH2:3][CH2:2]1.[CH2:24]([NH2:28])[CH:25]([CH3:27])[CH3:26]>CO>[NH2:17][C:14]1[N:15]=[CH:16][C:11]([C:8]2[C:7]([F:18])=[C:6]([C:5]([CH:1]3[CH2:4][CH2:3][CH2:2]3)=[CH:10][CH:9]=2)[O:19][CH2:20][CH:21]([OH:22])[CH2:23][NH:28][CH2:24][CH:25]([CH3:27])[CH3:26])=[N:12][CH:13]=1
Reactant: Nc1cnc(-c2ccc(C3CCC3)c(OCC3CO3)c2F)cn1
Reactant: CC(C)CN
Solvent: CO
Product: CC(C)CNCC(O)COc1c(C2CCC2)ccc(-c2cnc(N)cn2)c1F
Temperature: 60 °C
Yield: 67 %

Procedure:
A mixture of 5-(4-cyclobutyl-2-fluoro-3-(oxiran-2-ylmethoxy)phenyl)pyrazin-2-amine (150 mg, 0.48 mmol), isobutylamine (105 mg, 1.43 mmol) and MeOH (5 mL) was heated in sealed tube to 60° Celsius for 5 hours, then the solvent was removed. The residue was subjected to FCC to give the titled compound (125 mg, 67%). MS (CI): mass calcd. for C21H29FN4O2, 388.23; m/z found, 389.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.48-8.39 (m, 1H), 8.08 (d, J=1.4, 1H), 7.54 (m, 1H), 7.14 (d, J=8.2, 1H), 4.72 (s, 2H), 4.45-4.37 (m, 1H), 4.09-3.99 (m, 2H), 3.86-3.73 (m, 1H), 3.29-3.21 (m, 1H), 3.16-3.07 (m, 1H), 2.86-2.69 (m, 2H), 2.41-2.30 (m, 2H), 2.19-2.01 (m, 4H), 1.90-1.81 (m, 1H), 1.05 (d, J=6.7, 6H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:24][C:25]1([CH3:31])[O:29][C:28](=[O:30])[N:27]=[CH:26]1>>[CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:27]4[CH2:26][C:25]([CH3:31])([CH3:24])[O:29][C:28]4=[O:30])=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Reactant: CC1(C)C=NC(=O)O1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CC(C)(C)OC4=O)cc3)CC2)c(C)c1
Yield: 38.2 %

Procedure:
By reaction and treatment in the same manner as in Example 111 and using [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (842 mg) described in Preparation Example 77 and 5,5-dimethyloxazolin-2-one (345 mg) described in Preparation Example 43, the title compound (312 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[C:11]([NH:15][C:16](=[O:27])[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=3)[CH:12]=[CH:13][CH:14]=2)=[CH:4][CH:3]=1.[CH3:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1.O>N1C=CC=CC=1>[CH3:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([NH:1][C:2]2[N:7]=[CH:6][C:5]([O:8][C:9]3[CH:10]=[C:11]([NH:15][C:16](=[O:27])[C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:24])[F:25])[CH:18]=4)[CH:12]=[CH:13][CH:14]=3)=[CH:4][CH:3]=2)(=[O:37])=[O:36])=[CH:31][CH:30]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(Oc2cccc(NC(=O)c3cccc(C(F)(F)F)c3)c2)cn1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2ccc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)cn2)cc1
Temperature: 80 °C
Yield: 97.3 %

Procedure:
To a solution of N-{3-[(6-aminopyridin-3-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide (2.00 g, 5.36 mmol) in pyridine (60 mL) was added under ice-cooling 4-methylbenzenesulfonyl chloride (1.12 g, 5.89 mmol), and the mixture was stirred with heating at 80° C. for 2 days. The reaction mixture was cooled to room temperature, water (200 mL) was added thereto and the mixture was extracted with ethyl acetate (300 mL). The organic layer was washed with saturated brine (300 mL), and dried over anhydrous sodium sulfate. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (2.75 g, 99%) as a yellow oil. The obtained compound was used in the next reaction without further purification.
Reaction SMILES: [P:1]([O:5][P:6]([OH:9])([OH:8])=[O:7])([OH:4])([OH:3])=[O:2].[CH2:10]([N:14]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH3:13]>O>[O-:3][P:1]([O:5][P:6]([OH:9])([O-:8])=[O:7])(=[O:2])[O-:4].[CH2:19]([NH+:14]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:15][CH2:16][CH2:17][CH3:18])[CH2:20][CH2:21][CH3:22].[CH2:19]([NH+:14]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:15][CH2:16][CH2:17][CH3:18])[CH2:20][CH2:21][CH3:22].[CH2:19]([NH+:14]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:15][CH2:16][CH2:17][CH3:18])[CH2:20][CH2:21][CH3:22]
Reactant: CCCCN(CCCC)CCCC
Reactant: O=P(O)(O)OP(=O)(O)O
Solvent: O
Product: CCCC[NH+](CCCC)CCCC
Product: O=P([O-])([O-])OP(=O)([O-])O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Tris-(tributylammonium) pyrophosphate was prepared by treating pyrophosphoric acid (293 mg) in water (2.0 mL) with tributylamine (1.2 mL). The mixture was stirred vigorously at 0° C. for 10 min, and then at room temperature (RT) for 1 h. The water was removed by lyophilization; the residue was further dried by coevaporation with pyridine (3×5 mL) and toluene (5 mL), and then by evacuation (0.25 mm pressure, 12 h). The tris-(tributylammonium) pyrophosphate residue was dissolved in dimethylformamide (2.5 mL) and the solution used for subsequent reactions.