Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([SH:10])=[C:6]([CH2:8][OH:9])[CH:7]=1.O.[OH-].[K+].Br[C:15](P(=O)(OCC)OCC)([F:17])[F:16]>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:10][CH:15]([F:17])[F:16])=[C:6]([CH2:8][OH:9])[CH:7]=1
Reactant: OCc1cc(Br)ccc1S
Reactant: CCOP(=O)(OCC)C(F)(F)Br
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: OCc1cc(Br)ccc1SC(F)F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
(5-Bromo-2-sulfanylphenyl)methanol (0.50 g, 2.8 mmol) was dissolved in acetonitrile (11.4 mL) followed by the addition of water (11.4 mL) and solid potassium hydroxide (2.56 g, 45.6 mmol). The mixture was plunged into a −78° C. bath and when the mixture began to freeze diethyl [bromo(difluoro)methyl]phosphonate (1.22 g, 4.56 mmol) was added all at once and the cold bath was removed. The mixture was allowed to warm to ambient temperature and was stirred for 20 minutes. The mixture was then partitioned between EtOAc and water. The organic layer was washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 0-25% EtOAc/hexanes). Desired fractions were identified, combined, and concentrated in vacuo to afford the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[CH:6][CH:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[N:3]=1.[CH3:17][CH:18]([SH:20])[CH3:19].[H-].[Na+]>>[CH:18]([S:20][C:2]1[C:7]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[CH:6][CH:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[N:3]=1)([CH3:19])[CH3:17]
Reactant: CC(C)S
Reactant: O=C(O)C=Cc1ccc(C(F)(F)F)nc1Cl
Agent: [H-]
Agent: [Na+]
Product: CC(C)Sc1nc(C(F)(F)F)ccc1C=CC(=O)O
Yield: 36.3 %

Procedure:
3-(2-Chloro-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (245 mg, 0.974 mmol) was reacted with 2-propanthiol (240 mg, 3.15 mmol) and sodium hydride (143 mg, 3.56 mmol) to afford the title compound (103 mg) after purification by column chromatography (Hex/EtOAc=2.5/1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]1)[CH:5]=O.[C:21]([C:25]1[CH:26]=[C:27]([NH2:32])[C:28]([NH2:31])=[CH:29][CH:30]=1)([CH3:24])([CH3:23])[CH3:22]>>[C:21]([C:25]1[CH:30]=[CH:29][C:28]2[NH:31][C:5]([C:4]3[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH2:12][CH2:13][N:14]4[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]4)=[C:2]([CH3:1])[CH:3]=3)=[N:32][C:27]=2[CH:26]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: Cc1cc(C=O)ccc1OCCCN1CCN(C)CC1
Reactant: CC(C)(C)c1ccc(N)c(N)c1
Product: Cc1cc(-c2nc3cc(C(C)(C)C)ccc3[nH]2)ccc1OCCCN1CCN(C)CC1
Yield: 80.5 %

Procedure:
This compound was prepared by the method described in Example 1, using 3-methyl-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-benzaldehyde (516 mg, 1.87 mmol, 1.0 equiv), 4-tert-butyl-benzene-1,2-diamine (307 mg, 1.87 mmol, 1.0 equiv), and Na2S2O5 (461 mg, 2.43 mmol, 1.3 equiv) in General Procedure 3. Purification by Method 2 afforded 633 mg (81%) of the title compound. MS (electrospray): mass calculated for C26H36N4O, 420.29; m/z found, 421.5 [M+H]+. 1H NMR (400 MHz, CD3OD): 7.90-7.85 (m, 2H), 7.65-7.40 (m, 2H), 7.33 (d, J=8.5 Hz, 1H), 7.04 (d, J=8.1 Hz, 1H), 4.14-4.11 (m, 2H), 2.90-2.28 (m, 16H), 2.06-2.03 (m, 2H), 1.39 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([N:8]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]3[S:15][CH:16]=[CH:17][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][C:36]=1[Cl:37])[C:31](Cl)=[O:32]>ClCCl>[S:15]1[C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][N:8]([C:6]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:31](=[O:32])[C:30]4[CH:34]=[CH:35][C:36]([Cl:37])=[C:28]([Cl:27])[CH:29]=4)=[CH:19][CH:18]=3)=[O:7])[C:9]=2[CH:17]=[CH:16]1
Reactant: Nc1ccc(C(=O)N2CCCCc3sccc32)cc1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)N2CCCCc3sccc32)cc1)c1ccc(Cl)c(Cl)c1
Reaction time: 8 h
Yield: 51.8 %

Procedure:
To a solution of 0.30 g of 4-(4-aminobenzoyl)-5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine and 0.208 ml of triethylamine in 10 ml of dichloromethane is added, under argon, 0.251 g of 3,4-dichlorobenzoyl chloride. The mixture is stirred overnight and concentrated to dryness under vacuum. The residue is dissolved in ethyl acetate and the solution washed with H2O, 2N citric acid, NaHCO3 solution, brine and dried (Na2SO4). The solvent is removed and the residual yellow solid crystallized from ethyl acetate-hexane to give 0.254 g of crystals, m.p. 154°-160° C.
Reaction SMILES: [I-].[Na+].O.O.O.C([O-])(=O)C.[Na+].[CH3:11][O:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1.Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>O>[CH3:11][O:12][C:13]1[CH:19]=[CH:18][C:16]([NH:17][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:15][CH:14]=1
Reactant: CCOC(=O)CBr
Reactant: COc1ccc(N)cc1
Agent: CC(=O)[O-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CNc1ccc(OC)cc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 75.5 %

Procedure:
To a solution of sodium iodide (122 g, 0.81 mol) and sodium acetate trihydrate (221 g, 1.62 mol) in water (200 mL) was added 4-methoxyaniline (3) (100 g, 0.81 mol) followed by ethyl 2-bromoacetate (90 mL, 812 mmol) the reaction was stirred at 90° C. for 3 h. The reaction mixture was cooled to RT and partitioned with EtOAc (1 L), the organic phase was separated, washed with water (400 mL), 1 M HCl (aq.) (3×500 mL), and the organic phase discarded. The combined acidic extracts were cooled to 0° C. and solid NaOH was added to pH 14 and the aqueous phase was extracted with EtOAc (3×400 mL). The combined organics were washed with brine (250 mL), dried (MgSO4), filtered and solvents removed in vacuo to give ethyl 2-((4-methoxyphenyl)amino)acetate (17) (128 g, 75%) as a purple oil that crystallised on standing: m/z 210 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 6.75-6.69 (m, 2H), 6.55-6.46 (m, 2H), 3.99 (t, J=6.5 Hz, 1H), 4.10 (q, J=7.1 Hz, 2H), 3.82 (d, J=6.5 Hz, 2H), 3.63 (s, 3H), 1.19 (t, J=7.1 Hz, 3H).
Reaction SMILES: [C:1]([C:4]1([OH:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:5]1[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2].C(N(CC)CC)C.Br[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:24](=[O:25])[O:23]1>CC(C)=O>[C:1]([C:4]1([OH:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:5]1[C:6]([O:8][CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:24](=[O:25])[O:23]1)=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)C1(O)C=CC=CC1C(=O)O
Reactant: O=C1OC(Br)c2ccccc21
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)C1(O)C=CC=CC1C(=O)OC1OC(=O)c2ccccc21
Temperature: 25 °C
Yield: 84.4 %

Procedure:
o-Acetylsalicylic acid (18 g) and triethylamine (21 ml) were stirred at a temperature of 20°-25° C. for 30 minutes in 500 ml of acetone. When dissolution was completed, 3-bromophthalide (32 g) was added and the mixture refluxed 2 hours. The reaction mixture was then cooled to 20°-25° C. and poured into distilled water (500 ml). The resulting mixture was extracted with 200 ml of dichloromethane twice, discarding the acetone layer. After the organic solution was washed with 200 ml portions of distilled water twice, 5 g of anhydrous sodium sulfate were added and the mixture filtered. After filtration the organic filtrate was evaporated, the residue was taken up with previously warmed methanol. Decolorizing carbon (1 g) and filtering aid (1 g) were added. The methanolic solution was filtered, and the filtrate was cooled, first to room temperature, and subsequently in an ice/water bath. The solid precipitate was collected by filtration, and dried under vacuum at 40° C. to obtain a yield (83.9%; 26.2 g) of crude phthalidyl o-acetylsalicylate (m.p. 85° C.-88° C.).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[C:6]([Cl:9])[CH:5]=[C:4]([F:10])[C:3]=1[N:11]1[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]([CH3:22])[C:12]1=[O:23].C(N(CC)CC)C.Cl[C:32](Cl)([O:34]C(=O)OC(Cl)(Cl)Cl)Cl>C(OCC)(=O)C>[Cl:9][C:6]1[CH:5]=[C:4]([F:10])[C:3]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]([CH3:22])[C:12]2=[O:23])=[C:2]([N:1]=[C:32]=[O:34])[C:7]=1[CH3:8]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c1N
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c1N=C=O

Procedure:
3-(2-Amino-4-chloro-6-fluoro-3-methylphenyl)-1-methyl-6-trifluoromethyl-2,4(1H, 3H)-pyrimidinedione (1.0 g, 2.9 mmol) and triethylamine (0.58 g, 5.7 mmol) were dissolved in ethyl acetate (15 ml) and the solution was slowly added to a solution of triphosgene (0.85 g, 2.9 mmol) in ethyl acetate (15 ml). Solution was heated under reflux for 2 hr and filtered. Solvent was evaporated to afford the title compound as a residue which was used for the next step.
Reaction SMILES: C(Cl)Cl.[CH3:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]2[C:19](=[O:20])[N:18]([CH3:21])[C:16](=[O:17])[C:15]=2Br)=[CH:6]1.ClS(O)(=O)=O.CC(C)C(N)=O.[CH3:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>C(#N)C>[CH3:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]2[C:19](=[O:20])[N:18]([CH3:21])[C:16](=[O:17])[C:15]=2[C:36]2[CH:35]=[CH:34][CH:39]=[CH:38][CH:37]=2)=[CH:6]1
Reactant: CCCCCC
Reactant: CN1C(=O)C(Br)=C(c2cn(C)c3ccccc23)C1=O
Agent: CC(C)C(N)=O
Agent: O=S(=O)(O)Cl
Solvent: ClCCl
Solvent: CC#N
Product: CN1C(=O)C(c2ccccc2)=C(c2cn(C)c3ccccc23)C1=O
Temperature: 25 °C

Procedure:
Into methylene chloride (83 ml) was dissolved the resultant IM-4 (25 g, 80.5 mmol) obtained as described above, and to this was added dropwise chlorosulfonic acid (8.3 ml) at room temperature. After this mixture was stirred for an hour at room temperature, to the reaction system were added dropwise at a low speed dimethylacetoamide (90 ml)/acetonitrile (45 ml). To this was added dropwise oxy-salt phosphor (15 ml) while being heated and refluxed. After this mixture was heated and refluxed for an hour, hexane (150 ml) was added, then, the mixture was stirred and stood still, and thereafter, the upper layer of hexane was separated and concentrated. The concentrated substances were refined with silica gel column chromatography to obtain 21 g of IM-5.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH3:14][N:15](C)C=O>[C-]#N.[Zn+2].[C-]#N>[C:14]([C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8])#[N:15]
Reactant: COC(=O)c1cc(Br)ccc1OC
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Product: COC(=O)c1cc(C#N)ccc1OC
Temperature: 100 °C
Reaction time: 2 h
Yield: 42 %

Procedure:
Methyl 5-bromo-2-methoxybenzoate (29.3 g) obtained in step A of Example 1-1-1, and 33.1 g of zinc cyanide were dissolved in 650 mL of N,N-dimethylformamide. N,N-Dimethylformamide was degassed under reduced pressure, and then the interior of the reactor was purged with nitrogen. After 9.8 g of tetrakistriphenylphosphine palladium was added, N,N-dimethylformamide was deaerated again under reduced pressure, and then the interior of the reactor was purged with argon. This solution was stirred for 2 hours at 100° C., whereafter the solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate. The insolubles were removed by filtration, and washed with ethyl acetate. The filtrate and the washings were combined, water was added, and then the organic layer was separated. The aqueous layer was extracted twice with ethyl acetate. After the respective organic layers were combined, the combined organic layer was washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was separated by filtration, and then washed with ethyl acetate. The filtrate and the washings were combined, and ethyl acetate was distilled off under reduced pressure. The resulting residue was washed with diethyl ether. The resulting solid was dried under reduced pressure to obtain 13.5 g (42%) of methyl 5-cyano-2-methoxybenzoate. The mother liquor and the washings were combined, and concentrated, whereafter the residue was recrystallized from t-butyl methyl ether. The resulting crystals were separated by filtration, then washed with a 1:1 solvent mixture of n-hexane and diethyl ether, and then dried under reduced pressure to obtain 4.6 g (14%) of methyl 5-cyano-2-methoxybenzoate.
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([CH2:20][O:21][CH3:22])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([NH:32][CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])=[O:31])=[CH:26][CH:25]=1>>[CH:1]1([CH:7]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([C:30]([NH:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:31])=[CH:28][CH:29]=2)[C:9]2[C:10]([CH2:20][O:21][CH3:22])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(N)cc1
Reactant: COCc1nn(-c2ccccc2)cc1C(O)C1CCCCC1
Product: COCc1nn(-c2ccccc2)cc1C(Nc1ccc(C(=O)NCCC(=O)O)cc1)C1CCCCC1
Yield: 45.7 %

Procedure:
Using cyclohexyl[3-(methoxymethyl)-1-phenyl-1H-pyrazol-4-yl]methanol (0.50 g) synthesized above and ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (0.39 g) synthesized in Example 1(2) and in the same manner as in Example 1(7), the title object compound (0.37 g, 46%) was obtained as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:20]3[C:15](=[CH:16][C:17]([CH2:21][C:22]4[CH:27]=[C:26](Cl)[N:25]=[CH:24][N:23]=4)=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)=[O:10])=[CH:4][C:3]=1[C:29]([F:32])([F:31])[F:30].[CH3:33][NH2:34]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:20]3[C:15](=[CH:16][C:17]([CH2:21][C:22]4[CH:27]=[C:26]([NH:34][CH3:33])[N:25]=[CH:24][N:23]=4)=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)=[O:10])=[CH:4][C:3]=1[C:29]([F:32])([F:31])[F:30]
Reactant: O=C(Nc1ccc(F)c(C(F)(F)F)c1)c1cccc2cc(Cc3cc(Cl)ncn3)ccc12
Reactant: CN
Solvent: C1CCOC1
Product: CNc1cc(Cc2ccc3c(C(=O)Nc4ccc(F)c(C(F)(F)F)c4)cccc3c2)ncn1

Procedure:
A solution of 40 mg (0.087 mMol) 6-(6-chloro-pyrimidin-4-ylmethyl)-naphthalene-1-carboxylic acid (4-fluoro-3-trifluoromethyl-phenyl)-amide and 750 μl methylamine (2 M in THF; 1.5 mMol) in 1.5 ml THF is stirred in a sealed vessel for 20 h at rt and 3.5 h at 65° C. Concentration and chromatography (Combi Flash; EtOAc→EtOAc/EtOH 9:1) gives the title compound: MS: [M+1]+=455; TLC(EtOAc/EtOH 9:1): Rf=0.27.
Reaction SMILES: C(Cl)Cl.[CH:4]1([NH2:9])[CH2:8][CH2:7][CH2:6][CH2:5]1.C[Si]([N:14]=[C:15]=[O:16])(C)C>CO>[CH:4]1([NH:9][C:15]([NH2:14])=[O:16])[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: NC1CCCC1
Reactant: C[Si](C)(C)N=C=O
Solvent: CO
Solvent: ClCCl
Product: NC(=O)NC1CCCC1
Reaction time: 8 h

Procedure:
To a CH2Cl2 solution of cyclopentylamine was added trimethylsilyl isocyanate. The reaction mixture was stirred overnight. To this was added 200 ml of CH3OH, and the mixture was stirred for another 2 hrs. The reaction mixture was concentrated and was titrated using diethyl ether to give an off-white precipitate. The precipitate was filtered through a Buchner funnel to give cyclopentyl urea Compound 30a as a white crystalline solid compound (13.0 g, 86%). To this urea Compound 30a (5.0 g, 38.7 mmol) in acetic acid (11 mL), was added malonic acid (4.0 g, 38.7 mmol) followed by acetic anhydride (18 mL) and the reaction was stirred at 70° C. for 12 hrs. The reaction mixture was concentrated, cooled in an ice bath and titrated using 4/1 EtO2/EtOAc. A pale yellow crystalline solid precipitated out. The precipitate was filtered and washed 2-3 times using cold diethyl ether to obtain a pale yellow solid Compound 30b (2.5 g, 33%).
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[CH3:10][C:11]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:12]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21]([NH2:26])=[N:22][CH:23]=[CH:24][CH:25]=2)=[CH:16][CH:15]=1>C1COCC1>[CH3:10][C:11]1[CH:30]=[C:29]([C:31]([F:33])([F:32])[F:34])[CH:28]=[CH:27][C:12]=1[O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[C:21]3=[N:26][S:6](=[O:8])(=[O:7])[CH2:5][CH2:4][N:22]3[CH:23]=[CH:24][CH:25]=2)=[CH:18][CH:19]=1
Reactant: O=S(=O)(Cl)CCCl
Reactant: Cc1cc(C(F)(F)F)ccc1Oc1ccc(-c2cccnc2N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C(F)(F)F)ccc1Oc1ccc(C2=CC=CN3CCS(=O)(=O)N=C23)cc1
Reaction time: 0.08 h

Procedure:
To a suspension of NaH (60%, 284 mg) in THF (dry) (25 mL) was added 2-chloroethanesulfonyl chloride (0.448 mL) at 0° C. and the mixture was stirred for 5 min at the same temperature. A solution of 3-(4-(2-methyl-4-(trifluoromethyl)phenoxy)phenyl)pyridin-2-amine (489 mg) in THF (dry) (40 mL) was added at 0° C. and the mixture was stirred at room temperature overnight. The mixture was quenched with water at 0° C. Water, EtOAc and THF were added and the extracted organic layer was washed with brine. Silica-gel was added to the organic layer and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) and washed with IPE to give the title compound (390 mg) as a white solid. A part of this was recrystallized from MeCN/IPE.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH2:18](O)[CH3:19]>>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([O:12][CH2:18][CH3:19])=[O:11])=[CH:4][CH:3]=1
Reactant: CCO
Reactant: Cc1ccc(C=CC(=O)O)cn1
Agent: O=S(=O)(O)O
Product: CCOC(=O)C=Cc1ccc(C)nc1

Procedure:
A stirred mixture of 3-(6-methyl-3-pyridyl)acrylic acid (50.70 g), dry ethanol (350 ml) and concentrated sulphuric acid (25 ml) was heated under reflux for 18 hours and ethanol (~250 ml) was removed by evaporation. The residue was poured into ice-aqueous ammonia and the mixture was extracted with ether. The ether extracts were washed with water and evaporated to an oil which crystallised on standing to give ethyl 3-(6-methyl-3-pyridyl)acrylate, m.p. 36°-37°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([OH:22])[C@@H:9]2[O:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Br[CH2:26][C:27]#[N:28]>CC#N>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([O:22][CH2:26][C:27]#[N:28])[C@@H:9]2[O:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#CCBr
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H]([C@@H](O)c2cccc(Cl)c2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCO[C@@H]([C@@H](OCC#N)c2cccc(Cl)c2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (R)-tert-butyl 2-((S)-(3-chlorophenyl)(hydroxy)methyl)morpholine-4-carboxylate (1.3 g, 3.98 mmol) in MeCN (20 mL), NaH (230 mg, 9.55 mmol) was added at 0° C. The mixture was stirred for 1 h at rt. The mixture was cooled to −40° C., and bromoacetonitrile (1.14 g, 9.55 mmol) was added in portions. The mixture was stirred for 0.5 h at −20° C. The solution was evaporated and H2O (50 mL) was added. 1N aq HCl was added and the mixture was extracted with CH2Cl2. The organic layer was washed with aq NaHCO3 and brine, dried over Na2SO4 and concentrated. The crude product was used directly in the next step.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1([OH:16])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:18]1[CH:23]=[CH:22][N+:21]([O-:24])=[CH:20][CH:19]=1.C(=O)([O-])O.[Na+].O>C(O)CC(C)C>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1([OH:16])[CH2:11][CH2:12][N:13]([C:18]2[CH:23]=[CH:22][N+:21]([O-:24])=[CH:20][CH:19]=2)[CH2:14][CH2:15]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [O-][n+]1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NCC1(O)CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)CCO
Product: CC(C)(C)OC(=O)NCC1(O)CCN(c2cc[n+]([O-])cc2)CC1
Yield: 36.8 %

Procedure:
To a suspension in isoamyl alcohol (35 ml) of conventionally known compounds: 4-[(t-butoxycarbonylamino)methyl]-4-hydroxypiperidine (2.00 g) and 4-chloropyridine 1-oxide (1.12 g), was added sodium hydrogencarbonate (1.75 g) and the mixture was heated under reflux for 4 hours. The reaction mixture was allowed to cool and water was added thereto. The reaction mixture was extracted with methylene chloride and the organic layer was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by silica gel column chromatography (eluent:methylene chloride:methanol=9:1–4:1) to obtain the title compound (1.03 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][NH:6][C:7]1[C:8]2[C:13]([N:14]=[C:15]3[C:20]=1[C:19](=[O:21])[CH2:18][CH2:17][CH2:16]3)=[CH:12][CH:11]=[CH:10][CH:9]=2.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][NH:6][C:7]1[C:8]2[C:13]([N:14]=[C:15]3[C:20]=1[CH:19]([OH:21])[CH2:18][CH2:17][CH2:16]3)=[CH:12][CH:11]=[CH:10][CH:9]=2
Reactant: O=C1CCCc2nc3ccccc3c(NCc3cccc(Cl)c3)c21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OC1CCCc2nc3ccccc3c(NCc3cccc(Cl)c3)c21
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a ice cooled suspension of 9-(3-chlorobenzylamino)-3,4-dihydroacridin-1(2H)-one (3.6 g) in 75 ml of tetrahydrofuran was added a 1M solution of lithium aluminum hydride in THF (6 ml). This was stirred at ice bath temperature for 45 minutes.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[S:14][C:13]([C:15]2[N:20]=[C:19]([NH:21][C:22]3[NH:26][N:25]=[C:24]([CH:27]4[CH2:29][CH2:28]4)[CH:23]=3)[C:18]([C:30]#[CH:31])=[CH:17][N:16]=2)=[CH:12][CH:11]=1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH:27]1([C:24]2[NH:25][N:26]=[C:22]([NH:21][C:19]3[C:18]([C:30]#[CH:31])=[CH:17][N:16]=[C:15]([C:13]4[S:14][C:10]([CH2:9][OH:8])=[CH:11][CH:12]=4)[N:20]=3)[CH:23]=2)[CH2:29][CH2:28]1
Reactant: C#Cc1cnc(-c2ccc(CO[Si](C)(C)C(C)(C)C)s2)nc1Nc1cc(C2CC2)n[nH]1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1cnc(-c2ccc(CO)s2)nc1Nc1cc(C2CC2)[nH]n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21.8 %

Procedure:
A mixture of 2-(5-((tert-butyldimethylsilyloxy)methyl)thiophen-2-yl)-N-(3-cyclopropyl-1H-pyrazol-5-yl)-5-ethynylpyrimidin-4-amine (240 mg, 0.53 mmol, 1.0 eq), TBAF (694 mg, 2.66 mmol, 5.0 eq) in THF (20 ml) was stirred at room temperature for 30 min. The reaction mixture was evaporated under reduce pressure and the resulting residue was dissolved in EtOAc. The organic layers were washed with water, brine, dried (Na2SO4) and filtered. The filtrate was concentrated the residue was recrystalized by ether to give title compound (5-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-ethynylpyrimidin-2-yl)thiophen-2-yl)methanol (Compound 196) (39 mg, 22%). LC-MS (m/z)=338.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 0.74 (s, 2H), 0.92-0.97 (m, 2H), 1.94 (s, 1H), 4.67 (d, J=5.2 Hz, 2H), 4.83 (s, 1H), 5.61-5.63 (m, 1H), 6.52 (s, 1H), 7.03 (d, J=1.2 Hz, 1H), 7.72 (d, J=2.4 Hz, 1H), 8.45-8.50 (m, 2H), 12.24 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8](O)[C:7](=[O:14])[C:6](=[O:15])[N:5]2[CH:16]1[CH2:18][CH2:17]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:8][C:7](=[O:14])[C:6](=[O:15])[N:5]2[CH:16]2[CH2:18][CH2:17]2)=[CH:10][C:11]=1[F:12]
Reactant: O=c1c(=O)n(C2CC2)c2cc(Cl)c(F)cc2n1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: O=c1[nH]c2cc(F)c(Cl)cc2n(C2CC2)c1=O
Temperature: 135 °C
Reaction time: 4 h

Procedure:
To a solution of 685 mg (2.531 mmol) 6-chloro-4-cyclopropyl-7-fluoro-1-hydroxy-1,4-dihydro-quinoxaline-2,3-dione in 10 mL N,N-dimethylformamide was added 996 mg (3.796 mmol) triphenylphosphine. The reaction mixture was stirred for 4 hours at 135° C. The reaction mixture was concentrated under vacuum (15 mbar/55° C.). The residue was suspended in 20 mL dichloromethane. The suspension was stirred for 30 min at 0° C. and filtered and washed with 20 mL dichloromethane. White solid (63%). MS (ESI): m/z=255.034 [M+H]+.