Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34][CH:33]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([O:29][C:35]2[CH:36]=[CH:37][C:32]([O:31][CH3:30])=[CH:33][CH:34]=2)[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc(Br)cc3)CC2)c1
Reactant: COc1ccc(O)cc1
Product: COc1ccc(OC(CCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccc(Br)cc2)cc1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(4-bromophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-methoxyphenol: ESMS m/e: 565.0 (M+H)+.
Reaction SMILES: [C:1]([CH2:3][N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7][C:6]2[CH:15]=[C:16]([CH:19]=O)[CH:17]=[CH:18][C:5]1=2)#[N:2].Cl.C[O:23][C:24](=[O:30])[C@H:25]([CH:27]([CH3:29])[CH3:28])[NH2:26].C1COCC1.C([BH3-])#N.[Na+]>CO>[C:1]([CH2:3][N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7][C:6]2[CH:15]=[C:16]([CH2:19][NH:26][C@H:25]([C:24]([OH:23])=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:17]=[CH:18][C:5]1=2)#[N:2]
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: N#CCN1c2ccccc2CCc2cc(C=O)ccc21
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)[C@H](NCc1ccc2c(c1)CCc1ccccc1N2CC#N)C(=O)O
Temperature: 25 °C
Reaction time: 48 h
Yield: 86.6 %

Procedure:
A mixture of 1.0 g of Compound 40-a, 0.7 g of valine methylester hydrochloride, 0.5 g of molecular sieves and 15 ml of THF was stirred at room temperature for 2 days. After ice cooling, 3 ml of methanol and subsequently 0.4 g of sodium cyanoborohydride were added to the mixture. After the mixture was stirred overnight, insoluble matters were filtered off, and the filtrate was concentrated. The residue was diluted with dichloromethane, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The Solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [eluent: hexane/ethyl acetate (1/1)] to give 1.2 g (82%) of the product as a yellow oily substance.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([N:20]=[C:21]=[O:22])[CH3:19]>>[CH2:18]([NH:20][C:21](=[O:22])[O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:9][CH2:10]2)[CH3:19]
Reactant: Oc1ccc2c(c1)CCN2Cc1ccccc1
Reactant: CCN=C=O
Product: CCNC(=O)Oc1ccc2c(c1)CCN2Cc1ccccc1

Procedure:
The title compound was synthesized from 1-benzylindolin-5-ol (15.0 mg, 66.6 μmol) using the same procedure employed for Example 2 (2), but with ethylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained having the following characteristics (12.4 mg, 63%).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][CH:12]=3)=[CH:7][CH2:6]2)[O:4][CH2:3][CH2:2]1>[Pd].C(O)C>[O:4]1[C:5]2([CH2:6][CH2:7][CH:8]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][CH:12]=3)[CH2:9][CH2:10]2)[O:1][CH2:2][CH2:3]1
Reactant: C1=C(c2c[nH]c3ccccc23)CCC2(C1)OCCO2
Agent: [Pd]
Solvent: CCO
Product: c1ccc2c(C3CCC4(CC3)OCCO4)c[nH]c2c1
Reaction time: 18 h
Yield: 99.4 %

Procedure:
A mixture of 3-(1,4-dioxa-spiro[4,5]dec-7-en-8-yl)-1H-indole (8.0 g, 31.3 mmol) and 10% palladium on carbon (1.3 g) in ethanol (700 ml) was hydrogenated for 18 hours. The catalyst was filtered off and the solvent removed under vacuum to afford 8.01 g (99%) of product as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=O)[CH2:6][CH2:5]2.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][C:13]1=[O:21].N1CCCCC1.Cl>CN(C)C=O>[NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[C:14]1[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[NH:12][C:13]1=[O:21])[CH2:6][CH2:5]2
Reactant: O=C1Cc2ccccc2N1
Reactant: Nc1ccc2c(c1)CCC2=O
Agent: Cl
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: Nc1ccc2c(c1)CCC2=C1C(=O)Nc2ccccc21
Temperature: 130 °C
Yield: 5 %

Procedure:
A mixture of 0.5 g 5-amino-1-indanone, 1.3 g oxindole and 3 ml piperidine in 5 ml of dimethylforamide was heated in a sealed tube at 130° C. for 3 days to yield a reddish-black suspension. The mixture was added to 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine, dried with magnesium sulfate and concentrated. Chromatography afforded 45 mg of 3-(5-aminoindan-1-ylidene)-1,3-dihydroindol-2-one as a brown solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:20]([O:21][CH3:22])=[CH:19][C:12]2[CH2:13][CH2:14][CH2:15][CH2:16][C:17](=[O:18])[C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].[C:26](=O)([O:29]C)[O:27][CH3:28]>>[CH3:28][O:27][C:26]([CH:16]1[CH2:15][CH2:14][CH2:13][C:12]2[CH:19]=[C:20]([O:21][CH3:22])[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:10][C:11]=2[C:17]1=[O:18])=[O:29]
Reactant: COc1cc2c(cc1OCc1ccccc1)C(=O)CCCC2
Reactant: COC(=O)OC
Agent: C[O-]
Agent: [Na+]
Product: COC(=O)C1CCCc2cc(OC)c(OCc3ccccc3)cc2C1=O
Temperature: 0 °C

Procedure:
A mixture of 3-benzyloxy-2-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one (3.2 g), sodium methoxide (2.8 g) and dimethyl carbonate (100 ml) is heated for four hours under reflux in a stream of nitrogen. The reaction mixture is poured into ice-water containing concentrated hydrochloric acid (10 ml), and extracted with ethyl acetate. The organic layer is washed with water, dried and concentrated under reduced pressure to afford 3-benzyloxy-2-methoxy-5-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene-6-carboxylic acid methyl ester (3.7 g) as a pale yellow oily product.
Reaction SMILES: C[O:2][C:3](=[O:20])[CH:4]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1)[CH2:5][CH:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.O.[OH-].[Li+]>O1CCCC1.C(O)C.O.S([O-])(O)(=O)=O.[K+]>[Cl:19][C:14]1[CH:13]=[C:12]([CH:4]([CH2:5][CH:6]2[CH2:7][CH2:8][O:9][CH2:10][CH2:11]2)[C:3]([OH:20])=[O:2])[CH:17]=[CH:16][C:15]=1[Cl:18]
Reactant: COC(=O)C(CC1CCOCC1)c1ccc(Cl)c(Cl)c1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)C(CC1CCOCC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.7 %

Procedure:
2-(3,4-Dichloro-phenyl)-3-(tetrahydro-pyran-4-yl)-propionic acid methyl ester (2.26 g, 7.12 mmol) was dissolved in tetrahydrofuran:ethanol:water (6:3:2) reaction (100 mL) and treated with lithium hydroxide monohydrate (1.50 g, 35.6 mmol) at 25° C. It was stirred at 25° C. for 2 h. The reaction was then diluted with a 1 M aqueous solution of potassium hydrogen sulfate (200 mL) and then extracted with ethyl acetate (1×300 mL), the organic layers combined and dried over sodium sulfate, filtered and concentrated in vacuo with silica gel (4 g) and purified by Biotage Flash Chromatography (40M column, Silica gel, 10% methanol/ethyl acetate) to afford 2-(3,4-dichloro-phenyl)-3-(tetrahydro-pyran-4-yl)-propionic acid (2.00 g, 93%) as an off white solid.
Reaction SMILES: Br[C:2]1[C:7]([CH2:8][O:9][C:10]2[C:15]([CH:16]=[O:17])=[CH:14][C:13]([O:18][CH3:19])=[N:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:20][N:21](C=O)C>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>[CH:16]([C:15]1[CH:14]=[C:13]([O:18][CH3:19])[N:12]=[CH:11][C:10]=1[O:9][CH2:8][C:7]1[C:2]([C:20]#[N:21])=[N:3][CH:4]=[CH:5][CH:6]=1)=[O:17]
Reactant: COc1cc(C=O)c(OCc2cccnc2Br)cn1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: COc1cc(C=O)c(OCc2cccnc2C#N)cn1
Temperature: 125 °C
Yield: 84 %

Procedure:
To a mixture of 5-((2-bromopyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde (100 mg, 0.31 mmol, 1 equiv), Zn (CN)2 (71 mg, 0.62 mmol, 2.0 equiv), Pd(PPh3)4 (72 mg, 0.06 mmol, 0.2 equiv) in a 5 mL microwave tube was added DMF (2 mL). The mixture was heated 15 min at 125° C. in a microwave reactor. The solid was filtered off and the filtrate was concentrated to dryness. The crude was purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 3-((4-formyl-6-methoxypyridin-3-yloxy)methyl)picolinonitrile (71 mg, 84%) as a white solid. 1H NMR (400 MHz; CDCl3) δ=10.54 (s, 1H), 8.86 (d, 1H), 8.22 (s, 1H), 8.20 (d, 1H), 7.74 (dd, 1H), 6.37 (s, 1H) 5.52 (s, 2H), 4.04 (s, 3H). LRMS (M+H+) m/z 270.1.
Reaction SMILES: [NH2:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][C:7]2[N:12]3[CH:13]=[C:14]([C:16]4[C:24]5[C:19](=[N:20][CH:21]=[CH:22][CH:23]=5)[NH:18][CH:17]=4)[CH:15]=[C:11]3[C:10](=[O:25])[N:9](CC3C=CC(OC)=CC=3OC)[CH:8]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl.C1(C)C=CC=CC=1>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[N:12]3[CH:13]=[C:14]([C:16]4[C:24]5[C:19](=[N:20][CH:21]=[CH:22][CH:23]=5)[NH:18][CH:17]=4)[CH:15]=[C:11]3[C:10](=[O:25])[NH:9][CH:8]=2)=[CH:37][CH:38]=1
Reactant: COc1ccc(Cn2cc(Cc3ccc(N)cc3)n3cc(-c4c[nH]c5ncccc45)cc3c2=O)c(OC)c1
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(Cc2c[nH]c(=O)c3cc(-c4c[nH]c5ncccc45)cn23)cc1
Temperature: 120 °C

Procedure:
To a solution of EXAMPLE 23J (300 mg, 0.594 mmol) in CH2Cl2 (5 ml) was added trifluoroacetic acid (10 mL), and the mixture was heated at 120° C. in a microwave reactor (Biotage, Initiator) for 40 minutes. After cooling, the reaction mixture was diluted with toluene (50 mL) and concentrated. The residue was purified flash chromatography (CH2Cl2/tetrahydrofuran/CH3OH/Et3N, 50/50/1/1) to afford the title compound. LC-MS (ESI): m/z 356 (M+H), RT: 1.30 min; 1H NMR (400 MHz, dimethylsulfoxide, d6): δ 3.92 (s, 2H), 4.97 (s, 2H), 6.28 (d, J=5.6 Hz, 1H), 6.54 (d, J=8.0 Hz, 2H), 7.07 (d, J=8.4 Hz, 2H), 7.13 (dd, J=4.8, 3.2 Hz, 1H), 7.27 (d, J=2.0 Hz, 1H), 7.69 (d, J=2.0 Hz, 1H), 7.83 (d, J=2.4 Hz, 1H), 8.18 (dd, J=6.8, 1.2 Hz, 1H), 8.27 (dd, J=3.6, 1.2 Hz, 1H), 10.46 (d, J=6.0 Hz, 1H), 11.74 (br s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.NC1C=CC=C2C(N(O)C(=O)C=12)=[O:15]>>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH:1]=[O:15])=[CH:3][CH:4]=1
Reactant: Nc1cccc2c1C(=O)N(O)C2=O
Reactant: COc1ccc(C)cc1
Product: COc1ccc(C=O)cc1
Yield: 61 %

Procedure:
195 mg (1.60 mmol) of 4-methylanisole were reacted analogously to Example 1 in the presence of 32.1 mg (0.180 mmol) of 3-amino-N-hydroxyphthalimide. After a reaction time of 22 hours, the reaction solution was extracted with chloroform and examined by NMR spectroscopy and gas chromatography. Yield 61% of 4-methoxybenzaldehyde (approx. 90%, based on conversion).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[C:13]1([C:19]#[C:20][C:21]2[CH:22]=[C:23]([CH2:27][C:28]([OH:30])=[O:29])[CH:24]=[CH:25][CH:26]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH:31](=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O1CCCC1>[OH:38][C@@H:31]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C@H:27]([C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([C:20]#[C:19][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:22]=1)[C:28]([OH:30])=[O:29]
Reactant: O=C(O)Cc1cccc(C#Cc2ccccc2)c1
Reactant: O=Cc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(O)[C@@H](c1cccc(C#Cc2ccccc2)c1)[C@@H](O)c1ccccc1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
To diisopropylamine (0.241 mL, 1.693 mmol) in tetrahydrofuran (10 mL) under nitrogen at −78° C. was added n-BuLi (0.677 mL, 1.693 mmol). After 60 min, the colorless solution was warmed to −20° C. and a solution of 2-(3-(phenylethynyl)phenyl)acetic acid (200 mg, 0.847 mmol; Araldi, G. L.; Liao, Y.; Brugger, N. Hydrazide Deriviatives as Prostaglandin Receptor Modulators. WO 2005/012232 A2, 2005) in tetrahydrofuran (5 mL) was added resulting in a red solution which was allowed to stir for 45 min as the cooling bath temperature rose to 5° C. The reaction was recooled to −30° C., benzaldehyde (0.103 mL, 1.016 mmol) was added dropwise resulting in immediate disappearance of the red color and the cooling bath was removed. After 48 h, the reaction mixture was quenched with 1N HCl (20 mL), extracted with ethyl acetate (3×20 mL), washed with brine, dried over MgSO4, filtered and concentrated providing (2S,3R)-3-hydroxy-3-phenyl-2-(3-(phenylethynyl)phenyl)propanoic acid as an amber oil which was used in the next step without further purification or characterization.
Reaction SMILES: C(N(CC)CC)C.[OH:8][N:9]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]2[C:10]1=[O:19].[NH2:20][C:21]1[C:30]2[N:31]=[C:32]([CH2:43]Cl)[N:33]([CH2:34][CH2:35][CH2:36][NH:37][C:38](=[O:42])[CH:39]([CH3:41])[CH3:40])[C:29]=2[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N:22]=1>CN(C=O)C>[NH2:20][C:21]1[C:30]2[N:31]=[C:32]([CH2:43][O:8][N:9]3[C:10](=[O:19])[C:11]4[C:12](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:14])[N:33]([CH2:34][CH2:35][CH2:36][NH:37][C:38](=[O:42])[CH:39]([CH3:41])[CH3:40])[C:29]=2[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N:22]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC(C)C(=O)NCCCn1c(CCl)nc2c(N)nc3cccnc3c21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)C(=O)NCCCn1c(CON2C(=O)c3ccccc3C2=O)nc2c(N)nc3cccnc3c21
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.5 %

Procedure:
Triethylamine (0.340 mL, 2.41 mmol) and N-hydroxyphthalimide (0.333 g, 2.04 mmol) were added to a suspension of N-{3-[4-amino-2-(chloromethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]propyl}-2-methylpropanamide (0.670 g, 1.86 mmol) in DMF (10 mL). The reaction was allowed to stir at room temperature for 4 hours, then was concentrated under reduced pressure. The residue was triturated with methanol to afford 0.848 g of N-[3-(4-amino-2-{[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]methyl}-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)propyl]-2-methylpropanamide as a tan solid.
Reaction SMILES: [CH3:1][C:2]([S@:5]([NH:7][C:8]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:34])([F:33])[F:32])[CH:25]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=1)[CH2:9][C:10]([NH2:12])=[O:11])=[O:6])([CH3:4])[CH3:3].CO>N.C(O)CO.CCOC(C)=O>[CH3:4][C:2]([S:5]([NH:7][C:8]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:21])[F:22])[CH:14]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:33])([F:34])[F:32])[CH:25]=1)[CH2:9][C:10]([NH2:12])=[O:11])=[O:6])([CH3:1])[CH3:3]
Reactant: CC(C)(C)[S@@](=O)NC(CC(N)=O)(c1cccc(OC(F)(F)F)c1)c1cccc(OC(F)(F)F)c1
Agent: N
Solvent: OCCO
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)S(=O)NC(CC(N)=O)(c1cccc(OC(F)(F)F)c1)c1cccc(OC(F)(F)F)c1
Temperature: 120 °C
Yield: 76.3 %

Procedure:
(R)-3-(2-methylpropan-2-ylsulfinamido)-3,3-bis(3-(trifluoromethoxy)phenyl)propanamide (prepared as described for Procedure 11, 0.70 g, 1.33 mmol) was dissolved in 8N NH3 in ethylene glycol (6 mL) at room temperature in a microwave vial. The reaction mixture was heated at 120° C. for 1200 sec, and then at 130° C. for 1200 sec under microwave irradiation. After cooling, the cap was removed, and H2O was added. The mixture was extracted with EtOAc (3×), washed with H2O and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (silica gel, hexanes/EtOAc, then 10% MeOH in EtOAc) to give 3-(2-methylpropan-2-ylsulfinamido)-3,3-bis(3-(trifluoromethoxy)phenyl)-propanamide as white solid (0.52 g, yield: 76%) LCMS: 3.88 min [M+1]513.28 (4 min gradient, MeOH/H2O 0.1% TFA); 1H NMR (400 MHz, CDCl3) δ ppm 7.40-7.29 (m, 3H), 7.22-7.12 (m, 3H), 7.11-7.02 (m, 2H), 6.29 (m, 2H), 5.40 (s, br, 1H), 3.78 (d, J=14.50 Hz, 1H), 3.71 (s, 2H), 3.35 (d, J=14.50 Hz, 1H), 1.21-1.28 (m, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[O:5][C:6]1[N:7]=[C:8]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[C:9]([C:16]([NH2:18])=[O:17])=[N:10][C:11]=1[C:12]([OH:15])([CH3:14])[CH3:13].C(N(C(C)C)CC)(C)C.[C:45](Cl)(=[O:48])[CH:46]=[CH2:47].C(=O)([O-])O.[Na+].[OH-].[Na+]>O1CCCC1.C(Cl)(Cl)Cl>[C:45]([NH:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[O:5][C:6]1[N:7]=[C:8]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([N:26]3[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]3)=[CH:24][CH:25]=2)[C:9]([C:16]([NH2:18])=[O:17])=[N:10][C:11]=1[C:12]([OH:15])([CH3:13])[CH3:14])(=[O:48])[CH:46]=[CH2:47]
Reactant: C=CC(=O)Cl
Reactant: CN1CCN(c2ccc(Nc3nc(Oc4cccc(N)c4)c(C(C)(C)O)nc3C(N)=O)cc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: C=CC(=O)Nc1cccc(Oc2nc(Nc3ccc(N4CCN(C)CC4)cc3)c(C(N)=O)nc2C(C)(C)O)c1
Reaction time: 0.5 h

Procedure:
To a mixture of 5-(3-aminophenoxy)-6-(2-hydroxypropan-2-yl)-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide (27 mg), diisopropylethylamine (29 μL), and chloroform (5 ml) was added acryloyl chloride (7 μL) under ice-cooling, followed by stirring for 30 minutes. Further acryloyl chloride (7 μL) was added, followed by stirring under ice-cooling for 30 minutes. Diisopropylethylamine (29 μl) and acryloyl chloride (7 μL) were added thereto, followed by stirring for 30 minutes under ice-cooling. A saturated aqueous sodium hydrogen carbonate solution (10 mL) and tetrahydrofuran (20 mL) were added thereto under ice-cooling, followed by stirring for 10 minutes under ice-cooling. To the reaction mixture was added a 1 M aqueous sodium hydroxide solution (2 mL), followed by stirring at room temperature for 30 minutes. The reaction mixture was subjected to liquid separation and to the organic phase was added silica gel. Then, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; chloroform:methanol:28% aqueous ammonia=1:0:0-200:10:1), washed with ethyl acetate, and the solid was collected by filtration and then dried under reduced pressure to obtain 5-[3-(acryloylamino)phenoxy]-6-(2-hydroxypropan-2-yl)-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide (18 mg) as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[N:6]=[C:7]([O:9][CH:10]3[CH2:15][CH2:14][N:13]([C:16]4[S:17][C:18]([CH3:21])=[N:19][N:20]=4)[CH2:12][CH2:11]3)[S:8][C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:32]2[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH:33]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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>[CH3:21][C:18]1[S:17][C:16]([N:13]2[CH2:14][CH2:15][CH:10]([O:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([C:32]5[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH:33]=5)[CH:23]=[CH:22][C:5]=4[N:6]=3)[CH2:11][CH2:12]2)=[N:20][N:19]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Cc1nnc(N2CCC(Oc3nc4ccc(Br)cc4s3)CC2)s1
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nnc(N2CCC(Oc3nc4ccc(C5=CCN(C(=O)OC(C)(C)C)CC5)cc4s3)CC2)s1
Temperature: 100 °C
Reaction time: 8 h
Yield: 78.8 %

Procedure:
To a degassed solution of 6-bromo-2-(1-(5-methyl-1,3,4-thiadiazol-2-yl)piperidin-4-yloxy)benzo[d]thiazole (450 mg, 1.094 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (406 mg, 1.313 mmol) and potassium carbonate (454 mg, 3.28 mmol) in dioxane (9 mL) and water (3.0 mL) was added Pd(Ph3P)4 (63 mg, 0.055 mmol). The reaction mixture was stirred at 100° C. overnight. The reaction mixture was cooled to rt, diluted with water (20 mL), and extracted with CH2Cl2 (3×15 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography (silica gel, hexanes-EtOAc gradient 30 to 100% EtOAc) to afford tert-butyl 4-(2-(1-(5-methyl-1,3,4-thiadiazol-2-yl)piperidin-4-yloxy)benzo[d]thiazol-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate (443 mg, 0.862 mmol, 79% yield) as a yellow solid. 1H NMR (500 MHz, chloroform-d) δ ppm 7.59-7.65 (2H, m), 7.41 (1H, dd, J=8.5, 1.7 Hz), 6.00-6.11 (1H, m), 5.41-5.48 (1H, m), 4.07-4.12 (2H, m), 3.75-3.83 (2H, m), 3.66 (2H, t, J=5.5 Hz), 3.52-3.59 (2H, m), 2.60 (3H, s), 2.53-2.58 (2H, m), 2.19-2.27 (2H, m), 2.06-2.14 (2H, m), 1.50 (9H, s). LCMS (m/z)=514 (M+H)+.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[NH2:13][C:14]1[CH:19]=[C:18]([Cl:20])[C:17]([OH:21])=[C:16]([Cl:22])[CH:15]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[Cl:20][C:18]1[CH:19]=[C:14]([NH2:13])[CH:15]=[C:16]([Cl:22])[C:17]=1[O:21][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Nc1cc(Cl)c(O)c(Cl)c1
Reactant: COc1ccc2nc(Cl)sc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc2nc(Oc3c(Cl)cc(N)cc3Cl)sc2c1
Yield: 56 %

Procedure:
To a solution of 2-chloro-6-methoxybenzothiazole (prepared as described by Weinstock et. al., J. Med. Chem. 30: p1166 (1987)) and 4-Amino-2,6-dichlorophenol 1.3 g (available from Tokyo Chemical Industry Co., Ltd.) in DMSO (9 ml), was added K2CO3 3.12 g. The mixture was heated at 150 degree for 3 hr. The reaction mixture was purified by column chromatography(silica gel, AcOEt:Hexane=1:2) to provide the aniline 367 (1.43 g, 56%). mp 158-160° C.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH:3]=[CH2:4].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1.[O:23]1[CH:28]=[CH:27][CH2:26][CH2:25][CH2:24]1>C(Cl)Cl>[CH2:1]([O:5][CH:24]1[CH2:25][CH2:26][CH2:27][CH2:28][O:23]1)[CH2:2][C:3]#[CH:4]
Reactant: C=CCCO
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: C#CCCOC1CCCCO1
Reaction time: 8 h
Yield: 86 %

Procedure:
A solution of 3-butyn-1-ol 1 (1.00 g, 14.3 mmol) and PPTS (0.72 g, 2.9 mmol) in CH2Cl2 (20 mL) was treated dropwise with dihydropyran (1.7 mL, 19 mmol) and the resulting mixture was stirred for overnight. The reaction mixture was diluted with CH2Cl2 (80 mL) and washed with 0.02 N NaOH (50 mL) and brine (100 mL). The organic layer was dried over MgSO4 and concentrated and the residue was purified with 3-5% EtOAc in hexane on silica gel to give 1.90 g of compound 2 (12.3 mmol, 86% yield): 1H NMR (CDCl3) δ 4.63 (t, J=3.4 Hz, 1H), 3.92˜3.77 (m, 2H), 3.59˜3.45 (m, 2H), 2.47 (td, J=7.1, 2.8 Hz, 2H), 1.96 (t, J=2.5 Hz, 1H), 1.90˜1.44 (m, 6H).
Reaction SMILES: CN(OC)[C:3](=[O:13])[CH2:4][NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[CH:16]([Mg]Cl)([CH3:18])[CH3:17].Cl>O1CCCC1.C(OCC)C>[C:9]([O:8][C:6]([NH:5][CH2:4][C:3](=[O:13])[CH:16]([CH3:18])[CH3:17])=[O:7])([CH3:10])([CH3:11])[CH3:12]
Reactant: CON(C)C(=O)CNC(=O)OC(C)(C)C
Reactant: CC(C)[Mg]Cl
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)C(=O)CNC(=O)OC(C)(C)C
Temperature: 2.5 °C
Reaction time: 4 h

Procedure:
A solution of 10.9 g of N-tert.-butoxycarbonylglycine N-methyl-N-methoxyamide in 300 ml of anhydrous tetrahydrofuran and 100 ml of anhydrous diethyl ether was cooled at 0-5° C. while 100 ml of a 2M solution of isopropyl magnesium chloride in tetrahydrofuran was added slowly. The mixture was stirred at 0-5° C. for 4 h then poured into 1.5 liter of 1M hydrochloric acid. The product was extracted with three portions of 500 ml diethyl ether. Combined extracts were washed with 500 ml brine then dried over anhydrous magnesium sulphate, filtered and evaporated to give 8.38 g of 4-tert.-butoxycarbonylamino-2-methyl-3-butanone as a colourless oil which was used without further purification.