Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[N:4]=[C:5]([S:35][CH3:36])[C:6](=[N:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([CH2:26][NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:19]=1)[C:7]1[CH:12]=[C:11]([CH2:13][CH3:14])[CH:10]=[C:9]([OH:15])[C:8]=1[F:16].CN(C=O)C.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:50][CH2:51][O:52][Si:53]([CH:60]([CH3:62])[CH3:61])([CH:57]([CH3:59])[CH3:58])[CH:54]([CH3:56])[CH3:55]>O.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:37])[N:4]=[C:5]([S:35][CH3:36])[C:6](=[N:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([CH2:26][NH:27][C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])[CH:19]=1)[C:7]1[CH:12]=[C:11]([CH2:13][CH3:14])[CH:10]=[C:9]([O:15][CH2:50][CH2:51][O:52][Si:53]([CH:57]([CH3:58])[CH3:59])([CH:54]([CH3:56])[CH3:55])[CH:60]([CH3:61])[CH3:62])[C:8]=1[F:16]
Reactant: CCc1cc(O)c(F)c(C(=Nc2ccc(C#N)c(CNC(=O)OC(C)(C)C)c2)C(=NC(=O)OC)SC)c1
Reactant: CC(C)[Si](OCCI)(C(C)C)C(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1cc(OCCO[Si](C(C)C)(C(C)C)C(C)C)c(F)c(C(=Nc2ccc(C#N)c(CNC(=O)OC(C)(C)C)c2)C(=NC(=O)OC)SC)c1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
To a mixture of {2-[3-(t-butoxycarbonylaminomethyl)-4-cyanophenylimino]-2-(5-ethyl-2-fluoro-3-hydroxyphenyl)-1-methylsulfanylethylidene}carbamic acid methyl ester (346 mg) and DMF (6 mL) there were added cesium carbonate (235 mg) and (2-iodoethoxy)triisopropylsilane [CAS No. 93550-77-7] (323 mg) in that order, under a nitrogen atmosphere The mixture was stirred for 40 hours at room temperature, and then ethyl acetate (200 mL) and water (50 mL) were added. The mixture was sufficiently shaken, and then the organic layer was separated oft washed twice with water (50 mL) and once with saturated aqueous sodium chloride (50 mL) in that order, and dried over anhydrous magnesium sulfate. The mixture was filtered to obtain a filtrate, and the solvent in the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane mixture) to obtain the target compound (406 mg) as an off-white oil.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[CH:6]3[CH2:13][O:14][CH2:15][CH2:16][N:5]3[C:4]=2[N:3]=1.Cl[CH2:18][C:19](=[O:21])[CH3:20].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:18][C:19](=[O:21])[CH3:20])[C:7](=[O:12])[CH:6]3[CH2:13][O:14][CH2:15][CH2:16][N:5]3[C:4]=2[N:3]=1
Reactant: O=C1Nc2cnc(Cl)nc2N2CCOCC12
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)CN1C(=O)C2COCCN2c2nc(Cl)ncc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 72.5 %

Procedure:
To a mixture of 2-chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (822 mg, 3.42 mmol), chloroacetone (0.429 ml, 5.12 mmol) in DMF (10 ml) was added K2CO3 (1.42 g, 10.3 mmol) and the reaction mixture was stirred at room temperature for 2 days. The reaction mixture was poured into water and extracted with EtOAc. The organic layers were washed with water and saturated aqueous NaCl, dried and concentrated in vacuo to give a crude solid. The crude residue was triturated with hexane/ethyl acetate (3:1), collected by filtration, rinsed with hexane/ethyl acetate (3:1) and dried to afford 2-chloro-5-(2-oxopropyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (737 mg, 2.48 mmol, 73% yield) as a pale brown solid. MS [M+H] found 297.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]=[C:17]([O:20][CH2:21][CH3:22])[CH2:18]Br)=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].[I-:23].[Na+]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]=[C:17]([O:20][CH2:21][CH3:22])[CH2:18][I:23])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8]
Reactant: [I-]
Reactant: CCOC(CBr)=Nc1ccc(Cl)cc1C(=O)c1ccccc1
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOC(CI)=Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reaction time: 1 h

Procedure:
To a solution of 3.8 parts of 5-chloro-2-(2-bromo-1-ethoxyethylideneamino)benzophenone in 30 parts by volume of acetone is added with stirring a solution of 1.5 parts of sodium iodide in 12 parts by volume of acetone. After about one hour, the resulting precipitate is removed by filtration. The filtrate is concentrated under reduced pressure. The concentrate is treated with petroleum ether to give 5-chloro-2-(1-ethoxy-2-iodoethylideneamino)benzophenone as crystals. The crystals are recrystallized from n-hexane to give pale brown pillars melting at 67°-68° C.
Reaction SMILES: [NH2:1][C@H:2]([C:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[NH:22]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[C@H:23]([C:39]([NH:41][C@H:42]([C:47](O)=[O:48])[CH2:43][C:44](=[O:46])[NH2:45])=[O:40])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:27][CH:26]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl.CN(C=O)C>[NH:22]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[C@H:23]([C:39]([NH:41][C@H:42]([C:47]([NH:1][C@H:2]([C:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)=[O:48])[CH2:43][C:44](=[O:46])[NH2:45])=[O:40])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:27][CH:26]=1
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)Nc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)N[C@@H](CC(N)=O)C(=O)O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)Nc1ccccc1
Yield: 30.1 %

Procedure:
compound SP314C2. Same procedure as above with Trp-NHPh (102.9 mg, 0.368 mmol), N-Boc-Tyr(Bn)-Asn-OH (178.9 mg, 0.368 mmol), EDC (78.2 mg, 0.41 mmol) and HOBt (55 mg, 0.41 mmol) in CH2Cl2/DMF (1.5 mL, 1/1). The crude residue was purified by flash column chromatography on silica gel (0-5% MeOH/CH2Cl2) to give an off-white solid (82.8 mg, 30%). 1H NMR (300 MHz, DMSO-d6) δ 1.28 (s, 9H, (CH3)3), 2.57-3.26 (m, 6H, CH2 Tyr, CH2 Trp, CH2 Asn), 4.11 (m, 1H, CHα), 4.58 (m, 2H, 2 CHα), 5.03 (broad s, 2H, CH2 (Bn)), 6.86-7.65 (m, 22H), 8.2 (m, 2H), 9.82 (s, 1H), 10.78 (s, 1H). 13C NMR (75 MHz, DMSO-d6) δ 27.3 (CH2 Trp), 28.1 ((CH3)3), 36.4, 37 (CH2 Tyr, CH2 Asn), 49.5, 54.5, 55.7 (CHα Tyr, Asn, Trp), 69 (CH2 (Bn)), 78.1 (C(CH3)3), 109.7, 110, 111.2, 114.2, 118.2, 119.6, 120.8, 123.4, 123.6, 127.2, 127.5, 127.7, 128.3, 128.5, 130.1, 136, 137.2, 138.7 (25 aromatic C), 155.2, 156.8 (Car-O, CO carbamate), 170, 171, 171.7, 171.9 (4 CO amide). Anal. Calcd. for C42H46N6O7: C, 67.54; H, 6.21; N, 11.25. Found: C, 67.14; H, 6.27; N, 11.27.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:20])[C@@H:15]([NH2:19])[CH:16]([CH3:18])[CH3:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N(CC)CC)C.[CH3:28][N:29]([CH3:34])[S:30](Cl)(=[O:32])=[O:31].Cl>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:20])[C@@:15]([NH2:19])([S:30](=[O:32])(=[O:31])[N:29]([CH3:34])[CH3:28])[CH:16]([CH3:17])[CH3:18])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCNC(=O)[C@@H](N)C(C)C)cc1OC
Reactant: CN(C)S(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COc1ccc(CCNC(=O)[C@](N)(C(C)C)S(=O)(=O)N(C)C)cc1OC

Procedure:
7.2 g of (S)-2-amino-3-methyl-butyric acid N-[2-(3,4-dimethoxyphenyl)-ethyl]-amide and 4 ml of triethylamine are initially introduced in 120 ml of 1,4-dioxane at room temperature, while stirring. 2.8 ml of N,N-dimethylsulfamoyl chloride are added dropwise in the course of 5 minutes. The reaction mixture is then stirred at room temperature for 20 hours and subsequently introduced into 80 ml of 2N hydrochloric acid. The mixture is extracted twice with 200 ml of ethyl acetate each time. The organic phases are washed once with 80 ml of 2N hydrochloric acid, once with 80 ml of saturated sodium chloride solution, once with 80 ml of 5% sodium bicarbonate solution and once with 80 ml of saturated sodium chloride solution, combined, dried over sodium sulfate and concentrated. (S)-2-(N,N-dimethylsulfamoyl)-amino-3-methyl-butyric acid N-[2-(3,4-dimethoxyphenyl)-ethyl]-amide, which can be purified by recrystallization from ethyl acetate/hexane, is obtained, melting point 97°-99° C.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH:11]1([C:15]#[N:16])[CH2:14][CH2:13][CH2:12]1.F[C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1.Cl>C1COCC1>[C:15]([C:11]1([C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)[CH2:14][CH2:13][CH2:12]1)#[N:16]
Reactant: N#CC1CCC1
Reactant: N#Cc1ccc(F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: N#Cc1ccc(C2(C#N)CCC2)cc1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 55.3 %

Procedure:
Solid KHMDS (3.48 g, 17.5 mmol) is dissolved in THF (20.0 mL) and cooled to 0° C. Cyclobutanecarbonitrile (1.42 g, 17.5 mmol) is added, and the resulting solution stirred for 40 minutes. A solution of 4-fluorobenzonitrile (2.12 g, 17.5 mmol) in THF (10.0 mL) is added, and the mixture stirred for 2 hours at 0° C. 1N HCl (50.0 mL) is added to the reaction mixture and the aqueous phase extracted with EtOAc (4×40.0 mL). The combined organic phases are dried over MgSO4, filtered and concentrated on the rotovaporator. The product is purified by flash chromatography (CombiFlash), eluting with mixtures of heptanes and EtOAc (0% EtOAc to 40% EtOAc) to yield the desired product (1.76 g, 9.67 mmol, 55%). 1H NMR (400 MHz, DMSO-D6) ε ppm 1.92-2.12 (m, 1H) 2.19-2.37 (m, 1H) 2.57-2.69 (m, 2H) 2.71-2.82 (m, 2H) 7.67 (d, J=8.59 Hz, 2H) 7.91 (d, J=8.79 Hz, 2H).
Reaction SMILES: [Si]([O:8][C@H:9]1[C:13]2([CH2:15][CH2:14]2)[C:12](=[O:16])[N:11]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([C:25]([F:28])([F:27])[F:26])[CH:18]=2)[C@H:10]1[CH3:29])(C(C)(C)C)(C)C.CO.Cl.C(=O)([O-])O.[Na+]>O1CCCC1>[OH:8][C@H:9]1[C:13]2([CH2:15][CH2:14]2)[C:12](=[O:16])[N:11]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([C:25]([F:28])([F:26])[F:27])[CH:18]=2)[C@H:10]1[CH3:29]
Reactant: C[C@H]1[C@@H](O[Si](C)(C)C(C)(C)C)C2(CC2)C(=O)N1c1ccc(C#N)c(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H]1[C@@H](O)C2(CC2)C(=O)N1c1ccc(C#N)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.4 %

Procedure:
To a solution of 4-[(6S,7S)-7-(tert-butyldimethylsilyloxy)-6-methyl-4-oxo-5-azaspiro[2.4]hept-5-yl]-2-(trifluoromethyl)benzonitrile (309.4 mg) in tetrahydrofuran (3 mL)-methanol (3 mL) was added 6 mol/L hydrochloric acid (3 mL), and the mixture was stirred at room temperature for 18 hr. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=30/1→1/3) to give the title compound as a colorless solid (yield: 152.3 mg, 67%).
Reaction SMILES: [NH2:1][C@H:2]([CH2:13][O:14][CH3:15])[C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].C(N(CC)CC)C.[C:23](OCC)(=[O:25])[CH3:24].C(OC(=O)C)(=O)C>C1CCCCC1>[C:23]([NH:1][C@H:2]([CH2:13][O:14][CH3:15])[C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4])(=[O:25])[CH3:24]
Reactant: COC[C@@H](N)C(=O)NCc1ccccc1
Reactant: CCOC(C)=O
Solvent: C1CCCCC1
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: COC[C@@H](NC(C)=O)C(=O)NCc1ccccc1
Temperature: 27.5 °C
Reaction time: 6 h

Procedure:
To a solution of (2R)-2-Amino-N-benzyl-3-methoxypropanamide (60.0 gms) and triethylamine (7.29 gms) in cyclohexane (600 ml) charged ethyl acetate (540 ml) and added acetic anhydride (35.29 gms) slowly maintaining the temperature at 25-30° C. in 15-20 minutes. Raised the temperature of the reaction mass to 35-40° C. and maintained for 4 hours. After completion of the reaction the reaction mass was cooled to 0 to 5° C. within 1 hour and maintained for 1.5 hours. Filtered the reaction mass at 0-5° C. and washed with cooled 1:1 mixture of ethyl acetate: cyclohexane (2×120 ml). The wet solid was taken in diethyl ether (612 ml) and stirred for 6 hours at 20-25° C. Filtered the product (2R)-2-acetamido-N-benzyl-3-methoxypropanamide and washed with diethyl ether and dried at 50-55° C. till constant weight.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[C:7](=[O:12])[N:6]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[C:5]2=[O:20].[BH4-].[Na+].O>CO.O1CCCC1>[CH3:11][C:10]1[CH:9]=[C:8]2[C:4](=[CH:3][C:2]=1[CH3:1])[C:5](=[O:20])[N:6]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[CH:7]2[OH:12]
Reactant: Cc1cc2c(cc1C)C(=O)N(c1ccc(F)cc1)C2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc2c(cc1C)C(O)N(c1ccc(F)cc1)C2=O
Yield: 94.6 %

Procedure:
The product of above-mentioned (1-a) (1.0 g, 3.7 mmol) was suspended in methanol (9 ml) and tetrahydrofuran (9 ml), and sodium borohydride (0.15 g, 3.9 mmol) was added by portions thereto with stirring under ice cooling, followed by stirring at the same temperature for 30 minutes. To the reaction solution was added water, and the precipitated crystals were collected by filtration, washed with water, followed by drying to give 0.95 g of 5,6-dimethyl-2-(4-fluorophenyl)-3-hydroxyisoindolin-1-one.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH:3]=1.CN.C[CH2:20][N:21](C(C)C)C(C)C>Cl.CCCCO>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[CH:3]=[C:2]([NH:21][CH3:20])[N:7]=[CH:6][N:5]=2)=[CH:10][CH:11]=1
Reactant: COc1ccc(Nc2cc(Cl)ncn2)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: Cl
Solvent: CCCCO
Product: CNc1cc(Nc2ccc(OC)cc2)ncn1
Temperature: 120 °C
Yield: 91 %

Procedure:
100 mg of 6-chloro-N-(4-methoxyphenyl)pyrimidine-4-amine in the form of a hydrochloride, 57 mg of methylamine and 238 mg of DIPEA were dissolved in 1 mL of n-BuOH in a screw cap vial and the mixture obtained was heated to 120° C. for 1 hour. Progress of the reaction was monitored by TLC. Upon termination of the reaction n-BuOH. was evaporated off and the evaporation residue was subjected to crystallization from n-BuOH/EtOH solvent mixture. N4-(4-Methoxyphenyl)-N6-methylpyrimidine-4,6-diamine was obtained in the form of a light yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][C@@H:6]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)[N:7]1[CH2:12][CH2:11][CH2:10][CH:9]([CH2:13][CH2:14][CH2:15][C:16](=O)[CH3:17])[C:8]1=[O:19])[CH3:2].[NH2:28][C:29]1[C:34]([CH:35]=O)=[CH:33][CH:32]=[CH:31][N:30]=1.N1CCC[C@H]1C(O)=O>C(O)C>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][C@@H:6]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)[N:7]1[CH2:12][CH2:11][CH2:10][CH:9]([CH2:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:35][C:34]3[C:29](=[N:30][CH:31]=[CH:32][CH:33]=3)[N:28]=2)[C:8]1=[O:19])[CH3:2]
Reactant: CCOC(=O)C[C@@H](c1cccc(F)c1)N1CCCC(CCCC(C)=O)C1=O
Reactant: Nc1ncccc1C=O
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Product: CCOC(=O)C[C@@H](c1cccc(F)c1)N1CCCC(CCCc2ccc3cccnc3n2)C1=O

Procedure:
A mixture of 2-7 (450 mg, 1.2 mmol), 2-amino-3-formylpyridine (145 mg, 1.2 mmol; for prep., see JOC 1983,48, 3401) and proline (137 mg, 1.2 mmol) in absolute ethanol (20 mL) was heated at reflux for 12 h. Following evaporative removal of the solvent, the residue was chromatographed (silica gel, 50% ethyl acetate/chloroform to 70:25:5 chloroform/ethyl acetate/MeOH) to give 2-8 as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([O:12][C:13](=[O:15])[CH3:14])=[C:7]([O:16][CH3:17])[C:6]([O:18][CH3:19])=[C:5]2[O:20]C(=O)C.P([O-])([O-])([O-])=O.P([O-])([O-])(O)=O.[Na+].[Na+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([O:12][C:13](=[O:15])[CH3:14])=[C:7]([O:16][CH3:17])[C:6]([O:18][CH3:19])=[C:5]2[OH:20]
Reactant: COc1c(OC)c(OC(C)=O)c2cc(Cl)ccc2c1OC(C)=O
Agent: O=P([O-])([O-])O
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COc1c(OC)c(OC(C)=O)c2ccc(Cl)cc2c1O
Yield: 22.8 %

Procedure:
Ten grams of 6-chloro-2,3-dimethoxy-1,4-diacetyloxynaphthalene, 150 ml of 0.05M, pH 8, phosphate buffer solution and 150 ml of acetonitrile were heated at 80° C. for 10 days. The reaction was monitored by TLC. Additional disodium hydrogen phosphate was added to maintain the reaction mixture at pH 8. The reaction mixture was cooled and solvent evaporated and the resultant residue was extracted with ethyl acetate (3X), washed with 1M HCl (2X) and brine (2X). The solution was dried over sodium sulfate, filtered and evaporated. The residue which is an isomeric mixture was recrystallized from petroleum ether and gave 2.0 gm 6-chloro-2,3-dimethoxy-1-acetyloxy-4-hydroxynaphthalene, m.p. 155°-6° C.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[CH2:3].[S:7]([CH2:11][CH2:12][OH:13])[CH2:8][CH2:9][OH:10].C(N(CC)CC)C.C(O)(=O)C>ClCCl>[C:1]([O:10][CH2:9][CH2:8][S:7][CH2:11][CH2:12][OH:13])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)Cl
Reactant: OCCSCCO
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCCSCCO
Temperature: 25 °C
Reaction time: 16 h
Yield: 27.5 %

Procedure:
A solution of methacryloyl chloride (16.7 g; 0.160 mol) in dichloromethane (100 ml) was added dropwise at 5° C. to a solution of thiodiethanol (20 g; 0.164 mol) and triethylamine (33.7 g; 0.334 mol) in dichloromethane (50 ml). After addition was complete, the solution was stirred at ambient temperature for 16 hrs. The excess triethylamine was neutralised with glacial acetic acid and the volume reduced on a rotary evaporator. The soluble organic products were extracted in diethyl ether and separated by filtration. Thiodiethanol monomethacrylate was purified by preparative flash chromatography, using silica gel (eluant=1:1 diethyl ether:hexane). Fractions containing pure product were collected and combined to yield thiodiethanol monomethacrylate (8.5 g; 0.044 mol, 28% yield) as a light coloured oil. Several attempts at distillation of TEDMA at reduced pressure and in the presence of excess stabiliser resulted in rapid polymerisation of the monomer. Thiodiethanol monomethacrylate was stored at 4° C. in the presence of 100 ppm 3,5-di-tert-butylcatechol.
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:6])([OH:5])[CH3:4].Cl[C:8]1[CH:9]=[CH:10][C:11]2[N:12]([C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:27])([F:26])[F:25])[CH:18]=3)=[CH:15][N:16]=2)[N:13]=1.CCN(C(C)C)C(C)C.[F-].[Cs+]>CS(C)=O>[CH3:4][C:3]([OH:5])([CH3:6])[CH2:2][NH:1][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:25])([F:27])[F:26])[CH:18]=3)=[CH:15][N:16]=2)[N:13]=1
Reactant: FC(F)(F)Oc1cccc(-c2cnc3ccc(Cl)nn23)c1
Reactant: CC(C)(O)CN
Agent: [Cs+]
Agent: [F-]
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(O)CNc1ccc2ncc(-c3cccc(OC(F)(F)F)c3)n2n1
Temperature: 120 °C
Reaction time: 5 h
Yield: 14.2 %

Procedure:
To the solution of compound 1-amino-2-methylpropan-2-ol (55 mg, 0.57 mmol) and compound 6-chloro-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazine (150 mg, 0.48 mmol) in 3 mL DMSO was added DIEA (0.21 mL, 0.96 mmol) and 10 mg CsF, the solvent was stirred for 5 h at 120° C., Then the mixture was purified by HPLC to afford the compound 2-methyl-1-((3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazin-6-yl)amino)propan-2-ol (25 mg, 12%) as a white solid.
Reaction SMILES: [C:1]([NH:9][CH:10]([CH3:16])[CH:11]([CH3:15])[C:12]([OH:14])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C@@:24]2([OH:32])[CH2:29][CH2:28][NH:27][CH2:26][C:25]2([CH3:31])[CH3:30])=[CH:20][CH:19]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C1COCC1>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C@@:24]2([OH:32])[CH2:29][CH2:28][N:27]([C:12](=[O:14])[CH:11]([CH3:15])[CH:10]([NH:9][C:1](=[O:8])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH3:16])[CH2:26][C:25]2([CH3:30])[CH3:31])=[CH:20][CH:19]=1
Reactant: CC1(C)CNCC[C@]1(O)c1ccc(Cl)cc1
Reactant: CC(NC(=O)c1ccccc1)C(C)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(NC(=O)c1ccccc1)C(C)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Temperature: 25 °C
Reaction time: 70 h
Yield: 35.9 %

Procedure:
To 3-benzamido-2-methylbutanoic acid (0.055 g, 0.249 mmol) in THF (2 mL) are sequentially added (S)-4-(4-chlorophenyl)-3,3-dimethylpiperidin-4-ol (WO 04/043965, 0.060 g, 0.249 mmol), N,N-diisopropylethylamine (0.087 mL, 0.497 mmol) and BOP (0.110 g, 0.249 mmol) at RT. The reaction mixture was stirred at RT for 70 h, and concentrated. The oily residue was dissolved in MeOH (2.0 mL) and subjected to preparative HPLC (Phenomex S10 30×100 mm; 10 min. gradient; solvent A=10% MeOH, 90% H2O, 0.1% TFA, solvent B=90% MeOH, 10% H2O, 0.1% TFA). Two fractions (diastereomer A and B) are collected and individually processed by concentrating and partitioning between dichloromethane (10 mL) and sat. aq. NaHCO3 (10 mL). The dichloromethane layer was dried over sodium sulfate and concentrated to yield: Diastereomer A: (0.042 g, 0.089 mmol, 35.9% yield) as a foamy solid. Retention time=3.23 min (YMC S5 Combi ODS 4.6×50 mm; 4 min. gradient; solvent A=10% MeOH, 90% H2O, 0.2% H3PO4, solvent B=90% MeOH, 10% H2O, 0.2% H3PO4. MS (ESI) m/z 443.11 (M+H)+; and Diastereomer B: (0.03 g, 0.064 mmol, 25.9% yield) as a foamy solid. Retention time=3.42 min (YMC S5 Combi ODS 4.6×50 mm; 4 min. gradient; solvent A=10% MeOH, 90% H2O, 0.2% H3PO4, solvent B=90% MeOH, 10% H2O, 0.2% H3PO4. MS (ESI) m/z 443.12 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:3]=1[CH:4]1[O:13][CH:5]1[CH2:6][O:7]2.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([SH:21])=[CH:17][CH:16]=1.O>C(Cl)Cl>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][CH:4]2[C:3]3[C:8](=[C:9]([F:12])[CH:10]=[CH:11][C:2]=3[F:1])[O:7][CH2:6][CH:5]2[OH:13])=[CH:17][CH:16]=1
Reactant: Fc1ccc(F)c2c1OCC1OC21
Reactant: Sc1ccc(Cl)cc1
Solvent: O
Solvent: ClCCl
Product: OC1COc2c(F)ccc(F)c2C1Sc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5,8-Difluoro-2H-chromene oxide (23 g, 0.125 mole) and 4-Chloro-benzenethiol (18.1 g, 0.125 mmole) were dissolved in 500 ml DCM and InCl3 (2.9 g, 0.013 mole) was added. The reaction was stirred at room temperature overnight. 200 ml DCM and 200 ml water were added. The organic layer washed with brine, dried over Na2SO4 and concentrated. The product was purified by column chromatography (EtOAc/hexane from 0/100 to 50/50 in 55 minute). Yield: 23.2 g, 57%. 1H NMR (CDCl3 400 MHz δ 7.48 (d, J=8.8 Hz, 2H), 7.34 (d, J=8.8 Hz, 2H), 7.01 (m, 1H), 6.64 (m, 1H), 4.63 (d, J=11.7 Hz, 1H), 4.32-4.41 (m, 2H), 4.12 (m, 1H).
Reaction SMILES: C([SiH](CC)CC)C.[CH2:8]([C:10]1[O:11][C:12]2[CH:26]=[CH:25][CH:24]=[CH:23][C:13]=2[C:14]=1[CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)O)[CH3:9].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:15]([C:14]1[C:13]2[CH:23]=[CH:24][CH:25]=[CH:26][C:12]=2[O:11][C:10]=1[CH2:8][CH3:9])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCc1oc2ccccc2c1C(O)c1ccccc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1oc2ccccc2c1Cc1ccccc1
Yield: 102.8 %

Procedure:
Triethylsilane (18.46 g; 0.159 mol) was added slowly to the solution of (2-ethyl-benzofuran-3-yl)-phenyl-methanol (20 g; 0.079 mol) in methylene chloride (200 mL) while stirring and cooling in ice bath under an atmosphere of nitrogen. Trifluoroacetic acid (40 mL) was then added dropwise. The mixture was then stirred at room temperature for one hour and the solvent was then evaporated. The residue was extracted with ether and the ethereal extracts were combined, washed with sodium bicarbonate solution, water, dried over anhydrous magnesium sulfate and the solvent was evaporated to give the product (19.2 g) as an oil. Mass spectrum (ESI, [M+] m/z 236. 1HNMR (400 MHz, DMSO-d6): δ 1.22 (t, 3H, J=7.47 Hz), 2.91 (q, 2H, J=7.47 Hz), 3.97 (s, 2H), 7.08 (dt, 1H, J=7.25, 1.1 Hz), 7.12-7.2 (m, 2H), 7.24-7.26 (m, 4H). 7.34-7.37 (m, 1H), 7.43-7.46 (m, 1H). Elemental Analysis for C17H16O: Calculated: C, 86.41; H, 6.82. Found: C, 86.16; H, 6.71.