Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[N:12][NH:11][C:10](=O)[C:9]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:10]1[N:11]=[N:12][C:13]([CH3:14])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:22]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1n[nH]c(=O)c(-c2ccccc2F)c1-c1ccc(Cl)cc1
Product: Cc1nnc(Cl)c(-c2ccccc2F)c1-c1ccc(Cl)cc1
Temperature: 110 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
1.95 g of 5-(4-chlorophenyl)-4-(2-fluorophenyl)-6-methyl-2H-pyridazin-3-one and 10 g of phosphorus oxychloride were mixed and stirred at 110° C. for 1 hour. The reaction mixture was allowed to cool down to room temperature and concentrated under reduced pressure. To the residue was added ethyl acetate and ice water, and was separated to two layer. The organic layer was washed sequentially with water and saturated brine, and dried over anhydrous sodium sulfate, then, concentrated under reduced pressure, to obtain 1.96 g of 3-chloro-5-(4-chlorophenyl)-4-(2-fluorophenyl)-6-methylpyridazine (hereinafter, referred to as compound (xvii) of the present invention).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[CH:13]=[CH:12][C:11](/[CH:14]=[C:15](\[CH3:24])/[CH2:16][O:17][CH2:18][C:19]([CH3:23])([CH3:22])[CH2:20][OH:21])=[CH:10][CH:9]=2)[CH:2]=1.[CH2:25]=[C:26]1[O:30][C:28](=[O:29])[CH2:27]1>C(OCC)(=O)C.C(N(CC)CC)C>[C:28]([O:21][CH2:20][C:19]([CH3:23])([CH3:22])[CH2:18][O:17][CH2:16]/[C:15](/[CH3:24])=[CH:14]/[C:11]1[CH:12]=[CH:13][C:8]([CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:9][CH:10]=1)(=[O:29])[CH2:27][C:26]([CH3:25])=[O:30]
Reactant: C=C1CC(=O)O1
Reactant: C/C(=C\c1ccc(Cc2cccnc2)cc1)COCC(C)(C)CO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)CC(=O)OCC(C)(C)COC/C(C)=C/c1ccc(Cc2cccnc2)cc1
Yield: 60.9 %

Procedure:
In 50 ml of ethyl acetate was dissolved 9.2 g of 3-[(E)-3-[4-(pyridin-3-ylmethyl)phenyl]-2-methylallyloxy]-2,2-dimethylpropanol, and one drop of triethylamine was added to the resulting solution. To the solution was added dropwise a mixture of 3.1 g of diketene and 9.2 ml of ethyl acetate under reflux over one hour, and the resulting mixture was then subjected to reaction at the same temperature for 30 minutes. Subsequently, the solvent was removed by distillation under reduced pressure, and the residue thus obtained was purified by a column chromatography [Merck Silica Gel, 70-230 mesh, eluant: toluene:ethyl acetate (4:1 by volume)] to obtain 7.05 g (yield 60.8%) of oily 3-[(E)-3-[4-(pyridin-3-ylmethyl)phenyl]-2-methylallyloxy]-2,2-dimethylpropyl acetoacetate.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C([O:13][C:14]([C:16]1[C:20]([S:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:19]([N+:29]([O-:31])=[O:30])[S:18][CH:17]=1)=O)C.O.C(O)(=O)[C@@H]([C@H](C(O)=O)O)O>ClCCl>[CH2:22]([S:21][C:20]1[C:16]([CH2:14][OH:13])=[CH:17][S:18][C:19]=1[N+:29]([O-:31])=[O:30])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)c1csc([N+](=O)[O-])c1SCc1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: [H-]
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1scc(CO)c1SCc1ccccc1
Temperature: -50 °C
Reaction time: 2 h
Yield: 53.4 %

Procedure:
Diisobutylaluminum hydride (154 mL of a 1.0 M solution in dichloromethane, 154 mmol) was added via cannula over 25 min to a solution of 4-benzylsulfanyl-5-nitro-thiophene-3-carboxylic acid ethyl ester (22.63 g, 70.0 mmol) at −50° C. The reaction mixture was stirred at −50° C. for 2 h, then was warmed to 0° C. and was maintained at that temperature for 35 min. Water (200 mL) was added via addition funnel over 15 min and the resulting suspension was warmed to 25° C. whereupon additional water (200 mL) and D/L-tartaric acid (20 g) were added. After stirring vigorously at 25° C. for 30 min, the reaction mixture was partitioned between 1.0 M aqueous hydrochloric acid solution (300 mL) and dichloromethane (2×400 mL). The combined organic layers were dried over sodium sulfate, filtered and were concentrated in vacuo. Purification of the residue by flash column chromatography (Merck silica gel 60, 40-63 μm; 10-50% ethyl acetate in hexanes) afforded the desired product, (4-benzylsulfanyl-5-nitro-thiophen-3-yl)-methanol (10.52 g, 37.4 mmol, 53%), as a dark brown oil. 1H NMR (400 MHz, CDCl3) δ: 4.21 (2H, s), 4.40 (2H, s), 7.09-7.12 (1H, m), 7.21-7.24 (4H, m), 7.39 (1H, s).
Reaction SMILES: C([O:5][C:6](=[O:9])[CH2:7][NH2:8])(C)(C)C.CN1CC[O:14][CH2:13][CH2:12]1.CC1(C)CO[C:21]([CH2:30][S:31][C@H:32]2[C:35](=[O:36])[N:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C@@H:33]2[C:43]2[CH:53]=[CH:52][C:46]([O:47]CC(O)=O)=[CH:45][CH:44]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:20]C1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[O:36]=[C:35]1[N:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C@H:33]([C:43]2[CH:53]=[CH:52][C:46]([O:47][CH2:12][C:13]([NH:8][CH2:7][C:6]([OH:5])=[O:9])=[O:14])=[CH:45][CH:44]=2)[C@H:32]1[S:31][CH2:30][C:21](=[O:20])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)CN
Reactant: CN1CCOCC1
Reactant: CC1(C)COC(CS[C@H]2C(=O)N(c3ccccc3)[C@@H]2c2ccc(OCC(=O)O)cc2)(c2ccccc2)OC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: O=C(O)CNC(=O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccccc3)C(=O)N2c2ccccc2)cc1
Reaction time: 0.17 h

Procedure:
Glycine tert-butyl ester (0.015 g, 0.112 mmol) and N-Methylmorpholine (0.028 g, 0.281 mmol) were added to a solution of [4-((2R,3R)-3-{[(5,5-dimethyl-2-phenyl-1,3-dioxan-2-yl)methyl]thio}-4-oxo-1-phenylazetidin-2-yl)phenoxy]acetic acid (0.050 g, 0.094 mmol) in CH2Cl2 (5 ml). After 10 minutes, TBTU (0.039 g, 0.122 mmol) was added. The reaction was stirred overnight. The resulting tert-butyl ester was purified on silica gel and eluted with EtOAc/CH2Cl2 (25/75). The pure fractions were collected and concentrated. CH2Cl2 (4 ml) and TFA (1 ml) were added. The solvent was evaporated after 2 h and the residue was purified by preparative HPLC using an eluent of 20-70% CH3CN in 0.1M NH4OAc buffer. Freeze-drying of the pure fractions gave the title product as a colourless solid. M/z: 503.5 (M-1). 1H NMR (CD3CN), 400 MHz] δ 3.84 (d, 2H), 4.18 (d, 1H), 4.24 (s, 2H), 4.50 (s, 2H), 5.04 (d, 1H), 6.99-7.12 (m, 3H), 7.25-7.66 (m, 9H), 7.94-7.96 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:10]1([CH3:19])[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C(C)=CC=CC=1>O>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[C:13]1[CH:14]=[CH:15][C:10]([CH3:19])=[CH:11][CH:12]=1)#[N:5]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: N#Cc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: O
Product: Cc1ccc(-c2ccccc2C#N)cc1
Yield: 90.3 %

Procedure:
15 g of 2-chlorobenzonitrile, 14.8 g of p-tolueneboronic acid and 28.9 g of sodium carbonate in 40 ml of glycol and 10 ml of water were heated to 120° C. At 80° C., 0.1 mol % of a catalyst solution prepared as described in Example 3 was added. After the reaction was complete, 50 ml of xylene were added and the organic phase was separated off. Distillation gave 19 g of 2-cyano-4'-methylbiphenyl (b.p. 140° C./mbar).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[CH:2].[CH3:9][C:10]1([CH3:17])[C:14]([CH3:16])([CH3:15])[O:13][BH:12][O:11]1>C1(C)C=CC=CC=1>[CH3:9][C:10]1([CH3:17])[C:14]([CH3:16])([CH3:15])[O:13][B:12](/[CH:2]=[CH:1]/[C:3]2[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=2)[O:11]1
Reactant: C#Cc1cccnc1
Reactant: CC1(C)OBOC1(C)C
Solvent: Cc1ccccc1
Product: CC1(C)OB(/C=C/c2cccnc2)OC1(C)C
Temperature: 50 °C
Yield: 49.8 %

Procedure:
An oven-dried round-bottom flask was cooled under N2 (g) and then charged with 3-ethynyl pyridine (104 mg, 1 mmol), toluene (4 mL), and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.73 mL, 5 mmol). The mixture was purged with argon for 15 min. HRuCl(CO)(PPh3)3 (73 mg, 0.05 mmol) was then added and the reaction heated to 50° C. for 18 h. The reaction was quenched with NaHCO3 (sat.) (10 mL), extracted with EtOAc, and the organic layer washed with brine (10 mL) and then dried over MgSO4. The solvent was removed and the resulting residue purified by column chromatography (silica gel, Hexanes/EtOAc, 1:1) to give the title compound as a white solid (115 mg, 50%). 1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H) 8.52 (d, 1H, J=4.8 Hz), 7.81 (d, 1H, J=7.8 Hz), 7.38 (d, J=18.6 Hz, 1H), 7.28-7.26 (m, 1H), 6.26 (d, 1H, J=18.5 Hz), 1.33 (s, 12H).
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23](C=O)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[CH3:32][NH:33][CH2:34][CH:35]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[OH:36].[BH-](OC(C)=O)(OC(C)=O)O[C:45](C)=O.[Na+]>>[CH2:1]([S:3]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH2:32][N:33]([CH2:34][CH:35]([OH:36])[C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)[CH3:45])[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:11]1)(=[O:5])=[O:4])[CH3:2]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CNCC(O)c1ccccc1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Agent: [Na+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CN(C)CC(O)c5ccccc5)c4)cc23)CC1
Yield: 34.3 %

Procedure:
Following the general procedure of example 1, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-indole-7-carboxamide (50.0 mg, 0.112 mmol), 2-(methylamino)-1-phenylethanol (129.9 mg, 0.86 mmol) and NaBH(OAc)3 (58.0 mg, 0.303 mmol) were reacted to give the title compound (22.1 mg, 36.6%).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6](Cl)=[O:7].C(N(CC)CC)C.Cl.[NH2:22][CH2:23][C:24]#[N:25]>C1C=CC=CC=1>[C:23]([CH2:24][NH:25][C:6](=[O:7])[CH2:5][O:4][C:3]1[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:2]=1[Cl:1])#[N:22]
Reactant: N#CCN
Reactant: O=C(Cl)COc1ccc(Cl)cc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: N#CCNC(=O)COc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
A solution of 11.95 g. (0.05 mole) of 2,4 dichlorophenoxyacetyl chloride in 50 ml. of benzene was added slowly to a stirred mixture of 10.1 g. (0.10 mole) of triethylamine and 4.2 g. (0.05 mole) aminoacetonitrile hydrochloride in 200 ml. of benzene. The mixture was stirred for 2 hours at room temperature and then washed successively with water, 5% sodium hydroxide solution, water, 5% hydrochloric acid solution, and water and then dried over magnesium sulfate. The resultant filtrate was concentrated under vacuum to give a solid which was crystallized from dilute ethanol to give 8.6 g. (66% yield) of product having a melting point of 107°-108° C.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([CH2:27][CH2:28][CH3:29])[N:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)[C:7](=[O:11])[C:8]=1[CH:9]=[O:10])[CH3:2].P([O-])(O)(O)=[O:31].[Na+].CC(=CC)C.Cl([O-])=O.[Na+]>C(O)(C)(C)C.C(OCC)(=O)C.O>[C:25]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:6]2[C:7](=[O:11])[C:8]([C:9]([OH:31])=[O:10])=[C:3]([CH2:1][CH3:2])[N:4]=[C:5]2[CH2:27][CH2:28][CH3:29])=[CH:14][CH:15]=1)#[N:26]
Reactant: CCCc1nc(CC)c(C=O)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Product: CCCc1nc(CC)c(C(=O)O)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.8 %

Procedure:
To a solution of 4′-[(4-ethyl-5-formyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (0.5 g), sodium dihydrogen phosphate (0.93 g) and 2-methyl-2-butene (4 mL) in tert-butyl alcohol (10 mL)—water (8 mL) was added sodium chlorite (0.7 g), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound as a colorless solid (0.53 g, 100%).
Reaction SMILES: C([O:3][C:4](=[O:25])[C:5]([F:24])([F:23])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:7]=1)C.Br[C:27]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][C:28]=1[CH:29]=[O:30]>>[F:24][C:5]([F:23])([C:6]1[CH:7]=[C:8]([C:27]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][C:28]=2[CH:29]=[O:30])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[C:4]([OH:3])=[O:25]
Reactant: CCOC(=O)C(F)(F)c1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: O=Cc1cc(C(F)(F)F)ccc1Br
Product: COc1ccc(C(F)(F)C(=O)O)cc1-c1ccc(C(F)(F)F)cc1C=O

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: difluoro-[4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester and 2-bromo-5-(trifluoromethyl)benzaldehyde; the ester was hydrolyzed under the reaction conditions.
Reaction SMILES: [OH:1]O.[O-]Cl=O.[Na+].[Br:7][C:8]1[C:15]([CH3:16])=[CH:14][C:11]([CH:12]=[O:13])=[C:10]([F:17])[CH:9]=1.Cl>O.CC#N>[Br:7][C:8]1[C:15]([CH3:16])=[CH:14][C:11]([C:12]([OH:1])=[O:13])=[C:10]([F:17])[CH:9]=1
Reactant: Cc1cc(C=O)c(F)cc1Br
Reactant: OO
Agent: Cl
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC#N
Solvent: O
Product: Cc1cc(C(=O)O)c(F)cc1Br
Temperature: 25 °C
Reaction time: 14 h
Yield: 100.3 %

Procedure:
NaH2PO4 (418 mg, 3.48 mmol) in H2O (17.6 ml), a 35% aqueous H2O2 solution (2.5 ml, 25.7 mmol) and NaClO2 (2.23 g, 24.7 mmol) in H2O (34.9 ml) were sequentially added to a mixture of 4-bromo-2-fluoro-5-methyl-benzaldehyde (3.74 g, 17.2 mmol) in MeCN (52 ml) at 0° C. The mixture was stirred at room temperature for 14 hours, and then made acidic (pH 3) with a 10% aqueous HCl solution and extracted with ethyl acetate (3×100 ml). The organic layers were washed with H2O (70 ml), and then dried over MgSO4 and concentrated under reduced pressure to give 4-bromo-2-fluoro-5-methyl-benzoic acid as a pale orange solid (4.02 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:18])[C:5]([NH2:17])=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[Cl:16].[F:19][C:20]([F:28])([F:27])[C:21]([F:26])([F:25])[C:22](O)=O>>[Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])=[CH:6][C:5]2[NH:17][C:22]([C:21]([F:26])([F:25])[C:20]([F:28])([F:27])[F:19])=[N:18][C:4]=2[CH:3]=1
Reactant: O=C(O)C(F)(F)C(F)(F)F
Reactant: Nc1cc(Cl)c(Oc2ccc(Cl)cc2Cl)cc1N
Product: FC(F)(F)C(F)(F)c1nc2cc(Cl)c(Oc3ccc(Cl)cc3Cl)cc2[nH]1
Yield: 15 %

Procedure:
A solution of 4-chloro-5-(2,4-dichlorophenoxy)benzene-1,2-diamine (100 mg, 0.33 mmol) in pentafluoropropanoic acid (5 ml) was stirred overnight at 80° C. in an oil bath. The reaction was then quenched by the addition of water (20 ml), adjusted to pH 7 with aqueous sodium bicarbonate and extracted with ethyl acetate (2×50 ml). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under vacuum to give a residue which was purified by Pre-TLC with 10% ethyl acetate in petroleum ether to produce 5-chloro-6-(2,4-dichlorophenoxy)-2-(pentafluoroethyl)-1H-1,3-benzodiazole as a white solid (21.4 mg, 15%).
Reaction SMILES: [CH3:1][C:2]([OH:8])([CH3:7])[CH:3]([OH:6])[CH2:4][OH:5].C(N(CC)CC)C.[O-2].[Al+3].[O-2].[O-2].[Al+3].[CH3:21][C:22](C)([CH:24]1COC(C)(C)O1)O>CC(C)=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(Cl)Cl>[CH3:21][C:22]1([CH3:24])[O:6][CH:3]([CH2:4][OH:5])[C:2]([CH3:7])([CH3:1])[O:8]1
Reactant: CC(C)(O)C(O)CO
Reactant: CC1(C)OCC(C(C)(C)O)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Al+3]
Agent: [O-2]
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC1(C)OC(CO)C(C)(C)O1
Reaction time: 120 h
Yield: 64.2 %

Procedure:
A solution of 1.2 g of (RS)-3-methyl-1,2,3-butanetriol in 20 ml of acetone is treated with 0.010 g of anhydrous p-toluenesulphonic acid and left at room temperature for 5 days. After the addition of 0.3 ml of triethylamine, the mixture is evaporated at 30°/11 Torr and the residue is distilled at 130°/11 Torr. The distillate (1.55 g) gives, after chromatography on 90 g of neutral aluminium oxide (activity III) with methylene chloride, as the non-polar fraction 0.81 g of (RS)-α,α,2,2-tetramethyl-1,3-dioxolane-4-methanol and as the polar fraction 0.52 g of the desired product.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C:13]2[C:18]([CH3:19])=[C:17]([O:20][CH2:21][CH:22]3[CH2:27][O:26][C:25]([CH3:29])([CH3:28])[O:24][CH2:23]3)[C:16]([CH3:30])=[CH:15][N:14]=2)(=O)=O)=CC=1.[SH:31][C:32]1[NH:33][C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=1.C(N(CC)CC)C.[OH-].[Na+]>C1(C)C=CC=CC=1.O1CCCC1>[CH3:29][C:25]1([CH3:28])[O:24][CH2:23][CH:22]([CH2:21][O:20][C:17]2[C:16]([CH3:30])=[CH:15][N:14]=[C:13]([CH2:12][S:31][C:32]3[NH:36][C:35]4[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=4[N:33]=3)[C:18]=2[CH3:19])[CH2:27][O:26]1
Reactant: Cc1ccc(S(=O)(=O)OCc2ncc(C)c(OCC3COC(C)(C)OC3)c2C)cc1
Reactant: Sc1nc2ccccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cnc(CSc2nc3ccccc3[nH]2)c(C)c1OCC1COC(C)(C)OC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.5 %

Procedure:
To a mixture of (4-((2,2-dimethyl-1,3-dioxan-5-yl)methoxy)-3,5-dimethylpyridin-2-yl)methyl 4-methylbenzenesulfonate (457 mg, 1.05 mmol), 2-mercaptobenzimidazole (158 mg, 1.05 mmol), and tetrahydrofuran (5 ml), triethylamine (0.293 ml, 2.1 mmol) was added and the mixture was stirred at room temperature for 15 hours and 30 minutes. To the reaction mixture, toluene and a diluted aqueous sodium hydroxide solution were added and the organic layer was taken out. The aqueous layer was extracted again with toluene. The organic layers were combined and washed with a saturated saline solution, dried over sodium sulfate, and filtrated. The filtrate was concentrated under reduced pressure. The residue was dissolved in n-heptane/ethyl acetate (1/1) and subjected to silica gel column chromatography (elution solvent: n-heptane/ethyl acetate=1/1→0/1) to obtain the title compound (419 mg, 96.5%) as a colorless viscous oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[OH:24][C:25]([CH3:31])([CH3:30])[CH2:26][C:27](O)=[O:28].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[OH:24][C:25]([CH3:31])([CH3:30])[CH2:26][C:27]([NH:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1)=[O:28]
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: CC(C)(O)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(O)CC(=O)Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Yield: 16.6 %

Procedure:
Using N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (100 mg, 0.323 mmol), 3-hydroxy-3-methylbutanoic acid (57 mg, 0.485 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (99 mg, 0.517 mmol), 1-hydroxybenzotriazole (71 mg, 0.522 mmol), triethylamine (0.08 mL, 0.549 mmol) and N,N-dimethylformamide (4.0 mL), and by a reaction in the same manner as in Example 187, the title compound (22 mg, 16%) was obtained as pale-yellow crystals.
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]1[O:9][CH2:8][N:7]([C:10]([CH3:15])([CH3:14])[C:11](O)=[O:12])[C:6](=[O:16])[C:5]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[F:23][C:24]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:25]=1[NH2:26].O>CN(C)C=O.C(OCC)(=O)C>[F:23][C:24]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:25]=1[NH:26][C:11](=[O:12])[C:10]([N:7]1[C:6](=[O:16])[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:4]([CH2:3][S:2][CH3:1])[O:9][CH2:8]1)([CH3:14])[CH3:15]
Reactant: Nc1cc(F)ccc1F
Reactant: CSCC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)O)CO1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CSCC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)Nc2cc(F)ccc2F)CO1
Temperature: 25 °C
Reaction time: 18 h
Yield: 7.7 %

Procedure:
A solution of dicyclohexylcarbodiinide (10.04 g) in N,N-dimethyeformaeide was added to a stirred solution of 2-(2,3-dihydro-6-methylthiomethyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanoic acid (13.00 g) in N,N-dimethylformamide at 20° C. 2,5-Difluoroaniline (7.84 g) was added to the solution at 20° C. and the solution was stirred at ambient temperature for 18 hours. The reaction mixture was diluted with ethyl acetate then added to water and the fine suspension removed by filtration. The organic layer was washed in turn with 0.5M hydrochloric acid, brine, 1.0M sodium carbonate and brine and then dried (magnesium sulphate). The organic solution was evaporated under reduced pressure and the residue was purified by chromatography on silica gel, eluting with dichioromethane to give N-(2,5-difluorophenyl)-2-(2,3-dihydro-6-methylthiomethyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanamide (Compound 3, 1.35 g) as a yellow solid, NMR (CDCl3) 1.68(s,6H), 2.10(s,3H), 3.22(s,2H), 5.30(s,2H), 6.64-6.76(m,1H), 6.95-7.05(m,1H), 7.25-7.38(m,5H), 8.11-8.21(m,2H).
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][N:5]([CH2:11][C:12]([F:14])=[CH2:13])[C:6](=[O:10])[O:7][CH2:8][CH3:9].C(O)=O.[Cl-].[Na+]>O>[F:14][C:12](=[CH2:13])[CH2:11][N:5]([CH2:4][CH:3]=[O:2])[C:6](=[O:10])[O:7][CH2:8][CH3:9]
Reactant: C=C(F)CN(CC(OC)OC)C(=O)OCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: O=CO
Product: C=C(F)CN(CC=O)C(=O)OCC

Procedure:
14.1 g (60 mmol) of ethyl N-(2,2-dimethoxyethyl)-N-(2-fluoroallyl)-carbamate are heated under reflux for three hours with 6.3 ml of formic acid in 120 ml of water. The solution is saturated with sodium chloride and extracted several times with methylene chloride, the organic solutions are washed with saturated sodium hydrogen carbonate solution, dried over magnesium sulphate and concentrated, and the residue is distilled.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[CH2:12](Br)[C:13]#[CH:14]>>[CH2:14]([NH:6][C:5]1[CH:7]=[CH:8][CH:9]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=1)[C:13]#[CH:12]
Reactant: C#CCBr
Reactant: Nc1cccc(C(F)(F)F)c1
Product: C#CCNc1cccc(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 34.8 %

Procedure:
A mixture of 3-trifluoromethylaniline (30 g) and propargyl bromide (12 g) was stirred at 80° C. for 3 hours, followed by filtration of the reaction mixture. The filtrate was subjected to column chromatography to give N-propargyl-3-trifluoromethylaniline (7 g). A solution of N-propargyl-3-trifluoromethylaniline thus obtained (5.1 g) and ethoxycarbonyl isothiocyalate (3.7 g) in tetrahydrofuran (100 ml) was stirred at room temperature for 8 hours, and the solvent was removed under reduced pressure. The concentrated residue was extracted with chloroform (200 ml), washed with water and dried over anhydrous magnesium sulfate. After removal of the solvent, the residue was subjected to column chromatography to give 5.7 g of 2-ethoxycarbonylimino- 3-(3-trifluoromethylphenyl)-5-methylenethiazolidine (Compound (i)).