Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH2:12])[CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[OH:18][CH2:19][C:20](=O)[CH3:21]>O>[CH3:21][C:20]1([CH2:19][OH:18])[NH:12][C:10]2[C:11]3[C:6]([CH:7]=[CH:8][CH:9]=2)=[CH:5][CH:4]=[CH:3][C:2]=3[NH:1]1
Reactant: CC(=O)CO
Reactant: Nc1cccc2cccc(N)c12
Agent: O=S(=O)(O)O
Solvent: O
Product: CC1(CO)Nc2cccc3cccc(c23)N1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A mixture of 79.1 g of 1,8-diaminonaphthalene, 57.4 g of 96% strength sulphuric acid and 700 ml of water is initially introduced into the reaction vessel at 50° C., and 57.8 g of hydroxy acetone are metered in over a period of 10 minutes. The mixture is then subsequently stirred at 50° C. for 2 hours and cooled to 0° C., and the product is isolated by filtration and dried at 70° C. in vacuo.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([O:9][C:10]2[C:11]([CH:21]([CH3:23])[CH3:22])=[CH:12][C:13]([O:19][CH3:20])=[C:14]([CH:18]=2)[C:15]([NH2:17])=O)=[CH:4][N:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:33])=CC=1>C1COCC1>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([O:9][C:10]2[C:11]([CH:21]([CH3:23])[CH3:22])=[CH:12][C:13]([O:19][CH3:20])=[C:14]([CH:18]=2)[C:15]([NH2:17])=[S:33])=[CH:4][N:3]=1
Reactant: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1C(N)=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1C(N)=S
Temperature: 25 °C
Reaction time: 16 h
Yield: 76 %

Procedure:
A mixture of 5-(2,4-Diamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-benzamide (0.25 g, 0.79 mmol, prepared according to the procedure of Example 52) and Lawesson's reagent (0.96 g, 2.37 mmol) in anhydrous THF (20 ml) was stirred at room temperature for 16 hrs and concentrated in vacuo. Flash chromatography on silica (5% CH3OH in methylene chloride with 1% NH4OH) gave 5-(2,4-Diamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-thiobenzamide (0.201 g, 76%) as a yellow solid.
Reaction SMILES: C(OC([CH:6]1[CH2:15][N:14]([CH3:16])[C:13]2[N:12]=[C:11]3[CH:17]=[C:18]([F:22])[C:19]([F:21])=[CH:20][C:10]3=[CH:9][C:8]=2[C:7]1=[O:23])=O)C.OO.S([O-])([O-])(=O)=S.[Na+].[Na+].[CH2:33]([OH:35])[CH3:34]>O.[I-].[K+]>[CH2:33]([O:35][C:6]1[C:7](=[O:23])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)[CH3:34]
Reactant: CCO
Reactant: CCOC(=O)C1CN(C)c2nc3cc(F)c(F)cc3cc2C1=O
Agent: O=S([O-])([O-])=S
Agent: OO
Agent: [I-]
Solvent: O
Product: CCOc1cn(C)c2nc3cc(F)c(F)cc3cc2c1=O
Temperature: 77 °C

Procedure:
A solution of 3.78 g of potassium iodide in 20 cm3 of water is added with stirring at approximately 20° C. to a suspension of 71 g of 3-ethoxycarbonyl-7,8-difluoro-1-methyl-4-oxo-1,2,3,4-tetrahydrobenzo[b][1,8]naphthyridine in 1,000 cm3 of ethanol. The suspension is heated to 77° C., and 30 cm3 of 33% by weight hydrogen peroxide is added in the course of 60 minutes at this temperature. The reaction mixture is kept refluxing for a further 30 minutes and is then cooled to approximately 20° C. A solution of 11.4 g of sodium thiosulphate in 50 cm3 of water is introduced in the course of 5 minutes at this temperature. The precipitate obtained is drained at approximately 20° C. and washed with twice 300 cm3 of water. The wet product obtained is dried under reduced pressure (20 kPa) at approximately 60° C. 73 g of 3-ethoxy-7,8-difluoro-1-methyl-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine are isolated in the form of a white solid, melting point above 270° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH3:13])[C:6](=[O:12])[O:7]2.[H-].[Na+].Cl[CH2:17][O:18][CH3:19]>CN(C)C=O>[CH3:13][C:5]1[C:6](=[O:12])[O:7][C:8]2[C:3]([CH:4]=1)=[C:2]([O:1][CH2:17][O:18][CH3:19])[CH:11]=[CH:10][CH:9]=2
Reactant: Cc1cc2c(O)cccc2oc1=O
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1cccc2oc(=O)c(C)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.3 %

Procedure:
To a solution of 5-hydroxy-3-methyl-2H-chromen-2-one (Intermediate 112, 2.225 g) in dry N,N-Dimethylformamide (60 ml) cooled to 0° C. was added sodium hydride (60%, 0.532 g, 13.89 mmol) followed by the addition of chloro(methyloxy)methane (1.919 ml, 25.3 mmol). The reaction mixture was warmed to room temperature and stirred for 30 minutes under nitrogen. It was then quenched by the addition of a saturated solution of NH4Cl, the product was extracted with diethyl ether, washed with brine, dried over sodium sulphate, filtered and concentrated under vacuum. The residue obtained was purified by silica gel chromatography (Biotage system, with a gradient from pure cyclohexane to cyclohexane/ethyl acetate 5/1) to give the title compound as a white solid (2.15 g). 1H NMR (400 MHz, CDCl3): δ ppm 7.94 (1H, s), 7.38 (1H, t), 6.93-7.05 (2H, m), 5.33 (2H, s), 3.55 (3H, s), 2.26 (3H, s); UPLC_ipqc: 0.94 min, 221 [M+H]+.
Reaction SMILES: [C:1]([CH2:3][C@H:4]1[O:9][C:8]([CH3:11])([CH3:10])[O:7][C@@H:6]([CH2:12][C:13]([OH:15])=[O:14])[CH2:5]1)#[N:2].N12CCCN=C1CC[CH2:19][CH2:18][CH2:17]2.IC(C)C>C(#N)C.C(OCC)C>[CH3:17][CH:18]([O:14][C:13](=[O:15])[CH2:12][C@H:6]1[CH2:5][C@@H:4]([CH2:3][C:1]#[N:2])[O:9][C:8]([CH3:11])([CH3:10])[O:7]1)[CH3:19]
Reactant: CC1(C)O[C@H](CC#N)C[C@H](CC(=O)O)O1
Reactant: C1CCC2=NCCCN2CC1
Solvent: CC(C)I
Solvent: CCOCC
Solvent: CC#N
Product: CC(C)OC(=O)C[C@H]1C[C@@H](CC#N)OC(C)(C)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (±)-cis-6-(cyanomethyl)-2,2-dimethyl-1,3-dioxane-4-acetic acid, 0.6 g (3 mmol), in acetonitrile, 2 mL, is added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 0.45 mL (3 mmol), and 2-iodopropane, 0.33 mL (3.3 mmol). The solution is stirred overnight at room temperature, diluted with diethyl ether, washed with brine, and dried (magnesium sulfate). Flash chromatography provides 0.55 g of (±)-cis-1-methylethyl-6-(cyanomethyl)-2,2-dimethyl-1,3-dioxane-4-acetate.
Reaction SMILES: O[CH2:2][NH:3][C:4](=[O:8])[C:5]([CH3:7])=[CH2:6].[C:9]1([P:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([SH:17])=[S:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:9]1([P:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([S:17][CH2:2][NH:3][C:4](=[O:8])[CH:5]([CH3:7])[CH2:6][S:17][P:15]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[S:16])=[S:16])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: S=P(S)(c1ccccc1)c1ccccc1
Reactant: C=C(C)C(=O)NCO
Product: CC(CSP(=S)(c1ccccc1)c1ccccc1)C(=O)NCSP(=S)(c1ccccc1)c1ccccc1

Procedure:
Following the general procedure in Example 1, 0.4 mole N-hydroxymethylmethacrylamide is reacted with 0.08 mole of diphenylphosphinodithioic acid, to yield N-(diphenylphosphinothioylthiomethyl) 3-(diphenylphosphinothioylthio)-2-methylpropionamide.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:10][CH:9]=1)=[O:6].[CH3:30][C:31]([CH3:35])([CH3:34])[CH2:32][NH2:33]>>[CH3:30][C:31]([CH3:35])([CH3:34])[CH2:32][NH:33][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:10][CH:9]=1)=[O:6]
Reactant: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1cccc(Br)c1
Reactant: CC(C)(C)CN
Product: CC(C)(C)CNc1cccc(C(=O)Nc2ccc(OCCN3CCOCC3)c3ccccc23)c1

Procedure:
Compound is formed by reacting 3-bromo-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-benzamide with 2,2-dimethylpropylamine under conditions described in general procedure B. 1H NMR (300 MHz, DMSO-d6) δ 10.05 (s, 1H), 8.22 (m, 1H), 7.86 (m, 1H), 7.56 (m, 2H), 7.41 (d, 1H, J=8.4), 7.28 (s, 1H), 7.21 (d, 2H, J=5.7), 6.87 (m, 1H), 5.70 (m, 1H), 4.32 (t, 2H, J=5.7), 3.62 (t, 4H, J=4.8), 2.89 (t, 4H, J=5.4), 2.58 (t, 4H, J=4.8), 1.48 (t, 1H, J=14.1), 0.97 (s, 9H). MS: 462.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8]C)=[CH:6][C:5]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][C:3]=1[O:18]C.B(Br)(Br)Br>>[Br:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([CH:10]=[CH:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:4][C:3]=1[OH:18]
Reactant: COc1cc(C=Cc2ccccc2)cc(OC)c1Br
Agent: BrB(Br)Br
Product: Oc1cc(C=Cc2ccccc2)cc(O)c1Br
Yield: 90 %

Procedure:
This material was synthesized from 1-(4-bromo-3,5-dimethoxyphenyl)-2-phenylethene (21B) and BBr3 in 90% yield by the same method as described in example 6.
Reaction SMILES: [CH3:1][C@@:2]([S:21]([CH3:24])(=[O:23])=[O:22])([CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:12]=[N:11]1)[C:3]([O:5]CC)=[O:4].[Li+].[OH-].Cl>C1COCC1.O>[CH3:1][C@@:2]([S:21]([CH3:24])(=[O:22])=[O:23])([CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:12]=[N:11]1)[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)[C@@](C)(CCn1cc(-c2ccccc2)cn1)S(C)(=O)=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@](CCn1cc(-c2ccccc2)cn1)(C(=O)O)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.2 %

Procedure:
To a solution of ethyl (2R)-2-methyl-2-(methylsulfonyl)-4-(4-phenyl-1H-pyrazol-1-yl)butanoate (1.22 g, 3.48 mmol, 1 eq) in THF-H2O (15 mL:15 mL) was added LiOH (0.258 g, 10.4 mmol, 3 eq). The mixture was allowed to stir at RT overnight. The mixture was acidified with 1M HCl and extracted with EtOAc. The organic layers were combined, dried (MgSO4), filtered and concentrated to give (2R)-2-methyl-2-(methylsulfonyl)-4-(4-phenyl-1H-pyrazol-1-yl)butanoic acid (0.855 g, 76 yield). 1H NMR (400 MHz, DMSO-d6) δ 8.20 (s, 1H), 7.86 (s, 1H), 7.53 (d, J=7.4 Hz, 2H), 7.32 (t, J=7.7 Hz, 2H), 7.15 (s, 1H), 4.35-4.23 (m, 1H), 4.20-4.08 (m, 1H), 3.11 (s, 3H), 2.71-2.57 (m, 1H), 2.38-2.25 (m, 1H), 1.50 (s, 3H). LC-MS M+H+323.1.
Reaction SMILES: [CH2:1]([C:8]1[CH2:12][C:11]([CH3:14])([CH3:13])[CH2:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:15]1[C:20]([C:21]([CH2:23]Br)=O)=[CH:19][CH:18]=[C:17]([Cl:25])[CH:16]=1>>[Cl:25][C:17]1[CH:18]=[CH:19][C:20]([C:21]2[C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:8]3[N:9]([CH2:10][C:11]([CH3:14])([CH3:13])[CH2:12]3)[CH:23]=2)=[CH:15][CH:16]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: CC1(C)CN=C(Cc2ccccc2)C1
Product: CC1(C)Cc2c(-c3ccccc3)c(-c3ccc(Cl)cc3)cn2C1

Procedure:
The 2-benzyl-4,4-dimethyl-1-pyrroline of the formula III is then cyclized with ω-bromo-4-chloroacetophenone to give the 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizine of the formula II. The reaction is known from the prior art mentioned at the outset. ω-Bromo-4-chloroacetophenone can be obtained, for example, as described in Bull. Soc. Chim. Fr. 21, 69 (1899).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([Cl:19])[C:13]=1[O:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30]Br)=[CH:26][CH:25]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:30][C:27]2[CH:28]=[CH:29][C:24]([O:23][CH2:22][CH2:21][O:20][C:13]3[C:14]([Cl:19])=[CH:15][C:16]([CH3:18])=[CH:17][C:12]=3[Cl:11])=[CH:25][CH:26]=2)[C:9]#[N:10])=[CH:4][CH:3]=1
Reactant: N#CCc1ccc(Br)cc1
Reactant: Cc1cc(Cl)c(OCCOc2ccc(CBr)cc2)c(Cl)c1
Product: Cc1cc(Cl)c(OCCOc2ccc(CC(C#N)c3ccc(Br)cc3)cc2)c(Cl)c1

Procedure:
Prepared according to the procedure described in EXAMPLE 1, step 4 using commercially available (4-bromophenyl)acetonitrile and 1,3-dichloro-2-{2-[4-(bromomethyl)phenoxy]ethoxy}-5-methylbenzene (II.2) as starting materials. Purification by column chromatography on silica gel, eluting with Hex/EtOAc 15%, afforded the desired compound as a colorless oil.
Reaction SMILES: BrC1C2C(=CC=CC=2)C=CC=1C[N:13]1[C:17]2=[N:18][C:19]([C:22]#[N:23])=[CH:20][CH:21]=[C:16]2[N:15]=[C:14]1[CH3:24].BrC1C2C(=CC=CC=2)C=CC=1CN1C2C(=NC(C#N)=CC=2)N=C1C>>[CH3:24][C:14]1[NH:15][C:16]2[C:17]([N:13]=1)=[N:18][C:19]([C:22]#[N:23])=[CH:20][CH:21]=2
Reactant: Cc1nc2ccc(C#N)nc2n1Cc1ccc2ccccc2c1Br
Agent: Cc1nc2nc(C#N)ccc2n1Cc1ccc2ccccc2c1Br
Product: Cc1nc2nc(C#N)ccc2[nH]1
Yield: 343.2 %

Procedure:
In the same manner as in the following Preparation Example 14-2, 3-(1-bromonaphthalen-2-yl)methyl-2-methyl-3H-imidazo[4,5-b]pyridine-5-carbonitrile (139 mg) and 1-(1-bromo-naphthalen-2-yl)methyl-2-methyl-1H-imidazo[4,5-b]pyridine-5-carbonitrile (96 mg) were respectively obtained as pale-brown crystals and pale-brown amorphous from 2-methyl-1H-imidazo[4,5-b]pyridine-5-carbonitrile (200 mg).
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][C:16]([OH:18])=O)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)(Cl)=O>N1C=CC=CC=1.C1(C)C=CC=CC=1>[CH:1]1([C:7]2[CH:8]=[C:9]3[C:10]([CH2:13][CH2:14][CH2:15][C:16]3=[O:18])=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)CCCc1ccc(C2CCCCC2)cc1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C1CCCc2ccc(C3CCCCC3)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.4 %

Procedure:
To a mixture of 4-(4-cyclohexylphenyl)butyric acid (10.2 g), thionyl chloride (7.4 g) and toluene (50 ml), pyridine (1 drop) was added. After refluxing for 1.5 hours, the solvent was evaporated off under reduced pressure. The residue was dissolved in dichloromethane (20 ml); this solution was added dropwise to a suspension of powdered anhydrous aluminum chloride (8.3 g) in dichloromethane (100 ml) under ice cooling conditions. After stirring at room temperature for 3 hours, the reaction mixture was poured into 1.2N HCl (150 ml), followed by stirring for 30 minutes. The organic layer was collected, while the aqueous layer was extracted with dichloromethane. The extract was combined with the organic layer, succesively washed with water and brine, and dried (MgSO4), after which the solvent was evaporated off. The residual oil was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:10, v/v) to yield 7-cyclohexyl-1-tetralone (9.4 g, 100%) as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:12](=[O:13])[O:11][C:10]([C:14]3[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=3[F:21])=[N:9][C:8]=2[CH:22]=1)([O-])=O>C(O)(=O)C.O=[Pt]=O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[C:12](=[O:13])[O:11][C:10]([C:14]3[C:15]([F:21])=[CH:16][CH:17]=[CH:18][C:19]=3[F:20])=[N:9][C:8]=2[CH:22]=1
Reactant: O=c1oc(-c2c(F)cccc2F)nc2cc([N+](=O)[O-])ccc12
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: Nc1ccc2c(=O)oc(-c3c(F)cccc3F)nc2c1

Procedure:
7-Nitro-2-(2,6-difluoro-phenyl)-benzo[d][1,3]oxazin-4-one (0.10 g) was dissolved in acetic acid (10 mL) under N2, PtO2 (5 mg) was added and the mixture was hydrogenated with H2 gas. Reaction time 1 day. The reaction mixture was filtered through Hyflo®, which was rinsed afterwards with ethyl acetate. The combined organic phases were evaporated to dryness and subsequently treated three times with toluene followed by evaporation.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([N:26]=[C:27]=[O:28])[CH:19]=[C:20]([O:24][CH3:25])[C:21]=1[O:22][CH3:23]>CN(C)C=O>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([NH:26][C:27](=[O:28])[NH:1][C:2]2[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)[CH:19]=[C:20]([O:24][CH3:25])[C:21]=1[O:22][CH3:23]
Reactant: COc1cc(N=C=O)cc(OC)c1OC
Reactant: CCOC(=O)C(=O)c1csc(N)n1
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)c1csc(NC(=O)Nc2cc(OC)c(OC)c(OC)c2)n1

Procedure:
Following a procedure similar to that described in Preparation 1, the desired compound was prepared from 4.3 g of ethyl 2-aminothiazol-4-ylglyoxylate, 5 g of 3,4,5-trimethoxyphenyl isocyanate and 30 ml of dimethylformamide. The resulting product was a yellow powder having the following physical properties.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH:5]1[CH2:8][C:7]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)([C:9]([NH:11][NH2:12])=O)[CH2:6]1.CO[C:20]1[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][CH2:3][O:4][CH:5]1[CH2:8][C:7]([C:9]2[N:27]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][C:20]3=[N:12][N:11]=2)([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[CH2:6]1
Reactant: COC1=NCCCCCC1
Reactant: COCOC1CC(C(=O)NN)(c2cccs2)C1
Solvent: Cc1ccccc1
Product: COCOC1CC(c2cccs2)(c2nnc3n2CCCCCC3)C1
Yield: 83.1 %

Procedure:
3-(Methoxymethoxy)-1-(2-thienyl)cyclobutanecarbohydrazide (5.45 g) and 8-methoxy-2,3,4,5,6,7-hexahydroazocine (4.51 g) were heated in toluene (60 ml) at 110° C. for 19 hours. After concentration, the concentrate was purified by silica gel column chromatography (methanol:chloroform=2:98) to obtain 3-[3-(methoxymethoxy)-1-(2-thienyl)cyclobutyl]-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]azocine (6.14 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:12])[C:9]([OH:11])=[O:10].S(Cl)(Cl)=O.[CH2:17](O)[CH3:18]>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:12])[C:9]([O:11][CH2:17][CH3:18])=[O:10]
Reactant: CCO
Reactant: O=C(O)C(=O)c1ccccc1Br
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C(=O)c1ccccc1Br

Procedure:
Into a 250-mL 3-necked round-bottom flask, was placed a solution of 2-(2-bromophenyl)-2-oxoacetic acid (10 g, 43.66 mmol, 1.00 equiv) in ethanol (80 mL). This was followed by the addition of thionyl chloride (20 mL) dropwise with stirring. The resulting solution was stirred for 12 h at 80° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was dissolved in 100 mL of ethyl acetate. The resulting mixture was washed with 2×50 mL of water. The mixture was dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5). This resulted in 9 g (80%) of ethyl 2-(2-bromophenyl)-2-oxoacetate as yellow oil. MS (ESI) m/z 258 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.[B-](F)(F)(F)[F:14].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>CC#N>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([F:14])=[C:7]([OH:12])[CH:6]=[CH:5]2
Reactant: F[B-](F)(F)F
Reactant: Oc1ccc2cc(Br)ccc2c1
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: Oc1ccc2cc(Br)ccc2c1F
Temperature: 60 °C
Yield: 83 %

Procedure:
To a solution of 6-bromonaphthalen-2-ol (2.23 g, 10.0 mmol) in CH3CN (50 mL) was added Selectfluor (4.20 g, 12.0 mmol). The reaction mixture was heated at 60° C. overnight and concentrated. The residue was partitioned between water (50 mL) and EtOAc (100 mL). The aqueous phase was separated and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography to give 6-bromo-1-fluoronaphthalen-2-ol using ethyl acetate and hexanes as solvents (2.0 g, 83% yield).
Reaction SMILES: [CH3:1][N:2]([C@@H:10]([CH3:39])[C:11]([NH:13][C@H:14]([C:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][C@H:21]1[C:26]([NH:28][C@H:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH2:31][CH2:30]1)=[O:27])=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].CCN(C(C)C)C(C)C.[CH3:49][N:50]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[C:51](Cl)=[O:52]>C(Cl)Cl>[C:5]([O:4][C:3](=[O:9])[N:2]([CH3:1])[C@@H:10]([CH3:39])[C:11]([NH:13][C@H:14]([C:18]([N:20]1[CH2:25][CH2:24][N:23]([C:51]([N:50]([CH3:49])[C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)=[O:52])[CH2:22][C@H:21]1[C:26]([NH:28][C@H:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH2:31][CH2:30]1)=[O:27])=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12])([CH3:7])([CH3:8])[CH3:6]
Reactant: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1CCNC[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Reactant: CN(C(=O)Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1CCN(C(=O)N(C)c2ccccc2)C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Temperature: 0 °C
Reaction time: 15 h

Procedure:
Intermediate 7 (175 mg, 0.322 mmol) is dissolved in anhydrous CH2Cl2 (15 mL), to which DIEA (70 μL, 0.40 mmol) is added. The solution is cooled to 0° C. and N-methyl-N-phenylcarbamoyl chloride (66 mg, 0.39 mmol) is added, the solution is subsequently warmed to room temperature for 4 h. N-Methyl-N-phenylcarbamoyl chloride (66 mg, 0.39 mmol) and DIEA (70 μL, 0.40 mmol) are added and the solution is stirred at room temperature for 15 h at room temperature. The solution is diluted with CH2Cl2 (50 mL) and washed with sat. NaHCO3 and brine. The solution is dried (MgSO4), filtered, and the solvent removed under reduced pressure to give the crude product as an oil. This material is purified by flash chromatography on silica gel (0-5% MeOH/CH2Cl2). The title compound is isolated as a white foam (168 mg, 77% yield): 1H NMR δ (CDCl3) 6.60-7.60 (m, 10H), 4.19-5.20 (m, 5H), 3.62 (“br d”, 1H, Jobs=13.2 Hz), 3.52 (“br d” 1H, Jobs=13.4 Hz), 2.56-3.28 (m, 10H), 1.72-2.10 (m, 5H), 1.47 and 1.45 (s, 9H total), 1.24-1.32 (br m, 3H), 0.88-1.12 (m, 2H), 1.09 (br d, 1H, J=6.7 Hz), 0.90 (dd, 2H, J=7.0, 2.6 Hz), 0.78 (br d, 2H, J=6.7 Hz), 0.66 (br d, 2H, 6.7 Hz; LCMS (APCl+) 678.6 (MH+, 100%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=1.Br[CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:16]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Nc1c(C(=O)c2cccc(O)c2)cnn1-c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)COc1cccc(C(=O)c2cnn(-c3ccc(F)cc3)c2N)c1
Temperature: 70 °C
Yield: 88.4 %

Procedure:
A mixture of 5-amino-1-(4-fluorophenyl)-4-[3-hydroxybenzoyl]pyrazole (1.0 g, 3.3 mmol), tert-butyl bromoacetate (1.4 g, 7.2 mmol) and potassium carbonate (1 g, 7.2 mmol) in acetonitrile was heated at 70° C. overnight. The reaction mixture was cooled, diluted with ethyl acetate and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography (elution gradient: 10% acetone/hexane) to give 5-amino-4-[3-(tert-butoxycarbonylmethyloxy)benzoyl]-1-(4-fluorophenyl)pyrazole (1.2 g) as a solid.