Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [K].[CH3:2][O:3][C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:5]=1[OH:13].Br[CH2:15][CH2:16][N:17]1[CH:21]=[CH:20][CH:19]=[CH:18]1>>[N:17]1([CH2:16][CH2:15][O:13][C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[O:3][CH3:2])[CH:21]=[CH:20][CH:19]=[CH:18]1
Reactant: BrCCn1cccc1
Reactant: COc1cc([N+](=O)[O-])ccc1O
Agent: [K]
Product: COc1cc(N)ccc1OCCn1cccc1
Yield: 76 %

Procedure:
Following procedure described in step A of Example 18, the title compound was prepared from the potassium salt of 2-methoxy-4-nitrophenol and 1-(2-bromoethyl)-1H-pyrrole in 76% yield. MS (ESI) 233 (M+H)+.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[OH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:21]=[C:20]([C:22]#[N:23])[C:19]3[N:24]=[CH:25][N:26]([CH3:27])[C:18]=3[CH:17]=2)=[CH:12][C:11]=1[C:28]([F:31])([F:30])[F:29].C(OCC)(=O)C.O>CN(C=O)C>[Cl:1][C:15]1[CH:14]=[C:13]([C:16]2[N:21]=[C:20]([C:22]#[N:23])[C:19]3[N:24]=[CH:25][N:26]([CH3:27])[C:18]=3[CH:17]=2)[CH:12]=[C:11]([C:28]([F:31])([F:30])[F:29])[C:10]=1[OH:9]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cn1cnc2c(C#N)nc(-c3ccc(O)c(C(F)(F)F)c3)cc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cnc2c(C#N)nc(-c3cc(Cl)c(O)c(C(F)(F)F)c3)cc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
N-Chlorosuccinimide (84 mg) was added to a solution of 6-(4-hydroxy-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile (200 mg) in DMF (4 ml). The mixture was stirred at room temperature for 24 hours, then ethyl acetate (50 ml) and water (20 ml) were added and the organic layer was washed twice with water (2×20 ml) and brine (20 ml), then dried over sodium sulfate, filtered and concentrated under reduced pressure to afford a crude (165 mg) with 6-(3-chloro-4-hydroxy-5-trifluoromethyl-phenyl)-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile which is contaminated starting material. This material was used for next step without further purification.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[I:11][C:12]1[C:16]([CH2:17][OH:18])=[CH:15][N:14]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[N:13]=1>C(Cl)Cl.CC(=O)OCC>[I:11][C:12]1[C:16]([CH:17]=[O:18])=[CH:15][N:14]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[N:13]=1
Reactant: OCc1cn(C2CCCCO2)nc1I
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=Cc1cn(C2CCCCO2)nc1I
Temperature: -65 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
To a solution of oxalyl chloride (33.51 g, 22.8 mL, 263 mmol) in DCM (320 mL) at −65° C. under a dry N2 atm. was added DMSO (27.28 g, 24.8 mL, 350.3 mmol) dropwise. The reaction was stirred at −65° C. for 0.5 h then treated dropwise with a solution of (3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)methanol (27 g 87.66 mmol) in DCM (75 mL. The mixture was stirred at −65° C. for 1 h then treated with TEA (53.14 g, 73.2 mL, 525 mmol) then warmed to rt and stirred for 0.5 h. DCM (300 mL) was added and the mixture washed with 1N HCl (150 mL×2). The organic layer was dried and then concentrated under vacuum. The residue was purified by SGC using Hex: EA (0%-15%) as eluent to afford 3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-carbaldehyde (22 g, yield: 82%). LCMS (method C): RT=1.97 min, m/z=307.0 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][CH2:14][CH2:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([O:19][C:20]([C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([CH3:31])[CH:30]=1)[C:25]([OH:27])=O)=[O:21])[CH3:18].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.C(Cl)CCl>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([CH2:14][CH2:15][CH3:16])[C:25]([C:24]1[CH:23]=[C:22]([CH:30]=[C:29]([CH3:31])[CH:28]=1)[C:20]([O:19][CH2:17][CH3:18])=[O:21])=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCNCCCCOCc1ccccc1
Reactant: CCOC(=O)c1cc(C)cc(C(=O)O)c1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCCN(CCCCOCc1ccccc1)C(=O)c1cc(C)cc(C(=O)OCC)c1
Temperature: 22.5 °C
Reaction time: 18 h
Yield: 41.7 %

Procedure:
A mixture of N-[4-(benzyloxy)butyl]-N-propylamine (2.31 g, 10.44 mmol), 3-(ethoxycarbonyl)-5-methylbenzoic acid (2.18 g, 10.44 mmol), HOBt (1.56 g, 11.49 mmol), N-methylmorpholine (1.37 mL, 12.52 mmol), and EDC (2.20 g, 11.49 mmol) in DMF (12 mL) is stirred at 20-25 degrees C. for 18 hours. The reaction mixture is diluted with ethyl acetate (80 mL) and washed with water (2×20 mL), hydrochloric acid (1 N, 20 mL), saturated sodium bicarbonate (20 mL) and saline (20 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification by flash chromatography (silica; hexanes/ethyl acetate, 1/1) gives ethyl 3-{[[4-(benzyloxy)butyl](propyl)amino]carbonyl}-5-methylbenzoate (1.79 g), NMR (500 MHz, DMSO-d6): delta7.80, 7.64, 7.40, 7.38-7.16, 4.50-4.43, 4.34-4.29, 3.53-3.30, 3.20-3.06, 2.41-2.36, 1.70-1.40, 1.36-1.29, 0.94-0.84 and 0.82-0.72; APCI-MS (m/z) [M+H]+=412.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[O:13][C@H:14]([CH2:16][CH:17]=[CH2:18])[CH3:15].FC1C(F)=CC([B:27]2[O:34][C:33](=[O:35])[CH2:32][N:31]([CH3:36])[CH2:30][C:29](=[O:37])[O:28]2)=C(O[C@H](CC=C)C)C=1>>[CH3:36][N:31]1[CH2:32][C:33](=[O:35])[O:34][B:27]([C:2]2[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=2[O:13][C@H:14]([CH2:16][CH:17]=[CH2:18])[CH3:15])[O:28][C:29](=[O:37])[CH2:30]1
Reactant: C=CC[C@H](C)Oc1ccc(OC(F)(F)F)cc1Br
Reactant: C=CC[C@H](C)Oc1cc(F)c(F)cc1B1OC(=O)CN(C)CC(=O)O1
Product: C=CC[C@H](C)Oc1ccc(OC(F)(F)F)cc1B1OC(=O)CN(C)CC(=O)O1
Yield: 68 %

Procedure:
Prepared in 68% yield from (S)-2-bromo-1-(pent-4-en-2-yloxy)-4-(trifluoromethoxy)benzene following the same procedure as (S)-2-(4,5-difluoro-2-(pent-4-en-2-yloxy)phenyl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione. 1H NMR (400 MHz, CDCl3) δ 7.57 (d, J=3.0 Hz, 1H), 7.23 (dd, J=8.8, 3.0 Hz, 1H), 6.93 (d, J=8.8 Hz, 1H), 5.90-5.77 (m, 1H), 5.19-5.11 (m, 2H), 4.69-4.60 (m, 1H), 4.12 (d, J=16.1 Hz, 1H), 4.01-3.85 (m, 3H), 2.71 (s, 3H), 2.53 (dt, J=14.4, 7.1 Hz, 1H), 2.44-2.34 (m, 1H), 1.32 (d, J=6.0 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −58.20 (s, 3F).
Reaction SMILES: Br.[CH3:2][O:3][N:4]=[C:5]([C:11]1[N:12]=[C:13]([NH2:16])[S:14][CH:15]=1)[C:6]([O:8]CC)=[O:7]>[OH-].[Na+].O>[CH3:2][O:3][N:4]=[C:5]([C:11]1[N:12]=[C:13]([NH2:16])[S:14][CH:15]=1)[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)C(=NOC)c1csc(N)n1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CON=C(C(=O)O)c1csc(N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.6 %

Procedure:
Ethyl 2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetate hydrobromide (anti isomer) (15.5 g.) was dissolved in a solution of sodium hydroxide (4.4 g.) in water (150 ml.) and the resulting solution was stirred for 1 hour at ambient temperature. An insoluble material was filtered off and the filtrate was adjusted to pH 5.0 to precipitate crystals. The crystals were collected by filtration and dried to give 2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetic acid (anti isomer) (8.0 g.).
Reaction SMILES: Cl.Cl[CH:3]([C:17]1[CH:18]=[CH:19][C:20]([CH3:27])=[C:21]([S:23]([NH2:26])(=[O:25])=[O:24])[CH:22]=1)[CH2:4][NH:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16].C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C>[CH3:16][O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][N:5]1[CH2:4][CH:3]1[C:17]1[CH:18]=[CH:19][C:20]([CH3:27])=[C:21]([S:23]([NH2:26])(=[O:25])=[O:24])[CH:22]=1
Reactant: COc1ccccc1OCCNCC(Cl)c1ccc(C)c(S(N)(=O)=O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1ccccc1OCCN1CC1c1ccc(C)c(S(N)(=O)=O)c1
Yield: 88.3 %

Procedure:
In 50 ml of ethyl acetate was suspended 4.35 g (0.01 mole) of 5-{1-chloro-2-[2-(2-methoxyphenoxy)ethylamino]ethyl}-2-methylbenzenesulfonamide hydrochloride and then 50 ml of an aqueous 10% sodium carbonate solution was added to the suspension with stirring. After further stirringovernight vigorously, the reaction mixture was recovered by decantation. After removing inorganic materials by passing the ethyl acetate layer thusrecovered through a silica gel column (50 ml of silica gel), the reaction product was evaporated to dryness to provide 3.2 g (88%) of colorless resinous 5-{1-[2-(2-methoxyphenoxy)-ethyl]aziridin-2-yl}-2-methylbenzenesulfonamide. The product has the following physicochemical properties.
Reaction SMILES: [C:1]([O:9][CH3:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:11]1(O)[CH:16]=[CH:15]C=[CH:13][CH:12]=1>CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4].CO>[C:1]([O:9][C:10]1[CH:15]=[CH:16][CH:11]=[CH:12][CH:13]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccccc1
Reactant: Oc1ccccc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CO
Product: O=C(Oc1ccccc1)c1ccccc1
Temperature: 190 °C
Reaction time: 4 h
Yield: 74 %

Procedure:
A Claisen head was attached to a flask having an internal volume of 1000 ml, and a receiver having a gage was attached to the Claisen head via a condenser to make a distillation apparatus. Into this apparatus were charged methyl benzoate 100 g (735 mmole), phenol 553 g (5876 mmole) and titanium tetraisopropoxide 2.1 g (7.4 mmole). The contents were reacted with stirring at 190° C. in a bath. The reaction was conducted at atmospheric pressure, and the methanol thus produced was removed together with phenol. After reacting for 4 hours, excess phenol was distilled at atmospheric pressure. The remaining phenol and methyl benzoate were distilled under vacuum to obtain phenyl benzoate. The boiling point was 140° C./4mmHg. The yield was 108 g (74% yield in terms of methyl benzoate).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[S:15][C:16]([CH2:19][OH:20])=[CH:17][N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>ClCCl.[O-2].[Mn+4].[O-2]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[S:15][C:16]([CH:19]=[O:20])=[CH:17][N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(CO)s2)CC1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(C=O)s2)CC1
Yield: 40 %

Procedure:
To a solution of 40.0 mmol 4-(5-hydroxymethyl-thiazol-2-yl)-piperazine-1-carboxylic acid tert-butyl ester in 300 ml dichloromethane was added 289 mmol manganese(IV) oxide and the mixture was heated at reflux for 3 h. The mixture was then filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography (SiO2, ethyl acetate/heptane) to afford the title compound as a light brown crystalline solid (yield 40%). MS (m/e): 298.3 (M+H+, 100%).
Reaction SMILES: [Br:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH3:11].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:23](O)[CH2:24][CH2:25][OH:26]>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3]([CH3:11])=[CH:4][C:5]([CH:6]2[O:26][CH2:25][CH2:24][CH2:23][O:7]2)=[CH:8][C:9]=1[CH3:10]
Reactant: OCCCO
Reactant: Cc1cc(C=O)cc(C)c1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1cc(C2OCCCO2)cc(C)c1Br
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 4-bromo-3,5-dimethyl-benzaldehyde (8.15 g, 38.25 mmol), p-toluenesulfonic acid (50 mg) and 1,3-propanediol (9.5 mL) in toluene (100 mL) is heated to 110° C. for 3 h. The reaction flask is equipped with a Dean-Stark apparatus and heating is continued at 110° C. for 16 h. The reaction mixture is cooled to rt, washed with sat. aq. NaHCO3 and the solvent is removed in vacuo. The crude product is purified by CC on silica gel eluting with heptane:EA 9:1 to give 2-(4-bromo-3,5-dimethyl-phenyl)-[1,3]dioxane (5.97 g) as a colourless oil.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:18][CH2:19][CH2:20][CH2:21][Cl:22].O>CN(C=O)C>[Cl:22][CH2:21][CH2:20][CH2:19][CH2:18][N:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=2)=[N:9][C:10]1=[O:14]
Reactant: Cc1cccc(-c2cc[nH]c(=O)n2)n1
Reactant: ClCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc(-c2ccn(CCCCCl)c(=O)n2)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 58.8 %

Procedure:
To a solution of 4-(6-methyl-pyridin-2-yl)-1H-pyrimidin-2-one (200 mg, 1.06 mmol) in dry DMF (20 ml), 60% NaH (55 mg, 1.39 mmol) was added portionwise. After heating the mixture at 100° C. for 1 hour, 1-bromo-4-chloro-butane (187 μl 1.39 mmol) was added and the mixture was stirred overnight at room temperature. Water was added and the mixture extracted with diethyl ether to remove the dialkylated product and finally with ethyl acetate. Ethyl acetate was washed with brine, dried (Na2SO4) and evaporated. The residue was triturated with petroleum ether to give 173 mg of the title compound as a solid (58% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([O:21][C:22]1[C:23](=O)[C:24](=[O:31])[C:25]=1[O:26]CCCC)[CH2:18][CH2:19][CH3:20]>C(O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:23]2[C:24](=[O:31])[C:25](=[O:26])[C:22]=2[O:21][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: CCCCOc1c(OCCCC)c(=O)c1=O
Solvent: CCO
Product: CCCCOc1c(N2CCN(C(=O)OCc3ccccc3)CC2)c(=O)c1=O
Temperature: 25 °C
Reaction time: 25 h
Yield: 84.3 %

Procedure:
A mixture comprising 1101 mg of N-benzyloxycarbonylpiperazine, 1131 mg of 3,4-dibutoxy-3-cyclobutene-1,2-dione and 5 ml of ethanol was stirred at room temperature for 25 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (solvent: chloroform-ethyl acetate (19:1)) to obtain 1570 mg of 1-benzyloxycarbonyl-4-(4-butoxy-1,2-dioxo-3-cyclobuten-3-yl)-piperazine.
Reaction SMILES: C[O:2][C:3](=[O:23])[C@H:4]([NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[OH-].[Na+].Cl>C(O)C>[CH3:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([S:12]([NH:11][C@H:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:3]([OH:23])=[O:2])(=[O:14])=[O:13])=[CH:20][CH:19]=1
Reactant: COC(=O)[C@H](NS(=O)(=O)c1ccc(OC)cc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(S(=O)(=O)N[C@@H](C(=O)O)c2ccccc2)cc1
Reaction time: 8 h
Yield: 98.5 %

Procedure:
To a suspension of 3 mmol of 2(R)-[(4-methoxybenzenesulfonyl)amino]-2-phenyl acetic acid methyl ester in 15 mL of ethanol is added 5 mL of aqueous 2.5M sodium hydroxide. The solid suspension dissolved, and is allowed to stir, stoppered, at ambient temperature overnight. The resulting suspension is acidified with aqueous 10% HCl and extracted with ethyl acetate, adding brine to facilitate phase separation. The organic phase is washed with water and with brine and dried over sodium sulfate. It is concentrated to afford 0.95 g (quantitative yield) of a white solid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH2:6][CH2:7][C:8]2[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]3[O:16][CH2:15]3)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[NH2:19][CH2:20][CH2:21][N:22]1[C:26]2[CH:27]=[CH:28][C:29]([C:31]3[CH:32]=[CH:33][C:34](=[O:37])[NH:35][N:36]=3)=[CH:30][C:25]=2[N:24]=[CH:23]1>>[CH:1]1([CH2:4][O:5][CH2:6][CH2:7][C:8]2[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]([OH:16])[CH2:15][NH:19][CH2:20][CH2:21][N:22]3[C:26]4[CH:27]=[CH:28][C:29]([C:31]5[CH:32]=[CH:33][C:34](=[O:37])[NH:35][N:36]=5)=[CH:30][C:25]=4[N:24]=[CH:23]3)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1
Reactant: NCCn1cnc2cc(-c3ccc(=O)[nH]n3)ccc21
Reactant: c1cc(OCC2CO2)ccc1CCOCC1CC1
Product: O=c1ccc(-c2ccc3c(c2)ncn3CCNCC(O)COc2ccc(CCOCC3CC3)cc2)n[nH]1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2cyclopropylmethoxyethyl)phenoxy]-2,3-epoxypropane and 6-[1-(2-aminoethyl)benzimidazol-5-yl]-3(2H)-pyridazinone.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]2[N:13]=[C:12]([C:14]3[S:18][C:17]([C:19]([OH:21])=O)=[CH:16][CH:15]=3)[CH:11]=[CH:10][N:9]=2)[CH:2]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:55]([NH:57][CH2:58][CH2:59][C:60]#[N:61])[CH3:56]>CC(N(C)C)=O>[C:60]([CH2:59][CH2:58][N:57]([CH2:55][CH3:56])[C:19]([C:17]1[S:18][C:14]([C:12]2[CH:11]=[CH:10][N:9]=[C:8]([NH:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[N:13]=2)=[CH:15][CH:16]=1)=[O:21])#[N:61]
Reactant: O=C(O)c1ccc(-c2ccnc(Nc3cccnc3)n2)s1
Reactant: CCNCCC#N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CCN(CCC#N)C(=O)c1ccc(-c2ccnc(Nc3cccnc3)n2)s1
Yield: 11 %

Procedure:
Combined 5-[2-(Pyridin-3-ylamino)-pyrimidin-4-yl]-thiophene-2-carboxylic acid (22 mg, 0.065 mmol), DIEA (27 uL, 0.195 mmol), and HATU (36.8 mg, 0.097 mmol) in DMA (0.5 mL) in a Smith microwave vial. Added 3-ethylamino propionitrile (10.9 uL, 0.097 mmol) and heated in microwave for 900 seconds at 90° C. The crude mixture was purified by prep LCMS to afford title compound (2.7 mg, 10.9%). MS: m/z 379 (M+H+). 1H NMR (500 MHz, DMSO-d6) δ 1.203 (br t, 3H), 2.88 (br t, J=6.5 Hz, 2H), 3.65 (Br s, 2H), 3.70 (Br s, 2H), 7.33 (dd, J=5, 8.5 Hz, 1H), 7.469 (dd, J=1.5, 6.5 Hz, 1H), 7.497 (dd, J=1.5, 4 Hz, 1H), 7.985 (dd, J=1.5, 4 Hz, 1H), 8.16 (m, 1H), 8.22 (m, 1H), 8.56 (dd, J=1.5, 5 Hz, 1H), 8.95 (d, J=2.5 Hz, 1H), 9.91, (s, 1H).
Reaction SMILES: C([O:5][C:6]([C:8]1[C:9]([O:26][CH:27]([CH3:32])[C:28]([F:31])([F:30])[F:29])=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1)=[CH:15][C:14]([Cl:25])=[CH:13][CH:12]=2)=[O:7])(C)(C)C.Cl>O1CCOCC1>[Cl:25][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([O:26][CH:27]([CH3:32])[C:28]([F:31])([F:30])[F:29])[C:8]([C:6]([OH:7])=[O:5])=[C:17]2[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1
Reactant: CC(Oc1nc2ccc(Cl)cc2c(-c2cccc(Cl)c2)c1C(=O)OC(C)(C)C)C(F)(F)F
Agent: Cl
Solvent: C1COCCO1
Product: CC(Oc1nc2ccc(Cl)cc2c(-c2cccc(Cl)c2)c1C(=O)O)C(F)(F)F

Procedure:
The title compound was prepared in analogy to example 91 step E from 6-chloro-4-(3-chloro-phenyl)-2-(2,2,2-trifluoro-1-methyl-ethoxy)-quinoline-3-carboxylic acid tert-butyl ester (60 mg, 0.12 mmol) and 4N HCl in dioxane. Off white solid (21 mg, 40%). LC-MS (ESI): 428 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH:4](Br)[C:5](Br)([CH3:7])[CH3:6].[CH3:11][O:12][C:13](=[O:17])[CH2:14][C:15]#[N:16].C[O-].[Na+].O>CO.CCOCC>[CH3:11][O:12][C:13]([C:14]1([C:15]#[N:16])[C:5]([CH3:7])([CH3:6])[CH:4]1[C:3]([O:2][CH3:1])=[O:10])=[O:17]
Reactant: COC(=O)CC#N
Reactant: COC(=O)C(Br)C(C)(C)Br
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Solvent: O
Product: COC(=O)C1C(C)(C)C1(C#N)C(=O)OC
Temperature: 64 °C
Yield: 56.8 %

Procedure:
27.2 g (0.1 mol) of α,β-dibromo-isovaleric acid methyl ester were added dropwise to a solution of 19.9 g (0.2 mol) of cyanoacetic acid methyl ester and 10.8 g (0.2 mol) of sodium methylate in 50 ml of methanol at 20° C. The mixture was then heated to 64° C. for 5 hours. The solvent was then stripped off in vacuo. 100 ml of water and 100 ml of ether were added to the residue. The ether phase was separated off, dried over sodium sulphate and evaporated. The residue was fractionated twice. 12 g (57% of theory) of 3,3-dimethyl-1-cyano-cyclopropane-1,2-dicarboxylic acid dimethyl ester were obtained in the form of a colorless oil of boiling point 152° C./10 mm Hg.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH:11]1[C:23]2[CH:22]([CH2:24][O:25][C:26](=[O:55])[NH:27][C@H:28]3[CH2:33][CH2:32][CH2:31][C:30]([F:35])([F:34])[C@@H:29]3[NH:36][C:37]([C:39]3[S:40][C:41]([CH2:53][CH3:54])=[C:42](B4OC(C)(C)C(C)(C)O4)[CH:43]=3)=[O:38])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]=2[CH:14]=[CH:13][CH:12]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C([O-])(=O)C.[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH:11]1[C:23]2[CH:22]([CH2:24][O:25][C:26](=[O:55])[NH:27][C@H:28]3[CH2:33][CH2:32][CH2:31][C:30]([F:35])([F:34])[C@@H:29]3[NH:36][C:37]([C:39]3[S:40][C:41]([CH2:53][CH3:54])=[C:42]([C:2]4[N:6]5[N:7]=[CH:8][CH:9]=[CH:10][C:5]5=[N:4][CH:3]=4)[CH:43]=3)=[O:38])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]=2[CH:14]=[CH:13][CH:12]=1
Reactant: Brc1cnc2cccnn12
Reactant: CCc1sc(C(=O)N[C@@H]2[C@@H](NC(=O)OCC3c4ccccc4-c4ccccc43)CCCC2(F)F)cc1B1OC(C)(C)C(C)(C)O1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: CCc1sc(C(=O)N[C@@H]2[C@@H](NC(=O)OCC3c4ccccc4-c4ccccc43)CCCC2(F)F)cc1-c1cnc2cccnn12
Temperature: 100 °C

Procedure:
3-Bromoimidazo[1,2-b]pyridazine (53 mg, 0.27 mmol), 9H-fluoren-9-ylmethyl[(1S,2R)-2-({[5-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-2-yl]carbonyl}amino)-3,3-difluorocyclohexyl]carbamate (187 mg, 0.294 mmol), Pd2(dba)3 (25 mg, 0.03 mmol), tricyclohexylphosphine (19 mg, 0.07 mmol), and aqueous tribasic potassium acetate (0.71 mL, 0.91 mmol, 1.27 M) were placed into a sealed tube and 1,4-dioxane (5.4 mL) added. The sealed tube was purged with nitrogen for 5 minutes and heated at 100° C. for 18 h. The solution was cooled to room temperature and additional 9H-fluoren-9-ylmethyl[(1S,2R)-2-({[5-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-2-yl]carbonyl}amino)-3,3-difluorocyclohexyl]carbamate (85 mg, 0.13 mmol), Pd2(dba)3 (12 mg, 0.01 mmol), tricyclohexylphosphine (8 mg, 0.03 mmol), and aqueous tribasic potassium acetate (0.42 mL, 0.54 mmol, 1.27 M) were added. The sealed tube was purged with nitrogen for 5 minutes and heat at 100° C. for 4 h. The solution was then cooled to room temperature and quenched with aqueous saturated sodium bicarbonate and extracted with dichloromethane (×3). The combined organic layers were dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was taken on to the deprotection step without purification. LRMS (APCI) calc'd for (C34H31F2N5O3S) [M+H]+, 628.2. found 628.2.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:9])C=C.[CH2:13]1[C@H:22]2[C@@H](CCCC2)CC[CH2:14]1>>[CH2:22]([C:6]1[C:5]([OH:4])=[CH:12][CH:11]=[CH:10][C:7]=1[CH:8]=[O:9])[CH:13]=[CH2:14]
Reactant: C1CC[C@H]2CCCC[C@@H]2C1
Reactant: C=CCOc1cccc(C=O)c1
Product: C=CCc1c(O)cccc1C=O
Temperature: 217 °C
Reaction time: 18 h

Procedure:
In a 500 ml three-necked Morton flask equipped with mechanical stirrer, thermometer and reflux condenser was added 100 g of 3-allyloxybenzaldehyde (0.62 moles, 1 eq.) and 150 g of cis/trans decalin (1.5 vol). The mixture was purged with nitrogen and then heated to a reflux temperature of 217° C. The reaction was maintained at this reflux temperature for seven hours then cooled and 231 mL of toluene was added. The reaction mixture was then allowed to cool to room temperature. After stirring for 18 hours and further cooling to 0-5° C., reaction mixture was filtered and the cake washed with 200 mL of heptane. The wet cake was stirred in 200 mL of heptane for 1-2 hours at room temperature. After filtration and drying of the cake at 40° C., 54.27 g of crude 2-allyl-3-hydroxybenzaldehyde were obtained. This represents a recovery of 82% of the available 2-allyl product produced by the Claisen rearrangement.
Reaction SMILES: [C:1]1([C:7]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:11][C:10](=[O:12])[C:9]([O:13]CC3C=CC=CC=3)=[C:8]2[OH:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.OC1C(=O)OC(C)(C2C=CC=CC=2)C=1O>>[OH:13][C:9]1[C:10](=[O:12])[O:11][C:7]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]=1[OH:21]
Reactant: O=C1OC(c2ccccc2)(c2ccccc2)C(O)=C1OCc1ccccc1
Agent: CC1(c2ccccc2)OC(=O)C(O)=C1O
Product: O=C1OC(c2ccccc2)(c2ccccc2)C(O)=C1O
Yield: 5.6 %

Procedure:
Hydrogenolysis of 5,5-diphenyl-4-hydroxy-3-phenylmethoxy-2(5H)-furanone was performed in a similar manner as described in the preparation of 3,4-dihydroxy-5-methyl-5-phenyl-2(5H)-furanone to provide 150 mg (5.6% overall yield) of 3,4-dihydroxy-5,5-diphenyl-2(5H)-furanone as colorless needles: mp 192-193° C. dec.(CHCl3 /hexanes). 1H NMR (acetone-d6) δ 7.41 (s, 10H). 13C NMR (acetone-d6) δ 168.38, 154.92, 140.44, 128.72, 128.58, 127.43, 119.46, 84.74. Anal Calcd for C16H12O4 +0.25 H2O C, 70.46; H, 4.62. Found: C, 70.42; H, 4.52.