Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1CCOCC1.[CH2:7]([C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH2:16][CH2:17][CH:18]2[C:23]([OH:25])=[O:24])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Se](=O)=O.O>C(Cl)(Cl)Cl>[C:7]([C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH2:16][CH2:17][CH:18]2[C:23]([OH:25])=[O:24])(=[O:1])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)C1CCc2c(Cc3ccccc3)cccc21
Reactant: C1COCCO1
Agent: O=[Se]=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(c1ccccc1)c1cccc2c1CCC2C(=O)O

Procedure:
To 60 ml. of dioxane are added 6.3 g. of 4-benzylindan-1-carboxylic acid and 2.8 g. of selenium dioxide and the mixture is refluxed for 12 hours. After cooling, water and chloroform are added and the insolubles are filtered off. The filtrate is extracted with chloroform and the chloroform layer is extracted with 5% aqueous potassium carbonate. The extract is decolorized with activated carbon and rendered acidic with hydrochloric acid. The precipitate is extracted with chloroform and the extract is washed with water and dried. The solvent is distilled off under reduced pressure and the residue is crystallized from a 20:7 solvent mixture of cyclohexane and benzene. The described procedure gives 4-benzoylindan-1-carboxylic acid as crystals melting at 100°-102° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:8].[C-:16]#[N:17].[K+].ClCCl>C(O)C>[C:16]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:8])#[N:17]
Reactant: CCOC(=O)CNC(=O)CCCCCBr
Reactant: [C-]#N
Agent: [K+]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)CNC(=O)CCCCCC#N
Yield: 99 %

Procedure:
23.73 g (84.7·10-3 mol) of N-(6-bromohexanoyl)-glycine, ethyl ester are dissolved in 200 ml of ethanol, and 6.5 g (0.1 mol) of powdered potassium cyanide are added. The reaction mixture is brought to the reflux point and stirred under reflux for 15 hours. After concentration of the mixture under reduced pressure, the residue is taken up with dichloromethane and the organic phase is washed with aqueous sodium chloride solution. The organic phase is dried and concentrated under reduced pressure to give 19 g of the expected product (yield=99%).
Reaction SMILES: [Cl:1][CH:2]([CH3:26])[CH:3]([NH:15][C:16]([CH:18]1[CH:21]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:20][NH:19]1)=[O:17])[CH:4]1[CH:9]([OH:10])[CH:8]([OH:11])[CH:7]([OH:12])[CH:6]([S:13][CH3:14])[O:5]1.[CH2:27]1[O:29][CH2:28]1>>[Cl:1][CH:2]([CH3:26])[CH:3]([NH:15][C:16]([CH:18]1[CH:21]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:20][N:19]1[CH2:27][CH2:28][OH:29])=[O:17])[CH:4]1[CH:9]([OH:10])[CH:8]([OH:11])[CH:7]([OH:12])[CH:6]([S:13][CH3:14])[O:5]1
Reactant: C1CO1
Reactant: CCCCC1CNC1C(=O)NC(C(C)Cl)C1OC(SC)C(O)C(O)C1O
Product: CCCCC1CN(CCO)C1C(=O)NC(C(C)Cl)C1OC(SC)C(O)C(O)C1O

Procedure:
A sample of 3-butyl-azetidine-2-carboxylic acid [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide prepared in example 91 was alkylated with ethyleneoxide as depicted in scheme 19 (R6=2-hydroxyethyl) to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([C:14]([CH3:16])=O)[C:12]=2[OH:13])=[CH:4][CH:3]=1.[NH:17]([C:19]([NH:21][C:22]1[S:26][C:25]([C:27]([OH:29])=[O:28])=[CH:24][CH:23]=1)=[S:20])[NH2:18]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([C:14](=[N:18][NH:17][C:19]([NH:21][C:22]3[S:26][C:25]([C:27]([OH:29])=[O:28])=[CH:24][CH:23]=3)=[S:20])[CH3:16])[C:12]=2[OH:13])=[CH:4][CH:3]=1
Reactant: CC(=O)c1csc(-c2ccc(Cl)cc2)c1O
Reactant: NNC(=S)Nc1ccc(C(=O)O)s1
Product: CC(=NNC(=S)Nc1ccc(C(=O)O)s1)c1csc(-c2ccc(Cl)cc2)c1O

Procedure:
From 2-(4-chlorophenyl)-3-hydroxy-4-methylcarbonylthiophene (25.3 mg, 0.10 mmol) and 5-hydrazinocabonothioylamino-2-thiophenecarboxylic acid (21.8 mg, 0.10 mmol), the desired product was obtained in the same manner as in Synthetic Example 50 as a pale yellow solid (37.1 mg, yield 82%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([I:11])=[CH:6][N:5]=1.Br[CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.O>CN(C=O)C>[Cl:3][C:4]1[CH:9]=[C:8]([NH:10][CH2:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:16][CH2:15]2)[C:7]([I:11])=[CH:6][N:5]=1
Reactant: Nc1cc(Cl)ncc1I
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CNc2cc(Cl)ncc2I)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.7 %

Procedure:
NaH (0.098 g, 3.9 mmol) was added to a solution of 2-chloro-5-iodopyridin-4-amine (0.500 g, 1.96 mmol) in DMF (12 mL) and the mixture was stirred for 30 min at r.t. The temperature was then raised to 80° C. and a solution of tert-butyl 4-(bromomethyl)-piperidine-1-carboxylate (1.093 g, 3.93 mmol) in DMF (2 mL) was added. The reaction mixture was stirred at 80° C. for 2 h, then cooled to r.t. NaH (0.050 g, 2.00 mmol) was added and the reaction mixture was heated for 1 h at 80° C. After cooling, water (40 mL) was added and the reaction mixture was partitioned between ethyl acetate and aq. NaHCO3. The organic phase was washed with brine, dried (MgSO4) and concentrated. The crude product was purified by flash silica chromatography, eluting with ethyl acetate and hexane (1/9), to give the title compound as a pink solid (0.405 g, 46%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH3:18][C@H:19]1[NH:24][C@@H:23]([CH3:25])[CH2:22][N:21]([C:26]([C:28]2[C:29]([CH3:35])=[C:30]([CH:33]=O)[NH:31][CH:32]=2)=[O:27])[CH2:20]1>C(O)C.N1CCCCC1>[CH3:25][C@H:23]1[NH:24][C@@H:19]([CH3:18])[CH2:20][N:21]([C:26]([C:28]2[C:29]([CH3:35])=[C:30]([CH:33]=[C:10]3[C:9]4[C:13](=[CH:14][CH:15]=[CH:16][C:8]=4[C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[NH:12][C:11]3=[O:17])[NH:31][CH:32]=2)=[O:27])[CH2:22]1
Reactant: O=C1Cc2c(cccc2-c2ccc(F)cc2)N1
Reactant: Cc1c(C(=O)N2C[C@@H](C)N[C@@H](C)C2)c[nH]c1C=O
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(C(=O)N2C[C@@H](C)N[C@@H](C)C2)c[nH]c1C=C1C(=O)Nc2cccc(-c3ccc(F)cc3)c21
Temperature: 25 °C
Reaction time: 72 h
Yield: 50.4 %

Procedure:
To a solution of 4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 4-[(cis)-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 3-{4-((cis)-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrol-2-ylmethylene}-4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one as a yellow solid (57.8 mg, 50%).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)=[N:5][CH:6]=[CH:7][CH:8]=1.[OH:16][C:17]1[C:18]([CH:25]=[O:26])=[CH:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CC#N>[Cl:15][C:11]1[CH:10]=[C:9]([C:4]2[C:3]([CH2:2][O:16][C:17]3[C:18]([CH:25]=[O:26])=[CH:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=3)=[CH:8][CH:7]=[CH:6][N:5]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: COc1cc(C=O)c(O)cn1
Reactant: ClCc1cccnc1-c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(C=O)c(OCc2cccnc2-c2cccc(Cl)c2)cn1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 3-(chloromethyl)-2-(3-chlorophenyl)pyridine (309 mg, 1.30 mmol, 1.00 equiv), 5-hydroxy-2-methoxypyridine-4-carbaldehyde (200 mg, 1.31 mmol, 1.00 equiv), and potassium carbonate (361 mg, 2.61 mmol, 2.00 equiv) in CH3CN (20 mL). The resulting solution was stirred for 4 h at 70° C., and then it was concentrated under vacuum. The crude product (300 mg) was purified by Prep-HPLC with the following conditions (Prep-HPLC-010): Column, SunFire Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% TFA and MeCN (20.0% MeCN up to 60.0% in 10 min, up to 95.0% in 2 min, down to 20.0% in 1 min); Detector, Waters 2545 UvDector 254 & 220 nm. This resulted in 71 mg (9%) of 5-[[2-(3-chlorophenyl)pyridin-3-yl]methoxy]-2-methoxypyridine-4-carbaldehyde; bis(trifluoroacetic acid) as a yellow solid. 1HNMR (400 MHz, DMSO-d6) δ 10.07 (s, 1H), 8.72 (m, 1H), 8.20 (m, 2H), 7.79 (s, 1H), 7.60 (m, 4H), 6.95 (m, 1H), 5.21 (m, 2H), 3.85 (s, 3H); MS (ESI) m/z 355 [M+H]+.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].ClCCCl.[C:9](Cl)(=[O:11])[CH3:10].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:15]=1>O>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:9](=[O:11])[CH3:10])=[CH:22][CH:21]=2)=[CH:18][CH:19]=1
Reactant: Brc1ccc(-c2ccccc2)cc1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCCl
Product: CC(=O)c1ccc(-c2ccc(Br)cc2)cc1
Yield: 102.1 %

Procedure:
Four point three grams (32 mmol) of aluminum chloride was placed into 30 milliliter of 1,2-dichloroethane and a solution made by dissolving 2.0 g (25 mmol) of acetyl chloride, subsequently 5.0 g (21 mmol) of 4-bromo biphenyl into 20 milliliter of 1,2-dichloroethane was added while cooling with ice. The mixed solution was stirred as it is while cooling with ice for 4 hours. After completion of the reaction, adding water and an extraction was carried out using dichloro-methane. Further, washing with water, dried with the use of sodium sulfate. Removing the solvent by distillation, 5.9 g of crude 1-(4′-bromo-biphenyl-4-yl)-ethanone was obtained.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][C:11]([CH:13]=O)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH:15]1[CH:19]=[C:18]([CH2:20][CH2:21][N:22]2[C:26](=[O:27])[CH2:25][NH:24][C:23]2=[S:28])[N:17]=[CH:16]1.N1CCCCC1>ClCCl>[NH:15]1[CH:19]=[C:18]([CH2:20][CH2:21][N:22]2[C:26](=[O:27])/[C:25](=[CH:13]/[C:11]3[O:12][C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([I:1])[CH:3]=4)=[CH:9][CH:10]=3)/[NH:24][C:23]2=[S:28])[N:17]=[CH:16]1
Reactant: O=Cc1ccc(-c2cccc(I)c2)o1
Reactant: O=C1CNC(=S)N1CCc1c[nH]cn1
Solvent: ClCCl
Solvent: C1CCNCC1
Product: O=C1/C(=C/c2ccc(-c3cccc(I)c3)o2)NC(=S)N1CCc1c[nH]cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 51 %

Procedure:
5-(3-Iodophenyl)furan-2-carbaldehyde (30 mg, 0.1 mmol) synthesized by the same method as in Example 1 and 3-(2-(1H-imidazol-4-yl)ethyl)-2-thioxoimidazolidin-4-one (21 mg, 0.1 mmol) were dissolved in dichloromethane (7 mL), piperidine (20 μL) was added thereto, and the mixture was stirred at room temperature (25° C.) for 3 hours. After the reaction was completed the solvent was removed by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography using chloroform/methanol (9/1 (volume ratio)) as an eluent, to give compound 3 in a yield of 25 mg (yield 51.0%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Br[CH:23]([CH3:25])[CH3:24].COC1C=C(C2[C@H]3[C@H](CCCC3)C(=O)N(C)N=2)C=CC=1OC>>[CH:23]([N:13]1[N:12]=[C:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[C@H:20]2[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]2)[C:14]1=[O:21])([CH3:25])[CH3:24]
Reactant: CC(C)Br
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CCCC[C@@H]23)cc1OC
Agent: COc1ccc(C2=NN(C)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Product: COc1ccc(C2=NN(C(C)C)C(=O)[C@H]3CCCC[C@@H]23)cc1OC

Procedure:
Prepared from compound 1 and 2-bromopropane as described for compound 8. Purified by chromatography (dichloromethane). Crystallized from diethyl ether/petroleum ether (60-95° C.). M.p. 79-81° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][C:6]12[CH2:13][CH2:12][C:9]([C:14]3[NH:22][C:21]4[C:20](=[S:23])[NH:19][C:18](=[O:24])[N:17]([CH2:25][CH2:26][CH3:27])[C:16]=4[N:15]=3)([CH2:10][CH2:11]1)[CH2:8][CH2:7]2.[OH-].[Na+].[CH3:31]I>CCO.O>[CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][C:6]12[CH2:7][CH2:8][C:9]([C:14]3[NH:22][C:21]4[C:20]([S:23][CH3:31])=[N:19][C:18](=[O:24])[N:17]([CH2:25][CH2:26][CH3:27])[C:16]=4[N:15]=3)([CH2:10][CH2:11]1)[CH2:12][CH2:13]2
Reactant: CI
Reactant: CCCn1c(=O)[nH]c(=S)c2[nH]c(C34CCC(CCC(=O)OC)(CC3)CC4)nc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCn1c(=O)nc(SC)c2[nH]c(C34CCC(CCC(=O)OC)(CC3)CC4)nc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-[4-(2-Oxo-3-propyl-6-thioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-propionic acid methyl ester (100 mg) was dissolved in 2 mL of EtOH and 1 mL of H2O. NaOH (20 mg) was added as a solution in 1 mL of H2O, followed by MeI (23 uL, 1.5 eq). The resulting reaction mixture was stirred at rt for 30 min. It was then extracted with EtOAc. The organic layer was dried (Na2SO4) and concentrated under reduced pressure to afford 105 mg of the titled compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=O)[CH2:16][CH2:17][C:18](=O)[CH3:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:22][CH2:23][CH2:24][CH2:25][OH:26].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:22]([CH2:23][CH2:24][CH2:25][OH:26])[C:18]([CH3:19])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCCO
Reactant: CC(=O)CCC(=O)c1ccc(OCc2ccccc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccc(OCc3ccccc3)cc2)n1CCCO
Yield: 79.1 %

Procedure:
A solution of 1-(4-benzyloxyphenyl)pentan-1,4-dione (5.00 g, 17.7 mmol), 3-amino-1-propanol (1.33 g, 17.7 mmol) and p-toluenesulfonic acid monohydrate (253 mg, 1.33 mmol) in toluene (100 ml) was refluxed for 12 hours under heating using Dean-Stark's apparatus, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give the object compound as a solid. 4.50 g (yield: 79.1%)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[CH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:20][C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:22]=1[OH:30].CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:30][C:22]3[CH:23]=[CH:24][C:25]([N+:27]([O-:29])=[O:28])=[CH:26][C:21]=3[F:20])=[CH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccnc2cc(OCc3ccccc3)ccc12
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(Oc2ccnc3cc(OCc4ccccc4)ccc23)c(F)c1
Temperature: 115 °C
Reaction time: 0.5 h
Yield: 89.1 %

Procedure:
To a suspension of 7-(benzyloxy)-4-chloroquinoline (45 g, 0.17 mol) and 2-fluoro-4-nitrophenol (28.9 g, 0.18 mol) in toluene (42 mL) was added DIPEA (25.9 g, 0.2 mol). The suspension was heated to 115° C. for 12 hours and then concentrated in vacuo. The residue was diluted with EtOH (45 mL), stirred at 60° C. for 30 minutes, and then allowed to cool down to 0° C. in an ice bath. The solid was collected through filtration, dried in vacuo at 45° C. for 24 hours to afford the title compound as a light grey solid (59.1 g, 91%)
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][N:8]=[C:7]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[CH:13][C:12]=3[F:20])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:21]C.Cl.N1C=CC=CC=1.Cl>CC(=O)CC>[Cl:1][C:2]1[C:10]2[O:9][N:8]=[C:7]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[CH:13][C:12]=3[F:20])[C:6]=2[CH:5]=[CH:4][C:3]=1[OH:21]
Reactant: CCOc1ccc(-c2noc3c(Cl)c(OC)ccc23)c(F)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCC(C)=O
Product: CCOc1ccc(-c2noc3c(Cl)c(O)ccc23)c(F)c1
Temperature: 180 °C

Procedure:
A mixture of 14.2 g of 7-chloro-3-(4-ethoxy-2-fluorophenyl)-6-methoxy-1,2-benzisoxazole and pyridine hydrochloride is heated at 180° C. for 2 hr. The reaction is worked up with 2-butanone and 5% hydrochloric acid and the product crystallized from toluene to give 7-chloro-3-(4-ethoxy-2-fluorophenyl)-6-hydroxy-1,2-benzisoxazole, mp 170°-172° C. The hydroxy compound is alkylated with 0.045 mole of ethyl bromoacetate and 0.043 mole of potassium carbonate in 75 ml dimethylformamide at 65° C. for 1 hr. Workup with water gives ethyl [7-chloro-3-(2-fluoro-4-ethoxyphenyl)-1,2-benzisoxazol-6-yl]oxy}acetate, mp 118°-119° C., after recrystallization from acetonitrile.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]([OH:11])([C:9]#[CH:10])[CH3:8])[CH:3]=1.Br[C:13]1[CH:26]=[C:25]2[C:16]([O:17][CH2:18][CH2:19][N:20]3[C:24]2=[N:23][C:22]([C:27]([NH2:29])=[O:28])=[CH:21]3)=[CH:15][CH:14]=1>CS(C)=O.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:11][C@@:7]([C:4]1[CH:3]=[C:2]([CH3:1])[O:6][N:5]=1)([CH3:8])[C:9]#[C:10][C:13]1[CH:14]=[CH:15][C:16]2[O:17][CH2:18][CH2:19][N:20]3[C:24](=[N:23][C:22]([C:27]([NH2:29])=[O:28])=[CH:21]3)[C:25]=2[CH:26]=1
Reactant: C#CC(C)(O)c1cc(C)on1
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)ccc1OCC2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1cc([C@@](C)(O)C#Cc2ccc3c(c2)-c2nc(C(N)=O)cn2CCO3)no1
Reaction time: 1 h

Procedure:
The title compound was prepared according to a procedure similar to that described in Procedure G Into a 8-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed 2-(5-methylisoxazol-3-yl)but-3-yn-2-ol (515 mg, 3.41 mmol, 3.50 equiv), 13-bromo-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaene-4-carboxamide (300 mg, 0.97 mmol, 1 equiv) and Pd(PPh3)2Cl2 (205 mg, 0.29 mmol, 0.3 equiv) in DMSO (2 mL) and triethylamine (2 mL). The final reaction mixture was irradiated with microwave radiation for 2 h at 70° C. The resulting mixture was washed with 1×100 mL of water and 2×100 mL of CH3CN. The solids were collected by filtration. The residue was further purified by Chiral-Prep-HPLC with the following conditions (2#-Gilson Gx 281(HPLC-09): Column, Chiralpak IA2*25 cm, 5 um Chiral-P(IA)004IA00CJ-MB003; Phase A:MTBE Phase B:EtOH (0.2% DEA)-HPLC (10.0% EtOH for 60 min, then down to 0%); Detector, uv 254/220 nm. This resulted in 34.2 mg (9%) of 9-[(S)-3-Hydroxy-3-(5-methyl-isoxazol-3-yl)-but-1-ynyl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid amide as a off-white solid LC-MS (ES, m/z): 379[M+H]+; 1H-NMR (400 MHz, DMSO-d6, ppm): δ 8.536 (s, 1H), 7.802 (s, 1H), 7.558 (br s, 1H), 7.340-7.300 (m, 1H), 7.143 (br s, 1H), 7.040 (d, 1H), 6.504 (s, 1H), 6.360 (s, 1H), 4.492 (s, 4H), 2.365 (s, 3H), 1.920 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[C:12]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)(=[O:14])[CH3:13].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N+:8]([C:7]1[C:2]([NH2:1])=[N:3][C:4]([O:22][C:19]2[CH:18]=[CH:17][C:16]([NH:15][C:12](=[O:14])[CH3:13])=[CH:21][CH:20]=2)=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(Oc2ccc([N+](=O)[O-])c(N)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
To a solution of 2-amino-6-chloro-3-nitropyridine (2.77 g, 16.0 mmol) in DMF (55 mL) was added 4-acetylaminophenol (2.67 g, 17.5 mmol) followed by K2CO3 (3.3 g, 5.0 mmol) and stirred at room temperature for 2 hrs. The solvent was removed by evaporation. To the residue, water was added to form a precipitate. The solid was collected by filtration, washed with water and ethyl acetate then dried under reduced pressure to give the title compound (4.32 g, 94%): MS m/e 289 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11](=O)[CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:18][OH:19].N1C=CC=CC=1>C(O)C>[CH2:1]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11](=[N:18][OH:19])[CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C1CC2CCC(C1)N2Cc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: ON=C1CC2CCC(C1)N2Cc1ccccc1

Procedure:
2,5-dimethoxytetrahydrofuran (95) is combined with acetone dicarboxylic acid (96) and benzyl amine HCl salt (97) in sodium acetate to give 8-benzyl-8-azabicyclo[3.2.1]octan-3-one 98. The ketone 98 in ethanol is added to hydroxylamine hydrochloride and pyridine, and heated under reflux conditions to afford 8-benzyl-8-azabicyclo[3.2.1]octan-3-one oxime 99. The oxime 99 in 1-pentanol is combined with sodium metal and heated under reflux to produce 8-benzyl-8-azabicyclo[3.2.1]octan-3-amine 100. The amine 100 in CH2Cl2 (13 mL) is treated with 1M Na2CO3 and isobutyryl chloride to yield amide 101. The amide 101 is dissolved in CHCl3 and pyridine followed by the addition of POCl3. To this was then added diisopropylethylamine and appropriately deuterated acetylhydrazine 110 to produce triazol 102. The triazole 102 in EtOH was treated with Pd(OH)2/C (140 mg) under an H2 atmosphere to yield amine 103. Amine 103 was combined with appropriately deuterated aldehyde 111 in CH2Cl2 (5 mL), Na2SO4 and NaCNBD3 to afford 107. A solution of 107 in HCl/MeOH was heated to reflux to afford the free amine 108. The amine 108 in CH2Cl2 was combined with saturated Na2CO3 and H2O followed by appropriately deuterated cyclohexanecarbonyl chloride 109 to produce a compound of Formula II.
Reaction SMILES: [CH3:1][CH:2]([CH3:8])[CH2:3][CH2:4][C:5]([OH:7])=O.[NH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>O.CN(C=O)C>[CH3:8][CH:2]([CH3:1])[CH2:3][CH2:4][C:5]([N:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7]
Reactant: C1CCNCC1
Reactant: CC(C)CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)CCC(=O)N1CCCCC1

Procedure:
4-Methylvaleric acid (238 g) and DMF (833 mL) were mixed. After an addition of piperidine (233 mL), HOBt.H2O (361 g) and WSC.HCl (452 g) to the mixture at ice temperature, the resulting mixture was stirred at RT overnight. To the reaction was added water (1000 mL) at ice temperature and the resulting mixture was extracted with toluene (500 mL×2). The organic layer was washed with aqueous 10 w/v % sodium carbonate (500 mL+300 mL) and water (500 mL×2). The organic layer was concentrated in vacuo to give the title compound (414.29 g) as a crude product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:10][C:11]2[C:16]([Cl:17])=[CH:15][N:14]=[C:13]([NH:18][C:19]3[N:23]([CH:24]([CH3:26])[CH3:25])[N:22]=[C:21]([CH3:27])[CH:20]=3)[CH:12]=2)=C([CH:9]=1)C#N.[OH-].[Na+].[C:30]([O:33]CC)(=[O:32])[CH3:31]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:10][C:11]2[C:16]([Cl:17])=[CH:15][N:14]=[C:13]([NH:18][C:19]3[N:23]([CH:24]([CH3:25])[CH3:26])[N:22]=[C:21]([CH3:27])[CH:20]=3)[CH:12]=2)=[C:31]([CH:9]=1)[C:30]([OH:33])=[O:32]
Reactant: CCOC(C)=O
Reactant: Cc1cc(Nc2cc(Nc3ccc(Cl)cc3C#N)c(Cl)cn2)n(C(C)C)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1cc(Nc2cc(Nc3ccc(Cl)cc3C(=O)O)c(Cl)cn2)n(C(C)C)n1
Yield: 90 %

Procedure:
A solution of 5-chloro-2-[(5-chloro-2-{[3-methyl-1-(1-methylethyl)-1H-pyrazol-5-yl]amino}-4-pyridinyl)amino]benzonitrile (850 mg, 2.118 mmol) in sodium hydroxide-1 M (20 mL, 20.00 mmol) and 1,4-dioxane (20 mL) was refluxed overnight. Ethyl acetate was added and the layers were separated. The organic layer was washed with 1 M NaOH (40 ml). Combined aqueous layers were washed with ethyl acetate. The organic layers were combined, evaporated, dissolved in MeOH and evaporated again. 5-Chloro-2-[(5-chloro-2-{[3-methyl-1-(1-methylethyl)-1H-pyrazol-5-yl]amino}-4-pyridinyl)amino]benzoic acid (800 mg, 1.903 mmol, 90% yield) was isolated as a yellow solid. 1H NMR (400 MHz, DMSO-d6) ppm 1.28 (d, J=6.57 Hz, 6 H) 2.12 (s, 3 H) 4.40 (quin, J=6.51 Hz, 1 H) 5.97 (s, 1 H) 6.79 (s, 1 H) 7.56-7.62 (m, 1 H) 7.62-7.69 (m, 1 H) 7.94 (d, J=2.27 Hz, 1 H) 8.04 (s, 1 H) 8.58 (s, 1 H) 9.94 (br. s., 1 H) 13.97 (br. s., 1 H); HPLC Rt=2.65 min, MS (ESI): 420.2, 421.1 [M+H]+.