Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][C:13]2[O:14][C:15]([CH2:21][OH:22])=[C:16]([OH:20])[C:17](=[O:19])[CH:18]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:23](OC1C(=O)C=C(CNS(C2C=CC=CC=2)(=O)=O)OC=1CO)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([O:20][C:16]1[C:17](=[O:19])[CH:18]=[C:13]([CH2:12][NH:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[O:14][C:15]=1[CH2:21][OH:22])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=c1cc(CNS(=O)(=O)c2ccccc2)oc(CO)c1OCc1ccccc1
Reactant: O=c1cc(CNS(=O)(=O)c2ccc(Cl)cc2)oc(CO)c1O
Product: O=c1cc(CNS(=O)(=O)c2ccc(Cl)cc2)oc(CO)c1OCc1ccccc1
Yield: 46.17 %

Procedure:
N-(5-Benzyloxy-6-hydroxymethyl-4-oxo-4H-pyran-2-ylmethyl)-4-chloro-benzenesulfonamide (10-07) (3.5 g, 46.17%) was synthesized as a white solid from 4-chloro-N-(5-hydroxy-6-hydroxymethyl-4-oxo-4H-pyran-2-ylmethyl)-benzenesulfonamide (9-07) (6.0 g, 17.39 mmol) following the procedure described for N-(5-benzyloxy-6-hydroxymethyl-4-oxo-4H-pyran-2-ylmethyl)-benzenesulfonamide (10-01).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][O:6][N:7]=[C:8]([C:16](=[O:18])[CH3:17])[C:9]([O:11]C(C)(C)C)=[O:10])=[O:4].Br.C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C.C(Cl)Cl.CCCCCC>[CH3:1][O:2][C:3]([CH2:5][O:6][N:7]=[C:8]([C:16](=[O:18])[CH3:17])[C:9]([OH:11])=[O:10])=[O:4]
Reactant: COC(=O)CON=C(C(C)=O)C(=O)OC(C)(C)C
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)CON=C(C(C)=O)C(=O)O
Yield: 51 %

Procedure:
To a solution of tert-butyl 2-methoxycarbonylmethoxyimino-3-oxobutyrate (syn isomer) (10 g) in glacial acetic acid (5 ml) was added 30% hydrobromic acid in acetic acid (10 ml) at ambient temperature with stirring. The reaction mixture was stirred at 40° C. for 3 hours. The resultant solution was concentrated under reduced pressure and the residual oil was dissolved into ethyl acetate (100 ml). The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride four times and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give a crude oil (8.6 g). The oil was dissolved in methylene chloride (100 ml). To the solution was added potassium carbonate (1.87 g) and the suspension was stirred at ambient temperature for 30 minutes. The solution was diluted with n-hexane (100 ml). The solvent was decanted and the residual glassy mass was dissolved in ethyl acetate and 10% hydrochloric acid. The separated organic layer was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was concentrated under reduced pressure to give 2-methoxycarbonylmethoxyimino-3-oxobutyric acid (syn isomer) (4.0 g) as an oil.
Reaction SMILES: [Na].[Br:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)([CH3:11])[CH3:10])[CH:4]=1.Cl.[CH3:20][N:21]([CH3:26])[CH2:22][CH2:23][CH2:24]Cl>CN(C=O)C.CCOC(C)=O.O>[Br:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:24][CH2:23][CH2:22][N:21]([CH3:26])[CH3:20])=[CH:16][CH:17]=2)([CH3:10])[CH3:11])[CH:4]=1
Reactant: CC(C)(c1ccc(O)cc1)c1cc(Br)ccn1
Reactant: CN(C)CCCCl
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C)CCCOc1ccc(C(C)(C)c2cc(Br)ccn2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 43.2 %

Procedure:
Sodium hydroxyde (pellets are finely grinded, 0.488 g, 12.2 mmol, 5 eq) is added to a solution of 4-[1-(4-bromo-pyridin-2-yl)-1-methyl-ethyl]-phenol (Step 31.2) (0.714 g, 2.44 mmol) in DMF (5 mL). The mixture is stirred for 20 min at rt. 3-Dimethylamino-1-propylchloride hydrochloride (0.611 g, 3.87 mmol, 1.6 eq) is added. The reaction mixture is heated to 90° C., stirred for 10 h, allowed to cool, diluted with EtOAc/H2O and extracted with EtOAc. The organic phase is washed with H2O and brine, dried (Na2SO4), filtered and concentrated. The residue purified by silica gel column chromatography (DCM/MeOH/NH3aq, 94:5:1) to afford 0.398 g of the title compound as an impure brown oil which is used without further purification: ESI-MS: 377.1/379.0 [M+H]+; TLC: Rf=0.22 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)([O-:4])=[O:3].[O:23]1[CH2:26][C:25](=O)[CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C.ClCCl>[N+:2]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:12][CH2:13][CH:14]([N:17]3[CH2:22][CH2:21][N:20]([CH:25]4[CH2:26][O:23][CH2:24]4)[CH2:19][CH2:18]3)[CH2:15][CH2:16]2)=[CH:9][CH:10]=1)([O-:4])=[O:3]
Reactant: O=C1COC1
Reactant: O=[N+]([O-])c1ccc(N2CCC(N3CCNCC3)CC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(N2CCC(N3CCN(C4COC4)CC3)CC2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 63.2 %

Procedure:
A mixture of 1-[1-(4-nitrophenyl)piperidin-4-yl]piperazine monohydrochloride (1 g), oxetan-3-one (300 mg), sodium triacetoxyborohydride (1.02 g), dichloromethane (20 mL), acetic acid (1 mL), and chloroform (30 mL) was stirred at room temperature for 2 days. To the reactant were added a saturated aqueous sodium hydrogen carbonate solution and chloroform, followed by liquid separation. The organic phase was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; chloroform:methanol=1:0-9:1) to obtain 1-[1-(4-nitrophenyl)piperidin-4-yl]-4-(oxetan-3-yl)piperazine (670 mg) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH2:8]O)[CH:5]=[CH:4][CH:3]=1.P(Br)(Br)[Br:11]>C1COCC1>[Br:11][CH2:8][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=1
Reactant: BrP(Br)Br
Reactant: Cc1cccc(CO)n1
Solvent: C1CCOC1
Product: Cc1cccc(CBr)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.5 %

Procedure:
(6-methyl-2-pyridinyl)methanol (ALDRICH, 300 mg, 2.436 mmol) were dissolved in 10 mL of anhydrous THF. Phosphorous tribromide (ALDRICH, 0.252 mL, 2.68 mmol) was added. Reaction mixture was stirred at room temperature overnight. Solvent was evaporated and residue was purified by silica column chromatography using hexane:EtOAc as eluents to give a white solid. This solid was partitioned between EtOAc and distilled water (basified with NH3 (32%, aqueous). Organic layer was dried with MgSO4 (anh). Solvent was evaporated to obtain the title compound (152 mg, 0.817 mmol, 33.5% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm: 7.68 (t, 1H), 7.33 (d, 1H), 7.17 (d, 1H), 4.62 (s, 2H), 2.44 (s, 3H). [ES+MS] m/z 186 (M).
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1)([CH3:5])[C:3]#[N:4].C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C>[NH2:12][C:9]1[CH:8]=[CH:7][C:6]([C:2]([CH3:5])([CH3:1])[C:3]#[N:4])=[CH:11][CH:10]=1
Reactant: CC(C)(C#N)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C#N)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
2-methyl-2-(4-nitro-phenyl)-propionitrile was dissolved in ethyl acetate (20 ml) and treated with stannous chloride dihydrate (3.52 g, 15.86 mmol). After stirring overnight at room temperature, the reaction mixture was basified with aqueous sodium carbonate. The organic layer was separated, washed with water, dried and concentrated to oil. The crude compound was purified by column chromatography over silica gel using ethyl acetate/pet ether (1:9) as eluent to give 2-(4-aminophenyl)-2-methyl propionitrile (0.45 g, 89%) as oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[N:8]=[C:7](O)[N:6]=[CH:5]2.P(Cl)(Cl)([Cl:16])=O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[N:8]=[C:7]([Cl:16])[N:6]=[CH:5]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncc2cc(Br)cc(Cl)c2n1
Product: Clc1ncc2cc(Br)cc(Cl)c2n1

Procedure:
A solution of 6-bromo-8-chloroquinazolin-2-ol (9.0 g, 35 mmol) in phosphorus oxychloride (100 mL) was refluxed for 5 hours. Most of phosphorus oxychloride was removed under reduced pressure, and the residue was added to a stirring ice water (500 mL). The resulting precipitate was collected via filtration and then refluxed in THF. The solid was filtered off, and the filtrate was concentrated to give the title compound a yellow solid (7.0 g, 78%). MS (ES+) C8H4BrClN2 requires: 275, 277, found: 276, 278 [M+H]+.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4]1.[C:12]([O:16][C:17](=[O:27])[NH:18][CH:19]1[CH2:26][CH2:25][CH2:24][C:21]2([O:23][CH2:22]2)[CH2:20]1)([CH3:15])([CH3:14])[CH3:13]>CN(C=O)C>[N:3]1([CH2:22][C:21]2([OH:23])[CH2:24][CH2:25][CH2:26][C@@H:19]([NH:18][C:17](=[O:27])[O:16][C:12]([CH3:14])([CH3:13])[CH3:15])[CH2:20]2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4]1
Reactant: CC(C)(C)OC(=O)NC1CCCC2(CO2)C1
Reactant: c1ccc2[nH]ncc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H]1CCCC(O)(Cn2ncc3ccccc32)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
NaH (1.1 mmol) was added to a vial containing indazole (2.2 mmol) in DMF (1 ml). The mixture was stirred at rt for 15 mins, then added tert-butyl-1-oxaspiro[2.5]octaN-5-ylcarbamate (0.22 mmol). The reaction was stirred at 60° C. overnight. Upon completion, the mixture was quenched by water (3 mL). The mixture was extracted using dichloromethane (3×5 mL). The extracts were combined and dried using anhydrous sodium sulfate. The product was purified using HPLC.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][S:16][C:17]2[NH:18][C:19]3[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:20]=3[N:21]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31].CCOCC>CCCCCC>[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31].[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31].[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31].[F:27][C:23]1[C:24]([F:26])=[CH:25][C:19]2[N:18]=[C:17]([S:16][CH2:15][CH2:14][N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[NH:21][C:20]=2[CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CCSc2nc3cc(F)c(F)cc3[nH]2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCCC
Solvent: CCOCC
Product: Fc1cc2nc(SCCN3CCNCC3)[nH]c2cc1F
Yield: 82 %

Procedure:
Under stirring in an ice-bath, 1-tert-butoxycarbonyl-4-[2-(5,6-difluorobenzimidazol-2-ylthio)ethyl]piperazine (7.26 g, 18.22 mmol) was added to trifluoroacetic acid (50 mL) over 15 minutes and dissolved. After the mixture had been stirred for ten minutes under cooling with ice, ether (100 mL) and hexane (100 mL) were added thereto, and the formed crystals were collected through filtration. The crystals were recrystallized from ethanol-ether, to thereby yield 1-[2-(5,6-difluorobenzimidazol-2-ylthio)ethyl]piperazine tris(trifluoroacetic acid) salt (9.58 g, yield 82%) as a pale yellow powder.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[O:7][N:6]=[C:5]([C:8]2[S:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)[C:4]=1[CH3:16].[ClH:19].Cl.[NH:21]1[CH2:26][CH2:25][CH2:24][CH:23]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[CH2:22]1.N1CCCCC1>C(N(CC)CC)C.C1COCC1>[ClH:19].[CH3:16][C:4]1[C:5]([C:8]2[S:12][C:11]([C:13]([N:21]3[CH2:26][CH2:25][CH2:24][CH:23]([N:27]4[CH2:28][CH2:29][O:30][CH2:31][CH2:32]4)[CH2:22]3)=[O:15])=[CH:10][CH:9]=2)=[N:6][O:7][C:3]=1[C:2]([F:1])([F:18])[F:17]
Reactant: C1CNCC(N2CCOCC2)C1
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: C1CCNCC1
Product: Cc1c(-c2ccc(C(=O)N3CCCC(N4CCOCC4)C3)s2)noc1C(F)(F)F
Yield: 65 %

Procedure:
Prepared from 5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and 4-piperidin-3-yl-morpholine, di-hydrochloride by the method described in Example 2 Method B reversing the order of addition such that solid acid chloride was added to a THF solution of triethylamine and piperdine derivative. An additional 2 equivalents of triethylamine was used. The reaction mixture was evaporated to an oil, triturated and filtered with the aid of water, then with a saturated aqueous NaHCO3 solution. The residual oil was then dissolved in EtOAc (2 mL), dried over MgSO4, filtered, and evaporated to an oil. The crude oil was then dissolved in diethyl ether (1 mL) and treated with a 4 N solution of hydrogen chloride in 1,4,-dioxane to precipitate product as a colorless solid. The solid was filtered with the aid of diethyl ether and air dried to afford product as a colorless solid (61 mg, 65%). LC/MS 4.66 min, [M+1]+ 430.
Reaction SMILES: [H-].[Na+].[C:3]([O:10][CH2:11][CH3:12])(=[O:9])[C:4]([O:6]CC)=O.[C:13]1(=[O:25])[C:23]2=[C:24]3[C:19](=[CH:20][CH:21]=[CH:22]2)[CH2:18][CH2:17][CH2:16][CH:15]3[CH2:14]1.Cl>O1CCOCC1>[C:4]([CH:14]1[CH:15]2[C:24]3[C:19]([CH2:18][CH2:17][CH2:16]2)=[CH:20][CH:21]=[CH:22][C:23]=3[C:13]1=[O:25])([C:3]([O:10][CH2:11][CH3:12])=[O:9])=[O:6]
Reactant: CCOC(=O)C(=O)OCC
Reactant: O=C1CC2CCCc3cccc1c32
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)C(=O)C1C(=O)c2cccc3c2C1CCC3
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.5 %

Procedure:
To a suspension of 50% sodium hydride (7.4 g) in anhydrous dioxane (50 ml), under nitrogen, a solution of diethyl oxalate (34.5 g) in anhydrous dioxane (20 ml) and then a solution of 2a,3,4,5-tetrahydro-acenaphthen-1-one (20.4 g) in anhydrous dioxane (130 ml) are added under stirring at room temperature. The reaction mixture is kept under stirring at a temperature varying between about 25° C. and about 45° C. for 4 hours, then it is diluted with ice water (1500 ml) and acidified to pH 4 with 2N HCl. The precipitate is filtered, washed with water and then purified by treatment with methanol to give 2-ethoxalyl-2a,3,4,5-tetrahydro-acenaphthen-1-one (30.8 g), m.p. 92°-94° C., wich is reacted with methylhydrazine (5.7 g) in acetic acid (300 ml) at 50° C. for 1 hour.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[C:34](Cl)(=[O:36])[CH3:35]>>[C:34]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)(=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1
Product: CC(=O)N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting from trans-4-(5-cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A140) and acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].ClC1C2C(=CC=CC=2)N=CC=1.[N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[N:22][CH:21]=1.[H-].[Na+]>CS(C)=O>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][C:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:20]=[CH:21][N:22]=1
Reactant: c1ccc2ncncc2c1
Reactant: Nc1ccccc1O
Agent: Clc1ccnc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Nc1ccccc1Oc1ncnc2ccccc12

Procedure:
Alternatively, the 4-(aminophenoxy)quinoline derivative or corresponding quinazoline derivative may be produced by reacting an aminophenol derivative with the 4-chloroquinoline derivative or corresponding quinazoline derivative in a suitable solvent, for example, dimethyl sulfoxide, in the presence of a base, for example, sodium hydride. Alternatively, the 4-(aminophenoxy)quinazoline derivative may also be produced by dissolving an aminophenol derivative in an aqueous sodium hydroxide solution and subjecting the solution to a two-phase reaction with a solution of the 4-chloroquinazoline derivative in a suitable organic solvent, for example, ethyl methyl ketone, in the presence of a phase transfer catalyst, for example, tetra-n-butylammonium chloride, or in the absence of the catalyst.
Reaction SMILES: O.[OH-].[Li+].[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[N:14]1[CH:18]=[C:17]([CH3:19])[N:16]=[CH:15]1)[CH:9]=O.C(OP([CH2:28][C:29](=[O:40])[NH:30][CH:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:33][CH2:32]1)(=O)OCC)C>C1COCC1>[CH:31]1([NH:30][C:29](=[O:40])/[CH:28]=[CH:9]/[C:8]2[CH:11]=[CH:12][C:13]([N:14]3[CH:18]=[C:17]([CH3:19])[N:16]=[CH:15]3)=[C:6]([O:5][CH3:4])[CH:7]=2)[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:33][CH2:32]1
Reactant: COc1cc(C=O)ccc1-n1cnc(C)c1
Reactant: CCOP(=O)(CC(=O)NC1CCc2ccccc21)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(/C=C/C(=O)NC2CCc3ccccc32)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.1 %

Procedure:
Lithium hydroxide monohydrate (9 mg) was added to a THF (2 mL) solution of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (21 mg) and indan-1-ylcarbamoylmethylphosphonic acid diethyl ester (30 mg) obtained above, and the reaction solution was agitated at room temperature overnight. After the reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (Carrier: Chromatorex™ NH, elution solvent: hexane-ethyl acetate system), and 13 mg of the title compound was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:13][CH2:12][NH:11][C:10](=[O:14])[C@H:9]2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:4][CH:3]=1.[C:21](Cl)(=[O:23])[CH3:22].C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[C:21]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:13][CH2:12][NH:11][C:10](=[O:14])[C@H:9]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:4][CH:3]=1)(=[O:23])[CH3:22]
Reactant: O=C1NCC[C@@H](c2ccc(O)cc2)[C@@H]1c1ccccc1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc([C@@H]2CCNC(=O)[C@H]2c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 2.67 g (0.01 mol) of trans-4-(4-hydroxyphenyl)-3-phenyl-2-piperidone 27 dissolved in 20 cm3 of anhydrous pyridine, 2 cm3 (0.028 mol) of acetyl chloride are added under nitrogen at 0° C. The mixture is stirred for 2 hours 30 mins at 0° C., and then 48 hours at room temperature. The reaction mixture is then poured onto 50 g of ice. A spatulaful of sodium bicarbonate is added, and the mixture is stirred and then extracted with methylene chloride (3 times 60 cm3).
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([OH:21])=O)=[CH:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[O:45]1[CH2:50][CH2:49][CH2:48][CH2:47][CH:46]1[O:51][NH2:52]>CN(C=O)C.C(N(CC)CC)C.O>[CH3:22][N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([S:9]([N:12]2[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([NH:52][O:51][CH:46]3[CH2:47][CH2:48][CH2:49][CH2:50][O:45]3)=[O:21])=[CH:13]2)(=[O:10])=[O:11])=[CH:7][CH:8]=1
Reactant: NOC1CCCCO1
Reactant: CN(C)c1ccc(S(=O)(=O)n2ccc(/C=C/C(=O)O)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)c1ccc(S(=O)(=O)n2ccc(/C=C/C(=O)NOC3CCCCO3)c2)cc1

Procedure:
Starting materials: (E)-3-[1-(4-dimethylamino-benzenesulfonyl)-1H-pyrrol-3-yl)-acrylic acid (compound B3) (0.150 g), HOBt.H2O (0.072 g), triethylamine (259 μl), DMF (10 ml), EDC.HCl (0.269 g), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (0.049 g). Reaction conditions: room temperature, 1 hour; room temperature, 17 hours.
Reaction SMILES: C([NH:8][C:9]1[C:14]2[O:15][CH2:16][CH2:17][N:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:13]=2[CH:12]=[CH:11][N:10]=1)C1C=CC=CC=1>CO.[Pd]>[NH2:8][C:9]1[C:14]2[O:15][CH2:16][CH2:17][N:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:13]=2[CH:12]=[CH:11][N:10]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2c1ccnc2NCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCOc2c1ccnc2N
Temperature: 35 °C
Reaction time: 48 h
Yield: 79.1 %

Procedure:
A mixture of tert-butyl 5-(benzylamino)-2,3-dihydropyrido[3,4-b][1,4]oxazine-1-carboxylate (3.6 g, 10.56 mmol) and 10% Pd on carbon (1.12 g, 1.06 mmol) in MeOH (100 mL) was stirred under hydrogen atmosphere (2 L) at 35° C. for 48 h. The mixture was then filtered through Celite and washed with MeOH (3×25 mL). The combined organic layer was concentrated under reduced pressure. The residue was re-dissolved in EtOAc (100 mL) and washed with brine (2×50 mL). The combined organic layer was dried over sodium sulfate, filtered, and the solvent removed under reduced pressure. The residue was purified by reverse phase column chromatography (eluting with 22% acetonitrile in water, with 0.1% NH3.H2O) to give tert-butyl 5-amino-2,3-dihydropyrido[3,4-b][1,4]oxazine-1-carboxylate (2.1 g, 79% yield) as a yellow solid. ESI MS: m/z 252 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[NH:9][C:10](=O)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>Cl.CO>[CH2:11]([C:10]1[NH:1][C:2]2[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=2[N:9]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccc(Br)cc1NC(=O)Cc1ccccc1
Agent: Cl
Solvent: CO
Product: Brc1ccc2[nH]c(Cc3ccccc3)nc2c1
Temperature: 25 °C
Reaction time: 60 h
Yield: 82.9 %

Procedure:
Concentrated hydrochloric acid (12 drops) was added to a solution of N-(2-amino-5-bromophenyl)-2-phenylacetamide (4.10 g, 13.44 mmol) in methanol (80 mL) and the mixture was stirred at room temperature for 2.5 days. The reaction mixture was concentrated and taken up in DCM. Solid sodium bicarbonate was added in portions to the suspension and the mixture stirred for 30 min. and water (20 mL) was added. The organic layer was isolated and dried over Na2SO4. The product (3.2 g, 82%) was Isolated by purified by column chromatography (50% hexanes in ethyl acetate). LC-MS [M+H]+=288.5, RT=2.11 min
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[N:3]1[CH2:9][CH2:10][NH:11][C:12]([C:14]1[CH:15]=[CH:16][C:17]([F:42])=[C:18]([NH:20][C:21]([C:23]2[N:27]3[CH:28]=[CH:29][C:30]([C:32]4[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[C:34]([F:41])[CH:33]=4)=[CH:31][C:26]3=[N:25][CH:24]=2)=[O:22])[CH:19]=1)=[O:13].[NH2:43][C:44]([CH3:48])([CH3:47])[CH2:45][OH:46]>>[CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[N:3]1[CH2:9][CH2:10][NH:11][C:12]([C:14]1[CH:15]=[CH:16][C:17]([F:42])=[C:18]([NH:20][C:21]([C:23]2[N:27]3[CH:28]=[CH:29][C:30]([C:32]4[CH:40]=[CH:39][C:35]([C:36](=[O:37])[NH:43][C:44]([CH3:48])([CH3:47])[CH2:45][OH:46])=[C:34]([F:41])[CH:33]=4)=[CH:31][C:26]3=[N:25][CH:24]=2)=[O:22])[CH:19]=1)=[O:13]
Reactant: CC(C)(N)CO
Reactant: C[C@@H]1CCC[C@H](C)N1CCNC(=O)c1ccc(F)c(NC(=O)c2cnc3cc(-c4ccc(C(=O)O)c(F)c4)ccn23)c1
Product: C[C@@H]1CCC[C@H](C)N1CCNC(=O)c1ccc(F)c(NC(=O)c2cnc3cc(-c4ccc(C(=O)NC(C)(C)CO)c(F)c4)ccn23)c1

Procedure:
The title compound was prepared from 4-(3-(5-(2-(2,6-cis-dimethylpiperidin-1-yl)ethylcarbamoyl)-2-fluorophenyl carbamoyl)imidazo[1,2-a]pyridin-7-yl)-2-fluorobenzoic acid (step 1) and 2-amino-2-methylpropan-1-ol analogously to Example 8.1, step 2;
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][N:4]=1)#[N:2].[CH3:10]N(C=O)C.C([O-])([O-])=O.[K+].[K+]>O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][N:4]=1)#[N:2]
Reactant: N#Cc1ccc(O)cn1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COc1ccc(C#N)nc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 78 %

Procedure:
2-Cyano-5-hydroxy pyridine (200 mg, 1.66 mmol), DMF (10 mL) and K2CO3 (253 mg, 1.83 mmol), and Mel (354 mg, 2.49 mmol) were combined at rt and the reaction mixture was stirred for 24 h at rt. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed with water, dried and concentrated to give 2-cyano-5-methoxy pyridine (175mg, 78%).