Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:15])[CH3:5].C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C>[Cl:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C@@H:7]1[CH2:8][C@H:6]1[CH:4]([NH:3][O:2][CH3:1])[CH3:5]
Reactant: CON=C(C)[C@@H]1C[C@H]1c1ccccc1Cl
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CONC(C)[C@@H]1C[C@H]1c1ccccc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 29.2 %

Procedure:
To a stirred solution of trans 1-[2-(2-chloro-phenyl)-cyclopropyl]-ethanone O-methyl-oxime (1.1 g; 5 mmol) prepared as described in example P19 in acetic acid (10 ml) at ambient temperature was added portionwise sodium cyanoborohydride (0.65 g; 10 mmol). The reaction mixture was stirred for 16 hours at ambient temperature then poured on saturated sodium hydrogen carbonate solution (50 ml) and extracted with dichloromethane (3×50 ml). Combined organic layers were dried over anhydrous sodium sulphate. The solvent was removed in vacuo and the residue was purified by flash chromatography over silica gel (elution gradient: cyclohexane/ethyl acetate 99:1 to 1:99) to afford 0.33 g (30% of theory) trans N-{1-[2-(2-Chloro-phenyl)-cyclopropyl]-ethyl}-O-methyl-hydroxylamine diastereomer A as a clear viscous oil and 0.46 g (41% of theory) and trans N-{1-[2-(2-Chloro-phenyl)-cyclopropyl]-ethyl}-O-methyl-hydroxylamine diastereomer B as a clear viscous oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([C:13]1[C:21]2[O:20][CH2:19][CH2:18][C:17]=2[CH:16]=[C:15]([N+:22]([O-])=O)[CH:14]=1)[CH2:8][CH2:9][N:10]([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:25])[N:7]([C:13]1[C:21]2[O:20][CH2:19][CH2:18][C:17]=2[CH:16]=[C:15]([NH2:22])[CH:14]=1)[CH2:8][CH2:9][N:10]([CH3:12])[CH3:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)CCN(C(=O)OC(C)(C)C)c1cc([N+](=O)[O-])cc2c1OCC2
Agent: [Pd]
Solvent: CCO
Product: CN(C)CCN(C(=O)OC(C)(C)C)c1cc(N)cc2c1OCC2
Yield: 73.5 %

Procedure:
A solution of 5-nitro-2,3-dihydrobenzofuran-7-yl)-(2-dimethylaminoethyl)carbamic acid tert-butyl ester (D6) (387 mg) in ethanol (50 ml) was hydrogenated over 10% palladium on charcoal for 2 h at atmospheric pressure and room temperature. The catalyst was removed by filtration and the flitrate evaporated under reduced pressure to give the title compound as a brown oil (260 mg, 73%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:18]([CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:17]3[C:12]([C:13]4[CH:27]=[CH:26][C:25]([C:28]([O:30]C)=[O:29])=[CH:24][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[OH-].[Na+]>CO.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:18]([CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)[CH:17]3[C:12]([C:13]4[CH:27]=[CH:26][C:25]([C:28]([OH:30])=[O:29])=[CH:24][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: COC(=O)c1ccc2c(c1)CCC1C2=NN(c2ccc(C#N)c(Cl)c2)C1C1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)cc4CCC3C2C2CCCC2)cc1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 105 %

Procedure:
To a solution of the methyl 2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylate from step 1 (3.75 g, 8.6 mmol) in methanol (10 mL) and tetrahydrofuran (30 mL) was added 10% aqueous sodium hydroxide (10 mL). The solution was stirred for 20 hours at ambient temperature. The resulting slurry was concentrated to half volume and acidified to a pH of about 2 with 1M hydrochloric acid. The resulting solid was collected by vacuum filtration to provide the title compound largely present as (±)-(3SR,3aRS)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid (yellow solid, 3.79 g, quantitative yield). LC/MS on 4.6×50 mm C-18 column, tR=6.74 minutes (10 to 90% acetonitrile/water over 8 minutes at 2 mL/minute with detection 254 nm, at 50° C.); ES-MS m/z 420 (M+H); HRMS Calculated for C24H22ClN3O2: 420.1473 (M+H)+. Found: 420.1449; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.10-1.55 (m, 6H), 1.64-1.75 (m, 2H), 1.75-1.87 (m, 1H), 1.99-2.09 (m, 1H), 2.15-2.23 (m, 1H), 2.78-2.91 (m, 2H), 3.00 (d, J=16.11 Hz, 1H), 4.89 (dd, J=9.26, 5.77 Hz, 1H), 7.14 (dd, J=9.00, 1.75 Hz, 1H), 7.34 (d, J=1.88 Hz, 1H), 7.63 (d, J=8.86 Hz, 1H), 7.73 (s, 1H), 7.76 (s, 1H), 7.94 (d, J=7.79 Hz, 1H).
Reaction SMILES: [OH:1][CH:2]([CH3:14])[CH:3]([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11]([OH:13])=O)[N:10]=1)[CH3:4].[NH2:15][C@H:16]([CH3:32])[CH2:17][N:18]1[CH:22]=[CH:21][C:20]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([Cl:31])[CH:24]=2)=[N:19]1>>[Cl:31][C:25]1[CH:24]=[C:23]([C:20]2[CH:21]=[CH:22][N:18]([CH2:17][C@H:16]([NH:15][C:11]([C:9]3[N:10]=[C:6]([NH:5][CH:3]([CH:2]([OH:1])[CH3:14])[CH3:4])[S:7][CH:8]=3)=[O:13])[CH3:32])[N:19]=2)[CH:30]=[CH:29][C:26]=1[C:27]#[N:28]
Reactant: CC(O)C(C)Nc1nc(C(=O)O)cs1
Reactant: C[C@@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: CC(O)C(C)Nc1nc(C(=O)N[C@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)cs1
Yield: 14.45 %

Procedure:
N—((R)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(3-hydroxybutan-2-ylamino)thiazole-4-carboxamide was prepared using the method of Example 34(d) starting from 2-(3-hydroxybutan-2-ylamino)thiazole-4-carboxylic acid (1.35 g, 6.24 mmol) and (R)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (1.356 g, 5.20 mmol). The product was purified by Flash-chromatography. Yield 14.45%. 1H-NMR (400 MHz; DMSO-d6): δ 0.98-1.19 (m, 9H), 3.57-3.72 (m, 2H), 4.23-4.47 (m, 3H), 4.67 (d, 1H), 6.94-6.97 (m, 1H), 7.11-7.14 (m, 1H), 7.37-7.53 (m, 1H), 7.69-7.80 (m, 1H), 7.80-7.85 (m, 1H), 7.90-8.00 (m, 2H), 8.06-8.09 (m, 1H).
Reaction SMILES: O=[C:2]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([OH:5])=[O:4].[NH2:14][C@H:15]([C:22]([N:24]1[CH2:31][CH2:30][CH2:29][C@H:25]1[C:26]([OH:28])=[O:27])=[O:23])[CH2:16][C:17]1[N:21]=[CH:20][NH:19][CH:18]=1.C([BH3-])#N.[Na+]>>[C:3]([CH:2]([NH:14][C@H:15]([C:22]([N:24]1[CH2:31][CH2:30][CH2:29][C@H:25]1[C:26]([OH:28])=[O:27])=[O:23])[CH2:16][C:17]1[N:21]=[CH:20][NH:19][CH:18]=1)[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([OH:5])=[O:4]
Reactant: N[C@@H](Cc1c[nH]cn1)C(=O)N1CCC[C@H]1C(=O)O
Reactant: O=C(O)C(=O)CCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Product: O=C(O)C(CCc1ccccc1)N[C@@H](Cc1c[nH]cn1)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
In the manner described in Example 54, 2-oxo-4-phenylbutyric acid and L-histidyl-L-proline are condensed in the presence of sodium cyanoborohydride to yield N-(1-carboxy-3-phenylpropyl)-L-histidyl-L-proline. The product is purified by gel filtration chromatography in methanol (LH-20). The nmr spectrum is consistent with structure. The mass spectrum shows a molecular ion at 657 for the disilylated species.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([NH2:14])=O)[CH:2]=1.B>O1CCCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH2:14])[CH:2]=1
Reactant: NC(=O)CCCCCc1cccnc1
Agent: B
Solvent: C1CCOC1
Product: NCCCCCCc1cccnc1
Temperature: 0 °C
Yield: 67.6 %

Procedure:
To an ice-cold solution of 16.27 g of 3-pyridinehexanamide in 250 ml of dry tetrahydrofuran was added 300 ml of a 1M solution of borane in tetrahydrofuran. The mixture was heated to reflux over night, cooled, quenched with water, and made strongly acidic with 6N hydrochloric acid solution. The acidic solution was allowed to stand over night, made basic with sodium hydroxide solution, and was extracted with 3×150 ml of dichloromethane. The combined organic layers were dried over potassium carbonate, evaporated, and the residue was distilled to give 10.20 g (68%) of 3-pyridinehexanamine, bp 140°-150° C./0.2 mm.
Reaction SMILES: [CH2:1]([C:10]1[CH:29]=[CH:28][C:13]([CH2:14][N:15]2[CH2:19][CH2:18][CH:17]([P:20](=[O:27])([O:24]CC)[O:21]CC)[CH2:16]2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].Br[Si](C)(C)C>C(#N)C>[CH2:1]([C:10]1[CH:29]=[CH:28][C:13]([CH2:14][N:15]2[CH2:19][CH2:18][CH:17]([P:20](=[O:21])([OH:24])[OH:27])[CH2:16]2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCCc1ccc(CN2CCC(P(=O)(OCC)OCC)C2)cc1
Agent: C[Si](C)(C)Br
Solvent: CC#N
Product: CCCCCCCCCc1ccc(CN2CCC(P(=O)(O)O)C2)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 45.9 %

Procedure:
A solution of 67 mg (0.16 mmol) of (R/S)-1-(4-nonylbenzyl)-pyrrolidin-3-ylphosphonic acid, diethyl ester (from Step C) in 1 mL of acetonitrile was treated with 0.094 mL (0.71 mmol) of bromotrimethylsilane. The reaction was allowed to stir at 80° C. for 1 h. The reaction was quenched with MeOH and concentrated several times from MeOH. The residue was purified by LC-2 to afford 27 mg (46%) of the title compound: ESI-MS 368 (M+H); LC-1: 3.1 min.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][C:22]=1[CH:31]=O>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[C:11]=1[CH:2]1[N:1]([CH2:31][C:22]2[CH:23]=[CH:24][C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:21]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: O=Cc1ccc2ccccc2n1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1ccc2ccccc2n1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with commercially available quinoline-2-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.63 min.; [M+H]+: 377.04 g/mol.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Cl-].[Al+3:6].[Cl-].[Cl-].[C:9]1([CH3:15])[CH:14]=CC=C[CH:10]=1>>[N-:1]=[N+:2]=[N-:3].[CH2:10]([Al+:6][CH2:14][CH:9]([CH3:10])[CH3:15])[CH:9]([CH3:15])[CH3:14]
Reactant: Cc1ccccc1
Reactant: [Al+3]
Agent: [Cl-]
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Product: CC(C)C[Al+]CC(C)C
Temperature: 25 °C

Procedure:
1.235 g of granular sodium azide (19 mmol) are added to a cold solution of dilsobutyl aluminium chloride (19 mmol, 1.8M in toluene) diluted in 5 ml of toluene and the mixture is stirred at room temperature over the night to give diisobutyl aluminium azide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:20][C@H:21]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)[CH3:22]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)=[C:6]([CH:10]=1)[C:7]([NH:20][C@H:21]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)[CH3:22])=[O:9]
Reactant: O=C(O)c1cc(Cl)ccc1Cc1cccc(Cl)c1
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)ccc2Cc2cccc(Cl)c2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 5-chloro-2-(3-chlorobenzyl)benzoic acid (step 2) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 3 of Example 8): 1H-NMR (CDCl3) δ 7.98 (2H, dd, J=6.5, 1.7 Hz), 7.36–7.26 (4H, m), 7.19–7.13 (3H, m), 7.05 (1H, br.s), 6.97–6.94 (1H, m), 5.93 (1H, d, J=7.2 Hz), 5.19 (1H, dq, J=7.2, 7.0 Hz), 4.11 (2H, s), 3.92 (3H, s), 1.44 (3H, d, J=7.0 Hz); MS (ESI) m/z 442 (M+H)+, 440 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][N:8]=[C:7]([O:10][CH2:11][CH:12]([NH:38]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:13][C:14]3[N:15]=[CH:16][N:17](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:18]=3)[C:6]=2[CH:58]=1.CC(O)C.[ClH:63]>C(Cl)Cl>[ClH:1].[ClH:63].[NH2:38][CH:12]([CH2:13][C:14]1[N:15]=[CH:16][NH:17][CH:18]=1)[CH2:11][O:10][C:7]1[C:6]2[CH:58]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:9][N:8]=1
Reactant: Clc1ccc2onc(OCC(Cc3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)NC(c3ccccc3)(c3ccccc3)c3ccccc3)c2c1
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)O
Product: NC(COc1noc2ccc(Cl)cc12)Cc1c[nH]cn1

Procedure:
To a solution of 0.91 g of 5-chloro-3-[2-tritylamino-3-(1-trityl-4-imidazolyl)propoxy]-1,2-benzoisoxazole in 2 ml of methylene chloride is added 2.2 ml of a 2-propanol solution (6.5M) of hydrogen chloride at room temperature, and they are subjected to reaction at the same temperature for 24 hours, after which the solvent is removed by distillation under reduced pressure. Diisopropyl ether is added to the residue obtained and the crystals precipitated are collected by filtration, to obtain 0.4 g of colorless, crystalline 3-[2-amino-3-(4-imidazolyl)propoxy]-5-chloro-1,2-benzoisoxazole dihydrochloride having a melting point of 246.0°-248.4° C. (decomp.).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:14]=[C:13]([NH2:15])[N:12]=[C:11]2[C:7]=1[N:8]=[CH:9][N:10]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23]C)[CH:18]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[NH4+].[Cl-]>C(Cl)Cl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:14]=[C:13]([NH2:15])[N:12]=[C:11]2[C:7]=1[N:8]=[CH:9][N:10]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=1
Reactant: COc1cccc(Cn2cnc3c(-c4ccco4)nc(N)nc32)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: ClCCl
Product: Nc1nc(-c2ccco2)c2ncn(Cc3cccc(O)c3)c2n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 53.4 %

Procedure:
An ice-cold solution of 6-(2-furyl)-9-(3-methoxybenzyl)-9H-purine-2-amine (160 mg, 0.5 mmol) in DCM (3 mL) was treated with BBr3 (1 mL, 1-M in DCM, 1 mmol), stirred at 0° C. for 3 h, treated with more BBr3 (2 ml, 1-M in DCM, 2 mmol), stirred for 16 h, treated with NH4Cl solution, extracted with EtOAc, dried (MgSO4), concentrated in vacuo, triturated with ether and filtered. The resulting solid was suspended in aqueous sodium bicarbonate, extracted with ether, the aqueous phase was acidified to pH 7 and the resulting solid filtered, suspended in methanol, treated with HCl in dioxane (4-M, 2 mL), diluted with ether and filtered to give the title compound (82 mg, 48%) as a yellow solid.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6](=[C:17](OCC)[CH2:18][CH3:19])[C:5]1=[O:23])(=O)C.[CH3:24][N:25]([CH3:37])[CH2:26][CH2:27][N:28]([CH3:36])[C:29]1[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=1>>[CH3:24][N:25]([CH3:37])[CH2:26][CH2:27][N:28]([C:29]1[CH:30]=[CH:31][C:32]([NH:35]/[C:17](=[C:6]2\[C:5](=[O:23])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=3)/[CH2:18][CH3:19])=[CH:33][CH:34]=1)[CH3:36]
Reactant: CN(C)CCN(C)c1ccc(N)cc1
Reactant: CCOC(CC)=C1C(=O)N(C(C)=O)c2cc(OC)c(OC)cc21
Product: CC/C(Nc1ccc(N(C)CCN(C)C)cc1)=C1/C(=O)Nc2cc(OC)c(OC)cc21

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone and N-(2-dimethylaminoethyl)-N-methyl-p-phenylenediamine
Reaction SMILES: [C:1]([O:4][CH:5]([CH2:21][N:22]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]1)[CH2:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12](=O)[NH:13][CH:14]=[N:15]2)=[CH:10][C:9]=1[O:19][CH3:20])(=[O:3])[CH3:2].CN(C=O)C.S(Cl)([Cl:36])=O>>[C:1]([O:4][CH:5]([CH2:21][N:22]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]1)[CH2:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12]([Cl:36])=[N:13][CH:14]=[N:15]2)=[CH:10][C:9]=1[O:19][CH3:20])(=[O:3])[CH3:2]
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCC(CN1CCN(C)CC1)OC(C)=O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)ncnc2cc1OCC(CN1CCN(C)CC1)OC(C)=O
Temperature: 80 °C
Yield: 88 %

Procedure:
A solution of 7-[2-acetoxy-3-(4-methylpiperazin-1-yl) propoxy]-6-methoxyquinazolin-4-one (930 mg, 2.4 mmol) in thionyl chloride (10 ml) containing DMF (150 μl) was heated at 80° C. for 5 hours. The volatiles were removed under vacuum and the residue azeotroped with toluene. The solid was partitioned between methylene chloride and water and the pH of the aqueous layer was adjusted to 7 with solid sodium bicarbonate. The organic layer was separated, washed with brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography eluting with methylene chloride/methanol saturated with ammonia (95/5). The fractions containing the expected product were combined and the volatiles were removed under vacuum to give 7-[2-acetoxy-3-(4-methylpiperazin-1-yl)propoxy]-6-methoxy-4-chloroquinazoline (859 mg, 88%).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:18]=[C:17]([OH:19])[C:16]([OH:20])=[CH:15][C:4]=2[S:5][C:6]=1[C:7]([N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[O:8].[N+:21]([O-])([OH:23])=[O:22]>C(OCC)(=O)C.ClCCl>[Cl:1][C:2]1[C:3]2[CH:18]=[C:17]([OH:19])[C:16]([OH:20])=[C:15]([N+:21]([O-:23])=[O:22])[C:4]=2[S:5][C:6]=1[C:7]([N:9]1[CH2:10][CH2:11][O:12][CH2:13][CH2:14]1)=[O:8]
Reactant: O=[N+]([O-])O
Reactant: O=C(c1sc2cc(O)c(O)cc2c1Cl)N1CCOCC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(c1sc2c([N+](=O)[O-])c(O)c(O)cc2c1Cl)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(3-Chloro-5,6-dihydroxy-benzo[b]thiophen-2-yl)-morpholin-4-yl-methanone (7.7 g) was dissolved in ethyl acetate (500 ml) and a solution of nitric acid in dichloromethane (2M, 13.6 ml) was gradually added at 20° C. into. The solution was stirred 30 min at room temperature and then it was poured into ice-cold water and the resultant solid was filtered and dried in vacuum. The product was recrystallized from acetic acid.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([O:32][CH3:33])[CH:31]=1)[CH2:6][N:7]1[C:11]([CH3:13])([CH3:12])[C:10](=[O:14])[N:9]([C:15]2[CH:16]=[N:17][N:18]([CH2:20][C:21]3[C:22]([CH3:27])=[N:23][O:24][C:25]=3[CH3:26])[CH:19]=2)[C:8]1=[O:28].B(Br)(Br)Br>ClCCl>[CH3:27][C:22]1[C:21]([CH2:20][N:18]2[CH:19]=[C:15]([N:9]3[C:10](=[O:14])[C:11]([CH3:13])([CH3:12])[N:7]([CH2:6][C:5]4[CH:29]=[C:30]([O:32][CH3:33])[CH:31]=[C:3]([OH:2])[CH:4]=4)[C:8]3=[O:28])[CH:16]=[N:17]2)=[C:25]([CH3:26])[O:24][N:23]=1
Reactant: COc1cc(CN2C(=O)N(c3cnn(Cc4c(C)noc4C)c3)C(=O)C2(C)C)cc(OC)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COc1cc(O)cc(CN2C(=O)N(c3cnn(Cc4c(C)noc4C)c3)C(=O)C2(C)C)c1
Temperature: -78 °C
Reaction time: 3 h
Yield: 47 %

Procedure:
1-(3,5-dimethoxybenzyl)-3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-5,5-dimethylimidazolidine-2,4-dione (Example 12-18) (114 mg, 0.252 mmol) was dissolved in dichloromethane (1 mL). The mixture was cooled down to −78° C. and boron tribromide (1.0 M solution in dichloromethane, 1.25 mL) was added dropwise. After complete addition, the mixture was allowed to warm to room temperature and stirring continued for 3 hours. The mixture was quenched with water and the organic phase was separated, dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure. The residue was suspended in methanol (1 mL) and purified by reverse phase HPLC (25 minute gradient: acetonitrile/water). Yield 47% (45 mg), white solid. 1H NMR (DMSO-d6, 400 MHz): . s, 6H), 2.16 (s, 3H), 2.42 (s, 3H), 3.67 (s, 3H), 4.43 (s, 2H), 5.20 (s, 2H), 6.22 (t, J=2.4 Hz, 1H), 6.39 (m, 2H), 7.83 (d, J=0.4 Hz, 1H), 8.21 (s, 1H), 9.40 (br s, 1H). Mp. 72-74° C. MS 440 (MH+). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.02 μM.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:11][CH2:12][C:13]([C:15]2[S:22][C:21]([CH3:23])=[C:20]3[C:16]=2[CH2:17][C@H:18]2[C:24]([CH3:26])([CH3:25])[C@H:19]23)=[O:14])[CH:5]=[C:6]([O:9][CH3:10])[C:7]=1[OH:8].[CH2:27]([CH:29]1[O:31][CH2:30]1)Cl>C(O)(C)C.[OH-].[Na+].C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:11][CH2:12][C:13]([C:15]2[S:22][C:21]([CH3:23])=[C:20]3[C:16]=2[CH2:17][C@H:18]2[C:24]([CH3:26])([CH3:25])[C@H:19]23)=[O:14])[CH:5]=[C:6]([O:9][CH3:10])[C:7]=1[O:8][CH2:27][CH:29]1[CH2:30][O:31]1
Reactant: ClCC1CO1
Reactant: COc1cc(CCC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(Cl)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CCOCC
Product: COc1cc(CCC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(Cl)c1OCC1CO1
Temperature: 60 °C
Reaction time: 1 h
Yield: 63.5 %

Procedure:
A solution of 3-(3-chloro-4-hydroxy-5-methoxy-phenyl)-1-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one (550 mg, 1.41 mmol, Intermediate 14) in isopropanol (10 mL) and 3 N aq. NaOH (4 mL) is treated with epichlorohydrine (0.88 g, 7.04 mmol). The dark red reaction mixture is stirred at 60° C. for 1 h. The mixture is diluted with diethyl ether (150 mL) and washed with sat. aq. NaHCO3 followed by water. The organic layer is dried over MgSO4 and evaporated. The crude product is purified by CC on silica gel eluting with heptane:EA 4:1 to give 3-(3-chloro-5-methoxy-4-oxiranylmethoxy-phenyl)-1-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one (400 mg) as a pale yellow oil; LC-MS: tR=1.14 min, [M+1]+=447.21; 1H NMR (CDCl3): δ 6.85-6.81 (m, 1H), 6.71-6.67 (m, 1H), 4.13 (dd, J=4.1, 11.1 Hz, 1H), 4.01 (dd, J=5.9, 11.1 Hz, 1H), 3.83 (s, 3H), 3.44-3.36 (m, 1H), 3.08-2.75 (m, 8H), 2.37 (s, 3H), 1.92-1.86 (m, 2H), 1.11 (s, 3H), 0.70 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:7]([CH:11]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:12][C:13](O)=[O:14])([O:9][CH3:10])=[O:8]>>[CH3:10][O:9][C:7](=[O:8])[CH:11]([O:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH2:12][C:13]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:14]
Reactant: COC(=O)C(CC(=O)O)Oc1ccccc1
Reactant: C1COCCN1
Product: COC(=O)C(CC(=O)N1CCOCC1)Oc1ccccc1
Yield: 86 %

Procedure:
Using the mixed anhydride procedure described in Example 2, morpholine was coupled to 3-carbomethoxy-3-phenoxypropionic acid to give the desired product in 86% yield, mp 83°-84° C. Anal. Calcd for C15H19NO5 : C, 61.42; H, 6.53; N, 4.78. Found: C, 61.47; H, 6.50; N, 4.61.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][C:27]=2Br)[O:24][CH2:23][C:22]2[N:17]3[CH:18]([CH3:30])[C:19](=[O:29])[NH:20][N:21]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:31]1(B(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:27]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:26][C:25]3[O:24][CH2:23][C:22]4=[N:21][NH:20][C:19](=[O:29])[CH:18]([CH3:30])[N:17]4[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: CC1C(=O)NN=C2COc3cc(Br)c(C4CCN(C(=O)OC(C)(C)C)CC4)cc3N21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC1C(=O)NN=C2COc3cc(-c4ccccc4)c(C4CCN(C(=O)OC(C)(C)C)CC4)cc3N21
Temperature: 25 °C
Yield: 99.9 %

Procedure:
A mixture of 4-(7-bromo-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.02 g, 0.042 mmol), phenylboronic acid (0.01 g, 0.083 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloride dichloromethane complex (0.007 g, 0.008 mmol) and K2CO3 (0.012 g, 0.083 mmol) in dioxane (1 mL) and water (0.2 mL) was heated to reflux for 8 h. The reaction mixture was cooled to ambient temperature and filtered. The filtrate was concentrated in vacuo and the residue was purified by preparative TLC (eluting with 50% EtOAc in petroleum ether) to give tert-butyl-4-(1-methyl-2-oxo-8-phenyl-1,2,3,5-tetrahydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-9-yl)piperidine-1-carboxylate (0.02 g, 100%) as a pale-white solid. LC/MS (Table 1, Method 3) Rt=1.596 min.; MS m/z: 477 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][CH:7]=1.C(O[CH:18]=[C:19]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21])C>O>[O:8]([C:5]1[N:6]=[CH:7][C:2]([NH:1][CH:18]=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:3][CH:4]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1ccc(Oc2ccccc2)nc1
Solvent: O
Product: CCOC(=O)C(=CNc1ccc(Oc2ccccc2)nc1)C(=O)OCC
Temperature: 25 °C

Procedure:
A mixture of 5-amino-2-phenoxypyridine (10.49 g) and diethyl ethoxymethylenemalonate (12.2 g) was boiled under reflux for 2.5 hours. The mixture was cooled to ambient temperature and water (50 ml) was added. The mixture was extracted with dichloromethane to give diethyl 2-(6-phenoxy-3-pyridylaminomethylene)malonate as an oil.