Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH2:14][OH:15])=[C:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1.[OH-:16].[Na+].C(Cl)(Cl)Cl>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]([CH2:14][O:15][C:5]([CH3:6])([CH3:4])[C:8]([OH:9])=[O:16])=[C:11]([CH3:13])[N:12]=2)=[CH:6][CH:7]=1
Reactant: Cc1nc(-c2ccc(Cl)cc2)oc1CO
Reactant: [OH-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Product: Cc1nc(-c2ccc(Cl)cc2)oc1COC(C)(C)C(=O)O
Yield: 65 %

Procedure:
6.9 g (30.8 mmol) of 2-(4-chlorophenyl)-4-methyl-5-oxazolemethanol were combined with 6.2 g (155 mmol) of powdered sodium hydroxide in 45 ml of acetone and the suspension was heated to reflux. 4.9 g (41.1 mmol) of chloroform in 10 ml of acetone were added dropwise during 30 minutes and the suspension was heated at reflux for 4 hours. The solvent was removed by evaporation under reduced pressure, and the residue was partitioned between 150 ml of diethyl ether and 400 ml of water. The organic phase was separated and the aqueous phase was extracted twice with diethyl ether. The aqueous phase was acidified to pH 2 with concentrated hydrochloric acid and extracted three times with 50 ml of dichloromethane each time. The combined dichloromethane extracts were dried over magnesium sulphate, filtered and evaporated to yield 3.7 g of crude product. Recrystallization from ethyl acetate yielded 3.1 g (32.5%) of 2-[[2-(4-chlorophenyl)-4 -methyl-5-oxazolyl]methoxy]-2-methylpropionic acid of melting point 166°-167° C.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:9]([C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1)=[O:10].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:8][C:7]1[C:2]([C:14]2[CH:15]=[CH:16][C:11]([CH:9]=[O:10])=[CH:12][CH:13]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Clc1cccnc1Cl
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=Cc1ccc(-c2ncccc2Cl)cc1
Yield: 83 %

Procedure:
{circle around (2)} 100 g (0.676 mol) of 2,3-dichloropyridine was dissolved in 500 mL of ethanol, and 101.4 g (0.676 mol) of (4-formylphenyl)boronic acid and 78 g (0.0676 mol) of Pd(PPh3)4 were sequentially added. A solution of 86 g (0.811 mol) of sodium carbonate in 500 mL of distilled water was placed in the reactor, and the mixture was heated to reflux for 4˜6 hours so as to allow it to react. After completion of the reaction, the reaction solution was concentrated under reduced pressure to remove ethanol, and extracted with ethyl acetate. The extract was treated with magnesium sulfate, filtered and concentrated under reduced pressure, yielding 4-(3-chloropyridin-2-yl)benzaldehyde as represented below in a 83% yield.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([S:14](Cl)(=O)=O)[CH:11]=2)[CH2:6]1.COC(=O)CC1CC2C(=CC=C(SCC3SC(C4C=CC(C(F)(F)F)=CC=4)=NC=3C)C=2)C1>>[CH3:1][O:2][C:3](=[O:18])[CH2:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([SH:14])[CH:11]=2)[CH2:6]1
Reactant: COC(=O)CC1Cc2ccc(S(=O)(=O)Cl)cc2C1
Agent: COC(=O)CC1Cc2ccc(SCc3sc(-c4ccc(C(F)(F)F)cc4)nc3C)cc2C1
Product: COC(=O)CC1Cc2ccc(S)cc2C1

Procedure:
Compound 2C was prepared according to the method of Example 1 utilizing compound 2B. The crude product was used immediately. Preparation of {5-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-indan-2-yl}-acetic acid methyl ester (Compound 2D)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].ClS([N:15]=[C:16]=[O:17])(=O)=O.Cl.O>C1(C)C=CC=CC=1>[N:1]1([C:16]([NH2:15])=[O:17])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: O=C1Cc2ccccc2N1
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: NC(=O)N1C(=O)Cc2ccccc21
Temperature: 25 °C
Yield: 53.7 %

Procedure:
A mixture of 2-oxindole (5.86 g, 44.0 mmoles) in toluene (160 ml) was azeotroped for one hour to dry the toluene. Then, chlorosulfonyl isocyanate (7.47 g, 52.8 mmole) was added. Hydrogen chloride was immediately evolved. The mixture was stirred and refluxed for 15 minutes and then cooled to room temperature. Water (50 ml) was added to the cooled mixture (some HCl was initially evolved) and the mixture stirred for 1.5 hours. The solid which formed was collected by filtration and dried (4.10 g). The filtrate was extracted with ethyl acetate (100 ml), the resulting extract washed with brine (2×100 ml) and dried (MgSO4). Evaporation of the extract under reduced pressure gave 4.16 g of solid. The combined solids were recrystallized by dissolution in acetonitrile (200 ml) followed by concentration of the solution under reduced pressure to about 75 ml. The small amount of amorphous material which separated was filtered off, the filtrate decolorized and concentrated under reduced pressure to about 50 ml volume, then seeded. The dark red crystals which separated were filtered and dried (3.0 g; 38%). It was identical to the product of Example 1.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13](F)[CH:14]=2)[C:9](=[O:17])[N:8]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:7]=1[C:22]([O:24]CC)=[O:23])[CH2:2][CH2:3][CH3:4].[OH-:27].[Na+].Cl.[H-].[Na+]>O1CCCC1.C(O)C.C(O)C1C=CC=CC=1.O>[CH2:9]([O:27][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:17])[N:8]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:7]([C:22]([OH:24])=[O:23])=[C:6]2[O:5][CH2:1][CH2:2][CH2:3][CH3:4])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: [OH-]
Reactant: CCCCOc1c(C(=O)OCC)n(CC(C)C)c(=O)c2ccc(F)cc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCOc1c(C(=O)O)n(CC(C)C)c(=O)c2ccc(OCc3ccccc3)cc12
Temperature: 150 °C
Reaction time: 12 h
Yield: 176.1 %

Procedure:
To a solution of ethyl 4-butoxy-6-fluoro-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate (9.09 g, 25 mmol) in tetrahydrofuran (30 mL) and ethanol (30 mL) was added sodium hydroxide (3.00 g, 75 mmol). The obtained mixture was refluxed under heating for 12 h. The reaction mixture was poured into water, acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in benzyl alcohol (20 mL) and the obtained solution was added dropwise to a solution of sodium hydride (5.0 g, 125 mmol)(60% in oil) in benzyl alcohol (20 mL). The obtained mixture was stirred at 150° C. for 12 h. The reaction mixture was poured into 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from tetrahydrofuran-diisopropyl ether to give 6-benzyloxy-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylic acid (9.32 g, 88.1%) as crystals.
Reaction SMILES: [CH2:1]([N:8](C)[CH2:9][CH2:10][N:11]([CH2:13][C:14]1[C:15]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH:27]([CH3:29])[CH3:28])=[CH:22][CH:21]=2)=[N:16][N:17]([CH3:19])[CH:18]=1)[CH3:12])C1C=CC=CC=1>CO.[Pd]>[CH:27]([O:26][C:23]1[CH:22]=[CH:21][C:20]([C:15]2[C:14]([CH2:13][N:11]([CH3:12])[CH2:10][CH2:9][NH:8][CH3:1])=[CH:18][N:17]([CH3:19])[N:16]=2)=[CH:25][CH:24]=1)([CH3:29])[CH3:28]
Reactant: CC(C)Oc1ccc(-c2nn(C)cc2CN(C)CCN(C)Cc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: CNCCN(C)Cc1cn(C)nc1-c1ccc(OC(C)C)cc1
Yield: 59 %

Procedure:
To a suspension of N1-benzyl-N2-((3-(4-isopropoxyphenyl)-1-methyl-1H-pyrazol-4-yl)methyl)-N1,N2-dimethylethane-1,2-diamine (62 mg, 0.15 mmol) and Pd/C (10 mg) in methanol was purged H2 gas for 2 h. The resulting mixture was filtered through celite and washed with methanol (5 mL×2). The combined filtrate was concentrated to afford N1-((3-(4-isopropoxyphenyl)-1-methyl-1H-pyrazol-4-yl)methyl)-N1,N2-dimethylethane-1,2-diamine (28 mg, 58%). 1H NMR (400 MHz, DMSO-d6): δ 8.12 (s, 1H), 7.48 (d, J=8.4 Hz, 2H), 6.98 (d, J=8.8 Hz, 2H), 4.71-4.61 (m, 1H), 4.44-4.27 (m, 2H), 3.90 (s, 3H), 3.50-3.18 (m, 5H), 3.11-3.04 (m, 1H), 2.65-2.45 (m, 4H) 1.29 (d, J=6 Hz, 6H) ppm. LCMS (method C): RT=1.76 min, m/z=317.3 [M+H]+.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.F[C:14]1[N:15](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:16]=[CH:17][N:18]=1.FC1NC=CN=1.[NH2:44][CH:45]1[C:62](=[O:63])[N:47]2[C:48]([C:59]([OH:61])=[O:60])=[C:49]([CH2:52][S:53][C:54]3[S:55][CH:56]=[N:57][N:58]=3)[CH2:50][S:51][C@H:46]12>CN(C=O)C>[NH:15]1[CH:16]=[CH:17][N:18]=[C:14]1[NH:44][CH:45]1[C:62](=[O:63])[N:47]2[C:48]([C:59]([OH:61])=[O:60])=[C:49]([CH2:52][S:53][C:54]3[S:55][CH:56]=[N:57][N:58]=3)[CH2:50][S:51][C@H:46]12
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12
Reactant: Fc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Fc1ncc[nH]1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)C1=C(CSc2nncs2)CS[C@@H]2C(Nc3ncc[nH]3)C(=O)N12
Reaction time: 0.08 h
Yield: 11.4 %

Procedure:
To a solution of toluene-p-sulphonic acid hydrate (54 mg.) in dry DMF (1 ml.) was added 2-fluoro-1-triphenylmethylimidazole (110 mg.) and the solution heated in a preheated bath at 80°. After 5 minutes, to allow complete formation in situ of 2-fluoroimidazole, 7-amino-3-(1,3,4-thiadiazol-2-yl)thiomethylceph-3-em-4-carboxylic acid (110 mg.) was added and heating continued for 2.5 hours. A further portion of the fluoroimidazole (50 mg.) was then added, heating was continued for a further 30 minutes, and the mixture was cooled and evaporated at room temperature. To the residue was added water (10 ml.) and ethyl acetate (25 ml.) and the mixture filtered and the phases separated. The aqueous layer was concentrated to 4 ml., filtered and subjected to preparative HPLC on Whatman "Partisil 10" using water/MeOH/HOAc 80:20:1 v/v/v as eluant. The product crystallised on addition of acetone. It was washed with acetone and ether to give 7-(imidazol-2-yl)amino-3-(1,3,4-thiadiazol-2-yl)thiomethylceph-3-em-4-carboxylic acid (15 mg.) having the following n.m.r. in d6DMSO+CD3COOD: 3.52 (d, 1H); 3.79 (d, 1H); 4.33 (d, 1H); 4.6 (d, 1H); 5.12 (d, 1H); 5.58 (d, 1H); 6.83 (s, 2H); 9.49 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:3]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([OH:19])[CH:17]=3)[CH:12]=[CH:11][CH:10]=2)[C:4](=[O:8])[N:5]([CH3:7])[N:6]=1.[CH3:20][O-:21].[Na+]>C1COCC1>[OH:19][C:16]1[CH:17]=[C:18]2[C:13]([CH:12]=[CH:11][CH:10]=[C:9]2[N:3]2[C:2]([O:21][CH3:20])=[N:6][N:5]([CH3:7])[C:4]2=[O:8])=[CH:14][CH:15]=1
Reactant: Cn1nc(Cl)n(-c2cccc3ccc(O)cc23)c1=O
Reactant: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1nn(C)c(=O)n1-c1cccc2ccc(O)cc12
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of the tide compound of Step F (3.3 g) in THF (38 mL) was added a solution of sodium methoxide (6.5 mL, 30% in methanol) while stiring under N2. The mixture was heated at 50° C. for 6 h and cooled to room temperature and left to stir overnight. The reaction was quenched with water and extracted three times with methylene chloride and then three times with ethyl acetate. The combined organic extracts were dried (MgSO4), filtered and concentrated under reduced pressure. Trituration (ethyl acetate:hexane 1:1) of the crude product provided 1.61 g of the title compound of Step G as a light brown solid melting at greater than 250° C. 1H NMR (Me2SO-d6): δ 10.00 (s,1H), 7.93 (m,2H), 7.47 (dd,1H), 7.36 (t,1H), 7.15 (dd,1H), 6.73 (d,1H), 3.86 (s,3H), 3.39 (s,3H).
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH2:5][F:6])[C:3]#[N:4].ON1C2N=CC=CC=2N=N1.CN(C)CCCN=C=NCC.Cl.[C:30]([C:32]1[CH:33]=[N:34][C:35]2[C:40]([CH:41]=1)=[CH:39][C:38]([O:42][CH:43]([S:47][CH3:48])[C:44](O)=[O:45])=[CH:37][CH:36]=2)#[CH:31]>CN(C)C=O.[Cl-].[Na+].O.C(N(CC)CC)C>[C:3]([C:2]([NH:1][C:44](=[O:45])[CH:43]([O:42][C:38]1[CH:39]=[C:40]2[C:35](=[CH:36][CH:37]=1)[N:34]=[CH:33][C:32]([C:30]#[CH:31])=[CH:41]2)[S:47][CH3:48])([CH3:7])[CH2:5][F:6])#[N:4]
Reactant: CC(N)(C#N)CF
Reactant: C#Cc1cnc2ccc(OC(SC)C(=O)O)cc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: C#Cc1cnc2ccc(OC(SC)C(=O)NC(C)(C#N)CF)cc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.1 %

Procedure:
To a solution of 2-amino-3-fluoro-2-methylpropionitrile (168 mg) in dry dimethylformamide (12 mL) were added triethylamine (0.22 mL), 1-hydroxy-7-azabenzotriazole (224 mg), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide.HCl (316 mg), then (3-ethynyl-quinolin-6-yloxy)-methylsulfanyl-acetic acid (450 mg). The reaction mixture was stirred at room temperature for 2 hours. The mixture was poured over brine and extracted twice with ethyl acetate (thrice). The organic layer was washed with water then with brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude was purified by chromatography eluting with cyclohexane/ethyl acetate (3:2 by volume), to give N-(1-cyano-2-fluoro-1-methyl-ethyl)-2-(3-ethynyl-quinolin-6-yloxy)-2-methylsulfanyl-acetamide (483 mg) as an oil.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH:4]([C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][CH2:18][CH3:19])[C:11](=[O:20])[N:10]([CH2:21][CH2:22][CH3:23])[C:9]=3[N:8]=2)[CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O>CN(C)C=O>[CH2:30]([N:15]1[C:14]2[C:13](=[O:16])[N:12]([CH2:17][CH2:18][CH3:19])[C:11](=[O:20])[N:10]([CH2:21][CH2:22][CH3:23])[C:9]=2[N:8]=[C:7]1[CH:4]1[CH2:5][CH2:6][C:2](=[O:1])[CH2:3]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCCn1c(=O)c2[nH]c(C3CCC(=O)C3)nc2n(CCC)c1=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCn1c(=O)c2c(nc(C3CCC(=O)C3)n2Cc2ccccc2)n(CCC)c1=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
10.0 g (0.031 mol) of 8-(3-oxocyclopentyl)-1,3-dipropyl-7H-purine-2,6-dione are dissolved in 30 ml of absolute dimethylformamide and after the addition of 4.6 g (0.033 mol) of potassium carbonate the mixture is stirred for 20 minutes at ambient temperature. 5.7 g (0.033 mol) of benzylbromide are added dropwise, the mixture is stirred for a further 40 minutes and the reaction is ended by the addition of water. The solution is evaporated down, the residue is taken up in water and extracted with dichloromethane. After drying and evaporation, the combined organic phases yield an oily residue which is purified on silica gel with a mixture of dichloromethane/methanol in the ratio 99:1 and then recrystallised from ethanol. 9.4 g (73.3% of theory) of the title compound are obtained in the form of colourless crystals, melting point: 145° C.
Reaction SMILES: [CH2:1]([CH:8]1[C:13](=[O:14])[C:12]([Br:15])=[CH:11][N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC[O-].[Na+].[CH2:20](Cl)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)C>[CH2:20]([N:10]1[CH:11]=[C:12]([Br:15])[C:13](=[O:14])[C:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C1C(Br)=CN=CC1Cc1ccccc1
Reactant: ClCc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: O=c1c(Br)cn(Cc2ccccc2)cc1Cc1ccccc1

Procedure:
A mixture of 3-benzyl-5-bromopyridin-4-one 12 (0.57 g, 2.16 mmol) and NaOEt (0.89 mL, 2.37 mmol) in absolute ethanol (20 mL) was refluxed with benzyl chloride (0.30 mL, 2.59 mmol) for 1 h under nitrogen. The solvent was distilled off to give a yellow residue which was purified by flash column chromatography on silica gel (dichloromethane:methanol, 98:2). Yield 1.31 g (96.7%), yellow solid, mp 120-121° C. 1H NMR (CDCl3, 500 MHz): δ 7.67 (d, 1H, J=2.4), 7.32-7.07 (m, 10H), 4.83 (s, 1H), 3.78 (s, 2H). 13C NMR (CDCl3, 125 MHz): δ 172.2, 139.6, 139.1, 137.6, 134.7, 129.9, 129.9, 129.3, 129.3, 129.2, 129.0, 128.6, 128.6, 127.5, 127.6, 126.4, 114.1, 60.3, 34.4. HRMS (M+H)+ calcd for C19H16BrNO 354.0494, found 354.0499.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:7]([CH2:8][N:9]2[CH:13]=[C:12]([NH2:14])[CH:11]=[N:10]2)=[C:6]([CH3:15])[O:5][N:4]=1.[N:16]([C:19]1[CH:28]=[CH:27][CH:26]=[CH:25][C:20]=1[C:21](OC)=[O:22])=[C:17]=[O:18].C(N(CC)CC)C>C(#N)C.O>[CH3:2][C:3]1[C:7]([CH2:8][N:9]2[CH:13]=[C:12]([N:14]3[C:21](=[O:22])[C:20]4[C:19](=[CH:28][CH:27]=[CH:26][CH:25]=4)[NH:16][C:17]3=[O:18])[CH:11]=[N:10]2)=[C:6]([CH3:15])[O:5][N:4]=1
Reactant: Cc1noc(C)c1Cn1cc(N)cn1
Reactant: COC(=O)c1ccccc1N=C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: Cc1noc(C)c1Cn1cc(-n2c(=O)[nH]c3ccccc3c2=O)cn1
Yield: 18 %

Procedure:
1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-amine hydrochloride (75 mg, 0.33 mmol), methyl 2-isocyanatobenzoate, and triethylamine (200 mg, 2 mmol) in acetonitrile (3 mL) were irradiated in the microwave reactor at 100° C. for 30 minutes. The reaction was cooled, diluted with H2O (75 mL), and extracted with ethyl acetate (3×, 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated on the rotovap. The residue was purified by silica gel chromotography (75% ethyl acetate in hexanes) to afford 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)quinazoline-2,4(1H,3H)-dione (20 mg, 18%) as a light pink solid. 1H NMR (DMSO-d6, 400 MHz): δ2.16 (s, 3H), 2.40 (s, 3H), 5.17 (s, 2H), 7.17-7.22 (m, 2H), 7.50 (s, 1H), 7.66 (dt, J=8, 1.2 Hz, 1H), 7.92 (d, J=6.8 Hz, 1H), 7.95 (s, 1H), 11.52 (bs, 1H). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 1.5 μM.
Reaction SMILES: S([O-])([O-])=O.[Na+].[Na+].[C:7](=O)([O-])O.[Na+].[C:12]([N:15]1[CH2:21][CH2:20][C:19]2[CH:22]=[CH:23][C:24]([S:26](Cl)(=[O:28])=[O:27])=[CH:25][C:18]=2[CH2:17][CH2:16]1)(=[O:14])[CH3:13].CI>O.O1CCCC1>[C:12]([N:15]1[CH2:21][CH2:20][C:19]2[CH:22]=[CH:23][C:24]([S:26]([CH3:7])(=[O:28])=[O:27])=[CH:25][C:18]=2[CH2:17][CH2:16]1)(=[O:14])[CH3:13]
Reactant: CC(=O)N1CCc2ccc(S(=O)(=O)Cl)cc2CC1
Reactant: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CI
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)N1CCc2ccc(S(C)(=O)=O)cc2CC1
Temperature: 75 °C
Reaction time: 24 h
Yield: 73.2 %

Procedure:
To a stirred solution of sodium sulphite (1.60 g, 12.6 mmol) and sodium hydrogen carbonate (1.14 g, 13.56 mmol) in water (25 ml) was added 3-acetyl-7-chlorosulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine (2.6 g, 9.04 mmol) in tetrahydrofuran (10 ml). The reaction mixture was then heated at 75° C. for 2 h, cooled to 30° C. and methyl iodide (2.8 ml, 45.20 mmol) added. After stirring at 50° C. for 24 h, the reaction mixture was cooled to room temperature and partitioned between water (50 ml) and ethyl acetate (100 ml). The aqueous layer was then separated and further extracted with ethyl acetate (2×80 ml). The combined organics were then dried (Na2SO4) and the solvent removed in vacuo to give the title compound (1.77 g, 73%) as a pale yellow solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:11](=[O:36])[NH:12][CH:13]2[C:21]3[N:20]=[CH:19][C:18]([C:22]4[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([F:29])[C:23]=4[C:30]4[N:31]=[N:32][N:33]([CH3:35])[N:34]=4)=[CH:17][C:16]=3[CH2:15][CH2:14]2)[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>>[Cl:28][C:26]1[CH:25]=[C:24]([F:29])[C:23]([C:30]2[N:31]=[N:32][N:33]([CH3:35])[N:34]=2)=[C:22]([C:18]2[CH:19]=[N:20][C:21]3[CH:13]([NH:12][C:11]([C:8]4([NH2:7])[CH2:10][CH2:9]4)=[O:36])[CH2:14][CH2:15][C:16]=3[CH:17]=2)[CH:27]=1
Reactant: Cn1nnc(-c2c(F)cc(Cl)cc2-c2cnc3c(c2)CCC3NC(=O)C2(NC(=O)OC(C)(C)C)CC2)n1
Solvent: O=C(O)C(F)(F)F
Product: Cn1nnc(-c2c(F)cc(Cl)cc2-c2cnc3c(c2)CCC3NC(=O)C2(N)CC2)n1

Procedure:
In analogy to the procedure described for the preparation of intermediate A-11 [C], (1-{(rac)-3-[5-chloro-3-fluoro-2-(2-methyl-2H-tetrazol-5-yl)-phenyl]-6,7-dihydro-5H-[1]pyrindin-7-ylcarbamoyl}-cyclopropyl)-carbamic acid tert-butyl ester (example 54) has been treated with trifluoroacetic acid (90%) to give the title compound as light brown amorphous solid. MS: 428.1 (MH+, 1Cl).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:17])=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:5]([CH3:11])=[N:6][C:7]=1[NH:8][CH2:9][CH3:10].[CH2:18](OC(OCC)OCC)C>>[Cl:17][C:3]1[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:5]([CH3:11])[N:6]=[C:7]2[N:8]([CH2:9][CH3:10])[CH:18]=[N:1][C:2]=12
Reactant: CCNc1nc(C)c(C(=O)OCC)c(Cl)c1N
Reactant: CCOC(OCC)OCC
Product: CCOC(=O)c1c(C)nc2c(ncn2CC)c1Cl

Procedure:
25.7 g. of 5-amino-6-ethylamino-4-chloro-2-methylpyridine-3-carboxylic acid, ethyl ester (0.1 mol.) is refluxed for 12 hours with 100 ml. of orthoformic acid triethyl ester with stirring. The excess ester is removed in vacuo and the oily residue distilled to obtain 7-chloro-3-ethyl-5-methyl-3H-imidazo[ 4,5-b]pyridine-6-carboxylic acid, ethyl ester, b.p. 195° 0.01. Yield 23 g. (86%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.C([O-])([O-])=O.[K+].[K+].[F:17][C:18]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:19]=1[NH2:20]>C(#N)C>[F:17][C:18]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:19]=1[NH:20][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1
Reactant: Nc1ccc([N+](=O)[O-])cc1F
Reactant: ClCCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(NCCCN2CCOCC2)c(F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 62.8 %

Procedure:
To a suspension of 4-(3-chloropropyl)morpholine (1.64 g, 10 mmol) and K2CO3 (4.14 g, 30 mmol) in acetonitrile (20 mL) was added 2-fluoro-4-nitroaniline (1.56 g, 10 mmol) dropwise. The mixture was stirred at rt for 24 h, then filtered and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:1) to give the title compound as yellow oil (1.78 g, 63%).
Reaction SMILES: [CH3:1][C:2]12[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][C:10]1([CH3:18])[C:9]1[CH:8]=[C:7]([CH3:19])[CH:6]=[CH:5][C:4]=1[NH:3]2.C(=O)(O)[O-].[Na+].[C:25](OC(=O)C)(=[O:27])[CH3:26]>>[C:25]([N:3]1[C:4]2[CH:5]=[CH:6][C:7]([CH3:19])=[CH:8][C:9]=2[C@@:10]2([CH3:18])[CH2:11][C:12]3[C:17]([C@@:2]12[CH3:1])=[CH:16][CH:15]=[CH:14][CH:13]=3)(=[O:27])[CH3:26]
Reactant: Cc1ccc2c(c1)C1(C)Cc3ccccc3C1(C)N2
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(=O)N1c2ccc(C)cc2[C@@]2(C)Cc3ccccc3[C@@]12C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4b,5,9b,10-Tetrahydro-4b,8,9b-trimethylindeno[1,2-b]indole (0.25 g, 1.00 mmol) was dissolved in acetic anhydride (1 cm3) and stirred at room temperature for 16 hours. The reaction mixture was poured into saturated sodium bicarbonate solution (25 cm3) and stirred for 1/2 hour. The mixture was extracted with diethyl ether (3×10 cm3) and the combined organic extracts were washed with brine, dried (Na2SO4) and evaporated. The crude material was purified by flash chromatography on silica gel eluting with 4% ethyl acetate/60°-80° petrol to yield a pale yellow gum. Yield: 0.15 g, 53%. 1H NMR (CDCl3) δ: 7.84 (1H, s), 6.90-7.23 (6H, m), 3.26 (1H, d, J=15.9 Hz), 2.96 (1H, d, J =15.9 Hz), 2.40 (3H, s), 2.31 (3H, s), 1.77 (3H, s), 1.32 (3H, s).