Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:31]=[C:32]([O:34][CH3:35])[CH:33]=1)[C:8]([NH:10][CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[C:22]([O:24][CH2:25][CH3:26])[C:21](F)=[C:20]([O:28][CH2:29][CH3:30])[CH:19]=2)[CH2:13][CH2:12]1)=[O:9])#[N:2].C(OC1C=C(C=O)C=C(OCC)C=1[C:50]1[CH:55]=[CH:54][C:53]([F:56])=[CH:52][CH:51]=1)C.C([BH3-])#N.[Na+].C(N(C(C)C)C(C)C)C>C(O)C.C(O)(=O)C>[C:1]([CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:31]=[C:32]([O:34][CH3:35])[CH:33]=1)[C:8]([NH:10][CH:11]1[CH2:12][CH2:13][N:14]([CH2:17][C:18]2[CH:19]=[C:20]([O:28][CH2:29][CH3:30])[C:21]([C:50]3[CH:55]=[CH:54][C:53]([F:56])=[CH:52][CH:51]=3)=[C:22]([O:24][CH2:25][CH3:26])[CH:23]=2)[CH2:15][CH2:16]1)=[O:9])#[N:2]
Reactant: CCOc1cc(C=O)cc(OCC)c1-c1ccc(F)cc1
Reactant: CCOc1cc(CN2CCC(NC(=O)c3cc(OC)cc(OCC#N)c3)CC2)cc(OCC)c1F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Product: CCOc1cc(CN2CCC(NC(=O)c3cc(OC)cc(OCC#N)c3)CC2)cc(OCC)c1-c1ccc(F)cc1

Procedure:
In analogy to the procedure described in example 50k), 3-cyanomethoxy-5-methoxy-N-piperidin-4-yl-benzamide (example 245) was reacted with 2,6-diethoxy-4′-fluoro-biphenyl-4-carbaldehyde (example 102), sodium cyanoborohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50° C. to yield the title compound as off-white solid. MS: 562.3 (MH+).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][NH:5][CH:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:3]1.N#N.Cl.[CH:16]1[C:29]2[S:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[O:21][C:20]=2[CH:19]=[CH:18][C:17]=1[S:30]([NH:33][C@H:34]([C:42](Cl)=[O:43])[CH2:35][CH2:36][CH2:37][NH:38][C:39](=[NH:41])[NH2:40])(=[O:32])=[O:31]>C(Cl)(Cl)Cl>[CH:16]1[C:29]2[S:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[O:21][C:20]=2[CH:19]=[CH:18][C:17]=1[S:30]([NH:33][C@H:34]([C:42]([N:5]1[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH:4]1[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:43])[CH2:35][CH2:36][CH2:37][NH:38][C:39](=[NH:40])[NH2:41])(=[O:31])=[O:32]
Reactant: CCOC(=O)C1CC(C)CCN1
Reactant: N=C(N)NCCC[C@H](NS(=O)(=O)c1ccc2c(c1)Sc1ccccc1O2)C(=O)Cl
Agent: Cl
Agent: N#N
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1CC(C)CCN1C(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1ccc2c(c1)Sc1ccccc1O2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 3.6 g of ethyl 4-methyl-2-piperidinecarboxylate in 50 ml of chloroform, which was cooled in an ice-salt bath, was added in portions N2 -(2-phenoxathiinylsulfonyl)-L-arginyl chloride hydrochloride obtained above. The reaction mixture was stirred overnight at room temperature. At the end of this period, 50ml of chloroform was added and the chloroform solution was washed twice with 25 ml of saturated sodium chloride solution, dried over Na2SO4 and evaporated in vacuo. The oily residue was washed with ether to give 3.5 g of powdery ethyl 1-[N2 -(2-phenoxathiinylsulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylate.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([OH:12])[C:6]=2[CH2:5][CH:4]=1.[H][H]>CO.CCOC(C)=O.[Pd]>[F:1][C:2]([F:13])([F:14])[CH:3]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([OH:12])[C:6]=2[CH2:5][CH2:4]1
Reactant: [H][H]
Reactant: Oc1cccc2c1CC=C2C(F)(F)F
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Oc1cccc2c1CCC2C(F)(F)F
Yield: 96.2 %

Procedure:
A mixture of 1-trifluoromethyl-3H-inden-4-ol (70 mg, 0.349) and 10% Pd/C (20 mg) in methanol (2 ml) was hydrogenated under 50 psi hydrogen atmosphere for 3 hours. The mixture was dissolved in EtOAc, filtered through a celite pad. The filtrate was concentrated tinder reduced pressure, and dried to give 1-trifluoromethyl-indan-4-ol (68 mg, 97%).
Reaction SMILES: [SH:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Br[CH2:14][C:15](=[O:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17].C(N(CC)CC)C.Cl>CN(C=O)C.CCOC(C)=O>[CH2:19]([O:18][C:16](=[O:17])[C:15](=[O:21])[CH2:14][S:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)[CH3:20]
Reactant: O=c1[nH]c(S)nc2ccccc12
Reactant: CCOC(=O)C(=O)CBr
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)CSc1nc2ccccc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 36 h
Yield: 11 %

Procedure:
An homogeneous solution of 2-mercapto-3H-quinazolin-4-one (1.30 g, 7.17 mmol) and ethyl bromopyruvate (1 mL, 7.17 mmol, 90% purity) in DMF (30 mL) was stirred at room temperature for 6 h. Triethylamine (5 mL) was added to the solution and the mixture was stirred at room temperature for 36 h. The mixture was acidified to pH 1-2 with concentrated hydrochloric acid and then rotary evaporated to dryness. The residue was separated by column chromatography eluted with EtOAc giving the title compound as yellow solid (0.231 g, yield 11.0%). 1H NMR (DMSO-d6, 300.16 MHz) δ (ppm): 8.05 (dd, J=7.9 & 1.4 Hz, 1H), 8.01 (s, 1H), 7.81 (td, J=8.3 & 1.5 Hz, 1H), 7.53 (d, J=8.2 Hz, 1H), 7.46 (td, J=7.5 & 1.4 Hz, 1H), 4.21 (q, J=7.1 Hz, 2H), 3.82 (d, J=12.2 Hz, 1H), 3.46 (d, J=12.2 Hz, 1H) and 1.18 (t, J=7.1 Hz, 3H). 13C NMR (DMSO-d6, 75.48 MHz) δ (ppm): 168.06, 159.54, 159.26, 149.07, 135.98, 126.85, 126.74, 126.36, 119.09, 91.33, 62.79, 37.92 and 14.31. MS (ESI) m/z: 293 (M++H, 100).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].CS(O[CH2:16][CH:17]1[CH2:22][O:21][C:20]([CH3:24])([CH3:23])[CH2:19][O:18]1)(=O)=O.NC1C=CC=CN=1>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[N:7]=[C:6]([NH:8][CH2:16][CH:17]2[CH2:22][O:21][C:20]([CH3:24])([CH3:23])[CH2:19][O:18]2)[CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)COC(COS(C)(=O)=O)CO1
Reactant: Nc1cccc(Br)n1
Agent: Nc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)COC(CNc2cccc(Br)n2)CO1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 45.6 %

Procedure:
6-Bromopyridin-2-amine (771 mg, 4.46 mmol) was dissolved in 10 mL of anhydrous DMF and cooled to 0° C. NaH (60% in mineral oil, 214 mg, 5.35 mmol) was added. After 10 min the solution was warmed to ambient temperature and stirred for 15 min until bubbling ceased, to give a dark green solution. (5,5-Dimethyl-1,4-dioxan-2-yl)methyl methanesulfonate (500 mg, 2.23 mmol) in 2 mL of DMF was added. After the addition was completed the solution was stirred at ambient temperature for 20 min, then heated at 60° C. for 1.5 hr. It was diluted with EtOAc and washed four times with water. The aqueous layers were combined and extracted once with EtOAc. The organic layers were combined, dried over Na2SO4 and concentrated. The resulting residue was purified on a silica gel column (heptane:EtOAc 1:0 to 1:1) to give the product contaminated with the starting aminopyridine. Another purification on silica gel column (DCM:ether 20:1) gave the pure product (306 mg, 46%). LC-MS (m/z): 301.0/303.0 (M+H), retention time=0.89 min.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:14].[C:15]1(=O)[O:20][C:18](=[O:19])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12>C1(C)C=CC=CC=1.CN1C(=O)CCC1>[O:14]=[C:6]1[CH:5]([CH2:4][CH2:3][N:2]2[C:18](=[O:19])[C:17]3[C:16](=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:15]2=[O:20])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7]1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NCCC1C(=O)Nc2ccccc21
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: Cc1ccccc1
Product: O=C1Nc2ccccc2C1CCN1C(=O)c2ccccc2C1=O
Yield: 56.4 %

Procedure:
A mixture of 3-(2-aminoethyl)indolin-2-one hydrochloride (3.20 g, 15.06 mmol), phthalic anhydride (3.34 g, 22.59 mmol) and TEA (4.56 g, 45.18 mmol) in toluene/NMP (20 mL/10 mL). The mixture was heated under reflux for 3 h. The reaction mixture was concentrated and the resulting mixture was washed with saturated aqueous ammonium chloride and brine. The separated organic layer was dried over anhydrous sodium sulfate and filtered. Concentration under vacuum gave the crude product, which was purified by silica gel column chromatography (30% ethyl acetate in petroleum ether) to afford the title compound (2.60 g, 8.50 mmol, 56% yield) as a brown solid. MS (ESI) m/z 307.2 [M+H]+.
Reaction SMILES: [H-].[Na+].ClC1C=C(N)C(I)=CN=1.S(OC[C@H]1OCCN(C(OC(C)(C)C)=O)C1)(C1C=CC(C)=CC=1)(=O)=O.[Cl:37][C:38]1[CH:43]=[C:42]([NH:44][CH2:45][C@H:46]2[O:51][CH2:50][CH2:49][N:48]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:47]2)[C:41](I)=[CH:40][N:39]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:66][O:67][C:68]1[CH:73]=[CH:72][C:71](B(O)O)=[CH:70][CH:69]=1>CN(C=O)C.C(#N)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[Cl:37][C:38]1[CH:43]=[C:42]([NH:44][CH2:45][C@@H:46]2[O:51][CH2:50][CH2:49][N:48]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:47]2)[C:41]([C:71]2[CH:72]=[CH:73][C:68]([O:67][CH3:66])=[CH:69][CH:70]=2)=[CH:40][N:39]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](CNc2cc(Cl)ncc2I)C1
Reactant: COc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)OC[C@@H]2CN(C(=O)OC(C)(C)C)CCO2)cc1
Agent: Nc1cc(Cl)ncc1I
Solvent: CN(C)C=O
Solvent: O
Solvent: CC#N
Product: COc1ccc(-c2cnc(Cl)cc2NC[C@H]2CN(C(=O)OC(C)(C)C)CCO2)cc1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 94.3 %

Procedure:
NaH (0.024 g, 0.569 mmol) was added to a solution of 2-chloro-5-iodopyridin-4-amine (0.121 g, 0.474 mmol) in DMF (2.8 mL) at room temperature and stirred for 10 min. The temperature was raised to 80° C. and (S)-tert-butyl 2-(tosyloxymethyl)morpholine-4-carboxylate (0.264 g, 0.711 mmol) in DMF (0.6 mL) was added. The reaction mixture was stirred for 2 h, then further NaH (0.024 g, 0.569 mmol) was added at room temperature. The reaction mixture was further heated at 80° C. for 1 h then cooled. Water was added and the mixture was partitioned between ethyl acetate (20 mL) and aq. NaHCO3 (20 mL). The organic phase was washed with brine, dried (MgSO4) and concentrated. The mixture was purified by flash column chromatography on silica gel, eluting with ethyl acetate/hexane (2/4), to give an inseparable mixture of starting material and product. LCMS (4) Rt=2.66 min; m/z (ESI+) 397 [MH+]. A solution of the crude (R)-tert-butyl 2-((2-chloro-5-iodopyridin-4-ylamino)methyl)morpholine-4-carboxylate (0.040 g, 0.088 mmol), sodium carbonate (0.5 M, 0.26 mL), 4-methoxyphenyl boronic acid (0.013 g, 0.088 mmol) and tetrakis(triphenylphosphine) palladium(0) (0.011 g, 0.01 mmol) in acetonitrile (2 mL) was heated under microwave irradiation at 100° C. for 20 min. The reaction mixture was concentrated. The crude product was purified by flash column chromatography on silica gel, eluting with ethyl acetate/hexane (1/1), to give the title compound as a colorless oil (0.036 g, 94%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[N:12]O)[CH2:7][CH2:6][CH2:5]2.[OH-:14].[Na+].CO.C(Cl)Cl>O>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8](=[O:14])[NH:12][CH2:7][CH2:6][CH2:5][C:4]=2[CH:3]=1
Reactant: [OH-]
Reactant: Nc1ccc2c(c1)CCCC2=NO
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: Nc1ccc2c(c1)CCCNC2=O
Temperature: 100 °C

Procedure:
6-Amino-3,4-dihydro-2H-naphthalen-1-one oxime (1.80 g, 10.2 mmol) and polyphosphoric acid (30 ml) were mixed together. The viscous mixture was heated to 100° C. with vigorous stirring as the mixture became homogeneous. After cooling to room temperature, the mixture was diluted with water (30 ml). 15% aqueous sodium hydroxide was added until the mixture became basic. Extraction with ethyl acetate (50 ml), drying over anhydrous magnesium sulfate, and concentration yielded a brown oil. Preparative TLC (5% MeOH/CH2Cl2) afforded 7-Amino-2,3,4,5-tetrahydro-benzo[c]azepin-1-one (Bioorganic & Medicinal Chem. Lett., 2003, 13 4197) as a light brown oil, 21 mg. 1H NMR (400 MHz, DMSO-d6) δ 7.53 (s, 1H), 7.14-7.22 (m, 1H), 6.42-6.47 (m, 1H), 6.33 (s, 1H), 5.44 (s, 2H), 2.87-2.93 (m, 2H), 2.53-2.60 (m, 2H), 1.78-1.87 (m, 2H); MS (m/e) 177 (M+1).
Reaction SMILES: [C:1]([C:6]1[S:10][C:9]([C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=2)=[CH:8][CH:7]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].[Li].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH:52]1[CH2:56][CH2:55][CH2:54][C@H:53]1[CH2:57][N:58]1[CH2:62][CH2:61][CH2:60][CH2:59]1>CN(C=O)C.ClCCl>[CH3:4][CH:2]([CH3:3])[C:1]([C:6]1[S:10][C:9]([C:11]2[CH:12]=[CH:13][C:14]([C:15]([N:52]3[CH2:56][CH2:55][CH2:54][C@H:53]3[CH2:57][N:58]3[CH2:62][CH2:61][CH2:60][CH2:59]3)=[O:17])=[CH:18][CH:19]=2)=[CH:8][CH:7]=1)=[O:5]
Reactant: C1CN[C@H](CN2CCCC2)C1
Reactant: CC(C)C(=O)c1ccc(-c2ccc(C(=O)O)cc2)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)C(=O)c1ccc(-c2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)cc2)s1
Yield: 71 %

Procedure:
The title compound is prepared in a manner substantially analogous to General Procedure D in 10 mL 50% DMF/dichloromethane using 4-(5-isobutyryl-thiophen-2-yl)-benzoic acid, lithium salt (96 mg, 0.34 mmol), EDC-HCl (97 mg, 0.51 mmol), HOBt (69 mg, 0.51 mmol), DIEA (0.09 mL, 0.51 mmol) and (S)(+)-1-(2-pyrrolidinylmethyl)pyrrolidine (48 mg, 0.31 mmol) to give the title compound (90 mg, 71% yield). MS (ES+) 411.2 (M+H)+
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH:52]([C:54]3[CH:59]=[CH:58][N:57]=[CH:56][CH:55]=3)[CH3:53])[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[CH3:68][O:69][C:70]1[CH:75]=[CH:74][C:73]([CH:76]=O)=[CH:72][CH:71]=1>CN(C=O)C>[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH:52]([C:54]3[CH:59]=[CH:58][N:57]=[CH:56][CH:55]=3)[CH3:53])[CH2:48][CH2:47]2)=[C:38]2[N:43]=[C:76]([C:73]3[CH:74]=[CH:75][C:70]([O:69][CH3:68])=[CH:71][CH:72]=3)[NH:42][C:39]2=[N:40][CH:41]=1
Reactant: CC(c1ccncc1)N1CCN(c2c(Br)cnc(N)c2[N+](=O)[O-])CC1
Reactant: COc1ccc(C=O)cc1
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc3c(N4CCN(C(C)c5ccncc5)CC4)c(Br)cnc3[nH]2)cc1
Reaction time: 16 h
Yield: 41.1 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-bromo-3-nitro-4-(4-(1-(pyridin-4-yl)ethyl)piperazin-1-yl)pyridin-2-amine (30 mg, 0.074 mmol), DMF (1 mL), 1M Na2S2O4 (3 eq, 0.22 mmol, 0.22 mL) and 4-methoxybenzene carboxaldehyde (1.05 eq, 0.077 mmol, 0.0096 mL). After 16 h, filtration of the precipitate and washing with ethanol (1 mL) and cold water (1 mL) gave the product (15 mg, 42%) as a pale yellow solid; 1H-NMR (500 MHz, DMSO-d6) 1.37 (d, J=6.7 Hz, 3H, CHCH3), 2.56-2.65 (2 m, 4H, piperazine N(CH2)2), 3.58 (q, J=6.9 Hz, 1H, CHCH3), 3.66 (br s, 4H, piperazine N(CH2)2), 3.85 (s, 3H, OCH3), 7.11 (d, J=8.8 Hz, 2H, methoxyphenyl), 7.40 (d, J=5.4 Hz, 2H, pyridine H-3 & H-5), 8.14 (d, J=8.5 Hz, 2H, methoxyphenyl), 8.20 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.55 (d, J=5.4 Hz, 2H, pyridine H-2 & H-6), 13.40 (br s, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C(N(CC)CC)C.Cl.[N:17]1([CH2:23][CH2:24][C:25]2[N:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]3=[C:27]([C:34](Cl)=[O:35])[N:26]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:34]([C:27]2[N:26]=[C:25]([CH2:24][CH2:23][N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)[N:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=23)=[O:35])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Cl)c1nc(CCN2CCOCC2)n2ccccc12
Reactant: Nc1cccc(Cl)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(Cl)c1)c1nc(CCN2CCOCC2)n2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.2 %

Procedure:
To a solution of 3-chloroaniline (0.060 mL, 0.54 mmol) and triethylamine (0.16 mL, 1.14 mmol) in CH2Cl2 (10 mL) was added 3-(2-morpholin-4-yl-ethyl)-imidazo[1,5-a]pyridine-1-carbonyl chloride hydrochloride (150 mg, 0.45 mmol). The mixture was stirred at ambient temperature for 1 h then washed with sat. aq. NaHCO3 (20 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica to yield the title compound (61 mg, 35%). 1H NMR (DMSO-d6) δ 10.0 (1H), 8.45 (1H), 8.15 (2H), 7.81 (1H), 7.35 (1H), 7.20 (1H), 7.10 (1H), 6.94 (1H), 3.49 (4H), 3.26 (2H), 2.81 (2H), 2.44 (4H); m/z (M+H)=385.18.
Reaction SMILES: Cl.[C:2]([C:4]1[CH:5]=[C:6]([NH:12][NH2:13])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])#[N:3].[CH3:14][S:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]=[CH:23][C:24]#[N:25])=[CH:18][CH:17]=1.C[O-].[Na+].N#N>CO.O.C(OCC)(=O)C>[C:2]([C:4]1[CH:5]=[C:6]([N:12]2[CH:22]([C:19]3[CH:20]=[CH:21][C:16]([S:15][CH3:14])=[CH:17][CH:18]=3)[CH2:23][C:24]([NH2:25])=[N:13]2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])#[N:3]
Reactant: CSc1ccc(C=CC#N)cc1
Reactant: COc1ccc(NN)cc1C#N
Agent: C[O-]
Agent: Cl
Agent: N#N
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: COc1ccc(N2N=C(N)CC2c2ccc(SC)cc2)cc1C#N
Temperature: 140 °C
Yield: 90.1 %

Procedure:
A stirred mixture of (3-cyano-4-methoxyphenyl)hydrazine hydrochloride (3.7 g), 3-[4-(methylthio)phenyl]acrylonitrile (2.3 g) and sodium methoxide (0.9 g) in methanol 13 ml was gradually heated to 140° C. under atmospheric pressure and N2 atmosphere, and continued to heat for 8 hours at 140° C. Ethyl acetate and water were added to the reaction mixture. The organic layer was separated, washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure to give crude 1-(3-cyano-4-methoxyphenyl)-5-[4-(methylthio)-phenyl]-2-pyrazoline-3-amine (4.0 g).
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH:13]([CH3:14])[NH:12][C:11](=[O:15])[C:10]1([CH3:17])[CH3:16])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([Cl:27])[CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:27][C:21]1[CH:20]=[C:19]([N:12]2[C@H:13]([CH3:14])[C@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[C:10]([CH3:16])([CH3:17])[C:11]2=[O:15])[CH:26]=[CH:25][C:22]=1[C:23]#[N:24]
Reactant: N#Cc1ccc(Br)cc1Cl
Reactant: CC1NC(=O)C(C)(C)C1O[Si](C)(C)C(C)(C)C
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: C[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)C(=O)N1c1ccc(C#N)c(Cl)c1

Procedure:
Using (4RS,5RS)-4-(tert-butyldimethylsilyloxy)-3,3,5-trimethylpyrrolidin-2-one (380 mg), 4-bromo-2-chlorobenzonitrile (320 mg), cesium carbonate (722 mg), tris(dibenzylideneacetone)dipalladium(0) (68 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (85 mg), and in the same manner as in Reference Example 3, the title compound was obtained as a colorless solid (yield: 400 mg, 69%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.Br[CH2:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH:23]1([CH2:22][N:15]2[CH2:16][C:17](=[O:18])[N:13]([C:11]3[CH:10]=[N:9][N:8]([CH2:7][C:6]4[C:2]([CH3:1])=[N:3][O:4][C:5]=4[CH3:20])[CH:12]=3)[C:14]2=[O:19])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Reactant: BrCC1CCCCC1
Product: Cc1noc(C)c1Cn1cc(N2C(=O)CN(CC3CCCCC3)C2=O)cn1
Yield: 20 %

Procedure:
Prepared as in example 10-52 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) and bromomethylcyclohexane. Yield: 20%. 1H NMR (DMSO-d6, 400 MHz): δ0.88 (q, J=10.4 Hz, 2H), 1.09-1.19 (m, 3H), 1.58-1.65 (m, 6H), 2.12 (s, 3H), 2.38 (s, 3H), 3.13 (d, J=7.2 Hz, 2H), 4.06 (s, 2H), 5.17 (s, 2H), 7.75 (s, 1H), 8.14 (s, 1H). MS M+H calculated 372.2; found 372.1. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.28 μM.
Reaction SMILES: [CH3:1][C:2]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:3]=1[O:4][CH2:5][C:6]([O:8]C)=[O:7].[CH2:15]([CH:17]([C:21](Cl)=[O:22])[C:18](Cl)=[O:19])[CH3:16].[Cl-].[Al+3].[Cl-].[Cl-].Cl.[OH-].[K+]>C(Cl)Cl.CO>[O:19]=[C:18]1[C:11]2[C:12](=[C:13]([CH3:14])[C:2]([CH3:1])=[C:3]([O:4][CH2:5][C:6]([OH:8])=[O:7])[CH:10]=2)[C:21](=[O:22])[CH:17]1[CH2:15][CH3:16]
Reactant: CCC(C(=O)Cl)C(=O)Cl
Reactant: COC(=O)COc1cccc(C)c1C
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CO
Product: CCC1C(=O)c2cc(OCC(=O)O)c(C)c(C)c2C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of methyl (2,3-dimethylphenoxy)acetate (3.0 g., 0.0155 mole) and 2-ethylmalonyl chloride (2.7 g., 0.016 mole) in methylene chloride (200 ml.) is cooled to 0°C. then treated with aluminum chloride (6.6 g., 0.05 mole) in several portions during a 15 minute period. The reaction is stirred for 2 hours at 0°C., 18 hours at 25°C. then at reflux for 6 hours, cooled and poured into cold 1 N-hydrochloric acid (500 ml.), the organic layer is washed with water, saturated aqueous sodium chloride, dried over magnesium sulfate, then the solvent evaporated at reduced pressure. The crude methyl ester is hydrolyzed by treatment with potassium hydroxide (0.34 g., 0.005 mole) and methanol (20 ml.) at reflux for 1/2 hour, cooled and acidified with aqueous hydrochloric acid affording (1,3-dioxo-2-ethyl-4,5-dimethyl-6-indanyloxy)acetic acid which melts at 187°-193°C. after recrystallization from acid-water.
Reaction SMILES: [CH2:1]([C:4]1[C:9]([Cl:10])=[C:8]([Cl:11])[CH:7]=[CH:6][C:5]=1[OH:12])[CH2:2][CH3:3].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20].[H-].[Na+].[I-].[K+]>O.C(OCC)(=O)C.CN(C)P(N(C)C)(N(C)C)=O.O1CCCC1>[CH2:1]([C:4]1[C:9]([Cl:10])=[C:8]([Cl:11])[CH:7]=[CH:6][C:5]=1[O:12][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH2:2][CH3:3]
Reactant: O=C(O)CCCCCBr
Reactant: CCCc1c(O)ccc(Cl)c1Cl
Agent: [H-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: CCCc1c(OCCCCCC(=O)O)ccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1.1 g. of 2-propyl-3,4-dichlorophenol in 30 ml. of tetrahydrofuran and 30 ml. of hexamethylphosphoramide were added 4.1 g. of 6bromohexanoic acid. To the solution were then added 1.3 g. of a 50% oil dispersion of sodium hydride. A catalytic amount of potassium iodide was added and the reaction was stirred under a nitrogen atmosphere at 60°-70° C. overnight. The reaction was cooled to room temperature and ethyl acetate and water were added. The solution was evaporated to dryness. Fresh ethyl acetate and water were added and the layers were separated. Fresh ethyl acetate was added to the aqueous layer and the aqueous layer was adjusted to pH 2. The layers were separated and the organic layer was washed with a saturated sodium chloride solution. The organic layer was then filtered through sodium sulfate and evaporated to dryness. The resulting residue was extracted with hexane and evaporated to dryness to afford 500 mg. of the title compound.