Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1C1NC(C2C=CC3C4C(=CC(Br)=CC=4)C(F)(F)C=3C=2)=CN=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N1C(C2NC3C=C(B4OC(C)(C)C(C)(C)O4)C=CC=3N=2)C2CC1CC2)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].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>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc3c(c2)C(F)(F)c2cc(Br)ccc2-3)[nH]1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC1
Temperature: 90 °C
Yield: 336.2 %

Procedure:
A mixture of 2-[5-(7-Bromo-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (324 mg, 0.627 mmol), 3-[6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-benzoimidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (1.1 eq., 304 mg), [1,1′ bis(diphenylphosphino)ferrocene]dichloropalladium(II) (3%, 15 mg), tetrakis(triphenylphosphine)palladium (3%, 22 mg) and potassium carbonate (3.3 eq., 285 mg) in 10 mL DME and 3 mL water was heated to 90° C. under Argon for 3 hours. The reaction mixture was cooled and diluted with ethyl acetate and washed with saturated sodium bicarbonate solution. The organic layer was dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 20 to 100% ethyl acetate/hexane) to give 2-(5-{9,9-Difluoro-7-[2-(2-Boc-2-aza-bicyclo[2.2.1]hept-3-Y0-3H-benzoimidazol-5-yl]-9H-fluoren-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (361 mg, yield 77%). LCMS-ESI−: calc'd for C43H46F2N6O4: 748.86. Found: 749.2 (M+H+).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]([O:11][C:12](=[O:14])[CH3:13])[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[I-:15].[Na+]>CC(C)=O>[I:15][CH2:2][CH2:3][CH2:4][CH:5]([O:11][C:12](=[O:14])[CH3:13])[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: [I-]
Reactant: CCCCCC(CCCCl)OC(C)=O
Agent: [Na+]
Solvent: CC(C)=O
Product: CCCCCC(CCCI)OC(C)=O
Yield: 97.5 %

Procedure:
A mixture of 1-chloro-4-acetoxynonane (Ex. 1, Step B-3) (35.3 g., 0.16 mole) and sodium iodide (120 g., 0.8 mole) in acetone (350 ml.) is stirred and heated at reflux with exclusion for light for 10 hours. The resulting suspension is filtered and the collected sodium chloride washed with acetone. The combined filtrate and washings are evaporated in vacuo leaving a residual mass which is partitioned between ether and water. The organic extract is washed with dilute aqueous sodium thiosulfate and water, dried over sodium sulfate and evaporated in vacuo providing the title compound as a colorless liquid (48.7 g., 98%), pmr (CDCl3) δ 2.0 (s, 3H), 3.18 (t, 2H) and 4.98 (m, H).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:26]=[CH:25][C:18]([CH2:19][CH2:20][NH:21][CH2:22][CH:23]=[CH2:24])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[N+](C1C=CC([CH:38]2[S:42]/[C:41](=[N:43]\[C:44](=O)[O-:45])/[N:40]([C:47]3[CH:52]=[C:51]([CH3:53])[CH:50]=[CH:49][C:48]=3[CH:54]([CH3:56])[CH3:55])[C:39]2=[O:57])=CC=1)([O-])=O>>[CH2:22]([N:21]([CH2:20][CH2:19][C:18]1[CH:25]=[CH:26][C:15]([C:12]2[N:13]=[CH:14][N:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:27])[F:28])=[CH:9][CH:8]=3)[N:11]=2)=[CH:16][CH:17]=1)[C:44](/[N:43]=[C:41]1\[S:42][CH2:38][C:39](=[O:57])[N:40]\1[C:47]1[CH:52]=[C:51]([CH3:53])[CH:50]=[CH:49][C:48]=1[CH:54]([CH3:55])[CH3:56])=[O:45])[CH:23]=[CH2:24]
Reactant: C=CCNCCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: Cc1ccc(C(C)C)c(N2C(=O)C(c3ccc([N+](=O)[O-])cc3)S/C2=N\C(=O)[O-])c1
Product: C=CCN(CCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1)C(=O)/N=C1\SCC(=O)N1c1cc(C)ccc1C(C)C

Procedure:
The title compound was prepared as described in Example 95 using N-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)prop-2-en-1-amine (CB26) and (Z)-4-nitrophenyl(3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)carbamate (CA50), purified by flash column chromatography using 0-100% ethyl acetate/B, where B=1:1 dichloromethane/hexanes, as eluent and isolated as a brown oil (0.040 g, 43%).
Reaction SMILES: [CH2:1]([C:3]1[C:4](N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2].[CH2:22]([C@H:24]1[CH2:32][C:31]2[C:26](=[CH:27][C:28]([O:33][CH3:34])=[CH:29][CH:30]=2)[C@H:25]1[NH2:35])[CH3:23]>>[CH2:1]([C:3]1[C:4]([NH:35][C@@H:25]2[C:26]3[C:31](=[CH:30][CH:29]=[C:28]([O:33][CH3:34])[CH:27]=3)[CH2:32][C@@H:24]2[CH2:22][CH3:23])=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2]
Reactant: CCc1cnc(CC)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Reactant: CC[C@H]1Cc2ccc(OC)cc2[C@H]1N
Product: CCc1cnc(CC)c(N[C@@H]2c3cc(OC)ccc3C[C@@H]2CC)n1

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting cis-2-ethyl-6-methoxy-2,3-dihydro-1H-inden-1-amine and making non-critical variations provided the title compound as a oil: 1H NMR (CDCl3) δ 0.93, 1.27-1.34, 2.58, 2.68, 3.00, 3.79, 4.44, 5.83, 6.80, 6.92, 7.17, 7.68; HRMS (EI) calcd for C20H27N3O 325.2154, found 325.2157.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH2:12][O:13][CH3:14])[CH2:3][CH2:2]1.[NH2:18][C@@H:19]([CH2:23][CH:24]1[CH2:26][CH2:25]1)[C:20]([NH2:22])=[O:21]>>[C:20]([C@@H:19]([NH:18][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH2:12][O:13][CH3:14])[N:8]=1)=[O:17])[CH2:23][CH:24]1[CH2:26][CH2:25]1)(=[O:21])[NH2:22]
Reactant: NC(=O)[C@@H](N)CC1CC1
Reactant: COCCOc1nc(C(=O)O)ccc1C1CC1
Product: COCCOc1nc(C(=O)N[C@@H](CC2CC2)C(N)=O)ccc1C1CC1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-(2-methoxyethoxy)-pyridine-2-carboxylic acid (Example 142 d) and (S)-2-amino-3-cyclopropyl-propionamide (CAN 156077-93-9) as starting materials, MS (EI): m/e=348.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:45])[NH:4][C@H:5]([C:10]([NH:12][N:13]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40](Br)[CH:39]=1)[CH2:14][C@:15]([OH:36])([C:23](=[O:35])[NH:24][C@H:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][C@H:26]1[OH:34])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:11])[C:6]([CH3:9])([CH3:8])[CH3:7].[C:46]1([C:52]#[CH:53])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.N(CC)CC.CN(C=O)C>C(O)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CC#N>[CH3:1][O:2][C:3](=[O:45])[NH:4][C@H:5]([C:10]([NH:12][N:13]([CH2:14][C@:15]([OH:36])([C:23](=[O:35])[NH:24][C@H:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][C@H:26]1[OH:34])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([C:53]#[C:52][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH:39]=1)=[O:11])[C:6]([CH3:9])([CH3:8])[CH3:7]
Reactant: COC(=O)N[C@H](C(=O)NN(Cc1cccc(Br)c1)C[C@@](O)(Cc1ccccc1)C(=O)N[C@H]1c2ccccc2C[C@H]1O)C(C)(C)C
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: O=CO
Solvent: CCNCC
Product: COC(=O)N[C@H](C(=O)NN(Cc1cccc(C#Cc2ccccc2)c1)C[C@@](O)(Cc1ccccc1)C(=O)N[C@H]1c2ccccc2C[C@H]1O)C(C)(C)C
Yield: 27.2 %

Procedure:
Method C was followed using compound 26 (79.2 mg, 0.116 mmol), phenylacetylene (0.0150 mL, 0.139 mmol), Et2NH (0.110 mL, 1.01 mmol), Pd(PPh3)2Cl2 (6.10 g, 0.00869 mmol), CuI (1.90 mg, 0.00998 mmol) and DMF (2 mL). RP-LC-MS (35 min gradient of 20-90% CH3CN in 0.05% aqueous formic acid) afforded the title compound (22.2 mg, 27%) as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:4][N:3]=1.[C:19]1([C@@H:25]([NH2:27])[CH3:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)CCC>[C:19]1([C@@H:25]([NH:27][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH2:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[N:4][N:3]=2)[CH3:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Clc1nnc(Cc2ccncc2)c2ccccc12
Reactant: C[C@H](N)c1ccccc1
Solvent: CCCCO
Product: C[C@H](Nc1nnc(Cc2ccncc2)c2ccccc12)c1ccccc1
Temperature: 110 °C
Reaction time: 24 h

Procedure:
A mixture of 0.511 g (2 mmol) 1-chloro-4-(4-pyridylmethyl)phthalazine, 1.273 ml (10 mmol) (S)-1phenylethylamine and 5 ml 1-butanol is stirred for 24 h at 110° C. The reaction mixture is evaporated under vacuum and the residue distributed between dichloromethane and 20% aqueous potassium carbonate solution. The organic phase dried over anhydrous sodium sulfate is evaporated in the RE and then under HV and the residue purified on silica gel by flash chromatography using dichloromethane/methanol (50:1). The product-containing fractions are dissolved in 5 ml methanol, acidified with 0.75 ml 3N methanolic HCl and evaporated under vacuum. After recrystallization of the residue from methanol/acetonitrile, drying of the crystallizate under HV (8 h, 100° C.) and equilibration for 15 h at 20° C. and in room atmosphere, title compound is obtained with a water content of 10.66%; m.p. 190° C. (decomp.); ESI-MS: (M+H)+=341; [a]D20=+42.1±0.8° (c=1.272%, methanol).
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:16]=[CH:15][CH:14]=[C:13]4[C:8]=3[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]4)[CH2:2][CH2:3]2)=[O:25])=[CH:22][CH:21]=1
Reactant: Nc1nc(N)c2c(N3CCNCC3)cccc2n1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Product: Nc1nc(N)c2c(N3CCN(C(=O)c4ccc(Cl)cc4)CC3)cccc2n1
Yield: 53 %

Procedure:
Title compound was prepared via Resin Method using 5-piperazin-1-yl-quinazoline-2,4-diamine (50 mg; 0.2 mmol) and 4-chlorobenzoyl chloride (71.8 mg; 0.41 mmol) to obtain 40.4 mg. (53% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.77 (s, 1H), 7.53 (m, 4H), 7.39 (t, J=8.0 Hz, 1H), 7.15 (br s, 1H), 6.98 (d, J=8.5 Hz, 1H), 6.85 (d, J=8.0 Hz, 1H), 5.92 (br s, 2H), 4.56 (br s, 1H), 3.64 (m, 1H), 3.09 (m, 4H), 2.77 (m, 2H) ESIMS+384.1 m/z
Reaction SMILES: FC(F)(F)S([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])(=O)=O.[Cl:16][C:17]1[C:22]([C:23]([N:25]2[CH2:29][CH:28]([N:30]3[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]3)[CH:27](O)[CH2:26]2)=[O:24])=[CH:21][C:20]([C:38]#[N:39])=[CH:19][C:18]=1[NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44].N1C=CN=C1>CN(C=O)C.C(OCC)(=O)C>[Si:7]([O:6][CH:27]1[CH:28]([N:30]2[CH2:31][CH2:32][N:33]([CH3:36])[CH2:34][CH2:35]2)[CH2:29][N:25]([C:23]([C:22]2[C:17]([Cl:16])=[C:18]([NH:40][C:41](=[O:47])[O:42][C:43]([CH3:44])([CH3:45])[CH3:46])[CH:19]=[C:20]([C:38]#[N:39])[CH:21]=2)=[O:24])[CH2:26]1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: CN1CCN(C2CN(C(=O)c3cc(C#N)cc(NC(=O)OC(C)(C)C)c3Cl)CC2O)CC1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1CCN(C2CN(C(=O)c3cc(C#N)cc(NC(=O)OC(C)(C)C)c3Cl)CC2O[Si](C)(C)C(C)(C)C)CC1
Temperature: 25 °C
Yield: 81.1 %

Procedure:
tert-Butyldimethylsilyl trifluoromethanesulfonate (0.240 mL, 1.026 mmol) was added to a solution of (+/−)-tert-butyl (2-chloro-5-cyano-3-(3-hydroxy-4-(4-methylpiperazin-1-yl)pyrrolidine-1-carbonyl)phenyl)carbamate (119 mg, 0.256 mmol) and imidazole (69.8 mg, 1.026 mmol) in DMF (3 mL) and the reaction solution was stirred at room temperature over the weekend. The reaction mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo, the crude product was purified by flash chromatography on silica gel using an automated ISCO system (40 g column, eluting with 1-6% methanol/dichloromethane). (+/−)-tert-butyl (3-(3-((tert-butyldimethylsilyl)oxy)-4-(4-methylpiperazin-1-yl)pyrrol idine-1-carbonyl)-2-chloro-5-cyanophenyl)carbamate (120 mg) was obtained as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[CH2:13][C:14]([O-:16])=[O:15].[Na+].O.Cl>CS(C)=O>[C:10]([CH:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH2:13][C:14]([OH:16])=[O:15])#[N:11]
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Reactant: O=C([O-])CCl
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CC(CC(=O)O)c1ccc(Cl)c(Cl)c1
Yield: 66 %

Procedure:
A mixture of 18.6 g (0.10 mol) of 3,4-dichlorophenylacetonitrile and 12 g (1.03 mol) of dry sodium chloroacetate is reacted for 5 hours at room temperature in 150 ml of dry dimethyl sulfoxide, in the presence of 10.5 g (1.05 mol) of sodium tert-butylate. After the reaction, the reaction mixture is poured into 1 liter of iced water and acidified to pH<3 with hydrochloric acid. The cyanoacid is extracted with ethyl acetate, which is washed to pH>3, dried over magnesium sulfate and concentrated to dryness. The residue is solidified in 1,2-dichloroethane to give 16.1 g of the expected compound (III), which is characterized by proton NMR.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[N:12]=[N:11][C:10]([NH2:13])=[N:9]2)=[C:5]([CH3:14])[O:4][N:3]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20](Cl)=[O:21].N1C=CC=CC=1>C(#N)C.ClCCl>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[N:12]=[N:11][C:10]([NH:13][C:20](=[O:21])[C:19]3[CH:23]=[CH:24][CH:25]=[C:17]([O:16][CH3:15])[CH:18]=3)=[N:9]2)=[C:5]([CH3:14])[O:4][N:3]=1
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: Cc1noc(C)c1Cn1nnc(N)n1
Solvent: CC#N
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cccc(C(=O)Nc2nnn(Cc3c(C)noc3C)n2)c1
Yield: 34.6 %

Procedure:
2-((3,5-dimethylisoxazol-4-yl)methyl)-2H-tetrazol-5-amine (Example 10-39a) (102 mg, 0.528 mmol), 3-methoxybenzoyl chloride (0.065 mL, 0.528 mmol) and pyridine (0.043 mL, 0.528 mmol) in acetonitrile (3 mL) were stirred at 100° C. for one hour. The reaction was diluted with dichloromethane (30 mL) and washed with brine (30 mL). The organics were dried over sodium sulfate, concentrated and purified by reverse phase HPLC (Solvent system: acetonitrile/water 10% to 100% gradient), 25 minute run) affording N-(2-((3,5-dimethylisoxazol-4-yl)methyl)-2H-tetrazol-5-yl)-3-methoxybenzamide as a white crystalline solid (60 mg, 35% yield) MS M+H calculated 329.1. Found 329. 1H NMR (400 MHz, DMSO-d6): δ 2.02 (s, 3H), 2.46 (s, 3H), 3.81 (s, 3H), 5.78 (s, 2H), 7.16 (m, 1H), 7.42 (t, J=8 Hz, 2H), 7.54 (m, 1H), 11.3 (s, 1H). The compound had an IC50 on hT2R8 bitter receptor of 1.87 μM.
Reaction SMILES: [CH3:1][C:2]([CH3:14])([O:4][C:5]([NH:7][C@H:8]1[C@@H:11]([CH3:12])[NH:10][C:9]1=[O:13])=[O:6])[CH3:3].C([Li])CCC.[P:20](Cl)(=[O:25])([O:23][CH3:24])[O:21][CH3:22].[Cl-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:12][C@H:11]1[N:10]([P:20](=[O:25])([O:23][CH3:24])[O:21][CH3:22])[C:9](=[O:13])[C@H:8]1[NH:7][C:5]([O:4][C:2]([CH3:1])([CH3:14])[CH3:3])=[O:6]
Reactant: COP(=O)(Cl)OC
Reactant: C[C@H]1NC(=O)[C@H]1NC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COP(=O)(OC)N1C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H]1C
Temperature: 25 °C

Procedure:
(3S-cis)-3-[[(1,1-Dimethylethoxy)carbonyl]amino]-4-methyl-2-azetidinone (918 mg) dissolved in dry tetrahydrofuran (25 ml) was cooled to -78° C. under an inert atmosphere and 1.56 M n-butyl lithium (3 ml) was added while stirring. After thirty minutes dimethyl phosphorochloridate (3.0 ml) was added and the mixture was stirred at -78° C. for 2 hours. Saturated sodium chloride solution (20 ml) was added and the mixture allowed to warm to room temperature and extracted three times with 30 ml ethyl acetate portions. The combined extracts were dried (Na2SO4) and solvent was removed in vacuo yielding an oil. Chromatography of the oil dissolved in 4 ml of ethyl acetate on a 34 g silica gel column eluting with ethyl acetate yielded 875 mg of the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:22][OH:23])[C:8]([O:20][CH3:21])=[C:9]([NH:11][C:12](=[O:19])OCC(Cl)(Cl)Cl)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:24][C@@H:25]1[CH2:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C@@H:26]1[OH:34].C(O)(=O)[C@@H]([C@H](C(O)=O)O)O.C(N(CC)C(C)C)(C)C>C(#N)C>[C:1]([C:5]1[CH:6]=[C:7]([CH2:22][OH:23])[C:8]([O:20][CH3:21])=[C:9]([NH:11][C:12]([NH:24][C@@H:25]2[CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C@@H:26]2[OH:34])=[O:19])[CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1c(CO)cc(C(C)(C)C)cc1NC(=O)OCC(Cl)(Cl)Cl
Reactant: N[C@@H]1Cc2ccccc2[C@@H]1O
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(CO)cc(C(C)(C)C)cc1NC(=O)N[C@@H]1Cc2ccccc2[C@@H]1O
Reaction time: 17 h
Yield: 73 %

Procedure:
A suspension of 2,2,2-trichloroethyl 5-tert-butyl-3-(hydroxymethyl)-2-methoxyphenylcarbamate (1.50 g, 3.90 mmol), (1S,2R)-2-amino-2,3-dihydro-1H-indene-1-ol.L-tartaric acid salt (1.28 g, 4.29 mmol) and N,N-diisopropylethylamine (2.37 mL, 13.6 mmol) in acetonitrile (19.5 mL) was heated to reflux. After 17 hours, the mixture was allowed to cool and the reaction solution was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, hexane/ethyl acetate=50/50-0/100) to obtain 1.09 g of the captioned compound (73% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:11][CH:10]([CH3:12])[CH:9]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[NH:3]1.[O:14]1[CH:16]([CH2:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:15]1>C(O)C>[OH:14][CH:16]([CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:15][N:3]1[CH:4]2[CH:9]([CH2:8][CH2:7][CH2:6][CH2:5]2)[CH:10]([CH3:12])[CH2:11][C:2]1([CH3:13])[CH3:1]
Reactant: c1ccc(OCC2CO2)cc1
Reactant: CC1CC(C)(C)NC2CCCCC12
Solvent: CCO
Product: CC1CC(C)(C)N(CC(O)COc2ccccc2)C2CCCCC12

Procedure:
1-(2'-hydroxy-3'-phenoxy propyl)-2,2,4-trimethyl decahydroquinoline was prepared using a process similar to those described above. 27.2 grams (0.15 mole) of about 75% cis structure 2,2,4-trimethyl decahydroquinoline was reacted with 22.5 grams (0.15 mole) of 1,2-epoxy-3-phenoxy propane in the presence of 0.5 gram of ethanol at 160° C. for 19 hours. The reaction mixture was distilled to yield 21.2 grams of a liquid product boiling at 168° C. at 0.2 mm Hg. The infrared and mass spectrometer spectra are consistent with the desired product. Calculated values for C21H34NO2 were 75.85% carbon, 10.31% hydrogen, and 4.21% nitrogen, while measured values were 74.67% carbon, 10.18% hydrogen, and 4.26% nitrogen.
Reaction SMILES: [CH3:1][C:2]([NH:9][C:10]([C:12]1[CH:17]=[CH:16][C:15](Br)=[C:14]([O:19][CH2:20][C:21]2([CH3:25])[CH2:24][O:23][CH2:22]2)[N:13]=1)=[O:11])([C:4]1[S:5][CH:6]=[CH:7][N:8]=1)[CH3:3].Cl.[F:27][C:28]1([F:32])[CH2:31][NH:30][CH2:29]1>>[CH3:1][C:2]([NH:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([N:30]2[CH2:31][C:28]([F:32])([F:27])[CH2:29]2)=[C:14]([O:19][CH2:20][C:21]2([CH3:25])[CH2:24][O:23][CH2:22]2)[N:13]=1)=[O:11])([C:4]1[S:5][CH:6]=[CH:7][N:8]=1)[CH3:3]
Reactant: CC1(COc2nc(C(=O)NC(C)(C)c3nccs3)ccc2Br)COC1
Reactant: FC1(F)CNC1
Agent: Cl
Product: CC1(COc2nc(C(=O)NC(C)(C)c3nccs3)ccc2N2CC(F)(F)C2)COC1

Procedure:
The title compound was synthesized in analogy to Example 288b, using 5-bromo-6-(3-methyl-oxetan-3-ylmethoxy)-pyridine-2-carboxylic acid (1-methyl-1-thiazol-2-yl-ethyl)-amide (Example 281c) and 3,3-difluoroazetidine hydrochloride as starting materials, MS (EI): m/e=439.3 [M+H]+.
Reaction SMILES: [C:1]1([CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH2:8])[CH:2]=1>C1(C)C=CC=C(C)C=1>[C:9](#[N:10])[C:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]#[N:8])[CH:2]=1
Reactant: NCc1cccc(CN)c1
Solvent: Cc1cccc(C)c1
Product: N#Cc1cccc(C#N)c1

Procedure:
Patent Document 1 discloses a method of producing m-xylylenediamine from m-xylene. In the proposed method, isophthalonitrile produced by the ammoxidation of m-xylene is extracted into an organic solvent. Then, high-boiling point impurities are separated out in the first distillation step and the organic solvent is separated out in the second distillation step. Then, isophthalonitrile is taken out of the bottom of apparatus. The obtained purified isophthalonitrile is then hydrogenated after the addition of a specific solvent and liquid ammonia. This method requires increased costs for constructing production facilities because of its large number of steps. In addition, the method requires two distillation steps before the hydrogenation and further requires another distillation step for purification after the hydrogenation step. Therefore, a great quantity of energy for distillation should be consumed.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]=[C:13]([C:18]([O:20][CH3:21])=[O:19])[CH:12]=[CH:11]3)=[CH:4][CH:3]=1.[CH:22]1([C:27]2[O:31][N:30]=[C:29]([C:32]3[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][C:33]=3[Cl:39])[C:28]=2[CH2:40]O)[CH2:26][CH2:25][CH2:24][CH2:23]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[CH:22]1([C:27]2[O:31][N:30]=[C:29]([C:32]3[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][C:33]=3[Cl:39])[C:28]=2[CH2:40][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:9]=[C:10]4[C:15](=[CH:16][CH:17]=3)[N:14]=[C:13]([C:18]([O:20][CH3:21])=[O:19])[CH:12]=[CH:11]4)=[CH:4][CH:3]=2)[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: OCc1c(-c2c(Cl)cccc2Cl)noc1C1CCCC1
Reactant: COC(=O)c1ccc2cc(-c3ccc(O)cc3)ccc2n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc2cc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C4CCCC4)cc3)ccc2n1
Temperature: 90 °C
Yield: 36.8 %

Procedure:
To a solution of methyl 6-(4-hydroxyphenyl)-2-quinolinecarboxylate (0.10 mg, 0.36 mmol), [5-cyclopentyl-3-(2,6-dichlorophenyl)-4-isoxazolyl]methanol (0.11 mg, 0.36 mmol) and triphenylphosphine (0.10 mg, 0.39 mmol) in dichloromethane (2.5 mL) was added diisopropyl azodicarboxylate (0.071 mL, 0.39 mmol) slowly. The solution was heated in a microwave reactor at 90° C. for 10 minutes and then was adsorbed onto silica gel and purified by chromatography (silica gel, 0-45% ethyl acetate in hexanes gradient elution) to afford methyl 6-[4-({[5-cyclopentyl-3-(2,6-dichlorophenyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylate (76 mg, 37%). 1H-NMR (400 MHz, DMSO d6) δ 8.55 (d, J=8 Hz, 1H), 8.28 (s, 1H), 8.18-8.10 (m, 3H), 7.73 (d, J=9 Hz, 2H), 7.63-7.51 (m, 3H), 6.96 (d, J=9 Hz, 2H), 4.98 (s, 2H), 3.93 (s, 3H), 3.58-3.50 (m, 1H), 2.11-2.03 (m, 2H), 1.84-1.64 (m, 6H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]#[N:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.CO.[Br:14]Br>[OH-].[Na+]>[Br:14][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([C:10]#[N:11])[CH:5]=2)[NH:1][N:2]=1
Reactant: BrBr
Reactant: N#Cc1ccc2[nH]ncc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N#Cc1ccc2[nH]nc(Br)c2c1
Temperature: 40 °C
Yield: 47 %

Procedure:
A 2-L round bottomed flask was charged with 1H-indazole-5-carbonitrile (17.6 g, 123 mmol), 333 mL methanol (MeOH), 333 mL of 2.0 M aq. NaOH, and a solution of bromine (Br2, 54.7 g, 344 mmol, 2.80 equiv.) in 166 mL of 2.0 M aq. NaOH. The mixture was warmed on an oil bath to 40° C. (external temperature) for 6 h, and then cooled to room temperature in a water bath. The pH of the solution adjusted to ca. 5.5 with 103 mL of 4.0 M aq. HCI. The resulting precipitate was collected by filtration, washed with 200 mL of H2O, and dried. The product was purified by chromatography on 265 g of silica gel using 30–40% EtOAc in hexanes. This afforded the title compound (12.83 g, 47% yield): ES-MS (m/z) 222 [M+1]+.