Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[NH:5][C:6]2[C:11]([C:12]=1[CH:13]=O)=[CH:10][C:9]([O:15][CH3:16])=[CH:8][CH:7]=2)([CH3:3])[CH3:2].[C:17]([C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)(=[O:19])[CH3:18].N1CCCCC1>CO>[CH:1]([C:4]1[NH:5][C:6]2[C:11]([C:12]=1/[CH:13]=[CH:18]/[C:17]([C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)=[O:19])=[CH:10][C:9]([O:15][CH3:16])=[CH:8][CH:7]=2)([CH3:3])[CH3:2]
Reactant: COc1ccc2[nH]c(C(C)C)c(C=O)c2c1
Reactant: CC(=O)c1ccncc1
Solvent: CO
Solvent: C1CCNCC1
Product: COc1ccc2[nH]c(C(C)C)c(/C=C/C(=O)c3ccncc3)c2c1
Temperature: 40 °C
Yield: 66.3 %

Procedure:
2-Isopropyl-5-methoxyindole-3-carboxaldehyde (105 mg, 0.48 mmol) was dissolved in anhydrous methanol (5 mL) under an atmosphere of Argon (g). 4-Acetylpyridine (87.2 mg, 0.72 mmol) and piperidine (61.3 mg, 0.72 mmol) were added to the reaction mixture and the solution was refluxed for 24 hours. A precipitate slowly formed which was collected, washed with cold MeOH (30 mL) and dried overnight in an oil driven vacuum pump equipped to a vacuum desiccator heated to 40° C. to yield a bright yellow powder (102 mg, 66%): TLC Rf 0.38 in 4:1 ethyl acetate/hexanes. Melting point=252-253° C. 1H NMR (600 MHz, d6-DMSO) δ 11.78 (s, 1H), 8.82-8.81 (m, 2H), 8.15-8.13 (d, 1H, J=15.24 Hz), 7.94 (m, 2H), 7.45 (d, 1H, J=2.28 Hz), 7.41-7.38 (d, 1H, J=15.18 Hz), 7.36-7.34 (d, 1H, J=8.7 Hz), 6.88-6.87 (dd, 1H, J1=2.34 Hz, J2=8.64 Hz), 3.87 (s, 3H), 3.54-3.49 (m, 1H), 1.35-1.34 (d, 6H, J=6.96 Hz); 13C NMR (150 MHz, d6-DMSO) δ 188.6, 155.7, 155.4, 151.1, 145.6, 139.6, 131.8, 126.6, 121.9, 113.5, 113.0, 111.6, 105.0, 104.4, 56.1, 26.0, 22.8. Elemental analysis calculated for C20H20N2O2: C, 74.98; H, 6.29; N, 8.74. Found: C, 74.78; H, 6.42; N, 8.68.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[C:19]4[CH:18]=[CH:17][N:16]=[C:15]([O:20]C)[C:14]=4[C:13]([C:22]4[CH:27]=[CH:26][C:25]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:24][CH:23]=4)=[N:12]3)[CH2:7][CH2:6]2)[O:4]CC1.C1COCC1.Cl.[OH-].[Na+]>O>[O:20]=[C:15]1[C:14]2[C:13]([C:22]3[CH:27]=[CH:26][C:25]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:24][CH:23]=3)=[N:12][N:11]([CH:8]3[CH2:7][CH2:6][C:5](=[O:4])[CH2:10][CH2:9]3)[C:19]=2[CH:18]=[CH:17][NH:16]1
Reactant: COc1nccc2c1c(-c1ccc(S(N)(=O)=O)cc1)nn2C1CCC2(CC1)OCCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(-c2nn(C3CCC(=O)CC3)c3cc[nH]c(=O)c23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a solution of 4-(1-(1,4-dioxaspiro[4.5]dec-8-yl)-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)benzenesulfonamide (280 mg) in a mixed solvent of THF (15 mL) and water (1.5 mL) was added 1N hydrochloric acid (0.420 mL) at 0° C., and the mixture was stirred overnight at room temperature. To the reaction mixture was added 1N aqueous sodium hydroxide solution at 0° C., and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (219 mg).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[NH2:11][C:12]1[CH:30]=[CH:29][C:15]([O:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24](=[O:28])[CH2:25][CH2:26][CH3:27])[CH:18]=2)=[CH:14][CH:13]=1.C(N(CC)CC)C>O1CCCC1>[C:24]([NH:23][C:19]1[CH:18]=[C:17]([O:16][C:15]2[CH:14]=[CH:13][C:12]([NH:11][C:2](=[O:3])[O:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:30][CH:29]=2)[CH:22]=[CH:21][N:20]=1)(=[O:28])[CH2:25][CH2:26][CH3:27]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCCC(=O)Nc1cc(Oc2ccc(N)cc2)ccn1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCC(=O)Nc1cc(Oc2ccc(NC(=O)Oc3ccccc3)cc2)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Phenyl chloroformate (0.14 ml) was added dropwise to an ice-cooled stirred solution of 4-(4-aminophenoxy)-2-(butyrylamino)pyridine (0.3 g), triethylamine (0.14 ml) and tetrahydrofuran (10 ml). The cooling bath was removed and the mixture was stirred at room temperature overnight. Silica gel was added to the reaction solution, the solvent was distilled off under reduced pressure and the reaction product was adsorbed onto the silica gel. The silica gel was charged into a dry column packed with silica gel, and column purification was performed (hexane:ethyl acetate=2:1, followed by 1:1). The solvent was distilled off under reduced pressure to obtain the target substance as a colorless solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([F:24])=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([CH2:20]Cl)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.[NH2:25][C:26]([C:28]1([NH:41][CH3:42])[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]1)=[O:27].CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:25][C:26]([C:28]1([N:41]([CH2:20][C:17]2[CH:18]=[C:19]3[C:14](=[CH:15][C:16]=2[O:22][CH3:23])[N:13]=[CH:12][N:11]=[C:10]3[NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([Cl:2])[C:4]=2[F:24])[CH3:42])[CH2:29][CH2:30][N:31]([C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])[CH2:32][CH2:33]1)=[O:27]
Reactant: CNC1(C(N)=O)CCN(C(=O)OC(C)(C)C)CC1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CCl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)C1(C(N)=O)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 1 h
Yield: 78.8 %

Procedure:
N-(3-chloro-2-fluorophenyl)-6-(chloromethyl)-7-methoxyquinazolin-4-amine hydrochloride (0.30 g, 0.775 mmol) was added over a period of 40 minutes to a stirred solution of tert-butyl 4-(aminocarbonyl)-4-(methylamino)piperidine-1-carboxylate (0.498 g, 1.93 mmol) and DIPEA (0.50 g, 3.89 mmol) in DMF (1 ml) at 120° C. The reaction mixture was stirred for 1 hour, cooled, concentrated and purified by column chromatography on silica eluting with acetonitrile to afford tert-butyl 4-(aminocarbonyl)-4-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]piperidine-1-carboxylate (0.35 g, 79%) as a white foam; Mass Spectrum: (M+H)+ 573.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:45])[C@@H:5]([NH:37]C(OC(C)(C)C)=O)[CH2:6][CH2:7][C:8](=[O:36])[NH:9][C:10]1[C:15]([C:16]2[O:20][N:19]=[C:18]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)=[CH:24][CH:23]=3)[CH:17]=2)=[CH:14][CH:13]=[CH:12][N:11]=1)[CH3:2].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:3][C:4](=[O:45])[C@@H:5]([NH2:37])[CH2:6][CH2:7][C:8](=[O:36])[NH:9][C:10]1[C:15]([C:16]2[O:20][N:19]=[C:18]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([CH2:28][O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)=[CH:26][CH:27]=3)[CH:17]=2)=[CH:14][CH:13]=[CH:12][N:11]=1)[CH3:2]
Reactant: CCOC(=O)[C@H](CCC(=O)Nc1ncccc1-c1cc(Cc2ccc(COc3ccccn3)cc2)no1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)[C@@H](N)CCC(=O)Nc1ncccc1-c1cc(Cc2ccc(COc3ccccn3)cc2)no1
Reaction time: 8 h
Yield: 89.5 %

Procedure:
To a mixture of (S)-2-tert-butoxycarbonylamino-4-(3-{3-[4-(pyridin-2-yloxymethyl)-benzyl]-isoxazol-5-yl}-pyridin-2-ylcarbamoyl)-butyric acid ethyl ester (40 mg, 0.065 mmol) described in Manufacturing Example 4-2 and dichloromethane (1 mL) was added trifluoroacetic acid (0.5 mL) at room temperature, which was stirred overnight at the same temperature. The solvent was evaporated from the reaction mixture under a reduced pressure, and the residue thus obtained was washed with diethyl ether, so as to obtain the titled compound (30 mg) as the trifluoroacetic acid salt.
Reaction SMILES: ICCCC(OC)=O.N1CCCC1.[N:14]1([CH2:19][CH2:20][CH2:21][C:22]([O:24]C)=[O:23])[CH2:18][CH2:17][CH2:16][CH2:15]1.[ClH:26]>C1C=CC=CC=1>[ClH:26].[N:14]1([CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COC(=O)CCCN1CCCC1
Agent: COC(=O)CCCI
Agent: Cl
Solvent: c1ccccc1
Solvent: C1CCNC1
Product: O=C(O)CCCN1CCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
30.0 g. (0.13 mole) of Methyl γ-iodobutyrate (F.F. Blicke, W. B. Wright and M. F. Zienty, J. Amer. Chem. Soc. 63, 2488 (1941) was combined with 36 g. of pyrrolidine (Aldrich) in 300 ml. of benzene, heated at 60° for 0.5 hours and stirred at room temperature for 16 hours. A dark orange layer formed. The benzene solution was decanted, concentrated and distilled (b.p. 100° at 15 mm Hg) to give 10 g. of colorless liquid. The infrared and nmr spectra indicated the product to be methyl γ-pyrrolidinobutyrate. This material was dissolved in 100 ml. of 18% hydrochloric acid and heated at reflux for 28 hours. The solution was concentrated under reduced pressure to give a semi-solid which was triturated with acetone and filtered. Recrystallization from acetic acid/acetone gave 8.3 g. (33%) of the desired acid hydrochloride as colorless crystals, m.p. 126°-127° . The infrared and nmr spectra are consistent with the proposed structure.
Reaction SMILES: C(OC([N:8]1[CH:13]([C@@H:14]([OH:29])[C@@H:15]([NH:25][C:26](=[O:28])[CH3:27])[CH2:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=2)[CH2:12][O:11][C@@H:10]([O:30][CH2:31][CH3:32])[CH2:9]1)=O)(C)(C)C.[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36]>ClCCl>[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36].[F:24][C:19]1[CH:18]=[C:17]([CH:22]=[C:21]([F:23])[CH:20]=1)[CH2:16][C@H:15]([NH:25][C:26](=[O:28])[CH3:27])[C@@H:14]([C@H:13]1[CH2:12][O:11][C@H:10]([O:30][CH2:31][CH3:32])[CH2:9][NH:8]1)[OH:29]
Reactant: CCO[C@H]1CN(C(=O)OC(C)(C)C)C([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(C)=O)CO1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCO[C@@H]1CN[C@@H]([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(C)=O)CO1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97 %

Procedure:
Dissolve (R)-5-[(1S,2S)-2-acetylamino-3-(3,5-difluorophenyl)-1-hydroxypropyl]-2-ethoxymorpholine-4-carboxylic acid tert-butyl ester (0.060 g, 0.131 mmol) in dichloromethane (5 mL) and add trifluoroacetic acid (0.74 g, 6.5 mmol). Stir at room temperature for 1.5 hours and concentrate to give the title compound (60 mg, 97%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[C:11]1([C:17]2[N:21]([C:22]3[CH:27]=[CH:26][C:25]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:24][CH:23]=3)[N:20]=[C:19](NC(NC3C=CC=C(C(F)(F)F)C=3)=O)[CH:18]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[NH:8][CH2:5][CH2:4][CH2:3][C:19]2[CH:18]=[C:17]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:21]([C:22]3[CH:23]=[CH:24][C:25]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:26][CH:27]=3)[N:20]=2)=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: NS(=O)(=O)c1ccc(-n2nc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc2-c2ccccc2)cc1
Solvent: CO
Product: NS(=O)(=O)c1ccc(-n2nc(CCCNC(=O)Nc3ccc(Cl)cc3)cc2-c2ccccc2)cc1
Yield: 92 %

Procedure:
The titled compound was prepared in 92% yield from 4-chlorophenyl isocyanate using the procedure detailed for compound 7. mp 103.2-110.4° C. 1H NMR (300 MHz, DMSO-d6): δ 8.60 (s, 1H), 7.79 (d, J=9 Hz, 2H), 7.47-7.35 (m, 9H), 7.29-7.21 (m, 4H), 6.57 (s, 1H), 6.29 (t, J=6 Hz, 1H), 3.26-3.13 (m, 2H), 2.68 (t, J=8 Hz, 2H), 1.92-1.77 (m, 2H). MS (ESI) m/z: 510.14 (M+H+). Anal. Calcd for C25H24ClN5O3S.MeOH: C, 58.22; H, 4.98; N, 13.31. Found: C, 58.18; H, 4.78; N, 13.25.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16].Cl>N1CCCCC1.N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:6]=[CH:14]/[C:15]([OH:17])=[O:16])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: COc1ccc(C=O)cc1OC
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: COc1ccc(/C=C/C(=O)O)cc1OC
Temperature: 120 °C
Reaction time: 8 h
Yield: 81.6 %

Procedure:
A solution of 3,4-dimethoxybenzaldehyde (5.0 g, 30 mmol) and malonic acid (4.7 g, 45 mmol) in a mixture of piperidine (0.5 mL) and pyridine (15 mL) was heated to 120° C. and stirred overnight. The mixture was cooled to rt and acidified with conc. HCl. The resulting precipitate was filtered and washed with water to give (E)-3-(3,4-dimethoxyphenyl)-2-propenoic acid (5.1 g, 81%) as a pale brown solid; δH (400 MHz, DMSO-d6) 3.78 (s, 3H, OCH3), 3.79 (s, 3H, OCH3), 6.42 (d, J=16.0 Hz, 1H, CH═CHCO2H), 6.96 (d, J5,6=8.0 Hz, 1H, H5), 7.19 (d, J5,6=8.0 Hz, 1H, H6), 7.30 (s, 1H, H2), 7.51 (d, J=16.0 Hz, 1H, CH═CHCO2H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10]CC)=O)=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.C(N(CC)CC)C.Cl.[CH2:23]([O:27][C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30]([NH2:32])=[NH:31])[CH:24]([CH3:26])[CH3:25]>C(#N)C>[CH3:14][S:13][C:4]1[N:3]=[C:2]2[N:31]=[C:30]([C:29]3[CH:33]=[CH:34][CH:35]=[CH:36][C:28]=3[O:27][CH2:23][CH:24]([CH3:26])[CH3:25])[NH:32][C:8](=[O:10])[C:7]2=[CH:6][N:5]=1
Reactant: CC(C)COc1ccccc1C(=N)N
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CSc1ncc2c(=O)[nH]c(-c3ccccc3OCC(C)C)nc2n1
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 21.5 %

Procedure:
Ethyl 4-chloro-2-methylthio-5-pyrimidine carboxylate (1.50 g) followed by triethylamine (0.65 g) was added to a stirred mixture of 2-isobutoxybenzamidine hydrochloride (1.46 g) and triethylamine (0.65 g) in acetonitrile (150 ml). The reaction mixture was stirred at 5° C. for 15 minutes and then at ambient temperature for 3 days. A solid (0.55 g) was collected by filtration and the filtrate was reduced in volume to yield a second crop of solid (0.47 g). The solids were combined and recrystallised from ethanol to yield the title compound, 0.57 g, m.p. 185°-186° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]3[S:15][CH:16]=[CH:17][C:13]=3[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.[CH3:18][O:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C1(C)C=CC=CC=1.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[C:14]3[S:15][CH:16]=[CH:17][C:13]=3[CH2:12][CH2:11][N:10]2[C:24]([C:23]2[CH:27]=[CH:28][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)=[O:25])=[CH:7][CH:8]=1
Reactant: COc1ccc(C2NCCc3ccsc32)cc1
Reactant: COc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)N2CCc3ccsc3C2c2ccc(OC)cc2)cc1
Reaction time: 8 h

Procedure:
7-(4-methoxyphenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine (80 mg) in toluene (10 ml), 4-methoxybenzoic acid (55 mg), EDAC (94 mg) and HOBt (44 mg) were mixed in DMF (3 ml). The mixture was stirred overnight, evaporated to dryness and dissolved in ethyl acetate (10 ml).
Reaction SMILES: Br[C:2]1[CH2:6][O:5][C:4](=[O:7])[CH:3]=1.CCN(C(C)C)C(C)C.[CH2:17]1[C:22]2([CH2:27][CH2:26][CH2:25][NH:24][CH2:23]2)[CH2:21][CH2:20][N:19]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:18]1>C1COCC1>[O:7]=[C:4]1[O:5][CH2:6][C:2]([N:24]2[CH2:25][CH2:26][CH2:27][C:22]3([CH2:17][CH2:18][N:19]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:20][CH2:21]3)[CH2:23]2)=[CH:3]1
Reactant: O=C1C=C(Br)CO1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCCNC2)CC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC2(CCCN(C3=CC(=O)OC3)C2)CC1
Temperature: 76 °C
Reaction time: 8 h

Procedure:
To commercially available 4-bromofuran-2(5H)-one (128 mg, 0.786 mmol) in THF (4 mL) was added Hunig's Base (275 μL, 1.57 mmol) and tert-butyl 3,8-diazaspiro[5,5]undecane-3-carboxylate (200 mg, 0.786 mmol). The reaction mixture was stirred at 76° C. overnight, concentrated and purified by column chromatography (0-10% MeOH in DCM) to afford the title compound. LCMS: [(M+1)]+=337
Reaction SMILES: CS[C:3](SC)=[C:4]1[C:13](=[O:14])[C:12]([CH2:16][CH2:17][CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)([CH3:15])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:25].[NH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[S:35]([NH2:38])(=[O:37])=[O:36]>C1(C)C=CC=CC=1>[CH:19]1([CH2:18][CH2:17][CH2:16][C:12]2([CH3:15])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([OH:25])=[C:4]([C:3]3[NH:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[S:35](=[O:36])(=[O:37])[N:38]=3)[C:13]2=[O:14])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Nc1ccccc1S(N)(=O)=O
Reactant: CSC(SC)=C1C(=O)c2ccccc2C(C)(CCCC2CCCCC2)C1=O
Solvent: Cc1ccccc1
Product: CC1(CCCC2CCCCC2)C(=O)C(C2=NS(=O)(=O)c3ccccc3N2)=C(O)c2ccccc21
Temperature: 25 °C
Yield: 865 %

Procedure:
A solution of Example 36H (0.075 g, 0.186 mmol) and 2-amino-benzenesulfonamide (0.034 g, 0.195 mmol) in toluene (7 mL) was refluxed for 6 hours. The solution was cooled to 25° C. and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexane followed by 20% and 30% ethyl acetate in hexane to give the desired product (0.77 g, 87%).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[Cl:7][C:8]1[CH:25]=[CH:24][C:11]([O:12][CH2:13][CH2:14][NH:15][CH2:16][CH2:17][CH2:18][N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CCOCC>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([O:12][CH2:13][CH2:14][N:15]([CH2:16][CH2:17][CH2:18][N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)[CH2:2][C:3]([O:5][CH3:6])=[O:4])=[CH:24][CH:25]=1
Reactant: COC(=O)CBr
Reactant: Clc1ccc(OCCNCCCn2ccnc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: COC(=O)CN(CCCn1ccnc1)CCOc1ccc(Cl)cc1
Reaction time: 18 h

Procedure:
Methyl bromoacetate (2.1 g) was added to a stirred mixture of N-[2-(4-chlorophenoxy)ethyl]-3-(imidazol-1-yl)propylamine (3.87 g) and anhydrous potassium carbonate (5.73 g) in dry acetone (180 ml). The mixture was stirred and boiled under reflux for 7 hours, then left to stand at ambient temperature for 18 hours then hot filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica using ethyl acetate/triethylamine, 9 to 1 as the mobile phase. The product was obtained as an oil which was dissolved in ether, and extracted into 5M hydrochloric acid. The acid extracts were basified with 5M sodium hydroxide solution and the product extracted into ether to give methyl N-[2-(4-chlorophenoxy)ethyl]-N-[3-(imidazol-1-yl)propyl]glycinate as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10](O)[N:9]2[CH:13]=[N:14][N:15]=[C:8]2[N:7]=1)=[O:5])[CH3:2].P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:10]1[N:9]2[CH:13]=[N:14][N:15]=[C:8]2[N:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cc(O)n2cnnc2n1
Product: CCOC(=O)c1cc(Cl)n2cnnc2n1
Temperature: 60 °C

Procedure:
7-Ethoxycarbonyl-5-hydroxy-s-triazolo[4,3-a]pyrimidine (10 g) was added to 50 ml of phosphorus oxychloride at room temperature, the mixture was heated at 60° C. for one hour, and excess phosphorus oxychloride was removed by distillation under reduced pressure. The remaining dark red oil was shaken with 200 ml of chloroform and 100 ml of water, and the aqueous layer was again extracted with 100 ml of fresh chloroform. The chloroform layers were joined together and washed with 80 ml of saturated sodium bicarbonate solution and 100 ml of saturated sodium chloride solution and dried over anhydrous sodium sulfate. The dried solution was concentrated under reduced pressure to about 50 ml, and the residue was recrystallized from 100 ml of n-hexane. The crystals were collected by filtration, affording 6.2 g of the objective compound as faint yellow crystals.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[CH:19]=[CH2:20]>CC(C)=O>[CH2:20]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)[CH:19]=[CH2:18]
Reactant: C=CCBr
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc(C(=O)OC)cc1
Temperature: 25 °C
Yield: 84.6 %

Procedure:
A 2 L flask was equipped with a mechanical stirrer, a reflux condenser and a stopper, then charged with 50.05 g (0.329 mol) of methyl 4-hydroxybenzoate, 960 mL of acetone, 22.50 g (1.625 mol) of anhydrous potassium carbonate, 80.5 mL (112.6 g, 0.932 mol) of allyl bromide and the mixture was stirred and refluxed for 14 hours. The mixture was cooled to room temperature, filtered and concentrated to an oil. The residual oil was purified by distillation (97° C.@0.03 mm Hg) to afford 53.52 g (86%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:23])[C:9]([C:15]2[S:19][C:18]([C:20]#[N:21])=[C:17]([CH3:22])[CH:16]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:24])[CH:3]=1.[F:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][C:31]=1[C:32]([O:34]C)=[O:33].[Li+].[OH-]>>[Cl:24][C:4]1[CH:3]=[C:2]([C:28]2[CH:29]=[CH:30][C:31]([C:32]([OH:34])=[O:33])=[C:26]([F:25])[CH:27]=2)[CH:7]=[CH:6][C:5]=1[CH:8]([CH3:23])[C:9]([C:15]1[S:19][C:18]([C:20]#[N:21])=[C:17]([CH3:22])[CH:16]=1)([OH:14])[C:10]([F:13])([F:12])[F:11]
Reactant: COC(=O)c1ccc(B(O)O)cc1F
Reactant: Cc1cc(C(O)(C(C)c2ccc(Br)cc2Cl)C(F)(F)F)sc1C#N
Agent: [Li+]
Agent: [OH-]
Product: Cc1cc(C(O)(C(C)c2ccc(-c3ccc(C(=O)O)c(F)c3)cc2Cl)C(F)(F)F)sc1C#N

Procedure:
The compound was prepared in analogy to Example 60, step 2, from 5-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-3-methyl-thiophene-2-carbonitrile and 3-fluoro-4-methoxycarbonylphenylboronic acid (CAS Reg. No. 505083-04-5). The resulting ester was hydrolyzed by addition of aqueous LiOH solution (1N) to the reaction mixture. Light yellow solid. MS (m/e, ISP neg. ion)=496.3 [M−H+].
Reaction SMILES: [NH2:1][CH:2]([CH3:5])[C:3]#[N:4].[C:6]([N:10]=[C:11]=[O:12])([CH3:9])([CH3:8])[CH3:7]>O1CCCC1>[C:3]([CH:2]([NH:1][C:11]([NH:10][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:12])[CH3:5])#[N:4]
Reactant: CC(C)(C)N=C=O
Reactant: CC(N)C#N
Solvent: C1CCOC1
Product: CC(C#N)NC(=O)NC(C)(C)C

Procedure:
To a stirring solution of 21.1 g (0.3 mole) 2-aminopropionitrile in 300 ml. dry tetrahydrofuran under a nitrogen atmosphere, there is added 30.7 g (0.3 mole) t-butyl isocyanate (97%). The resulting mixture is heated at reflux for five hours. At the end of this period, the tetrahydrofuran is removed at reduced pressure. The solid is recrystallized from methanol:water, 60:40, to give N-(1-cyanoethyl)-N'-(1,1-dimethylethyl)urea, m.p. 161°-3°.
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([Br:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[OH:24])[CH2:4][CH3:5])[CH3:2].Cl[C:26](Cl)([O:28]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C>C1COCC1>[Br:22][C:18]1[CH:19]=[C:20]([CH3:21])[C:15]([O:14][C:9]2[C:8]3[O:24][C:26](=[O:28])[N:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[C:7]=3[CH:12]=[C:11]([CH3:13])[N:10]=2)=[C:16]([CH3:23])[CH:17]=1
Reactant: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(Br)cc2C)c1O
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(CC)n1c(=O)oc2c(Oc3c(C)cc(Br)cc3C)nc(C)cc21
Reaction time: 8 h
Yield: 177.2 %

Procedure:
To a 0° C. solution of 4-(1-ethyl-propylamino)-6-methyl-2-(4-bromo-2,6-dimethyl-phenoxy)-pyridin-3-ol (40 mg, 0.101 mmol) was added triphosgene (10 mg, 0.035 mmol) and triethylamine (7 mg, 0.07 mmol) in 1 ml of dry THF. The resulting mixture was stirred overnight. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated. The residue was purified through silica gel column chromatography to give 26 mg (61%) of the title compound as a white solid. 1H NMR (CDCl3) δ 7.22(s,2H), 6.60(s,1H), 4.02(m,1H), 2.31(s,3H), 2.12(s,6H), 1.8–2.2(m,4H), 0.94(t,6H)ppm.
Reaction SMILES: Cl.C([Cl:5])(=O)C.[CH2:6]([O:13][C:14]([N:16]([CH:20]1[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]1)[CH2:17][CH2:18][CH3:19])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(OCC)(=O)C>CO>[ClH:5].[CH2:6]([O:13][C:14]([N:16]([CH:20]1[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]1)[CH2:17][CH2:18][CH3:19])=[O:15])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(=O)Cl
Reactant: CCCN(C(=O)OCc1ccccc1)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCN(C(=O)OCc1ccccc1)C1CCNCC1
Reaction time: 0.17 h

Procedure:
To a solution of 2.4 mmol of HCl in 2 mL of methanol (prepared by the addition of 0.17 mL of acetyl chloride at 0° C. and stirring for 10 min) was added 90 mg of 4-(N-(benzyloxycarbonyl)-N-(prop-1-yl)amino)-1-t-butoxycarbonylpiperidine. The mixture was stirred at rt for 16 h at which time the reaction was complete by TLC (20% ethyl acetate in hexanes) and was evaporated to dryness in vacuo to afford 75 mg of the title compound as the hydrochloride salt.