Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:16]=[C:17]2[S:21][CH2:20][NH:19][C:18]2=[O:22])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].[H-].[Na+].[CH3:25][S:26][CH2:27][CH2:28]Cl>CN(C=O)C.C(OCC)C.Cl>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([CH:16]=[C:17]2[S:21][CH2:20][N:19]([CH2:28][CH2:27][S:26][CH3:25])[C:18]2=[O:22])[CH:8]=[C:9]([C:12]([CH3:13])([CH3:14])[CH3:15])[C:10]=1[OH:11])([CH3:1])[CH3:3]
Reactant: CSCCCl
Reactant: CC(C)(C)c1cc(C=C2SCNC2=O)cc(C(C)(C)C)c1O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CSCCN1CSC(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Temperature: 100 °C
Reaction time: 144 h

Procedure:
26.7 g of 5-{[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene}-4-thiazolidinone (i.e., the compound of Example 2) was dissolved in 418 ml of DMF to which was added 3.34 g of a 60% sodium hydride dispersion. The resultant mixture was stirred at 100° C. under an argon atmosphere. To this was added 8.33 ml of methylthioethyl chloride and the resulting black solution was stirred at 100° C. for 6 days. The material was allowed to cool to 30° C. after which insoluble material was filtered off. The solid was washed with DMF until its color was gone leaving a white solid which was discarded. The pH of the filtrate and washings was adjusted to 1.5 by the addition of 1N hydrochloric acid with stirring. The mixture was then diluted with a mixture of 1000 ml of diethyl ether and 500 ml of 1N hydrochloric acid which was then shaken and separated. The organic layer was washed with two portions of water and one portion of brine and subsequently dried over sodium sulfate, filtered, evaporated and chased with chloroform to give a black foam/oil. This material was triturated with about 75 ml of chloroform and then filtered and the insoluble solid was washed with additional chloroform until its brown color was gone. The filtrate was then loaded onto a silica gel column which was eluted with 8000 ml of a gradient of 10-30% ethyl acetate in hexane. The various fractions containing the desired product were combined and again loaded onto a silica gel column and eluted with 8000 ml of a gradient of 10-35% acetone in hexane. The fractions containing the desired product were recrystalled with hexane/ethyl acetate to give 1.2 g of the title compound as a tan/orange solid, m.p. 165.5°-168° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[N:7]2.[F:33][C:34]1[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1>>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:14][CH2:15][N:16]([S:40]([C:37]3[CH:38]=[CH:39][C:34]([F:33])=[CH:35][CH:36]=3)(=[O:42])=[O:41])[CH2:17][CH2:18]1)=[N:7]2
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: Cc1c(N2CCNCC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1
Product: Cc1c(N2CCN(S(=O)(=O)c3ccc(F)cc3)CC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

Procedure:
Prepared according to Procedure M using 5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)-2-(piperazin-1-yl)quinolin-4-amine (50 mg, 0.11 mmol) and 4-fluorobenzene-1-sulfonyl chloride to give 5,7-difluoro-2-(4-(4-fluorophenylsulfonyl)-piperazin-1-yl)-3-methyl-N-(5-morpholinopyridin-3-yl)quinolin-4-amine. 1H NMR (DMSO-d6) δ ppm 1.97 (br s, 3H), 3.04 (t, J=4.8 Hz, 4H), 3.11 (br s, 4H), 3.33-3.37 (m, 4H), 3.69 (t, J=4.4 Hz, 4H), 6.48 (s, 1H), 7.13-7.19 (m, 1H), 7.25-7.28 (m, 1H), 7.49-7.54 (m, 3H), 7.77 (d, J=2.0 Hz, 1H), 7.84-7.88 (m, 2H,), 8.34 (s, 1H). Mass Spectrum (ESI) m/e=599.4 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:11]=1[C:12]([Cl:14])=O.C(N(CC)CC)C>ClCCl>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]=[C:12]([Cl:14])[C:11]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:10]=2[Cl:9])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: Nc1ccc(Br)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: ClC(=Nc1ccc(Br)cc1)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-bromoaniline (40 mg, 0.12 mmol) and 2,4-dichloro benzoyl chloride (69 μL, 0.12 mmol) in dichloromethane is added triethylamine (20 μL, 0.144 mmol). After stirred at room temperature for 30 min, the solvent is removed. The residue is added 0.5 mL of thionyl chloride. The reaction mixture is heated at 80° C. for 1h, concentrated. The product is used in the next step reaction.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1([NH2:11])[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5].[Cl:12][C:13]1[C:14]([CH3:23])=[C:15]([S:19](Cl)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1.C(N(CC)CC)C.O>C(Cl)Cl>[CH3:2][O:3][C:4]([C:6]1([NH:11][S:19]([C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([Cl:12])[C:14]=2[CH3:23])(=[O:20])=[O:21])[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5]
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Reactant: COC(=O)C1(N)CCCC1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1(NS(=O)(=O)c2cccc(Cl)c2C)CCCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 100 %

Procedure:
methyl-1-aminocyclopentanecarboxylate hydrochloride (300 mg, 1.67 mmol) was dissolved in CH2Cl2 (7 ml), added with 3-chloro-2-methylbenzene-1-sulfonyl chloride (413 mg, 1.83 mmol) and triethylamine (0.9 ml, 6.68 mmol), and stirred at room temperature for 12 hours. The resultant solution was added with H2O, extracted with CH2Cl2 (×2), dried with MgSO4, and filtered. Through vacuum distillation, the solvent was removed. The resultant mixture was purified with column chromatography so as to obtain methyl-1-(3-chloro-2-methylphenylsulfonamido)cyclopentanecarboxylate (554 mg, 1.67 mmol, 90%).
Reaction SMILES: [CH3:1][C:2]1([CH2:13][NH:14]C(=O)OCC2C=CC=CC=2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1.[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28]>C(Cl)Cl>[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28].[CH3:1][C:2]1([CH2:13][NH2:14])[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1
Reactant: CC1(CNC(=O)OCc2ccccc2)Cn2cc([N+](=O)[O-])nc2O1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(CN)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
A mixture of benzyl (2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)carbamate prepared in Example 200 (190 mg, 0.57 mmol), trifluoroacetic acid (4 ml) and methylene chloride (5 ml) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. To the residue was treated with diethyl ether to afford 2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethylamine trifluoroacetate (120 mg, yield 67%) as a light yellow powder.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:30][CH2:31][CH3:32])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:14][C:15]3[CH:23]=[CH:22][C:21]4[C:17](=[CH:18][N:19]([CH2:24][C:25]([O:27]CC)=[O:26])[N:20]=4)[CH:16]=3)=[O:13])[CH:7]=2)[CH2:3][CH2:2]1.[OH-].[Na+].O.Cl>C(O)C>[CH:1]1([CH2:4][N:5]([CH2:30][CH2:31][CH3:32])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:14][C:15]3[CH:23]=[CH:22][C:21]4[C:17](=[CH:18][N:19]([CH2:24][C:25]([OH:27])=[O:26])[N:20]=4)[CH:16]=3)=[O:13])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc3nn(CC(=O)OCC)cc3c2)ncn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc3nn(CC(=O)O)cc3c2)ncn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of ethyl {5-[({6-[(cyclopropylmethyl)(propyl)amino]pyrimidin-4-yl}carbonyl)amino]-2H-indazol-2-yl}acetate (Example 120, 90 mg; 0.20 mmol) in ethanol (10 ml) was treated with 10% NaOH solution (5 ml). After stirring at RT for 2 hours the solvent was reduced in vacuo to one quarter of its original volume and water (20 ml) added. The mixture was acidified with dilute HCl and the solid removed by filtration, washed with water and dried to give the title compound as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:12]2[C:13]3[C:5]([CH2:6][CH2:7][C:8]=3[CH:9]=[CH:10][CH:11]=2)=[CH:4][CH:3]=1.[CH:14](/[O-])=[C:15](\[N+:18]([O-:20])=[O:19])/[CH:16]=O.O.[Na+].Cl.NC1C=CC=CC=1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+]>C(O)(=O)C>[N+:18]([C:15]1[CH:14]=[C:3]2[C:2](=[N:1][CH:16]=1)[C:12]1=[C:13]3[C:5]([CH2:6][CH2:7][C:8]3=[CH:9][CH:10]=[CH:11]1)=[CH:4]2)([O-:20])=[O:19]
Reactant: O=C/C(=C\[O-])[N+](=O)[O-]
Reactant: Nc1ccc2c3c(cccc13)CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Nc1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1cnc2c(c1)cc1c3c(cccc32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 5-aminoacenaphthene (Grabe, C. Liebigs Ann. der Chemie 1903, 327, 77) (5.0 g, 29.5 mmol) and sodium nitromalondialdehyde monohydrate (Fanta, P. E. Org. Syntheses Coll. vol. 4 1963, 844) (5.51 g, 35 mmol) in acetic acid (140 mL) was stirred for 1 h at room temperature and aniline hydrochloride (5.21 g, 40.2 mmol) was added. This mixture was stirred for 10 min and heated at reflux for 2 h. Phosphorous oxychloride (3 mL, 32.2 mmol) was added and heating was continued for 3 h. The resulting mixture was cooled to room temperature and poured into ice/water (200 mL). The aqueous mixture was neutralized with 2M sodium hydroxide solution and extracted with dichloromethane. The extracts were dried over sodium sulfate and condensed to dryness. The condensed product was purified using flash chromatography (20% hexane/dichloromethane, silica gel) to obtain a fluffy, bright yellow solid, 3.20 g (43%): MS m/e 251 (M+H +); 1H NMR (CD2C12, 300 MHz) δ 3.48-3.55 (m, 4H), 7.56 (s, 1H), 7.68 (d, J=7.0 Hz, 1H), 7.77 (t, J=7.8 Hz, 1H), 8.79 (d, J=8.1 Hz, 1H), 8.94 (d, J=2.5 Hz, 1H), 9.65 (d, J=2.5 Hz, 1H).
Reaction SMILES: [C:1]([N:5]1[C:24](=[O:25])[N:8]2[CH:9]=[C:10]([C:17]([CH3:23])([CH3:22])[C:18]([O:20]C)=[O:19])[N:11]=[C:12]([NH:13][CH:14]([CH3:16])[CH3:15])[C:7]2=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].Cl>O1CCOCC1.O>[C:1]([N:5]1[C:24](=[O:25])[N:8]2[CH:9]=[C:10]([C:17]([CH3:23])([CH3:22])[C:18]([OH:20])=[O:19])[N:11]=[C:12]([NH:13][CH:14]([CH3:15])[CH3:16])[C:7]2=[N:6]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)C(C)(C)c1cn2c(=O)n(C(C)(C)C)nc2c(NC(C)C)n1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)Nc1nc(C(C)(C)C(=O)O)cn2c(=O)n(C(C)(C)C)nc12
Temperature: 25 °C

Procedure:
To a solution of 400 mg of methyl 2-(2-tert-butyl-8-isopropylamino-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-6-yl)-2-methyl-propionate in dioxane (10.0 mL) was added 6.0 N KOH (1.0 mL) and the mixture was heated at reflux for 16 h. The reaction mixture was cooled to ambient temperature, diluted with water, the pH was adjusted to 2.0 with 6.0 N HCl, and the mixture was extracted with EtOAc (2×). The organic extracts were dried over magnesium sulfate, filtered, and concentrated to leave 2-(2-tert-butyl-8-isopropylamino-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-6-yl)-2-methyl-propionic acid as a white solid. MS (M+H+)=336.3.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][N:15]=[C:14](Cl)[N:13]=2)[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4].[NH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1>>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[N:13]=2)[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cccc(-c2ccnc(Cl)n2)c1
Reactant: NCCc1ccc(O)cc1
Product: CCCCOc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Intermediate 46 was coupled with tyramine following procedure F. LC-MS showed the product had the expected M+H+ of 364. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 8.28 (m, 1H) 7.6 (m, 2H) 7.35 (m, 1H) 7.0 (m, 4H) 6.7 (d, 2H) 5.49 (br s, 1H) 4.0 (t, 2H) 3.7 (d, 2H) 2.85 (t, 2H) 1.78 (d, 2H) 1.5 (d, 2H) (t, 3H).
Reaction SMILES: [N:1]1([CH2:5][CH2:6][C:7]2[NH:8][C:9]([C:13]3[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=3[CH3:22])[C:16]([OH:18])=O)=[C:10]([Cl:12])[N:11]=2)[CH2:4][CH2:3][CH2:2]1.ClC1N=C(COC)NC=1C1C=C(C=CC=1C)C(O)=O.Cl.[NH:43]1[CH2:46][CH:45]([C:47]2[CH:54]=[CH:53][C:50]([C:51]#[N:52])=[CH:49][CH:48]=2)[CH2:44]1.Cl.N1CCC(C2C=CC(C#N)=CC=2)CC1>>[N:1]1([CH2:5][CH2:6][C:7]2[NH:8][C:9]([C:13]3[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=3[CH3:22])[C:16]([N:43]3[CH2:46][CH:45]([C:47]4[CH:54]=[CH:53][C:50]([C:51]#[N:52])=[CH:49][CH:48]=4)[CH2:44]3)=[O:18])=[C:10]([Cl:12])[N:11]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: Cc1ccc(C(=O)O)cc1-c1[nH]c(CCN2CCC2)nc1Cl
Reactant: N#Cc1ccc(C2CNC2)cc1
Agent: COCc1nc(Cl)c(-c2cc(C(=O)O)ccc2C)[nH]1
Agent: Cl
Agent: N#Cc1ccc(C2CCNCC2)cc1
Product: Cc1ccc(C(=O)N2CC(c3ccc(C#N)cc3)C2)cc1-c1[nH]c(CCN2CCC2)nc1Cl

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 27, except 3-(2-(2-(azetidin-1-yl)ethyl)-4-chloro-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 157.3) was used in place of 3-(4-chloro-2-(methoxymethyl)-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 27.5) and 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2) was used in place of 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.2). m/z (ES+) 460 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[N:18]1([CH2:23][CH2:24][C:25]2[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=2)[NH2:28])[CH2:22][CH2:21][CH2:20][CH2:19]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:28][C:27]1[CH:29]=[CH:30][CH:31]=[C:25]([CH2:24][CH2:23][N:18]2[CH2:19][CH2:20][CH2:21][CH2:22]2)[CH:26]=1
Reactant: Nc1cccc(CCN2CCCC2)c1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Product: O=C(c1cnc2ccc(Br)cc2c1Nc1cccc(CCN2CCCC2)c1)C1CC1
Yield: 74.6 %

Procedure:
Following general procedure C, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (197 mg, 0.635 mmol) was reacted with 3-[2-(pyrrolidin-1-yl)ethyl]aniline (120 mg, 0.635 mmol) to afford the desired product (220 mg, 74%) as a yellow solid: ESI MS m/z 464 [C25H26BrN3O+H]+.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:6]([OH:8])=[O:7])[CH2:4][SH:5].Cl[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].Cl>[OH-].[Na+]>[C:10]([NH:2][C@H:3]([C:6]([OH:8])=[O:7])[CH2:4][S:5][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]
Reactant: N[C@@H](CS)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(N[C@@H](CSC(=O)OCc1ccccc1)C(=O)O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
Cysteine HCl (2.0 g, 12.6 mmol) was dissolved in 2N NaOH and benzyl chloroformate (4.5 mL) was slowly added over 15 min. The pH value of the solution was kept at 9-10 by addition of 2 N NaOH (~7 mL) at 0° C. After vigorous stirring for 1 h at 0° C., the aqueous solution was acidified with 2N HCl at pH ~2 to form a colorless syrup. The aqueous solution was decanted and the sticky syrup was triturated with petroleum ether (100 ml×3) to give N,S-diCBZ-cysteine (3.94 g, 80%) as a white solid. Analytically pure sample could also be obtained by flash chromatography (on silica gel, 5% CH3OH in EtOAc):mp.93°-94° C.; 1H NMR (CDCl3) δ7.33 (10H, m), 5.67 (1H, d, J=7.7 Hz), 5.21 (2H, s), 5.12 (2H, s), 4.66 (1H, ddd, J=7.7, 6.7, 4.4 Hz), 3.31 (1H, dd, J=6.7, 14.5 Hz).
Reaction SMILES: [OH:1][C:2]1([CH3:18])[CH2:7][CH2:6][C@@H:5]([NH:8]C(=O)OC(C)(C)C)[CH2:4][C:3]1([CH3:17])[CH3:16].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C@@H:5]1[CH2:6][CH2:7][C:2]([CH3:18])([OH:1])[C:3]([CH3:17])([CH3:16])[CH2:4]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCC(C)(O)C(C)(C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)C[C@H](N)CCC1(C)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 133.1 %

Procedure:
To a solution of tert-butyl ((1R)-4-hydroxy-3,3,4-trimethylcyclohexyl)carbamate (520 mg, 2.15 mmol) in DCM (6.00 mL) was added TFA (3.00 mL) at 0° C. The resulting mixture was stirred at room temperature for 1 h. The reaction was concentrated in vacuo to give a crude product (450 mg, crude), which was used directly in the next step without further purification. MS (ESI) m/z 158.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:15]2[O:19][N:18]=[C:17]([C:20]3[S:24][C:23]([CH2:25]O)=[CH:22][C:21]=3[CH3:27])[N:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.[NH:53]1[CH2:56][CH:55]([C:57]([O:59][CH3:60])=[O:58])[CH2:54]1.C(N(CC)C(C)C)(C)C>>[F:1][C:2]1[CH:3]=[C:4]([C:15]2[O:19][N:18]=[C:17]([C:20]3[S:24][C:23]([CH2:25][N:53]4[CH2:56][CH:55]([C:57]([O:59][CH3:60])=[O:58])[CH2:54]4)=[CH:22][C:21]=3[CH3:27])[N:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Cc1cc(CO)sc1-c1noc(-c2ccc(Oc3ccccc3)c(F)c2)n1
Reactant: COC(=O)C1CNC1
Agent: BrC(Br)(Br)Br
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CN(Cc2cc(C)c(-c3noc(-c4ccc(Oc5ccccc5)c(F)c4)n3)s2)C1

Procedure:
The crude product of the title compound was synthesized by conducting the reaction similar to that mentioned in Example 1 (1f) using {5-[5-(3-fluoro-4-phenoxyphenyl]-1,2,4-oxadiazol-3-yl)-4-methyl-2-thienyl}methanol (0.21 g, 0.55 mmol) that was obtained in Example 11 (11f), carbon tetrabromide (0.22 g, 0.66 mmol), triphenylphosphine (0.17 g, 0.66 mmol), methyl 3-azetidinecarboxylate hydrochloride (0.13 g, 0.83 mmol), and N,N-diisopropylethylamine (0.30 mL, 1.7 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography using a mixed solvent of ethyl acetate and hexane (5:5) to afford the title compound (0.23 g) in a yield of 86% as a colourless oily product.
Reaction SMILES: C([O:8][C:9]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[C:31]([CH3:32])=[CH:30][C:29]([N+:33]([O-])=O)=[C:28]3[C:24]=2[CH2:25][CH2:26][CH2:27]3)=[CH:18][C:10]=1[CH:11]=[C:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)C1C=CC=CC=1.[H][H]>C(O)C.C(OCC)(=O)C.[Pd]>[NH2:33][C:29]1[CH:30]=[C:31]([CH3:32])[C:23]([O:22][C:19]2[CH:20]=[CH:21][C:9]([OH:8])=[C:10]([CH2:11][CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH:18]=2)=[C:24]2[C:28]=1[CH2:27][CH2:26][CH2:25]2
Reactant: Cc1cc([N+](=O)[O-])c2c(c1Oc1ccc(OCc3ccccc3)c(C=C3CCOCC3)c1)CCC2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cc(N)c2c(c1Oc1ccc(O)c(CC3CCOCC3)c1)CCC2
Yield: 80 %

Procedure:
4-[2-Benzyloxy-5-(5-methyl-7-nitroindan-4-yloxy) benzylidene]tetrahydropyran (230 mg) was dissolved in ethanol (10 mL) and ethyl acetate (2 mL). After adding 10% Pd/C (50 mg) under ice-cooling, the mixture was stirred at room temperature under an atmospheric pressure of hydrogen for 24 hours. The insoluble material was removed by filtration. The filtrate was evaporated under reduced pressure to dryness. The residue was purified by column chromatography on silica gel (eluent: exane/ethyl acetate) to give the title compound (138 mg).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH2:23][CH2:24][CH3:25])=[CH:11][C:6]=2[O:5][C:4]([C:26](N)=[O:27])=[CH:3]1.S(=O)(=O)(O)[OH:30]>O1CCOCC1>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH2:23][CH2:24][CH3:25])=[CH:11][C:6]=2[O:5][C:4]([C:26]([OH:27])=[O:30])=[CH:3]1
Reactant: CCCc1ccccc1OCCCOc1ccc2c(=O)cc(C(N)=O)oc2c1
Reactant: O=S(=O)(O)O
Solvent: C1COCCO1
Product: CCCc1ccccc1OCCCOc1ccc2c(=O)cc(C(=O)O)oc2c1

Procedure:
A suspension of 1.0 parts of 4-oxo-7-(3-[2-propylphenoxy]propoxy)-4H-1-benzopyran-2-carboxamide in 10 parts of dioxane and 10 parts of 10% v /v sulphuric acid was heated on a steam can for eight hours. The solid obtained on cooling was collected, washed with water and crystallised from acetone to give 0.75 parts of 4-oxo-7-(3-[2-propylphenoxy]propoxy)-4H-1-benzopyran-2-carboxylic acid, m.pt. 164°-166°.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9](#[N:13])[CH2:10][C:11]#[N:12].N1CCCCC1>C(O)CCC>[C:2]1([CH:1]=[C:10]([C:9]#[N:13])[C:11]#[N:12])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: N#CCC#N
Solvent: CCCCO
Solvent: C1CCNCC1
Product: N#CC(C#N)=Cc1ccccc1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
Into a 50-mL round-bottom flask, was placed benzaldehyde (4 g, 37.69 mmol, 1.00 equiv), propanedinitrile (3.3 g, 49.95 mmol, 1.30 equiv), n-butanol (10 mL), piperidine (1 mL). The resulting solution was stirred for 16 h at 20° C. The resulting mixture was concentrated under vacuum. The resulting mixture was washed with 1×33 mL of H2O/EtOH(10/1). The solids were collected by filtration. The solid was dried in an oven. This resulted in 4.2 g (69%) of 2-(phenylmethylidene)propanedinitrile as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:17]([O:18][CH2:19][CH3:20])=[CH:16][C:5]([C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11]C2)=[O:7])=[C:4]([F:21])[CH:3]=1.Cl.Cl.CN1CC[C@@H](N)C1>>[NH2:1][C:2]1[C:17]([O:18][CH2:19][CH3:20])=[CH:16][C:5]([C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11]2)=[O:7])=[C:4]([F:21])[CH:3]=1
Reactant: CCOc1cc(C(=O)NC2CCN(C)CC2)c(F)cc1N
Agent: CN1CC[C@@H](N)C1
Agent: Cl
Product: CCOc1cc(C(=O)N[C@@H]2CCN(C)C2)c(F)cc1N

Procedure:
The title compound was prepared by an analogous method to the preparation of Intermediate 169, on a 0.5 mmol scale, utilising (3R)-1-methylpyrrolidin-3-amine dihydrochloride (Intermediate 184; 129 mg, 0.75 mmol), as a white solid (95 mg, 68%).
Reaction SMILES: CC1(C)[O:7][CH2:6][CH:5]([C:8]2[CH:37]=[CH:36][C:11]([O:12][C:13]3[N:18]=[CH:17][N:16]=[C:15]([N:19]4[CH2:24][CH2:23][CH:22]([C:25]5[O:29][N:28]=[C:27]([CH:30]([CH3:32])[CH3:31])[N:26]=5)[CH2:21][CH2:20]4)[C:14]=3[N+:33]([O-:35])=[O:34])=[CH:10][CH:9]=2)[CH2:4][O:3]1.Cl>CC(C)=O>[CH:30]([C:27]1[N:26]=[C:25]([CH:22]2[CH2:21][CH2:20][N:19]([C:15]3[N:16]=[CH:17][N:18]=[C:13]([O:12][C:11]4[CH:36]=[CH:37][C:8]([CH:5]([CH2:6][OH:7])[CH2:4][OH:3])=[CH:9][CH:10]=4)[C:14]=3[N+:33]([O-:35])=[O:34])[CH2:24][CH2:23]2)[O:29][N:28]=1)([CH3:32])[CH3:31]
Reactant: CC(C)c1noc(C2CCN(c3ncnc(Oc4ccc(C5COC(C)(C)OC5)cc4)c3[N+](=O)[O-])CC2)n1
Agent: Cl
Solvent: CC(C)=O
Product: CC(C)c1noc(C2CCN(c3ncnc(Oc4ccc(C(CO)CO)cc4)c3[N+](=O)[O-])CC2)n1
Temperature: 27 °C
Reaction time: 4 h
Yield: 5.4 %

Procedure:
To a solution of 5-(1-(6-(4-(2,2-dimethyl-1,3-dioxan-5-yl)phenoxy)-5-nitropyrimidin-4-yl)piperidin-4-yl)-3-isopropyl-1,2,4-oxadiazole (500 mg, 0.0095 moles) in acetone (10 ml) was added conc. HCl (3 ml) and the reaction mixture was stirred for 4 hours at 27° C. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate. The organic extract was successively washed with water & brine, dried over sodium sulfate and evaporated under reduced pressure to yield 250 mg product as yellow solid.