Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[C:13]([C:15]3[O:19][N:18]=[C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:16]=3[C:26]([F:29])([F:28])[F:27])[O:12][N:11]=2)=[CH:6][CH:5]=1.[NH:30]1[CH2:35][CH2:34][CH2:33][CH:32]([CH2:36][CH2:37][OH:38])[CH2:31]1.CS(C)=O>CC(O)C>[OH:38][CH2:37][CH2:36][CH:32]1[CH2:33][CH2:34][CH2:35][N:30]([CH2:3][CH:2]([C:4]2[CH:9]=[CH:8][C:7]([C:10]3[N:14]=[C:13]([C:15]4[O:19][N:18]=[C:17]([C:20]5[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=5)[C:16]=4[C:26]([F:27])([F:28])[F:29])[O:12][N:11]=3)=[CH:6][CH:5]=2)[OH:1])[CH2:31]1
Reactant: OCCC1CCCNC1
Reactant: FC(F)(F)c1c(-c2ccccc2)noc1-c1nc(-c2ccc(C3CO3)cc2)no1
Solvent: CS(C)=O
Solvent: CC(C)O
Product: OCCC1CCCN(CC(O)c2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)cc2)C1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a mixture of 3-(4-(oxiran-2-yl)phenyl)-5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazole, Preparation 28C (30 mg, 0.075 mmol) in 2-propanol (2 mL) was added 2-(piperidin-3-yl)ethanol (19.41 mg, 0.150 mmol). The reaction mixture was heated to 80° C. DMSO (1 mL) was added to help solubilize. The reaction mixture was stirred overnight. The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 MeOH:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 MeOH:water with 10-mM ammonium acetate; Gradient: 45-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the Example 31 was 13.0 mg, and its purity was 100%. 1H NMR (400 MHz, MeOD) δ ppm 8.18 (2H, d, J=8.03 Hz), 7.52-7.75 (7H, m), 5.01 (1H, ddd, J=8.60, 4.20, 4.02 Hz), 3.54-3.72 (2H, m), 3.13 (2H, br. s.), 2.73 (2H, br. s.), 2.32 (1H, br. s.), 2.11 (1H, br. s.), 1.61-1.92 (4H, m), 1.48 (2H, dd, J=13.68, 6.90 Hz), 1.04 (1H, br. s.). MS (m+1)=529.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.CN(C)C=O.C(Cl)([Cl:18])=O>C1(C)C=CC=CC=1>[CH3:1][C:2]1[S:3][C:4]([C:8]([Cl:18])=[O:10])=[C:5]([CH3:7])[N:6]=1
Reactant: Cc1nc(C)c(C(=O)O)s1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cc1nc(C)c(C(=O)Cl)s1

Procedure:
In a similar apparatus to Example 1, 15.7 g (0.1 mole) of 2,4-dimethylthiazole-5-carboxylic acid were suspended in 100 ml of toluene, followed by the addition of 0.1 g of N,N-dimethylformamide. Under heating and reflux, phosgene was blown at a rate of 1.3 l/hr for 5 hours (0.29 mole). After completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated to obtain 17.2 g of 2,4-dimethylthiazole-5-carboxylic acid chloride. Its purity and yield were 97.5% and 98.0%, respectively.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[F:9][C:10]([F:42])([F:41])[C:11]1[CH:12]=[C:13]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[CH2:14][O:15][CH2:16][C:17]([OH:33])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:18][CH2:19][NH:20][C:21](=[O:26])[C:22]([F:25])([F:24])[F:23]>CC(C)=O>[F:9][C:10]([F:41])([F:42])[C:11]1[CH:12]=[C:13]([CH:34]=[C:35]([C:37]([F:39])([F:40])[F:38])[CH:36]=1)[CH2:14][O:15][CH2:16][C:17]([OH:33])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:18][CH2:19][N:20]([CH3:1])[C:21](=[O:26])[C:22]([F:24])([F:25])[F:23]
Reactant: O=C(NCCC(O)(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1)C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CN(CCC(O)(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1)C(=O)C(F)(F)F
Temperature: 60 °C

Procedure:
Excess amount of potassium carbonate (150 mg, 1.1 mmol) and excess amount of methyl iodide (0.040 ml, 0.064 mmol) were mixed with N-(4-(3,5-bis(trifluoromethyl)benzyloxy)-3-hydroxy-3-phenylbutyl)-2,2,2-trifluoroacetamide (15 mg, 0.030 mmol) in acetone (2 ml). The reaction mixture was heated in microwave at 60° C. for 10 minutes. The salt precipitate was filtered off and the filtrate was concentrated. The residue was purified by preparative HPLC to give the desired N-methylacetamide. 1H NMR (300 MHz, MeOH) δ ppm 7.84 (s, 3 H) 7.46–7.54 (m, 2 H) 7.35 (ddd, J=8.14, 6.50, 4.76 Hz, 2 H) 7.22–7.30 (m, 1 H) 4.61–4.73 (m, 2 H) 3.62–3.75 (m, 2 H) 3.40–3.55 (m, 1 H) 3.11–3.37 (m, 1 H) 3.01 (s, 2 H) 2.93 (s, 1 H) 2.15–2.31 (m, 2 H); LRMS [ESI, (MH+−H2O)] m/z calcd for C22H19NO2F9 500.13, found 499.97.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[O:9]1[CH2:14][CH2:13][C:12](=[CH:15][C:16](O)=[O:17])[CH2:11][CH2:10]1.OC1C=C(O)C=C2C=1C(=O)CC(C)(C)O2>>[OH:2][C:1]1[CH:3]=[C:4]2[C:6]([C:16](=[O:17])[CH2:15][C:12]3([O:5]2)[CH2:13][CH2:14][O:9][CH2:10][CH2:11]3)=[CH:7][CH:8]=1
Reactant: O=C(O)C=C1CCOCC1
Reactant: Oc1cccc(O)c1
Agent: CC1(C)CC(=O)c2c(O)cc(O)cc2O1
Product: O=C1CC2(CCOCC2)Oc2cc(O)ccc21

Procedure:
The subject compound was synthesized from resorcinol and (tetrahydropyran-4-yliden)acetic acid according to the method described in Example 42, (1).
Reaction SMILES: CN(C)CC[C:5]([NH:7][NH:8][C:9](=[O:25])[C:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=1[F:24])=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClC(Cl)(Cl)C#[N:49].[CH3:52][C:53]([N:55]([CH3:57])[CH3:56])=O>>[F:24][C:18]1[CH:19]=[C:20]([I:23])[CH:21]=[CH:22][C:17]=1[NH:16][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][C:10]=1[C:9]1[O:25][C:5]([NH:49][CH2:52][CH2:53][N:55]([CH3:57])[CH3:56])=[N:7][N:8]=1
Reactant: CC(=O)N(C)C
Reactant: CN(C)CCC(=O)NNC(=O)c1ccncc1Nc1ccc(I)cc1F
Reactant: N#CC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CN(C)CCNc1nnc(-c2ccncc2Nc2ccc(I)cc2F)o1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
3-(2-Fluoro-4-iodo-phenylamino)-isonicotinic acid N′-(3-dimethylamino-propionyl)-hydrazide (130 mg, 0.27 mmol) was dissolved in DMA (2 mL), and then PS-Triphenyl-phosphane (420 mg, 1.6 mmol, 6 eq), Trichloro-acetonitrile (77 mg, 0.53 mmol, 2 eq) and DIEPA (0.19 mL, 1.07 mmol, 4 eq) were added. The reaction mixture was stirred at 100° C. overnight, and then filtered. The filtrate was directly subjected to preparative HPLC to afford 32 mg of the desired product. LC/MS (Method A) [3.63 min; 467(M+1)]
Reaction SMILES: [OH-].[K+].[CH3:3]C1C=CC(S(N(N=O)C)(=O)=O)=CC=1.C(O)CO.CCOCC.[NH:26]1[C:30]2[CH:31]=[C:32]([N:35]3[CH:39]([C:40]4[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[C:41]=4[F:47])[C:38]([CH:48]([CH3:50])[CH3:49])=[C:37]([OH:51])[C:36]3=[O:52])[CH:33]=[CH:34][C:29]=2[N:28]=[CH:27]1>CO>[NH:26]1[C:30]2[CH:31]=[C:32]([N:35]3[CH:39]([C:40]4[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[C:41]=4[F:47])[C:38]([CH:48]([CH3:50])[CH3:49])=[C:37]([O:51][CH3:3])[C:36]3=[O:52])[CH:33]=[CH:34][C:29]=2[N:28]=[CH:27]1
Reactant: CC(C)C1=C(O)C(=O)N(c2ccc3nc[nH]c3c2)C1c1cccc(F)c1F
Reactant: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: CCOCC
Solvent: CO
Product: COC1=C(C(C)C)C(c2cccc(F)c2F)N(c2ccc3nc[nH]c3c2)C1=O

Procedure:
The compound was synthesized starting from KOH (15 eq in water), diazald (9 eq), ethylene glycol/Et2O (1/7.5 v/v, 17 ml), 1-(1H-Benzo[d]imidazol-6-yl)-5-(2,3-difluorophenyl)-4-isopropyl-3-hydroxy-1H-pyrrol-2(5H)-one (0.15 g, 0.34 mmol, 1 eq) and MeOH (10 ml), the product was further purified by prep TLC; yield: 0.040 g (10.4%); MS m/z: 384.1 [M+H]+; 1H-NMR: (400 MHz, CDCl3) δ: 7.88 (s, 1H), 7.80 (bs, 1H), 7.52 (bs, 1H), 7.2-6.88 (m, 4H), 6.0 (s, 1H), 4.08 (s, 3H), 2.61 (bs, 1H), 1.1-1.04 (m, 6H); HPLC (METHOD [A]): rt 14.51 min (96.9%)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[C:5]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[CH:18]=1)=[C:11]2[CH2:25][CH2:26][NH2:27])([CH3:7])[CH3:6])[CH3:2].[CH3:29][S:30]([NH:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][CH2:42][CH:43]=O)=[CH:36][CH:35]=1)(=[O:32])=[O:31]>>[CH2:1]([O:3][C:4](=[O:28])[C:5]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([C:17]1[CH:18]=[C:19]([CH3:24])[CH:20]=[C:21]([CH3:23])[CH:22]=1)=[C:11]2[CH2:25][CH2:26][NH:27][CH2:43][CH2:42][CH2:41][CH2:40][C:37]1[CH:38]=[CH:39][C:34]([NH:33][S:30]([CH3:29])(=[O:32])=[O:31])=[CH:35][CH:36]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CS(=O)(=O)Nc1ccc(CCCC=O)cc1
Reactant: CCOC(=O)C(C)(C)c1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCN)c2c1
Product: CCOC(=O)C(C)(C)c1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCNCCCCc3ccc(NS(C)(=O)=O)cc3)c2c1
Yield: 43 %

Procedure:
The reductive amination reaction of 2-[3-(2-aminoethyl)-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-2-methylpropionic acid ethyl ester and 4-[4-(methanesulfonamido)phenyl]butyraldehyde was carried out according to the procedure of Example 4 Step B to give the titled compound in 43% yield as a stiff foam; virtually homogenous by TLC in 92.5:7.5 CH2Cl2-MeOH. 500 MHz 1H NMR (CDCl3) was consistent with the assigned structure. Mass spectrum (PB-NH3/CI): m/e=604 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:33]([NH:40][C@H:41]1[CH2:46][CH2:45][C@H:44](O)[CH2:43][CH2:42]1)([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34].N(C(OCC)=O)=N[C:50](OCC)=[O:51]>C1COCC1>[C:33]([NH:40][C@H:41]1[CH2:46][CH2:45][C@@H:44]([C:50]([O:1][C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=2)=[O:51])[CH2:43][CH2:42]1)([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](O)CC1
Reactant: COC(=O)c1ccc(O)cc1OC
Reactant: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC(=O)[C@H]2CC[C@@H](NC(=O)OC(C)(C)C)CC2)cc1OC
Temperature: 0 °C

Procedure:
To a stirred solution of methyl 4-hydroxy-2-methoxybenzoate (1.09 g, 6.0 mmol) in dry THF (7 mL) was added triphenylphosphine (1.57 g, 6.0 mmol) and the solution was cooled to 0° C. A 4.0 mL volume of N-Boc-trans-1-amino-4-cyclohexanol (1 g, 4.0 mmol) and diethyl azodicarboxylate (945 μL, 6.0 mmol) in THF was added dropwise via addition funnel over 0.5 h. The reaction was filtered and the solvent was removed under reduced pressure. The residue was chromatographed on a silica gel column packed in 70:30 hexanes:EtOAc and eluted with same. The appropriate fractions were combined and the solvent removed under reduced pressure to afford methyl 4-[N-Boc-cis-1-amino-4-cyclohexanoyloxy]-2-methoxybenzoate.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]=[CH:22]C3C=NC=CC=3)[CH:16]=2)[CH2:9]1)(OC(C)(C)C)=O.CN1C(=O)CCC1.C([Mg]Cl)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.[Fe+3].C(OCC)(=O)C>[CH2:21]([C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[CH2:14][CH:10]1[O:11][CH2:12][CH2:13][NH:8][CH2:9]1)[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cc2cccc(C=Cc3cccnc3)c2)C1
Agent: [Fe+3]
Agent: CC[Mg]Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCc1cccc(CC2CNCCO2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N-Boc-2-(3-hydroxy)benzylmorpholine, trifluoromethylsulfonate ester intermediate (a) (62 mg, 0.16 mmol) was dissolved in tetrahydrofuran (3 mL) and NMP (0.3 mL) under an atmosphere of nitrogen, at room temperature then iron (III) ac ethyl acetateetate (3 mg, 7.3 umol) was added in one portion to give an orange solution. To the reaction mixture was added ethylmagnesium chloride (2.0M solution in tetrahydrofuran, 0.11 mL, 0.22 mmol) dropwise over 2 minutes and the reaction stirred at room temperature for 30 minutes. Then more iron (III) ac ethyl acetateetate (6 mg, 14.6 umol) was added in one portion followed by ethylmagnesium chloride (2.0M solution in tetrahydrofuran, 0.24 mL, 0.48 mmol) dropwise over 3 minutes. After 30 minutes citric acid (10% w/w aqueous solution, 10 mL) and ethyl acetate (10 mL) was added and the mixture stirred vigorously for 5 minutes and left to stand for 18 hrs. The layers were separated and the aqueous layer extracted with ethyl acetate (10 mL). Combined organic layers were washed with water (10 mL), then brine (10 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was dissolved in dichloromethane (2.5 mL) and treated with TFA (1 mL) and stirred at room temperature for 3 hrs. The reaction was then poured through an SCX-2 column and washed with dichloromethane. The column was then washed with ammonia (2N, methanol) and the ammonia washes concentrated in vacuo. The residue was purified by preparative HPLC to yield the desired morpholine example 69 as an off-white solid (6 mg).
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22]Br)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[CH3:20][CH2:21][CH2:2][CH:3]([CH3:18])[CH3:4].[Br:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][N:34]2[CH2:33][CH2:32][N:31]([C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:30])[CH2:36][CH2:35]2)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:15][CH:14]3[CH2:16][CH:10]([CH2:11][CH:12]([CH2:13]3)[CH2:17]1)[CH2:9]2)=[O:5]
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CBr)ccc1Br
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Br)c(C(=O)NCC34CC5CC(CC(C5)C3)C4)c2)CC1
Product: CCCC(C)C
Yield: 151.8 %

Procedure:
A mixture of 2-bromo-5-bromomethyl-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (Example 65a, 5.0 g), 1-tertbutyloxycarbonylpiperazine (2.3 g), potassium carbonate (3.2 g), potassium iodide (0.30 g) and acetone (75 ml) was refluxed in the dark for 14 h. The mixture was concentrated in vacuo, partitioned between ethyl acetate and water, then washed with brine. The organic layer was dried over magnesium sulfate and concentrated in vacuo. Recrystallization from ethyl acetate:isohexane gave the subtitle compound as colourless solid (4.7 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][N+]([O-])=O)[CH:5]=[C:4]([Cl:12])[N:3]=1.[OH-:13].[Na+].[NH4+:15].[OH-:16]>OS(O)(=O)=O>[Cl:12][C:4]1[C:5]([N+:15]([O-:16])=[O:13])=[C:6]([NH2:8])[CH:7]=[C:2]([Cl:1])[N:3]=1
Reactant: O=[N+]([O-])Nc1cc(Cl)nc(Cl)c1
Reactant: [NH4+]
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Nc1cc(Cl)nc(Cl)c1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 2 h

Procedure:
N-(2,6-dichloropyridin-4-yl)nitramide (205 g crude, 0.617 mol) was added carefully to conc. H2SO4 (800 mL) at room temperature. Then the reaction mixture was stirred at 80° C. for 2 h. TLC (Petroleum ether/ethyl acetate=2:1) showed the reaction was complete. The mixture was cooled to room temperature and poured into crushed ice. The mixture was cooled to 0° C. and neutralized with NaOH and NH4OH. The resulting precipitate was collected by filtration and washed with water. The resulting precipitate was dissolved in ethyl acetate, dried over Na2SO4 and concentrated to give crude 2,6-dichloro-3-nitropyridin-4-amine, which was used for the next step without further purification. 1H NMR (400 MHz, CDCl3) δ: 7.64 (s, 2H), 6.86 (s, 1H).
Reaction SMILES: [NH2:1][C:2](=[N:16][OH:17])[C@@H:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].C(#N)C.[C:21](N1C=CN=C1)(N1C=CN=C1)=[S:22].C1CCN2C(=NCCC2)CC1>O.Cl>[S:22]=[C:21]1[O:17][N:16]=[C:2]([C@@H:3]2[CH2:7][CH2:6][CH2:5][C@@H:4]2[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:12])[CH3:13])[NH:1]1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@H]1C(N)=NO
Agent: Cl
Solvent: CC#N
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N[C@H]1CCC[C@H]1c1noc(=S)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.6 %

Procedure:
To a mixture of tert-butyl {(1S,2R)-2-[amino(hydroxyimino)methyl]cyclopentyl}carbamate (320 mg) and acetonitrile (8.0 ml) were added 1,1′-carbonothioyl bis(1H-imidazole) (391 mg) and DBU (787 μl) in this order, followed by stirring at room temperature for 1 hour. The reaction mixture was diluted with water (15 ml), and 1 M hydrochloric acid was added thereto to adjust the pH to about 4, followed by extraction with ethyl acetate (40 ml). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was then removed by evaporation under reduced pressure. The residue was purified by silica gel column chromatography (3% methanol-chloroform) and then washed with cooled ethyl acetate (2 ml) to obtain tert-butyl [(1S,2R)-2-(5-thioxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopentyl]carbamate (160 mg) as a white solid.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]4[O:27][CH2:28][O:29][C:23]=4[CH:22]=3)(C(OC)=O)[C:12]([O:14]C)=[O:13])=[CH:4][C:3]=2[O:2]1.[OH-].[K+]>C(O)CCC.O>[CH2:28]1[O:27][C:24]2[CH:25]=[CH:26][C:21]([CH2:20][CH:11]([CH2:10][C:5]3[CH:6]=[CH:7][C:8]4[O:9][CH2:1][O:2][C:3]=4[CH:4]=3)[C:12]([OH:14])=[O:13])=[CH:22][C:23]=2[O:29]1
Reactant: COC(=O)C(Cc1ccc2c(c1)OCO2)(Cc1ccc2c(c1)OCO2)C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCCCO
Product: O=C(O)C(Cc1ccc2c(c1)OCO2)Cc1ccc2c(c1)OCO2
Yield: 55.2 %

Procedure:
A solution of 20.58 g (0.051 mol) of dimethyl bis-(3,4-methylenedioxyphenylmethyl)malonate in 50 mL of n-butanol was treated with a solution of 8.58 g (0.153 mol) of KOH in 50 mL H2O and heated at reflux overnight. The solvent was removed under reduced pressure and the residue mixed with H2O and acidified to pH 2 with dilute HCl. The mixture was extracted with EtOAc and the EtOAc washed with saturated NaCl. Drying over MgSO4 and removal of the solvent under reduced pressure left 9.24 g (55% yield) of the product as a solid, mp 191°-193° C. The structure was confirmed by NMR spectroscopy.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=O)[CH3:11])([O-:3])=[O:2].[NH2:13][C:14]1[NH:18][N:17]=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:21][CH:20]=2)[C:15]=1[C:33]#[N:34].[C:35](C1C(C2C=CC(OC3C=CC=CC=3)=CC=2)=NN2C(C3C=C(NC(=O)C)C=CC=3)=CC=NC=12)#N>>[CH2:26]([O:25][C:22]1[CH:21]=[CH:20][C:19]([C:16]2[C:15]([C:33]#[N:34])=[C:14]3[N:13]=[CH:35][CH:11]=[C:10]([C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N+:1]([O-:3])=[O:2])[N:18]3[N:17]=2)=[CH:24][CH:23]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: N#Cc1c(-c2ccc(OCc3ccccc3)cc2)n[nH]c1N
Reactant: CC(=O)c1ccccc1[N+](=O)[O-]
Reactant: CC(=O)Nc1cccc(-c2ccnc3c(C#N)c(-c4ccc(Oc5ccccc5)cc4)nn23)c1
Product: N#Cc1c(-c2ccc(OCc3ccccc3)cc2)nn2c(-c3ccccc3[N+](=O)[O-])ccnc12

Procedure:
The desired product was prepared from 1-(2-nitrophenyl)ethanone and 5-amino-3-(4-(benzyloxy)phenyl)-1H-pyrazole-4-carbonitrile according to the procedures similar to those (step 4 and step 5) for N-(3-(3-cyano-2-(4-phenoxyphenyl) pyrazolo[1,5-a]pyrimidin-7-yl)phenyl)acetamide under appropriate conditions recognized by one of ordinary skill in the art.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([SnH:17]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16].[CH2:26]([O:28][CH2:29]Cl)[CH3:27].[Cl-].[NH4+]>C(OCC)C.O1CCCC1>[CH2:22]([Sn:17]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:29][O:28][CH2:26][CH3:27])[CH2:23][CH2:24][CH3:25]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: CCOCCl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCC[Sn](CCCC)(CCCC)COCC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 66.8 %

Procedure:
To a mixture of diisopropylamine (2.1 mL, 15 mmol) and tetrahydrofuran (30 mL) was added dropwise n-butyl lithium (2.4 M n-hexane solution, 5.0 mL, 12 mmol) at −78° C., and then the reaction mixture was stirred for 30 minutes. Tributyltin hydride (3.3 mL, 12 mmol) was added dropwise to this mixture at −78° C., and then the reaction mixture was stirred for 40 minutes at 0° C. The reaction mixture was cooled to −78° C., after which ethoxymethyl chloride (1.1 mL, 12 mmol) was added dropwise to the reaction mixture. The reaction mixture was raised to room temperature, diethyl ether and an ammonium chloride aqueous solution were added to the reaction mixture, and the organic layer was separated. The organic layer was washed with saturated aqueous sodium chloride, after which the organic layer was concentrated under a reduced pressure. The residue was purified by neutral silica gel column chromatography (heptane:diethyl ether=30:1) to obtain the title compound (2.8 g, 66%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH2:4][CH2:5][C:6]([CH2:8]Cl)=[O:7]>CO>[C:3]([OH:10])(=[O:2])[CH2:4][CH2:5][C:6]([CH3:8])=[O:7].[CH3:1][O:2][C:3](=[O:10])[CH2:4][CH2:5][C:6]([CH3:8])=[O:7]
Reactant: COC(=O)CCC(=O)CCl
Solvent: CO
Product: CC(=O)CCC(=O)O
Product: COC(=O)CCC(C)=O

Procedure:
In connection with this it is remarkable, that the 5-chlorolevulinic acid methyl ester can be also selectively produced by means of low temperature crystallisation from the chlorination mixture, which you get from the bromination mixture of levulinic acid or levulinic acid methyl ester in methanol and the subsequent bromine/chlorine exchange, in a gentle manner as already described for the 5-bromolevulinic acid methyl ester. As in the case of the 5-bromolevulinic methyl ester you proceed in the same way by using the same solvents and solvent mixtures and temperatures between −20° C. and −40° C. You get the 5-chlorolevulinic acid methyl ester in 35–38% yield and >98 purity. Impurities are the 3-chlorolevulinic acid methyl ester and the unconverted levulinic acid methyl ester. The 5-chlorolevulinic acid esters of the alcohols with chain lengths of C2–C4 can not be produced by low-temperature crystallisation because no crystallisation occurs under these conditions. The same is valid for the corresponding bromination mixtures of the 5-bromolevulinic acid esters which are produced from alcohols with chain lengths of C2–C4.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]1([O:12][C:13]2[CH:14]=[C:15]([CH:21]=[CH:22][C:23]=2[O:24][CH3:25])[CH:16]=[CH:17][N+:18]([O-])=O)[CH2:11][CH2:10][CH2:9][CH2:8]1>CCOCC.O1CCCC1>[CH:7]1([O:12][C:13]2[CH:14]=[C:15]([CH2:16][CH2:17][NH2:18])[CH:21]=[CH:22][C:23]=2[O:24][CH3:25])[CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: COc1ccc(C=C[N+](=O)[O-])cc1OC1CCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(CCN)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.5 %

Procedure:
To a suspension of lithium aluminum hydride (10.83 g, 28.5 mmol) in ether (250 mL) at 0° C. under an argon atmosphere was added dropwise a solution of 3-cyclopentyloxy-4-methoxy-β-nitrostyrene (15.00 g, 57.0 mmol) in tetrahydrofuran (85 mL). The resulting mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was cooled to 0° C. and quenched by the successive dropwise addition of water (11 mL), 15% sodium hydroxide (11 mL) and water (33 mL). The mixture was filtered through a pad of Celite™ and the filtrate was washed successively with water, 10% hydrochloric acid and water. The aqueous washes were combined, made basic with saturated aqueous potassium carbonate and extracted three times with ether and twice with methylene chloride. The organic layers were combined and dried (potassium carbonate). Removal of the solvent in vacuo provided the amine (10.80 g, 81%). A portion of the crude amine was purified by flash chromatography, eluting with 1:10:90 water/methanol/chloroform.