Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5]([Br:10])[NH:4][N:3]=1.[H-].[Na+].[CH3:13]I>CN(C=O)C>[Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5]([Br:10])[N:4]([CH3:13])[N:3]=1
Reactant: CI
Reactant: O=[N+]([O-])c1c(Br)n[nH]c1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1nc(Br)c([N+](=O)[O-])c1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.5 %

Procedure:
To a solution of 3,5-dibromo-4-nitropyrazole 1 (0.934 g, 3.45 mmol) in 5 mL of absolute DMF were added dropwise 0.16 g of sodium hydride (6.67 mmol) in DMF (100 mL) over a period of 1 h. After cessation of gas generation, 0.26 mL of CH3I (3.89 mmole) was added dropwise and stirred at room temperature for overnight. The solvent was then evaporated under vacuum and the residue was poured into water, The separated solid was filtered, washed with water and dried under vacuum to afford 0.713 g of 2 (yield 72.6%). Preparation of N-benzyl-3-bromo-1-methyl-4-nitro-1H-pyrazol-5-amine (3): 3,5-dibromo-1-methyl-4-nitropyzole 2 (2.85 g 10 mmol) was heated in a solution of 10 mL of benzylamine for 6 h at 80° C. After cooling to room temperature, the reaction mixture was poured into water and the yellow solid formed. Then it was filtered, washed with water, dried and recrystallized from toluene to afford 3 g of 3 in yield of 96%. Preparation of 5-amino-1-methyl-4-nitro-1H-pyrazole-3-carbonitrile (4): A mixture of CuCN (0.135 g, 1.5 mmol) and 3 (0.312 g, 1 mmol) in solution of DMF (10 mL) were refluxed for 8 h before it was poured on water and filtered. The filtrate and the separated yellow solid, which was dissolved in concentrated ammonium hydroxide, were extracted by EtOAc. The organic layer was dried using Na2SO4 and purified by flash column chromatography (EtOAc: PE=2:1˜1:1) to afford 0.108 g of 4 in yield of 42%. Preparation of 4,5-diamino-3-cyano-1-methylpyrazole (5): A mixture 4 (0.257 g, 1 mmol) and 10% Pd/C (0.3 g) catalyst in 20 mL ethanol were stirred in hydrogen atmosphere at room temperature for 48 h. After filtration, the solvent was removed under reduced pressure to 2-3 mL before 98% H2SO4 was added dropwise until pH=1. The formed solid was filtered and washed with small amount of ethanol to afford 0.106 g of 5 in yield of 45%: 1HNMR (300 MHz, DMSO-d6) δ 3.00 (3H); 13CNMR (75 MHz, DMSO-d6) δ 35.9, 110.3, 114.2, 114.5, 138.4; MS (EI) 137.
Reaction SMILES: NC1C2C(=[O:16])C3C(=CC=CC=3)C(=O)C=2C=CC=1.[NH2:18][C:19]1[C:32]2[C:31](=[O:33])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24](=[O:34])[C:23]=2[C:22](Br)=[CH:21][C:20]=1[Br:36].B(O)(O)O>S(=O)(=O)(O)O>[NH2:18][C:19]1[C:32]2[C:31](=[O:33])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24](=[O:34])[C:23]=2[C:22]([OH:16])=[CH:21][C:20]=1[Br:36]
Reactant: Nc1c(Br)cc(Br)c2c1C(=O)c1ccccc1C2=O
Reactant: Nc1cccc2c1C(=O)c1ccccc1C2=O
Agent: O=S(=O)(O)O
Agent: OB(O)O
Product: Nc1c(Br)cc(O)c2c1C(=O)c1ccccc1C2=O

Procedure:
Further, German Offenlegungsschrift No. 28 17 890 discloses a one-vessel process and starting from 1-aminoanthraquinone, which is first converted by bromination into 1-amino-2,4-dibromoanthraquinone, which is in turn, without being isolated, reacted in sulfuric acid, in the presence of boric acid, to give 1-amino-2-bromo-4-hydroxyanthraquinone. The process is simple to perform and affords the desired product in good yield. The shortcoming of this process is, however, that the mixture of dilute sulfuric acid and boric acid formed during working up cannot be easily regenerated. For example, glassy residues are obtained and it is often necessary to neutralise the waste sulfuric acid, e.g. with calcium carbonate or slaked lime. In addition, the 1-amino-2-bromo-4-hydroxyanthraquinone obtained by this process is contaminated by compounds that are brominated in the 3-position. Such impurities result in changes in shade during the dye synthesis, i.e. standard shade dyes are not obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][CH:14]([CH:17]([CH3:23])[C:18](OCC)=[O:19])[CH2:13][CH2:12]1.CC(C[AlH]CC(C)C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[N:11]1[CH2:12][CH2:13][CH:14]([CH:17]([CH3:23])[CH2:18][OH:19])[CH2:15][CH2:16]1
Reactant: CCOC(=O)C(C)C1CCN(c2cc(OC)c(Cl)cc2Cl)CC1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: COc1cc(N2CCC(C(C)CO)CC2)c(Cl)cc1Cl
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 106.5 %

Procedure:
A solution of ethyl 2-(1-(2,4-dichloro-5-methoxyphenyl)piperidin-4-yl)propanoate (94 mg, 0.26 mmol) in anhydrous THF (2.0 mL) was placed under nitrogen atmosphere, cooled to −10° C., and treated with DIBAL-H (0.780 mL of a 1.0 M solution in THF, 0.780 mmol). After 30 min, the cooling bath was removed and the reaction warmed to RT where it stirred for 2 h. After this time, the mixture was quenched by adding EtOAc (3 mL) and stirred vigorously for 20 min. The pH of the mixture was adjusted to pH 6 using 1 M HCl. Once at the prescribed pH, EtOAc (20 mL) was added and the mixture was stirred at RT overnight. At the conclusion of this period, the organic phase was separated, washed with brine, dried (MgSO4) and concentrated to give 2-(1-(2,4-dichloro-5-methoxyphenyl)piperidin-4-yl)propan-1-ol (88 mg, 0.277 mmol, quantitative) as a yellow oil. LC-MS: 318.19, [M+H]; tR=3.89 min (method b). 1H-NMR (400 MHz, CDCl3) δ ppm 7.32 (1 H, s), 6.59 (1 H, s), 3.87 (3 H, s), 3.62-3.69 (1 H, m), 3.52-3.59 (1 H, m), 3.36-3.44 (2 H, m), 2.53-2.63 (2 H, m), 1.70-1.78 (2 H, m), 1.54-1.62 (3 H, m), 1.49-1.53 (1 H, m), 0.96 (3 H, d, J=6.80 Hz).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH2:12][CH2:13][C:14](=O)[CH3:15])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Br:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:18][C:19]1[CH:25]=[CH:24][C:22]([N:23]2[C:11]([C:8]3[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=3)=[CH:12][CH:13]=[C:14]2[CH3:15])=[CH:21][CH:20]=1
Reactant: Nc1ccc(Br)cc1
Reactant: CC(=O)CCC(=O)c1ccc(S(C)(=O)=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(Br)cc1
Yield: 54.3 %

Procedure:
A mixture of 1-[4-(methylsulfonyl)phenyl]pentane-1,4-dione (3 g, 11.8 mmol), 4-bromoaniline (2.03 g, 11.8 mmol), and p-toluenesulfonic acid (150 mg) in toluene (250 mL) was heated at reflux temperature using Dean-Stark apparatus. After cooling down, volatiles were removed by evaporation. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate/hexane (1/3) to give the subtitle compound (2.5 g, 54% yield).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[N:3]=1.[CH3:20][Mg]Cl>C1COCC1>[CH3:1][C:2]1[C:7]([CH:8]([OH:9])[CH3:20])=[CH:6][CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:19])[F:18])=[CH:12][CH:11]=2)[N:3]=1
Reactant: C[Mg]Cl
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1C=O
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1C(C)O

Procedure:
0.470 g (1.77 mmol) of the above prepared 2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine-3-carbaldehyde was dissolved in 9 ml of abs. THF and treated at −10° C. with 0.89 ml of 3M methyl magnesium chloride solution (in THF). After 15 Min., the reaction mixture was carefully poured onto crashed ice/NH4Cl, extracted twice with AcOEt, washed with water and brine, dried over sodium sulfate, and evaporated to dryness to leave 0.508 g of the title product, pure according to NMR.
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][CH:9]([C:44]([F:47])([F:46])[F:45])[CH2:10][C:11]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][C:12]=1[CH2:13][NH:14][C:15](=[O:38])[C@@H:16]1[CH2:20][CH2:19][CH2:18][N:17]1[C:21](=[O:37])[C@H:22]([NH:29]C(OC(C)(C)C)=O)[CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>C(Cl)Cl>[NH2:29][C@H:22]([CH:23]1[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1)[C:21]([N:17]1[CH2:18][CH2:19][CH2:20][C@H:16]1[C:15]([NH:14][CH2:13][C:12]1[CH:39]=[C:40]([Cl:43])[CH:41]=[CH:42][C:11]=1[CH2:10][CH:9]([NH2:8])[C:44]([F:46])([F:47])[F:45])=[O:38])=[O:37]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1CC(N)C(F)(F)F)C1CCCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(Cc1ccc(Cl)cc1CNC(=O)[C@@H]1CCCN1C(=O)[C@H](N)C1CCCCC1)C(F)(F)F

Procedure:
TFA (2.5 mL) was added to a stirred solution of N-[2-(2-amino-3,3,3-trifluoropropyl)-5-chlorobenzyl]-1-{(2R)-2-[(tert-butoxycarbonyl)amino]-2-cyclohexylethanoyl}-L-prolinamide (0.282 g, 0.48 mmol) in CH2Cl2 (5 mL) and after 1 h the solvent was evaporated in vacuo and the residue was partitioned between EtOAc and saturated aqueous Na2CO3. The organic layer was dried (Na2SO4) and evaporated in vacuo to give the title compound as a foam; MS m/z=489.6.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH:16]=[CH:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[CH:61]=[CH:60][C:53]2[NH:54][C:55]([C@@H:57]([NH2:59])[CH3:58])=[N:56][C:52]=2[CH:51]=1.ClCl>O1CCCC1.ClCCl.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH:16]=[CH:15][CH2:14]1)=[O:12])[C:5]([NH:59][C@H:57]([C:55]1[NH:54][C:53]2[CH:60]=[CH:61][C:50]([Cl:49])=[CH:51][C:52]=2[N:56]=1)[CH3:58])=[O:7]
Reactant: O=C(O)c1ccc(C(=O)N2CC=CC2)c(Cl)c1
Reactant: C[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCO
Solvent: C1CCOC1
Product: C[C@H](NC(=O)c1ccc(C(=O)N2CC=CC2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1 g from 3-chloro-4-(2,5-dihydropyrrol-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and (1S)-1-(5-chloro-1H-benzimidazol-2-yl)ethylamine in tetrahydrofuran. Yield: quantitative; Rf value: 0.50 (silica gel: dichloromethane/ethanol=9:1); C21H18Cl2N4O2 (429.305); mass spectrum: (M+H)+=429/431/433 (chlorine isotope).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([OH:14])(=[O:13])=[O:12].[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.Cl>>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:3]([S:11]([OH:14])(=[O:13])=[O:12])[CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)O)c1
Reactant: C1CCNC1
Agent: Cl
Product: O=[N+]([O-])c1ccc(N2CCCC2)c(S(=O)(=O)O)c1
Temperature: 0 °C
Reaction time: 7 h

Procedure:
72.4 Grams 2-chloro-5-nitrobenzenesulfonic acid was added in portions to 134 ml pyrrolidine, while keeping the temperature below 65° C. After the addition, the reaction was heated at reflux temperature with stirring for 7 hours and allowed to stand overnight at room temperature. The reaction was poured into 800 ml ice water and the solution made strongly acidic with concentrated HCl until light yellow crystals separated. The product was filtered, washed with a little dilute HCl and the moist cake was recrystallized from about 800 ml water to give 70.7 grams 5-nitro-2-pyrrolidinylbenzenesulfonic acid. m.p. = 178°-179° C. The nitro compound was reduced catalytically in ethanol with 5% palladium on carbon catalyst to give 5-amino-2-pyrrolidinyl-benzenesulfonic acid. m.p. = 255°-256° C.
Reaction SMILES: [C:1]([C:3]1[C:8]([NH:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[NH:11][C:12]([NH:14]C(=O)C1C=CC=CC=1)=[O:13])#[N:2].[OH-].[Na+]>CCO>[NH2:2][C:1]1[C:3]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[NH:9][CH3:10])[NH:11][C:12](=[O:13])[N:14]=1
Reactant: CNc1cccc(NC(=O)NC(=O)c2ccccc2)c1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CNc1cccc2[nH]c(=O)nc(N)c12
Temperature: 25 °C
Yield: 56.3 %

Procedure:
A solution of N-(2-cyano-3-(methylamino)phenylcarbamoyl)benzamide (Example 157a) (0.05 g, 0.17 mmol) and NaOH (2N, 0.17 mL) in EtOH (6 mL) was stirred at 90° C. under nitrogen for half an hour. The reaction mixture was cooled down to room temperature, and concentrated under vacuum. H2O (1 mL) was added and the reaction mixture was neutralized to pH˜4 with 10% AcOH. The resultant precipitation was filtered and dried under vacuum. The crude product was purified by preparative thin layer chromatography using a DCM/MeOH (9:1) solution as eluant, to give 4-amino-5-(methylamino)quinazolin-2(1H)-one (18.2 mg, 56%). 1H NMR (400 MHz, DMSO-d6) δ 2.76 (s, 3H), 6.10 (d, J=7.6 Hz, 1H), 6.12 (d, J=8 Hz, 1H), 7.13 (t, J=8 Hz, 1H), 7.25 (bs, NH), 9.66 (bs, NH) 10.13 (bs, 2H). MS 191 (MH+).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[O:11])[CH:6]=[CH:7][CH:8]=1.[NH2:14][C:15]1[N:20]=[C:19]([O:21][C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[NH:27][CH2:26][CH2:25]3)[CH:18]=[C:17]([Cl:31])[N:16]=1>C1COCC1.CCOC(C)=O.O>[F:1][C:2]([F:12])([F:13])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:27]2[C:28]3[C:24](=[CH:23][C:22]([O:21][C:19]4[CH:18]=[C:17]([Cl:31])[N:16]=[C:15]([NH2:14])[N:20]=4)=[CH:30][CH:29]=3)[CH2:25][CH2:26]2)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: Nc1nc(Cl)cc(Oc2ccc3c(c2)CCN3)n1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1nc(Cl)cc(Oc2ccc3c(c2)CCN3C(=O)Nc2cccc(C(F)(F)F)c2)n1
Reaction time: 0.5 h

Procedure:
A solution of 226 mg (1.21 mMol) 3-trifluoromethyl-phenylisocyanat in 5 ml THF is added dropwise to 302 mg (1.15 mMol) 5-(2-amino-6-chloro-pyrimidin-4-yloxy)-2,3-dihydro-indole (Step 24.2) in 5 ml THF. After 30 min, the reaction mixture is diluted with EtOAc and water, the aqueous layer separated off and extracted twice with EtOAc. The organic phases are washed with water and brine, dried (Na2SO4) and concentrated. Chromatography (Combi Flash; EtOAc/hexane 1:4→2:5) gives the title compound: MS: [M+1]+=450; TLC(hexane/EtOAc 3:2): Rf=0.08; HPLC: AtRet=15.6.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH:8]1[C:13]([OH:14])=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:15].[OH-].[Na+]>C(O)C>[CH2:2]([O:14][C:13]1[CH:8]=[C:9]([CH3:15])[CH:10]=[CH:11][CH:12]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: Cc1cccc(O)c1
Reactant: CCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCOc1cccc(C)c1
Yield: 90.5 %

Procedure:
1-Bromohexane (45.0 g) is added to a solution of m-cresol (24.55 g), ethanol (500 ml) and 2N sodium hydroxide (113.5 ml), and the resulting mixture heated under reflux for 24 hours. The solution is then concentrated in vacuo and the residue extracted with ether (3×200 ml). The ether extracts are dried over magnesium sulfate, filtered, and concentrated to a dark brown oil, which is distilled in vacuo (b.p. 72° C., 0.05 mm Hg) to yield 3-n-hexyloxytoluene (39.5 g).
Reaction SMILES: CS([O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([Br:24])=[CH:11][CH:12]=[C:13]2[NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:8][CH:7]=1)(=O)=O.[OH-].[Na+].Cl>C1COCC1>[Br:24][C:10]1[C:9]2[C:14](=[CH:15][C:6]([OH:5])=[CH:7][CH:8]=2)[C:13]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:12][CH:11]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Br)c2ccc(OS(C)(=O)=O)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(Br)c2ccc(O)cc12

Procedure:
A solution of 4-bromo-1-tert-butoxycarbonylaminonaphth-7-yl methanesulfonate, as described above in Step B, (2.00 g, 4.80 mmol) in THF (50 mL) and 10% aqueous NaOH (85 mL) was heated to 65° C. for 60 hours. The cooled mixture was adjusted to pH of about 7 by addition of conc. aqueous HCl and concentrated to dryness under reduced pressure to provide the desired phenol.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH:9]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:4]=2[C:3]=1[C:16]([O:18]CC)=O.[CH:21]([NH2:23])=O>>[OH:18][C:16]1[C:3]2[C:4]3[CH:9]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][CH2:7][C:5]=3[S:6][C:2]=2[N:1]=[CH:21][N:23]=1
Reactant: CCOC(=O)CC1CCc2sc(N)c(C(=O)OCC)c21
Reactant: NC=O
Product: CCOC(=O)CC1CCc2sc3ncnc(O)c3c21
Temperature: 180 °C
Reaction time: 5 h
Yield: 43 %

Procedure:
To a 10-L 4-necked round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was added a solution of 15.2 (500 g, 1.68 mol, 1.00 equiv) in formamide (5 L) at room temperature. The resulting solution was stirred for 5 h at 180° C. in an oil bath. The reaction mixture was cooled to room temperature and then quenched by the addition of 10 L of water/ice. The resulting solution was extracted with 3×5 L of ethyl acetate and the organic layers were combined. The mixture was washed with 3×3000 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The solids were collected by filtration to afford 200 g (43%) of ethyl 2-[12-hydroxy-7-thia-9,11-diazatricyclo[6.4.0.0^[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]acetate (15.3) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]([N:12]([CH3:16])[C:13](=[O:15])[CH:14]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH:17]1[CH2:23][CH2:22][CH2:21][CH:20]=[CH:19][CH:18]=1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]23[CH:19]4[CH2:20][CH2:21][CH2:22][CH:23]([CH:17]=[CH:18]4)[CH:14]2[C:13](=[O:15])[N:12]([CH3:16])[C:10]3=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN1C(=O)C=C(c2ccc(Cl)c(Cl)c2)C1=O
Reactant: C1=CCCCC=C1
Solvent: ClCCl
Product: CN1C(=O)C2C3C=CC(CCC3)C2(c2ccc(Cl)c(Cl)c2)C1=O
Temperature: 180 °C

Procedure:
A mixture of 0.7 g (0.0027 mole) of 2-(3,4-dichlorophenyl-N-methylmaleimide and 5.0 g (0.05 mole) of 1,3-cycloheptadiene in a pressure vessel was heated in an oil bath at a bath temperature of 180° C. for 24 hours. The reaction vessel was cooled to room temperature and the contents were dissolved in and removed with the aid of dichloromethane and acetone. The solution was concentrated in vacuo and gave a tacky glass. The glass was dissolved in dichloromethane and filtered through hydrous magnesium silicate. The filtrate was again concentrated in vacuo and gave a glass. The glass was dissolved in dichloromethane and was chromatographed on a Waters Prep 500A LC, using a silica gel column and eluting with 10% ethyl acetate/hexane and gave 0.56 g of 3a-(3,4-dichlorophenyl)-3a,4,7,7a-tetrahydro-2-methyl-4,7-propano-1H-isoindol-1,3(2H)-dione as a yellow glass, mp 110°-115° C., mass spectrum, m/e 349.
Reaction SMILES: [CH:1](=[O:3])[CH3:2].[C:4](#[N:7])[CH:5]=[CH2:6].[OH-].[Na+]>>[CH:1]([CH:2]([CH2:6][CH2:5][C:4]#[N:7])[CH2:6][CH2:5][C:4]#[N:7])=[O:3]
Reactant: C=CC#N
Reactant: CC=O
Agent: [Na+]
Agent: [OH-]
Product: N#CCCC(C=O)CCC#N
Yield: 40 %

Procedure:
In the presence of alkaline catalysts, acrylonitrile reacts with aldehydes, the α-carbon atoms of which possess one or two hydrogen atoms, forming 3-substituted propionitriles (U.S. Pat. No. 2,353,687). This so-called "cyanoethylation" reaction also occurs with other compounds which have an active hydrogen atom. For example, 2-ethyl butyraldehyde and acrylonitrile react in the presence of catalytic amounts of 50 percent caustic potash solution forming 2-(β-cyanoethyl)-2-ethyl butyraldehyde. A yield of 76.6 percent results after a reaction period of 4.5 hours. (H. A. Bruson, Th. W. Riener, J. Am. Chem. Soc., 66, 57 [1944]). The reaction is strongly exothermal. Acetaldehyde reacts with acrylonitrile in the presence of a 50 percent caustic soda solution forming γ-formylpimelonitrile. For a yield of 40-50%, the reaction period amounts to 2-3 hours. Under the same conditions, propionaldehyde forms 4.9 percent 2-methyl-4-cyanobutyraldehyde (U.S. Pat. No. 2,409,086). 2,2-dimethyl-4-cyano-butyraldehyde is formed in up to 60 percent yield from the reaction between isobutyraldehyde and acrylonitrile.
Reaction SMILES: [CH:1]12[CH2:6][CH:5]1[C:4](=[O:7])[O:3][C:2]2=O.[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O>C(O)(=O)C>[CH2:9]([N:16]1[C:4](=[O:7])[CH:5]2[CH:1]([CH2:6]2)[C:2]1=[O:3])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C1OC(=O)C2CC12
Reactant: NCc1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: O=C1C2CC2C(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
3-oxabicyclo[3.1.0]hexane-2,4-dione (23-1) (20 g, 0.179 mol) was dissolved in acetic acid (100 mL), and benzylamine (28.8 g, 0.269 mol) was added dropwise under cooling in a water bath, after the completion of addition, the temperature was raised to reflux and stirred overnight. The reaction mixture was cooled to room temperature, poured into 1 L of water to precipitate large amount of white solid, filtered, and the filter cake was recrystallized from isopropanol to give Compound 23-2 (27 g).
Reaction SMILES: [CH2:1]([N:3]([OH:34])/[C:4](=[N:32]\[H])/[C:5](=[N:12]\[O:13][CH2:14][C:15]1[N:16]=[C:17]([NH:20]C(=O)OCCC2C=CC=CC=2)[S:18][CH:19]=1)/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:2].[C:35](N1C=CN=C1)(N1C=CN=C1)=[O:36]>C(#N)C>[NH2:20][C:17]1[S:18][CH:19]=[C:15]([CH2:14][O:13]/[N:12]=[C:5](/[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)\[C:4]2[N:3]([CH2:1][CH3:2])[O:34][C:35](=[O:36])[N:32]=2)[N:16]=1
Reactant: [H]/N=C(C(=N\OCc1csc(NC(=O)OCCc2ccccc2)n1)/c1ccccc1)\N(O)CC
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: CCn1oc(=O)nc1/C(=N\OCc1csc(N)n1)c1ccccc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 84.4 %

Procedure:
To a solution of 2-phenylethyl (4-{[({(1Z,2Z)-2-[ethyl(hydroxy)amino]-2-imino-1-phenylethylidene}amino)oxy]methyl}-1,3-thiazol-2-yl)carbamate (160 mg, 71% purity, 0.24 mmol, 1 eq.) in acetonitrile (3 ml), was added 1,1′-carbonyldiimidazole (555 mg, 0.342 mmol, 1.4 eq.). After stirring at 80° C. for 6 hour, the reaction was quenched by addition of water and extracted with EtOAc. The organics were combined, dried over MgSO4 and concentrated. The residue was purified by chromatography on silica gel to give 3-[(Z)-{[(2-amino-1,3-thiazol-4-yl)methoxy]imino}(phenyl)methyl]-2-ethyl-1,2,4-oxadiazol-5(2H)-one (70 mg, 55% yield).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[C:13]([Si:17](Cl)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:16])([CH3:15])[CH3:14].N1C=CN=C1>CN(C=O)C>[Si:17]([O:1][CH:2]1[CH2:3][CH2:4][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:7]1)([C:13]([CH3:16])([CH3:15])[CH3:14])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C1CCC(O)CC1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1

Procedure:
A solution of ethyl 4-hydroxycyclohexanecarboxylate (5 g), tert-butyl(chloro)diphenylsilane (8.30 mL) and imidazole (2.17 g) in DMF (50 mL) was stirred at room temperature overnight. The reaction mixture was extracted with ethyl acetate and water. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (12.2 g).
Reaction SMILES: C([O:4][CH:5]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]#[C:12][CH2:13][N:14]([CH3:18])[C:15](=[O:17])[CH3:16])[CH2:6]1)(=O)C.C(=O)([O-])[O-].[Na+].[Na+].CO>ClCCl>[OH:4][CH:5]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]#[C:12][CH2:13][N:14]([CH3:18])[C:15](=[O:17])[CH3:16])[CH2:6]1
Reactant: CC(=O)OC1CCN(CC#CCN(C)C(C)=O)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(=O)N(C)CC#CCN1CCC(O)C1
Reaction time: 8 h
Yield: 73.2 %

Procedure:
A mixture of 820 mg of (racemic)-N-[4-[3-(acetyloxy)-1-pyrrolidinyl]-2-butynyl]-N-methyl acetamide, 635 mg of sodium carbonate and 40 ml of methanol was stirred overnight. An equal volume of dichloromethane was added, the mixture filtered and the solvents concentrated. This residue was purified by chromatography (alumina), giving 500 mg of the desired product as a yellow oil.