Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:41])[N:5]([C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=1)[C:35]([NH2:37])=[O:36])[C:6]([CH:12]([NH:14][C:15]1[N:23]=[CH:22][N:21]=[C:20]3[C:16]=1[N:17]=[CH:18][N:19]3COCC[Si](C)(C)C)[CH3:13])=[N:7]2.OC1C=C(N2C(=O)C3C(=CC=CC=3C)N=C2C(NC2N=CN=C3C=2N=CN3)C)C=CC=1>CO>[CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:41])[N:5]([C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=1)[C:35]([NH2:37])=[O:36])[C:6]([CH:12]([NH:14][C:15]1[N:23]=[CH:22][N:21]=[C:20]3[C:16]=1[N:17]=[CH:18][NH:19]3)[CH3:13])=[N:7]2
Reactant: Cc1cccc2nc(C(C)Nc3ncnc4c3ncn4COCC[Si](C)(C)C)n(-c3cccc(C(N)=O)c3)c(=O)c12
Agent: Cc1cccc2nc(C(C)Nc3ncnc4[nH]cnc34)n(-c3cccc(O)c3)c(=O)c12
Solvent: CO
Product: Cc1cccc2nc(C(C)Nc3ncnc4[nH]cnc34)n(-c3cccc(C(N)=O)c3)c(=O)c12

Procedure:
Compound 143 was treated with 4N HCL in MeOH for 1.5 hours using the procedure described for compound 121 (step D) to provide compound 142. m/z=441 (M+H). The structure of compound 142 is shown below.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-])=O)[CH2:3]1>CO.[Pd]>[CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH2:17])[CH2:3]1
Reactant: CC1(C)CN(c2ccccc2[N+](=O)[O-])c2ccccc21
Agent: [Pd]
Solvent: CO
Product: CC1(C)CN(c2ccccc2N)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.3 %

Procedure:
To a solution of 2d (123 mg, 0.458 mmol) in MeOH was added 10% Pd/C (20 mg). The reaction mixture was stirred at rt under H2 for 2 h. The catalyst was filtered through a cake of Celite® and the filtrate was evaporated under reduced pressure to afford 2e (80 mg, 75%) as a yellowish powder. MS (ES) m/z 239 [M+H]+.
Reaction SMILES: Cl.C(OC([NH:9][C@H:10]1[CH2:16][S:15][CH:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)[CH2:13][NH:12][C:11]1=[O:22])=O)(C)(C)C.C(OCC)C>O1CCOCC1>[NH2:9][C@H:10]1[CH2:16][S:15][CH:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)[CH2:13][NH:12][C:11]1=[O:22]
Reactant: CC(C)(C)OC(=O)N[C@H]1CSC(c2cccs2)CNC1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: N[C@H]1CSC(c2cccs2)CNC1=O
Reaction time: 1 h

Procedure:
319 ml of a 4N solution of hydrogen chloride in dioxane were added to 102 g of 6(R)-t-butoxycarbonylamino-5-oxo-2-(2-thienyl)perhydro-1,4-thiazepine [prepared as described in step (c) above], and the mixture was stirred for 1 hour, with ice-cooling. 500 ml of diethyl ether were then added and the resulting crystals (a yield of 82.3 g) were collected. These crystals were suspended in a mixture of 2 liters of methylene chloride and 0.1 liter of methanol, and a solution of 70 g of potassium carbonate in 200 ml of water was added to the suspension, and the mixture was then stirred for 2 hours. The resulting precipitate was filtered off, and the organic layer was separated from the aqueous layer. The precipitate was dissolved in 200 ml of water, and this solution was combined with the aqueous layer; the mixture was extracted twice, each time with 220 ml of 10% v/v methanol in methylene chloride. The organic layer and the extracts were combined and dried over anhydrous magnesium sulfate, after which sufficient solvent was evaporated off to reduce the volume to about 300 ml. 500 ml of ethyl acetate were added to the residue, and then sufficient of the solvent was evaporated off to reduce the volume to about 400 ml. The residue was left standing at room temperature overnight, and then the precipitated crystals were collected by filtration, to give 19.1 of the title compound, melting at 157° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)[CH:5]=[N:4][CH:3]=1.N.[BH3-]C#[N:18].[Na+].Cl>CO>[ClH:1].[Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([NH2:18])[CH2:10][CH2:9]2)[CH:5]=[N:4][CH:3]=1
Reactant: O=C1CCN(c2cncc(Cl)n2)CC1
Reactant: [BH3-]C#N
Agent: Cl
Agent: N
Agent: [Na+]
Solvent: CO
Product: NC1CCN(c2cncc(Cl)n2)CC1
Reaction time: 60 h

Procedure:
To a solution of 17.1 g (81 mmol) 6-chloro-2-(4-oxopiperidino)pyrazine in 250 ml methanol which has been saturated with gaseous NH3 is added 62.4 g (0.81 mol) NH4OAc and 5.0 g (80 mmol) NaCNBH3. After stirring at 20°-25° C. for 60 hours, the MeOH is removed in vacuo. Water is added to the residue, and the pH is adjusted to 14. The product is extracted into ethyl acetate which is dried and concentrated. Chromatography of the residue over silica gel, eluting with 5% MeOH/CHCl3 saturated with NH3, gives the product base which is converted to the hydrochloride salt with ethanolic HCl. Recrystallization from water/acetone affords the desired product, m.p. 291° C. (dec.).
Reaction SMILES: [BH4-].[Na+].[CH:3]([C:5]1[CH:6]=[CH:7][C:8]2[N:9]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[CH:28][C:27]([N:30]5[C:42]6[CH:41]=[CH:40][C:39]([CH:43]=[O:44])=[CH:38][C:37]=6[C:36]6[C:31]5=[CH:32][CH:33]=[CH:34][CH:35]=6)=[CH:26][CH:25]=4)=[CH:20][CH:19]=3)[C:10]3[C:15]([C:16]=2[CH:17]=1)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:4].C(O)C.ClCCl.Cl>C1COCC1.CCO.O>[OH:44][CH2:43][C:39]1[CH:40]=[CH:41][C:42]2[N:30]([C:27]3[CH:28]=[CH:29][C:24]([C:21]4[CH:20]=[CH:19][C:18]([N:9]5[C:8]6[CH:7]=[CH:6][C:5]([CH2:3][OH:4])=[CH:17][C:16]=6[C:15]6[C:10]5=[CH:11][CH:12]=[CH:13][CH:14]=6)=[CH:23][CH:22]=4)=[CH:25][CH:26]=3)[C:31]3[C:36]([C:37]=2[CH:38]=1)=[CH:35][CH:34]=[CH:33][CH:32]=3
Reactant: O=Cc1ccc2c(c1)c1ccccc1n2-c1ccc(-c2ccc(-n3c4ccccc4c4cc(C=O)ccc43)cc2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: OCc1ccc2c(c1)c1ccccc1n2-c1ccc(-c2ccc(-n3c4ccccc4c4cc(CO)ccc43)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Sodium borohydride (2.40 g, 63.4 mmol)) was added to the 4,4′-bis(3-formyl-carbazol-9-yl)biphenyl (3.42 g, 6.33 mmol) in THF (1.2 L) and the resulting suspension was stirred at room temperature for 24 h. (The reaction was followed by TLC using 5% ethanol/dichloromethane as the eluent). Once the reaction was complete, the mixture was slowly poured into water (400 ml) and the mixture was left to stir at room temperature for a further 30 min. The reaction mixture was acidified to pH 1 with hydrochloric acid (5M). The product was extracted with dichloromethane (3×300 ml). The combined organic phase was washed with water (400 ml) and brine (400 ml), dried (MgSO4), filtered and the filtrate evaporated to dryness. The crude product, was purified by chromatography on silica using 50% THF/toluene as the eluent. The product was recrystallised from ethanol to give 4,4′-bis(3-(hydroxymethyl)carbazol-9-yl) as a pale yellow solid (3.22 g, 94%) with m.p. 268° C. (dec.). Found: C, 82.51; H, 4.64; and N, 4.86. C38H28N2O2.EtOH requires C, 81.33; H, 5.80; N, 4.74%). 1H n.m.r. (300 MHz, Me0SO): δ 8.23 (2 H, d, J 7.61 Hz, aromatic H); 8.18 (2H, s, aromatic H); 8.06 (4H, d, J 8, 19 Hz, aromatic H); 7.75 (4H, J 8, 19 Hz, aromatic H); 7.38-7.50 (8H, m, aromatic H), 7.29 (2H, m, aromatic H); 5.25 (2H, t, J 5.58 Hz, OH); 4.68 (4H, d, J 5.56 Hz, CH2). λmax(CH2Cl2): 216 nm (ε/Lmol−1 cm−1 177 455), 240 (57 873), 271 (56 595), 294 (55 330) 329 (37 758). FTIR (solid): 3343, 1604, 1500, 1485, 1455, 1362, 1330, 1230, 803, 745 cm−1.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]2[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:4]=2[O:3]1.ClC1C=CC=C(C(OO)=[O:30])C=1>ClCCl>[CH3:1][C:2]1([CH3:21])[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N+:9]=2[O-:30])[C:5]2[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:4]=2[O:3]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1(C)CC(c2ccccn2)c2cc([N+](=O)[O-])ccc2O1
Solvent: ClCCl
Product: CC1(C)CC(c2cccc[n+]2[O-])c2cc([N+](=O)[O-])ccc2O1
Yield: 30.9 %

Procedure:
245 mg of 3,4-dihydro-2,2-dimethyl-6-nitro-4-(2-pyridyl)-2H-1-benzopyran were dissolved in 5 ml of dichloromethane at room temperature and 149 mg of m-chloroperbenzoic acid were added. After stirring at room temperature for 3 days further m-chloroperbenzoic acid was added until starting material could no longer be detected by thin-layer chromatography. The mixture was washed in succession with sodium bisulphite solution, sodium bicarbonate solution and sodium chloride solution, dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using 4% (v/v) ethanol/dichloromethane for the elution and the resulting foam was triturated with n-hexane to give 80 mg of 2-(3,4-dihydro-2,2-dimethyl-6-nitro-2H-1-benzopyran-4-yl)pyridine N-oxide of melting point 116-119° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]2[CH:7]=[C:8]([C:12]([OH:14])=[O:13])[S:9][C:10](=[O:11])[C:5]=2[CH:4]=1.C(=O)(O)[O-].[Na+:21]>O>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]2[CH:7]=[C:8]([C:12]([O-:14])=[O:13])[S:9][C:10](=[O:11])[C:5]=2[CH:4]=1.[Na+:21]
Reactant: COc1ccc2cc(C(=O)O)sc(=O)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COc1ccc2cc(C(=O)[O-])sc(=O)c2c1
Reaction time: 1.25 h

Procedure:
To a stirred suspension of 2.0347 g. (8.613 mM) of 7-methoxy-1-oxo-1H-2-benzothiopyran-3-carboxylic acid in 50 ml. of distilled water is added 0.7236 g. (8.613 mM) of sodium bicarbonate. The resulting mixture is stirred at 25°-35° for 1.25 hours, filtered, and the filtrate freeze-dried to give sodium 7-methoxy-1-oxo-1H-2-benzothiopyran-3-carboxylate as a pale yellow solid, m.p. >350°.
Reaction SMILES: [C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)=[C:8]([N:17]2[CH2:21][CH2:20][CH2:19][C:18]2=[O:22])[C:7]([CH3:23])=[C:6]([Cl:24])[CH:5]=1)(=O)[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:31].[Na+]>CO.C(#N)C>[NH2:31][CH:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)=[C:8]([N:17]2[CH2:21][CH2:20][CH2:19][C:18]2=[O:22])[C:7]([CH3:23])=[C:6]([Cl:24])[CH:5]=1)[CH3:2]
Reactant: [BH3-]C#N
Reactant: CC(=O)c1cc(Cl)c(C)c(N2CCCC2=O)c1-c1cccc(F)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: Cc1c(Cl)cc(C(C)N)c(-c2cccc(F)c2)c1N1CCCC1=O
Temperature: 65 °C

Procedure:
A mixture of 1-(6-acetyl-4-chloro-3′-fluoro-3-methylbiphenyl-2-yl)pyrrolidin-2-one (40 mg, 0.1 mmol) and ammonium acetate (89 mg, 1.2 mmol) and sodium cyanoborohydride (15 mg, 0.23 mmol) in methanol (0.4 mL) and acetonitrile (0.4 mL) was heated at 65° C. overnight in a sealed tube. The mixture was cooled to room temperature and quenched with saturated sodium bicarbonate and extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness. The crude product was used directly in next step (34 mg, 80%). LCMS calculated for C19H18ClFNO (M−NH2)+: m/z=330.1. found: 330.0.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)=[O:4].C[Si](C)(C)[N-][Si](C)(C)C.[K+].[CH2:28](Br)[CH:29]=[CH2:30]>C1COCC1>[CH2:30]([C:5]1([C:3]([O:2][CH3:1])=[O:4])[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10]1)[CH:29]=[CH2:28]
Reactant: C=CCBr
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCC1(C(=O)OC)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.5 %

Procedure:
To a −78° C. solution of N-Boc-4-piperidinecarboxylic acid methyl ester (5.70 g, 23.4 mmol) in THF (80 mL) was added potassium hexamethyldisilazide (0.5 M in toluene, 70.2 mL, 35.1 mmol). After 2 h allyl bromide (6.69 mL, 77.3 mmol) was added, the reaction stirred at this temperature for 0.5 h, then warmed to 0° C. After 3 h the reaction was quenched by the addition of saturated aqueous ammonium chloride and extracted with dichloromethane (3×). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of 0 to 8% methanol:dichloromethane to give the title compound (6.0 g). MS: m/z=284.2 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][O:9][N:10]=[C:11]([C:15]1[N:19]=[C:18]([NH2:20])[S:17][N:16]=1)[C:12]([OH:14])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].O1CCCC1.[C:26]1([C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[N+]=[N-])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(OCC)(=O)C>[C:1]([O:5][C:6]([CH2:8][O:9][N:10]=[C:11]([C:15]1[N:19]=[C:18]([NH2:20])[S:17][N:16]=1)[C:12]([O:14][CH:32]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)O)c1nsc(N)n1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CON=C(C(=O)OC(c1ccccc1)c1ccccc1)c1nsc(N)n1

Procedure:
To a solution of 2-tert-butoxycarbonylmethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid (syn isomer (20 g) in ethyl acetate (200 ml) and tetrahydrofuran (100 ml) was added dropwise a solution of diphenyldiazomethane in ethyl acetate (0.9 m mole/ml, 80 ml) at ambient temperature, and the mixture was stirred for an hour. The reaction mixture was washed with a saturated aqueous sodium bicarbonate and an aqueous sodium chloride, and then dried over magnesium sulfate. The solution was evaporated to give benzhydryl 2-tert-butoxycarbonylmethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetate (syn isomer) (15.0 g), mp 164° C. (dec.).
Reaction SMILES: [Br:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[OH:8].N1C=CN=C1.[CH3:14][C:15]([Si:18](Cl)([CH3:20])[CH3:19])([CH3:17])[CH3:16].O>CN(C=O)C>[Br:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[O:8][Si:18]([C:15]([CH3:17])([CH3:16])[CH3:14])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O[C@@H]1CCCC[C@H]1Br
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CCCC[C@H]1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.2 %

Procedure:
To a solution (1R*,2R*)-2-bromocyclohexanol (27 g, 0.151 mol) of and imidazole (24.9 g, 0.366 mol) in DMF (500 mL) was added TBSCl (24.9 g, 0.166 mol), the reaction mixture was stirred overnight at rt. Water was added and extracted by EtOAc three times. The combined organic layers were dried, filtered, and concentrated to give ((1R*,2R*)-2-bromocyclohexyloxy)(tert-butyl)dimethylsilane (32 g, 72%). 1H NMR (CDCl3, 400 MHz) δ 0.05-1.05 (d, 6H), 0.90 (s, 9H), 1.20-1.40 (m, 3H), 1.60-1.85 (m, 3H), 1.98-2.10 (m, 1H), 2.25-2.40 (m, 1H), 3.63-3.73 (m, 1H), 3.85-3.97 (m, 1H).
Reaction SMILES: Cl.CO.[Na].ClCC(N)=O.[CH3:10][O:11][C:12]([C:14]1(O)[C:26]2[CH:25]=[C:24](F)[CH:23]=[CH:22][C:21]=2[C:20]2[C:15]1=[CH:16][C:17](F)=[CH:18][CH:19]=2)=[O:13].[OH-].[Na+]>CO>[CH3:10][O:11][C:12]([CH:14]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=2[C:21]2[C:26]1=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:13]
Reactant: COC(=O)C1(O)c2cc(F)ccc2-c2ccc(F)cc21
Agent: Cl
Agent: NC(=O)CCl
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1c2ccccc2-c2ccccc21
Reaction time: 0.25 h

Procedure:
9H-fluoren-9-carboxylic acid methyl ester (19), which was prepared by refluxing 9-Hfluoren-9-carboxylic acid (Aldrich Chemical, Inc.) in HCl/MeOH, (10.0 g, 44.6 mmol) was added to a solution of sodium (1.2 eq, 53.5 mmol, 1.23 g) in 100 mL methanol. After 15 min., 2-chloroacetamide (1.1 eq, 4.59 g) was added and the mixture was allowed to stir at room temperature under nitrogen for two (2) days. The reaction mixture was poured into 400 mL of cold 2.5% w/v aqueous sodium hydroxide and the insoluble material was removed by filtration. The filtrate was chilled and acidified with concentrated hydrochloric acid to precipitate the spiro-succinimide which was collected and air dried to provide 6.7 g (60%). Recrystallization from methanol gave purified (20), 4.28 g (39%). m.p. 237°-239° C. Calc. % C 77.09, % H 4.45, % N 5.62:meas. % C 77.17, % H 4.55, % N 5.58.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[N+:5]([C:8]1[CH:9]=[CH:10][C:11]2[O:16][CH2:15][CH2:14][NH:13][C:12]=2[CH:17]=1)([O-:7])=[O:6].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([N:13]1[C:12]2[CH:17]=[C:8]([N+:5]([O-:7])=[O:6])[CH:9]=[CH:10][C:11]=2[O:16][CH2:15][CH2:14]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: O=[N+]([O-])c1ccc2c(c1)NCCO2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)N1CCOc2ccc([N+](=O)[O-])cc21
Reaction time: 1 h
Yield: 90 %

Procedure:
Under vigorous stifling at room temperature, acetyl chloride (1.02 g, 13 mmol) was added dropwise to a mixture of 6-nitro-3,4-dihydro-2H-benzo[1,4]oxazine (1.8 g, 10 mmol) and NaHCO3 (7.14 g, 85 mmol) in CH2Cl2 (50 mL). After addition, the reaction was stirred for 1 h at this temperature. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was treated with Et2O:hexane (1:2, 50 mL) under stifling for 30 min and then filtered to give 4-acetyl-6-nitro-3,4-dihydro-2H-benzo[1,4]oxazine as a pale yellow solid (2 g, 90%).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:15]([O:17][CH3:18])=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][CH:5]=1.[ClH:29]>CO.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[NH2:1][C@H:2]([C:15]([O:17][CH3:18])=[O:16])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[CH:8][CH:9]=1.[ClH:29]
Reactant: COC(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Product: COC(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1

Procedure:
300 g (778 mmoles) of Z-Tyr(But)-OMe (Ann. Chem. 696, 226 (1966)) are dissolved in 1 liter of methanol and hydrogenated catalytically (Pd/BaSO4 catalyst) at pH 4.5, using an auto-burette (about 2 N methanolic HCl being added). After completion of hydrogenation, the catalyst is filtered off and the filtrate is concentrated. The residue is triturated with ether.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12][N:11]=[C:10]([C:13]3[CH:14]=[C:15]([C:19]#[C:20][CH2:21][OH:22])[CH:16]=[CH:17][CH:18]=3)[CH2:9]2)=[CH:4][CH:3]=1.[H-].COCCO[Al+]OCCOC.[Na+].[H-].Cl>CCOCC.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[O:12][N:11]=[C:10]([C:13]3[CH:14]=[C:15](/[CH:19]=[CH:20]/[CH2:21][OH:22])[CH:16]=[CH:17][CH:18]=3)[CH2:9]2)=[CH:6][CH:7]=1
Reactant: OCC#Cc1cccc(C2=NOC(c3ccc(F)cc3)C2)c1
Agent: COCCO[Al+]OCCOC
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: OC/C=C/c1cccc(C2=NOC(c3ccc(F)cc3)C2)c1
Temperature: 25 °C
Yield: 77.3 %

Procedure:
The acetylenic alcohol product of Example 33, Step 2 (14, 2.2 g, 7.4 mmol) was dissolved in ether (20 ml) and treated dropwise with a solution of 3.2 ml of sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al, 3.2 ml, 70% in toluene) in toluene (10 ml) under a nitrogen atmosphere. The reaction mixture was refluxed for 2 hours, allowed to cool to room temperature and then a solution of aqueous 1N HCl (50 ml) was carefully added. The mixture was filtered and insolubles washed with ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (30 ml×2). The combined organic phases were washed with aqueous NaHCO3 (100 ml) and brine (100 ml), then were dried (MgSO4) and solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent=ethyl acetate:n-hexane, 1:1) to afford 1.7 g (77% yield) of the title compound (19).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:4]=[CH:5][N:6]2[CH:10]=[CH:9][S:8][C:7]=12.[OH-].[Na+].[C:13](Cl)(=[O:25])[O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1>C1COCC1.O>[N+:22]([C:19]1[CH:18]=[CH:17][C:16]([CH2:15][O:14][C:13]([NH:1][CH2:2][C:3]2[N:4]=[CH:5][N:6]3[CH:10]=[CH:9][S:8][C:7]=23)=[O:25])=[CH:21][CH:20]=1)([O-:24])=[O:23]
Reactant: NCc1ncn2ccsc12
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(NCc1ncn2ccsc12)OCc1ccc([N+](=O)[O-])cc1
Yield: 68.1 %

Procedure:
7-Aminomethylimidazo[5,1-b]thiazole (1.53 g) was dissolved in 50 ml of THF and 30 ml of water. A 1 N aqueous sodium hydroxide solution (12 ml) and 2.59 g of 4-nitrobenzyl chlorocarbonate were added under ice cooling to the solution. The mixture was allowed to react at the same temperature for 30 min. The reaction solution was extracted with 200 ml of ethyl acetate, followed by washing with 15% brine. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under the reduced pressure to about 20 ml. The resultant crystal was collected by filtration, washed with 20 ml of ethyl acetate, and dried under the reduced pressure to give 2.26 g of 7-(4-nitrobenzyloxycarbonylamino)methylimidazo-[5,1-b]thiazole.
Reaction SMILES: [CH:1]([NH:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1)=O>N>[CH3:15][O:14][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][C:9]=1[O:12][CH3:13])[CH:1]=[N:3][CH2:4][CH2:5]2
Reactant: COc1ccc(CCNC=O)cc1OC
Agent: N
Product: COc1cc2c(cc1OC)CCN=C2
Temperature: 140 °C
Reaction time: 0.5 h

Procedure:
The N-formyl-2(3,4-dimethoxy-phenyl)-ethylamine so obtained is stirred with polyphosphoric acid (1 kg) and heated to 140° C. (oil bath temperature). The reaction mixture foams vigorously starting from an internal temperature of 70° C. After 30 minutes, an internal temperature of about 140° C. is attained. The mixture is then poured onto water (1 liter) and made alkaline with concentrated ammonia (1.8 liters) while ice is added. The reaction product is extracted repeatedly with ethyl acetate, the ethyl acetate phase is washed with water, dried, over magnesium sulphate and evaporated giving the title compound (142.5 g) as an oil.
Reaction SMILES: C([O:3][C:4](=[O:33])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][CH:26]([S:29][CH2:30][CH2:31][CH3:32])[CH2:25][CH2:24]4)=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)C.[OH-].[Na+].Cl>C(O)C.O1CCCC1>[CH2:30]([S:29][CH:26]1[CH2:25][CH2:24][N:23]([C:20]2[CH:19]=[CH:18][C:17]([N:14]3[CH2:13][CH2:12][N:11]([C:8]4[CH:7]=[CH:6][C:5]([C:4]([OH:33])=[O:3])=[CH:10][CH:9]=4)[CH2:16][CH2:15]3)=[CH:22][CH:21]=2)[CH2:28][CH2:27]1)[CH2:31][CH3:32]
Reactant: CCCSC1CCN(c2ccc(N3CCN(c4ccc(C(=O)OCC)cc4)CC3)cc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCSC1CCN(c2ccc(N3CCN(c4ccc(C(=O)O)cc4)CC3)cc2)CC1
Yield: 86.3 %

Procedure:
To a solution of 4-[1-[4-(4-propylthiopiperidin-1-yl)phenyl]piperazin-4-yl]benzoic acid ethyl ester (1.22 g) in a mixture of ethanol (10 ml) and tetrahydrofuran (40 ml) was added 10% aqueous NaOH (2.1 ml) and 1N-NaOR (10 ml), and the mixture was refluxed for 6 hours. The reaction mixture was cooled and adjusted to pH 2.5-3.0 with 1N-HCl. The resulting precipitates were collected by filtration, washed in turn with water (30 ml) and IPE (50 ml) and dried in vacuo to give 4-[1-[4-(4-propylthiopiperidin-1-yl)phenyl]piperazin-4-yl]benzoic acid (0.99 g).