Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[O:8][C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:10][N:11]=2)[N:3]=1.CN(C=O)C.[Na+].[I-].[Cl:25][C:26]1[CH:31]=[C:30]([CH2:32]Cl)[CH:29]=[CH:28][N:27]=1>O>[Cl:25][C:26]1[CH:31]=[C:30]([CH2:32][N:6]2[C:2]([CH3:1])=[N:3][C:4]([C:7]3[O:8][C:9]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)=[N:10][N:11]=3)=[N:5]2)[CH:29]=[CH:28][N:27]=1
Reactant: ClCc1ccnc(Cl)c1
Reactant: Cc1nc(-c2nnc(-c3ccccc3)o2)n[nH]1
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(-c2nnc(-c3ccccc3)o2)nn1Cc1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.7 %

Procedure:
To a solution of 2-(5-methyl-1H-1,2,4-triazol-3-yl)-5-phenyl-1,3,4-oxadiazole (1.00 mg, 0.44 mmol) in DMF (3 mL) Cs2CO3 (430 mg, 1.32 mmol), NaI (78 mg, 0.52 mmol) and 2-chloro-4-(chloromethyl)pyridine (78 mg, 0.48 mmol) were added. The reaction was allowed to stir overnight at RT and then diluted with H2O (10 mL), extracted with EtOAc (3×10 mL), 4:1 CHCl3:i-PrOH (5×10 mL), dried with MgSO4 and concentrated. The crude product was purified on a Biotage pre-packed silica gel column (EtOAc:Hexane 12% to 100% EtOAc) to afford 2-(1-((2-chloropyridin-4-yl)methyl)-5-methyl-1H-1,2,4-triazol-3-yl)-5-phenyl-1,3,4-oxadiazole (88 mg, 57%) as an off-white powder. MS (ES+) C17H13ClN6O requires: 352 found: 353 [M+H]+.
Reaction SMILES: [OH-].[K+].Cl[CH2:4][CH:5]([O:8][CH3:9])[O:6][CH3:7].O.[CH2:11]([OH:14])[CH2:12][OH:13]>>[CH3:7][O:6][CH:5]([O:8][CH3:9])[CH2:4][O:13][CH2:12][CH2:11][OH:14]
Reactant: COC(CCl)OC
Reactant: OCCO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COC(COCCO)OC
Temperature: 115 °C
Yield: 44.9 %

Procedure:
Potassium hydroxide (30 g, 0.51 mol) was suspended in ethylene glycol (100 ml) and the mixture was heated to 115° C. with stirring. After the KOH dissolved completely, 2-chloro-1,1-dimethoxy-ethane (30.0 mL, 0.263 mol) was added dropwise (ca. 30 minutes) and the solution was stirred at 115° C. for 72 h. The resulting suspension was cooled to room temperature and 150 mL water was added. The solution was extracted with dichloromethane (3×100 mL) and the organic layers combined was washed with brine (2×100 mL) and dried with MgSO4. After filtration the solvent was removed under reduced pressure to give the product as a yellow oil (Yield, 17.7 g, 44.9%). 1H NMR (400.03 MHz, CDCl3, 298 K) δ=2.20 (s, 1H, OH), 3.40 (s, 6H, OCH3), 3.55 (d, J=5.3 Hz, 2H, CHCH2), 3.63-3.61 (m, J=4.0 Hz, OCH2), 3.74-3.72 (m, J=4.0 Hz, 2H, CH2OH), 4.52 (t, 1H, CH(OCH3)2. 13C{1H} NMR (100.59 MHz, CDCl3, 298 K) δ=54.12 (2C, CH3), 61.82 (1C, CH2OH), 70.78 (1C, CHCH2O), 73.00 (1C, OCH2CH2), 102.73 (1C, CH). Anal. Calcd. for C6H14O4: C, 47.99; H, 9.40. Found C, 45.02; H, 8.74
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[CH:10][C:9]([C:12]([O:14]CC)=[CH2:13])=[CH:8][N:7]=2)[CH2:3][CH2:2]1.[Br:17]N1C(=O)CCC1=O>C1COCC1.O.C(OCC)(=O)C>[Br:17][CH2:14][C:12]([C:9]1[CH:8]=[N:7][C:6]([O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)=[N:11][CH:10]=1)=[O:13]
Reactant: C=C(OCC)c1cnc(OCC2CC2)nc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=C(CBr)c1cnc(OCC2CC2)nc1
Temperature: 0 °C
Yield: 71.7 %

Procedure:
A solution of 480 mg (2.18 mmol) of 2-cyclopropylmethoxy-5-(1-ethoxyvinyl)pyrimidine in 8 mL of a THF/H2O mixture: (6/2: v/v) is cooled to 0° C. under argon. After addition of 380.02 mg (2.11 mmol) of N-bromosuccinimide, the reaction mixture is maintained at 0° C. for 1 hour. The solution obtained is taken up in ethyl acetate and washed with aqueous NaHCO3 solution and then with saturated NaCl solution. The organic phase is dried over magnesium sulfate and evaporated to dryness. The residue is purified by chromatography on silica gel (eluent: 80/20 DCM/MeOH) to give 410 mg of 2-bromo-1-(2-cyclopropylmethoxypyrimidin-5-yl)ethanone, the characteristics of which are as follows:
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.ClC(OC(Cl)(Cl)Cl)=O.C([O:22][C:23]([N:25]1[CH2:47][CH2:46][CH2:45][C@H:26]1[C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[CH:34]([OH:44])[CH2:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=1)=[O:28])=O)(C)(C)C>>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:23]([N:25]2[CH2:47][CH2:46][CH2:45][C@H:26]2[C:27]([N:29]2[CH2:33][CH2:32][CH2:31][C@H:30]2[CH:34]([OH:44])[CH2:35][O:36][C:37]2[CH:38]=[CH:39][C:40]([F:43])=[CH:41][CH:42]=2)=[O:28])=[O:22])=[CH:4][CH:3]=1
Reactant: NCc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(O)COc1ccc(F)cc1
Agent: O=C(Cl)OC(Cl)(Cl)Cl
Product: O=C(NCc1ccc(F)cc1)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(O)COc1ccc(F)cc1

Procedure:
By the same procedure as in Example 28-B), while using 4-fluorobenzylamine (0.54 ml), trichloromethyl chloroformate (0.28 ml) and (2S)-1-[N-(tert-butoxycarbonyl)-L-prolyl]-2-[2-(4-fluorophenoxy)-1-hydroxyethyl]pyrrolidine (1.85 g), there was obtained 1.38 g of the title compound.
Reaction SMILES: P(Br)(Br)[Br:2].[CH2:5]([O:7][C:8](=[S:18])[CH2:9][CH2:10][CH2:11][CH2:12][CH:13](O)[CH2:14][CH2:15][CH3:16])[CH3:6].O.C(OCC)C>ClC(Cl)(Cl)Cl>[CH2:5]([O:7][C:8](=[S:18])[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([Br:2])[CH2:14][CH2:15][CH3:16])[CH3:6]
Reactant: BrP(Br)Br
Reactant: CCCC(O)CCCCC(=S)OCC
Solvent: CCOCC
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CCCC(Br)CCCCC(=S)OCC
Temperature: 0 °C
Reaction time: 2 h
Yield: 200 %

Procedure:
64.8 grams (0.24 mole) of phosphorus tribromide at 0° C. were dropped into a solution of 140.0 grams (0.6 mole) of 6-hydroxy-8-methylthiooctanoic acid ethyl ester (VIb) in 150 ml of tetrachloromethane, the mixture stirred for 2 hours at 0° C. and allowed to stand for 10 hours at room temperature. There were dropped into the reaction mixture, cooled to 0° C., 150 ml of water and subsequently 600 ml of diethyl ether. The organic phase was separated off, washed with saturated aqueous sodium bicarbonate solution, dried with sodium sulfate and the solvent removed in a vacuum. After vacuum distillation of the residue there were obtained 135.0 grams (76% of theory) of 6-bromo-8-methylthiooctanoic acid ethyl ester as a yellowish oil having a boiling point of 140° C. to 145° C. at 1 mbar.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([CH3:19])[CH2:11][CH2:12][CH2:13][C:14]([CH3:18])=[CH:15][CH2:16]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[CH3:22]O.O.CC[O:27][CH2:28][CH3:29]>[Cl-].[Na+].O>[CH2:1]([O:8][CH2:9][CH:10]([CH3:19])[CH2:11][CH2:12][CH2:13][C:14]([CH3:18])=[CH:15][CH2:16][CH2:22][C:28](=[O:27])[CH3:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOCC
Reactant: CC(=CCCl)CCCC(C)COCc1ccccc1
Reactant: CO
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)CCC=C(C)CCCC(C)COCc1ccccc1
Yield: 61 %

Procedure:
The β-ketoester derived from 8-benzyloxy-3,7-dimethyl-2-octenyl chloride (25.2 g, 67.5 mM) is treated with 2 N sodium hydroxide/methanol (675 ml) and after 10 minutes water (675 ml) is added. The reaction mixture is heated at reflux for 3 hours. The solvent is removed in vacuo and the residue obtained is treated with ether and brine. The layers are separated, the aqueous phase is extracted with ether, and the combined extracts are washed with brine and dried (Na2SO4). The solvent is removed in vacuo to give the crude product (16 g). Purification over silica gel using 5% ethyl acetate/hexane as the eluent gives 1-benzyloxy-2,6-dimethyl-10-oxo-undec-6-ene (12.4 g, 61%) with a 83/17 E/Z isomer ratio by gas chromatography:
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:8]([Cl:15])=[C:7]([O:16][CH3:17])[N:6]=1.O>C(O)CC>[Cl:15][C:8]1[C:7]([O:16][CH3:17])=[N:6][C:5]([NH:2][NH2:3])=[C:10]([C:11]([F:14])([F:13])[F:12])[CH:9]=1
Reactant: COc1nc(Cl)c(C(F)(F)F)cc1Cl
Reactant: NN
Solvent: CCCO
Solvent: O
Product: COc1nc(NN)c(C(F)(F)F)cc1Cl
Temperature: 90 °C
Reaction time: 3 h

Procedure:
10.7 g (0.214 mol) of hydrazine hydrate were added at 50° C. in the course of 10 minutes with stirring to 25.0 g (0.102 mol) of 2,5-dichloro-6-methoxy-3-trifluoromethylpyridine in 100 ml of propanol and the mixture was stirred for 3 hours at 90° C. After cooling, the resulting suspension was poured into 1.2 liters of water, and the precipitate was filtered off with suction, taken up in methylene chloride and washed with water. The organic phase was dried and concentrated, and the residue was stirred with ether/pentane (1:1). After filtration with suction and drying, 7.8 g (32% of theory) of the title compound of m.p. 140°-142° C. (Table II, No. 2.011) were obtained.
Reaction SMILES: C([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([I:17])=[CH:13][CH:12]=1)(OC(C)(C)C)=O.[Cl:21]C(Cl)(Cl)C(=N)O[C:25]([CH3:28])([CH3:27])[CH3:26].B(F)(F)F.CCOCC>C(Cl)Cl.C1CCCCC1>[ClH:21].[I:17][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][C@@H:9]([C:18]([O:20][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:19])[NH2:8])=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=N)C(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(I)cc1)C(=O)O
Agent: FB(F)F
Solvent: ClCCl
Solvent: C1CCCCC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(I)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a suspension of N-Boc-4-iodo-(L)-phenylalanine (1.0 g, 2.56 mmol) in methylene chloride (7 mL) and cyclohexane (14 mL) were added t-butyl trichloroacetimidate (0.48 mL, 2.68 mmol) and boron trifluoride-etherate (48 μL). The reaction mixture was stirred for 5 hours at room temperature under a nitrogen atmosphere and then treated a second time with the same amounts of t-butyl trichloroacetimidate and boron trifluoride-etherate as above. After stirring overnight, a third addition was made, and the mixture was stirred a further 3 hours. The mixture was then filtered and the filtrate evaporated. The product was obtained pure by silica gel chromatography eluting with 10% diethyl ether in hexane; yield 650 mg. The product was treated with 1M HCl in ethyl acetate (7.3 mL) for 18 hours at room temperature. The mixture was evaporated and coevaporated several times with diethyl ether to afford the title compound; yield 522 mg.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[CH2:16][CH2:15][C:14]3[C:9](=[C:10]([O:23][CH3:24])[C:11](=[O:22])[N:12]([CH3:21])[C:13]=3[NH:17][C:18](=[O:20])[CH3:19])[C:8]2=[O:25])=[CH:4][CH:3]=1.[C:28]([O-])([O-])=O.[Cs+].[Cs+].CI>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:16][CH2:15][C:14]3[C:9](=[C:10]([O:23][CH3:24])[C:11](=[O:22])[N:12]([CH3:21])[C:13]=3[N:17]([CH3:28])[C:18](=[O:20])[CH3:19])[C:8]2=[O:25])=[CH:26][CH:27]=1
Reactant: COc1c2c(c(NC(C)=O)n(C)c1=O)CCN(Cc1ccc(F)cc1)C2=O
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1c2c(c(N(C)C(C)=O)n(C)c1=O)CCN(Cc1ccc(F)cc1)C2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To N-[6-(4-fluorobenzyl)-4-methoxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridin-1-yl]acetamide (0.073 g, 0.196 mmol) in 2 mL DMF was added Cs2CO3 (0.084 g, 0.25 mmol) and methyl iodide (0.044 mL, 0.7 mmole) and the reaction was stirred overnight at room temperature. The solvent was removed and the residue was partitioned between CHCl3 and 10% KHSO4, the organic was dried with Na2SO4, filtered and evaporated to give the crude product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.[Li]CCCC.CN([CH:21]=[O:22])C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.C(OCC)(=O)C>[OH:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([CH:21]=[O:22])[CH:11]=[CH:10]2
Reactant: CN(C)C=O
Reactant: Oc1ccc2cc(Br)ccc2c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=Cc1ccc2cc(O)ccc2c1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 82.2 %

Procedure:
To a stirred cooled mixture of 6-bromo-2-hydroxynaphthalene (25.3 g, 0.113 mol) in THF (600 mL) at −78° C. was added n-BuLi (2.5 M, 100 mL, 0.250 mol) dropwise. The mixture turned yellow and the temperature rose to −64° C. After ca 5 min a suspension appeared. After addition, the mixture was maintained at −78° C. After 20 minutes, a solution of DMF (28.9 mL, 0.373 mol) in THF (100 mL) was added over 20 minutes. After addition, the mixture was allowed to warm slowly to RT. After 1 hour, the mixture was poured in ice/water (200 mL). To the mixture citric acid was added to a pH of 5. The mixture was stirred for 0.5 hour. Ethyl acetate (200 mL) was added and the organic layer was separated and washed with brine (100 mL), dried over Na2SO4 and concentrated. To the residue was added heptane with 20% ethyl acetate (ca 50 mL) and the mixture was stirred for 1 hour. The mixture was filtered and the solid was washed with ethyl acetate and dried in vacuo to afford 16 g of the title compound.
Reaction SMILES: [C:1]([CH:4]([CH3:26])[CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([CH3:16])[C:10]=2[N:9]=[C:8]1[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)(O)=[O:2].[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[N:27]1([C:1]([CH:4]([CH3:26])[CH2:5][CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([CH3:16])[C:10]=3[N:9]=[C:8]2[CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[O:2])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: Cc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCC(C)C(=O)O
Reactant: C1CCNCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCC(C)C(=O)N1CCCCC1
Temperature: 25 °C
Reaction time: 64 h
Yield: 126.4 %

Procedure:
To a stirring solution of 1-[3-carboxybutyl]-2-[(4-chlorophenoxy)methyl]-4-methylbenzimidazole (1.2 g, 3.2 mmol) in N,N-dimethylformamide (75 ml) were added sequentially piperidine (299 mg, 1.1 eq), 1-hydroxybenzotriazole (475 mg, 1.1 eq), and dicyclohexylcarbodiimide (726 mg, 1.1 eq). The resulting mixture was then stirred under a nitrogen atmosphere at room temperature for 64 hours. The reaction mixture was then filtered and the resulting filtrate was concntrated under reduced pressure. This residue was taken into ethyl acetate (200 ml) and washed once with water (200 ml), dried over potassium carbonate. The solvents were removed in vacuo to yield 1.78 grams of a tan foam.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:18])[CH:11]=[CH:12][C:13]=1[O:14][CH:15]([CH3:17])[CH3:16].[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:18][C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=2)=[O:28])[CH:11]=[CH:12][C:13]=1[O:14][CH:15]([CH3:16])[CH3:17]
Reactant: O=C=Nc1ccc(F)cc1
Reactant: CC(C)Oc1ccc(N)cc1-c1c(Br)cnn1C
Solvent: ClCCl
Product: CC(C)Oc1ccc(NC(=O)Nc2ccc(F)cc2)cc1-c1c(Br)cnn1C
Yield: 33.3 %

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-isopropoxy-phenylamine (0.027 g, 0.09 mmol) was treated with 4-fluorophenyl isocyanate (0.013 g, 11.0 μL, 0.10 mmol, 1.1 equiv.) in CH2Cl2 (1 mL), in a similar similar manner as described in Example 1.2 to afford Compound 60 (0.015 g, 0.03 mmol, 38%) as a white solid. LCMS m/z (%)=447 (M+H79Br, 98), 449 (M+H81Br, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.11 (s, 2H), 7.65 (dd, J=2.4, 8.9 Hz, 1H), 7.54 (dd, J=4.9, 8.7 Hz, 2H), 7.41 (d, J=2.6 Hz, 1H), 7.12 (d, J=8.9 Hz, 1H), 7.04 (t, J=8.8 Hz, 2H), 4.40-4.52 (m, 1H), 3.70 (s, 3H), 1.26 (d, J=6.0 Hz, 3H), 1.11 (d, J=6.0 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](OS(C(F)(F)F)(=O)=O)=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.[CH3:19][C:20]1[CH:21]=[C:22]([SH:26])[CH:23]=[CH:24][CH:25]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:26][C:22]2[CH:21]=[C:20]([CH3:19])[CH:25]=[CH:24][CH:23]=2)=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1
Reactant: Cc1cccc(S)c1
Reactant: Cc1ccc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c1
Product: Cc1cccc(Sc2ccc(C)cc2[N+](=O)[O-])c1

Procedure:
The product from Example 4a (9.46 g, 33.17 mmol) was reacted with 3-methylthiophenol (4.12 g, 33.17 mmol) in place of thiophenol following the procedure from Example 1e for 18 h giving the crude title compound which was purified by silica gel column chromatography eluting with 5% EtOAc hexane providing a solid (7.50 g, 87%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[NH:4][C:5]1[S:6][C:7]2[C:13](I)=[CH:12][CH:11]=[C:10]([O:15][CH3:16])[C:8]=2[N:9]=1.C([Sn](CCCC)(CCCC)[C:23]1[O:24][CH2:25][CH2:26][O:27][CH:28]=1)CCC.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.C(N(CC)CC)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH3:1][O:2][C:3](=[O:17])[NH:4][C:5]1[S:6][C:7]2[C:13]([C:23]3[O:24][CH2:25][CH2:26][O:27][CH:28]=3)=[CH:12][CH:11]=[C:10]([O:15][CH3:16])[C:8]=2[N:9]=1
Reactant: COC(=O)Nc1nc2c(OC)ccc(I)c2s1
Reactant: CCCC[Sn](CCCC)(CCCC)C1=COCCO1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COC(=O)Nc1nc2c(OC)ccc(C3=COCCO3)c2s1
Temperature: 100 °C
Yield: 45.2 %

Procedure:
To a stirred solution of 13.0 g (35.7 mmol) (7-iodo-4-methoxy-benzothiazol-2-yl)-carbamic acid methyl ester in 200 ml dioxane were added 20.1 g (53.6 mmol) tributyl-(5,6-dihydro-[1,4]dioxin-2-yl)-stannane, 616 mg (1.07 mmol) bis(dibenzylideneacetone)palladium, 1.33 g (5.71 mmol) trifurylphosphine and 7.46 ml (53.6 mmol) triethylamine. The mixture was heated at 100° C. for 16 h and then poured onto water and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (1/4-1/2 acetone/hexane) followed by trituration in ether afforded 5.20 g (45%) [7-(5,6-dihydro-[1,4]dioxin-2-yl)-4-methoxy-benzothiazol-2-yl]-carbamic acid methyl ester as a white solid. ES-MS m/e (%): 323 (M+H+, 100).
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[S:27][C:28]2[CH:34]=[C:33]([Cl:35])[C:32]([Cl:36])=[CH:31][C:29]=2[N:30]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[S:27][C:28]5[CH:34]=[C:33]([Cl:35])[C:32]([Cl:36])=[CH:31][C:29]=5[N:30]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Reactant: Clc1nc2cc(Cl)c(Cl)cc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4nc5cc(Cl)c(Cl)cc5s4)cc3CC[C@@H]12
Yield: 30.7 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2,5,6-trichloro benzothiazole (110 mg, 0.46 mmol) and 1 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (80% ethyl acetate/hexanes eluent) to give 54 mg (31%) of the title compound as an amorphous foam. FDMS: m/e=463.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[CH:16]=[CH:15][NH:14][C:13](=[O:17])[CH2:12][C:11]=2[CH:18]=1.[C:22]([O-])(=[O:24])[CH3:23].[Na+]>C(OC(=O)C)(=O)C>[C:22]([N:14]1[CH:15]=[CH:16][C:10]2[CH:9]=[CH:8][C:7]([O:6][CH2:5][C:4]3[CH:19]=[CH:20][CH:21]=[C:2]([F:1])[CH:3]=3)=[CH:18][C:11]=2[CH2:12][C:13]1=[O:17])(=[O:24])[CH3:23]
Reactant: CC(=O)[O-]
Reactant: O=C1Cc2cc(OCc3cccc(F)c3)ccc2C=CN1
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N1C=Cc2ccc(OCc3cccc(F)c3)cc2CC1=O
Temperature: 140 °C
Yield: 77.7 %

Procedure:
In a dried flask under an inert atmosphere, 103 mg (0.36 mmol) of 8-(3-fluoro-benzyloxy)-1,3-dihydro-benzo[d]azepin-2-one and 72 mg (0.9 mmol) of sodium acetate were suspended in 0.3 ml of acetic acid anhydride. The solution was heated to 140° C. for 4 h. For the working-up, the reaction mixture was cooled, then evaporated under reduced pressure. The residue was treated with 1.5 ml of ice/water and 4 ml of ethyl acetate. The aqueous layer was separated and re-extracted with 4 ml of ethyl acetate. The combined organic layers were dried over sodium sulfate, thereafter the solvent evaporated under reduced pressure. For purification, the crude material obtained was chromatographed on silica gel using a gradient of heptane to a 4:1-mixture of heptane and ethyl acetate as the eluent. There were obtained 91 mg (77% of theory) of 3-acetyl-8-(3-fluoro-benzyloxy)-1,3-dihydro-benzo[d]azepin-2-one as a light yellow solid; MS: m/e=325 (M)+.
Reaction SMILES: [CH2:1]([OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:12](=O)(OC)OC.[Mg].[Al]>>[CH3:12][O:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCO
Reactant: COC(=O)OC
Agent: [Al]
Agent: [Mg]
Product: CCCCCCCCCCOC
Reaction time: 1.1 h

Procedure:
Using the apparatus employed in Examples 15-27, a mixture of 1-decanol (1 mole) and dimethyl carbonate (3 mole) was passed through 11.5 grams of a magnesium:aluminum mixed metal oxide (3/16 inch pellets, Mg/Al 3:1) at a temperature of 250° C. and at a liquid feed rate of 0.34 milliliters/minute. After a period of 1.1 hour, a total of 36.5 grams of liquid was collected. Analysis was performed by capillary gas chromatography (FID) using a DB-1701 column. The results were (area %) as follows:
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH3:10])=[CH:5][CH:4]=1.II.[C:13]([O:17][C:18]([NH:20][C@H:21]([C:23](N(OC)C)=[O:24])[CH3:22])=[O:19])([CH3:16])([CH3:15])[CH3:14]>C1COCC1>[CH2:9]([C:6]1[CH:7]=[CH:8][C:3]([C:23](=[O:24])[C@@H:21]([NH:20][C:18](=[O:19])[O:17][C:13]([CH3:14])([CH3:15])[CH3:16])[CH3:22])=[CH:4][CH:5]=1)[CH3:10]
Reactant: CON(C)C(=O)[C@H](C)NC(=O)OC(C)(C)C
Reactant: CCc1ccc(Br)cc1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CCc1ccc(C(=O)[C@H](C)NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred suspension of magnesium turnings (243 mg, 10 mmol) in dry THF (10 ml) was added a solution of 1-bromo-4-ethylbenzene (1.85 g, 10 mmol) in dry THF (10 ml), followed by a small crystal of iodine. The reaction mixture was heated with reflux for 4 h, then cooled to r.t. A solution of N2-(tert-butoxycarbonyl)-N-methoxy-N-methyl-L-alaninamide (464 mg, 2 mmol) in dry THF (15 ml) was added dropwise, and the stirring was continued for 5 h at r.t. Then the reaction mixture was quenched with sat. aqueous NH4Cl (25 ml) stirred for 30 min, and the layers were separated. The aqueous layer extracted with ethyl acetate (50 ml). The combined organic layers were dried with Na2SO4, and the solvent was removed under reduced pressure to give the subtitle compound as colourless oil, 718 mg, 70% purity (as determined by NMR). Used in the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH:10]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: CCCCCC(C(=O)OCC)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CCCCCC(C(=O)OCC)c1ccc(N)cc1
Yield: 97.1 %

Procedure:
12 g of (RS)-ethyl 2-(4-nitrophenyl)-heptanoate dissolved in 100 ml of ethanol was treated with 2.4 g of 10% palladium on carbon. The mixture was stirred at room temperature for 18 hours under 40 psi of hydrogen. The mixture was filtered on a pad of Celite and concentrated in vacuo. The product was purified by flash chromatography (SiO2, 25% ethyl acetate/hexanes), yielding 10.4 g of a pale yellow oil. 1H NMR (CDCl3): 7.10 (d, J=8.4 Hz, 2H), 6.63 (d, J=8.5 Hz, 2H), 4.20-4.00 (m, 2H), 3.61 (br. s, 2H), 3.40 (t, J=7.7 Hz, 1H), 2.05-1.90 (m, 1H), 1.75-1.60 (m, 1H), 1.30-1.15 (m, 6H), 1.20 (t, J=7.2 Hz, 3H), 0.85 (t, J=6.7 Hz, 3H).