Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:6]2O)[CH3:2].P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:6]1[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([CH2:1][CH3:2])[N:4]=2)[N:9]=[CH:8][C:7]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnc2ccc(CC)nc2c1O
Product: CCOC(=O)c1cnc2ccc(CC)nc2c1Cl

Procedure:
A mixture of ethyl 6-ethyl-4-hydroxy-1,5-naphthyridine-3-carboxylate (3.0 g) and phosphorus oxychloride (25 ml) was stirred and heated at 40°-50° C. for 1 hour. The mixture was then cooled and then worked up as described in Example B1 to give ethyl 4-chloro-6-ethyl-1,5-naphthyridine-3-carboxylate, m.p. 94°-96° C.
Reaction SMILES: [N:1]([CH:4]1[N:10]=[C:9]([C:11]2[C:12]([O:19][CH3:20])=[N:13][C:14]([O:17][CH3:18])=[N:15][CH:16]=2)[C:8]2[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:7]=2[N:6]([CH3:26])[C:5]1=[O:27])=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>>[NH2:1][CH:4]1[N:10]=[C:9]([C:11]2[C:12]([O:19][CH3:20])=[N:13][C:14]([O:17][CH3:18])=[N:15][CH:16]=2)[C:8]2[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:7]=2[N:6]([CH3:26])[C:5]1=[O:27]
Reactant: COc1ncc(C2=NC(N=[N+]=[N-])C(=O)N(C)c3ccc(Cl)cc32)c(OC)n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1ncc(C2=NC(N)C(=O)N(C)c3ccc(Cl)cc32)c(OC)n1

Procedure:
As illustrated in the scheme above and following General Procedure 7, 3-azido-7-chloro-5-(2,4-dimethoxy-5-pyrimidinyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one (1.22 g, 3.15 mmol) and PS—PPh3 (23.0 g of 1.37 mmol/g, 31.5 mmol) were combined. After workup and purification by “catch and release,” the title compound was obtained as a brown solid (1.15 g, quantitative). 1H-NM (CDCl3): δ 8.56 (s, 1H), 7.50 (dd, J=2.4 Hz, J=8.9 Hz, 1H), 7.30 (d, J=8.8 Hz, 1H), 7.15 (d, J=2.5 Hz, 1H), 4.46 (s, 1H), 4.06 (s, 3H), 3.77 (s, 3H), 3.46 (s, 3H), 2.85-2.12 (br s, 2H). MS (ESI) (M+H)+=362.
Reaction SMILES: [NH2:1][C:2]1[C:19]([C:20]#[N:21])=[CH:18][C:5]([O:6][CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([NH:16][CH3:17])=[O:15])[CH2:9][CH2:8]2)=[C:4]([O:22][CH3:23])[CH:3]=1.CO[CH:26](OC)[N:27]([CH3:29])[CH3:28]>CC1CCCO1.C(O)(=O)C>[C:20]([C:19]1[C:2]([N:1]=[CH:26][N:27]([CH3:29])[CH3:28])=[CH:3][C:4]([O:22][CH3:23])=[C:5]([CH:18]=1)[O:6][CH:7]1[CH2:8][CH2:9][N:10]([CH2:13][C:14]([NH:16][CH3:17])=[O:15])[CH2:11][CH2:12]1)#[N:21]
Reactant: CNC(=O)CN1CCC(Oc2cc(C#N)c(N)cc2OC)CC1
Reactant: COC(OC)N(C)C
Solvent: CC(=O)O
Solvent: CC1CCCO1
Product: CNC(=O)CN1CCC(Oc2cc(C#N)c(N=CN(C)C)cc2OC)CC1
Temperature: 76 °C
Yield: 100.5 %

Procedure:
2-[4-(4-Amino-5-cyano-2-methoxyphenoxy)piperidin-1-yl]-N-methylacetamide (6, 18.21 g, 52.05 mmoles) was suspended in 2-methyltetrahydrofuran (99.62 g). To this was added acetic acid (162.79 mg), and N,N-dimethylformamide dimethyl acetal (DMF-DMA) (8.63 g, 70.27 mmoles) and the resulting reaction mixture was heated at 76° C. for 16 hrs. Additional N,N-dimethylformamide dimethyl acetal (639.41 mg, 5.20 mmoles) was added to the reaction mixture to ensure the reaction completed. The reaction mixture was cooled to 30° C. during which time crystallisation occurred. The resulting solid was isolated by filtration, washed with 2-methyltetrahydrofuran (14.23 g) and dried to afford the title compound (19.53 g, 97% yield); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.65 (m, 2H) 1.86 (m, 2H) 2.24 (m, 2H) 2.60 (d, J=4.7 Hz, 3H) 2.66 (m, 2H) 2.87 (s, 2H) 2.95 (s, 3H) 3.04 (s, 3H) 3.81 (s, 3H) 4.19 (tt, J=8.2, 3.8 Hz, 1H) 6.72 (s, 1H) 7.15 (s, 1H) 7.67 (q, J=4.7 Hz, 1H) 7.90 (s, 1H); Mass Spectrum: m/z (M+H)+ 374.2.
Reaction SMILES: [CH:1]1([C:7]2[CH:13]=[C:12]([CH2:14][CH3:15])[C:10]([NH2:11])=[C:9]([CH2:16][CH3:17])[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.C(=O)([O-])[O-].[Ca+2].[C:24](Cl)(Cl)=[S:25]>C(Cl)Cl>[CH:1]1([C:7]2[CH:8]=[C:9]([CH2:16][CH3:17])[C:10]([N:11]=[C:24]=[S:25])=[C:12]([CH2:14][CH3:15])[CH:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: S=C(Cl)Cl
Reactant: CCc1cc(C2CCCCC2)cc(CC)c1N
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: ClCCl
Solvent: O
Product: CCc1cc(C2CCCCC2)cc(CC)c1N=C=S

Procedure:
231 g of 4-cyclohexyl-2,6-diethyl-aniline in 300 ml of methylene chloride are added dropwise at 10°-15° C. to a suspension of 600 ml of methylene chloride, 500 ml of water, 200 g of calcium carbonate and 140 g of thiophosgene. The mixture is then heated to the boil, until the evolution of gas has ended. The batch, when cold, is filtered to remove solids, and the methylene chloride layer is dried over calcium chloride and fractionated; boiling point 175°-179° C./1.5 mm Hg; yield 251 g.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[C:15](=[O:16])[N:14]([CH2:17][CH2:18][CH2:19][F:20])[N:13]=[N:12]1>C(O)(=O)C.O.[Fe]>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([N:11]2[C:15](=[O:16])[N:14]([CH2:17][CH2:18][CH2:19][F:20])[N:13]=[N:12]2)=[C:2]([F:1])[CH:7]=1
Reactant: O=c1n(CCCF)nnn1-c1ccc([N+](=O)[O-])cc1F
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: Nc1ccc(-n2nnn(CCCF)c2=O)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.6 %

Procedure:
To a stirred solution of 15.0 g (0.096 mole) of 1-(2-fluoro-4-nitrophenyl)-4-(3-fluoropropyl)-1,4-dihydro-5H-tetrazol-5-one in 200 mL of glacial acetic acid and 10 mL of water, heated at 45° C., was added portionwise 15.0 g (0.27 mole) of iron powder. The reaction mixture was allowed to cool to room temperature and stir for approximately two hours. This mixture was filtered through a pad of Celite filter aid. The filtrate was diluted with 200 mL of water, and the resultant mixture was extracted with diethyl ether. The organic extract was dried over anhydrous magnesium sulfate and was filtered. The filtrate was evaporated under reduced pressure leaving an oil. This oil was purified by column chromatography on silica gel, eluting with methylene chloride, to yield 12.4 g of 1-(4-amino-2-fluorophenyl)-4-(3-fluoropropyl)-1,4-dihydro-5H- tetrazol-5-one as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[Cl:9][CH2:10][C:11](Cl)=[O:12]>C(OCC)(=O)C>[Cl:9][CH2:10][C:11]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:12]
Reactant: Nc1ccc(Cl)cc1
Reactant: O=C(Cl)CCl
Solvent: CCOC(C)=O
Product: O=C(CCl)Nc1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
p-Chloroaniline (3.82 g) was dissolved in ethyl acetate (30 mL), and, at room temperature, chloroacetyl chloride (2.39 mL) was added to the solution, followed by stirring for 1 hour. After the reaction mixture was heated and stirred at 60° C. for 3.5 hours, crystals precipitated were collected by filtration, to thereby give the title compound (4.78 g). The filtrate was concentrated to about ¼, and crystals precipitated were collected by filtration, to thereby give the title compound (1.01 g).
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[NH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>C(Cl)Cl>[I:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:3]=1[C:4]([NH:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:6]
Reactant: COc1cc(I)c(C(=O)O)cc1OC
Reactant: CCOC(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC(=O)c1cc(OC)c(OC)cc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
To a stirred solution of 2-iodo-4,5-dimethoxybenzoic acid (24.6 g, 80 mmol), ethyl 2-aminoacetate hydrochloride (11 g, 88 mmol), EDCl (17 g, 88 mmol) and HOBt (14 g, 88 mmol) in dry DCM (500 mL) was added Et3N (55 mL, 400 mmol) dropwise at rt. The resulting mixture was stirred at room temperature overnight then the reaction was quenched with water, and thoroughly extracted with DCM. The combined organic phases were washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by flash chromatography using petroleum ether/ethyl acetate 3:1 (v:v) as eluent to give ethyl 2-(2-iodo-4,5-dimethoxybenzamido)acetate (29 g, 95%).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:11]([NH:13][C@H:14]([C:23]([O:25][CH3:26])=[O:24])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:33][O:34][C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=[O:40])=[CH:37][CH:36]=1>O.C(Cl)(Cl)Cl>[CH3:33][O:34][C:35]1[CH:43]=[CH:42][C:38]([C:39]([NH:2][C@H:3]([C:11]([NH:13][C@H:14]([C:23]([O:25][CH3:26])=[O:24])[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[O:12])[CH2:4][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:40])=[CH:37][CH:36]=1
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](N)Cc1ccccc1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccc(OC)cc1
Yield: 81.8 %

Procedure:
In a mixture of 10 ml of water and 50 ml of chloroform were suspended 3.79 g of methyl phenylalanyltyrosinate hydrochloride and 0.53 g of sodium carbonate. To the mixture was added dropwise 1.75 g of 4-methoxybenzoylchloride in parallel with 10 ml of sodium carbonate solution (0.75 g), while stirring and cooling with ice. The mixture was stirred for 2 hours and the chloroform layer was collected. The layer was washed with 5% hydrochloric acid and water, dried and concentrated to dryness. The residue was crystallized from ethyl acetate to give 3.9 g of methyl N-(4-methoxybenzoyl)-phenylalanyltyrosinate with a mp. 195°-197° C. in a yield of 82%. Analysis, calculated for C27H28O6N2 : C, 68.05; H, 5.92; N, 5.88; found C, 68.42; H, 6.08; N, 5.74.
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:5]([OH:11])=[CH:6][CH:7]=[CH:8][C:9]=1[OH:10])=O.C(=O)([O-])[O-].[K+].[K+].[CH3:18][O:19][C:20]1[CH:29]=[CH:28][C:23]([C:24](=[O:27])[CH2:25]Br)=[CH:22][CH:21]=1>CC(C)=O>[CH3:18][O:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([C:25]2[O:10][C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([OH:11])[C:4]=3[C:2]=2[CH3:1])=[O:27])=[CH:22][CH:21]=1
Reactant: CC(=O)c1c(O)cccc1O
Reactant: COc1ccc(C(=O)CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(C(=O)c2oc3cccc(O)c3c2C)cc1
Yield: 65.8 %

Procedure:
A mixture of 2,6-dihydroxyacetophenone (5.35 gm; 35.0 mmoles), potassium carbonate (4.83 gm; 35.0 mmoles), and p-methoxyphenacylbromide (8.05 gm; 35.0 mmoles) in acetone (150 mL) was refluxed for a period of 22 hours. The reaction mixture was cooled, filtered through Celite, and concentrated in vacuo. The residue was dissolved in methylene chloride and washed with 1N sodium hydroxide. The aqueous phase was then acidified with 20% citric acid. The solid was filtered, washed with water, and air-dried to yield 6.5 gm (65%) of 2-(p-methoxybenzoyl)-3-methyl-4-hydroxybenzofuran, mp. 192°-195° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[C:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][C:15]=2[CH3:23])[CH:10]=[CH:9][N:8]=1)=[O:5].[H][H]>CO.CC(O)=O.[Pt]>[NH2:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][C:11]2[CH:10]=[CH:9][N:8]=[C:7]([NH:6][C:4](=[O:5])[CH2:3][O:2][CH3:1])[CH:12]=2)=[C:15]([CH3:23])[CH:16]=1
Reactant: COCC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])cc2C)ccn1
Reactant: [H][H]
Agent: [Pt]
Solvent: CC(=O)O
Solvent: CO
Product: COCC(=O)Nc1cc(Oc2ccc(N)cc2C)ccn1

Procedure:
A solution of 2-methoxy-N-(4-(2-methyl-4-nitrophenoxy)pyridin-2-yl)acetamide (357 mg, estimated purity 92%, 1.04 mmol) in a mixture of MeOH (20 mL) and AcOH (2.0 mL) was subjected to hydrogenation by passage through a Thales H-cube (1.0 mL min−1, 25° C., 55 mm 10% Pt/C Cat-Cart, full hydrogen mode) and was then evaporated in vacuo. The residue was taken up into a mixture of MeOH (20 mL) and AcOH (2 mL) and re-subjected to hydrogenation under the same flow conditions, at an elevated temperature (1.0 mL min−1, 40° C., 55 mm 10% Pt/C Cat-Cart, full hydrogen mode). The mixture was concentrated by evaporation in vacuo to afford the title compound, Intermediate H2, as a viscous liquid; Rt 1.05 min (Method 1); m/z 288 (M+H)+ (ES+); which was used directly in the next step (below).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:18][C:19]([O:21]C)=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:18][C:19]([OH:21])=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COC(=O)CC(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CC(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reaction time: 2 h
Yield: 92 %

Procedure:
Methyl 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-phenylpropanoate (700 mg, 1.87 mmol) was dissolved in 45 mL MeOH/H2O (8:1) and treated with NaOH (2 M, 10.8 mmol, 5.4 mL). The reaction was complete in 2 hours and was acidified with 1 M HCl and extracted 3×EtOAc, the combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to give pure 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-phenylpropanoic acid (620 mg, 92%) as a clear oil. MS found: (M+H)+=361
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH2:13](O)[CH2:14][OH:15].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1(C)C=CC=CC=1.C(OCC)C>[O:15]1[C:2]2([CH2:7][CH2:6][CH2:5][CH2:4][CH:3]2[C:8]([O:10][CH2:11][CH3:12])=[O:9])[O:1][CH2:13][CH2:14]1
Reactant: OCCO
Reactant: CCOC(=O)C1CCCCC1=O
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCOC(=O)C1CCCCC12OCCO2
Temperature: 25 °C

Procedure:
Ethyl 2-oxocyclohexane carboxylate (11.3 g) and ethylene glycol (11 mL) were dissolved in toluene (100 mL). To the reaction mixture camphorsulfonic acid (1.03 g) was added and refluxed for 8 hours with Dean-Stark apparatus. The reaction mixture was cooled to room temperature, diluted with diethyl ether and washed with saturated aqueous sodium hydrogencarbonate solution. The extract washed with saturated brine, dried over anhydrous magnesium sulfate, and from which the solvent was distilled off to provide a crude product of the title compound.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[O:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[CH:10]=[O:11].[CH:12](Cl)([CH3:14])[CH3:13]>C(=S)=S>[CH:12]([C:8]1[CH:7]=[C:6]([CH:10]=[O:11])[O:5][CH:9]=1)([CH3:14])[CH3:13]
Reactant: O=Cc1ccco1
Reactant: CC(C)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(C)c1coc(C=O)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a suspension containing aluminium chloride (24 g, 180 mmol) in 100 mL of CS2 was added 2-furaldehyde (9.8 mL, 156 mmol). To this mixture was added dropwise isopropyl chloride (14.3 mL, 156 mmol), and the resulting mixture stirred at rt for 24 h. The dark mixture was carefully poured into a vigorously stirred 250 g of ice, and then extracted with ether (5×100 mL). The combined organic layers were washed with water, brine, dried (Na2SO4), filtered through a pad of silica gel, and concentrated. The residue was purified by flash chromatography (0-5% EtOAc in heptane) to give 4-isopropylfuran-2-carbaldehyde as an orange oil: Yield 3.5 g (16%). 1H NMR (400 MHz, CDCl3) δ ppm 1.25 (d, J=6.88 Hz, 6H), 2.80-2.91 (m, 1H), 7.16-7.18 (m, 1H), 7.47 (q, J=0.91 Hz, 1H), 9.61 (d, J=0.59 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[CH2:5][CH2:6][NH2:7].[C:12](Cl)(Cl)=[S:13].O>C(OCC)C>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[CH2:5][CH2:6][N:7]=[C:12]=[S:13]
Reactant: COc1ccccc1CCN
Reactant: S=C(Cl)Cl
Solvent: CCOCC
Solvent: O
Product: COc1ccccc1CCN=C=S
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
To a solution of 2-methoxyphenethylamine (1.98 g) in diethylether (20 ml) was added dropwise under ice-cooling thiophosgene (1.54 g). The mixture was stirred at room temperature for 1 hour. To the solution was added water (30 ml). The mixture was extracted with diethylether (60 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give (2-methoxyphenethyl)isothiocyanate (1.80 g, yield: 71%) as brown oil.
Reaction SMILES: [CH2:1]([CH:14]1OCC[O:15]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]/[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>CO>[CH:14](=[O:15])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]/[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCC/C=C/CCCCCCC1OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: CCCCC/C=C/CCCCCCC=O

Procedure:
0.89 g 2-[(E)tridec-7-enyl]-1,3-dioxolane (9), 30 mg p-toluenesulphonic acid and 25 ml of water were boiled in 75 ml methanol for 72 h under reflux under blanketing gas (86% conversion). The reaction mixture was extracted twice with 200 ml diethyl ether, washed with 30 ml sodium bicarbonate solution and dried over sodium sulphate and the solvent was distilled off under vacuum. Flash chromatography on silica gel gave (E)-8-tetradecenal (10) (E/Z ratio according to GC>97/3).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].Cl[C:8]1[N:9]([CH3:27])[CH:10]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[CH:11]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[N:12]=1>>[CH3:19][C:16]1[CH:15]=[CH:14][C:13]([C:11]2[N:12]=[C:8]([C:2]([O:4][CH2:5][CH3:6])=[O:3])[N:9]([CH3:27])[C:10]=2[C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)=[CH:18][CH:17]=1
Reactant: CCOC(=O)Cl
Reactant: Cc1ccc(C2N=C(Cl)N(C)C2c2ccc(C)cc2)cc1
Product: CCOC(=O)c1nc(-c2ccc(C)cc2)c(-c2ccc(C)cc2)n1C

Procedure:
Using essentially the same procedure as Example 1, Step C, but using ethyl chloroformate, 2-chloro-4,5-di-(4-methylphenyl)-1-methylimidazoline (0.10 g, 0.33 mmol) from Example 2, Step B was converted to the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[Br:14]Br>CCOC(C)=O>[N+:1]([C:4]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[C:7]([Br:14])[C:5]=1[NH2:6])([O-:3])=[O:2]
Reactant: BrBr
Reactant: Nc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: CCOC(C)=O
Product: Nc1c(Br)cc([N+](=O)[O-])cc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 92 %

Procedure:
To a solution of 2,4-dinitroaniline (2.2 g, 12 mmol) in 40 ml of ACOH was added 1.0 ml of Br2 dropwise and reaction mixture was stirred for 1 h. The reaction mixture was concentrated in vacuo, yielding a dark residue which was diluted with EtOAc and washed with aqueous NaHCO3. Organic layer was dried over MgSO4 and concentrated in vacuo to provide 2.9 g (11 mmol, 92%) of 2,4-dinitro-6-bromo-aniline which was characterized by NMR and used in a following reaction without further purification.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Br:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([NH:18]C(=O)OC(C)(C)C)[CH:16]=2)[NH:11][C:10]=1[C:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([O:37][C:38]2[CH:43]=[C:42]([C:44]#[N:45])[CH:41]=[C:40]([Cl:46])[CH:39]=2)[C:31]=1[F:47])=[O:27]>C(Cl)(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]([C:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([O:37][C:38]3[CH:43]=[C:42]([C:44]#[N:45])[CH:41]=[C:40]([Cl:46])[CH:39]=3)[C:31]=1[F:47])=[O:27])=[C:9]2[Br:8]
Reactant: CC(C)(C)OC(=O)Nc1ccc2[nH]c(C(=O)NCc3ccc(Cl)c(Oc4cc(Cl)cc(C#N)c4)c3F)c(Br)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]c4ccc(N)cc4c3Br)c2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 119.8 %

Procedure:
Trifluoroacetic acid (0.5 mL, 6.49 mmol) was added to a suspension of 1,1-dimethylethyl (3-bromo-2-{[({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)amino]carbonyl}-1H-indol-5-yl)carbamate (0.082 g, 0.126 mmol) in chloroform (2 mL). The resulting solution was stirred at room temperature overnight. The solvent was evaporated to give the title compound (0.100 g, 107%). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.34 (s, 1H), 9.86 (br. s., 2 H), 8.66 (t, 1H), 7.78-7.84 (m, 1H), 7.56 (t, 1H), 7.41-7.52 (m, 5H), 7.25 (dd, 1H), 4.49-4.72 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=O.[C:15]([O:21][CH:22]1[CH2:25][CH2:24][CH2:23]1)(=[O:20])[CH2:16][C:17]([CH3:19])=[O:18]>>[CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=[C:16]([C:17](=[O:18])[CH3:19])[C:15]([O:21][CH:22]1[CH2:23][CH2:24][CH2:25]1)=[O:20]
Reactant: CC(=O)CC(=O)OC1CCC1
Reactant: Cc1cc(=O)c2cccc(C=O)c2o1
Product: CC(=O)C(=Cc1cccc2c(=O)cc(C)oc12)C(=O)OC1CCC1

Procedure:
The title compound is prepared in analogy to example 25 (stage 25a) starting from 2-methyl-4-oxo-4H-chromene-8-carbaldehyde (2 g, 10.62 mmol) and cyclobutyl acetoacetate (1.66 g, 10.62 mmol). 3.4 g (98% of theory) of the title compound are obtained as an E/Z isomer mixture.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([CH3:12])[C:5]=1[NH2:13].[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([CH3:12])[C:5]=1[NH:13][C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)c1ccc(OC)c(C)c1N
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Product: COC(=O)c1ccc(OC)c(C)c1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.6 %

Procedure:
To an ice cold solution of the above ester (81) (1.5 g, 7.68 mmol) and TEA (2 ml) in dry DCM (30 ml) was added benzoyl chloride (1.4 g, 10 mmol) and the mixture was stirred for four hours at room temperature. Benzoyl chloride (0.14 g, 1 mmol) was added and the mixture was stirred for one hour more at room temperature. A 5% aqueous solution of citric acid was added and the mixture was extracted three times with ethyl acetate. The organic phase was washed with a saturated aqueous solution of sodium hydrogen carbonate and brine, dried with sodium sulfate and evaporated under reduced pressure. The product was purified by column chromatography on silica gel with eluted with hexane-ethyl acetate which gave the title compound (1.6 g).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(CC)CC)C.[CH2:13]([O:20][C:21]([C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([CH2:32][CH2:33][OH:34])[CH:30]=2)[NH:25][C:24]=1[C:35]([F:38])([F:37])[F:36])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1>[CH2:13]([O:20][C:21]([C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([CH2:32][CH2:33][O:34][S:2]([CH3:1])(=[O:4])=[O:3])[CH:30]=2)[NH:25][C:24]=1[C:35]([F:37])([F:36])[F:38])=[O:22])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(OCc1ccccc1)c1c(C(F)(F)F)[nH]c2ccc(CCO)cc12
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1ccc2[nH]c(C(F)(F)F)c(C(=O)OCc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methanesulfonyl chloride (0.1 mL, 1.15 mmol, 1 eq) and triethylamine (0.32 mL, 2.30 mmol, 2 eq) were added to 5-(2-hydroxy-ethyl)-2-trifluoromethyl-1H-indole-3-carboxylic acid benzyl ester (420 mg, 1.15 mmol, 1 eq) obtained from previous step in THF (50 mL) solution in 100-mL round bottom flask at room temperature. The reaction mixture was stirred at room temperature for 3 hours (followed by TLC). After the solvent was removed, the residue was dissolved in ethyl acetate (100 mL), and then washed with sat NaHCO4 and brine respectively. The organic layer was dried over MgSO4, and concentrated to give a pale brown solid. The crude was carried over to the next step.