Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]([Cl:35])([Cl:34])[CH2:3][O:4][C:5](=[O:33])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:29])[NH:21][C:22]3[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=3)=[CH:16][C:15]=2[N+:30]([O-])=O)=[CH:9][CH:8]=1.[Cl-].[NH4+]>O1CCCC1.C(O)C.O.[Fe]>[Cl:35][C:2]([Cl:1])([Cl:34])[CH2:3][O:4][C:5](=[O:33])[NH:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:29])[NH:21][C:22]3[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=3)=[CH:16][C:15]=2[NH2:30])=[CH:11][CH:12]=1
Reactant: O=C(Nc1ccc(Oc2ccc(C(=O)Nc3ccc(Br)cc3)cc2[N+](=O)[O-])cc1)OCC(Cl)(Cl)Cl
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: Nc1cc(C(=O)Nc2ccc(Br)cc2)ccc1Oc1ccc(NC(=O)OCC(Cl)(Cl)Cl)cc1
Temperature: 25 °C
Yield: 82.1 %

Procedure:
A mixture of the product of Example 361D (6.0 g, 10.0 mmol), iron powder (2.8 g, 50 mmol, 5 equiv, from Acros, electrolytically reduced, reagent, powder), and ammonium chloride (0.81 g, 15.0 mmol, 1.5 equiv) in tetrahydrofuran/ethanol/water (60/60/20 mL) was heated under reflux for 5 hours. The reaction mixture was cooled to room temperature and filtered through Celite, rinsing the Celite pad with 50 mL of ethanol. The resulting filtrate was evaporated under reduced pressure and the residue was partitioned between ethyl acetate (100 mL) and water (100 mL). The aqueous phase was extracted with ethyl acetate (2×100 mL). The combined organic phases were washed with brine (50 mL), dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure to give the title compound (4.71 g, 83%) as a tan solid.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].[Cl:12][S:13](O)(=[O:15])=[O:14]>>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([S:13]([Cl:12])(=[O:15])=[O:14])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCc2ccccc21
Reactant: O=S(=O)(O)Cl
Product: CCN1CCc2cc(S(=O)(=O)Cl)ccc21
Temperature: 50 °C
Reaction time: 8 h
Yield: 6 %

Procedure:
1-ethylindoline (15 g, 102.04 mmol) was added at 0° C. to ClSO3H (60 g). The resulting solution was stirred at 50° C. overnight, then the reaction was quenched by adding 300 g iced water. The resulting solution was extracted with dichloromethane (3×600 mL) and the organic layers were combined, dried (MgSO4) and concentrated. The residue was then purified by column chromatography using a 1:100 ethyl acetate/petroleum ether solvent system to give 1.5 g (6%) of 1-ethylindoline-5-sulfonyl chloride as a yellow solid. 1H NMR (CDCl3) δ 7.28 (d, 1H), 7.18 (d, 1H), 7.11 (s, 1H), 3.39 (q, 2H), 3.52 (t, 2H), 3.06 (t, 2H), 1.23 (t, 3H).
Reaction SMILES: C[O-].[Na+].Cl.Cl[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[SH:13][C:14]1[N:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:22](=[O:30])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1.O>CO>[C:24]1([N:23]2[C:22](=[O:30])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[C:14]2[S:13][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: ClCc1ccccn1
Reactant: O=c1c2ccccc2nc(S)n1-c1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=c1c2ccccc2nc(SCc2ccccn2)n1-c1ccccc1
Reaction time: 2.5 h
Yield: 49.8 %

Procedure:
6.1 ml Of 28% methanolic solution of sodium methoxide and 2.46 g of 2-chloromethylpyridine hydrochloride were added to a solution of 3.62 g of 2-mercapto-3-phenyl-4(3H)-quinazolinone in 100 ml of methanol, and the stirring was continued at room temperature for 2.5 hours. About 50 ml of water were added to the reaction solution and crystals precipitated were collected by filtration and recrystallized from ethyl acetate to give 2.45 g of the title compound.
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]3[N:29]([C:30]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:28]=[N:27][N:26]=3)=[CH:15][CH:14]=2)[C:8]([CH2:49][OH:50])=[CH:7][N:6]=1)[CH2:2][CH2:3][CH3:4].C(C1N=C(NCC2C=CC(C3C=CC=CC=3)=C(C3N(C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)N=NN=3)C=2)C(CO)=CN=1)CCC>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH2:1]([C:5]1[N:10]=[C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]3[N:29]([C:30]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)[N:28]=[N:27][N:26]=3)=[CH:15][CH:14]=2)[C:8]([CH:49]=[O:50])=[CH:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(CO)c(NCc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)n1
Agent: [Mn+4]
Agent: CCCCc1ncc(CO)c(NCc2ccc(-c3ccccc3)c(-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)c2)n1
Agent: [O-2]
Solvent: ClCCl
Product: CCCCc1ncc(C=O)c(NCc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)n1
Temperature: 25 °C

Procedure:
2-Butyl-5-hydroxymethyl-4-{N-[(2'-[N-triphenylmethyl-tetrazol-5-yl]biphenyl-4-yl)methyl]amino}pyrimidine, the product of Example 2A, is dissolved in methylene chloride. Excess activated manganese dioxide is added and the reaction mixture is stirred at ambient temperature until the reaction is complete according to TLC analysis. The reaction mixture is then filtered and the filtrate is concentrated in vacuo to give the intermediate 2-butyl-4-{N-[(2'-[N-triphenylmethyl-tetrazol-5-yl]biphenyl-4-yl)methyl]amino}pyrimidine-5-carboxaldehyde. The triphenylmethyl group is removed, as described in Example 1D, to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9](=[O:22])[CH2:10][CH:11]([C:13](=[O:21])[C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=1)Br.C(#N)C.[C:27]([O-:30])(=[S:29])[CH3:28].[K+]>CCOCC>[CH3:1][O:2][C:3](=[O:23])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9](=[O:22])[CH2:10][CH:11]([S:29][C:27](=[O:30])[CH3:28])[C:13](=[O:21])[C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=1
Reactant: CC([O-])=S
Reactant: COC(=O)[C@@H]1CCCN1C(=O)CC(Br)C(=O)c1ccc(Br)cc1
Agent: [K+]
Solvent: CCOCC
Solvent: CC#N
Product: COC(=O)[C@@H]1CCCN1C(=O)CC(SC(C)=O)C(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5.28 g. of 1-[3-(4-bromobenzoyl)-3-bromopropionyl)-L-proline methyl ester (Example 30) in 35 ml. of acetonitrile is added 1.48 g. of potassium thioacetate. The mixture is stirred at room temperature for 2 hours, filtered and the filtrate is evaporated to dryness in vacuo leaving an amber gum. This is dissolved in ether and chromatographed on a 1"×16" silica gel column, eluting with ether and taking 100 ml. cuts. Cut number 3 gives the desired product (1.64 g.) as a glass.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([CH2:12]O)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C1(P([N:28]=[N+:29]=[N-:30])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>O1CCCC1>[N:28]([CH2:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([Cl:1])[CH:11]=1)=[N+:29]=[N-:30]
Reactant: COC(=O)c1ccc(CO)cc1Cl
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CN=[N+]=[N-])cc1Cl
Yield: 97.5 %

Procedure:
A solution of 2-chloro-4-(hydroxymethyl)benzoic acid, methyl ester (11.09 g, 55.3 mmol), diphenylphosphoryl azide (22.58 g, 82.0 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (8.57 g, 56.3 mmol) in tetrahydrofuran was stirred overnight at room temperature. Silica gel was added and the solvent was evaporated. The residue was chromatographed (10% ethyl acetate/hexanes) to give 4-(azidomethyl)-2-chlorobenzoic acid, methyl ester (12.17 g, 98%) as a white solid.
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[C:8]3[C:13](=[CH:14][C:4]=2[N:3]=1)[CH:12]=[CH:11][CH:10]=[CH:9]3.[SH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1.O>C(O)C.[OH-].[Na+]>[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][S:15][C:2]1[NH:6][C:5]2[CH:7]=[C:8]3[C:13](=[CH:14][C:4]=2[N:3]=1)[CH:12]=[CH:11][CH:10]=[CH:9]3
Reactant: SCc1ccccn1
Reactant: Clc1nc2cc3ccccc3cc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: c1ccc(CSc2nc3cc4ccccc4cc3[nH]2)nc1
Yield: 51.4 %

Procedure:
0.92 g of 2-chloro-1H-naphth[2,3-d]imidazole and 0.57 g of 2-mercaptomethylpyridine were heated under reflux for 18 hours in 15 ml of ethanol and 4.5 ml of 1 N caustic soda. 50 ml of water were added to the reaction solution, which was then extracted twice with a total amount of 50 ml of ethyl acetate. The organic phases were washed with saturated sodium chloride solution, dried over magnesium sulphate, and evaporated to dryness on a rotary evaporator. Crystallisation from 50 ml of acetonitrile provided 0.68 g of 2-[(2-pyridylmethyl)thio]-1H-naphth[2,3-d]imidazole having a m.p. of 169°-170°.
Reaction SMILES: C[CH:2]1[CH2:7][CH2:6][CH2:5][N:4](C)[C:3]1([CH3:10])C.C([Li])CCC.[CH3:16][C:17]1[CH:22]=C[N:20]=[C:19]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25](C3C=CC=CN=3)[N:24]=2)[CH:18]=1.Br[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][Br:42]>C1COCC1.C(OC(=O)C)C>[Br:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:22][C:17]1[CH:18]=[C:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[N:20]=[C:10]([C:3]2[CH:2]=[CH:7][CH:6]=[CH:5][N:4]=2)[CH:16]=1
Reactant: Cc1ccnc(-c2cccc(-c3ccccn3)n2)c1
Reactant: CC1CCCN(C)C1(C)C
Reactant: BrCCCCCCBr
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: BrCCCCCCCc1cc(-c2ccccn2)nc(-c2ccccn2)c1

Procedure:
0.5 ml of tetramethylpiperidine (3 mmol) and 20 ml of anhydrous THF were put into a 100 ml Schlenk flask and stirred well. After the resultant material was cooled using liquid nitrogen and ethylacetate to −78□, 1.88 mL of normal butyllithium (3 mmol, 1.6 M hexane solution) was added dropwise slowly using an injector. 15 ml of THF, in which 0.5 g of the compound synthesized in Example 2 (compound 221 in FIG. 2, 2 mmol) was dissolved, was put into the flask using an injector at −78□. After being stirred at −78□ for 30 minutes, the resultant material was added dropwise slowly into 1 ml of a 1,6-dibromohexane solution (4 mmol), in which 50 ml of THF was diluted, using a cannula at −78□. After being stirred at −78□ for 12 hours, the resultant material was distilled under reduced pressure to be a saturation solution. Next, the resultant material was refined using column chromatography (developer: THF/normal hexane=⅓) to obtain a compound 4′-(7-bromoheptyl)-2,2′;6′,2″-terpyridine (intermediate compound 231 in FIG. 2) with a yield of 76%.
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH:8]([C:9]([OH:11])=[O:10])[CH2:7][CH2:6][NH:5][CH2:4]1.O=S(Cl)[Cl:14].[CH3:16][CH2:17]O>>[ClH:14].[CH3:2][CH:3]1[CH:8]([C:9]([O:11][CH2:16][CH3:17])=[O:10])[CH2:7][CH2:6][NH:5][CH2:4]1
Reactant: CC1CNCCC1C(=O)O
Reactant: CCO
Reactant: O=S(Cl)Cl
Agent: Cl
Product: CCOC(=O)C1CCNCC1C

Procedure:
The mixture of 3-methylpiperidine-4-carboxylic acid hydrochloride (3.3 g, 18.4 mmol, 1.0 eq) and SOCl2 (6.6 g, 55.3 mmol, 3.0 equiv) in EtOH (30 mL) was stirred at reflux for 3 h, and then the reaction mixture was concentrated by vacuum to give compound ethyl 3-methylpiperidine-4-carboxylate hydrochloride as a yellow oil which was used for next step. ESI-MS (M+H)+: 172.2.
Reaction SMILES: C([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[CH:13][NH:14][C:15](=[O:16])[C:10]=2[CH2:9]1)C1C=CC=CC=1.C(N(CC)CC)C.CO.C(O)=O>>[N:12]1[C:11]2[CH2:17][CH2:18][NH:8][CH2:9][C:10]=2[C:15](=[O:16])[NH:14][CH:13]=1
Reactant: O=c1[nH]cnc2c1CN(Cc1ccccc1)CC2
Solvent: CCN(CC)CC
Solvent: O=CO
Solvent: CO
Product: O=c1[nH]cnc2c1CNCC2
Temperature: 60 °C

Procedure:
A mixture of 6-benzyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3H)-one (Intermediate 2, 18.0 g, 0.0738 mol), triethylamine (48 mL, 0.34 mol) Palladium hydroxide (10 g, 0.07 mol) in methanol (242 mL, 5.91 mol) was heated to 60° C. Formic acid (7.6 mL, 0.20 mol) was added dropwise to the mixture over a 15 minute period. The mixture was heated at at 65° C. for three hours, allowed to cool, and filtered over Celite. The filtrate was concentrated under reduced vacuum to yield the title compound as a yellow solid which was used directly in the next reaction. (9.62 g, 77.6%).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:10]([C:11]([OH:13])=O)=[CH:9][N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:5]2=[N:6][CH:7]=1.[NH2:22][C:23]([CH3:27])([CH3:26])[CH2:24][OH:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CCOC(C)=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.CN(C=O)C>[Br:1][C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:22][C:23]([CH3:27])([CH3:26])[CH2:24][OH:25])=[O:13])=[CH:9][N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:5]2=[N:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(Br)cnc21
Reactant: CC(C)(N)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(CO)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.9 %

Procedure:
To a mixture of 2-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (2 g, 5.37 mmol), 2-amino-2-methylpropan-1-ol (575 mg, 6.45 mmol) and HATU (2.25 g, 5.91 mmol) was added DIPEA (2.08 g, 2.81 mL, 16.1 mmol) and DMF (18 mL). The mixture was stirred at room temperature for 16 h then was diluted with EtOAc and 10% citric acid. The phases were separated and the organic phase was then washed successively with 10% citric acid, NaHCO3 and brine. The organic phase was dried (MgSO4), filtered and purified by chromatography (silica, 20-60% ethyl acetate in hexanes) to give 2-bromo-N-(1-hydroxy-2-methylpropan-2-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (1.95 g, 4.4 mmol, 82%) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm: 8.47 (s, 1H), 8.34 (s, 1H), 8.13 (s, 1H), 5.69 (s, 2H), 3.78 (s, 2H), 3.57 (t, J=8.4 Hz, 3H), 1.52 (s, 60.96 (t, J=8.4 Hz, 3H), 0.00 (s, 9H).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[CH2:4][CH:5]=[CH2:6].[NH2:8][C:9]1[CH:14]=[N:13][CH:12]=[C:11](Cl)[N:10]=1>O1CCOCC1.C(OCC)(=O)C>[CH2:3]([O:7][C:11]1[N:10]=[C:9]([NH2:8])[CH:14]=[N:13][CH:12]=1)[CH2:4][CH:5]=[CH2:6]
Reactant: C=CCCO
Reactant: Nc1cncc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C=CCCOc1cncc(N)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.6 %

Procedure:
A suspension of NaH (60%, 618 mg, 15.45 mmol) in dioxane (30 mL) at 0° C. was treated with 3-buten-1-ol (1.33 mL, 15.45 mmol), stirred for 2 hours, treated with 2-amino-6-chloropyrazine (1 g, 7.72 mmol), stirred at 100° C. for 2.5 days, cooled to room temperature, and diluted with ethyl acetate. The mixture was washed with water, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography eluting with hexanes/ethyl acetate (2:1) to provide the desired product (390 mg, 31%). MS (DCI/NH3) m/z 166.12 (M+H)+; 1H NMR (500 MHz, benzene-d6) δ 2.66 (m, 2H), 4.42 (t, J=6.87 Hz, 2H), 5.24 (dd, J=10.22, 1.98 Hz, 1H), 5.30 (m, 1H), 6.04 (m, 1H), 7.64 (s, 1H), 7.65 (s, 1H).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].[O-]CC.[Na+].[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH2:19][CH:20]([C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][C:39](OCC)=[O:40])=[CH:33][CH:32]=3)=[CH:26][CH:25]=2)[C:21]([OH:23])=[O:22])[CH:14]=[C:15]([O:17][CH3:18])[CH:16]=1>C(O)C>[CH3:18][O:17][C:15]1[CH:14]=[C:13]([CH2:19][CH:20]([C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:32]=[CH:33][C:34]([CH2:37][CH2:38][C:39](=[O:40])[NH:1][C:2]([NH2:4])=[O:3])=[CH:35][CH:36]=3)=[CH:26][CH:25]=2)[C:21]([OH:23])=[O:22])[CH:12]=[C:11]([O:10][CH3:9])[CH:16]=1
Reactant: NC(N)=O
Reactant: CCOC(=O)CCc1ccc(Oc2ccc(C(Cc3cc(OC)cc(OC)c3)C(=O)O)cc2)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cc(CC(C(=O)O)c2ccc(Oc3ccc(CCC(=O)NC(N)=O)cc3)cc2)cc(OC)c1

Procedure:
3-(3,5-Dimethoxyphenyl)-2-{4-[4-(2-ethoxycarbonylvinyl)-phenoxy]-phenyl}-acrylic acid (4, 2.37 g, 5.0 mmol) was dissolved in a mixture of ethanol-dioxane (2:1, 150 mL), and palladium charcoal (10%, 500 mg) was added. The mixture was stirred under hydrogen for 15 hr. Catalyst was then removed by filtration, and solvent was evaporated under reduced pressure to yield 3-(3,5-dimethoxy-phenyl)-2-{4-[4-(2-ethoxycarbonylethyl)-phenoxy]-phenyl}-propionic acid (18) quantitatively. Urea (0.21 g, 3.58 mmol) was dissolved in sodium ethoxide (2.7 M, 2.2 mL, 5.92 mmol) at 80° C. under argon, and to this a solution of 18 (1.13 g, 2.37 mmol) in anhydrous ethanol (15 mL) was added and heated at this temperature for 13 hr. Ethanol was evaporated under reduced pressure, water (20 mL) was added, acidified to pH 1 by 5% aqueous HCl and extracted with ethyl acetate (50 mL). The organic layer was washed with water (2×25 mL), brine (2×20 mL), dried over anhydrous magnesium sulfate and evaporated. The crude product was purified by silica gel chromatography and eluted with hexane-ethyl acetate (3:7) containing acetic acid (1%), followed by recrystallization from ethanol. Yield: 256 mg, 22.8%.
Reaction SMILES: [N:1]1[C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=[C:3]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:2]=1.[NH2:16][C@@H:17]([CH3:34])[CH2:18][N:19]1[CH:23]=[CH:22][C:21]([C:24]2[CH:31]=[C:30]([F:32])[C:27]([C:28]#[N:29])=[C:26]([Cl:33])[CH:25]=2)=[N:20]1.CN(C=O)C>C(Cl)Cl>[Cl:33][C:26]1[CH:25]=[C:24]([C:21]2[CH:22]=[CH:23][N:19]([CH2:18][C@@H:17]([NH:16][C:7]([C:6]3[N:1]=[CH:2][C:3]([C:10]4[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=4)=[CH:4][CH:5]=3)=[O:9])[CH3:34])[N:20]=2)[CH:31]=[C:30]([F:32])[C:27]=1[C:28]#[N:29]
Reactant: O=C(O)c1ccc(-c2cccnc2)cn1
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1ccc(-c2cccnc2)cn1
Yield: 22.7 %

Procedure:
The title compound was prepared using the procedure described in Example 3(h) starting from 3,3′-bipyridine-6-carboxylic acid (0.861 mmol, 172 mg) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (0.718 mmol, 200 mg) using DMF (2 ml) as the solvent. After the reaction had stopped, DCM was added and the reaction mixture was evaporated. The residue was purified by flash chromatography and trituration from methanol, respectively. 75 mg of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.18 (d, 3H), 4.35-4.59 (m, 3H), 7.02 (d, 1H), 7.55-7.62 (m, 1H), 7.87-7.93 (m, 2H), 7.98 (s, 1H), 8.06-8.10 (m, 1H), 8.19-8.25 (m, 1H), 8.35 (dd, 1H), 8.68 (dd, 1H), 8.99-9.05 (m, 2H), 9.13 (d, 1H).
Reaction SMILES: [Na].N.[CH3:3][CH:4]([CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])[CH2:5][CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:16])[CH3:15])=[CH:10][CH:9]=1>O1CCCC1>[CH3:3][CH:4]([CH2:17][CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:5][CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:15])[CH3:16])=[CH:10][CH:9]=1
Reactant: CC(C)=CCCC(C)CC=Cc1ccc(C(C)C)cc1
Agent: N
Agent: [Na]
Solvent: C1CCOC1
Product: CC(C)CCCC(C)CC=Cc1ccc(C(C)C)cc1
Reaction time: 1 h

Procedure:
To a stirred solution of 16 g (0.7 g at) of sodium in 600 ml of liquid ammonia was added dropwise a solution of 93 g (0.34 mol.) of 4,8-dimethyl-1-(p-isopropylphenyl)nona-1,7-diene in 125 ml of anhydrous tetrahydrofuran. Total addition time was one hour. The excess sodium was destroyed by the cautious addition of methanol. Then 200 ml of hexane were added and the ammonia was allowed to evaporate. To the residue a saturated solution of NH4Cl was added cautiously. The organic layer was separated, and the aqueous layer was diluted with water and extracted twice with hexane. The combined hexane layers were washed with water, dilute HCl, brine and then dried. Evaporation of the hexane and distillation of the residue yielded the title product. Yield was 88 g (94%), bp 130°-135° C/0.1 mm. nD25 = 1.4938.
Reaction SMILES: [CH2:1]([C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15](Cl)=[O:16])[CH2:11][CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(Cl)(=O)C(Cl)=O.[F:24][C:25]1[C:30]([F:31])=[C:29]([C:32]#[N:33])[CH:28]=[CH:27][C:26]=1[OH:34].N1C=CC=CC=1>C1(C)C=CC=CC=1.C(Cl)Cl>[CH2:1]([C@H:9]1[CH2:10][CH2:11][C@H:12]([C:15]([O:34][C:26]2[CH:27]=[CH:28][C:29]([C:32]#[N:33])=[C:30]([F:31])[C:25]=2[F:24])=[O:16])[CH2:13][CH2:14]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCC[C@H]1CC[C@H](C(=O)Cl)CC1
Reactant: N#Cc1ccc(O)c(F)c1F
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCCCCCC[C@H]1CC[C@H](C(=O)Oc2ccc(C#N)c(F)c2F)CC1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of 0.1 mol of trans-4-octylcyclohexanecarbonyl chloride (prepared from the carboxylic acid with oxalyl chloride in toluene) and 75 ml of methylene chloride is added to a mixture of 0.1 mol of 2,3-difluoro-4-cyanophenol (prepared according to Example 4), 0.12 mol of pyridine, 10 mmol of 4-N,N-dimethylaminopyridine and 250 ml of methylene chloride. After the mixture has been stirred at room temperature for 10 hours, it is washed with dilute hydrochloric acid, saturated sodium bicarbonate solution and water. Customary working up gives 4-(trans-4-octylcyclohexanecarbonyloxy)-2,3-difluorobenzonitrile.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]1[CH3:15])C.[H-].C([Al+]CC(C)C)C(C)C>C(COC)OC.ClCCl.C1CCCCC1>[CH3:15][C:7]1[N:6]([CH2:5][CH:4]=[O:3])[C:14]2[C:9]([CH:8]=1)=[CH:10][CH:11]=[CH:12][CH:13]=2
Reactant: CCOC(=O)Cn1c(C)cc2ccccc21
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: COCCOC
Solvent: C1CCCCC1
Solvent: ClCCl
Product: Cc1cc2ccccc2n1CC=O
Temperature: -70 °C
Reaction time: 4 h
Yield: 68.6 %

Procedure:
A solution of (2-methyl-indol-1-yl)-acetic acid ethyl ester (400 mL, 1.97 mmol) in dimethoxyethane-dichloromethane (1:1, 30 mL) was cooled to −70° C. and treated with a solution of diisobutyl aluminum hydride in cyclohexane (3.9 mL, 1.0 M). The reaction was stirred at −70° C. for 4 h, quenched with an aqueous solution of hydrochloric acid (80 mL, 1 N) and extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered and concentrated, and the residue was purified to give (2-methyl-indol-1-yl)-acetaldehyde (234 mg, 75% yield). LCMS (m/z): 206.1 (M+1).
Reaction SMILES: C([Li])CCC.[Cl-].[Cl:7][CH2:8][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:28]([CH:35]1[C:41]2[CH:42]=[C:43]([C:46]([O:48][CH3:49])=[O:47])[CH:44]=[CH:45][C:40]=2[O:39][CH2:38][C:37](=O)[CH2:36]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.Cl>O1CCCC1.ClCCl.O>[CH2:28]([CH:35]1[C:41]2[CH:42]=[C:43]([C:46]([O:48][CH3:49])=[O:47])[CH:44]=[CH:45][C:40]=2[O:39][CH2:38][C:37](=[CH:8][Cl:7])[CH2:36]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: COC(=O)c1ccc2c(c1)C(Cc1ccccc1)CC(=O)CO2
Reactant: ClC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccc2c(c1)C(Cc1ccccc1)CC(=CCl)CO2
Temperature: 0 °C
Reaction time: 1 h
Yield: 52.5 %

Procedure:
1.1 equivalents of n-butyllithium are added to a suspension of 40 mg (0.12 mmol) of chloromethyltriphenylphosphonium chloride in 3 ml of tetrahydrofuran cooled to 0° C. After stirring for one hour, the ylide is added at 0° C. via a hollow tube to 30 mg (0.1 mmol) of methyl 5-benzyl-3-oxo-2,3,4,5-tetrahydro-1-benzoxepin-7-carboxylate, prepared according to example 9. After stirring at ambient temperature for 30 minutes, water, 1N hydrochloric acid and dichloromethane are added. The phases are separated by settling and then the aqueous phase is extracted three times with dichloromethane. The combined organic phases are washed with brine, are then dried and are finally concentrated under vacuum. The crude reaction product is then purified by chromatography on silica gel (ethyl acetate/heptane 5/95) to provide 18 mg (53%) of methyl 5-benzyl-3-(chloromethylene)-2,3,4,5-tetrahydro-1-benzoxepin-7-carboxylate in the form of a mixture of two isomers in a Z/E ratio (60/40); exact mass (CI): calculated 343.11009; found 343.11027.