Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH2:16])=[N:13][C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1.N1C=CC=CC=1.[CH3:23][O:24][CH2:25][CH2:26][N:27]1[CH2:31][CH2:30][N:29]([C:32](Cl)=[O:33])[C:28]1=[O:35]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:16][C:32]([N:29]3[CH2:30][CH2:31][N:27]([CH2:26][CH2:25][O:24][CH3:23])[C:28]3=[O:35])=[O:33])=[N:13][C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1
Reactant: COCCN1CCN(C(=O)Cl)C1=O
Reactant: Cc1nc(N)ccc1Oc1ccnc(Cl)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COCCN1CCN(C(=O)Nc2ccc(Oc3ccnc(Cl)c3)c(C)n2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.8 %

Procedure:
A 0° C. mixture of Example A7 (0.350 g, 1.485 mmol) and pyridine (0.251 mL, 3.12 mmol) in DCM (10 mL) was treated with a solution of Example B4 (0.368 g, 1.782 mmol) in DCM (5 mL) and stirred at RT overnight. The mixture was treated with satd. NaHCO3, extracted with DCM (2×) and the combined organics were dried over Na2SO4, concentrated to dryness and purified twice via silica gel chromatography (MeOH/DCM) to afford N-(5-((2-chloropyridin-4-yl)oxy)-6-methylpyridin-2-yl)-3-(2-methoxyethyl)-2-oxoimidazolidine-1-carboxamide (487 mg, 81%) as a yellow oil. MS (ESI) m/z: 406.1 (M+H+).
Reaction SMILES: C[O:2][C:3](=[O:26])[CH:4]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[CH:11][C:10]=1[N+:23]([O-:25])=[O:24])C(OC)=O>Cl>[CH3:22][O:21][C:17]1[CH:16]=[C:15]([C:12]2[CH:13]=[CH:14][C:9]([CH2:4][C:3]([OH:26])=[O:2])=[C:10]([N+:23]([O-:25])=[O:24])[CH:11]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)C(C(=O)OC)c1ccc(-c2cccc(OC)c2)cc1[N+](=O)[O-]
Agent: Cl
Product: COc1cccc(-c2ccc(CC(=O)O)c([N+](=O)[O-])c2)c1
Temperature: 110 °C

Procedure:
2-(3′-Methoxy-3-nitro-biphenyl-4-yl)-malonic acid dimethyl ester (4.4023 gms.) is suspended in 45 mL of 6N HCl and heated at 110° C. for 4 days. The reaction mixture is cooled to room temperature and the precipitate is collected by filtration. As the solid material is in rather large chunks, the solid purification is simplified by first dissolving the solid chunks in an excess of hot methanol, and subsequently concentrating the solution in vacuo to get a more manageable powder. This powder is then triturated with approximately 10 mL of methanol and filtered yielding (3′-methoxy-3-nitro-biphenyl-4-yl)-acetic acid in the amount of 2.0120 gms.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:17]1([S:23](Cl)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(#N)C>[I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([S:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:25])=[O:24])[CH:3]=1
Reactant: Ic1c[nH]c2ncccc12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=S(=O)(c1ccccc1)n1cc(I)c2cccnc21
Yield: 73.9 %

Procedure:
3-Iodo-1H-pyrrolo[2,3-b]pyridine (4.55 g, 18.7 mmol) and K2CO3 (7.73 g, 55.9 mmol) were dissolved in acetonitrile (200 mL). Benzenesulfonyl chloride (4.76 mL, 37.3 mmol) was added, and the reaction mixture was heated to reflux for 10 hours. The reaction mixture was cooled and partitioned between EtOAc and water. The organic layer was washed with water (2×), brine, and dried over Na2SO4 and concentrated. The resulting residue was purified by column chromatography (4:1 to 0:1 hexane/DCM) giving 3-iodo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (5.31 g, 74.1%).
Reaction SMILES: [F:1][B-:2]([F:5])([F:4])[F:3].[NH+]1C=CC=CC=1.[CH3:12][N:13]([CH3:19])/[CH:14]=[CH:15]/[C:16](=[O:18])[CH3:17].[CH3:20][N:21]([CH3:26])[CH:22]=[CH:23][CH:24]=O>C(OC(=O)C)(=O)C.C(O)(=O)C>[F:1][B-:2]([F:5])([F:4])[F:3].[CH3:12][N:13]([CH3:19])[CH:14]=[C:15]([C:16](=[O:18])[CH3:17])[CH:24]=[CH:23][CH:22]=[N+:21]([CH3:26])[CH3:20]
Reactant: CC(=O)/C=C/N(C)C
Reactant: CN(C)C=CC=O
Agent: F[B-](F)(F)F
Agent: c1cc[nH+]cc1
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)C(C=CC=[N+](C)C)=CN(C)C
Temperature: 0 °C
Yield: 71.7 %

Procedure:
Pyridinium tetrafluoroborate (2.21 g, 13.3 mmol) was added to a solution of (3E)-4-(dimethylamino)-3-buten-2-one (1.54 ml, 13.3 mmol) in 13.5 ml acetic anhydride/acetic acid (2:1). The resulting suspension was cooled to 0° C. and 3-dimethylaminoacroleine (1.33 ml, 13.3 mmol) was added over a period of 1 h under vigorous stirring and cooling with an ice bath receiving a red-brown precipitate. The cool reaction mixture was filtered and the remaining solid was washed with diethylether several times and dried under reduced pressure. The pentamethinium salt was obtained as orange crude product (2.69 g, 96%) and was used without any further purification.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11].[CH:12](O)(C)[CH3:13].[OH-].[Na+]>C1OCCOCCOCCOCCOCCOC1.O>[CH2:12]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11])[CH3:13]
Reactant: CC(C)O
Reactant: COc1cc(C=O)ccc1O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOc1ccc(C=O)cc1OC
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 92 %

Procedure:
76 grams of 4-hydroxy-3-methoxybenzaldehyde (0.5 mol) and 500 mL of isopropanol are added into a four-necked flask and then stirred for 20 minutes, a constant pressure dropping funnel is used for slowly dropping 150 milliliters of aqueous solution of 6.5 grams of 18-crown-6 ether and 133 grams of sodium hydroxide, and stirring is performed for 30 minutes, the reaction system is heated to 60° C., at which 85 grams of bromethyl is dropped for reacting for 5 to 6 hours while TLC tracking is implemented, after the reaction ends, the reaction system is cooled (to 15° C.) and is added with 500 mL of water for stopped reaction, the product is extracted by ether (3×300 mL), organic phase is washed with water to be neutral, anhydrous MgSO4 is dried, ether is partially distilled, a large amount of petroleum ether is added to precipitate crude product, the crude product is subjected to recrystallization by ether/petroleum ether to obtain 83 grams of 4-ethoxy-3-methoxybenzaldehyde:, and the yield is 92%.
Reaction SMILES: [OH:1][C@H:2]1[C:18]([CH3:20])([CH3:19])[O:17][C:5]2=[CH:6][C:7]3[C:8]([CH3:16])=[CH:9][C:10]([C:14]#[N:15])=[N:11][C:12]=3[CH:13]=[C:4]2[C@H:3]1[NH:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(O)(=O)C.[Pd]>[NH2:15][CH2:14][C:10]1[CH:9]=[C:8]([CH3:16])[C:7]2[CH:6]=[C:5]3[O:17][C:18]([CH3:20])([CH3:19])[C@H:2]([OH:1])[C@@H:3]([NH:21][CH2:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:4]3=[CH:13][C:12]=2[N:11]=1
Reactant: Cc1cc(C#N)nc2cc3c(cc12)OC(C)(C)[C@H](O)[C@@H]3NCCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: Cc1cc(CN)nc2cc3c(cc12)OC(C)(C)[C@H](O)[C@H]3NCCc1ccccc1
Reaction time: 2 h

Procedure:
To a solution of (3R*,4R*)-3-hydroxy-2,2,9-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinoline-7-carbonitrile described in Synthesis Example 14 (110 mg, 0.283 mmol) in acetic acid (5 mL), 10% Pd/C (22 mg) was added at room temperature, and the resulting mixture was stirred for 2 hours under hydrogen atmosphere. Upon the completion of the reaction, the resulting solution was filtered through celite, the solvent was distilled off and then sodium carbonate aqueous solution was added to the residue, and the resulting solution was extracted with chloroform, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain crude product of (3R*,4S*)-7-aminomethyl-2,2,9-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinolin-3-ol (75.1 mg).
Reaction SMILES: Cl.C([N:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[Br:18])[CH2:10]1)C1C=CC=CC=1.[OH-].[Na+].ClC(OC(Cl)=O)C>CCOC(C)=O>[Br:18][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:16]=1[CH2:17][NH:9][CH2:10]2
Reactant: Brc1cccc2c1CN(Cc1ccccc1)C2
Agent: CC(Cl)OC(=O)Cl
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Brc1cccc2c1CNC2
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 111.5 %

Procedure:
To a solution of 2-benzyl-4-bromoisoindoline hydrochloride (11 g, 30.96 mmol) in 200 mL EtOAc was added 1M NaOH (100 mL) and the mixture stirred for 30 min. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and solvent evaporated to an oil which was azeotroped once with toluene (50 mL). The oil was dissolved in chlorobenzene (50 mL) and 4A molecular sieves (5 g) added to the stirred solution. After 10 min, 1-chloroethylchloroformate (5.6 mL, 51 mmol) was added dropwise over 5 min. The reaction mixture was then heated to 90° C. for 2 h, cooled to room temperature and filtered. The solids were washed with chlorobenzene (5 mL) and methanol (40 mL). The filtrate was heated to 70° C. for 1 h., allowed to cool and stirred at room temperature overnight. The solids were filtered, washed with chlorobenzene (2 mL) and hexane and dried to give 6.84 g of title compound. LRMS (ESI) m/z 198.1 [(M+H)+; calcd for C8H9BrN: 198.0].
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[CH:10][CH:11]=1)=[O:5].C(N(CC)CC)C.CCOCC.[CH3:25][O:26][C:27]1[CH:37]=[CH:36][C:30]([CH2:31][CH2:32][C:33](Cl)=[O:34])=[CH:29][CH:28]=1>ClCCl>[CH3:25][O:26][C:27]1[CH:37]=[CH:36][C:30]([CH2:31][CH2:32][C:33]([NH:12][C:9]2[CH:8]=[CH:7][C:6]([C:4]([O:3][CH2:2][CH3:1])=[O:5])=[CH:11][CH:10]=2)=[O:34])=[CH:29][CH:28]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: COc1ccc(CCC(=O)Cl)cc1
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(NC(=O)CCc2ccc(OC)cc2)cc1
Reaction time: 8 h

Procedure:
A solution of 13.73 g. of benzocaine and 11.56 ml. of triethylamine in 100 ml. of ether is slowly added to a stirred solution of 15 g. of p-methoxyhydrocinnamoyl chloride in 100 ml. of ether. The mixture is stirred overnight, 250 ml. of dichloromethane are added, and the mixture is extracted with 200 ml. of water, then 200 ml. of 10% hydrochloric acid, dried over magnesium sulfate, and evaporated to yield a solid. This solid is crystallized from 200 ml. of toluene, giving 21.4 g. of the desired product as white crystals, m.p. 134°-135.5° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[C:3](/[CH:10]=[C:11]2\[C:12](=[O:20])[NH:13][C:14]3[C:19]\2=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:2]1.[C:21]([O-])(=[O:23])[CH3:22].[K+]>C(OC(=O)C)(=O)C>[C:21]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[C:3](/[CH:10]=[C:11]2\[C:12](=[O:20])[NH:13][C:14]3[C:19]\2=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:2]1)(=[O:23])[CH3:22]
Reactant: CC(=O)[O-]
Reactant: O=C1Nc2ccccc2/C1=C/c1c[nH]c2ncccc12
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)n1cc(/C=C2\C(=O)Nc3ccccc32)c2cccnc21
Yield: 65 %

Procedure:
A mixture of (Z)-3-[(7-azaindol-3-yl)methylen]-2-oxindole (2.61 g, 0.010 mol), potassium acetate (0.98 g, 0.010 mol) and acetic anhydride (10 ml) is heated at reflux temperature for 15 h and then concentrated under vacuum. The residue is taken up with ethyl acetate and water, the organic phase separated, washed with water, dried over Na2SO4 and evaporated under vacuum. The residue is crystallized from ethanol to give pure title compound in 65% yield.
Reaction SMILES: Cl[C:2]1[C:3]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)=[N:4][S:5][N:6]=1.[C:15]1([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C.CO>[C:15]1([N:21]2[CH2:26][CH2:25][N:24]([C:2]3[C:3]([O:7][CH2:8][C:9]4[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=4)=[N:4][S:5][N:6]=3)[CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Clc1nsnc1OCc1ccncc1
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CN(C)C=O
Solvent: CO
Product: c1ccc(N2CCN(c3nsnc3OCc3ccncc3)CC2)cc1
Temperature: 70 °C
Yield: 9 %

Procedure:
4-(4-chloro-[1,2,5]thiadiazol-3-yloxymethyl)-pyridine (50 mg, 0.22 mmol) was dissolved in 200 μL of DMF along with 1-phenylpiperazine (75 μL, 0.49 mmol). The reaction was heated to 70° C. overnight. The reaction mixture was diluted with methanol to a volume of 2 mL and the reaction mixture was purified by reverse phase chromatography, affording 1-phenyl-4-{4-[(pyridin-4-ylmethyl)oxy]-1,2,5-thiadiazol-3-yl}piperazine (7 mg). 1H NMR (DMSO-d6) δ 8.62 (d, 2H), 7.46 (d, 2H), 7.23 (t, 2H), 7.01 (d, 2H), 6.82 (t, 1H), 5.58 (s, 2H), 3.64 (m, 4H), 3.23 (m, 4H) ppm.
Reaction SMILES: [CH2:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].CO.O.[NH2:16][NH2:17]>O>[CH2:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[N:16][N:17]=[CH:9][C:8]2[CH:11]=[CH:12][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:6][CH:7]=2)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1ccc(C=O)cc1
Reactant: NN
Solvent: CO
Solvent: O
Product: CC(C)Cc1ccc(C=NN=Cc2ccc(CC(C)C)cc2)cc1
Reaction time: 24 h

Procedure:
A 3-liter three-necked flask was charged with 638.5 g (3.94 mol) of 4-isobutylbenzaldehyde and 1 liter of methanol, which were stirred for mixing by a mechanical stirrer. While the reactor was cooled with water so as to maintain the temperature of the reaction solution below 50° C., 98.5 g (1.97 mol) of hydrazine monohydrate was slowly added dropwise. After the completion of addition, the reaction solution was heated under reflux for 30 minutes and then allowed to stand one day.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][N:7]([CH3:9])[CH2:6][N:5]([C:10]2[S:11][C:12]3[C:18]([OH:19])=[CH:17][C:16]([C:20]4[CH:21]=[N:22][C:23]([N:26]5[CH2:31][CH2:30][C:29]([CH3:37])([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:28][CH2:27]5)=[N:24][CH:25]=4)=[CH:15][C:13]=3[N:14]=2)[C:4]1=[O:38])[CH3:2].[C:39](=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O.CI>[Cl-].[NH4+].CCOC(C)=O>[CH2:1]([N:3]1[CH2:8][N:7]([CH3:9])[CH2:6][N:5]([C:10]2[S:11][C:12]3[C:18]([O:19][CH3:39])=[CH:17][C:16]([C:20]4[CH:25]=[N:24][C:23]([N:26]5[CH2:27][CH2:28][C:29]([CH3:37])([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:30][CH2:31]5)=[N:22][CH:21]=4)=[CH:15][C:13]=3[N:14]=2)[C:4]1=[O:38])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)C1(C)CCN(c2ncc(-c3cc(O)c4sc(N5CN(C)CN(CC)C5=O)nc4c3)cn2)CC1
Agent: [Cl-]
Agent: [Cs+]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: CCOC(=O)C1(C)CCN(c2ncc(-c3cc(OC)c4sc(N5CN(C)CN(CC)C5=O)nc4c3)cn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.8 %

Procedure:
To a solution of ethyl 1-[5-[2-(3-ethyl-5-methyl-2-oxo-1,3,5-triazinan-1-yl)-7-hydroxy-1,3-benzothiazol-5-yl]pyrimidin-2-yl]-4-methyl-piperidine-4-carboxylate (533 mg, 0.593 mmol), dicesium carbonate (390 mg, 1.19 mmol) and N,N-dimethylformamide (10 mL) at 0° C. was added MeI (55 μL, 0.89 mmol) and the reaction mixture was allowed to warm to rt before stirring for 1 hr. A further portion of MeI (110 μL, 1.78 mmol) was added and the mixture stirred at rt for a further 18 hrs. The reaction was diluted with ammonium chloride solution (50 mL) and EtOAc (50 mL). The organic layer was separated and the aqueous layer washed with further portions of EtOAc (2×50 mL). The organic layers were combined, dried (MgSO4) and concentrated in vacuo to give crude product mixture followed by flash chromatography (12 g silica column), eluting with 0-100% EtOAc gradient in n-heptane to give the desired product (226 mg, light brown solid). 1H NMR (CDCl3) δ 8.63 (s, 2H), 7.51 (d, J=1.3 Hz, 1H), 6.82 (d, J=1.3 Hz, 1H), 5.23 (s, 2H), 4.42 (dt, J=13.6, 4.0 Hz, 2H), 4.35 (s, 2H), 4.25 (q, J=7.1 Hz, 2H), 4.04 (s, 3H), 3.56-3.50 (m, 2H), 3.43-3.34 (m, 2H), 2.70 (s, 3H), 2.25 (d, J=13.6 Hz, 2H), 1.58-1.48 (m, 2H), 1.38-1.24 (m, 9H). MS: 554.1 [M+H]+.
Reaction SMILES: [C:1]([C:3]1([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4]1)#[N:2].N>C(O)C.[Rh]>[NH2:2][CH2:1][C:3]1([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CCOC(=O)C1(C#N)CCCC1
Agent: [Rh]
Agent: N
Solvent: CCO
Product: CCOC(=O)C1(CN)CCCC1

Procedure:
20 g of ethyl 1-cyanocyclopentanecarboxylate are placed in 200 ml of a 10% solution of ammonia in ethanol and hydrogenated at 60° C. under a pressure of 100 bar in the presence of rhodium-on-alumina for 72 hours. After filtration on cellite® and evaporation, the residue is chromatographed on silica using a DCM/methanol/20% aqueous ammonia mixture (98/2/0.5; v/v/v) as the eluent.
Reaction SMILES: N1C2C(=CC=CC=2)C(CCCC(O)=O)=[CH:2]1.[CH2:16]([N:23]([CH2:37][CH2:38][O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[O:46][CH3:47])[C:24](=[O:36])[CH2:25][CH2:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][CH:28]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([N:23]([CH2:37][CH2:38][O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[O:46][CH3:47])[C:24](=[O:36])[CH2:25][CH:26]([C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][CH:28]=1)[CH3:2])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(O)CCCc1c[nH]c2ccccc12
Reactant: COc1ccccc1OCCN(Cc1ccccc1)C(=O)CCc1c[nH]c2ccccc12
Product: COc1ccccc1OCCN(Cc1ccccc1)C(=O)CC(C)c1c[nH]c2ccccc12

Procedure:
Replacing 3-indole propionic acid with 3-indole butyric acid (1.8 g, 8.9 mmol) in (4a) above afforded N-benzyl-3-(1H-indol-3-yl)-N-[2-(2-methoxy-phenoxy)-ethyl]buty-anide (1.3 g; 78%) as a white foam. MS FAB m/e 443 (M+H)+ MS FAB m/e 465 (M+Na)+
Reaction SMILES: [C:1](Cl)(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[NH:23][N:22]=[C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)[N:20]=1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>O1CCOCC1.O>[CH3:31][O:30][C:26]1[CH:25]=[C:24]([C:21]2[N:20]=[C:19]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][O:11][C:1](=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[NH:23][N:22]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: CCCCCCCC(=O)Cl
Reactant: COc1cccc(-c2n[nH]c(-c3ccccc3CO)n2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: O
Product: CCCCCCCC(=O)OCc1ccccc1-c1nc(-c2cccc(OC)c2)n[nH]1
Temperature: 50 °C
Reaction time: 1 h
Yield: 56.5 %

Procedure:
A solution of octanoyl chloride (4.25 ml, 25 mmole) in dioxane (10 ml) is added dropwise during ten minutes into a stirred suspension of 5-(2-hydroxymethylphenyl)-3-(3-methoxyphenyl)-1H-1,2,4-triazole (2.81 g, 10 mmole) and triethylamine (4.2 ml, 30 mmole) in dioxane (50 ml). After 1 hour, 8% NaHCO3 (50 ml) is added and the reaction mixture is heated to 50° C. for two hours, cooled to room temperature, diluted with water (60 ml) and extracted with methylene chloride. The organic extracts are washed with water, dried over Na2SO4 and concentrated to dryness yielding a raw residue which is purified by silica-gel column chromatography eluting with a mixture 0% to 10% ethyl acetate in toluene and crystallized from isopropyl ether/petroleum ether. Yield: 56.5%. M.p. 61° C. and 87° C. (as a mixture of crystal forms).
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][C:9]#[CH:10])([CH3:4])([CH3:3])[CH3:2].[CH3:12][O:13][C:14]([C:16]1[S:17][C:18](Br)=[CH:19][CH:20]=1)=[O:15]>C(#N)C.CCOC(C)=O.C(N(CC)CC)C>[CH3:12][O:13][C:14]([C:16]1[S:17][C:18]([C:10]#[C:9][CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:11])=[CH:19][CH:20]=1)=[O:15]
Reactant: COC(=O)c1ccc(Br)s1
Reactant: C#CCNC(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)c1ccc(C#CCNC(=O)OC(C)(C)C)s1
Temperature: 25 °C
Yield: 63406.2 %

Procedure:
A mixture of prop-2-ynyl-carbamic acid tert-butyl ester (1.67 g, 0.011 mmol), 5-bromo-thiophene-2-carboxylic acid methyl ester (2.50 g, 0.011 mmol), tetrakistriphenylphosphine(0) palladium (0.622 g, 0.0538 mmol), Cul (0.102 g, 0.538 mmol) and triethylamine (1.57 mL, 0.011 mmol) in 50 mL acetonitrile under nitrogen was heated at reflux for 16 h. The reaction was cooled to room temperature, diluted with 75 mL EtOAc, washed with 5.5% HCl, water and brine, dried over MgSO4, filtered and concentrated in vacuo to an oil. The product was purified via flash chromatography (9:1 to 4:1 hexanes:EtOAc) to afford the title compound as an oil (2.06 g). MS 313 (M+18).
Reaction SMILES: CO[C:3]([C:5]1[C:9]([CH3:10])=[C:8]([C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]([C:21]([F:24])([F:23])[F:22])[CH:12]=2)[N:7]([CH2:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:6]=1[CH3:32])=[O:4].[C@@H:33]([NH2:37])([CH2:35][CH3:36])[CH3:34]>>[C@@H:33]([NH:37][C:3]([C:5]1[C:9]([CH3:10])=[C:8]([C:11]2[CH:12]=[C:13]([C:21]([F:22])([F:23])[F:24])[CH:14]=[C:15]([C:17]([F:20])([F:18])[F:19])[CH:16]=2)[N:7]([CH2:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:6]=1[CH3:32])=[O:4])([CH2:35][CH3:36])[CH3:34]
Reactant: COC(=O)c1c(C)c(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n(CC2CCCCC2)c1C
Reactant: CC[C@H](C)N
Product: CC[C@H](C)NC(=O)c1c(C)c(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n(CC2CCCCC2)c1C

Procedure:
The title compound was synthesized in analogy to example 203, from 5-(3,5-bis-trifluoromethyl-phenyl)-1-cyclohexylmethyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid methyl ester and (S)-sec-butylamine as R1R2NH, MS (ISP) 503.4 (M+H)+.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([O:34][CH3:35])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[C:38]1([CH:44]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH2:45][NH2:46])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[C:47]1([CH:44]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:45][NH:46][C:3]([C:5]2[N:14]3[C:8]([CH2:9][N:10]([C:19]([C:21]4[CH:26]=[CH:25][C:24]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[CH3:33])=[C:23]([O:34][CH3:35])[CH:22]=4)=[O:20])[C:11]4[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=4[CH2:13]3)=[CH:7][CH:6]=2)=[O:4])[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: COc1cc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)ccc1-c1ccccc1C
Reactant: NCC(c1ccccc1)c1ccccc1
Product: COc1cc(C(=O)N2Cc3ccc(C(=O)NCC(c4ccccc4)c4ccccc4)n3Cc3ccccc32)ccc1-c1ccccc1C
Yield: 61 %

Procedure:
The title compound was prepared in the manner of Example 36 from 2,2,2-trichloro-1-{10-[(2-methoxy-2′-methyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 35 and 2,2-diphenylethylamine. Purification was performed using HPLC with a normal phase column. Elution with a mixture of etoxynonafluorobutane and methanol gave the title compound (61% yield) as a yellow powder, m.p. 129-132° C. MS [(+)ESI, m/z]: 632 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([O:20][CH2:21][CH:22]=[C:23]([Cl:25])[Cl:24])[CH:17]=[C:16]([Cl:26])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1.Cl.[C:28]([O:32][NH2:33])([CH3:31])([CH3:30])[CH3:29].Cl>N1C=CC=CC=1>[C:28]([O:32][N:33]=[CH:12][C:11]1[CH:14]=[CH:15][C:8]([CH2:7][CH2:6][CH2:5][O:4][C:3]2[C:2]([Cl:1])=[CH:19][C:18]([O:20][CH2:21][CH:22]=[C:23]([Cl:25])[Cl:24])=[CH:17][C:16]=2[Cl:26])=[CH:9][CH:10]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)ON
Reactant: O=Cc1ccc(CCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C)ON=Cc1ccc(CCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 75.9 %

Procedure:
To a mixture of 0.43 g of 4-(3-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)propyl)benzaldehyde and 5 ml of pyridine was added 0.15 g of O-tert-butylhydroxylamine hydrochloride. After stirring at room temperature for 24 hours, the reaction mixture was poured into diluted hydrochloric acid, and extracted twice with diethyl ether. The diethyl ether layers were combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated to give a crude product. This crude product was subjected to silica gel chromatography, which afforded 0.38 g (yield, 75%) of 4-(3-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)propyl)benzaldehyde O-tert-butyloxime, nD25.5 1.5673.