Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:6][CH:5]2[CH2:12][CH3:13].Br[C:15]1[C:24]2[CH2:23][CH2:22][CH2:21][CH:20]([NH2:25])[C:19]=2[CH:18]=[N:17][CH:16]=1.[C@H]1(N)CCCC[C@@H]1N>O1CCOCC1.[Cu]I>[NH2:25][CH:20]1[C:19]2[CH:18]=[N:17][CH:16]=[C:15]([N:6]3[CH:5]([CH2:12][CH3:13])[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=4)[C:7]3=[O:11])[C:24]=2[CH2:23][CH2:22][CH2:21]1
Reactant: NC1CCCc2c(Br)cncc21
Reactant: CCC1NC(=O)c2ccc(Cl)cc21
Agent: [Cu]I
Agent: N[C@H]1CCCC[C@@H]1N
Solvent: C1COCCO1
Product: CCC1c2cc(Cl)ccc2C(=O)N1c1cncc2c1CCCC2N
Temperature: 140 °C

Procedure:
A mixture of 5-chloro-3-ethyl-2,3-dihydro-isoindol-1-one (intermediate A-13-1, 390 mg, 2 mmol), 4-bromo-5,6,7,8-tetrahydroisoquinolin-8-amine (intermediate B-12[A], 339 mg, 1.5 mmol), CuI (38 mg, 0.2 mmol), (1S,2S)-cyclohexane-1,2-diamine (45 mg, 0.4 mmol) and CsCO3 (750 mg, 4 mmol) were dissolved in dioxane (10 mL) and heated at 140° C. for 12 hours. After cooling to room temperature, the reaction mixture was filtered through a pad of silica gel (0.5-1 cm) and rinsed with diethyl ether. The combined filtrate was concentrated in vacuo to afford a crude product which was used in the next step reaction without further purification. MS: 342.1 (M+H+)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=[O:17])[C:15]3(O)[CH:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)[C:9]2=[S:19])=[C:4]([F:20])[CH:3]=1.C(OC(=O)C)(=O)C>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9](=[S:19])[C:10]3[CH2:11][CH2:12][CH2:13][CH2:14][C:15]=3[C:16]2=[O:17])=[C:4]([F:20])[CH:3]=1
Reactant: O=C1N(c2ccc(Cl)cc2F)C(=S)C2CCCCC12O
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: O=C1C2=C(CCCC2)C(=S)N1c1ccc(Cl)cc1F
Reaction time: 8 h
Yield: 94.8 %

Procedure:
In 75 ml of pyridine was dissolved 28.2 g of 2-(4-chloro-2-fluorophenyl)-3a-hydroxy-1-thioxo-octahydroisoindole-3-one, and 30 ml of acetic acid anhydride was added to the solution, which was allowed to stand at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in dichloromethane, washed with water and dried over anhydrous sodium sulfate. After distilling off the dichloromethane, the resulting crystals were washed with a small amount of cold ethanol and dried, thereby affording 25.2 g (yield of 95%) of the subject compound. Recrystallization from ethanol yielded red-purple crystals, m.p. 101°-102° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N@:11]1[CH2:13][CH:12]1[C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]2[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:18][CH2:17]1)=[O:15])(=[O:10])=[O:9].[I-].[Na+].[CH2:34]([N:38]=[C:39]=[O:40])[CH2:35][CH2:36][CH3:37]>>[CH2:34]([N:38]1[C@H:12]([C:14]([N:16]2[CH2:17][CH2:18][N:19]([C:22]3[C:27]([C:28]([F:29])([F:31])[F:30])=[CH:26][CH:25]=[CH:24][N:23]=3)[CH2:20][CH2:21]2)=[O:15])[CH2:13][N:11]([S:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])(=[O:9])=[O:10])[C:39]1=[O:40])[CH2:35][CH2:36][CH3:37]
Reactant: O=C(C1C[N@@]1S(=O)(=O)c1ccccc1Cl)N1CCN(c2ncccc2C(F)(F)F)CC1
Reactant: CCCCN=C=O
Agent: [I-]
Agent: [Na+]
Product: CCCCN1C(=O)N(S(=O)(=O)c2ccccc2Cl)C[C@H]1C(=O)N1CCN(c2ncccc2C(F)(F)F)CC1

Procedure:
In analogy to example 2, [(S)-1-(2-chloro-benzenesulfonyl)-aziridin-2-yl]-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-methanone (example 72, step 3) was reacted with sodium iodide and n-butylisocyanate to give the title compound as a colorless foam. MS: 574.2 ([M+H]+)
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[C:22]([CH3:23])=[CH:21][C:11]([C:12]([NH:14][C:15]2[CH:20]=[CH:19][N:18]=[N:17][CH:16]=2)=[O:13])=[C:10]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:9]=1.[CH3:32][N:33]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[N:34]1>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:23][C:22]1[C:8]([C:36]2[CH:35]=[N:34][N:33]([CH3:32])[CH:37]=2)=[CH:9][C:10]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:11]([CH:21]=1)[C:12]([NH:14][C:15]1[CH:20]=[CH:19][N:18]=[N:17][CH:16]=1)=[O:13]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1cc(C(=O)Nc2ccnnc2)c(OCc2ccccc2)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1cc(C(=O)Nc2ccnnc2)c(OCc2ccccc2)cc1-c1cnn(C)c1
Temperature: 120 °C

Procedure:
Sodium carbonate (0.32 ml, 0.32 mmol) was added to 4-bromo-5-methyl-2-[(phenylmethyl)oxy]-N-4-pyridazinylbenzamide (may be prepared as described in Example 10; 64 mg, 0.16 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (40.1 mg, 0.19 mmol) and Pd(Ph3P)4 (11.14 mg, 9.64 μmol) in 1,2-dimethoxyethane (3 ml). The mixture was heated in a microwave at 120° C. for 1 hour, the solvent was removed in vacuo and the solid triturated with DMSO/methanol (1:1, 1 ml) to yield the title compound as a white solid. 9 mg.
Reaction SMILES: [CH2:1]([N:4]([CH2:8][C:9]1[CH:10]=[C:11]([C:29](OCC)=[O:30])[C:12](=[O:28])[N:13]2[C:18]=1[CH:17]=[CH:16][CH:15]=[C:14]2[C:19]1[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=1[CH3:27])[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].[H-].C([Al+]CC(C)C)C(C)C.CO.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>O1CCCC1>[CH2:1]([N:4]([CH2:8][C:9]1[CH:10]=[C:11]([CH2:29][OH:30])[C:12](=[O:28])[N:13]2[C:18]=1[CH:17]=[CH:16][CH:15]=[C:14]2[C:19]1[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=1[CH3:27])[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3]
Reactant: CCCN(CCC)Cc1cc(C(=O)OCC)c(=O)n2c(-c3c(C)cc(C)cc3C)cccc12
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [H-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCN(CCC)Cc1cc(CO)c(=O)n2c(-c3c(C)cc(C)cc3C)cccc12
Temperature: -40 °C
Reaction time: 1 h
Yield: 46.3 %

Procedure:
Ethyl 1-((dipropylamino)methyl)-6-mesityl-4-oxo-4H-quinolizine-3-carboxylate (0.228 g, 0.51 mmol) was dissolved in tetrahydrofuran (3.5 mL). The solution was cooled to −40° C. and diisobutylaluminum hydride (DIBAL-H) (1M, 1.5 mL, 1.5 mmol) was added rapidly. The reaction stirred for 1 h and was warmed to room temperature. Methanol and Rochelle's salt were added and the mixture stirred at room temperature for 3 h. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried, concentrated, and flash chromatographed (2% methanol/ethyl acetate) to give 0.096 g (46% yield) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9](=[O:17])[C:10](=[N+:15]=[N-:16])[C:11]([O:13][CH3:14])=[O:12].C(P(CCCC)CCCC)CCC>C(OC(C)C)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9](=[O:17])[C:10](=[N:15][NH2:16])[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)C(=[N+]=[N-])C(=O)c1c(F)cccc1Cl
Agent: CCCCP(CCCC)CCCC
Solvent: CC(C)OC(C)C
Product: COC(=O)C(=NN)C(=O)c1c(F)cccc1Cl
Yield: 63.6 %

Procedure:
To 4.90 g (19.1 m=ol) of methyl 3-(2-chloro-6-fluorophenyl)-2-diazo-3-oxopropionate in 100 mL of diisopropyl ether was added 5.2 mL (21 mmol) of tributylphosphine. The bright yellow phosphazine adduct that precipitated from solution after 30 min. was collected, dissolved in dichloromethane and concentrated onto silica gel. The hydrazone product was eluted with a 75% hexanes/ethyl acetate mixture to give 3.14 g of the title compound as an off-white solid. The filtrate from the adduct formation was similarly loaded onto silica gel and eluted to give an additional 1.04 g of the title compound. An overall isolated yield of 4.18 g (85%) of the title compound as a 10:1 mixture of hydrazone isomers was obtained.
Reaction SMILES: [C:1]1([O:7][S:8]([C:11]2[CH:16]=[C:15]([S:17](=[O:20])(=[O:19])[NH2:18])[C:14]([N:21]([CH3:28])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:13][C:12]=2Cl)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[CH2:35][NH2:36]>>[C:1]1([O:7][S:8]([C:11]2[CH:16]=[C:15]([S:17](=[O:20])(=[O:19])[NH2:18])[C:14]([N:21]([CH3:28])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:13][C:12]=2[NH:36][CH2:35][C:31]2[S:30][CH:34]=[CH:33][CH:32]=2)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCc1cccs1
Reactant: CN(c1ccccc1)c1cc(Cl)c(S(=O)(=O)Oc2ccccc2)cc1S(N)(=O)=O
Product: CN(c1ccccc1)c1cc(NCc2cccs2)c(S(=O)(=O)Oc2ccccc2)cc1S(N)(=O)=O
Yield: 94 %

Procedure:
182 g of 2-chloro-4-(N-methylanilino)-5-sulfamoylbenzene sulfonic acid phenyl ester (0.4 mol) are reacted with 0.5 liter of 2-thienylmethyl amine according to Example 1. Working up in the manner described in Example 1 gives 200 g of 2-(thienylmethylamino)-4-(N-methylanilino)-5-sulfamoylbenzene sulfonic acid phenyl ester in chromatographically pure form. Yield: 94% of the theory. The product sinters at a temperature above 90° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](O)=[N:10][CH:11]=[CH:12][N:13]=2)=[CH:4][CH:3]=1.CC(C1C(C2C=CC([Cl:39])=CC=2)=NC=CN=1)(C(OCC)=O)C(OCC)=O.CC(C1C(C2C=CC(Cl)=CC=2)=NC=CN=1)C(OCC)=O.CC(C1C(C2C=CC(Cl)=CC=2)=NC=CN=1)C(O)=O.CC(C1C(C2C=CC(Cl)=CC=2)=NC=CN=1)C(N)=O>>[Cl:39][C:9]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[N:13][CH:12]=[CH:11][N:10]=1
Reactant: CCOC(=O)C(C)(C(=O)OCC)c1nccnc1-c1ccc(Cl)cc1
Reactant: Oc1nccnc1-c1ccc(Cl)cc1
Agent: CC(C(=O)O)c1nccnc1-c1ccc(Cl)cc1
Agent: CC(C(N)=O)c1nccnc1-c1ccc(Cl)cc1
Agent: CCOC(=O)C(C)c1nccnc1-c1ccc(Cl)cc1
Product: Clc1ccc(-c2nccnc2Cl)cc1

Procedure:
2-Chloro-3-(p-chlorophenyl)pyrazine is prepared by the method of Karmas and Spoerri. (loc. cit.), using 3-(p-chlorophenyl)pyrazinol as the starting material. Starting with this material and using the procedures of Examples V, VI, IX, and XI, the products obtained are diethyl α-methyl-3-(p-chlorophenyl)pyrazinylmalonate, ethyl α-methyl-3-(p-chlorophenyl)pyrazineacetate, α-methyl-3-(p-chlorophenyl)pyrazineacetic acid, and α-methyl-3-(p-chlorophenyl)pyrazineacetamide.
Reaction SMILES: B(Br)(Br)Br.[F:5][C:6]1[CH:11]=[CH:10][C:9]([O:12]C)=[C:8]([CH:14]([CH3:19])[C:15]([F:18])([F:17])[F:16])[CH:7]=1.O>ClCCl>[F:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([CH:14]([CH3:19])[C:15]([F:16])([F:17])[F:18])[CH:7]=1
Reactant: COc1ccc(F)cc1C(C)C(F)(F)F
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CC(c1cc(F)ccc1O)C(F)(F)F
Temperature: 25 °C

Procedure:
Boron tribromide (19.1 mL, 198 mmol) was added to a −78° C. solution of 4-fluoro-1-methoxy-2-(1,1,1-trifluoropropan-2-yl)benzene (C43) (20.0 g, 90.0 mmol) in dichloromethane (400 mL). The cooling bath was removed and the reaction mixture was allowed to warm to room temperature over 66 hours. It was then cooled in an ice bath and treated drop-wise with water (50 mL) while venting into an aqueous potassium carbonate trap. When the vigorous reaction had subsided, additional water (300 mL) was added, and the mixture was stirred until all the solids had dissolved. The aqueous layer was extracted with dichloromethane (200 mL), and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure, while keeping the water bath between 23° C. and 35° C. The product was obtained as an oil, which contained some impurities by 1H NMR assessment; this was used without additional purification. Yield: 20.6 g, assumed quantitative. 1H NMR (400 MHz, CDCl3), product peaks only: δ 1.45 (d, J=7.4 Hz, 3H), 3.98-4.12 (m, 1H), 6.74 (dd, J=8.8, 4.5 Hz, 1H), 6.85-6.91 (m, 1H), 7.04-7.09 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([C:22]2[CH:23]=[N:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=2)[CH2:20][NH2:21])=[CH:15][CH:14]=1>>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([C:16]1[CH:15]=[CH:14][C:13]([F:12])=[CH:18][CH:17]=1)[C:22]1[CH:23]=[N:24][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:26][CH:27]=1)=[O:6]
Reactant: O=C(O)c1cccc(F)c1Cl
Reactant: NCC(c1ccc(F)cc1)c1ccc(C(F)(F)F)nc1
Product: O=C(NCC(c1ccc(F)cc1)c1ccc(C(F)(F)F)nc1)c1cccc(F)c1Cl

Procedure:
From 2-chloro-3-fluorobenzoic acid and 2-(4-fluorophenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)ethanamine. LCMS (MH+): m/z=441.1, tR (minutes, Method G)=2.63
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:42]=[CH:41][C:25]([O:26][C:27]2[CH:40]=[CH:39][C:30]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36](O)=[O:37])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C[O:45][C:46](=[O:55])[C@H:47]([CH2:49][CH2:50][C:51]([O:53]C)=[O:52])[NH2:48]>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([NH:48][C@H:47]([C:46]([OH:45])=[O:55])[CH2:49][CH2:50][C:51]([OH:53])=[O:52])=[O:37])=[CH:39][CH:40]=2)=[CH:41][CH:42]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CC[C@H](N)C(=O)OC
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCCCCC(=O)O)cc2)cc1
Agent: Cl
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCCCCC(=O)N[C@@H](CCC(=O)O)C(=O)O)cc2)cc1

Procedure:
The product from Example 234B and L-glutamic acid dimethyl ester hydrochloride were processed as described in Example 251A and B to provide the titled compound. 1H NMR (500 MHz, DMSO-d6) δ11.60-13.04 (br.s, 2 H), 8.94 (s, 1 H), 8.06 (d, 1 H), 7.23 (m, 7 H), 7.03 (t, 1 H), 6.95 (m, 6 H), 6.82 (d, 2 H), 4.21 (m, 1 H), 4.04 (s, 2 H), 4.00 (s, 2 H), 3.93 (t, 2 H), 2.91 (s, 3 H), 2.39 (s, 3 H), 2.28 (m, 2 H), 2.19 (t, 2 H), 1.96 (m, 1 H), 1.60-1.82 (m, 5 H); MS (ESI+) m/z 718 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[C:14]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]=[C:12]([OH:23])[CH:11]=1.CI.[C:33](=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[C:14]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]=[C:12]([O:23][CH3:33])[CH:11]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)CCc1ccc(OCc2cc(O)cc(Oc3ccccc3)c2)c(F)c1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: CI
Product: CCOC(=O)CCc1ccc(OCc2cc(OC)cc(Oc3ccccc3)c2)c(F)c1
Reaction time: 4 h
Yield: 100 %

Procedure:
To a solution of ethyl 3-{3-fluoro-4-[(3-hydroxy-5-phenoxybenzyl)oxy]phenyl}propanoate (0.30 g, 0.73 mmol) and methyl iodide (2.2 mL, 14.6 mmol) in acetone (10 mL) was added potassium carbonate (0.52 g, 3.76 mmol), and the mixture was heated under reflux and stirred for 4 hours. The reaction solution was diluted with ethyl acetate, filtered, washed with water, and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (hexane/ethyl acetate=7:3) to give the title compound (0.31 g, yield 99%) as an oily matter.
Reaction SMILES: [ClH:1].OS(O)(=O)=O.[Na+].[Cl-].[CH3:9][C:10]([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH2:11]>>[CH3:11][C:10]([Cl:1])([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9]
Reactant: C=C(C)CC(C)(C)C
Reactant: Cl
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Product: CC(C)(C)CC(C)(C)Cl

Procedure:
Dry gaseous HCl, generated by the reaction of H2SO4 and NaCl, was passed through a 30% solution of 2,4,4-trimethyl-1-pentene in dry and distilled CH2Cl2 at 0° C. for 24 hours. The solvent and excess gaseous HCl were removed and the product was purified by distillation from CaH2 under vacuum to avoid decomposition. TMPCl, when stored in a freezer (-20° C.) under N2, was found to be stable at least for a year. Structure was confirmed by 1H NMR.
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[CH:11][C:7]([CH2:8][NH:9][NH2:10])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C([O:15][C:16](=O)[CH:17]=[C:18]([NH2:22])OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[NH2:22][C:18]1[NH:10][N:9]([CH2:8][C:7]2[CH:11]=[CH:12][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=2)[C:16](=[O:15])[CH:17]=1
Reactant: CC(C)c1ccc(CNN)cc1
Reactant: CCOC(=O)C=C(N)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CC(C)c1ccc(Cn2[nH]c(N)cc2=O)cc1
Reaction time: 2 h

Procedure:
32 g of p-isopropylbenzylhydrazine were added, under nitrogen, to a solution of 31.8 g of β-amino-β-ethoxyacrylic acid ethyl ester and 1 g of p-toluenesulphonic acid in 150 ml of ethanol. After stirring for a further two hours, the mixture was left to stand overnight. The compound identified above, which separated out as a precipitate, was filtered off and recrystallised from ethanol. Melting point: 105°, 18.3 g (40%).
Reaction SMILES: O=[C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.ClC1C=CC=CN=1.ClC1N=C(C2C=CC=CC=2)C(C(OCC)=O)=CC=1.N[C:55]1[N:60]=[C:59]([NH:61][CH2:62][CH2:63][NH:64][C:65]2[CH:70]=[CH:69]C(C3NC=CN=3)=C(C3C=CC(Cl)=CC=3Cl)[N:66]=2)[CH:58]=[CH:57][C:56]=1[N+:84]([O-:86])=[O:85]>CC#N.CCN(C(C)C)C(C)C>[N+:84]([C:56]1[CH:57]=[CH:58][C:59]([NH:61][CH2:62][CH2:63][NH:64][C:65]2[N:66]=[C:2]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:69][CH:70]=2)=[N:60][CH:55]=1)([O-:86])=[O:85]
Reactant: Nc1nc(NCCNc2ccc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]
Reactant: CCOC(=O)CC(=O)c1ccccc1
Agent: CCOC(=O)c1ccc(Cl)nc1-c1ccccc1
Agent: Clc1ccccn1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1ccc(NCCNc2ccc([N+](=O)[O-])cn2)nc1-c1ccccc1

Procedure:
ethyl 6-({2-[(5-nitro(2-pyridyl))amino]ethyl}amino)-2-phenylpyridine-3-carboxylate was prepared from ethyl 3-oxo-3-phenylpropanoate as the starting material and DDQ in the oxidation step. The final product is achieved directly from the chloropyridine by reacting ethyl 6-chloro-2-phenylpyridine-3-carboxylate with 2-(2-aminoethylamine)-5-nitropyridine in CH3CN and Hünig's base at 80° C. for 18 hours. The procedures are analogous to the general method for {2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}[6-(2,4-dichlorophenyl)-5-imidazolyl(2-pyridyl)]amine.
Reaction SMILES: [NH2-:1].[Li+].N.[Li].[NH2:5][C:6]1[C:7]2[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][C:8]=2[S:9][C:10]=1[C:11](OC)=[O:12]>O1CCCC1>[NH2:5][C:6]1[C:7]2[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][C:8]=2[S:9][C:10]=1[C:11]([NH2:1])=[O:12]
Reactant: COC(=O)c1sc2cccc(OC)c2c1N
Reactant: [NH2-]
Agent: N
Agent: [Li+]
Agent: [Li]
Solvent: C1CCOC1
Product: COc1cccc2sc(C(N)=O)c(N)c12
Yield: 58 %

Procedure:
Lithium amide in liquid ammonia is prepared as described by Unangst P. C., Carethers M. E., J. Heterocyclic. Chem. 21, 709 (1984), from lithium metal ribbon (0.16 g, 23 mmol). A solution of methyl 3-amino-4-methoxybenzo[b]thiophene-2-carboxylate (1.3 g, 5.5 mmol) [Beck J. R., supra] in 10 mL of tetrahydrofuran is added dropwise. The mixture is stirred for 18 hours as the excess ammonia is permitted to evaporate. The residue is treated with 250 g of ice and water. The solid product is filtered, washed with water, and recrystallized from aqueous ethanol to yield 0.70 g (58%) of product; mp=151°-153° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]2=O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(OCC)(=[O:22])C.Cl>O1CCCC1>[C:7]1([C@H:13]2[CH2:18][CH2:17][C@H:16]([OH:22])[CH2:15][CH2:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C1CCCCC1c1ccccc1
Reactant: CCOC(C)=O
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: O[C@H]1CC[C@H](c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Tetrahydrofuran (200 ml) was dropwise added into a 1 l capacity three-necked flask containing lithiumaluminum hydride (9.9 g, 0.26 mol), at 0° C., followed by sufficiently suspending these materials, dropwise adding a solution of phenylcyclohexanone (91.3 g, 0.52 mol) in tetrahydrofuran (200 ml), agitating the mixture at room temperature for 2 hours, again cooling it down to 0° C., dropwise adding ethyl acetate (20 ml), further adding dilute hydrochloric acid (100 ml), removing insolubles in the resulting reaction solution by suction-filtration, adding ethyl acetate (100 ml) to the filtrate for extraction, three times washing the resulting organic layer with water (100 ml), drying it over magnesium sulfate, filtering off magnesium sulfate, concentrating the residue under reduced pressure to obtain white crystals (98.5 g), recrystallizing from alcohol and drying to obtain 4-trans-phenylcyclohexanol (55 g). M.P.: 117°-119° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7](=[O:12])C(Cl)(Cl)Cl)[NH:5][CH:6]=1.CCN(C(C)C)C(C)C.FC(F)(F)C(O)=O.[NH2:29][CH2:30]/[CH:31]=[CH:32]/[C:33]([O:35][CH2:36][CH3:37])=[O:34]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:7]([NH:29][CH2:30]/[CH:31]=[CH:32]/[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:12])[NH:5][CH:6]=1
Reactant: CCOC(=O)/C=C/CN
Reactant: O=C(c1cc(Br)c[nH]1)C(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)/C=C/CNC(=O)c1cc(Br)c[nH]1
Temperature: 25 °C
Reaction time: 6 h
Yield: 94.7 %

Procedure:
Prepared according to WO 2010/031816. A 250 mL RBF containing 1-(4-bromo-1H-pyrrol-2-yl)-2,2,2-trichloroethanone (Combi-Blocks Inc. San Diego, Calif., 2.40 g, 8.24 mmol) was treated with DCM (80 mL) followed by DIPEA (10 mL, 57.7 mmol). To this stirring solution at RT was slowly added (E)-ethyl 4-aminobut-2-enoate 2,2,2-trifluoroacetate (4.01 g, 16.47 mmol) in DCM (20 mL), and the resulting solution was stirred at RT for 6 h. The reaction mixture was then concentrated in vacuo, and the residue was purified by silica gel chromatography (40-70% EtOAc in hexanes) to provide (E)-ethyl 4-(4-bromo-1H-pyrrole-2-carboxamido)but-2-enoate (2.35 g, 7.80 mmol, 95% yield) as a light yellow crystalline solid: 1H NMR (400 MHz, CDCl3) δ ppm 9.48 (1H, br. s.), 6.89-7.01 (2H, m), 6.58 (1H, dd, J=2.7, 1.4 Hz), 5.89-6.02 (2H, m), 4.16-4.24 (4H, m), 1.23-1.32 (3H, m). m/z (ESI, +ve ion) 301.0/302.9 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]([N:19]2[CH2:24][CH2:23][CH:22]([N:25]3[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[NH:27][C:26]3=O)[CH2:21][CH2:20]2)=[O:18])=[C:9]1[CH3:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:38])=O.[OH-].[Na+]>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]([N:19]2[CH2:24][CH2:23][CH:22]([N:25]3[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[N:27]=[C:26]3[Cl:38])[CH2:21][CH2:20]2)=[O:18])=[C:9]1[CH3:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1c(C(=O)N2CCC(n3c(=O)[nH]c4ccccc43)CC2)c2ccccc2n1Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: Cc1c(C(=O)N2CCC(n3c(Cl)nc4ccccc43)CC2)c2ccccc2n1Cc1ccccc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
A mixture of 0.45 g (0.97 mmol) of 1-[1-(1-benzyl-2-methyl-1H-indole-3-carbonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one (the preparation of which is described hereinafter) and phosphorus oxychloride (6 ml) was stirred at 100° C. for 2 hours and then allowed to cool. The reaction mixture was poured into ice-cold water, 10N NaOH was added until the ph=14, and the mixture was extracted with AcOEt. The combined organic phases were dried over Na2SO4 and concentrated in vacuo. Re-crystallization in Et2O afforded 0.32 g (68%) of (1-benzyl-2-methyl-1H-indol-3-yl)-[4-(2-chloro-benzoimidazol-1-yl)-piperidin-1-yl]-methanone as white crystals. ES-MS m/e (%): 483.6 (M+H+).