Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:12]=[C:11]([N:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)[CH:10]=[CH:9][N:8]=2)=[CH:4][CH:3]=1.[Cu][C:21]#[N:22].CCOC(C)=O>CN(C=O)C>[CH3:19][N:16]1[CH2:17][CH2:18][N:13]([C:11]2[CH:10]=[CH:9][N:8]=[C:7]([C:5]3[S:6][C:2]([C:21]#[N:22])=[CH:3][CH:4]=3)[CH:12]=2)[CH2:14][CH2:15]1
Reactant: N#C[Cu]
Reactant: CN1CCN(c2ccnc(-c3ccc(Br)s3)c2)CC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1CCN(c2ccnc(-c3ccc(C#N)s3)c2)CC1

Procedure:
A mixture of 1-[2-(5-bromo-thiophen-2-yl)-pyridin-4-yl]-4-methyl-piperazine (41 mg, 0.13 mmol) and copper(I) cyanide (55 mg, 0.62 mmol) was heated in DMF at 180° C. by microwave for 30 minutes. After cooling, EtOAc was added and the resulting mixture was passed through Celite®. The filtrate was washed with water and the organic layer was concentrated. The resulting residue was purified by preparative TLC to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[O:16]=[C:17]1[C:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:21][CH2:20][CH2:19][N:18]1[CH2:35][C:36](O)=[O:37].Cl.C(N=C=NCCCN(C)C)C>ClC(Cl)C>[Cl:1][C:2]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:3]=1[CH2:4][N:5]1[CH2:6][CH2:7][N:8]([C:36](=[O:37])[CH2:35][N:18]2[CH2:19][CH2:20][CH2:21][C:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]2=[O:16])[CH2:9][CH2:10]1
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: Clc1ccc(CN2CCNCC2)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC(Cl)Cl
Product: O=C(CN1CCCC(c2ccccc2)(c2ccccc2)C1=O)N1CCN(Cc2ccc(Cl)cc2Cl)CC1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
A solution of 1-(2,4-dichlorobenzyl)piperazine (0.415 g, 1.693 mmol), 2-(2-oxo-3,3-diphenylpiperidin-1-yl)acetic acid (0.498 g, 1.608 mmol; Example 68E) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.389 g, 2.031 mmol) were stirred together in dichloroethane (0.5 mL) at room temperature for 2 hours. The reaction was then heated to 85° C. and stirred overnight. The reaction was cooled, loaded onto a SF25-40 column (Analogix®) and the product eluted using a gradient of 5% ethyl acetate/hexanes to 100% ethyl acetate over 30 minutes, then holding at 100% ethyl acetate for 15 minutes (Flow=45 mL/minute) to yield the title compound. 1H NMR (300 MHz, CDCl3) δ 7.42-7.36 (m, 2H), 7.32 (s, 11H), 4.23 (s, 2H), 3.65 (s, 2H), 3.57 (s, 2H), 3.49 (dd, J=6.5, 13.6, 4H), 2.72-2.56 (m, 2H), 2.48 (s, 4H), 1.94-1.74 (m, 2H); MS (ESI+) m/z 536.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][OH:11])=[CH:4][CH:3]=1.[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.[OH-].[K+].O>C(OCC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][CH2:10][O:11][S:18]([C:15]2[CH:16]=[CH:17][C:12]([CH3:22])=[CH:13][CH:14]=2)(=[O:20])=[O:19])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC#Cc1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)OCC#Cc2ccc(Cl)cc2)cc1
Temperature: -15 °C
Reaction time: 1.5 h

Procedure:
To a mixture of 3-(4-chloro-phenyl)-prop-2-yn-1-ol (3.3 g) and toluene-4-sulfonyl chloride (3.7 g) in diethyl ether (100 ml) which is pre-cooled to −15° C. is added powdered potassium hydroxide (2.8 g) in small portions during 10 minutes. The reaction mixture is stirred at 0° C. during 90 minutes. Then water (200 ml) is added and the mixture is extracted with diethyl ether (2×100 ml) and washed with brine (50 ml). The organic layers are collected, dried (Na2SO4) and evaporated. Toluene-4-sulfonic acid 3-(4-chloro-phenyl)-prop-2-ynyl ester is obtained.
Reaction SMILES: C([O:3][C:4](=[O:39])[CH2:5][O:6][C:7]1[CH:8]=[C:9]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[S:35]([CH3:38])(=[O:37])=[O:36])[CH:10]=[CH:11][C:12]=1[CH2:13][CH2:14][NH:15][S:16]([C:19]1[CH:24]=[C:23]([C:25](=[NH:27])[NH2:26])[CH:22]=[CH:21][C:20]=1[OH:28])(=[O:18])=[O:17])C.[OH-].[Na+].[ClH:42]>C(#N)C>[ClH:42].[C:25]([C:23]1[CH:22]=[CH:21][C:20]([OH:28])=[C:19]([S:16]([NH:15][CH2:14][CH2:13][C:12]2[CH:11]=[CH:10][C:9]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[S:35]([CH3:38])(=[O:37])=[O:36])=[CH:8][C:7]=2[O:6][CH2:5][C:4]([OH:39])=[O:3])(=[O:17])=[O:18])[CH:24]=1)(=[NH:26])[NH2:27]
Reactant: CCOC(=O)COc1cc(-c2ccccc2S(C)(=O)=O)ccc1CCNS(=O)(=O)c1cc(C(=N)N)ccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: CS(=O)(=O)c1ccccc1-c1ccc(CCNS(=O)(=O)c2cc(C(=N)N)ccc2O)c(OCC(=O)O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 290 mg of ethyl[4-[2-(5-carbamimidoyl-2-hydroxybenzenesulfonylamino)ethyl]-2′-methanesulfonoylbiphenyl-3-yloxy]acetate in 1.0 mL of acetonitrile was added 0.756 mL of 2 mol/L sodium hydroxide solution, and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added 1.26 mL of 2 mol/L hydrochloric acid, and the mixture was concentrated under reduced pressure. To the residue was added water, and the mixture was purified by column chromatography on trimethylaminopropylated silica gel (eluent: 10% lmol/L hydrochloric acid-acetonitrile). The eluent was concentrated under reduced pressure to give 260 mg of [4-[2-(5-carbamimidoyl-2-hydroxybenzenesulfonylamino)-ethyl]-2′-methanesulfonoylbiphenyl-3-yloxy]acetic acid hydrochloride as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][OH:13])=[CH:8][C:7]=1[CH3:14].[H][H]>[Ni].O1CCCC1>[CH3:1][O:2][C:3](=[O:15])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][OH:13])=[CH:8][C:7]=1[CH3:14]
Reactant: [H][H]
Reactant: COC(=O)C=Cc1ccc(CO)cc1C
Agent: [Ni]
Solvent: C1CCOC1
Product: COC(=O)CCc1ccc(CO)cc1C

Procedure:
A mixture of 3-(4-Hydroxymethyl-2-methyl-phenyl)-acrylic acid methyl ester (4.7 g, 22.8 mmol), Raney nickel (0.668 g) and tetrahydrofuran (618 mL) is shaken under 60 psig. Hydrogen 24 hr. The catalyst is filtered off, and the mixture is concentrated to afford the product as a pale yellow oil, 4.3 g, 91%. The structure is confirmed by 1H NMR spectroscopy.
Reaction SMILES: O=[CH:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([NH:14][C:15](=[O:30])[CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:19][CH:18]=3)[CH:12]=2)[CH:7]=[N:6]1.[CH3:31][CH:32]1[CH2:37][CH2:36][CH2:35][NH:34][CH2:33]1.C(O)(=O)C>CO>[CH3:31][CH:32]1[CH2:37][CH2:36][CH2:35][N:34]([CH2:2][CH2:3][CH2:4][N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([NH:14][C:15](=[O:30])[CH2:16][C:17]4[CH:18]=[CH:19][C:20]([O:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)=[CH:21][CH:22]=4)[CH:12]=3)[CH:7]=[N:6]2)[CH2:33]1
Reactant: O=CCCn1ncc2ccc(NC(=O)Cc3ccc(Oc4ccccc4)cc3)cc21
Reactant: CC1CCCNC1
Solvent: CO
Solvent: CC(=O)O
Product: CC1CCCN(CCCn2ncc3ccc(NC(=O)Cc4ccc(Oc5ccccc5)cc4)cc32)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of N-[1-(3-oxopropyl)-1H-indazol-6-yl]-2-(4-phenoxyphenyl)acetamide (20 mg, 0.05 mmol) and 3-methylpiperidine (10 mg, 0.10 mmol) in methanol containing 2% v/v acetic acid (1 mL) was added and MP-CNBH3 (52 mg, 0.065 mmol). The mixture was shaken at 40 C for 18 hours, cooled to room temperature and filtered, eluting with additional methanol (3×0.5 mL). The filtrate was concentrated under reduced pressure and was purified by RP-HPLC to provide the title compound. 1H NMR (300 MHz, DMSO-D6) δ ppm 0.85 (d, J=6.44 Hz, 3 H), 0.99 (m, 1H), 1.71 (m, 4 H), 2.26 (m, 2H,) 2.73 (m, 1 H), 3.06 (m, 2 H), 3.35 (m, 3 H), 3.69 (s, 2 H), 4.38 (t, J=6.95 Hz, 2 H), 6.99 (m, 4 H), 7.10 (m, 2 H), 7.39 (m, 4 H), 7.69 (m, 1 H), 8.01 (s, 1 H), 8.26 (s, 1 H), and 10.39 (s, 1 H); MS (ESI) 483 (M+H)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:10][NH2:11])[CH:6]=[CH:7][C:8]=1[Cl:9].N[C:13]([CH3:17])=[CH:14][C:15]#[N:16]>>[NH2:16][C:15]1[N:10]([C:5]2[CH:6]=[CH:7][C:8]([Cl:9])=[C:3]([Cl:2])[CH:4]=2)[N:11]=[C:13]([CH3:17])[CH:14]=1
Reactant: NNc1ccc(Cl)c(Cl)c1
Reactant: CC(N)=CC#N
Agent: Cl
Product: Cc1cc(N)n(-c2ccc(Cl)c(Cl)c2)n1

Procedure:
3,4-Dichlorophenyl hydrazine HCl (50.0 g.) was reacted with 3-amino-2-butene nitrile (18.31 g.) as described in Example XLIII to give 18.7 g. product, mp 110°-112°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]([NH:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)=[O:12].[C:20]1([CH2:26][CH2:27]Br)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]([NH:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:27][CH2:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)=[O:12]
Reactant: BrCCc1ccccc1
Reactant: O=C(NC1CCNCC1)c1c[nH]c2ccc(F)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(NC1CCN(CCc2ccccc2)CC1)c1c[nH]c2ccc(F)cc12
Temperature: 0 °C

Procedure:
To a solution of 0.6 g of 5-fluoro-N-(4-piperidyl)indole-3-carboxamide in a mixture of 50 ml of toluene and 10 ml of dimethylformamide were added 0.43 g of 2-phenylethylbromide and 1 g of potassium carbonate, and the whole mixture was stirred while heating and refluxing for 7 hours. After cooling, to the reaction mixture was added 50 ml of ice-cold water and stirred for 1 hour. The precipitated crystals were filtered, and washed with water and ethyl acetate. An organic layer was separated from the filtrate, dried over magnesium sufate and concentrated under reduced pressure. The residue was treated with a small amount of ethyl acetate to crystallize, and the crystals were filtered and combined with the crystals obtained as above. All of the crystals were recrystallized from methanol to give 5-fluoro-N-[1-(2-phenylethyl)-4-piperidyl]indole-3-carboxamide, melting at 238°-240° C.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24])[N:6]2[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1.[NH2:25][C@@H:26]1[CH2:31][CH2:30][CH2:29][N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27]1.C(N(CC)CC)C>C(O)C>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:5]1[N:6]([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)[C:7]2[C:3]([N:4]=1)=[C:2]([NH:25][C@@H:26]1[CH2:31][CH2:30][CH2:29][N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27]1)[N:10]=[CH:9][N:8]=2
Reactant: Clc1ccc(-n2c(-c3ccccc3Cl)nc3c(Cl)ncnc32)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)C1
Temperature: 80 °C
Yield: 86.1 %

Procedure:
To a solution of 6-chloro-8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purine (100 mg, 0.267 mmol, 1 eq.) in 3 mL of ethanol was added tert-butyl (3R)-3-aminopiperidine-1-carboxylate (64 mg, 0.32 mmol, 1.2 eq.) and triethylamine (0.06 mL, 0.4 mmol, 1.5 eq.). The reaction was heated to 80° C. for 16 h. The reaction was concentrated in vacuo. The crude material was purified by silica gel column chromatography using 0-100% ethyl acetate/hexanes to yield 124 mg (86%) of tert-butyl (3R)-3-{[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]amino}piperidine-1-carboxylate. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.33 (br. s., 9 H) 1.49-1.67 (m, 2 H) 1.74 (d, J=6.97 Hz, 1 H) 2.00 (d, J=2.83 Hz, 1 H) 3.20 (br. s, 2 H) 3.50 (br. s, 1 H) 3.88 (br. s, 1 H) 4.32 (br. s., 1 H) 5.87 (d, J=7.44 Hz, 1 H) 7.02-7.54 (m, 8 H) 8.38 (s, 1 H), [M+H]+ 539.3.
Reaction SMILES: [C:1]([S:4][CH2:5][C@H:6]1[N:11]([CH2:12][CH:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([C:22]#[N:23])[C:16]=2[CH3:24])O)[CH2:10][CH2:9][N:8]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:7]1)(=[O:3])[CH3:2].S(Cl)([Cl:34])=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[C:1]([S:4][CH2:5][C@H:6]1[N:11]([CH2:12][CH:13]([Cl:34])[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([C:22]#[N:23])[C:16]=2[CH3:24])[CH2:10][CH2:9][N:8]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)SC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1CC(O)c1ccc(F)c(C#N)c1C
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(=O)SC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1CC(Cl)c1ccc(F)c(C#N)c1C
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of (3S)-tert-butyl 3-(acetylthiomethyl)-4-(2-(3-cyano-4-fluoro-2-methylphenyl)-2-hydroxyethyl)piperazine-1-carboxylate (30.8 mg, 0.0680 mmol) in toluene (0.62 mL) was added thionyl chloride (14.9 μL, 0.205 mmol). The mixture was cooled with an ice bath and then pyridine (22.1 μL, 0.273 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 20 min, and then allowed to warm to room temperature over an hour and finally heated at 70° C. for 30 min. The reaction mixture was concentrated and the residue was diluted with ethyl acetate, washed with a minimum amount of saturated sodium bicarbonate aqueous solution, and then brine. The organic layer was separated, filtered through a pad of anhydrous sodium sulfate and concentrated. Used directly in the next step.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]1[O:9][CH2:8][CH2:7][O:6]1.[C-]#[N:11].[K+]>CS(C)=O.O>[O:6]1[CH2:7][CH2:8][O:9][CH:5]1[CH2:4][CH2:3][C:2]#[N:11]
Reactant: [C-]#N
Reactant: ClCCCC1OCCO1
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCCC1OCCO1
Temperature: 100 °C
Yield: 43.7 %

Procedure:
A mixture of 2-(3-chloropropyl)-1,3-dioxolane (5.7 g, 37.8 mmol) and potassium cyanide (3.8 g, 58.4 mmol) in dimethylsulfoxide (12 mL) was heated at 100° C. for 48 hours. The reaction mixture was diluted with water (80 mL) and extracted with ether (3×60 mL). The combined ether layer was washed with water (3×60 mL), dried (magnesium sulfate), concentrated in vacuo and purified by silica gel chromatography (ethyl acetate in hexane, 1:2) to afford the title compound (2.1 g, 40%) as a pale yellow liquid;
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:15]([C:19]2[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([O:27][CH3:28])[CH:20]=2)=[CH:16][C:17]#[N:18])[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.C1CCCCC=1>[OH-].[OH-].[Pd+2].C(O)C>[CH3:28][O:27][C:21]1[CH:20]=[C:19]([C:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([OH:8])[CH:10]=2)=[CH:16][C:17]#[N:18])[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=1
Reactant: COc1cc(OC)cc(C(=CC#N)c2cccc(OCc3ccccc3)c2)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1=CCCCC1
Solvent: CCO
Product: COc1cc(OC)cc(C(=CC#N)c2cccc(O)c2)c1
Yield: 63.5 %

Procedure:
3-(3-Benzyloxyphenyl)-3-(3,5-dimethoxyphenyl)acrylonitrile (3.45 g), 20% palladium hydroxide on charcoal (0.103 g, 3% w.t.), cyclohexene (12 ml), and ethanol (24 ml) were heated to reflux overnight. The black suspension was cooled, filtered through a Celite pad, and concentrated to an oil, which was purified via flash column chromatography (5% EtOAc in hexane gradient to 30% EtOAc in hexane in about 30 min.) to give 3-(3,5-dimethoxy-phenyl)-3-(3-hydroxy-phenyl)-acrylonitrile as an off-white solid (1.66 g, 64%): mp, 127-129° C.; 1HNMR (DMSO-d6) δ 9.73 (s, 0.67H, OH of one isomer), 9.65 (s, 0.26H, OH of the other isomer), 7.33-7.23 (m, 1H, Ar), 6.92-6.62 (m, 4H, Ar), 6.46 (d, J=2 Hz, 2H, Ar), 6.32 (s, 0.73H, double bond proton of one isomer), 6.27 (s, 0.27H, double bond proton of the other isomer), 3.77 (s, 1.85H, 2OCH3 of one isomer), 3.73 (s, 4.29H, 2OCH3 of the other isomer), isomer ratio 27.6%:72.4%; 3C NMR (DMSO-d6) δ 161.5, 160.4, 157.4, 157.2, 139.9, 138.7, 138.1, 129.7, 119.7, 118.7, 118.0, 117.5, 116.7, 115.7, 115.0, 107.1, 106.6, 101.8, 101.0, 96.3, 96.0, 55.4; Anal. Calcd. For C17H15NO3: C, 72.58; H, 5.37; N, 4.98. Found: C, 72.40; H, 5.26; N, 4.85.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH2:11].Cl.Cl[CH2:14][CH2:15][N:16]([CH2:18][CH2:19]Cl)[CH3:17]>ClC1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N:11]1[CH2:19][CH2:18][N:16]([CH3:17])[CH2:15][CH2:14]1
Reactant: CN(CCCl)CCCl
Reactant: Nc1cc([N+](=O)[O-])ccc1Br
Agent: Cl
Solvent: Clc1ccccc1
Product: CN1CCN(c2cc([N+](=O)[O-])ccc2Br)CC1
Yield: 26.5 %

Procedure:
A suspension of 2-bromo-5-nitrobenzenamine (26.0 g) and 2-chloro-N-(2-chloroethyl)-N-methylethanamine hydrochloride (23.0 g) in chlorobenzene (150 ml) was treated according to the method of Intermediate 56. Purification by FCC eluting with System A (300:8:1 gradient to 200:8:1) gave the title compound as a brown solid (9.498 g) m.p. 100°-103° C.
Reaction SMILES: [CH:1]1([C:6]2[CH:29]=[CH:28][C:9]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][C:18]4[N:17]5[CH2:21][CH2:22][CH:23]([CH2:24][C:25]([OH:27])=[O:26])[C:16]5=[CH:15][C:14]=4[CH:13]=3)=[CH:8][C:7]=2[C:30]([F:33])([F:32])[F:31])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1C(=O)N([Cl:41])C(=O)C1>C(Cl)Cl>[Cl:41][C:15]1[C:14]2[CH:13]=[C:12]([O:11][CH2:10][C:9]3[CH:28]=[CH:29][C:6]([CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[C:7]([C:30]([F:33])([F:31])[F:32])[CH:8]=3)[CH:20]=[CH:19][C:18]=2[N:17]2[CH2:21][CH2:22][CH:23]([CH2:24][C:25]([OH:27])=[O:26])[C:16]=12
Reactant: O=C(O)CC1CCn2c1cc1cc(OCc3ccc(C4CCCC4)c(C(F)(F)F)c3)ccc12
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: O=C(O)CC1CCn2c1c(Cl)c1cc(OCc3ccc(C4CCCC4)c(C(F)(F)F)c3)ccc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 87.9 %

Procedure:
To a solution of 2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid (34 mg, 0.074 mmol) dissolved in DCM (0.500 mL) and cooled to 0° C. was added NCS (9.92 mg, 0.074 mmol). The reaction was stirred at 0° C. for 15 min in a 20 mL sealed scintillation vial. After 15 min, the reaction mixture was diluted with DCM and washed with water (2×10 mL), washed with sodium thiolsulfate pentahydrate (aq.) (2×10 mL), dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure to give the title compound as a light yellow solid (32 mg). LCMS m/z=492.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.54-1.73 (m, 4H), 1.80-1.89 (m, 2H), 1.95-2.05 (m, 2H), 2.24-2.35 (m, 1H), 2.52-2.58 (m, 1H), 2.77-2.87 (m, 1H), 2.94 (dd, J=16.36, 4.11 Hz, 1H), 3.21-3.29 (m, 1H), 3.64-3.72 (m, 1H), 3.95-4.05 (m, 1H), 4.11-4.19 (m, 1H), 5.18 (s, 2H), 6.87 (dd, J=8.78, 2.46 Hz, 1H), 6.98 (d, J=2.27 Hz, 1H), 7.29 (d, J=8.84 Hz, 1H), 7.63 (d, J=7.96 Hz 1H), 7.69-7.76 (m, 2H), 12.35 (bs, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[CH:4][CH:3]=1.O.[NH2:16][NH2:17]>C(O)C>[NH:16]([C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[CH:4][CH:3]=1)[NH2:17]
Reactant: CC(C)(C)OC(=O)c1ccc(Cl)nc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)c1ccc(NN)nc1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
18.0 g (84.2 mmol) of tert-butyl 6-chloropyridine-3-carboxylate are initially charged in 85 ml of ethanol. 42.2 g (842.0 mmol) of hydrazine hydrate are added, and the mixture is stirred at 100° C. for 2 h. The mixture is then concentrated, and the residue is taken up in a mixture of ethyl acetate and water. The phases are separated, and the organic phase is washed once with water and once with saturated sodium chloride solution, dried over magnesium sulfate and concentrated again. The residue is triturated with petroleum ether, and the solid formed is filtered off and dried under high vacuum.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[C:13]([C:14](=[O:16])[CH:15]=1)=[CH:12][C:11]([O:17][CH2:18][CH3:19])=[CH:10][C:9]=2Br)=[O:5])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:67][N:68]1[CH2:73][CH2:72][NH:71][CH2:70][CH2:69]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[C:13]([C:14](=[O:16])[CH:15]=1)=[CH:12][C:11]([O:17][CH2:18][CH3:19])=[CH:10][C:9]=2[N:71]1[CH2:72][CH2:73][N:68]([CH3:67])[CH2:69][CH2:70]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(=O)c2cc(OCC)cc(Br)c2o1
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(=O)c2cc(OCC)cc(N3CCN(C)CC3)c2o1
Temperature: 80 °C
Yield: 94.3 %

Procedure:
Into a 100 mL, 3 neck round bottom flask equipped with a reflux condenser, magnetic stirrer and nitrogen inlet is added 350 mg (1.03 mmol, 1.0 equiv.) of 8-Bromo-6-ethoxy-4oxo-4H-chromene-2-carboxylic acid ethyl ester (Reference Example 23b), 18.9 mg (0.02 mmol, 0.02 equiv.) of tris dibenzylidineacetone dipalladium, 77 mg (0.123 mmol, 0.12 equiv.) of racemic 2,2′-bis(diphenylphosphino)-1,1′-binapthyl and 1 g of 4 A molecular sieves and 60 mL of dry toluene. To the stirred suspension is then added 113 mg, 1255 μL, (1.13 mmol, 1.1 equiv.) of 1-methylpiperazine, followed by 470 mg (1.44 mmol, 1.4 equiv.) of cesium carbonate. The mixture is then heated to 80° C. for 3 days. At the end of this time completion was monitored by LC/MS analysis of an aliquot. When the reaction was determined to be complete it was cooled to room temperature then filtered through a plug of diatomaceous earth, with toluene washing to remove solid by products. Purification by flash chromatography, using a gradient of 5 to 40% methanol in methylene chloride as eluent, yielded 350 mg (75%) of the desired product as a yellow solid. Mass Spec.: calc. for [C19H24N2O5+H]+ Theor. m/z=361; Obs.=361
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:7][CH2:6][CH:5](O)[CH:4]=[C:3]1[CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13].C(O)=[O:16]>O>[CH3:1][C:2]1([CH3:14])[C:3]2([CH2:13][CH:12]([OH:16])[CH2:11][CH2:10][CH2:9]2)[CH:4]=[CH:5][CH2:6][CH2:7]1
Reactant: C=CCCCC1=CC(O)CCC1(C)C
Reactant: O=CO
Solvent: O
Product: CC1(C)CCC=CC12CCCC(O)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 4,4-dimethyl-3-pent-4-enyl-cyclohex-2-enol (810 mg) obtained in Step 3 was added formic acid (60 mL), followed by stirring the reaction mixture at room temperature for 2 hours and then at 50° C. for 3 hours. After cooling down to room temperature and adding water, the reaction mixture was extracted with chloroform. The organic layer was washed with water, dried and concentrated. The residue was reduced in the same condition as in Step 3 to give 11,11-dimethyl-spiro[5.5]undec-7-en-2-ol (340 mg).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)[N:8]=1)=O.[NH:26]([C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=1)N>C(O)C>[O:13]=[C:12]1[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)[N:8]=[C:7]1[C:5]1[N:26]([C:28]2[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=2)[N:2]=[CH:3][CH:4]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OC(F)(F)F)cc2)ccc1=O
Reactant: N#Cc1ccc(NN)cc1
Solvent: CCO
Product: N#Cc1ccc(-n2nccc2-c2nn(-c3ccc(OC(F)(F)F)cc3)ccc2=O)cc1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-8) and 4-hydrazino-benzonitrile in ethanol as solvent according to the method described for example 43. MS: M=424.1 (M+H)+