Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:23][C:24]#N)[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:22])[C:9]([C:15]1[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[CH:16]=1)([OH:14])[C:10]([F:13])([F:12])[F:11].[OH2:26].[OH-:27].[Na+]>Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:23][C:24]([OH:27])=[O:26])[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:22])[C:9]([C:15]1[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[CH:16]=1)([OH:14])[C:10]([F:13])([F:12])[F:11]
Reactant: CC(c1ccc(CC#N)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Reactant: [OH-]
Reactant: O
Agent: Cl
Agent: [Na+]
Product: CC(c1ccc(CC(=O)O)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Temperature: 80 °C
Reaction time: 1 h

Procedure:
{3-Chloro-4-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenyl}-acetonitrile was suspended in aq. conc. HCl (3 mL) and stirred for 1 hour at 80° C. The mixture was allowed to cool and poured into water. The pH of the solution was adjusted to 6-7 with diluted NaOH. The aqueous layer was extracted three times with ethyl acetate and the extracts were dried over Na2SO4 and evaporated. The residue was purified by flash chromatography (silica gel, gradient of ethyl acetate in heptane) to give the title compound as a colorless solid (16 mg). MS (m/e)=408.1 (MH+).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[Br:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1F)[CH:15]=[O:16].C(=O)([O-])[O-].[K+].[K+]>CN1CCCN(C)C1=O.C(#N)C>[Br:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[N:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)[CH:15]=[O:16]
Reactant: O=Cc1ccc(F)c(Br)c1
Reactant: C1CC2(CCN1)OCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN1CCCN(C)C1=O
Product: O=Cc1ccc(N2CCC3(CC2)OCCO3)c(Br)c1
Temperature: 80 °C
Yield: 95 %

Procedure:
A mixture of 1,4-dioxa-8-azaspiro[4.5]decane (6.87 g, 48 mmol), 3-bromo-4-fluorobenzaldehyde (8.12 g, 40 mmol), and potassium carbonate (6.63 g, 48 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (12 mL) and acetonitrile (8 mL) was heated at 80° C. under N2 atmosphere for one day. Reaction mixture was cooled down to room temperature and poured onto water (150 mL). The mixture was extracted with methylene chloride. The organic layer was dried (MgSO4) and concentrated to give the title compound as an off-white solid (12.4 g, 96%); mp 63-64° C.; 1H NMR (300 MHz, CDCl3) δ 1.93 (t, J=5.7 Hz, 4H), 3.25 (t, J=5.4 Hz, 4H), 4.02 (s, 4H), 7.12 (d, J=4.2 Hz, 1H), 7.75 (dd, J=8.4, 2.1 Hz, 2H), 8.06 (d, J=1.8 Hz, 1H), 9.84 (s, 1H); MS (ES) m/z: 325.7 (MH+); HRMS Calcd. for C14H16BrNO3 (MH+): 325.0314. Found: 325.0288.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7].[Br:13]N1C(=O)CCC1=O>C1(C)C=CC=CC=1>[Br:13][C:10]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][C:4]=1[O:3][C:2]([F:11])([F:12])[F:1].[Br:13][C:8]1[CH:9]=[CH:10][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:5][C:6]=1[NH2:7]
Reactant: Nc1cccc(OC(F)(F)F)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: Cc1ccccc1
Product: Nc1cc(OC(F)(F)F)ccc1Br
Product: Nc1ccc(Br)c(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-trifluoromethoxy-aniline (1.77 g) in toluene (20 ml) was treated with N-bromosuccinimide (1.87 g) at ambient temperature and the reaction mixture was stirred for 2 hours at ambient temperature, quenched by addition of water and the mixture extracted with ethyl acetate (3×50 ml). The combined organic extracts were washed with aqueous sodium hydrogen carbonate (saturated), dried over sodium sulfate and then concentrated in vacuo. The residue was purified by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 95:5) to afford 4-bromo-3-trifluoromethoxy-aniline (270 mg) and 2-bromo-5-trifluoromethoxy-aniline (1.45 g), which were both characterized by mass and NMR spectra. 4-bromo-3-trifluoromethoxy-aniline: MS (ES+) 256/258 (MH+); 1H NMR (400 MHz, CDCl3) 3.5 (brs, 2H), 6.5 (d, 1H), 6.7 (s, 1H), 7.3 (d, 1H). 2-bromo-5-trifluoromethoxy-aniline: MS (ES+) 256/258 (MH+); 1H NMR (400 MHz, CDCl3) 4.2 (brs, 2H), 6.5 (d, 1H), 6.6 (s, 1H), 7.4 (d, 1H).
Reaction SMILES: N1C=CN=C1[C:6]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]2[C@H:15]3[C@H:24]([CH2:25][CH2:26][C@:10]12[CH3:11])[C@@H:23]1[C:18]([CH:19]=[C:20]([O:27][CH2:28][O:29][CH3:30])[CH:21]=[CH:22]1)=[CH:17][CH2:16]3)=[O:7].Cl.[CH3:32][O:33][C:34](=[O:37])[CH2:35][NH2:36].C(N(CC)CC)C.C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1>O1CCOCC1.O>[CH3:32][O:33][C:34]([CH2:35][NH:36][C:6]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]2[C@H:15]3[C@H:24]([CH2:25][CH2:26][C@:10]12[CH3:11])[C@@H:23]1[C:18]([CH:19]=[C:20]([O:27][CH2:28][O:29][CH3:30])[CH:21]=[CH:22]1)=[CH:17][CH2:16]3)=[O:7])=[O:37]
Reactant: COC(=O)CN
Reactant: COCOC1=CC2=CC[C@@H]3[C@H](CC[C@]4(C)[C@@H](OC(=O)c5ncc[nH]5)CC[C@@H]34)[C@H]2C=C1
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: O
Product: COCOC1=CC2=CC[C@@H]3[C@H](CC[C@]4(C)[C@@H](OC(=O)NCC(=O)OC)CC[C@@H]34)[C@H]2C=C1
Reaction time: 72 h
Yield: 64.3 %

Procedure:
To a solution of 17β-imidazolylcarbonyloxy-3-methoxymethyloxy-1,3,5-estratriene (1.14 g) in dioxane (25 ml) were added glycine methyl ester hydrochloride (1.05 g), triethylamine (1.16 ml), and diazabicycloundecene (1.25 ml). The resultant mixture was refluxed under heating and stirring for 3 days. After cooling, the reaction mixture was mixed with water and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was chromatographed on a silica gel column (100 g), eluting with hexane-ethyl acetate to give 17β-methoxycarbonylmethylaminocarbonyloxy-3-methoxymethyloxy-1,3,5-estratriene (0.77 g, Yield: 64%).
Reaction SMILES: N#N.Br[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[F:11].C([Li])CCC.C([O:19][B:20](OCC)[O:21]CC)C>CCCCCC.O1CCCC1>[F:11][C:5]1[CH:6]=[C:7]([CH3:10])[CH:8]=[CH:9][C:4]=1[B:20]([OH:21])[OH:19]
Reactant: CCOB(OCC)OCC
Reactant: Cc1ccc(Br)c(F)c1
Agent: N#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1ccc(B(O)O)c(F)c1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
To a 500 mL three-necked round-bottomed flask equipped with septum and N2 inlet were added 10.0 g (52.9 mmol) 4-bromo-3-fluorotoluene and 100 mL dry tetrahydrofuran. The solution was cooled to −70° C., and 25.4 mL (63.5 mmol) of a 2.5 M solution of butyl lithium in hexane was added slowly so the temperature did not exceed −60° C. The clear solution was stirred at −70° C. for 1 hour, then treated with 10.8 mL (63.5 mmol) triethylborate. The reaction was stirred for 2 hours at −70° C., then warmed to room temperature and stirred for 16 hours. The reaction was quenched with saturated aqueous ammonium chloride solution, adjusted to pH 1-2 with 1 N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and evaporated. The residue was triturated with hexane to a white solid, 6.1 g (75%), as a mixture of monoaryl and diaryl boronic acids.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]([C:17]([OH:19])=O)=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[F:20][C:21]([F:30])([F:29])[C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1.Cl>ClCCl.CN(C)C=O.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]([C:17](=[O:19])[NH:26][C:25]3[CH:27]=[CH:28][C:22]([C:21]([F:20])([F:29])[F:30])=[CH:23][CH:24]=3)=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(C(=O)O)nn1-c1ncccc1Cl
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C(=O)Nc2ccc(C(F)(F)F)cc2)nn1-c1ncccc1Cl
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A solution of 1.00 g (3.55 mmol) of 1-(3-chloropyridin-2-yl)-5-(methoxycarbonyl)-1H-pyrazole-3-carboxylic acid in 13 ml of dichloromethane and 1.3 ml of N,N-dimethylformamide was cooled to 0° C., a solution of 0.86 g (5.33 mmol) of 4-(trifluoromethyl)aniline in 3 ml of dichloromethane was added dropwise and 0.68 g (3.55 mmol) of N-ethyl-N′-3-(dimethylaminopropyl)carbodiimide×HCl and 87 mg (710 μmol) of 4-dimethylaminopyridine were added a little at a time. The mixture was stirred at 0° C. for 2 hours and at 20° C. for 16 hours. The mixture was then diluted with dichloromethane and washed successively with 1 N aqueous hydrochloric acid and water. The organic phase was dried over sodium sulphate, the solvent was removed under reduced pressure and the residue was purified on silica gel using cyclohexane/ethyl acetate=3:1→2:1. (logP: 3.54).
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([CH:16]([CH3:18])[CH3:17])([CH2:8][CH2:9][C:10]2[S:14][CH:13]=[N:12][C:11]=2[CH3:15])[O:5][C:4](=[O:19])[CH:3]=1.[C:20]([C:24]1[CH:29]=[C:28]([CH2:30][OH:31])[C:27]([CH3:32])=[CH:26][C:25]=1[S:33]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:23])([CH3:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:20]([C:24]1[CH:29]=[C:28]([CH2:30][OH:31])[C:27]([CH3:32])=[CH:26][C:25]=1[S:33][C:3]1[C:4](=[O:19])[O:5][C:6]([CH:16]([CH3:17])[CH3:18])([CH2:8][CH2:9][C:10]2[S:14][CH:13]=[N:12][C:11]=2[CH3:15])[CH2:7][C:2]=1[OH:1])([CH3:23])([CH3:22])[CH3:21]
Reactant: Cc1ncsc1CCC1(C(C)C)CC(O)=CC(=O)O1
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(CO)cc2C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(SC2=C(O)CC(CCc3scnc3C)(C(C)C)OC2=O)c(C(C)(C)C)cc1CO

Procedure:
The title compound was prepared according to General Method 16a using 4-hydroxy-6-isopropyl-6-[2-(4-methyl-thiazol-5-yl)-ethyl]-5,6-dihydro-pyran-2-one (Example E-1; 0.22 g, 0.78 mmol), toluene-4-thiosulfonic acid S-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl)ester (Example BB-2, 0.33 g, 0.90 mmol), potassium carbonate (1.0 g, 7.2 mmol), and DMF (4 mL). The product was chromatographed on silica gel, eluting with 10% MeOH in CH2Cl2, to give the title compound, mp 138-141° C.
Reaction SMILES: Cl.[C:2]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][NH:12][C:13](=[O:33])[C@@H:14]2[CH2:18][CH2:17][CH2:16][N:15]2[C:19](=[O:32])[C@H:20](NC(OCC)=O)[CH2:21][C:22](C)(C)[CH3:23])[CH2:7][CH2:6]1)(=[NH:4])[NH2:3].[C:34](=[O:37])([O-])[O-:35].[Na+].[Na+].Cl.ON.[OH2:43]>C(O)C>[C:8]([O:35][C:34]([NH:3][CH:2]1[CH2:5][CH2:6][CH2:23][CH2:22][C@@H:21]1[CH2:20][C:19]([N:15]1[CH2:16][CH2:17][CH2:18][C@H:14]1[C:13]([NH:12][CH2:11][C:8]1[CH:7]=[CH:6][C:5]([C:2](=[N:4][OH:43])[NH2:3])=[CH:10][CH:9]=1)=[O:33])=[O:32])=[O:37])([CH3:11])([CH3:9])[CH3:7]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)N[C@H](CC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)NC[C@H]1CC[C@H](C(=N)N)CC1
Reactant: O
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CCCC[C@@H]1CC(=O)N1CCC[C@H]1C(=O)NCc1ccc(C(N)=NO)cc1
Yield: 84 %

Procedure:
To a solution of the compound (0.94 g, 2 mmol) obtained in the item (c) of Example 1 in ethanol (15 ml), a solution of sodium carbonate (0.17 g, 1.6 mmol) in water (3 ml) and hydroxyamine hydrochloride (0.22 g, 3.2 mmol) are added. After the reaction mixture is heated at reflux for 8 hours, thesolvent is evaporated and the resulting residue is purified with silica gelcolumn chromatography (chloroform-methanol) to give 0.84 g of the titled compound (84%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N:9]2[C:13]3=[N:14][C:15]([CH3:27])=[CH:16][C:17]([N:18]4[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25]I)[CH2:20][CH2:19]4)=[C:12]3[C:11]([CH3:28])=[CH:10]2)=[C:4]([CH3:29])[CH:3]=1.[P:30]([O:37]CC)([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33]>>[CH2:32]([O:31][P:30]([CH2:25][CH2:24][CH:21]1[CH2:22][CH2:23][N:18]([C:17]2[CH:16]=[C:15]([CH3:27])[N:14]=[C:13]3[N:9]([C:5]4[C:6]([CH3:8])=[CH:7][C:2]([Br:1])=[CH:3][C:4]=4[CH3:29])[CH:10]=[C:11]([CH3:28])[C:12]=23)[CH2:19][CH2:20]1)(=[O:37])[O:34][CH2:35][CH3:36])[CH3:33]
Reactant: CCOP(OCC)OCC
Reactant: Cc1cc(N2CCC(CCI)CC2)c2c(C)cn(-c3c(C)cc(Br)cc3C)c2n1
Product: CCOP(=O)(CCC1CCN(c2cc(C)nc3c2c(C)cn3-c2c(C)cc(Br)cc2C)CC1)OCC
Temperature: 160 °C

Procedure:
Under N2 atmosphere, a mixture of 1-(4-bromo-2,6-dimethyl-phenyl)-4-[4-(2-iodo-ethyl)-piperidin-1-yl]-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine (0.25 g) and triethyl phosphite (10 mL) was heated at 160° C. for 4.5 hours. After the reaction was completed, excess triethyl phosphate was removed under reduced pressure. The residue was purified with column chromatography (silica gel: Wako gel C200, eluent: hexane:ethyl acetate=1/1) to obtain a colorless oil. The oily product was crystallized from diisopropylether (10 mL) to provide (2-{1-[1-(4-bromo-2,6-dimethyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-ethyl)-phosphonic acid diethyl ester (0.16 g) as a white crystal.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][N:12]=[CH:11]3)=[CH:5][CH:4]=1.[H-].[Na+].F[C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1>CN(C)C=O.O>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[N:13]([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)[N:12]=[CH:11]3)=[CH:5][CH:4]=1
Reactant: COc1ccc(Oc2ccc3[nH]ncc3c2)cc1
Reactant: N#Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Oc2ccc3c(cnn3-c3ccc(C#N)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 5-(4-methoxy-phenoxy)-1H-indazole (0.20 grams, 0.83 mmol) in 1 mL of dimethylformamide was added sodium hydride (0.040 grams of a 60% dispersion in mineral oil, 1.0 mmol). After shaking at room temperature for 10 minutes, the mixture was treated with 4-fluorobenzonitrile (0.11 grams, 0.9 mmol). The mixture was heated to 50° C. for 6 hours. After cooling to room temperature, the mixture was diluted with water and was extracted 3 times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 0-30% ethyl acetate in hexanes, affording 4-[5-(4-Methoxy-phenoxy)-indazol-1-yl]-benzonitrile (110 miligrams) MS: 342.4 [M+H]+ and 4-[5-(4-Methoxy-phenoxy)-indazol-2-yl-]-benzonitrile (75 miligrams) MS: 342.4 [M+H]+ as colorless syrups.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][NH:3]1.[F:8][C:9]1[CH:10]=[C:11]([NH:16][CH:17]([C:19]2[CH:20]=[C:21]([C:34]([O:36][CH3:37])=[O:35])[CH:22]=[C:23]3[C:28]=2[O:27][C:26](S(CC)=O)=[CH:25][C:24]3=[O:33])[CH3:18])[CH:12]=[C:13]([F:15])[CH:14]=1.C(N(C(C)C)C(C)C)C>C(#N)C>[F:8][C:9]1[CH:10]=[C:11]([NH:16][CH:17]([C:19]2[CH:20]=[C:21]([C:34]([O:36][CH3:37])=[O:35])[CH:22]=[C:23]3[C:28]=2[O:27][C:26]([N:3]2[CH2:4][CH2:5][O:6][CH2:7][C@@H:2]2[CH3:1])=[CH:25][C:24]3=[O:33])[CH3:18])[CH:12]=[C:13]([F:15])[CH:14]=1
Reactant: C[C@H]1COCCN1
Reactant: CCS(=O)c1cc(=O)c2cc(C(=O)OC)cc(C(C)Nc3cc(F)cc(F)c3)c2o1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)c1cc(C(C)Nc2cc(F)cc(F)c2)c2oc(N3CCOC[C@@H]3C)cc(=O)c2c1
Temperature: 75 °C
Reaction time: 7 h
Yield: 34.4 %

Procedure:
(S)-3-methylmorpholine (87 mg, 0.86 mmol) was added to a stirred solution of methyl 8-(1-(3,5-difluorophenylamino)ethyl)-2-(ethylsulfinyl)-4-oxo-4H-chromene-6-carboxylate (250 mg, 0.57 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.150 mL, 0.86 mmol) in acetonitrile (3 mL) at RT. The resulting brown mixture was stirred at 75° C. for 7 hours. The reaction mixture was concentrated, diluted with DCM, washed with a 1M hydrochloric acid 1M, brine dried over magnesium sulfate and concentrated to afford the crude product which was purified by flash chromatography on silica gel eluting with 0 to 5% MeOH in DCM. The solvent was evaporated to dryness to afford methyl 8-(1-(3,5-difluorophenylamino)ethyl)-2-((S)-3-methylmorpholino)-4-oxo-4H-chromene-6-carboxylate (90 mg, 34%) as a yellow foam. Spectrum: [M−H]− 457.
Reaction SMILES: C(OC([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][CH:11]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=1)[CH2:12]2)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:24][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][C:20]=1[Cl:23])[CH2:16][CH:11]1[CH2:10][CH:9]2[NH:8][CH:13]([CH2:14][CH2:15]2)[CH2:12]1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(Cc1ccc(Cl)c(Cl)c1)C2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(CC2CC3CCC(C2)N3)cc1Cl
Yield: 98.4 %

Procedure:
3-(3,4-Dichloro-benzyl)-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (0.35 g, 0.94 mmol) was stirred in 2 mL of CH2Cl2 with 0.5 mL of TFA at rt for 3 h. After being quenched with 20% NaOH to basic medium, the mixture was extracted with EtOAc. The organic layer was washed with NaCl (sat.), dried over Na2SO4 and concentrated to give 0.25 g of 3-(3,4-Dichloro-benzyl)-8-aza-bicyclo[3.2.1]octane.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[C:6]([S:11][CH3:12])[CH:5]=2.[O:13](C(OC(C)(C)C)=O)[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=O>CC#N.CN(C1C=CN=CC=1)C>[C:17]([O:16][C:14]([N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([S:11][CH3:12])[CH:5]=2)[CH:10]=[C:2]1[CH3:1])=[O:13])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CSc1ccc2cc(C)[nH]c2c1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CSc1ccc2cc(C)n(C(=O)OC(C)(C)C)c2c1

Procedure:
2-Methyl-6-methylthioindole (13.9 g) prepared according to Allais A. et al. Eur. J. Med. Chem.—Chim. Ther. (1975), 10(2), 187–99, was dissolved in CH3CN (150 mL) followed by the addition of (BOC)2O (18 g) with 480 mg DMAP. After 5 h the mixture was evaporated to dryness and the resulting 2-methyl-6-methylsulfanyl-indole-1-carboxylic acid tert-butyl ester was purified by chromatography over silica gel.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]12[CH2:12][CH2:11][C:8]([C:13]([O:15][CH3:16])=[O:14])([CH2:9][CH2:10]1)[CH2:7][CH2:6]2.N1C=CC=CC=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl.C(OCC)(=O)C>[CH3:23][S:24]([O:1][CH2:2][CH2:3][CH2:4][C:5]12[CH2:10][CH2:9][C:8]([C:13]([O:15][CH3:16])=[O:14])([CH2:11][CH2:12]1)[CH2:7][CH2:6]2)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)C12CCC(CCCO)(CC1)CC2
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COC(=O)C12CCC(CCCOS(C)(=O)=O)(CC1)CC2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Hydroxyester 2-4 (430 mg, 1.9 mmol) was dissolved in 2.5 mL of anhydrous methylene chloride under nitrogen atmosphere, treated with pyridine (0.5 mL) and methanesulfonyl chloride (0.368 mL, 4.8 mmol) and stirred for 4 h at room temperature. The mixture was diluted with 100 mL of ethyl acetate and washed with 1N aqueous HCl, saturated aqueous sodium bicarbonate, and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated. The crude methyl 4-{3-[(methylsulfonyl)oxy]propyl}bicyclo-[2.2.2]octane-1-carboxylate (2-5) thus afforded was used without purification in the next reaction. 1H NMR (500 MHz, CDCl3): δ 4.22 (2H, t, J=7.5 Hz), 3.68 (3H, s), 3.04 (3H, s), 1.82 (6H, m), 1.70 (2H, m), 1.44 (6H, m), 1.24 (2H, m) ppm.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([CH3:17])=[CH:6][CH:5]=2.[Li:18]CCCC>CCCCC>[CH3:1][C:2]1[CH-:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:7]([CH3:17])=[CH:6][CH:5]=2.[Li+:18]
Reactant: [Li]CCCC
Reactant: CC1=Cc2c(ccc(C)c2-c2ccccc2)C1
Solvent: CCCCC
Product: Cc1cc2c(-c3ccccc3)c(C)ccc2[cH-]1
Product: [Li+]
Temperature: 25 °C
Reaction time: 5 h

Procedure:
2,5-Dimethyl-4-phenylindene (1.3 g, 5.9 mmol), prepared as described under (a) above, was dissolved in 100 ml of pentane. To this solution was added 2.4 ml of nBuLi (n-butyl lithium, 2.5 M in hexane) and the reaction was stirred five hours at room temperature. A yellow-white solid precipitated from solution and was collected by frit filtration and washed with additional pentane. Yield: 1.2 g (98%).
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[CH2:13][NH2:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[CH:25]=O.[Na]>ClCCl>[CH:1]1([CH2:7][N:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[CH2:13][NH:14][CH2:25][C:16]2[CH:17]=[CH:18][C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NC[C@@H]1CCCN1CC1CCCCC1
Reactant: O=Cc1ccc2ccccc2c1
Agent: [Na]
Solvent: ClCCl
Product: c1ccc2cc(CNC[C@@H]3CCCN3CC3CCCCC3)ccc2c1
Reaction time: 8 h
Yield: 29.7 %

Procedure:
(S)—C-(1-Cyclohexylmethyl-pyrrolidin-2-yl)-methylamine (prepared according to scheme 2) 0.24 g (1 mmol), and naphthalene-2-carbaldehyde 0.19 g (1.2 mmol), were dissolved in 10 mL dichloromethane. To this mixture was added sodium triacethoxyborohydride 0.51 g (2 mmol), and molecular sieve. The reaction was stirred overnight under nitrogen. Molecular sieve was filtered, washed with 3 mL HCl, acidic layer was transformed to basic pH, with powder sodium bicarbonate, and extracted with ethyl acetate. The combined organic layer dried over magnesium sulfate, filtered and concentrated, yield to 100 mg of yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]2[CH:16]=[C:17]([C:33]([CH3:36])([CH3:35])[CH3:34])[C:18]([O:31][CH3:32])=[C:19]([NH:21][C:22]([C:24]3[N:25]=[N:26][C:27](Cl)=[CH:28][CH:29]=3)=[O:23])[CH:20]=2)=[CH:13][CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:37][C:38]([F:42])([F:41])[CH2:39][NH2:40].O>CN1C(=O)CCC1>[CH2:1]([O:8][C:9]1[C:14]([C:15]2[CH:16]=[C:17]([C:33]([CH3:36])([CH3:35])[CH3:34])[C:18]([O:31][CH3:32])=[C:19]([NH:21][C:22]([C:24]3[N:25]=[N:26][C:27]([NH:40][CH2:39][C:38]([F:42])([F:41])[F:37])=[CH:28][CH:29]=3)=[O:23])[CH:20]=2)=[CH:13][CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCC(F)(F)F
Reactant: COc1c(NC(=O)c2ccc(Cl)nn2)cc(-c2cccnc2OCc2ccccc2)cc1C(C)(C)C
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1c(NC(=O)c2ccc(NCC(F)(F)F)nn2)cc(-c2cccnc2OCc2ccccc2)cc1C(C)(C)C
Temperature: 25 °C
Yield: 37 %

Procedure:
step 2—A solution of 312 (0.059 g, 0.1 mmol) and 2,2,2-trifluoroethylamine (0.5 mL) in NMP (1.0 mL) in a screw-capped test tube was heated to 100° C. After 18 h the solution was cooled to RT poured into H2O and extracted with EtOAc. The combined organics were washed sequentially with H2O and brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with an EtOAc/hexane (6% to 60% EtOAc) to afford 0.029 g (37%) 6-(2,2,2-trifluoro-ethylamino)-pyridazine-3-carboxylic acid [5-(2-benzyloxy-pyridin-3-yl)-3-tert-butyl-2-methoxy-phenyl]-amide (314) as an oil.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:13](=[O:15])[CH3:14])=[C:6]2Cl.C([O-])([O-])=O.[K+].[K+].[CH:23]([N:26]([CH2:30][CH3:31])[CH:27](C)C)(C)C>O1CCOCC1.CN(C=O)C>[Br:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:13](=[O:15])[CH3:14])=[C:6]2[NH:9][C@H:10]1[CH2:11][CH2:12][C@H:3]([CH2:31][CH2:30][N:26]([CH3:23])[CH3:27])[CH2:4][CH2:5]1
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Cl
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CC(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](CCN(C)C)CC1
Temperature: 25 °C

Procedure:
Following general procedure A-1, tert-butyl (trans-4-(2-(dimethylamino)ethyl)cyclohexyl) carbamate (336 mg, 1.24 mmol) was reacted with 6 N aqueous HCl (2 mL) to afford a viscous colorless oil. The oil was dissolved in dioxane (10 mL) and DMF (5 mL) followed by the addition of 1-(6-bromo-4-chloroquinolin-3-yl)ethanone (285 mg, 1.0 mmol), K2CO3 (0.55 g, 4.0 mmol), and N,N-diisopropylethylamine (1.0 mL, 5.8 mmol) and the resultant suspension was heated at 100° C. for 16 h. The reaction mixture was cooled to room temperature, diluted with satd. aq. NaHCO3 and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. Purification by column chromatography (silica, 0-20% methanol/dichloromethane) afforded the desired product (227 mg, 54%) as a light yellow-brown solid. ESI MS m/z 418 [C21H28BrN3O+H]+