Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH2:13][CH2:14]OS(C)(=O)=O)[CH2:9]1)=[O:7].I.[CH2:34]([O:36][CH2:37][CH2:38][N:39]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[N:41]=[C:40]1[N:48]1[CH2:54][CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)[CH3:35].[I-].[K+].C(N(CC)CC)C>C(#N)C.CO.ClCCl>[CH3:32][O:31][C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:28]=1[O:29][CH3:30])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:51]2[CH2:52][CH2:53][CH2:54][N:48]([C:40]3[N:39]([CH2:38][CH2:37][O:36][CH2:34][CH3:35])[C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=4[N:41]=3)[CH2:49][CH2:50]2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCC(CCOS(C)(=O)=O)(c3ccccc3)C2)cc(OC)c1OC
Reactant: CCOCCn1c(N2CCCNCC2)nc2ccccc21
Agent: I
Agent: [I-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Solvent: CC#N
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(OC)c(OC)c(OC)c4)C3)CC2)nc2ccccc21
Reaction time: 43 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt)(1.83 g, 3.94 mmol), 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acid salt (2.04 g, 3.75 mmol), potassium iodide ((0.62 g, 3.75 mmol), and triethylamine (1.15 mL, 8.25 mmol) in acetonitrile (54 mL). Heat to reflux. After 43 hours, evaporate in vacuo, dilute the evaporated reaction mixture with dichloromethane, extract with a saturated aqueous sodium bicarbonate solution, water, and then with brine. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting sequentially with dichloromaethane, then 10% methanol/dichloromethane to give the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[C:4]([CH3:18])[CH:3]=1.ClS([N:23]=[C:24]=[O:25])(=O)=O>ClCCl>[NH2:23][C:24]([O:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[C:4]([CH3:18])[CH:3]=1)=[O:25]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Cc1cc(O)ccc1C(=O)OCc1ccccc1
Solvent: ClCCl
Product: Cc1cc(OC(N)=O)ccc1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 44.2 %

Procedure:
To a solution of phenylmethyl 4-hydroxy-2-methylbenzoate (687 mg, 2.82 mmol) in dichloromethane (8 ml) at 0° C., was added chlorosulfonyl isocyanate (1.20 g, 8.50 mmol). The reaction was allowed to warm to 25° C. and stirred for 20 h. The reaction mixture was concentrated then taken into ethyl acetate and washed with water. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, hexanes/ethyl acetate) to afford phenylmethyl 4-[(aminocarbonyl)oxy]-2-methylbenzoate (356 mg, 89%). 1H NMR (400 MHz, DMSO): 7.91-7.87 (d, 1H), 7.49-7.29 (m, 5H), 7.11-7.00 (m, 4H), 5.31 (s, 2H), 2.52 (s, 3H). MS (EI) for C16H15NO4: 286 (MH+).
Reaction SMILES: [F:1][C:2]1[C:11]2[CH2:10][CH:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[N:3]=1.[H-].[Na+].[CH2:29](Br)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].O>CN(C=O)C>[F:1][C:2]1[C:11]2[CH2:10][CH:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([C:20]2[CH:21]=[CH:22][C:23]([O:26][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[CH:24][CH:25]=2)[N:3]=1
Reactant: CCCCCCCCC1CCc2cc(-c3ccc(O)cc3)nc(F)c2C1
Reactant: CCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCOc1ccc(-c2cc3c(c(F)n2)CC(CCCCCCCC)CC3)cc1
Reaction time: 0.5 h
Yield: 80 %

Procedure:
10 mmol of 1-fluoro-3-(4-hydroxyphenyl)-7-octyl-5,6,7,8-tetrahydroisoquinoline are dissolved in 50 ml of DMF, and 11 mmol of sodium hydride are added. After the mixture has been stirred for 30 minutes, 11 mmol of 1-octyl bromide are added dropwise, and the mixture is stirred at 60° C. for a further 140 minutes and poured into water. The mixture is extracted with dichloromethane, the combined organic phases are dried, the solvent is removed in vacuo and the residue is chromatographed on silica gel, giving 8 mmol of 1-fluoro-3-[4-(octyloxy)phenyl]-7-octyl-5,6,7,8-tetrahydroisoquinoline.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:32][C:33]([OH:36])([CH3:35])[CH3:34])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20](B4OC(C)(C)C(C)(C)O4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[C:38]1[CH:43]=[C:42]([CH3:44])[N+:41]([O-:45])=[C:40]([CH3:46])[CH:39]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]2([CH2:32][C:33]([OH:36])([CH3:35])[CH3:34])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:18]=[CH:19][C:20]([C:38]4[CH:43]=[C:42]([CH3:44])[N+:41]([O-:45])=[C:40]([CH3:46])[CH:39]=4)=[CH:21][CH:22]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Cc1cc(Br)cc(C)[n+]1[O-]
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccc(F)cc2)OC1=O
Product: Cc1cc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccc(F)cc4)OC3=O)cc2)cc(C)[n+]1[O-]

Procedure:
The title compound was prepared from (S)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one one and 4-bromo-2,6-dimethylpyridine-N-oxide following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1.354, m/z=493; 1H NMR (CDCl3) 1.18 (d, 6H), 1.48 (d, 3H), 2.08-2.21 (m, 5H), 2.36 (m, 1H), 2.53 (s, 6H), 2.82 (m, 1H), 5.65 (m, 1H), 6.98 (m, 4H), 7.18 (m, 4H), 7.28 (m, 2H).
Reaction SMILES: Br.Br[C:3]1[CH:8]=[CH:7][C:6]([C:9]23[CH2:16][N:13]([CH2:14][CH2:15]2)[CH2:12][CH2:11][CH2:10]3)=[CH:5][N:4]=1.[C-:17]#[N:18].[K+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.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>[N:13]12[CH2:16][C:9]([C:6]3[C:5]([C:17]#[N:18])=[N:4][CH:3]=[CH:8][CH:7]=3)([CH2:15][CH2:14]1)[CH2:10][CH2:11][CH2:12]2
Reactant: [C-]#N
Reactant: Brc1ccc(C23CCCN(CC2)C3)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Br
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: N#Cc1ncccc1C12CCCN(CC1)C2
Temperature: 90 °C
Yield: 76.9 %

Procedure:
1.5 g (4.3 mmol) of (−)-5-(2-bromopyrid-5-yl)-1-azabicyclo[3.2.1]octane hydrobromide (prepared according to the method described in step 1.2 of Example 1), dissolved in 12 ml of dimethylformamide, 0.42 g (6.46 mmol) of potassium cyanide and 5 g (4.3 mmol) of tetrakis(triphenylphosphine)palladium are successively introduced into a 25 ml reactor. The mixture is then heated at 90° C. for 3 hours and then neutralized with saturated aqueous sodium carbonate solution. The aqueous phase is extracted with chloroform and the combined organic phases are dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel, eluting with a mixture of chloroform, methanol and aqueous ammonia in 95/5/0.5 proportions. 0.705 g of expected product is thus obtained in the form of an amorphous solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[NH2:8][C:9]1[C:29]([Br:30])=[CH:28][C:12]2[C:13]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[O:15][C:11]=2[CH:10]=1.CCN(CC)CC.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.CC#N.O>[Br:30][C:29]1[C:9]([N:8]2[CH2:2][CH2:3][CH2:4][C:5]2=[O:6])=[CH:10][C:11]2[O:15][C:14]([C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)=[C:13]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:12]=2[CH:28]=1
Reactant: CCOC(=O)c1c(-c2ccc(F)cc2)oc2cc(N)c(Br)cc12
Reactant: O=C(Cl)CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1c(-c2ccc(F)cc2)oc2cc(N3CCCC3=O)c(Br)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 40 %

Procedure:
4-chlorobutanoyl chloride (670 mg, 4.76 mmol) was added dropwise to a 0° C. solution of ethyl 6-amino-5-bromo-2-(4-fluorophenyl)benzofuran-3-carboxylate and Et3N (1.0 mL) in CH2Cl2 (10 mL) under N2 atmosphere. The resulting reaction was allowed to stir at room temperature for 16 hours, then the reaction mixture was concentrated in vacuo. The resulting resulting residue was dissolved in CH3CN (10 mL), and then K2CO3 (658 mg, 4.76 mmol) and KI (263 mg, 1.59 mmol) was added and the mixture was heated to reflux and allowed to stir at this temperature for 16 hours. After being cooled to room temperature, the mixture was diluted with water and extracted with EtOAc. The organic extract was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue obtained was purified using column chromatography (eluted with petroleum ether:EtOAc=2:1) to provide ethyl 5-bromo-2-(4-fluorophenyl)-6-(2-oxopyrrolidin-1-yl)benzofuran-3-carboxylate (280 mg, yield: 40%). 1H-NMR (CDCl3, 400 MHz) δ 8.32 (s, 1H), 8.04˜8.07 (m, 2H), 7.48 (s, 1H), 7.17˜7.21 (m, 2H), 4.42˜4.43 (m, 2H), 3.82˜3.86 (m, 2H), 2.61˜2.65 (m, 2H), 2.27˜2.31 (m, 2H), 1.40˜1.44 (m, 3H). MS (M+H)+: 446/448.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11](=[O:19])[CH2:12][N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[C:20](O)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1(C)C=CC=CC=1>CC(N(C)C)=O.C(#N)C>[C:20]([N:16]1[CH2:15][CH2:14][N:13]([CH2:12][C:11]([N:8]2[CH2:9][CH2:10][N:5]([CH:1]3[CH2:2][CH2:3][CH2:4]3)[CH2:6][CH2:7]2)=[O:19])[CH2:18][CH2:17]1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(O)c1ccccc1
Reactant: O=C(CN1CCNCC1)N1CCN(C2CCC2)CC1
Solvent: Cc1ccccc1
Solvent: CC(=O)N(C)C
Solvent: CC#N
Product: O=C(CN1CCN(C(=O)c2ccccc2)CC1)N1CCN(C2CCC2)CC1
Temperature: 50 °C

Procedure:
Dissolve 1-cyclobutyl-4-(piperazin-1-ylacetyl)piperazine (32 mg, 0.12 mmol) and benzoic acid (17.6 mg, 0.14 mmol) in dry DMA (0.75 mL), TEA (0.033 mL, 0.24 mmol) and toluene (0.75 mL). Add a solution of DMC (41 mg, 27.3 mmol) in acetonitrile (1.2 mL). Heat the mixture at 50° C. for 3 h. Cool and concentrate. Partition the residue between EtOAc (10 mL) and 1 N NaOH (10 mL). Extract the organic phase and place directly on an SCX ion exchange resin cartridge. Wash the resin first with EtOAc (4 mL). Discard this wash. Second, wash the resin with EtOAC/MeOH/TEA (10/1/1). Collect this wash and evaporate to yield the title compound. 1H NMR (CDCl3). δ 7.41-7.39 (m, 5H), 6.89 (d, 1H), 3.86-3.78 (m, 2H), 3.63-3.57 (m, 4H), 3.44-3.40 (m, 2H), 3.23 (s, 2H), 2.74-2.66 (m, 1H), 2.6-2.43 (m, 4H) 2.33-2.26 (m, 4H), 2.08-2.00 (m, 2H), 1.90-1.84 (m, 2H), 1.76-1.70 (m, 2H); LC-MS (M+1) 371.02.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].CC1C=CC(S(O[CH2:20][CH2:21][CH2:22][NH:23][C:24]2[C:25](=[O:41])[N:26]([C:37]([CH3:40])([CH3:39])[CH3:38])[S:27](=[O:36])(=[O:35])[C:28]=2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=O)=O)=CC=1>>[C:37]([N:26]1[C:25](=[O:41])[C:24]([NH:23][CH2:22][CH2:21][CH2:20][O:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[C:28]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[S:27]1(=[O:35])=[O:36])([CH3:38])([CH3:39])[CH3:40]
Reactant: Cc1ccc(S(=O)(=O)OCCCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)cc1
Reactant: Oc1ccccc1Cl
Product: CC(C)(C)N1C(=O)C(NCCCOc2ccccc2Cl)=C(c2ccccc2)S1(=O)=O
Yield: 77 %

Procedure:
The title compound was prepared as described for Example 12 from 2-chlorophenol and 3-[(2-tert-butyl-1,1-dioxido-3-oxo-5-phenyl-2,3-dihydroisothiazol-4-yl)amino]propyl 4-methylbenzenesulfonate with a reaction time of 15 mins. The reaction mixture was evaporated and the crude product was purified by silica gel column chromatography (Horizons Biotage) using 15% EtOAc in petroleum ether 40-60° C. as eluent to give the title compound (0.085 g, 77%). 1H NMR (500 MHz CDCl3): δ 7.53-7.50 (m, 2H), 7.44-7.42 (m, 3H), 7.36 (dd, 1H), 7.19 (dt, 1H), 7.6.92 (dt, 1H), 6.83 (dd, 1H), 5.56 (t, 1H), 3.89 (t, 2H), 3.28 (m, 2H), 1.88-1.84 (m, 2H), 1.74 (s, 9H); 13C NMR (125 MHz CDCl3): δ 159.8, 154.2, 135.3, 131.8, 130.6, 129.8, 128.8, 127.9, 125.2, 123.4, 122.1, 113.7, 107.4, 66.7, 61.7, 41.8, 29.2, 27.8; Mass Spectrum M+H+ 449.
Reaction SMILES: Cl[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=[O:8].C(=O)([O-])[O-].[K+].[K+].[S:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[SH:20]>CN(C)C=O>[S:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[S:20][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=[O:8]
Reactant: O=Cc1sccc1Cl
Reactant: Sc1cccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1sccc1Sc1cccs1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.2 %

Procedure:
A mixture of 3-chlorothiophene-2-carbaldehyde (1.0 g), potassium carbonate (2.8 g) and N,N-dimethylformamide (6.8 mL) was treated dropwise with thiophene-2-thiol (0.87 g), and the resulting mixture was stirred at room temperature for 3 hours. The mixture was poured onto water (150 mL) and extracted with diethyl ether. The combined organic extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, and then dried over magnesium sulfate. The solvent was removed under reduced pressure to afford the title compound as a red oil (1.5 g).
Reaction SMILES: CS([C:4]1([NH:9][C:10](=[O:19])[CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7][NH:6][C:5]1=[O:8])=O.[NH3:20]>O1CCCC1>[NH2:20][C:4]1([NH:9][C:10](=[O:19])[CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7][NH:6][C:5]1=[O:8]
Reactant: N
Reactant: CS(=O)C1(NC(=O)COc2ccccc2)CNC1=O
Solvent: C1CCOC1
Product: NC1(NC(=O)COc2ccccc2)CNC1=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
The sulphoxide (26) (186 mg) in dry tetrahydrofuran (6 ml) was treated with dry ammonia gas (14.8 ml) and the mixture stirred at room temperature for 3 days. The solvent was evaporated and the residue chromatographed on silica gel to give the product, (27) (113 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:11]2[CH:17]=[CH:18][C:19]([C:21]3[CH:22]=[N:23][C:24]([NH2:27])=[N:25][CH:26]=3)=[CH:20][C:10]=2[N:9]=1.[NH:28]1[CH:32]=[CH:31][N:30]=[N:29]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[C:13]([N:12]1[C:11]2[CH:17]=[CH:18][C:19]([C:21]3[CH:22]=[N:23][C:24]([NH2:27])=[N:25][CH:26]=3)=[CH:20][C:10]=2[N:9]=[C:8]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:29]1[N:30]=[CH:31][CH:32]=[N:28]1)([CH3:16])([CH3:15])[CH3:14]
Reactant: c1c[nH]nn1
Reactant: CC(C)(C)n1c(-c2ccccc2Br)nc2cc(-c3cnc(N)nc3)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)n1c(-c2ccccc2-n2nccn2)nc2cc(-c3cnc(N)nc3)ccc21
Temperature: 120 °C
Yield: 27.8 %

Procedure:
To a solution of 5-[2-(2-bromo-phenyl)-1-tert-butyl-1H-benzimidazol-5-yl]-pyrimidin-2-ylamine (refer to example 8, step 1) (57 mg, 0.14 mmol) in DMF (5 mL) are added 1H-1,2,3-triazole (0.012 mL, 0.2 mmol), CuO (1 mg, 0.013 mmol), Fe(acac)3 (14 mg, 0.04 mmol) and Cs2CO3 (88 mg, 0.27 mmol) at room temperature. The mixture is heated at 120° C. for 96 hours and then cooled down and filtered. The filtrate is extracted with H2O (10 mL) and EtOAc (3×10 mL). The combined organic layer is dried with MgSO4 and is filtered. The filtrate is concentrated and the residue is purified by silica gel chromatography eluting with 5% MeOH in CH2Cl2 to afford a less polar product 5-[1-tert-butyl-2-(2-1,2,3-triazol-2-yl-phenyl)-1H-benzimidazol-5-yl]-pyrimidin-2-ylamine (Example 14) (16 mg, 29%) LCMS (ESMS): m/z 411.68 (M++1) as the major product and a more polar product 5-[1-tert-butyl-2-(2-1,2,3-triazol-1-yl-phenyl)-1H-benzimidazol-5-yl]-pyrimidin-2-ylamine (Example 15) (7 mg, 13%) LCMS (ESMS): m/z 411.68 (M++1) as the minor product.
Reaction SMILES: COC(=O)[CH:4]([C:16]#[N:17])[C:5]1([CH3:15])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[O:8][CH2:7][CH2:6]1.[Cl-].[Na+]>CS(C)=O.O>[CH3:15][C:5]1([CH2:4][C:16]#[N:17])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[O:8][CH2:7][CH2:6]1
Reactant: COC(=O)C(C#N)C1(C)CCOc2ccccc21
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC1(CC#N)CCOc2ccccc21
Reaction time: 4 h
Yield: 69.7 %

Procedure:
A mixture of 6 g (23 mmol) of cyano(4-methylchroman-4-yl)acetic acid methyl ester and 7.25 g (124 mmol) of sodium chloride in 40 mL of wet DMSO was warmed to reflux. The reaction was monitored by TLC. After 4 hours, the reaction was cooled and diluted with water and extracted with diethyl ether. The combined organic layers were washed with four portions of water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 3 g (68%) of (4-methylchroman-4-yl)acetonitrile as an oil.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]2[CH2:19][CH2:18][CH:17]([CH:20]=O)[CH2:16][CH2:15]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[K+]>ClC(Cl)C>[N:22]1([CH2:20][CH:17]2[CH2:18][CH2:19][N:14]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[CH2:7][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[CH2:15][CH2:16]2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: C1CCNCC1
Reactant: O=CC1CCN(c2ccccc2CN2CCOCC2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [K+]
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: c1ccc(N2CCC(CN3CCCCC3)CC2)c(CN2CCOCC2)c1
Reaction time: 16 h

Procedure:
A solution of the product of Example 17 (288 mg) and piperidine (0.12 mL) in dichloroethane (DCE, 2 mL) was treated with sodium triacetoxyborohydride (297 mg). After 16 h, the resulting mixture was treated with 10% potassium hydroxide (2 mL), and extracted with DCM (2×2 mL). The combined extracts were dried (MgSO4), and chromatographed on silica gel (0-8% 2 M methanolic ammonia/DCM), giving the title compound as a colorless oil (100 mg).
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:2][C:3]([O:5]N1C(=O)CCC1=O)=O.[CH3:20][O:21][C:22](=[O:44])[C@H:23]([CH2:25][C:26]1[CH:33]=[C:31]([I:32])[C:30]([O:34][C:35]2[CH:42]=[C:40]([I:41])[C:39]([OH:43])=[C:37]([I:38])[CH:36]=2)=[C:28]([I:29])[CH:27]=1)[NH2:24].O.C(OCC)(=O)C>CO.CC(C)=O>[CH3:20][O:21][C:22](=[O:44])[C@H:23]([CH2:25][C:26]1[CH:27]=[C:28]([I:29])[C:30]([O:34][C:35]2[CH:36]=[C:37]([I:38])[C:39]([OH:43])=[C:40]([I:41])[CH:42]=2)=[C:31]([I:32])[CH:33]=1)[NH:24][C:3](=[O:5])[CH2:2][NH:1][C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14]
Reactant: CC(C)(C)OC(=O)NCC(=O)ON1C(=O)CCC1=O
Reactant: COC(=O)[C@@H](N)Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)[C@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)NC(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To the aforesaid Boc-Gly-OSu solution the thyroxine methyl ester solution was added while ice cooling. After permitting the same to warm to room temperature, the mixture was stirred for 1.5 hr. After letting the reaction mixture stand overnight, 25 ml. of distilled water and 50 ml. of ethyl acetate were added thereto and the mixture was extracted with ethyl acetate. The extraction was repeated three times using 25 ml. of ethyl acetate. The ethyl acetate layers were combined and dried over anhydrous magnesium sulfate. The liquid was concentrated using a rotary evaporator and subjected to gel chromatography using a column filled with Sephadex LH-20 (made by Pharmacia Co., Ltd.). As the solvent, a mixture obtained by mixing acetone and methanol in a proportion of 4:1 (volume) was used. While confirming by TLC, the objective fraction was taken and concentrated under reduced pressure followed by crystallization. The product was obtained in an amount of 950 mg. (yield 82.5%).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:11]([NH:13][C@H:14]([C:22]([O:24][CH3:25])=[O:23])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:12])[CH2:3][C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7].Cl.[H][H]>CO.O1CCOCC1.[Pd]>[NH2:1][C@H:2]([C:11]([NH:13][C@H:14]([C:22]([O:24][CH3:25])=[O:23])[CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:12])[CH2:3][C:4](=[O:10])[O:5][C:6]([CH3:7])([CH3:8])[CH3:9]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(=O)OC(C)(C)C
Yield: 110.1 %

Procedure:
48.6 g of Z-Asp(OtBu)-Phe-OCH3 in 700 ml of methanol are decarbobenzoxylated in a duck-shaped flask at room temperature after adding 33.5 ml of 3 N hydrogen chloride in dioxane and 5 g of 10 % strength palladium catalyst on charcoal. After the hydrogen uptake has ended the mixture is filtered and the filtrate evaporated. 38.7 g of a white foam are obtained. In a thin layer chromatogram on silica gel in chloroformmethanol (9:1) Rf = 0.60; in chloroform-acetone (1:1) Rf = 0.58; Rf102E =0.42. The product is employed for the subsequent condensation without additonal purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[N:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])[CH2:9][C:10]3([CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1.C(O)(=O)/C=C\C(O)=O.ClC1C=C2[N:39](C3C=CC=CC=3F)CC3(CCN(C)CC3)C2=CC=1>>[Cl:1][C:2]1[CH:7]=[C:6]2[N:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])[CH2:9][C:10]3([CH2:15][CH2:14][N:13]([C:16]#[N:39])[CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1
Reactant: CN1CCC2(CC1)CN(c1ccccc1F)c1cc(Cl)ccc12
Agent: O=C(O)/C=C\C(=O)O
Product: N#CN1CCC2(CC1)CN(c1ccccc1F)c1cc(Cl)ccc12

Procedure:
A sample of 6-chloro-1-(2-fluorophenyl)-1'-methylspiro[indoline-3,4'-piperidine], free base of Example 25, is treated according to the method of Example 25 to provide 6-chloro-1'-cyano-1-(2-fluorophenyl)spiro[indoline-3,4'-piperidine].
Reaction SMILES: [C:1]([O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:14][C:15]([CH3:17])=[O:16].[OH-].[Na+]>C(O)(=O)C>[C:1]([O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[CH:14][C:15](=[O:16])[CH3:17])=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)Oc1ccc(C=O)cc1
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(=O)C=Cc1ccc(OC(C)(C)C)cc1
Reaction time: 5 h
Yield: 81 %

Procedure:
89 g (0.5 mole) of p-tert.-butoxy-benzaldehyde are added dropwise, in the course of 15 minutes, to a mixture of 290 g (5 moles) of acetone and 30 ml of 0.5% strength aqueous sodium hydroxide solution at 20°-25° C., whilst stirring. After all has been added, the pH must be not less than 10; if it is not, sodium hydroxide solution must then be added. The reaction is complete after about 5 hours, as is demonstrable by thin layer chromatography or gas chromatography. Acetic acid is then added to the solution until it is neutral, the excess acetone is distilled off under reduced pressure and the reaction product is taken up in ether. The ether solution is washed salt-free with water, the ether is distilled off and the reaction product is fractionated, giving 88 g of main fraction. This corresponds to a yield of 81% of theory.