Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][P:5](=[O:12])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8].[N-:13]=[N+:14]=[N-:15].[Na+]>CCO.O>[N:13]([CH2:2][CH2:3][CH2:4][P:5](=[O:12])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8])=[N+:14]=[N-:15]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOP(=O)(CCCBr)OCC
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOP(=O)(CCCN=[N+]=[N-])OCC

Procedure:
To a solution of diethyl 3-bromopropylphosphonate (1 eq) in EtOH (2 M) was added sodium azide (5 eq) in water (4 M). The reaction mixture was heated at reflux overnight. The mixture was then diluted with water, extracted with DCM three times. The combined organic layers are washed with brine, dried over anhydrous Na2SO4, and concentrated en vaccuo. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 80-100% EtOAc/Hex to give the product as a colorless oil.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:8]1.CC([O-])(C)C.[Na+].[CH3:28][O:29][C:30]1[CH:31]=[C:32]([N:36]=[C:37]=[O:38])[CH:33]=[CH:34][CH:35]=1>C1(C)C=CC=CC=1>[CH3:28][O:29][C:30]1[CH:31]=[C:32]([NH:36][C:37]([N:17]2[CH2:16][CH2:15][C:14]3[C:19](=[CH:20][CH:21]=[C:12]([N:9]4[CH2:10][CH2:11][C@H:7]([N:3]5[CH2:4][CH2:5][CH2:6][C@@H:2]5[CH3:1])[CH2:8]4)[CH:13]=3)[CH2:18]2)=[O:38])[CH:33]=[CH:34][CH:35]=1
Reactant: C[C@H]1CCCN1[C@H]1CCN(c2ccc3c(c2)CCNC3)C1
Reactant: COc1cccc(N=C=O)c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cccc(NC(=O)N2CCc3cc(N4CC[C@H](N5CCC[C@@H]5C)C4)ccc3C2)c1
Temperature: 35 °C
Reaction time: 12 h

Procedure:
6-((2S,3′S)-2-Methyl-[1,3′]bipyrrolidinyl-1′-yl)-1,2,3,4-tetrahydro-isoquinoline (100 mg, 0.35 mmol, 1 eq) was dissolved in 3.5 mL of toluene and NaOt-Bu (50 mg, 0.51 mmol, 1.45 eq) was added followed by 3-methoxy phenylisocyanate (50 μL, 0.39 mmol, 1.1 eq). The reaction mixture was stirred at 35° C. for 12 h, where five grams of Celite was added, the mixture was concentrated under vacuum and purified by column chromatography on silica gel (5% MeOH in CH2Cl2; 40 g column; 35 mL/min). This gave 20 mg (13%) of the title compound as an orange semi-solid.
Reaction SMILES: N1C=CN=C1.[OH:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].O>C1COCC1>[Si:15]([O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.7 %

Procedure:
p-OSi-St chain transfer agent was synthesized in two steps. In a 500 ml flask equipped with a magnetic stirring bar, 70.4 g of imidazole was mixed with 52.4 g (0.42 mol) of 4-hydroxybenzaldehyde and 77.4 g of t-butyldimethylsilyl chloride in THF solution. The mixture was stirred at ambient temperature for 4 hours before being poured into cold water. The organic layer was separated and extracted with ether, then dried with magnesium sulfate. After evaporating the solvent, 94 g of 4-(t-butyldimethylsilyloxy)benzaldehyde (90% yield), a deep yellow color liquid, was obtained. The second reaction step was performed under a nitrogen atmosphere. In a 500 ml flask equipped with a magnetic stirring bar, 123.6 g of methyltriphenylphosphonium bromide suspended in THF was treated with 149.6 ml of n-butyllithium (2.5M in hexane). After 1 hour, 80.0 g of 4-(t-butyldimethylsilyloxy)benzaldehyde was introduced dropwise into the red solution. The mixture was stirred overnight at room temperature and then poured into cold water. The organic layer was separated by ether extraction and dried with magnesium sulfate. Further purification was performed by distillation under vacuum (10 Torr) at elevated temperature (80° C.). 65 g of p-OSi-St was obtained with a yield of more than 90%. Its structure was confirmed by 1H NMR spectrum.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:25]OS(C)(=O)=O)([CH2:19]OS(C)(=O)=O)[C:7](=[O:18])[N:8]2C(OC(C)(C)C)=O)=[CH:4][CH:3]=1.O.O.O.O.O.O.O.O.O.[S-2:40].[Na+].[Na+].[Cl-].[NH4+]>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[NH:8][C:7](=[O:18])[C:6]3([CH2:19][S:40][CH2:25]3)[C:5]2=[CH:4][CH:3]=1
Reactant: [S-2]
Reactant: CC(C)(C)OC(=O)N1C(=O)C(COS(C)(=O)=O)(COS(C)(=O)=O)c2ccc(Br)cc21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1Nc2cc(Br)ccc2C12CSC2
Temperature: 110 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl 6-bromo-3,3-bis((methylsulfonyloxy)methyl)-2-oxoindoline-1-carboxylate (3.70 g, 7.0 mmol) in anhydrous DMF (33 mL, deoxygenated with argon for 10 min) was added sodium sulfide nonahydrate (1.01 g, 4.20 mmol) under an argon atmosphere. The solution was stirred at 110° C. for 3 h, poured into saturated aqueous ammonium chloride solution and extracted with EtOAc. The combined organic extracts were dried over MgSO4, filtered and evaporated in vacuo. Purification by column chromatography (eluting with a gradient of 10-50% EtOAc in hexanes) gave 6-bromospiro[indoline-3,3′-thietan]-2-one as a yellow solid. Mass Spectrum (ESI) m/e=270.0 [(M+1) (79Br)] and 271.9 [(M+1) (81Br)].
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[CH:3]([N:29]1[CH2:33][CH2:32][C@H:31]([NH:34]C(=O)OC(C)(C)C)[CH2:30]1)[C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:10]([C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][C:17]([C:23](=[O:28])[NH:24][CH:25]([CH3:27])[CH3:26])=[CH:18][CH:19]=4)[N:14]=3)=[N:11][N:12]=2)[CH:9]=1.[ClH:44]>C(Cl)Cl.CC(O)C>[ClH:44].[ClH:44].[NH2:34][C@H:31]1[CH2:32][CH2:33][N:29]([CH:3]([C:4]2[CH:5]=[CH:6][C:7]3[N:8]([C:10]([C:13]4[CH:22]=[CH:21][C:20]5[C:15](=[CH:16][C:17]([C:23]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:28])=[CH:18][CH:19]=5)[N:14]=4)=[N:11][N:12]=3)[CH:9]=2)[C:2]([F:43])([F:42])[F:1])[CH2:30]1
Reactant: CC(C)NC(=O)c1ccc2ccc(-c3nnc4ccc(C(N5CC[C@H](NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)nc2c1
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)O
Product: CC(C)NC(=O)c1ccc2ccc(-c3nnc4ccc(C(N5CC[C@H](N)C5)C(F)(F)F)cn34)nc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.4 %

Procedure:
To a solution of tert-butyl (3S)-1-(2,2,2-trifluoro-1-(3-(7-(isopropylcarbamoyl)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-ylcarbamate (0.023 g, 0.039 mmol) in DCM (0.5 mL) was added 5 N HCl (0.39 mL, 1.92 mmol) in IPA. The mixture was stirred at ambient temperature for 1 hour. The solvent was removed under reduced pressure to give 2-(6-(1-((S)-3-aminopyrrolidin-1-yl)-2,2,2-trifluoroethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-N-isopropylquinoline-7-carboxamide dihydrochloride (0.023 g, 95.7%) as a solid. LCMS APCI (+) m/z 498 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1)#[CH:2].[Cl:11][C:12]1[CH:17]=[C:16](I)[CH:15]=[CH:14][C:13]=1[F:19].C(N(CC)CC)C>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:11][C:12]1[CH:17]=[C:16]([C:2]#[C:1][C:3]2[CH:4]=[N:5][CH:6]=[C:7]([O:9][CH3:10])[CH:8]=2)[CH:15]=[CH:14][C:13]=1[F:19]
Reactant: C#Cc1cncc(OC)c1
Reactant: Fc1ccc(I)cc1Cl
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COc1cncc(C#Cc2ccc(F)c(Cl)c2)c1
Temperature: 60 °C
Yield: 93 %

Procedure:
Add bis(triphenylphosphine)palladium (II) dichloride (110 mg, 0.15 mmol), copper (I) iodide (57 mg, 0.30 mmol), and 3-ethynyl-5-methoxypyridine, (prepared as described in PREPARATION 10), (400 mg, 3.0 mmol) to a solution of 2-chloro-1-fluoro-4-iodobenzene (0.46 mL, 3.6 mmol) in triethylamine (6.3 mL, 45.0 mmol) and heat at 60° C. for 5 h. Cool to room temperature and concentrate. Purify the residue by silica gel chromatography, eluting with a gradient of 100:0 to 80:20 dichloromethane:ethyl acetate, followed by a second silica gel chromatography, eluting with 67:33 to 60:40 hexanes:ethyl acetate, to give the title compound as a white solid (730 mg, 93%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([C:7]([C:10]2[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:13]=[CH:12][C:11]=2[OH:20])([CH3:9])[CH3:8])=[CH:5][CH:4]=1.[Cl-].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]#[N:32])=[C:27]([N+:33]([O-])=O)[CH:26]=1>>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]2=[N:31][N:32]([C:12]3[CH:13]=[C:14]([C:16]([CH3:17])([CH3:19])[CH3:18])[CH:15]=[C:10]([C:7]([C:6]4[CH:21]=[CH:22][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)([CH3:9])[CH3:8])[C:11]=3[OH:20])[N:33]=[C:27]2[CH:26]=1
Reactant: COc1ccc(C(C)(C)c2cc(C(C)(C)C)ccc2O)cc1
Reactant: N#[N+]c1ccc(Cl)cc1[N+](=O)[O-]
Agent: [Cl-]
Product: COc1ccc(C(C)(C)c2cc(C(C)(C)C)cc(-n3nc4ccc(Cl)cc4n3)c2O)cc1

Procedure:
Following the general procedure of Example 13, starting with the substituted phenol prepared in Example 3 and the diazonium salt prepared in Example 11, the title compound is prepared as a light yellow solid melting at 121-122° C. The structure is confirmed by 1Hnmr and mass spectroscopy analyses.
Reaction SMILES: Cl.Cl.Cl.[N:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([N:16]3[CH2:20][C@H:19]([CH2:21][NH2:22])[O:18][C:17]3=[O:23])=[N:14][CH:15]=2)[CH:5]=1.CN(C=O)C.[N+:29]([C:32]([CH3:41])=[CH:33]NC1C=CC=CN=1)([O-:31])=[O:30]>O>[N:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([N:16]3[CH2:20][C@@H:19]([CH:21]([CH:33]=[C:32]([N+:29]([O-:31])=[O:30])[CH3:41])[NH2:22])[O:18][C:17]3=[O:23])=[N:14][CH:15]=2)[CH:5]=1
Reactant: NC[C@H]1CN(c2ccc(-c3cccnc3)cn2)C(=O)O1
Reactant: CC(=CNc1ccccn1)[N+](=O)[O-]
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(=CC(N)[C@@H]1CN(c2ccc(-c3cccnc3)cn2)C(=O)O1)[N+](=O)[O-]
Reaction time: 8 h

Procedure:
100 mg (0.37 mmol) of the compound from Example XXVIII (free base; prepared by dissolving in water, NH3(aq) addition to pH 11, extraction with CH2Cl2, drying over MgSO4 and concentrating) are initially introduced into 1 ml of DMF under argon and 200 mg (1.11 mmol) of 2-(2-nitro-prop-1-en-1-yl-amino)-pyridine are added and the mixture is stirred overnight. It is treated with water, extracted 3× with ethyl acetate, and the organic phase is washed with satd. NaCl solution and dried over MgSO4. It is concentrated and the residue is purified by column chromatography on silica gel (eluent CH2Cl2 :MeOH=100:5). 126 mg (96% of theory) of the title compound are obtained.
Reaction SMILES: C(OC(=O)[N:7]([CH:30]([C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH:34][CH:33]=1)[CH3:31])[CH2:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:29])[C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[C:25]([F:28])([F:27])[F:26])[CH2:13][CH2:12]1)=[O:10])(C)(C)C.[ClH:45]>O1CCOCC1>[ClH:45].[C:35]1([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:34]=[CH:33][C:32]([CH:30]([NH:7][CH2:8][C:9]([N:11]2[CH2:12][CH2:13][N:14]([C:17](=[O:29])[C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=3[C:25]([F:28])([F:27])[F:26])[CH2:15][CH2:16]2)=[O:10])[CH3:31])=[CH:37][CH:36]=1
Reactant: CC(c1ccc(-c2ccccc2)cc1)N(CC(=O)N1CCN(C(=O)c2cc(F)ccc2C(F)(F)F)CC1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC(NCC(=O)N1CCN(C(=O)c2cc(F)ccc2C(F)(F)F)CC1)c1ccc(-c2ccccc2)cc1
Yield: 78.4 %

Procedure:
A solution of (1-biphenyl-4-yl-ethyl)-{2-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-carbamic acid tert-butyl ester (140 mg, 0.23 mmol in dioxane.HCl (10 ml) was stirred at room temperature for 1 hr. The reaction mixture was concentrated to get the residue. The residue was washed with hexane to afford 98 mg (78.4% Yield) of 2-(1-Biphenyl-4-yl-ethylamino)-1-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone hydrochloride. LCMS Purity: 93.9%. 1H NMR (CDCl3): δ 9.6 (d, 3H), 8.0 (t, 1H), 7.8-7.6 (m, 6H), 7.6-7.36 (m, 5H), 4.5 (t, 1H), 4.2-3.6 (m, 2H), 3.6-3.4 (m, 5H), 3.2-3.0 (m, 3H), 1.6 (t, 3H).
Reaction SMILES: O.NN.[NH2:4][C:5]1[C:6]([O:23][CH3:24])=[N:7][C:8]2[C:13]([N:14]=1)=[C:12]([N+:15]([O-])=O)[C:11]([Cl:18])=[C:10]([C:19]([F:22])([F:21])[F:20])[CH:9]=2>C(O)C.[Ru]>[NH2:4][C:5]1[C:6]([O:23][CH3:24])=[N:7][C:8]2[C:13]([N:14]=1)=[C:12]([NH2:15])[C:11]([Cl:18])=[C:10]([C:19]([F:22])([F:20])[F:21])[CH:9]=2
Reactant: COc1nc2cc(C(F)(F)F)c(Cl)c([N+](=O)[O-])c2nc1N
Agent: [Ru]
Agent: NN
Solvent: O
Solvent: CCO
Product: COc1nc2cc(C(F)(F)F)c(Cl)c(N)c2nc1N
Reaction time: 0.33 h
Yield: 100.5 %

Procedure:
Hydrazine hydrate (0.34 ml, 7.0 mmol) was added to a stirred solution of 3-amino-6-chloro-7-trifluoromethyl-2-methoxy-5-nitroquinoxaline (0.55g, 1.7 mmol) in ethanol (25 ml) containing suspended 10% ruthenium-on-carbon (55 mg) under nitrogen at reflux. After 20 minutes, additional hydrazine hydrate (0.17 ml, 3.4 mmol) was added, and the mixture was stirred at reflux for 30 minutes, then allowed to stand at room temperature overnight. The mixture was filtered through Arbocel filter aid, and the filter cake was washed with ethanol and dichloromethane. The filtrate was concentrated under reduced pressure to give the title compound (0.50 g, 100%) as an off-white solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([C:9]2[CH:14]=[C:13]([OH:15])[C:12]([OH:16])=[C:11]([Cl:17])[C:10]=2[Cl:18])=[O:8])=[CH:5][CH:4]=[N:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH:26](Br)[C:27]([O:29][CH2:30][CH3:31])=[O:28]>CN(C)C=O>[Cl:17][C:11]1[C:12]2[O:16][CH:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[O:15][C:13]=2[CH:14]=[C:9]([C:7]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)=[O:8])[C:10]=1[Cl:18]
Reactant: CCOC(=O)C(Br)Br
Reactant: Cn1nccc1C(=O)c1cc(O)c(O)c(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1Oc2cc(C(=O)c3ccnn3C)c(Cl)c(Cl)c2O1
Temperature: 0 °C
Reaction time: 2 h
Yield: 63.4 %

Procedure:
To a solution of 2.0 g of (1-methylpyrazol-5-yl)-(2,3-dichloro-4,5-dihydroxyphenyl)-methanone in 22 ml of dimethylformamide are added 2.12 g of powdered potassium carbonate and 3.7 g of ethyl dibromoacetate, and the mixture is stirred at 90° to 100° C. under argon gas atmosphere for 2 hours. After cooling, the mixture is poured into ice-water and the mixture is extracted with ethyl acetate. The extract is washed with an aqueous saturated sodium chloride solution, dried and evaporated to remove solvent under reduced pressure. The residue is purified by silica gel column chromatography (solvent; n-hexane-ethyl acetate) to give 1.64 g of ethyl 4,5-dichloro-6-(1-methyl-5-pyrazolylcarbonyl)-1,3-benzodioxole-2-carboxylate. Yield: 63%
Reaction SMILES: [C:1]1([N:6]2[CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH:2]=1.[C:11]([O:19][CH3:20])(=[O:18])[C:12]#[C:13][C:14]([O:16][CH3:17])=[O:15]>>[N:6]1([C:1]2[CH2:5][CH2:4][CH2:3][CH:2]=[C:13]([C:14]([O:16][CH3:17])=[O:15])[C:12]=2[C:11]([O:19][CH3:20])=[O:18])[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: C1=C(N2CCCC2)CCC1
Reactant: COC(=O)C#CC(=O)OC
Product: COC(=O)C1=CCCCC(N2CCCC2)=C1C(=O)OC

Procedure:
1-(1-Cyclopenten-1-yl)pyrrolidine and 2-butynedioic acid, dimethyl ester are reacted according to the procedure set forth in J.O.C., Vol. 28, p. 1464 (1963) to yield 3-(1-pyrrolidinyl)-2,7-cycloheptadiene-1,2-dicarboxylic acid, dimethyl ester.
Reaction SMILES: [C:1]([CH:11]1[NH:18][C:16](=[O:17])CCCC1)([CH:3]1NC(=O)[CH2:7][CH2:6][CH2:5][CH2:4]1)=O.N[C:20](N)(N)[CH2:21][CH2:22]CCCCCC>C(OCC)(=O)C>[N:18]([CH2:11][CH:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH2:20][CH2:21][CH3:22])=[C:16]=[O:17]
Reactant: O=C1CCCCC(C(=O)C2CCCCC(=O)N2)N1
Reactant: CCCCCCCCC(N)(N)N
Solvent: CCOC(C)=O
Product: CCCCCC(CCC)CN=C=O
Temperature: 25 °C

Procedure:
302.4 g (1.2 mol) carbonyl-bis-caprolactam was dissolved in 400 ml ethyl acetate at 78° C. In one hour 69.3 g (0.4 mol) triamino nonane, dissolved in 100 ml ethyl acetate, was added dropwise. The reaction was monitored by means of TLC. After 3 hours the clear solution was cooled to room temperature and extracted 4 times with 500 ml water (with some NaCl). The solution was then dried with NaSO4. The NaSO4 was removed by filtration and the ethyl acetate was removed by means of the rotavapor. The product was dried at 75° C. and in a vacuum. Caprolactam-blocked of 1,8-diisocyanato, 4-(isocyanatomethyl) nonane was obtained pure, as a lightly coloured oil (yield=99%).
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][NH:18][CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1)=O)(C)(C)C.[CH:29]([C:31]1[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=1)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:38][O:37][C:35](=[O:36])[C:34]1[CH:39]=[CH:40][C:31]([CH2:29][N:18]([CH2:17][C:9]2[NH:8][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=2)[CH:19]2[C:28]3[N:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH2:22][CH2:21][CH2:20]2)=[CH:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)n1c(CNC2CCCc3cccnc32)nc2ccccc21
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Reaction time: 18 h
Yield: 73.6 %

Procedure:
Following General Procedure B: To a solution of (1-tert-butoxycarbonyl-1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine (680 mg, 1.8 mmol) and methyl 4-formylbenzoate (295 mg, 1.8 mmol) in CH2Cl2 (10 mL) was added NaBH(OAc)3 (763 mg, 3.6 mmol) and the mixture stirred for 18 h. The resulting crude material was taken up in neat TFA (2 mL) and stirred 3 h. Saturated aqueous sodium bicarbonate (10 mL) was cautiously added, and the resulting mixture was extracted with CH2Cl2 (3×20 mL), and the combined organic extracts were dried (MgSO4), and concentrated in vacuo. Purification of the crude material by flash chromatography (silica gel, 50:2:1 CH2Cl2/MeOH/NH4OH) afforded the title compound (565 mg, 74%) as a white solid. 1H NMR (CDCl3) δ1.64-1.75 (m, 1H), 2.01-2.08 (m, 2H), 2.26-2.28 (m, 1H), 2.74-2.76 (m, 1H), 2.81-2.86 (m, 1H), 3.81 (s, 2H), 3.86 (s, 3H), 3.94 (d, 1H, J=17 Hz), 4.09 (dd, 11H, J=9, 7 Hz), 4.21 (d, 1H, J=17 Hz), 7.18-7.22 (m, 3H), 7.44 (br d, 1H, J=8 Hz), 7.49 (d, 2H, J=8 Hz), 7.50-7.53 (m, 11H), 7.64-7.66 (m, 1H), 7.91 (d, 2H, J=8 Hz), 8.70 (dd, 1H, J=5, 1 Hz); 13C NMR (CDCl3) δ21.2, 23.6, 29.0, 48.7, 51.9, 53.7, 111.0, 118.6, 121.5, 122.3, 129.3, 128.9, 129.5, 134.7, 137.2, 144.8, 146.8, 155.7, 157.1, 166.8. ES-MS m/z 427 (M+H). Anal. Calcd. for C26H26N4O2.0.6H2O.0.3CH2Cl2: C, 68.26; H, 6.05; N, 12.11. Found: C, 68.57; H, 6.12; N, 11.75.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:9]2[C:10]([CH3:13])=[CH:11][O:12][C:8]=2[CH:7]=1.[CH2:16]([O:18][C:19](=[O:31])[CH2:20][C@H:21]1[C:29]2[C:24](=[CH:25][C:26]([OH:30])=[CH:27][CH:28]=2)[CH2:23][CH2:22]1)[CH3:17].O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:16]([O:18][C:19](=[O:31])[CH2:20][C@H:21]1[C:29]2[C:24](=[CH:25][C:26]([O:30][CH2:2][CH2:3][CH2:4][O:5][C:6]3[CH:15]=[CH:14][C:9]4[C:10]([CH3:13])=[CH:11][O:12][C:8]=4[CH:7]=3)=[CH:27][CH:28]=2)[CH2:23][CH2:22]1)[CH3:17]
Reactant: CCOC(=O)C[C@@H]1CCc2cc(O)ccc21
Reactant: Cc1coc2cc(OCCCBr)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc4c(C)coc4c3)ccc21
Temperature: 80 °C
Reaction time: 68 h
Yield: 108.3 %

Procedure:
To a mixture of 6-(3-bromopropoxy)-3-methyl-1-benzofuran (87 mg, 0.32 mmol) (Example 63) and ethyl[(1S)-5-hydroxy-2,3-dihydro-1H-inden-1-yl]acetate (59 mg, 0.269 mmol) (Example 6) in DMF containing 1 vol % water (2.4 mL) was added Cs2CO3 (105 mg, 0.323 mmol). The mixture was stirred for 68 h at 80° C., and the reaction mixture cooled to rt, then concentrated under reduced pressure. The residue was suspended in EtOAc and filtered through a small plug of silica to give 119 mg (90%) of a light-yellow solid that was used in the next step without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([OH:13])=[C:9]([CH:12]=1)[CH:10]=[O:11])([CH3:4])([CH3:3])[CH3:2].[O:14]=[N+:15]=[O:16]>CC#N>[C:1]([C:5]1[CH:6]=[C:7]([N+:15]([O-:16])=[O:14])[C:8]([OH:13])=[C:9]([CH:12]=1)[CH:10]=[O:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(O)c(C=O)c1
Reactant: O=[N+]=O
Solvent: CC#N
Product: CC(C)(C)c1cc(C=O)c(O)c([N+](=O)[O-])c1
Reaction time: 1 h

Procedure:
To a solution of 15.0 g (84.2 mmol) of 5-tert-Butyl-2-hydroxy-benzaldehyde in MeCN at −30° C. was added 14.5 g (109.4 mmol) of nitronium tetrafluoborate. The temperature was allowed to climb slowly to −12° C. ove 1 h. The mixture was partitioned between sat'd NaHCO3 and EtOAc. The organic layer was washed with water and brine then dried over MgSO4. After filtration and evaporation, 5-tert-butyl-2-hydroxy-3-nitro-benzaldehyde was obtained as yellow solid. To a portion of this material (6.27 g, 28.1 mmol) in 40 mL of DMF was added 19.4 g of K2CO3 in two batches. To this slurry was added 6.12 mL (98.3 mmol) of MeI. The mixture was stirred overnight, filtered, and diluted with EtOAc. This mixture was washed with water, and the wash was then extracted with EtOAc (3×150 mL). The extracts were washed with water and brine, then dried over MgSO4, filtered, and concentrated. Chromatography (5% EtOAc in hexanes) provided 5.38 g of 5-tert-butyl-2-methoxy-3-nitro-benzaldehyde as an off-white solid.
Reaction SMILES: [C:1]1([N:7]2[C:15](=[O:16])[C:14]3[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=3[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[CH2:18][CH3:19]>CN(C=O)C>[CH2:18]([N:8]1[C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=2[C:15](=[O:16])[N:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH3:19]
Reactant: CCI
Reactant: O=c1c2c([nH]n1-c1ccccc1)CCCC2
Solvent: CN(C)C=O
Product: CCn1c2c(c(=O)n1-c1ccccc1)CCCC2
Temperature: 100 °C

Procedure:
To a solution of 2-phenyl-1,2,4,5,6,7-hexahydro-indazol-3-one (0.1 g) in DMF (1 mL) was added iodoethane (0.073 mL) and the mixture was placed into a pressure bomb and sealed. The reaction vessel was then heated in an oil bath to 100° C. over three days. The reaction vessel was then cooled and the DMF was evaporated in vacuo. The residue was dissolved in EtOAc and saturated and washed with saturated sodium bicarbonate solution. The phases were separated and the aqueous solution was extracted with EtOAc another two times at neutral pH. The combined organic phases were washed with brine, dried over sodium sulfate, filtered and evaporated in vacuo to afford a crude residue. Flash column chromatography over silica gel using ISCO combiflash chromatography and eluting with EtOAc/heptane and 3% AcOH afforded the desired 1-ethyl-2-phenyl-1,2,4,5,6,7-hexahydro-indazol-3-one (0.084 g) as a light brown solid. MS (ESI+): MS (ESI+): 243.4 [M+H]+).
Reaction SMILES: [O:1]=[S:2]1(=[O:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[CH3:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(Cl)(Cl)Cl>[O:30]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:36]3[CH:37]=[C:32]([CH3:31])[CH:33]=[CH:34][CH:35]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: Cc1cccc(B(O)O)c1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCS(=O)(=O)CC4)cc3c2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: Cc1cccc(-n2c(C(=O)N3CCS(=O)(=O)CC3)cc3cc(C(=O)N4CCN(C(C)C)CC4)ccc32)c1
Yield: 94 %

Procedure:
The title compound was synthesized in analogy to example 66, from [2-(1,1-dioxo-thiomorpholine-4-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanone (example 1), 3-methylphenylboronic acid, copper(II) acetate, pyridine and using chloroforme instead of dichloromethane as solvent, to give the desired product as a colorless foam (94%).