Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]12[CH2:11][CH:7]([CH2:8][CH2:9][CH2:10]1)[CH:6]1[CH2:12][CH:3]2[CH2:4][CH2:5]1.[CH2:13]([OH:17])[CH2:14][CH2:15][CH3:16]>[Ag]=O>[CH2:13]([O:17][C:2]12[CH2:11][CH:7]([CH2:8][CH2:9][CH2:10]1)[CH:6]1[CH2:12][CH:3]2[CH2:4][CH2:5]1)[CH2:14][CH2:15][CH3:16]
Reactant: BrC12CCCC(C1)C1CCC2C1
Reactant: CCCCO
Agent: O=[Ag]
Product: CCCCOC12CCCC(C1)C1CCC2C1
Yield: 65.3 %

Procedure:
A mixture of 3.0 g of 1-bromotricyclo[4.3.1.12,5 ]undecane, 2.0 g of silver oxide and 30 ml of anhydrous n-butanol was refluxed for 6 hours. Thereafter, the mixture was treated in the same manner as described in Example 1, and there was obtained 1.9 g (yield, 65.3%) of 1-n-butoxytricyclo[4.3.1.12,5 ]undecane having a boiling point of 97° to 98° C./1 mmHg.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[N:3]=1.C([Li])CCC.Br[CH2:16][CH2:17][CH2:18][O:19][Si](C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>C1COCC1.ClCCCl>[CH3:45][S:46]([O:19][CH2:18][CH2:17][CH2:16][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[N:3]=1)(=[O:48])=[O:47]
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Reactant: CS(=O)(=O)Cl
Reactant: COc1cccc(Br)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClCCCl
Product: COc1cccc(CCCOS(C)(=O)=O)n1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2-bromo-6-methoxypyridine (144-1, 1.6 g, 8.88 mmol) in THF (30 mL) at −78° C. was added a 2.5 molar solution of n-Butyllithium in THF (3.9 mL, 5.86 mmol) and the system was stirred at −78° C. for 20 minutes followed by the addition of (3-bromopropoxy)(tert-butyl)dimethylsilane (1.5 g, 5.92 mmol). After 1 h, the cold bath was removed and the system was stirred as it approached ambient temperature. The contents were extracted with water and EtOAc. The organic phase was dried over MgSO4, filtered, concentrated and purified by gradient elution on silica (0 to 10% EtOAc in Hx) to afford afford a pale yellow oil. To this pale yellow oil (1.5 g, 5.33 mmol) in THF (26 mL) was added a 1.0 molar solution of tetrabutylammoniumfluoride in THF (10.0 mL, 10.7 mmol) and the system was stirred for 1 h. The reaction contents were concentrated in vacuo and the resulting residue was purified by gradient elution on silica (0 to 100% EtOAc in Hx) to afford a pale yellow oil. To this pale yellow oil (0.3 g, 1.80 mmol) in DCE (9 mL) at 0° C. was added methanesulfonylchloride (0.17 mL, 2.16 mmol) and the system was stirred for 15 minutes at 0° C. The reaction contents were extracted with water and EtOAc. EtOAc. The organic phase was dried over MgSO4, filtered and concentrated to afford 144-2 as a pale yellow oil. ESI+ MS C10H15NO4S: 246.1 found, 246.1 required.
Reaction SMILES: [C:1]([N:9]1[C@@H:13]([CH3:14])[C:12](=[O:15])OC1=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]1([CH3:26])[CH:22]=[CH:21][C:20]([C@@H:23]([NH2:25])[CH3:24])=[CH:19][CH:18]=1.CN1CCOCC1.Cl>C(OCC)(=O)C>[C:17]1([CH3:26])[CH:22]=[CH:21][C:20]([C@@H:23]([NH:25][C:12](=[O:15])[C@H:13]([CH3:14])[NH:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH3:24])=[CH:19][CH:18]=1
Reactant: C[C@H]1C(=O)OC(=O)N1C(=O)c1ccccc1
Reactant: Cc1ccc([C@H](C)N)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: Cc1ccc([C@H](C)NC(=O)[C@H](C)NC(=O)c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 96 %

Procedure:
(S)-3-Benzoyl-4-methyl-2,5-oxazolidinedione (N-benzoyl-L-alanine-NCA) (110 mg, 0.50 mmol) was dissolved in ethyl acetate (2.5 mL), followed by the addition of a solution of (S)-1-(p-tolyl)ethylamine (68 mg, 0.50 mmol) in ethyl acetate (2.5 mL) at 0° C. A solution of N-methylmorpholine (61 mg, 0.6 mmol) in ethyl acetate (3.0 mL) was then added, followed by stirring for 30 minutes. The reaction mixture was poured into 1 N hydrochloric acid (10 mL), followed by extraction with ethyl acetate (10 mL). The organic layer was washed successively with a saturated aqueous solution of sodium hydrogencarbonate (10 mL) and a saturated aqueous solution of sodium chloride (10 mL), and was then dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure to afford the title compound (149 mg, 97%) as white crystals.
Reaction SMILES: [Cl:1][CH2:2]CO.[OH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][C:13]#N)=[CH:8][CH:7]=1.C(P(CC)CC)C.C(OCC)C>CC(C)=O.O>[Cl:1][CH2:2][CH2:13][S:12][C:9]1[CH:10]=[CH:11][C:6]([OH:5])=[CH:7][CH:8]=1
Reactant: OCCCl
Reactant: N#CSc1ccc(O)cc1
Agent: CCP(CC)CC
Solvent: CC(C)=O
Solvent: O
Solvent: CCOCC
Product: Oc1ccc(SCCCl)cc1

Procedure:
2-chloro-ethanol (3.9 g, 0.049 mole) was added to a solution of the product of Example 35 (7.4 g, 0.049 mole) in acetone (50 ml). After cooling with an ice bath triethylphosphine (5.6 g, 0.047 mole) was added dropwise over 25 minutes. Ethyl ether (200 ml) and water (75 ml) were added and the layers separated. The organic layer was washed with water (4×50 ml) and saturated sodium chloride (2×25 ml) dried over magnesium sulfate, filtered and concentrated to give a yellow oil. The structure was confirmed by its NMR spectrum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:21][C:22]2[CH:23]=[N:24][C:25]([CH2:28][O:29][CH3:30])=[CH:26][CH:27]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18](O)=[O:19])[CH2:15][N:16]=1)=[CH:8]2.Cl.[CH2:32]([N:34]=C=NCCCN(C)C)[CH3:33].O.ON1C2C=CC=CC=2N=N1.O1CCCC1.C(N)C>CN(C)C=O>[CH2:32]([NH:34][C:18](=[O:19])[CH2:17][CH:14]1[S:13][C:12]([C:9]2[NH:10][C:11]3[C:7]([CH:8]=2)=[CH:6][C:5]([O:21][C:22]2[CH:23]=[N:24][C:25]([CH2:28][O:29][CH3:30])=[CH:26][CH:27]=2)=[CH:4][C:3]=3[O:2][CH3:1])=[N:16][CH2:15]1)[CH3:33]
Reactant: COCc1ccc(Oc2cc(OC)c3[nH]c(C4=NCC(CC(=O)O)S4)cc3c2)cn1
Reactant: CCN=C=NCCCN(C)C
Agent: CCN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: CCNC(=O)CC1CN=C(c2cc3cc(Oc4ccc(COC)nc4)cc(OC)c3[nH]2)S1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.6 %

Procedure:
A mixture of [2-(7-methoxy-5-{[6-(methoxymethyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetic acid (300 mg), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (268 mg), 1-hydroxybenzotriazole monohydrate (214 mg), 2M ethylamine tetrahydrofuran solution (0.7 mL) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure. The residue was dissolved in water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by basic silica gel column chromatography (methanol/ethyl acetate/hexane=0/70/30 to 8/92/0, volume ratio) to give a pale yellow amorphous solid. The amorphous solid was crystallized from acetonitrile to give white crystals. The crystals were recrystallized from acetonitrile to give the title compound (222 mg, 70%) as colorless crystals. MS 455 (MH+). mp 130-132° C.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].[C:22](=[O:25])([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:14]([O:12][C:7]1[C:6]2[C:11](=[C:2]([O:25][CH2:22][CH2:10][CH2:11][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH:3]=[CH:4][CH:5]=2)[CH:10]=[CH:9][CH:8]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCBr
Reactant: O=C([O-])[O-]
Reactant: Oc1cccc2c(O)cccc12
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCOc1cccc2c(OCCCCCCCC)cccc12
Temperature: 90 °C
Yield: 140.2 %

Procedure:
1,5-dihydroxynaphthalene (2.95 g, 18.4 mmol), 1-bromooctane (8.2 g, 42.5 mmol), and potassium carbonate (50 g, 0.36 mol) was mixed in N,N-dimethylformamide and heated at 90° C. for 5 h. The potassium carbonate was filtered off and the reaction mixture was quenched with water and extracted two times with ether. The combined organic phase was then washed once with 1M HCl, two times with water, and evaporated. The residual brown solid was recrystallised in ethanol to form 1,5-bis(octyloxy)naphthalene (4.96 g, 12.9 mmol) as brown crystals. 1H-NMR (CDCl3, δ): 0.89 (t, 61-1), 1.2-1.4 (m, 16H), 1.4-1.6 (m, 4H), 1.91 (m, 4H), 4.12 (t, 4H), 6.81 (d, 2H), 7.34 (t, 2H), 7.83 (d, 2H) MS MALDI-TOF (m/z): 384.266
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Cl[C:17]1[N:22]=[C:21]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=2)[CH:20]=[CH:19][N:18]=1>>[Cl:30][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[CH2:23][C:21]1[CH:20]=[CH:19][N:18]=[C:17]([NH:15][C:5]2[CH:6]=[CH:7][C:8]([N:9]3[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:22]=1
Reactant: Clc1cccc(Cc2ccnc(Cl)n2)c1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Product: COc1cc(Nc2nccc(Cc3cccc(Cl)c3)n2)ccc1-n1cnc(C)c1
Yield: 55 %

Procedure:
The title compound was prepared in analogous manner as described in example 1e) from 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine and 2-chloro-4-(3-chloro-benzyl)-pyrimidine. It was obtained as a yellow solid in 55% yield.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[CH:13]=[C:12]([CH3:14])[N:11]([CH2:15][C:16]4[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=4)[C:19]([O:21]C)=[O:20])[C:8]=3[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[Li+].[OH-].O[Li].O>O1CCOCC1.O.CO>[NH4+:3].[CH3:1][C:2]1[N:6]2[C:7]3[CH:13]=[C:12]([CH3:14])[N:11]([CH2:15][C:16]4[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=4)[C:19]([O-:21])=[O:20])[C:8]=3[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1
Reactant: COC(=O)c1cccc(Cn2c(C)cc3c2ccc2nnc(C)n23)c1
Agent: [Li+]
Agent: [Li]O
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: Cc1cc2c(ccc3nnc(C)n32)n1Cc1cccc(C(=O)[O-])c1
Product: [NH4+]
Reaction time: 8 h

Procedure:
To a solution of methyl 3-[(1,7-dimethyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridin-6-yl)methyl]benzoate (0.090 g, 0.27 mmol, prepared as in Example 26, Step 1) in 1,4-dioxane (2 mL), H2O (1 mL) and MeOH (1 mL) was added LiOH, monohydrate (0.056 g, 1.3 mmol) and the reaction was stirred overnight. Further LiOH—H2O (0.050 g, 1.1 mmol) was added and the reaction was continued for 8 hours. The reaction mixture was diluted with additional water, filtered and purified via preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) (74 mg, 86%).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][N:11]3[C:23]3[N:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[CH:4][C:3]=2[O:2]1.CC([O-:33])(C)C.[K+]>CN(C=O)C>[N:28]1[CH:27]=[CH:26][CH:25]=[N:24][C:23]=1[N:11]1[CH2:12][C:13]2[C:14](=[O:33])[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=3[NH:21][C:22]=2[CH:10]1[C:5]1[CH:6]=[CH:7][C:8]2[O:9][CH2:1][O:2][C:3]=2[CH:4]=1
Reactant: CC(C)(C)[O-]
Reactant: c1cnc(N2CCc3c([nH]c4ccccc34)C2c2ccc3c(c2)OCO3)nc1
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1c2c([nH]c3ccccc13)C(c1ccc3c(c1)OCO3)N(c1ncccn1)C2
Reaction time: 0.08 h

Procedure:
To a solution of 1-(3,4-methylenedioxyphenyl)-2-(pyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-β-carboline (0.153 g, 0.415 mmol) (prepared as in Example 16) in anhydrous DMF (4.1 mL) was added KOtBu (0.079 g, 0.70 mmol, 1.7 eq.). After 5 min, oxygen gas was bubbled through the solution for 1 h. Diethyl ether (45 mL) was added to the reaction mixture and the supernatant decanted. Brine (2 mL) was added to the residue and the pH was adjusted to pH˜7 by addition of a few drops of 1N HCl. The water was removed in vacuo as an azeotrope with toluene. The resulting deep red residue was dissolved in a minimum amount of THF, and purified by column chromatography (silca gel; EtOH: CH2Cl2=1:9) to yield the product as a white solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([NH2:7])[CH:3]=1.[Cl:8][C:9]1[N:14]=[C:13](Cl)[C:12]([Cl:16])=[CH:11][N:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>CCO>[Cl:8][C:9]1[N:14]=[C:13]([NH:7][C:4]2[CH:3]=[C:2]([CH3:1])[O:6][N:5]=2)[C:12]([Cl:16])=[CH:11][N:10]=1
Reactant: Cc1cc(N)no1
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(Nc2nc(Cl)ncc2Cl)no1

Procedure:
The mixture 5-methylisoxazol-3-amine (98 mg, 1.0 mmol), 2,4,5-trichloropyrimidine (344 μL, 3.0 mmol), and sodium carbonate (106 mg, 1.0 mmol) in 3 mL of EtOH was heated at 60° C. over night. The reaction mixture was concentrated and then partitioned between EtOAc and brine. The collected organic extracts were dried (Na2SO4), concentrated in vacuo, and purified with silica gel chromatography (MeOH/DCM: 1/9) to afford N-(2,5-dichloropyrimidin-4-yl)-5-methylisoxazol-3-amine; ESMS m/z 245.0 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH:12]([CH3:14])[CH3:13])[C:10]([CH3:16])([CH3:15])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[F:17][C:18]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:25][OH:26]>>[F:17][C:18]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:25][O:26][C:2]1[CH:3]=[C:4]2[N:11]([CH:12]([CH3:14])[CH3:13])[C:10]([CH3:16])([CH3:15])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1
Reactant: OCc1cccc(F)c1F
Reactant: CC(C)N1c2cc(Cl)nc(=O)n2CC1(C)C
Product: CC(C)N1c2cc(OCc3cccc(F)c3F)nc(=O)n2CC1(C)C

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 7-chloro-1-isopropyl-2,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one and (2,3-difluorophenyl)methanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[C:14]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:13]=1)[C:7]([CH3:28])=[C:6]2[CH2:29][C:30]([O:32]CC)=[O:31].[OH-].[Na+:36]>C(O)C>[OH2:2].[Na+:36].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[C:14]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:13]=1)[C:7]([CH3:28])=[C:6]2[CH2:29][C:30]([O-:32])=[O:31]
Reactant: CCOC(=O)Cc1c(C)n(-c2cc(-c3ccccc3)nc3ccccc23)c2ccc(OC)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc2c(c1)c(CC(=O)[O-])c(C)n2-c1cc(-c2ccccc2)nc2ccccc12
Product: O

Procedure:
Ethyl 5-methoxy-2-methyl-1-(2-phenylquinol-4-yl)indol-3-ylacetate (2.1g.) in ethanol (20ml.) and 2N-sodium hydroxide solution (20ml.) was refluxed for 0.25 hour. Most of the ethanol was removed in vacuo and the residue was diluted with water (50ml.). The resulting mixture was filtered, and the residue was washed with water and dried at 60° C. to give 5-methoxy-2-methyl-1-(2-phenylquinol-4-yl)indol-3-ylacetic acid sodium salt monohydrate, m.p. 179°-180° C.
Reaction SMILES: [NH2:1][C:2]1[C:31]([Cl:32])=[CH:30][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:33][CH3:34])[CH:3]=1.[CH:35](=O)[CH3:36].C([BH3-])#N.[Na+]>>[NH2:1][C:2]1[C:31]([Cl:32])=[CH:30][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:35][CH3:36])[CH2:22][C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:33][CH3:34])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCNCc2ccc(F)cc2)CC1
Reactant: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCN(CCCCCN1CCC(CNC(=O)c2cc(Cl)c(N)cc2OC)CC1)Cc1ccc(F)cc1

Procedure:
4-Amino-5-chloro-N-((1-(5-(4-fluorobenzylamino)pentyl)piperidin-4-yl)methyl)-2-methoxybenzamide (1.8 g) as starting compound, acetaldehyde (0.25 ml) and sodium cyanoborohydride (0.28 g) were reacted and treated in the same manner as in Example 136 to give 1.0 g of 4-amino-5-chloro-N-((1-(5-(N-ethyl-N-(4-fluorobenzyl)amino)pentyl)-piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][N:4]([CH2:17][CH2:18][CH2:19][OH:20])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.[C:23]([NH:26][C:27]1[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=1)(=[O:25])[CH3:24]>>[C:9]([C:8]1[CH:11]=[CH:12][C:5]([N:4]([CH2:3][C:2]([CH3:22])([CH3:21])[CH3:1])[CH2:17][CH2:18][CH2:19][O:20][C:30]2[CH:31]=[CH:32][C:27]([NH:26][C:23](=[O:25])[CH3:24])=[CH:28][CH:29]=2)=[CH:6][C:7]=1[C:13]([F:14])([F:15])[F:16])#[N:10]
Reactant: CC(C)(C)CN(CCCO)c1ccc(C#N)c(C(F)(F)F)c1
Reactant: CC(=O)Nc1ccc(O)cc1
Product: CC(=O)Nc1ccc(OCCCN(CC(C)(C)C)c2ccc(C#N)c(C(F)(F)F)c2)cc1

Procedure:
Synthesized as described in Example 1C from 4-[(2,2-dimethylpropyl)(3-hydroxypropyl)amino]-2-(trifluoromethyl)benzonitrile and 4-acetamidophenol: MS (ESI) m/z 448 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br)(=[O:13])[CH3:12].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>O>[C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:10]1[C:3]2[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=2[CH:8]=[CH:9]1)(=[O:13])[CH3:12]
Reactant: CC(=O)OCCCCCBr
Reactant: Clc1ncnc2cc[nH]c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OCCCCCn1ccc2ncnc(Cl)c21
Temperature: 40 °C
Reaction time: 96 h

Procedure:
A mixture of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (0.50 g), 5-bromopentyl acetate (0.71 mL), cesium carbonate (1.59 g) and N,N-dimethylformamide (5.0 mL) was stirred at 40° C. for 4 days. Water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography (eluent, ethyl acetate:hexane=1:3→6:4) to give the title compound (637 mg) as a white solid.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH:6]=[C:5]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]3([C:29]4[C:20](=[CH:21][C:22]5[O:27][CH2:26][CH2:25][O:24][C:23]=5[CH:28]=4)[O:19][CH2:18]3)[C:10]2=[O:30])[CH:4]=[CH:3]1.[H-].[Na+].I[CH3:34]>CN(C)C=O.O>[CH3:34][N:7]1[C:2](=[O:1])[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]3([C:29]4[C:20](=[CH:21][C:22]5[O:27][CH2:26][CH2:25][O:24][C:23]=5[CH:28]=4)[O:19][CH2:18]3)[C:10]2=[O:30])=[CH:6]1
Reactant: CI
Reactant: O=C1N(Cc2ccc(=O)[nH]c2)c2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)ccc1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.4 %

Procedure:
To a cooled (0° C.) solution of 1′-[(6-oxo-1,6-dihydropyridin-3-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.07 g, 0.17 mmol) in anhydrous N,N-dimethylformamide (3 mL) was added sodium hydride (60% in mineral oil, 0.01 g, 0.25 mmol). The mixture was stirred at ambient temperature for 1 h, and iodomethane (0.02 mL, 0.27 mmol) was added. The mixture was stirred at ambient temperature for 16 h, diluted with water (15 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layers was washed with brine (35 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography and eluted with a 10% to 30% gradient of acetone in dichloromethane to afford 1′-[(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.03 g, 42%) as a colorless solid: mp 205-207° C.; 1H NMR (300 MHz, CDCl3) δ7.40-7.34 (m, 2H), 7.33-7.26 (m, 1H), 7.21-7.16 (m, 1H), 7.11-7.04 (m, 1H), 6.91-6.85 (m, 1H), 6.60-6.54 (m, 1H), 6.50 (s, 1H), 6.12 (s, 1H), 4.77 (ABq, J=75.6, 9.0 Hz, 2H), 4.66 (ABq, J=58.2, 15.3 Hz, 2H), 4.22-4.08 (m, 4H), 3.53 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 177.7, 162.5, 155.2, 144.7, 141.5, 139.6, 138.3, 137.4, 132.2, 128.9, 124.3, 123.8, 121.3, 120.7, 114.0, 111.2, 108.5, 99.5, 79.8, 64.5, 63.9, 57.9, 40.8, 37.9; MS (ES+) m/z 416.9 (M+1).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[N:11]1([C:20]2[N:28]=[C:27]3[C:23]([N:24]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:25](=[O:36])[N:26]3[C@H:29]3[CH2:34][CH2:33][C@H:32]([OH:35])[CH2:31][CH2:30]3)=[CH:22][N:21]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[CH:12]1.C(N(CC)CC)C>C(Cl)Cl>[N:11]1([C:20]2[N:28]=[C:27]3[C:23]([N:24]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:25](=[O:36])[N:26]3[CH:29]3[CH2:30][CH2:31][C:32](=[O:35])[CH2:33][CH2:34]3)=[CH:22][N:21]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[CH:12]1
Reactant: CC(C)(C)OC(=O)n1c(=O)n([C@H]2CC[C@H](O)CC2)c2nc(-n3cnc4ccccc43)ncc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)n1c(=O)n(C2CCC(=O)CC2)c2nc(-n3cnc4ccccc43)ncc21
Reaction time: 0.03 h
Yield: 57.8 %

Procedure:
A solution of oxalyl chloride (6.4 mg) in DCM (0.5 ml) was cooled to −60° C. and treated with a solution of DMSO (8 mg) in DCM (0.5 ml). The reaction mixture was stirred for 2 minutes, then treated with a solution of tert-butyl 2-(1H-benzo[d]imidazol-1-yl)-9-(trans-4-hydroxycyclohexyl)-8-oxo-8,9-dihydropurine-7-carboxylate (4 mg) in DCM (0.5 ml). After 15 minutes, triethylamine (0.4 mL) was added and the mixture was stirred at room temperature for 30 minutes. The mixture was diluted with 10 mL DCM and washed with 15 mL of water. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography to provide 2.3 mg of tert-butyl 2-(1H-benzo[d]imidazol-1-yl)-8-oxo-9-(4-oxocyclohexyl)-8,9-dihydropurine-7-carboxylate, which was deprotected with TFA/DCM (6 ml, 1:1) for 1 h. The mixture was concentrated and the residue was triturated with ethyl ether to provide 1.8 mg of the title compound. 1H-NMR (300 MHz, CDCl3) δ 9.0 (s, 1H), 8.5 (dd, 1H), 8.4 (s, 1H), 7.9 (dd, 1H), 7.4 (m, 2H), 4.9 (m, 1H), 3.0 (m, 2H), 2.6 (m, 4H), 2.3 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1([CH2:6][NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH3:18])[CH:16]=3)[N:11]=[C:10](Cl)[N:9]=2)[CH2:5][O:4][CH2:3]1.[S:20]1(=[O:31])[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH2:24][NH:23][CH2:22][CH2:21]1>C(O)CCC>[NH2:1][C:2]1([CH2:6][NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH3:18])[CH:16]=3)[N:11]=[C:10]([N:23]3[CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[S:20](=[O:31])[CH2:21][CH2:22]3)[N:9]=2)[CH2:5][O:4][CH2:3]1
Reactant: Cc1ccc2nc(Cl)nc(NCC3(N)COC3)c2c1
Reactant: O=S1CCNCc2ccccc21
Solvent: CCCCO
Product: Cc1ccc2nc(N3CCS(=O)c4ccccc4C3)nc(NCC3(N)COC3)c2c1
Temperature: 160 °C

Procedure:
A mixture of N-(3-aminooxetan-3-ylmethyl)-2-chloro-6-methylquinazolin-4-amine (140 mg, 0.5 mmol) and 2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide (270 mg, 1.5 mmol) in n-butanol (10 mL) was heated at 160° C. for 30 minutes. After the resulting mixture was concentrated in vacuo, the residue was purified by preparative HPLC to afford the pure product as a solid. MS obsd. (ESI+) [(M+H)+] 424, 1H NMR (400 MHz, CD3OD) δ ppm 8.01 (s, 1 H), 7.83-7.79 (m, 2 H), 7.66-7.52 (m, 4 H), 5.45-5.41 (d, 1 H), 5.10 (brs, 1 H), 4.80-4.72 (m, 6 H), 4.39 (s, 2 H), 3.51 (s, 2 H), 2.45 (s, 3 H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.Cl.[F:25][C:26]1[CH:39]=[CH:38][C:29]([C:30]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[O:31])=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl.O>[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([S:20]([N:35]4[CH2:34][CH2:33][N:32]([C:30](=[O:31])[C:29]5[CH:28]=[CH:27][C:26]([F:25])=[CH:39][CH:38]=5)[CH2:37][CH2:36]4)(=[O:22])=[O:21])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: O=S(=O)(Cl)c1ccc(Nc2ccnc3cc(Cl)ccc23)cc1
Reactant: O=C(c1ccc(F)cc1)N1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(c1ccc(F)cc1)N1CCN(S(=O)(=O)c2ccc(Nc3ccnc4cc(Cl)ccc34)cc2)CC1
Temperature: 25 °C
Yield: 5 %

Procedure:
4-(7-Chloro-4-quinolinylamino)benzenesulphonyl chloride hydrochloride (7.8 g, 0.02 mol) was added portion-wise with stirring to a cold mixture of 1-(4-fluorobenzoyl) piperazine hydrochloride (4.9 g, 0.02 mol) in chloroform (250 ml) and sodium carbonate (24.4 g) in water (250 ml). The cooling bath was removed and the mixture was allowed to warm to room temperature. After 1 hour the chloroform layer was separated and dried (MgSO4). The solvent was removed by evaporation to give a brown gum. Crystallisation from ethanol gave the pure title compound (0.53 g), m.p. 235°-237° C.