Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH:21]4[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH:6]=[CH:5]1.[CH3:28][O:29][CH2:30][C:31](O)=[O:32]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:31](=[O:32])[CH2:30][O:29][CH3:28])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH:6]=[CH:5]1
Reactant: COCC(=O)O
Reactant: NC1CCC(CCN2CCN(c3nccc4ccoc34)CC2)CC1
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4ccoc34)CC2)CC1

Procedure:
The title compound, white solid (54 mg, 67%), MS (ISP) m/z=401.4 [(M+H)+], mp 132° C., was prepared in accordance with the general method of example 6 from 4-[2-(4-furo[2,3-c]pyridin-7-yl-piperazin-1-yl)-ethyl]-cyclohexylamine trihydrochloride (intermediate C) (88 mg, 0.2 mmol) and methoxy-acetic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[Li]CCCC.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH:31]([C:34](=[O:39])N(OC)C)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>C1COCC1>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH:31]([C:34](=[O:39])[C:2]2[CH:15]=[CH:14][CH:13]=[C:4]([O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7])[CH:3]=2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(Br)c1
Reactant: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)c2cccc(O[Si](C)(C)C(C)(C)C)c2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 57.3 %

Procedure:
To the solution of (3-bromophenoxy)-tert-butyldimethylsilane (from Example 5, 6.12 g) in THF (120 mL) at −75° C. was slowly added nBuLi (9.37 mL of 2.5 M solution) under nitrogen. After 15 minutes, the solution of 4-(N-methoxy-N-methylcarbamoyl)piperidine-1-carboxylic acid tert-butyl ester (5.80 g) in THF (10 mL) was dropwise added. The reaction was stirred under nitrogen overnight while it warmed to room temperature. The reaction was quenched by slow addition of aqueous NH4Cl solution (80 mL). The resulting mixture was extracted by EtOAc (120 mL). The organic layer was washed by water (80 mL×3) and brine (80 mL×1), dried by Na2SO4 and concentrated to give crude product (9.13 g), which was purified to afford pure 4-[3-(tert-butyl-dimethylsilanyloxy)benzoyl]piperidine-1-carboxylic acid tert-butyl ester (5.12 g; 57%). 1H NMR (600 MHz, DMSO-d6) δ 7.60 (d, 1H, J=8.0 Hz), 7.41 (dd, 1H, J=8.0, 8.0 Hz), 7.32 (m, 1H), 7.11 (dd, 1H, J=8.0, 2.5 Hz), 3.94 (m, 2H), 3.57 (m, 1H), 2.90 (bs, 2H), 1.72 (m, 2H), 1.38 (s, 9H), 1.37 (m, 2H), 0.94 (s, 9H), 0.19 (s, 6H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[CH2:12]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[CH2:13][CH2:14][CH3:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C(=O)C>[CH2:12]([N:16]1[CH2:21][CH2:20][N:19]([C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:7])[CH:8]=2)[CH2:18][CH2:17]1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCN1CCNCC1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCCCN1CCN(c2ccc([N+](=O)[O-])c(N)c2)CC1
Temperature: 130 °C
Reaction time: 24 h
Yield: 67.3 %

Procedure:
A mixture of 5-chloro-2-nitroaniline (4.05 g, 23.5 mmol), 1-n-butyl-piperazine (10.0 g, 70 mmol) and anhydrous potassium carbonate (3.6 g, 26 mmol) in N,N-dimethylacetamide (10 ml) was stirred at 130° C. under nitrogen for 1 day. Sample NMR analysis showed complete conversion of the starting material. The resultant mixture was then cooled to room temperature, poured into cold water and stirred vigorously for 3 hours. The resulting yellow brown precipitate was collected by filtration, washed well with water then dried on the filter funnel. The resulting yellow brown solid was slurried in diethyl ether, filtered, washed with additional diethyl ether, dried to afford 5-(4-butyl-piperazin-1-yl)-2-nitro-phenylamine (4.4 g, 67%) as a yellow powder, and used in the next step without further purification.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]3[CH:31]=[CH:30][N:29]=[C:28](Cl)[N:27]=3)[CH:21]=2)[S:15]([CH3:18])(=[O:17])=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.[NH2:33][CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=1>>[OH:42][C:39]1[CH:40]=[CH:41][C:36]([CH2:35][CH2:34][NH:33][C:28]2[N:27]=[C:26]([C:22]3[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=3)[CH2:19][N:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[S:15]([CH3:18])(=[O:17])=[O:16])[CH:31]=[CH:30][N:29]=2)=[CH:37][CH:38]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N(Cc2cccc(-c3ccnc(Cl)n3)c2)S(C)(=O)=O)CC1
Reactant: NCCc1ccc(O)cc1
Product: CS(=O)(=O)N(Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1)C1CCNCC1

Procedure:
Intermediate 30 was coupled with tyramine following procedure F. The resulting product was deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 482. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.4 (d, 1H), δ 8.2 (s, 1H) 8.0 (d, 1H) 7.6 (d, 1H), 7.5 (t, 1H), 7.1 (m, 3H), 6.8 (d, 2H), 4.5 (s, 2H), 3.6 (t, 2H), δ 3.0 (s, 3H), 2.9 (m, 5H), δ 2.8 (t, 2H), 2.0 (m, 4H).
Reaction SMILES: [CH:1]([NH:4][CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[Cl:8][CH:9]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[C:10](Cl)=[O:11].Cl>O1CCOCC1>[CH:1]([N:4]([CH:5]([CH3:7])[CH3:6])[C:10](=[O:11])[CH:9]([Cl:8])[C:13]1[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=1)([CH3:3])[CH3:2]
Reactant: O=C(Cl)C(Cl)c1ccc(Cl)cc1
Reactant: CC(C)NC(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)N(C(=O)C(Cl)c1ccc(Cl)cc1)C(C)C
Temperature: 0 °C
Yield: 86.1 %

Procedure:
While stirring, 22.3 g of diisopropylamine is dripped into a solution of 24.5 g of α-chloro-α-(4-chlorophenyl)-acetyl chloride (see a)) in 50 ml of dioxane. After the exothermic reaction has subsided, the mixture is stirred overnight and then poured into 700 ml of ice water; the resultant mixture is acidified with dilute hydrochloric acid and the oil which separates out is extracted 8 times, each time with 100 ml of dichloromethane. The combined extracts are washed twice with sodium carbonate solution, dried over magnesium sulfate and concentrated. There is obtained 27.2 g of α-chloro-α-(4-chlorophenyl)-acetic acid diisopropyl amide as a brownish oil.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[CH3:10].[Cl-].O[NH3+:13]>C(O)(=O)C.C(OCC)C>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:13])=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(C=O)ccc1O
Reactant: [NH3+]O
Agent: [Cl-]
Solvent: CCOCC
Solvent: CC(=O)O
Product: Cc1cc(C#N)ccc1O
Yield: 66 %

Procedure:
A mixture of 4-hydroxy-3-methylbenzaldehyde (530 mg, 3.91 mmol) and hydroxyl ammonium chloride (406 mg, 5.81 mmol) in acetic acid (5 mL) was heated under reflux for 90 minutes. The cooled reaction mixture was then diluted with diethyl ether (30 mL) and washed with water (30 mL). The combined organic solution was washed with brine, dried over magnesium sulfate, concentrated in vacuo and the residue was purified by column chromatography on silica gel, eluting with dichloromethane:methanol, 100:0 to 97.5:2.5, to afford the title compound as a pale yellow oil in 66% yield, 345 mg.
Reaction SMILES: Br.Br[CH:3]1[C:8]([C:9]2[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[CH:11][C:10]=2[O:19][CH3:20])=[CH:7][CH2:6][N:5]([CH3:21])[CH2:4]1.C([O:26]C)(C)(C)C.ClCCl>O>[OH:26][CH:3]1[C:8]([C:9]2[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[CH:11][C:10]=2[O:19][CH3:20])=[CH:7][CH2:6][N:5]([CH3:21])[CH2:4]1
Reactant: COc1cc(OC)c(C2=CCN(C)CC2Br)c(OC)c1
Reactant: COC(C)(C)C
Agent: Br
Solvent: O
Solvent: ClCCl
Product: COc1cc(OC)c(C2=CCN(C)CC2O)c(OC)c1

Procedure:
first isolating the compound (VI) as a solid by stirring the reaction solution into a suitable organic solvent, methyl tert-butyl ether, dichloromethane etc., and subsequently reacting the resulting product with water and by stirring at 50°-100° C., preferably at 60°-80° C., to give 3(R,S)-hydroxy-1-methyl-4-(2,4,6-trimethoxyphenyl)-1,2,3,6-tetrahydropyridine (VII)
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:10]1[N:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([NH:22]C(=O)OC(C)(C)C)=[CH:18][CH:17]=3)=[CH:12][N:11]=1)[CH2:2]2.FC(F)(F)C(O)=O>C(Cl)Cl>[N:1]12[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]1)[CH:3]([O:9][C:10]1[N:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=3)=[CH:12][N:11]=1)[CH2:2]2
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cnc(OC3CN4CCC3CC4)nc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(-c2cnc(OC3CN4CCC3CC4)nc2)cc1

Procedure:
The product of Example 18B (340 mg, 0.86 mmol) in CH2Cl2 (6 mL) was treated with trifluroacetic acid (Aldrich, 2 mL) at ambient temperature for 30 minutes and concentrated under reduced pressure. The title product was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:1, Rf. 0.07) as solid (150 mg, yield, 58%). 1H NMR (300 MHz, MeOH-d4) δ 1.88-2.22 (m, 3H), 2.31-2.45 (m, 1H), 2.56-2.64 (m, 1H), 3.27-3.51 (m, 5H), 3.84-3.96 (m, 1H), 5.36-5.45 (m, 1H), 6.87 (d, J=8.5 Hz, 2H), 7.42 (d, J=8.5 Hz, 2H), 8.77 (s, 2H) ppm. MS (DCl/NH3) m/z 297 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[CH:6][C:7]=1[OH:8].[CH:10](OCC)(OCC)OCC>C1(C)C=CC=CC=1>[CH3:9][C:5]1[CH:4]=[CH:3][C:2]2[N:1]=[CH:10][O:8][C:7]=2[CH:6]=1
Reactant: CCOC(OCC)OCC
Reactant: Cc1ccc(N)c(O)c1
Solvent: Cc1ccccc1
Product: Cc1ccc2ncoc2c1
Yield: 69 %

Procedure:
A 50 ml flask was charged with 6-amino-m-cresol (2 g, 16.24 mmole), 20 ml toluene and 5.4 ml triethyl orthoformate. The reaction mixture was refluxed for 2 hours. The mixture was concentrated down to about 2.3 g crude. Purification by silicagel column chromatography using 20% EtOAc/hexane provided 1.45 g brown oil (69% yield) that solidified in the freezer.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=2[F:20])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[NH:54]1[CH2:57][CH:56]([NH:58][C:59](=[O:65])[O:60][C:61]([CH3:64])([CH3:63])[CH3:62])[CH2:55]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=2[F:20])=[C:4]([C:5]([N:54]2[CH2:57][CH:56]([NH:58][C:59](=[O:65])[O:60][C:61]([CH3:63])([CH3:62])[CH3:64])[CH2:55]2)=[O:7])[CH:8]=[CH:9][C:10]=1[F:11]
Reactant: O=C(O)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Reactant: CC(C)(C)OC(=O)NC1CNC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Yield: 80.6 %

Procedure:
A solution of 3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoic acid (200 mg, 0.51 mmol), prepared using procedures similar to those in U.S. Pat. No. 7,019,033, PyBOP (256 mg, 0.51 mmol), commercially available tert-butyl azetidin-3-ylcarbamate (131 mg, 0.77 mmol) and N,N-diisopropylethylamine (180 μL, 1.02 mmol) in dimethylformamide (3 mL) was stirred at room temperature for 15 hours. The reaction mixture was partitioned between 5% aqueous lithium chloride and ethyl acetate. The organic portion was washed with 20% aqueous citric acid, saturated aqueous sodium bicarbonate, brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford a brown residue which was purified by silica gel column chromatography eluting with 30% ethyl acetate in hexanes to afford 1,1-dimethylethyl [1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]carbamate (225 mg, 80% yield) as a colorless oil. 1H NMR (400 MHz, DMSO): 8.56 (s, 1H), 7.60-7.55 (m, 2H), 7.38 (d, 1H), 7.30-7.26 (m, 1H), 7.20-7.13 (m, 1H), 6.71-6.66 (m, 1H), 4.37-4.20 (m, 2H), 4.18-4.06 (m, 1H), 3.98-3.93 (m, 1H), 3.82-3.75 (m, 1H), 1.37 (s, 9H). MS (EI) C21H21N3O3F3I: 548 (MH+).
Reaction SMILES: [C-]#N.[K+].[N+](C1C=CC(C([C@H:13]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:14]([O:16][CH2:17][CH3:18])=[O:15])=O)=CC=1)([O-])=O.C([OH:31])C>>[OH:31][C@@H:13]([CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCO
Reactant: CCOC(=O)[C@@H](CCc1ccccc1)C(=O)c1ccc([N+](=O)[O-])cc1
Agent: [C-]#N
Agent: [K+]
Product: CCOC(=O)[C@@H](O)CCc1ccccc1
Reaction time: 2.25 h
Yield: 74 %

Procedure:
To a suspension of potassium cyanide (0.176 g, 2.70 mmole) in absolute ethanol (43mL) was added a solution of (S)-2-[4-nitrobenzoyl]-4-phenylbutyric acid, ethyl ester (3.86 g, 10.8 mmole) in absolute ethanol (38 mL) dropwise over a period of 0.5 hours. After stirring 2.25 hours the solvent was removed and the reside was diluted with water and acidified with dilute hydrochloric acid. The organics were extracted with ether. The extracts were combined, silica gel (60 mL) was added and the solvent was removed. The adsorbate was flash chromatographed, eluent (gradient 90/10-80/20 petroleum ether/ethyl acetate) and the solvents were chased with benzene to give the title compound as a yellow oil (1.67 g, 74%): NMR (CDCl3); δ 7.38-7.16 (m, 5H), 4.30-4.10(m, 3H), 2.9-2.6 (m, 3H,), 2.2 -1.9(m, 2H), 1.15(t, 4 Hz, 3H); [a]25D +178.23 at 10.98 mg/mL CHCl3.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:11]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1.C([Li])CCC.[I:25]CCI.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[I:25][C:10]1[N:5]2[N:4]=[C:3]([S:2][CH3:1])[C:11]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[C:6]2[CH:7]=[CH:8][CH:9]=1
Reactant: ICCI
Reactant: CSc1nn2ccccc2c1NC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CSc1nn2c(I)cccc2c1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
After dissolving tert-butyl N-[2-methylthiopyrazolo[1,5-a]pyridin-3-yl]carbamate (21.6 g) in tetrahydrofuran (1 L), a solution of n-butyllithium in hexane (1.6 M; 130 mL) was added dropwise at −78° C. under a nitrogen stream, and the mixture was stirred for 30 minutes. A solution of 1,2-diiodoethane (24 g) in tetrahydrofuran (50 mL) was added to the reaction mixture, and stirring was continued for 1 hour. Saturated aqueous ammonium chloride was added to the reaction mixture, the temperature was raised to room temperature, extraction was performed with ethyl acetate and the extract was washed with water and brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound was obtained from the n-hexane:ethyl acetate (5:1) fraction as yellow crystals.
Reaction SMILES: [Br:1][C:2]1[C:10]([OH:11])=[C:9]([F:12])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]([CH2:14][CH2:15][CH2:16][CH3:17])[C:6]2=[O:13].CI.[C:20](=O)(O)[O-].[Na+]>CN(C)C=O>[Br:1][C:2]1[C:10]([O:11][CH3:20])=[C:9]([F:12])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]([CH2:14][CH2:15][CH2:16][CH3:17])[C:6]2=[O:13]
Reactant: CCCCC1Cc2c(cc(F)c(O)c2Br)C1=O
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCCCC1Cc2c(cc(F)c(OC)c2Br)C1=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 81.6 %

Procedure:
A mixture of 4-bromo-2-butyl-6-fluoro-5-hydroxy-1-indanone (2.17 g, 7.23 mmol), N,N-dimethylformamide (14.5 mL), methyl iodide (0.675 mL, 10.84 mmol), and sodium bicarbonate (1.50 g, 18.1 mmol) was stirred at room temperature for 17 hours. The solvent was evaporated under vacuum. The residue in EtOAc (150 mL) was washed with water (5×100 mL) and brine (50 mL), dried over MgSO4, filtered, and evaporated under vacuum to an oil (2.29 g). The crude product was dissolved in CH2CL2 (5 mL) and the solution filtered through a pad of EM silica gel 60 (20 mL) using an additional 60 mL of CH2Cl2 to elute the silica gel. The CH2Cl2 filtrate was evaporated under vacuum to afford 4-bromo-2-butyl-6-fluoro-5-methoxy-1-indanone (1.86 g) as a pink oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[CH2:10][CH2:11][CH2:12][C:13](=[N:17][OH:18])[C:14]=2[C:15]=1[OH:16])=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:25](I)[CH3:26]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[CH2:10][CH2:11][CH2:12][C:13](=[N:17][O:18][CH2:25][CH3:26])[C:14]=2[C:15]=1[OH:16])=[O:5])[CH3:2]
Reactant: CCI
Reactant: CCOC(=O)c1cnc2c(c1O)C(=NO)CCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCON=C1CCCc2ncc(C(=O)OCC)c(O)c21
Temperature: 95 °C
Yield: 72.5 %

Procedure:
4-Hydroxy-5-hydroxyimino-5,6,7,8-tetrahydroquinoline-3-carboxylic acid ethyl ester (3.75 g) was suspended in 100 ml of dimethylformamide and then dissolved therein by stirring the suspension on an oil bath at 95° C. Thereafter, 1.04 g of potassium carbonate and then 2.32 g of ethyl iodide were added thereto. The resulting reaction mixture was stirred for 4 hours. After the dimethylformamide was distilled off under reduced pressure, water and ethyl acetate were added to the residue. The organic layer was separated and then stripped of solvent to obtain a yield of 3.0 g of the desired compound. This compound melted at 89°-91° C. (uncorrected values). Its infrared absorption spectrum (KBr tablet) had absorption peaks at 3440, 3000, 2960, 1740, 1640, 1465, 1220, 1190, 1110, 1060, and 990 cm-1, and its n.m.r. spectrum (CDCl3, 60Mc, TMS) had signals at δ values of 1.38 (3H, t, J=6.75 Hz), 1.42 (3H, t, J=7.5 HZ), 1.7-2.2 (2H, m), 2.7-3.15 (4H , m), 4.25 (2H, q. J=6.75 Hz), 4.40 (2H, q, J=7.5 Hz), and 8.77 (1H, s).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.CS(C)=O.[O:17]=[C:18]1[NH:26][CH:25]=[N:24][C:23]2[N:22]([CH2:27][CH2:28][C:29](OC3C=CC([N+]([O-])=O)=CC=3)=[O:30])[CH:21]=[N:20][C:19]1=2>CC(C)=O>[O:17]=[C:18]1[NH:26][CH:25]=[N:24][C:23]2[N:22]([CH2:27][CH2:28][C:29]([NH:1][CH2:2][CH2:3][C:4]3[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[NH:6][CH:5]=3)=[O:30])[CH:21]=[N:20][C:19]1=2
Reactant: O=C(CCn1cnc2c(=O)[nH]cnc21)Oc1ccc([N+](=O)[O-])cc1
Reactant: NCCc1c[nH]c2ccccc12
Solvent: CS(C)=O
Solvent: CC(C)=O
Product: O=C(CCn1cnc2c(=O)[nH]cnc21)NCCc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 48 %

Procedure:
0.700 g (4.37 mmol) of tryptamine were placed into a 50 ml round bottom flask equipped with a magnetic stirring bar. Then 5.0 ml of dimethylsulfoxide were added to dissolve the tryptamine. After all the tryptamine had gone into solution, 1.0 g (3.04 mmol) of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)propanoic acid, 4-nitrophenyl ester (AIT-0081) was added and the flask was sealed with a ground glass stopper. The mixture was stirred at room temperature for five hours. The reaction mixture was poured into 60 ml of acetone. The product was filtered, washed twice with 10 ml of acetone and air dried. The yield of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)-N-[2-(1H-indol-3-yl)ethyl]-propanamide (AIT-0072) was 0.813 g. Yield: 48% (Purity 99.3%). mp: 204°-206° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][C@@H:10]([O:13][CH:14]([CH3:16])[CH3:15])[CH2:9][C@H:8]2[CH2:17][S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])[C:3]1=[O:24].C(N(CC)CC)C.Cl[C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([C:43]([F:46])([F:45])[F:44])[CH:41]=2)[N:36]=[CH:35][N:34]=1>CCO>[CH:14]([O:13][C@@H:10]1[CH2:11][CH2:12][C@H:7]([N:4]2[CH2:5][CH2:6][C@H:2]([NH:1][C:33]3[C:42]4[C:37](=[CH:38][CH:39]=[C:40]([C:43]([F:45])([F:46])[F:44])[CH:41]=4)[N:36]=[CH:35][N:34]=3)[C:3]2=[O:24])[C@H:8]([CH2:17][S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])[CH2:9]1)([CH3:16])[CH3:15]
Reactant: FC(F)(F)c1ccc2ncnc(Cl)c2c1
Reactant: CC(C)O[C@@H]1CC[C@H](N2CC[C@H](N)C2=O)[C@H](CS(=O)(=O)C(C)C)C1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)O[C@@H]1CC[C@H](N2CC[C@H](Nc3ncnc4ccc(C(F)(F)F)cc34)C2=O)[C@H](CS(=O)(=O)C(C)C)C1
Yield: 56.1 %

Procedure:
A mixture of (S)-3-amino-1-((1S,2R,4R)-4-isopropoxy-2-(isopropylsulfonylmethyl)cyclohexyl)pyrrolidin-2-one (0.04 g, 0.128 mMol), triethylamine (71 uL, 0.512 mMol) and 4-chloro-6-(trifluoromethyl)quinazoline (0.035 g, 0.192 mMol) were taken in EtOH and microwaved at 100° C. for 45 min. The reaction mixture was concentrated and chromatographed to yield (S)-1-((1S,2R,4R)-4-isopropoxy-2-(isopropylsulfonyl methyl)cyclohexyl)-3-(6-(trifluoromethyl)quinazolin-4-ylamino)pyrrolidin-2-one as a white solid (0.04 g). MS found: (M+H)+=557.2
Reaction SMILES: [OH:1][NH2:2].C([O:5][C:6](=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[C:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)C>CO>[OH:1][NH:2][C:6](=[O:5])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[C:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: CCOC(=O)CCCCCC=C(c1ccccn1)c1ccccn1
Reactant: NO
Solvent: CO
Product: O=C(CCCCCC=C(c1ccccn1)c1ccccn1)NO
Reaction time: 72 h
Yield: 18 %

Procedure:
HONH2 (50% aqueous, 0.5 mL) was added to II (68 mg, 0.21 mmol) in MeOH (0.5 mL) at rt. The reaction mixture was stirred for 72 h, after which the solvents were evaporated under reduced pressure. The resulting residue was dissolved and co-evaporated with toluene (2×5 mL), then was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (100:1 to 100:10) to furnish III as a colourless oil (12 mg, 18%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][N+:6]([O-])=[C:5]([CH3:12])[CH:4]=1.C(OC(=O)C)(=[O:15])C>>[OH:15][CH2:12][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[CH:7][N:6]=1
Reactant: COc1cc(C)[n+]([O-])cc1OC
Reactant: CC(=O)OC(C)=O
Product: COc1cnc(CO)cc1OC
Temperature: 80 °C
Reaction time: 0.75 h
Yield: 74 %

Procedure:
19 g of 4,5-dimethoxy-2-methylpyridine 1-oxide are metered into 60 ml of acetic anhydride, warmed to 80° C., in the course of 30 minutes in a manner such that the temperature does not rise above 100° C. After a further 45 minutes at 85° C., excess acetic anhydride is distilled off in vacuo and the oily dark residue, which essentially consists of the intermediate 2-acetoxymethyl-4,5-dimethoxypyridine is stirred with 80 ml of 2N sodium hydroxide solution at 80° C. for 1 hour. After dilution with 80 ml of water and cooling, the mixture is extracted eight times with 100 ml of methylene chloride each time, the combined organic phases are washed twice with 1N sodium hydroxide solution, dried and concentrated and the crystalline, brownish residue is recrystallized from toluene. 14 g (74% of theory) of 2-hydroxymethyl-4,5-dimethoxy-pyridine of m.p. 122°-24° C. are obtained.
Reaction SMILES: C(O)C.[CH3:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:13]=[C:12]([S:14]([CH2:16][C:17]3[C:22]([CH3:23])=[C:21]([O:24][CH3:25])[C:20]([CH3:26])=[CH:19][N:18]=3)=[O:15])[NH:11][C:10]=2[CH:27]=1>CN(C=O)C>[CH3:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:13]=[C:12]([S@:14]([CH2:16][C:17]3[C:22]([CH3:23])=[C:21]([O:24][CH3:25])[C:20]([CH3:26])=[CH:19][N:18]=3)=[O:15])[NH:11][C:10]=2[CH:27]=1
Reactant: COc1ccc2nc(S(=O)Cc3ncc(C)c(OC)c3C)[nH]c2c1
Solvent: CN(C)C=O
Solvent: CCO
Product: COc1ccc2nc([S@@](=O)Cc3ncc(C)c(OC)c3C)[nH]c2c1

Procedure:
The procedure set forth in Example 2 is repeated except that ethanol is employed as a solvent in place of DMF and the resulting structure is shown by various X-ray crystal diffraction and/or Raman spectroscopy to contain between about 82 and 85 percent (w/w) of 6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole and between about 15 and 18 percent (w/w) of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-methyl]sulfinyl]-1H-benzimidazole.