Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=O)=[CH:2]1.S(Cl)(Cl)=O.[N:17]12[CH2:25][C:21]([CH2:26][NH2:27])([CH2:22][CH2:23][CH2:24]1)[CH2:20][CH2:19][CH2:18]2.C(N(CC)CC)C.C[O-].[Na+].CO>O1CCCC1>[N:17]12[CH2:25][C:21]([CH2:26][NH:27][C:10]([C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][CH:2]=3)=[O:12])([CH2:22][CH2:23][CH2:24]1)[CH2:20][CH2:19][CH2:18]2
Reactant: NCC12CCCN(CCC1)C2
Reactant: O=C(O)c1c[nH]c2ccccc12
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(NCC12CCCN(CCC1)C2)c1c[nH]c2ccccc12
Temperature: 55 °C
Reaction time: 1 h
Yield: 57.2 %

Procedure:
A cooled (0° C.) suspension/solution of indole-3-carboxylic acid (0.92 g, 5.7 mmol) in anhydrous tetrahydrofuran (10 mL) was treated dropwise with thionyl chloride (0.72 g, 6.0 mmol), and the solution was refluxed for one hour and concentrated in vacuo. A cooled (0° C.) solution of 1-azabicyclo[3.3.1]nonane-5-methanamine (0.96 g, 6.2 mmol) and triethylamine (1.22 g, 12 mmol) in anhydrous tetrahydrofuran (5 mL) was treated with a solution of the above prepared acid chloride in anhydrous tetrahydrofuran (10 mL), and the mixture was stirred at room temperature for 15 hours, at 55° C. for one hour, and cooled (0° C.). Sodium methoxide/methanol (25%, 2.6 g, 12 mmol) was added, and the solution was stirred for one hour and passed through a column of alumina (eluted with 1:1 methanol/tetrahydrofuran). The filtrate was concentrated in vacuo and taken up in 2-propanol and filtered. Ether was added dropwise to the filtrate until no more precipitation was observed, and the suspension was cooled (0° C.), filtered, and the solid was collected and dried in vacuo to afford (after a second crop) 0.97 g (57%) of the title compound as a colorless solid; mp 139.0°-141.5° C.
Reaction SMILES: [CH3:1][Si:2]([CH3:29])([CH3:28])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[C:18]([NH:22][C:23](=[O:27])[C:24]([CH3:26])=[CH2:25])[CH:19]=[CH:20][CH:21]=3)[C:10]=2[CH:9]=[CH:8]1.C1C(=O)N([Br:37])C(=O)C1>CC#N>[Br:37][C:9]1[C:10]2[C:15]([C:16]3[CH:17]=[C:18]([NH:22][C:23](=[O:27])[C:24]([CH3:26])=[CH2:25])[CH:19]=[CH:20][CH:21]=3)=[N:14][CH:13]=[N:12][C:11]=2[N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:28])[CH3:29])[CH:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: C=C(C)C(=O)Nc1cccc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)c1
Solvent: CC#N
Product: C=C(C)C(=O)Nc1cccc(-c2ncnc3c2c(Br)cn3COCC[Si](C)(C)C)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of N-(3-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)methacrylamide (5.20 g, 12.7 mmol) in CH3CN (80 mL), was added NBS (2.40 g, 13.5 mmol) in several portions at 80° C. The resulting solution was stirred for 2 hours at 80° C. before being concentrated in vacuo. The reaction was then purified by chromatography using silica gel, eluting with 0-33% EtOAc/petroleum ether. The product was collected and concentrated in vacuo to afford N-(3-(5-bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)methacrylamide as a yellow solid. LRMS (ESI) calc'd for C22H28N4O2SiBr [M+H]+: 487, found 487.
Reaction SMILES: [CH2:1]([O:5][CH:6]1[C:11](OC)([O:12]C)[CH2:10][CH2:9][N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:7]1)/[CH:2]=[CH:3]/[CH3:4].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>O.C(O)(C(F)(F)F)=O>[CH2:1]([O:5][CH:6]1[C:11](=[O:12])[CH2:10][CH2:9][N:8]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:7]1)/[CH:2]=[CH:3]/[CH3:4]
Reactant: C/C=C/COC1CN(C(=O)OC(C)(C)C)CCC1(OC)OC
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: C/C=C/COC1CN(C(=O)OC(C)(C)C)CCC1=O
Yield: 100 %

Procedure:
The same operation as in Example (90b) was performed using tert-butyl 3-[(2E)-2-buten-1-yloxy]-4,4-dimethoxypiperidine-1-carboxylate obtained in Example (119a) (5.05 g, 16.0 mmol), a water/TFA mixed solution (1/1, 20 mL) and di-tert-butyl dicarbonate (5.2 g, 23.8 mol). The resulting residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=10/1, 5/1, 2/1, 1/1) to obtain 4.31 g of the title compound as a light brown oily substance (100%).
Reaction SMILES: Br[C:2]1[C:7]([O:8][C:9](=O)[CH3:10])=[CH:6][CH:5]=[CH:4][N:3]=1.[Si](C#C)(C)(C)C>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[O:8]1[C:7]2[C:2](=[N:3][CH:4]=[CH:5][CH:6]=2)[CH:10]=[CH:9]1
Reactant: CC(=O)Oc1cccnc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: C#C[Si](C)(C)C
Solvent: C1CCOC1
Product: c1cnc2ccoc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.3 %

Procedure:
To a solution of PdCl2(PPh3)2 (1.4 g, 2.0 mmol) and CuI (0.4 g, 2.1 mmol) in TEA (100 mL) and THF (200 mL) under nitrogen was added a mixture of 2-bromo-3-acetoxy-pyridine (13.1 g, 60.6 mmol) and TMS-acetylene (7.0 g, 71 mmol) in THF (100 mL) in one portion. The mixture was stirred at room temperature for 1 hour. Then quenched with saturated NaHCO3 (50 mL) and MeOH (50 mL). The mixture was stirred at 80° C. for 2 hours. After cooling, the mixture was extracted with ether. The organic phase was dried and concentrated. The residue was subject to column chromatography to afford Furo[3,2-b]pyridine (1.54 g, 21%). 1H NMR (CDCl3, 400 MHz) δ 8.55 (m, 1H), 7.84 (m, 1H), 7.75 (m, 1H), 7.72 (m, 1H), 6.99 (m, 1H).
Reaction SMILES: [CH:1]1([N:4]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[C:5](=[O:8])[CH2:6][CH3:7])[CH2:3][CH2:2]1.[NH:15]1[CH:19]=[C:18]([CH2:20][CH2:21][NH:22][C:23](=[O:38])[NH:24][CH:25]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)[C:26](O)=[O:27])[N:17]=[CH:16]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH:1]1([N:4]([CH:9]2[CH2:14][CH2:13][N:12]([C:26](=[O:27])[CH:25]([NH:24][C:23]([NH:22][CH2:21][CH2:20][C:18]3[N:17]=[CH:16][NH:15][CH:19]=3)=[O:38])[CH2:29][C:30]3[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=3)[CH2:11][CH2:10]2)[C:5](=[O:8])[CH2:6][CH3:7])[CH2:3][CH2:2]1
Reactant: CCC(=O)N(C1CCNCC1)C1CC1
Reactant: COc1ccc(CC(NC(=O)NCCc2c[nH]cn2)C(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCC(=O)N(C1CC1)C1CCN(C(=O)C(Cc2ccc(OC)cc2)NC(=O)NCCc2c[nH]cn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.8 %

Procedure:
100 mg (0.51 mmol) of N-cyclopropyl-N-piperidin-4-ylpropionamide, 170 mg (0.51 mmol) of 2-{3-[2-(1H-imidazol-4-yl)ethyl]ureido}-3-(4-methoxyphenyl)propanoic acid (cf. preparation 2-3), 108 mg (0.56 mmol) of EDC and 76 mg (0.56 mmol) of HOBT are dissolved in 5 mL of DMF under nitrogen. The mixture is stirred at room temperature overnight, and the solution is then washed with aqueous 5% citric acid solution and extracted with ethyl acetate. The organic phase is washed with aqueous 1N NaOH solution and then dried and evaporated. The crude product obtained is purified by preparative HPLC (conditions cf. page 38). 2 mg of N-cyclopropyl-N-{1-[2-{3-[2-(1H-imidazol-4-yl)ethyl]ureido}-3-(4-methoxyphenyl)propionyl]piperidin-4-yl}-propionamide are obtained in a yield of 8%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20])[NH:12][CH3:13].[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1)([O-:23])=[O:22]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:30]([C:27]1[CH:26]=[CH:25][C:24]([N+:21]([O-:23])=[O:22])=[CH:29][CH:28]=1)(=[O:31])=[O:32])[C:6](=[O:11])[C:5]2([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20])[NH:12][CH3:13]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: CNC1(c2ccccc2Cl)C(=O)Nc2ccc(Cl)cc21
Solvent: ClCCl
Product: CNC1(c2ccccc2Cl)C(=O)N(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)c2ccc(Cl)cc21
Yield: 68.9 %

Procedure:
This compound is prepared according to the procedure described in EXAMPLE 11 from 7.03 g of 5-chloro-3-(2-chlorophenyl)-1,3-dihydro-3-(methylamino)-indol-2-one and 5.73 g of 4-nitrobenzenesulfonyl chloride. Chromatography on silica using DCM as the eluent gives 7.76 g of the expected product after crystallization from iso ether. M.p.=220°-221° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8]C)[CH:5]=[C:4]([CH3:10])[C:3]=1[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([O:19]C)=[C:15]([CH:21]([CH3:23])[CH3:22])[CH:14]=1)[CH3:12].B(Br)(Br)Br>C(Cl)Cl>[OH:8][C:6]1[CH:7]=[C:2]([CH3:1])[C:3]([CH:11]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([CH:21]([CH3:23])[CH3:22])[CH:14]=2)[CH3:12])=[C:4]([CH3:10])[CH:5]=1
Reactant: COc1cc(C)c(C(C)c2ccc(OC)c(C(C)C)c2)c(C)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc(O)cc(C)c1C(C)c1ccc(O)c(C(C)C)c1
Temperature: -78 °C
Reaction time: 20 h
Yield: 70.3 %

Procedure:
To 1-(2,6-dimethyl-4-methoxyphenyl)-1-(3-isopropyl-4-methoxyphenyl) ethane (250 mg, 0.8 mmol) in 15 mL of methylene chloride at -78° C. was added 8 mL of boron tribromide (1.0M in methylene chloride). The reaction mixture was stirred for 30 minutes at -78° C. and for 20 hours at room temperature. The reaction mixture was washed with water (2×25 mL), dried (MgSO4), and evaporated to give crude product (300 mg). Purification using flash column chromatography (silica gel, 90:10 hexane/ethylacetate) gave 1-(4-hydroxy-2,6-dimethylphenyl)-1-(4-hydroxy-3-isopropylphenyl) ethane (160 mg, 0.562 mmol, 70%); 1HNMR (CDCl3) δ 1.20 (dd, 6H), 1.60 (d, 3H), 2.25 (s, 6H), 2.35 (s, 3H), 3.20 (heptet, 1H), 4.45 (q, 1H), 6.45 (s, 1H), 6.65 (m, 2H), 7.00 (d, 1H), 7.20 (d, 1H).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:12]=[CH:11][C:6]2[NH:7][C:8]([CH3:10])=[N:9][C:5]=2[CH:4]=1.[N:13]([O-])=O.[Na+].O.O.[Sn](Cl)Cl>Cl>[CH3:10][C:8]1[NH:7][C:6]2[CH:11]=[CH:12][C:3]([NH:2][NH2:13])=[CH:4][C:5]=2[N:9]=1
Reactant: Cc1nc2cc(N)ccc2[nH]1
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: Cc1nc2cc(NN)ccc2[nH]1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
5-Amino-2-methyl-1H-benzimidazol hydrochloride (16.51 g) was dissolved in concentrated hydrochloric acid (200 ml), and this was cooled to 0° C. An aqueous solution (15 ml) of sodium nitrite (7.59 g) was added dropwise thereto at 0° C. over 20 minutes. This was stirred for 20 minutes. Then, a concentrated hydrochloric acid solution (20 ml) of tin (II) chloride dihydrate (55.7 g) was added dropwise thereto at 0° C. over one hour, and then this was stirred for 30 minutes. The precipitated solid was collected by filtration, and washed with water, and dried. Thus, crude (2-methyl-1H-benzimidazol-5-yl)-hydrazine dihydrochlide was obtained.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([CH3:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:16][C:17]#[N:18]>>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:16][C:17]#[N:18])[CH:10]([CH3:14])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CCBr
Reactant: CC1CN(Cc2ccccc2)CCN1
Product: CC1CN(Cc2ccccc2)CCN1CC#N

Procedure:
The title compound is synthesized by coupling of 4-Benzyl-2-methyl-piperazine (commercially available from CHESS GmbH) and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a colorless oil; ES-MS: M+=230.2: AtRet=1.86.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:12]2[C:17]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])=[C:16]([O:27][CH2:28][CH2:29][NH2:30])[N:15]=[C:14]([C:31]3[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=3)[N:13]=2)(=[O:10])=[O:9])=[N:6][CH:7]=1.[CH3:37][C:38]1[CH:43]=[CH:42][C:41]([S:44](Cl)(=[O:46])=[O:45])=[CH:40][CH:39]=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:12]2[C:17]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])=[C:16]([O:27][CH2:28][CH2:29][NH:30][S:44]([C:41]3[CH:42]=[CH:43][C:38]([CH3:37])=[CH:39][CH:40]=3)(=[O:46])=[O:45])[N:15]=[C:14]([C:31]3[CH:32]=[CH:33][N:34]=[CH:35][CH:36]=3)[N:13]=2)(=[O:10])=[O:9])=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2ccncc2)nc1OCCN
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2ccncc2)nc1OCCNS(=O)(=O)c1ccc(C)cc1

Procedure:
According to the procedure described in Example 4a) 107 mg 5-methyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide was reacted with 4-methylbenzenesulfonylchloride to give 70 mg 5-methyl-N-[6-(2-(4-methylbenzenesulfonylamino)-ethoxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide. LC-MS: tR=4.55 min [M+1]+663.56, [M−1]−=661.63.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:16]=[CH:15][C:14]2[O:13][C:12]3[C:7]4=[C:8]([C:17](=[O:20])[NH:18][N:19]=[C:6]4[C:5]=2[CH:4]=1)[CH:9]=[CH:10][CH:11]=3.C(N(C(C)C)CC)(C)C.Cl.N1C=CC([C:36]([NH2:38])=[NH:37])=N1.C(OCC)C>CN(C=O)C>[O:20]=[C:17]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[O:13][C:14]4[CH:15]=[CH:16][C:3]([CH2:2][NH:1][C:36]([NH2:38])=[NH:37])=[CH:4][C:5]=4[C:6]([C:7]=23)=[N:19][NH:18]1
Reactant: N=C(N)c1cc[nH]n1
Reactant: NCc1ccc2c(c1)-c1n[nH]c(=O)c3cccc(c13)O2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: CN(C)C=O
Product: N=C(N)NCc1ccc2c(c1)-c1n[nH]c(=O)c3cccc(c13)O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 0 %

Procedure:
To the solution of 49 (0.10 g, 0.38 mmol) in DMF (5 mL) was added diisopropyl ethylamine (0.83 mmol) and 1H-pyrazole carboxamidine hydrochloride (0.12 g, 0.81 mmol). The reaction mixture was stirred at room temperature overnight. Diethyl ether was added to form a white precipitate. The precipitate was collected and recrystallized in EtOAc to afford a white solid 50 (0.1 μg, 83%, HCl salt). MS (ES−): 306; 1H-NMR (DMSO-d6, 400 MHz): 12.62 (s, 1H), 8.04 (d, J=2.0 Hz, 1H), 7.92-7.84 (m, 2H), 7.71 (dd, J=7.5 and 2.0 Hz, 1H), 7.50 (dd, J=8.5 and 2.0 Hz, 1H), 7.45 (d, J=8.5 Hz, 1H), 4.47 (s, 2H); Anal. Calcd. for C16H13N5O2.1ClH: C, 55.58; H, 4.27; N, 19.76; Cl, 10.38. Found: C, 55.94; H, 4.17; N, 19.32; Cl, 10.12.
Reaction SMILES: [C:1]1([CH2:7][S:8](Cl)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:12][O:13][C:14]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:15]=1[CH2:16][NH2:17]>ClCCl>[CH3:12][O:13][C:14]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:15]=1[CH2:16][NH:17][S:8]([CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:10])=[O:9]
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: COc1ccc(CN)c(OC)c1
Solvent: ClCCl
Product: COc1ccc(CNS(=O)(=O)Cc2ccccc2)c(OC)c1
Reaction time: 2 h

Procedure:
While cooling with ice, 5.00 g of phenylmethanesulfonyl chloride were initially charged in 40 ml of dichloromethane, and a solution of 8.04 ml of 2,4-dimethoxybenzylamine in 10 ml of dichloromethane was slowly added dropwise. For improved stirrability, a further 25 ml of dichloromethane were added, and the reaction mixture was allowed to come to room temperature. After stirring for 2 hours, the reaction mixture was washed with 100 ml of water, with 100 ml of 0.2 N aqueous hydrochloric acid, with 100 ml of saturated aqueous sodium hydrogencarbonate solution and finally once more with 100 ml of water. The organic phase was dried over Na2SO4, concentrated by rotary evaporation and dried under high vacuum. The residue (8.42 g) was used in the next reaction without further purification.
Reaction SMILES: FC1C=CC=CC=1C(Cl)=O.[CH3:11][S:12]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](Cl)=[O:19])(=[O:14])=[O:13].[NH2:24][C:25]1[CH:26]=[C:27]([CH:38]=[CH:39][N:40]=1)[C:28]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]>>[CH2:31]([NH:30][C:28](=[O:29])[C:27]1[CH:38]=[CH:39][N:40]=[C:25]([NH:24][C:18](=[O:19])[C:17]2[CH:21]=[CH:22][CH:23]=[C:15]([S:12]([CH3:11])(=[O:14])=[O:13])[CH:16]=2)[CH:26]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CS(=O)(=O)c1cccc(C(=O)Cl)c1
Reactant: Nc1cc(C(=O)NCc2ccccc2)ccn1
Agent: O=C(Cl)c1ccccc1F
Product: CS(=O)(=O)c1cccc(C(=O)Nc2cc(C(=O)NCc3ccccc3)ccn2)c1
Yield: 36 %

Procedure:
Following the procedure as describe in Example 6, making variations as required to replace 2-fluorobenzoyl chloride with 3-(methylsulfonyl)benzoyl chloride to react with 2-amino-N-benzylisonicotinamide, N-benzyl-2-(3-(methylsulfonyl)benzamido)-isonicotinamide was obtained as a colorless solid in 36% yield: mp 170-171° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, DMSO-d6) δ 11.33 (s, 1H), 9.34 (t, J=5.9 Hz, 1H), 8.58 (s, 1H), 8.52-8.50 (m, 2H), 8.30-8.27 (m, 1H), 8.11-8.08 (m, 1H), 7.80-7.75 (m, 1H), 7.56 (dd, J=5.2, 1.5 Hz, 1H), 7.34-7.19 (m, 5H), 4.47 (d, J=5.9 Hz, 2H), 3.26 (s, 3H); MS (ES+) m/z 410.5 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[O:11][CH2:12][CH:13]([OH:23])[CH2:14][P:15]([O:20]CC)([O:17]CC)=[O:16])=[C:4]([O:24]C)[N:3]=1.Br[Si](C)(C)C>CN(C)C=O>[OH:23][CH:13]([CH2:14][P:15]([OH:17])([OH:20])=[O:16])[CH2:12][O:11][N:8]1[CH:7]=[N:6][C:5]2[C:4](=[O:24])[NH:3][C:2]([NH2:1])=[N:10][C:9]1=2
Reactant: CCOP(=O)(CC(O)COn1cnc2c(OC)nc(N)nc21)OCC
Agent: C[Si](C)(C)Br
Solvent: CN(C)C=O
Product: Nc1nc2c(ncn2OCC(O)CP(=O)(O)O)c(=O)[nH]1
Yield: 61.2 %

Procedure:
A solution of 2-amino-6-methoxy-9-[2-hydroxy-3-(diethoxyphosphoryl)propoxy]purine (70 mg, 0.182 mmol) and bromotrimethylsilane (0.4 ml, 3 mmol) in dimethylformamide (3 ml) was stirred at 23° C. for 3 hours. The solvent was evaporated and the residue was coevaporated with dimethylformamide (2×5 ml) and methanol:water (9.1) solution (1×5 ml). Crystallization from water:methanol (9:1) gave the title compound (34 mg, 62%); m.p. 258° C.-260° C. 1H NMR: δH [(CD3)2SO] 1.80 (2H, m, PCH2), 4.2 (3H, m, PCH2CHCH2), 6.62 (2H, br.s, D2O exchangeable NH2), 7.90 (1H, s, H-8), 10.64 (1H, br.s, D2O exchangeable NH). Found: C, 31.34; H, 4.05; N, 22.61%. C 8 H12N5O6P requires: C, 31.48; H, 3.96; N, 22.95%.
Reaction SMILES: CCN(CC)CC.O[C@@H:9]([CH3:23])[C@@H:10]([NH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:16])[C:11]([OH:13])=[O:12].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:18]([O:17][C:15](=[O:16])[NH:14][C@H:10]1[C:11](=[O:13])[O:12][C@H:9]1[CH3:23])[CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCOC(=O)N[C@@H](C(=O)O)[C@H](C)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCOC(=O)N[C@H]1C(=O)O[C@H]1C
Temperature: 0 °C
Reaction time: 3 h
Yield: 22.5 %

Procedure:
In a four necked round bottom flask, Et3N (3.75 mL, 26.9 mmol) was added to a solution of (2R,3S)-3-hydroxy-2-{[(pentyloxy)carbonyl]amino}butanoic acid (2 g, 8.96 mmol) in dry CH2Cl2 (100 mL) under argon. After cooling at 0° C., PyBOP (6.1 g, 11.6 mmol) was added and the mixture stirred 3 h at 0° C., then 3.5 h at rt. The solvent was removed under vacuum and crude purified by typical silica gel column chromatography, eluting with Cy/AcOEt (from 95:5 to 60:40). The resulting white solid (0.539 g) was further triturated with cyclohexane, yielding a pure compound (0.434 g, 22.5%) as white solid. MS (ESI) m/z: 214.21 [M−H]−. FTIR (cm−1): 3323, 3074, 2958, 2931, 2871, 1854, 1692, 1545, 1471, 1391, 1334, 1270, 1150, 1126, 1087, 1025, 982, 844, 823. 1H NMR (CDCl3): δ 0.91 (t, 3H); 1.31-1.35 (m, 4H); 1.47 (d, 3H); 1.60-1.67 (m, 2H); 4.06-4.14 (m, 2H); 4.84-4.91 (m, 1H); 5.42-5.49 (m, 2H).
Reaction SMILES: [ClH:1].C([O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([CH2:13][CH2:14][O:15]/[N:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])[CH2:8]1)=[O:6])C.O>C(O)C.[OH-].[Na+]>[ClH:1].[CH3:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1/[CH:17]=[N:16]/[O:15][CH2:14][CH2:13][N:9]1[CH2:10][CH2:11][CH2:12][C@@H:7]([C:5]([OH:6])=[O:4])[CH2:8]1
Reactant: CCOC(=O)[C@@H]1CCCN(CCO/N=C/c2ccccc2C)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccccc1/C=N/OCCN1CCC[C@@H](C(=O)O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The above ester (2.22 g, 6.3 mmol) was dissolved in a mixture of ethanol (65 ml) and 12N sodium hydroxide (4.9 ml) and stirred at ambient temperature for 1 h. Water (20 ml) was added and the mixture extracted with diethyl ether (3×30 ml). The phases were separated and pH in the aqueous phase was adjusted to 5 with 2N hydrochloric acid. The aqueous phase was extracted with dichloromethane (2×40 ml) and the solvent was evaporated from the combined organic phases in vacuo. The residue was dissolved in toluene (25 ml), then methanol (0.17 ml) and chlorotrimethylsilane (0.52 ml) were added and the mixture left for crystallisation. This afforded 0.51 g of the title compound as a solid. M.p. 108.5°-109.9° C.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:17][C:18]([O:20]C(C)(C)C)=O)=[C:5]([NH:9][C:10](OC(C)(C)C)=[O:11])[S:6][C:7]=1[CH3:8])[CH3:2]>C(O)(=O)C.C(OCC)(=O)C(OCC)=O>[CH2:1]([C:3]1[C:4]2[NH:17][C:18](=[O:20])[C:10](=[O:11])[NH:9][C:5]=2[S:6][C:7]=1[CH3:8])[CH3:2]
Reactant: CCc1c(C)sc(NC(=O)OC(C)(C)C)c1NC(=O)OC(C)(C)C
Solvent: CC(=O)O
Solvent: CCOC(=O)C(=O)OCC
Product: CCc1c(C)sc2[nH]c(=O)c(=O)[nH]c12
Temperature: 25 °C
Yield: 24.9 %

Procedure:
4.5 g of crude di-t-butyl 4-ethyl-5-methylthiophene-2,3-dicarbamate was dissolved in a mixture of 30 ml of acetic acid and 30 ml of diethyl oxalate, and refluxed for six hours. Upon cooling to room temperature, the crystalline precipitate was isolated (900 mg). Recrystallisation from hot acetic acid combined with charcoal (Norit SU 18) yielded 660 mg of the title compound, m.p.>300° C. MS: 210. 1H-NMR (DMSO-d6, δ): 1.0 (t, 3H), 2.2 (s, 3H), 2.6 (q, 2H), 11.9 (br.s, 1H), 12.1 (br.s, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[S:13][C:12]2[CH2:11][CH2:10][CH2:9][C:8](=[O:14])[NH:7][C:6]=2[CH:5]=1.Cl.[F:16][C:17]1[CH:18]=[CH:19][C:20]2[C:24]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[CH:23][O:22][C:21]=2[CH:31]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O.C1(C)C=CC=CC=1.CN(C)C=O>[F:16][C:17]1[CH:18]=[CH:19][C:20]2[C:24]([CH:25]3[CH2:26][CH2:27][N:28]([CH2:2][CH2:3][C:4]4[S:13][C:12]5[CH2:11][CH2:10][CH2:9][C:8](=[O:14])[NH:7][C:6]=5[CH:5]=4)[CH2:29][CH2:30]3)=[CH:23][O:22][C:21]=2[CH:31]=1
Reactant: Fc1ccc2c(C3CCNCC3)coc2c1
Reactant: O=C1CCCc2sc(CCCl)cc2N1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCCc2sc(CCN3CCC(c4coc5cc(F)ccc45)CC3)cc2N1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 2.0 g of 2-(2-chloroethyl)-4,6,7,8-tetrahydro-5H-thieno[3,2-b]azepin-5-one, 2.2 g of 4-(6-fluorobenzo(b)furan-3-yl)piperidine hydrochloride, 2.6 g of potassium carbonate, 1.44 g of potassium iodide, 20 ml of dimethylformamide and 20 ml of toluene was stirred at 80° C. for 8 hours and then poured into water. The toluene layer was washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized from ethyl acetate to give 2-(2-(4-(6-fluorobenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,6,7,8-tetrahydro-5H-thieno[3,2-b]azepin-5-one, m.p. 176°-178° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:19])=[C:5]([CH3:18])[C:6]2[O:11][C:10]([C:13](O)=[O:14])([CH3:12])[CH2:9][CH2:8][C:7]=2[C:16]=1[CH3:17].S(Cl)([Cl:22])=O>CN(C)C=O.ClCCCl>[CH3:1][O:2][C:3]1[C:4]([CH3:19])=[C:5]([CH3:18])[C:6]2[O:11][C:10]([C:13]([Cl:22])=[O:14])([CH3:12])[CH2:9][CH2:8][C:7]=2[C:16]=1[CH3:17]
Reactant: COc1c(C)c(C)c2c(c1C)CCC(C)(C(=O)O)O2
Reactant: O=S(Cl)Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1c(C)c(C)c2c(c1C)CCC(C)(C(=O)Cl)O2

Procedure:
To a solution composed of 3.0 g of (3,4-dihydro-6-methoxy-2,5,7,8-tetramethyl-2H-benzopyran-2-yl)carboxylic acid, 2 drops of N,N-dimethylformamide and 50 ml of 1,2-dichloroethane was added 1.1 ml of thionyl chloride and the mixture was refluxed for 2 hours. After cooling, the reaction mixture was evaporated under reduced pressure to remove the low-boiling substances. This procedure gave (3,4-dihydro-6-methoxy-2,5,7,8-tetramethyl-2H-benzopyran-2-yl)carbonyl chloride in a quantitative yield of 3.39 g.