Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:25])([CH2:19][N:20]2[CH:24]=[N:23][CH:22]=[N:21]2)[CH:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[OH:10])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:29]Cl.CCOCC>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:19][N:20]3[CH:24]=[N:23][CH:22]=[N:21]3)[CH:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=3[Cl:18])[O:10][CH2:29][O:25]2)=[CH:4][CH:3]=1
Reactant: ClCBr
Reactant: OC(c1ccc(Cl)cc1Cl)C(O)(Cn1cncn1)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Clc1ccc(C2(Cn3cncn3)OCOC2c2ccc(Cl)cc2Cl)cc1
Temperature: 0 °C
Yield: 54.4 %

Procedure:
To a solution of 500 mg of 2-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-3-(1H-1,2,4-triazol-1-yl)-1,2-propanediol in 5 ml of dry dimethylformamide is added 180 mg of 50% mineral oil dispersion of sodium hydride under ice cooling. Five minutes later 490 mg of bromochloromethane is added to the mixture, which is allowed to react at a temperature of 50° C. for 1 hour. The reaction mixture is mixed with ice water and shaken with ether. The ethereal layer is washed with water, dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica-gel, which is eluted with 3% methanol-methylene chloride. The eluate is concentrated and the residue is crystallized from ethyl acetate to give 280 mg of 4-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-4-(1H-1,2,4-triazol-1-yl)methyl-1,3-dioxolane as crystals melting at 201 ° to 203° C. The yield is 54%.
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:13]([C:25]1[C:26]([Cl:35])=[N:27][C:28]3[C:33]([CH:34]=1)=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:12]2)(C(C)(C)C)(C)C.F.F.F.C(N(CC)CC)C>C(#N)C>[Cl:35][C:26]1[C:25]([C:13]2[N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:15]3[C:11]([CH:12]=2)=[CH:10][C:9]([OH:8])=[CH:17][CH:16]=3)=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=1
Reactant: CC(C)(C)OC(=O)n1c(-c2cc3ccccc3nc2Cl)cc2cc(O[Si](C)(C)C(C)(C)C)ccc21
Agent: F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1c(-c2cc3ccccc3nc2Cl)cc2cc(O)ccc21

Procedure:
A solution of tert-butyl 5-{[tert-butyl(dimethyl)silyl]oxy}-2-(2-chloro-3-quinolinyl)-1H-indole-1-carboxylate 1-7 (2.50 g, 4.91 mmol, 1 equiv) and triethylamine trihydrofluoride (3.60 mL, 22.1 mmol, 4.50 equiv) in acetonitrile (100 mL) was stirred at 23° C. for 20 hours. The reaction mixture was concentrated, and the residue was partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated to tert-butyl 2-(2-chloro-3-quinolinyl)-5-hydroxy-1H-indole-1-carboxylate (1-8) as a tan colored foam. 1H NMR (400 MHz, CDCl3) δ 8.18 (d, 1H, J= 9.0 Hz), 8.17 (s, 1H), 8.07 (d, 1H, J=8.4 Hz), 7.86 (d, 1H, J=8.1 Hz), 7.77 (br t, 1H, J=8.4 Hz), 7.61 (br t, 1H, J=8.1 Hz), 7.03 (d, 1H, J=2.6 Hz), 6.93 (dd, 1H, J=8.8, 2.6 Hz), 6.55 (s, 1H), 1.26 (s, 9H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:22]([N:1]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C@H:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1N(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a suspension of tert-butyl N-[(1S,2S)-2-aminocyclopentyl]carbamate (CAS number 586961-34-4; 500 mg, 2.50 mmol) and potassium carbonate (518 mg, 3.74 mmol) in DMF (5 ml) was added (bromomethyl)benzene (CAS number 100-39-0; 356 μl, 3.00 mmol). The reaction was stirred at room temperature for 24 hours. To this was then added further (bromomethyl)benzene (CAS number 100-39-0; 356 μl, 3.00 mmol) and stirring was continued for 24 hours. The reaction mixture was diluted with ethyl acetate (40 ml) and washed with water (3×30 ml) and brine (30 ml). The organics were filtered through a hydrophobic frit and concentrated in vacuo. This was then purified by column chromatography (silica, 0-100% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH2:27][CH:28]4[CH2:30][CH2:29]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:32]([C@@H:34]([O:36]C(=O)C)[CH3:35])=[O:33]>>[OH:36][C@@H:34]([CH3:35])[C:32]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH2:27][CH:28]4[CH2:29][CH2:30]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)=[O:33]
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4ccccc4OCC4CC4)ncnc23)CC1
Product: C[C@H](O)C(=O)N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4ccccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from trans-4-(2-cyclopropylmethoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A161) and acetic acid (S)-1-chlorocarbonyl-ethyl ester the title compound is obtained as colorless solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([F:35])=[C:21]([NH:23][S:24]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:22]=2)[CH:5]=[CH:4][N:3]=1.[NH2:36][CH:37]1[CH2:42][CH2:41][CH:40]([NH:43][S:44]([CH3:47])(=[O:46])=[O:45])[CH2:39][CH2:38]1>C(O)CCC>[CH3:14][C:13]([C:11]1[S:12][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:36][C@H:37]3[CH2:42][CH2:41][C@H:40]([NH:43][S:44]([CH3:47])(=[O:46])=[O:45])[CH2:39][CH2:38]3)[N:7]=2)=[C:9]([C:17]2[CH:18]=[CH:19][C:20]([F:35])=[C:21]([NH:23][S:24]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:22]=2)[N:10]=1)([CH3:16])[CH3:15]
Reactant: CS(=O)(=O)NC1CCC(N)CC1
Reactant: CC(C)(C)c1nc(-c2ccc(F)c(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Solvent: CCCCO
Product: CC(C)(C)c1nc(-c2ccc(F)c(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(N[C@H]3CC[C@H](NS(C)(=O)=O)CC3)n2)s1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
N-{5-[5-(2-Chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (50 mg, 0.093 mmol) and N-(4-aminocyclohexyl)-methanesulfonamide (19.62 mg, 0.102 mmol) were dissolved in n-butanol (1 mL) and TEA (0.052 mL, 0.371 mmol) was added. The reaction was stirred in a closed vessel at 90° C. for 18 h. The reaction mixture was cooled to rt and solvent was removed. The residue was purified via Gilson Acidic HPLC (10 to 90% gradient, Acetonitrile/H2O+TFA; C18 column). Desired fractions were combined and solvent removed to give the title compound as a white solid (0.006 g). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.95 (s, 1H), 8.09 (d, J=5.0 Hz, 1H), 7.67-7.78 (m, 1H), 7.41 (d, J=3.5 Hz, 1H), 7.28 (q, J=8.7 Hz, 2H), 7.00 (dt, J=2.6, 1.3 Hz, 1H), 6.10-6.28 (m, 1H), 3.56-3.70 (m, 1H), 3.41-3.52 (m, 1H), 3.09 (td, J=4.2, 1.7 Hz, 1H), 2.92 (s, 3H), 1.83-1.98 (m, 4H), 1.21-1.50 (m, 13H). MS (ESI): 695 [M+H]+.
Reaction SMILES: BrC1C=CC=C2C=1C(C1C(O)=CC3OCOC=3C=1)[C:5](=[O:16])N2CCCCC.[OH:27][C:28]1[C:29]([CH:37]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[N:39]([CH2:46][CH2:47][CH2:48][N:49]3[C:57](=[O:58])[C:56]4[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=4)[C:50]3=[O:59])[C:38]2=[O:60])=[CH:30][C:31]2[O:35][CH2:34][O:33][C:32]=2[CH:36]=1>>[OH:27][C:28]1[C:29]([C:37]2([CH2:5][OH:16])[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[N:39]([CH2:46][CH2:47][CH2:48][N:49]3[C:57](=[O:58])[C:56]4[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=4)[C:50]3=[O:59])[C:38]2=[O:60])=[CH:30][C:31]2[O:35][CH2:34][O:33][C:32]=2[CH:36]=1
Reactant: CCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Reactant: O=C1c2ccccc2C(=O)N1CCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2ccccc21
Product: O=C1c2ccccc2C(=O)N1CCCN1C(=O)C(CO)(c2cc3c(cc2O)OCO3)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 1E, and making non-critical variations to replace 4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one with 2-{3-[3-(6-hydroxy-1,3-benzodioxol-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]propyl}-1H-isoindole-1,3(2H)-dione, the title compound was obtained (94%) as a foam solid: 1H NMR (300 MHz, CDCl3) δ 9.20 (s, 1H), 7.81-7.79 (m, 2H), 7.68-7.61 (m, 2H), 7.35-7.25 (m, 2H), 7.16-7.14 (m, 1H), 6.90 (d, 1H), 6.80 (s, 1H), 6.48 (s, 1H), 5.86 (dd, 2H), 4.64 (d, 1H), 3.67-4.13 (m, 5H), 2.18-2.05- (m, 2H); 13C NMR (75 MHz, CDCl3) δ 180.6, 168.6, 151.2, 147.8, 143.2, 141.2, 134.2, 134.2, 131.9, 130.0, 128.7, 125.1, 123.2, 113.9, 108.7, 108.3, 101.3, 100.6, 64.9, 58.0, 37.6, 36.1, 26.5; MS (ES+) m/z 487.3 (M+1).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[S:8][C:9]([CH2:11][O:12][C:13]3[C:14]([F:23])=[C:15]([C:19]([F:22])=[CH:20][CH:21]=3)[C:16]([NH2:18])=[O:17])=[N:10][C:5]2=[CH:4][CH:3]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O>[F:23][C:14]1[C:13]([O:12][CH2:11][C:9]2[S:8][C:6]3[C:5]([N:10]=2)=[CH:4][CH:3]=[C:2]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:7]=3)=[CH:21][CH:20]=[C:19]([F:22])[C:15]=1[C:16]([NH2:18])=[O:17]
Reactant: NC(=O)c1c(F)ccc(OCc2nc3ccc(Br)nc3s2)c1F
Reactant: OB(O)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1c(F)ccc(OCc2nc3ccc(-c4ccccc4)nc3s2)c1F
Temperature: 120 °C
Yield: 41.1 %

Procedure:
To a solution of 3-(5-bromo-thiazolo[5,4-b]pyridin-2-ylmethoxy)-2,6-difluoro-benzamide (0.20 g, 0.49 mmol) in 4 ml of DMF and water (2.0 ml) was added phenyl boronic acid (0.12 g, 0.99 mmol) and potassium phosphate (0.13 g, 0.59 mmol). The reaction mixture was degassed for 10 minutes followed by addition of dichlorobis(tri phenyl phosphine) palladium (II) (0.070 g, 0.099 mmol). The reaction mixture was heated at 120° C. for 2 h under the nitrogen atmosphere. After the completion of the reaction mixture (TLC monitoring), water (25 mL) was added and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified over silica gel (100-200 M, 60% EtOAc-Hexane) to get the desired product (0.080 g, 41%) as a beige solid. 1H NMR (DMSO-d6, 400 MHz): δ 5.74 (s, 2H), 7.10 (m, 1H), 7.41-7.56 (m, 4H), 7.85 (m, 3H), 8.19 (m, 1H), 8.71 (br s, 1H) and 8.98 (br s, 1H). MS ES+ (398.09), HPLC (method I) Rt=16.07 min.
Reaction SMILES: Cl[C:2]1[C:3]2[NH:10][CH:9]=PC=2[N:5]=[CH:6][N:7]=1.[NH2:11][C:12](N)=[S:13]>C(O)C>[CH:6]1[NH:7][C:2]2[C:12]([N:11]=[CH:9][NH:10][C:3]=2[N:5]=1)=[S:13]
Reactant: NC(N)=S
Reactant: Clc1ncnc2pc[nH]c12
Solvent: CCO
Product: S=c1nc[nH]c2nc[nH]c12

Procedure:
The hypoxanthine analog from Example 3 is reacted with POCl3 at reflux temperature for 50 min to form 7-chloro-1H-1,3-azaphospholo[4,5-d]pyrimidine (compound 14). Reaction of compound 14 with thiourea in boiling ethanol produced the 6-thiopurine analog 1,3-azaphospholo[4,5-d]pyrimidin-7(1H, 6H)-thione (compound 15). Compounds 14 and 15 are prepared as follows:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:26])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)(=O)C>C(O)=O>[CH2:1]([O:8][C:9](=[O:26])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:15][CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CCc1ccc(CC(=O)OCc2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: O=CO
Product: O=C(O)CCc1ccc(CC(=O)OCc2ccccc2)cc1
Temperature: 0 °C
Yield: 87 %

Procedure:
1,1-dimethylethyl 3-[4-(2-benzyloxy-2-oxoethyl)phenyl]propanoate (3.0 g, 8.5 mmol) was stirred in formic acid (10 mL) for 8 hours. Removal of the solvent in vacuo provided a colorless oil that was shaken vigorously with a mixture of ethyl acetate and hexanes (1:3, 20 mL) until it solidified. The mixture was cooled in ice water and the product, collected by suction filtration to give 3-[4-(2-benzyloxy-2-oxoethyl)phenyl]propanoic acid, as a white solid (2.2 g, 7.4 mmol) in 87% yield, mp. 62°-64.5° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH:6]([NH:10][C:11](=[O:31])[CH:12]([O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[C:21]([C:27]([F:30])([F:29])[F:28])[CH:20]=1)[C:13]([CH3:17])([CH3:16])[CH2:14][OH:15])([CH2:8][CH3:9])[CH3:7]>N1C=CC=CC=1>[CH:6]([NH:10][C:11]([CH:12]([O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[C:21]([C:27]([F:29])([F:30])[F:28])[CH:20]=1)[C:13]([CH3:16])([CH3:17])[CH2:14][O:15][S:2]([CH3:1])(=[O:4])=[O:3])=[O:31])([CH2:8][CH3:9])[CH3:7]
Reactant: CCC(C)NC(=O)C(Oc1ccc(C#N)c(C(F)(F)F)c1)C(C)(C)CO
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CCC(C)NC(=O)C(Oc1ccc(C#N)c(C(F)(F)F)c1)C(C)(C)COS(C)(=O)=O
Temperature: 2.5 °C
Reaction time: 5 h

Procedure:
Methanesulfonyl chloride (36.45 g, 318 mmol) was added in one portion to a cold (0-5° C.) sol'n of the N-sec-butyl-2-(4-cyano-3-trifluoromethyl phenoxy)-4-hydroxy-3,3-dimethylbutyramide (5, 79.0 g, 212 mmol) in 200 mL pyridine. The reaction mixture was stirred at 0-5° C. for 5 h. The reaction was quenched with 800 mL sat'd aq. NH4Cl and extracted with 1000 mL CH2Cl2. The organic phase was washed with 2N aq. HCl (3×300 mL) and then half sat'd aq. NaCl (3×300 mL). The organic was conc'd under vac (35-40° C.) to an amber gum.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([Br:9])[CH:3]=1.CCCCCC.C([Li])CCC.[F:21][C:22]([F:30])([F:29])[C:23]([C:25]([F:28])([F:27])[F:26])=[O:24]>C(OCC)C>[F:21][C:22]([F:30])([F:29])[C:23]([C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([Br:9])[CH:3]=1)([OH:24])[C:25]([F:28])([F:27])[F:26]
Reactant: Brc1cc(Br)cc(Br)c1
Reactant: O=C(C(F)(F)F)C(F)(F)F
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: OC(c1cc(Br)cc(Br)c1)(C(F)(F)F)C(F)(F)F
Temperature: -78 °C
Reaction time: 1 h
Yield: 60.2 %

Procedure:
Under a nitrogen atmosphere, 30.0 g (95.0 mmol) of 1,3,5-tribromobenzene and 400 mL of diethyl ether were placed in a 500-mL glass flask and cooled to −78° C. Further, 60 ml (96.0 mmol) of 1.6M n-butyl lithium hexane solution was dropped into the glass flask at −78° C. over 1 hour. The resulting solution was subjected to aging at −78° C. for 1 hour. The lithiation of the raw material was confirmed by gas chromatography. After that, 16.6 g (100.0 mmol) of hexafluoroacetone was charged into the solution at −78° C. and stirred for 1 hour. After the completion of the stirring, the reacted solution was separated into an organic layer and an aqueous layer by the addition of 400 mL of 2N hydrochloric acid. The aqueous layer was extracted with 100 mL of isopropyl ether. The extracted organic layers were combined, dried with anhydrous magnesium sulfate, concentrated by an evaporator, and then, subjected to distillation. With this, 23 g of 1-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-3,5-dibromobenzene was obtained. The yield was 60%.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[CH2:8][NH:9][CH2:10][CH2:11][NH:12][C:13]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C.FC(F)(F)S(N=[C:45]([NH:54][C:55](=[O:61])[O:56][C:57]([CH3:60])([CH3:59])[CH3:58])[NH:46][C:47](=[O:53])[O:48][C:49]([CH3:52])([CH3:51])[CH3:50])(=O)=O>C(Cl)(Cl)Cl>[NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[CH2:8][N:9]([CH2:10][CH2:11][NH:12][C:13]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:45]([NH:46][C:47]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:53])=[N:54][C:55]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:61]
Reactant: Cn1ncc(CNCCNC(c2ccccc2)(c2ccccc2)c2ccccc2)c1N
Reactant: CC(C)(C)OC(=O)NC(=NS(=O)(=O)C(F)(F)F)NC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cn1ncc(CN(CCNC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c1N
Temperature: 25 °C
Reaction time: 96 h
Yield: 25.2 %

Procedure:
To a solution of N-[(5-amino-1-methyl-1H-pyrazol-4-yl)methyl]-N′-tritylethane-1,2-diamine (7.50 g) and triethylamine (2.86 g) in chloroform (100 ml) was added di-tert-butyl ({[(trifluoromethyl)sulfonyl]imino}-methylene)biscarbamate (11.05 g). The mixture was stirred at room temperature for 4 days. The reaction mixture was washed successively with 10% aqueous citric acid solution and brine, and the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 3% methanol/chloroform to give N-[(5-amino-1-methyl-1H-pyrazol-4-yl)methyl]-N′,N″-bis(tert-butoxycarbonyl)-N-[2-(tritylamino)ethyl]guanidine (3.00 g) as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]([OH:14])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C([Cl:18])=O>ClCCl.CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]([Cl:18])=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(C(=O)Cl)C1
Reaction time: 1.5 h

Procedure:
1-tert-Butyloxycarbonyl-azetidine-3-carboxylic acid (345 mg) in dry dichloromethane (10 ml) was treated with oxalyl chloride (254 mg; 0.175 ml) and N,N-dimethylformamide (1 drop). The solution was stirred for 1.5 hours, and then the solvent was removed by evaporation under reduced pressure. The residue was dissolved in toluene (10 ml), and the toluene was evaporation under reduced pressure to give 1-tert-butyloxycarbonyl-azetidine-3-carbonyl chloride as a colourless oil. The oil was dissolved in dichloromethane (6 ml) and the solution was treated with silver cyanate (525 mg). The mixture was stirred for 10 minutes, and then mutilin 11-trifluoroacetate (535 mg) in dichloromethane (9 ml) was added. The mixture was stirred for 20 hours. Ethyl acetate (50 ml) was added and the mixture was filtered. The filtrate was washed with saturated sodium bicarbonate solution (20 ml) and saturated sodium chloride solution (20 ml). The solution was dried (sodium sulphate) and the solvent was removed under reduced pressure to yield a colourless gum. The gum was chromatographed on silica gel using 1:4 to 1:2 ethyl acetate/hexane to give the title compound as a colourless gum (485 mg); 1H NMR (CDCl3) inter alia 1.43 (9H, s), 3.93 (1H, quin, J 7.2 Hz), 4.98 (1H, d, J 6.9 Hz), 4.14 (4H, m), 5.23 (1H, d, J 17.5 Hz), 5.29 (1H, d, J 11.2 Hz), 5.58 (1H, d, J 8 Hz), 6.31 (1H, dd, J 17.5, 11.2 Hz), 7.57 (1H, s).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[C:15]3[S:16][CH:17]=[CH:18][C:14]=3[O:13][N:12]=2)[CH:8]=[CH:9][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[NH2:25][CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1>C(#N)C>[N:29]1[CH:30]=[CH:31][CH:32]=[C:27]([CH2:26][NH:25][CH2:2][CH2:3][O:4][C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([C:11]3[C:15]4[S:16][CH:17]=[CH:18][C:14]=4[O:13][N:12]=3)[CH:6]=2)[CH:28]=1
Reactant: BrCCOc1cccc(-c2noc3ccsc23)c1
Reactant: NCc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: c1cncc(CNCCOc2cccc(-c3noc4ccsc34)c2)c1

Procedure:
The title compound is prepared from 3-[3-(2-bromo-ethoxy)-phenyl]-thieno[2,3-d]isoxazole, potassium carbonate, 3-(aminomethyl)pyridine and acetonitrile essentially as described above in example 18 except that the Waters Sep-Pak filtration is eluted with 10% methanol in dichloromethane and the column is eluted using a graded solvent mixture of 2% methanol in dichloromethane, to 6% methanol in dichloromethane. Purity by LC/MS (APCI)=100%, [M+H]+=352.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15]([C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:21])=[CH:14]3)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[Cl:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([N:16]2[C:17]3[C:13](=[CH:12][C:11]([O:10][CH:7]4[CH2:6][CH2:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:9][CH2:8]4)=[CH:19][CH:18]=3)[CH:14]=[C:15]2[C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:21])=[CH:31][CH:30]=1
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCOCC4)cc3c2)CC1
Reactant: OB(O)c1ccc(Cl)cc1
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCOCC2)n3-c2ccc(Cl)cc2)CC1

Procedure:
In analogy to the procedure described for the synthesis of example 6, the title compound was synthesized from [5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-morpholin-4-yl-methanone (intermediate 2) and 4-chlorophenylboronic acid. The title compound was obtained in 90% yield as yellow foam. MS (m/e): 482.3 (MH+, 100%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5](=[CH:11][O:12]CC)[C:6](OCC)=O)[CH3:2].[CH3:16][S:17][C:18](=[NH:20])[NH2:19].CC[O-].[Na+]>CCO>[CH2:1]([O:3][C:4]([C:5]1[C:11]([OH:12])=[N:19][C:18]([S:17][CH3:16])=[N:20][CH:6]=1)=[O:15])[CH3:2]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CSC(=N)N
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cnc(SC)nc1O
Temperature: 5 °C
Reaction time: 3 h
Yield: 158.1 %

Procedure:
To a solution of 2-ethoxymethylenemalonic acid diethyl ester (59.0 g, 273 mmol) in EtOH (300 mL) was added 2-methyl-isothiourea (41.5 g, 150 mmol) in an ice-H2O bath. An EtOHic solution of EtONa (2M, 300 mL) was added dropwise maintaining the reaction temperature under 5° C. The mixture was warmed to RT and stirred for 3 h. After standing overnight, the solvent was removed under reduced pressureand the residue was dissolved in H2O (800 mL) at 0° C. The solution was acidified to pH 3 with conc. HCl and the precipitate collected by filtration and air-dried to yield 4-hydroxy-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester as a white solid (50.8 g, 87.6% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.48 (s, 1H), 4.20 (q, J=9.6 Hz, 2H), 2.51 (s, 3H), 1.23 (t, J=9.6 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]([N:4]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1)[CH2:5][CH2:6][C:7]1[CH:21]=[CH:20][C:10]([O:11][C:12]([CH3:19])([CH3:18])[C:13]([O:15]CC)=[O:14])=[CH:9][CH:8]=1)=[S:3].[CH3:33][O:34][C:35]1[CH:36]=[C:37]([CH:42]=[CH:43][CH:44]=1)[C:38](=O)[CH2:39]Br>>[CH3:33][O:34][C:35]1[CH:36]=[C:37]([C:38]2[N:1]=[C:2]([N:4]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:27][CH:28]=3)[CH2:5][CH2:6][C:7]3[CH:21]=[CH:20][C:10]([O:11][C:12]([CH3:19])([CH3:18])[C:13]([OH:15])=[O:14])=[CH:9][CH:8]=3)[S:3][CH:39]=2)[CH:42]=[CH:43][CH:44]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2)C(N)=S)cc1
Reactant: COc1cccc(C(=O)CBr)c1
Product: COc1cccc(-c2csc(N(CCc3ccc(OC(C)(C)C(=O)O)cc3)Cc3ccc(C(F)(F)F)cc3)n2)c1

Procedure:
Similarly prepared from ethyl 2-[4-(2-{(aminocarbonothioyl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate and 3-methoxyphenacyl bromide.