Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:11]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:12]=1[CH2:13][N:14]=[N+]=[N-])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[C:1]([O:5][C:6]([NH:8][CH:9]([C:11]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:12]=1[CH2:13][NH2:14])[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(Cl)cc1CN=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(NC(=O)OC(C)(C)C)c1ccc(Cl)cc1CN

Procedure:
To a stirred solution 2-(1-tert-butyloxycarbonylaminoethyl)-5-chlorobenzylazide from the previous step (0.28 g, 0.90 mmol) in THF (10.0 mL) and water (1 mL) at ambient temperature was added Ph3P (0.29 mg, 1.1 mmol). The mixture was refluxed for 3 h. The reaction was partitioned between Et2O and diluted 1N HCl. The Et2O layer was removed, and the aqueous layer basicified with saturated NaHCO3 solution. The aqueous layer was extracted with Et2O which was separated, dried over anhydrous Na2SO4, and filtered. The filtrate solvent was removed under reduced pressure. 2-(1-(tert-butyloxycarbonylamino)ethyl)-5-chlorobenzylamine was obtained as a pink oil (0.205 g; HPLC RT=2.76 min, method A; 1H NMR, 400 MHz, CDCl3, 7.33 ppm (s, 1H), 7.22 ppm (dd, 2H), 5.2 ppm (br s, 1H), 5.0 ppm (br s, 1H), 4.0 ppm (d, 1H), 3.85 ppm (d, 1H), 1.7 (br s, 1H), 1.4 ppm (s, 12H)).
Reaction SMILES: [C:1]1([C:7]([OH:9])=[O:8])([C:4]([OH:6])=[O:5])[CH2:3][CH2:2]1.S(Cl)(Cl)=O.[CH2:14](O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH-].[Na+]>O1CCCC1.C(N(CC)CC)C>[CH2:14]([O:5][C:4]([C:1]1([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1)=[O:6])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OCc1ccccc1
Reactant: O=C(O)C1(C(=O)O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: O=C(O)C1(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Yield: 74 %

Procedure:
1,1-Cyclopropanedicarboxylic acid (5.02 g) was dissolved in tetrahydrofuran (50 ml) under a nitrogen atmosphere, and triethylamine (5.38 ml) was added dropwise thereto while stirring in an ice water bath. After stirring at the same temperature for 30 min, thionyl chloride (2.82 ml) was added dropwise while stirring in an ice water bath. After stirring at the same temperature for 30 min, a solution of benzyl alcohol (4.39 ml) in tetrahydrofuran (25 ml) was added while stirring in an ice water bath, and the reaction mixture was allowed to gradually warm up to room temperature, followed by stirring overnight. To the reaction mixture was added a 2N aqueous solution of sodium hydroxide (100 ml), and tetrahydrofuran was removed under reduced pressure. To the resultant aqueous solution was added tert-butyl methyl ether (25 ml) and stirred. The organic layer and the aqueous layer were separated. The aqueous layer was cooled in an ice water bath, and adjusted to pH 4 with 2N hydrochloric acid (50 ml). Ethyl acetate (150 ml) was added thereto and stirred for a while. The organic layer was separated, washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed to give residue, which was dried under reduced pressure to provide the titled compound as a pale yellow oil (6.29 g, 74%).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:7][CH:8]=1.[CH2:13]([O:17][C:18](=[O:22])[C@H:19]([CH3:21])[NH2:20])[CH:14]([CH3:16])[CH3:15]>>[CH2:13]([O:17][C:18](=[O:22])[C@H:19]([CH3:21])[NH:20][C:10](=[O:12])[CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([S:2][CH3:1])[CH:4]=1)[CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)COC(=O)[C@H](C)N
Reactant: CSc1cccc(CC(=O)O)c1
Product: CSc1cccc(CC(=O)N[C@@H](C)C(=O)OCC(C)C)c1

Procedure:
Following General Procedure BI above, and using 3-methylthiophenylacetic acid (CAS# 18698-73-2) and alanine iso-butyl ester (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[N:12]([CH3:17])[C:11]([CH3:19])([CH3:18])[CH2:10]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:22]I>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]([CH3:22])[CH:9]2[CH2:14][C:13]([CH3:15])([CH3:16])[N:12]([CH3:17])[C:11]([CH3:19])([CH3:18])[CH2:10]2)=[CH:4][CH:3]=1
Reactant: CI
Reactant: CN1C(C)(C)CC(Nc2ccc(Cl)nn2)CC1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(c1ccc(Cl)nn1)C1CC(C)(C)N(C)C(C)(C)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of 6-chloro-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)pyridazin-3-amine, Intermediate 1-5, (4.0 g, 14.1 mmol) in DMF (140 mL) cooled to 0° C. was added 60% wt NaH (735 mg, 18.39 mmol) portionwise. The reaction was warmed to RT and stirred for 60 minutes. After 60 minutes methyl iodide (0.88 mL, 14.1 mmol) was added and the reaction was stirred an additional 3 h, then slowly quenched with water at room temperature. The crude reaction mixture was diluted in EtOAc. The organic layer was washed with water (5×), brine, dried over MgSO4, filtered and concentrated under reduced pressure to give 6-chloro-N-methyl-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)pyridazin-3-amine, Intermediate 1-4 (3.98 g). The crude material was carried on without further purification. LCMS Rt=1.16 min (condition B), MS (M+1)=297.0. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.10 (d, J=9.6 Hz, 1H), 6.69 (d, J=9.6 Hz, 1H), 4.79-5.00 (m, 1H), 2.86 (s, 3H), 2.22 (s, 3H), 1.61-1.73 (m, 2H), 1.48-1.57 (m, 2H), 1.14 (s, 6H), 1.10 (s, 6H).
Reaction SMILES: N[C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[C:7]([CH3:15])[C:5]=2[N:6]=1.NC1C=CC(C(OC)=O)=CC=1C.[Br:28]Br>CC(O)=O>[Br:28][C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[C:7]([CH3:15])[C:5]=2[N:6]=1
Reactant: COC(=O)c1cc(C)c2nc(N)sc2c1
Reactant: BrBr
Agent: COC(=O)c1ccc(N)c(C)c1
Solvent: CC(=O)O
Product: COC(=O)c1cc(C)c2nc(Br)sc2c1
Temperature: 0 °C
Reaction time: 48 h

Procedure:
Methyl 2-amino-4-methyl-benzothiazole-6-carboxylate (I-16A). Into a 500-mL round-bottom flask was placed a solution of methyl 4-amino-3-methylbenzoate (4.00 g, 24.2 mmol, 1.00 equiv) and NaSCN (7.00 g, 86.4 mol, 3.57 equiv) in AcOH (90 mL) that was cooled to 0° C. This was followed by the addition of a solution of Br2 (3.9 g, 25 mmol, 1.0 equiv) in AcOH (25 mL) dropwise, maintaining at 0° C. over 20 min. The resulting solution was allowed to warm to RT on its own accord (over approximately 10 min.) and stirred for 48 hrs at RT. At this time, the solids of the reaction were filtered out. The resulting solution was diluted with 100 mL H2O. The pH value of the solution was adjusted to 8-9 with ammonia (using Whatman PH strip paper to monitor PH adjustment) which furnished an immediate precipitation. The solids were collected by filtration and washed once with ice cold MeOH (50 mL) to afford as a yellow solid. MS m/z 223.0 (M+11). 1H NMR (400 MHz, MeOH-d4) δ 8.17 (app d, J=1.0 Hz, 1H), 8.03 (br s, 2H, NH2), 7.68 (s, 1H), 3.82 (s, 3H), 2.42 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[N:13]2[CH:14]=[N:15][CH:16]=[C:12]2[CH2:11][CH2:10][CH2:9]1.[S:17]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18]1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[S:17]1[CH:21]=[CH:20][C:19]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH:8]2[N:13]3[CH:14]=[N:15][CH:16]=[C:12]3[CH2:11][CH2:10][CH2:9]2)=[CH:18]1
Reactant: OB(O)c1ccsc1
Reactant: Brc1ccccc1C1CCCc2cncn21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: c1ccc(C2CCCc3cncn32)c(-c2ccsc2)c1

Procedure:
To a solution of 5-(2-bromophenyl)-5,6,7,8,-tetrahydroimidazo[1,5-a]pyridine (95 mg, 0.343 mmol) in DME (2 mL) is added thiophene-3-boronic acid (53 mg, 0.414 mmol), aqueous Na2CO3 (2M, 0.5 mL, 1.0 mmol), and Pd(PPh3)4 (20 mg). The reaction mixture is run under microwave irradiation at 120° C. for 20 min. The mixture is partitioned between EtOAc and brine. The organic layer is washed by brine, dried over Na2SO4 and concentrated to give an oil. The crude reaction mixture is subjected to flash chromatography eluting with acetone:hexane to yield the desired compound. MS (ESI) m/z 280 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11]C)=[O:10])=[C:6]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[N:21]([CH3:25])[CH2:20][CH2:19]3)[N:5]=[C:4]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:3]=1.[OH-].[Na+]>CO>[CH3:1][C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([OH:11])=[O:10])=[C:6]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[N:21]([CH3:25])[CH2:20][CH2:19]3)[N:5]=[C:4]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:3]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1-c1ccc2c(c1)CCN2C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc(-c2ccccc2)nc1-c1ccc2c(c1)CCN2C
Yield: 46.9 %

Procedure:
This compound was prepared according to general method D from methyl 2-(4-methyl-6-(1-methylindolin-5-yl)-2-phenylpyrimidin-5-yl)pentanoate (0.064 g; 0.154 mmol), sodium hydroxide 10N (0.154 mL; 1.54 mmol) in methanol (1.5 mL). Purification by flash-chromatography on silica gel using a gradient of methanol (1-10%) in dichloromethane followed by a purification by preparative HPLC (HPLC method 1) furnished 0.029 g (45%) of the title compound as a red oil.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH2:7][C:8]1[CH:9]=[C:10]([CH:16]=[C:17]([S:26](=[O:29])(=[O:28])[NH2:27])[C:18]=1[O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:11](OCC)=[O:12].C(OCC)(=O)C.O>O1CCOCC1.C(O)(=O)C>[NH2:7][C:8]1[CH:9]=[C:10]([CH:16]=[C:17]([S:26](=[O:29])(=[O:28])[NH2:27])[C:18]=1[O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:11][OH:12]
Reactant: CCOC(=O)c1cc(N)c(Oc2ccccc2)c(S(N)(=O)=O)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: Nc1cc(CO)cc(S(N)(=O)=O)c1Oc1ccccc1

Procedure:
To a stirred mixture of lithium aluminium hydride (12.5 g) and dry dioxane (250 ml), a solution of ethyl 3-amino-4-phenoxy-5-sulfamylbenzoate (50 g) in dry dioxane (250 ml) is dropwise added at 90° C. during about one hour. After additional stirring and heating for 3 hours, the mixture is cooled, and ethyl acetate (25 ml) followed by water (50 ml) and 4 N acetic acid (310 ml) are very cautiously added dropwise. The solvents are thereafter removed in vacuo, and the residue is extracted with ethyl acetate (1 liter). The insoluble inorganic material is removed by filtration, and the filtrate is washed with aqueous sodium hydrogen carbonate and with water, and is then dried in the presence of magnesium sulphate. After filtration, the solvent is removed in vacuo to yield crude 3-amino-4-phenoxy-5-sulfamylbenzyl alcohol. After recrystallization from aqueous ethanol it is obtained with a melting point of 170° C.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6](OS(C(F)(F)F)(=O)=O)[CH:5]=[CH:4][C:3]=1[C:17]1[S:21][C:20]([N:22]2[CH2:25][C:24]3([CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]3)[CH2:23]2)=[N:19][N:18]=1.CC1(C)C(C)(C)OB([C:46]2[CH:47]=[N:48][NH:49][CH:50]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[C:7]([F:8])=[C:6]([C:46]2[CH:47]=[N:48][NH:49][CH:50]=2)[CH:5]=[CH:4][C:3]=1[C:17]1[S:21][C:20]([N:22]2[CH2:25][C:24]3([CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[CH2:27][CH2:26]3)[CH2:23]2)=[N:19][N:18]=1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN(c1nnc(-c3ccc(OS(=O)(=O)C(F)(F)F)c(F)c3F)s1)C2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CN(c1nnc(-c3ccc(-c4cn[nH]c4)c(F)c3F)s1)C2
Temperature: 120 °C
Yield: 18.9 %

Procedure:
A mixture of tert-butyl 2-(5-(2,3-difluoro-4-(((trifluoromethyl)sulfonyl)oxy)phenyl)-1,3,4-thiadiazol-2-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (68 mg, 0.119 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (35 mg, 0.179 mmol) in dioxane (1 mL) was stirred under nitrogen atmosphere. To this suspension was added Pd(PPh3)4 (7 mg, 0.006 mmol) followed by a solution of Na2CO3 (38 mg, 0.358 mmol) in water (0.25 mL). The reaction mixture was sealed and heated at 120° C. for 1 hour under microwave irradiation. The reaction mixture was diluted with water (10 mL) and extracted with DCM (20 mL). The organic phase was separated and concentrated in vacuo to afford the crude product as an off-white solid. The crude material was purified by UV directed preparative HPLC under basic conditions (NH4OH modified) to afford he title compound as a white solid (11 mg, 19% yield). MS m/z 489.1 [M+H]+, 1H NMR (400 MHz, DMSO-d6) δ 13.30 (s, 1H), 8.18 (s, 2H), 7.85 (ddd, J=8.6, 6.7, 1.8 Hz, 1H), 7.70 (ddd, J=8.7, 7.0, 1.8 Hz, 1H), 3.91 (s, 4H), 3.28-3.31 (m, 4H), 1.74 (t, J=5.6 Hz, 4H), 1.40 (s, 9H).
Reaction SMILES: C(OC(C1SC(C2C=CC=CC=2)=CC=1N)=O)C.COC1C=C(OC)C=CC=1C[O:23][N:24]1[C:29](=[O:30])[C:28]2[S:31][C:32]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:33][C:27]=2[NH:26][C:25]1=[O:40]>>[OH:23][N:24]1[C:29](=[O:30])[C:28]2[S:31][C:32]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:33][C:27]=2[NH:26][C:25]1=[O:40]
Reactant: COc1ccc(COn2c(=O)[nH]c3cc(-c4ccccc4)sc3c2=O)c(OC)c1
Agent: CCOC(=O)c1sc(-c2ccccc2)cc1N
Product: O=c1[nH]c2cc(-c3ccccc3)sc2c(=O)n1O

Procedure:
3-Amino-5-phenyl-thiophene-2-carboxylic acid ethyl ester was converted to 3-(2,4-Dimethoxy-benzyloxy)-6-phenyl-1H-thieno[3,2-d]pyrimidine-2,4-dione via general procedure A1. The intermediate was deprotected via general procedure D1 to give the title compound. 1H NMR (DMSO-d6) δ 10.50 (bs, 1H), 9.04 (s, 1H), 7.76-7.45 (m, 5H); Electrospray MS: 259 (M−H); retention time: 1.27 min.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][Si:9]([C:12]#[CH:13])([CH3:11])[CH3:10].[C:14]([O:17][C@@H:18]1[C@@H:24]([O:25][C:26](=[O:28])[CH3:27])[C@H:23]([O:29][C:30](=[O:32])[CH3:31])[C@@H:22]([CH2:33][O:34][C:35](=[O:37])[CH3:36])[O:21][C@@:19]1([C:38]1[CH:43]=[CH:42][C:41]([CH3:44])=[C:40]([CH2:45][C:46]2[CH:51]=[CH:50][C:49](OS(C(F)(F)F)(=O)=O)=[CH:48][CH:47]=2)[CH:39]=1)[OH:20])(=[O:16])[CH3:15]>CN(C)C=O.[Cu](I)I.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>[C:14]([O:17][C@@H:18]1[C@@H:24]([O:25][C:26](=[O:28])[CH3:27])[C@H:23]([O:29][C:30](=[O:32])[CH3:31])[C@@H:22]([CH2:33][O:34][C:35](=[O:37])[CH3:36])[O:21][C@@:19]1([C:38]1[CH:43]=[CH:42][C:41]([CH3:44])=[C:40]([CH2:45][C:46]2[CH:51]=[CH:50][C:49]([C:13]#[C:12][Si:9]([CH3:11])([CH3:10])[CH3:8])=[CH:48][CH:47]=2)[CH:39]=1)[OH:20])(=[O:16])[CH3:15]
Reactant: CC(=O)OC[C@H]1O[C@](O)(c2ccc(C)c(Cc3ccc(OS(=O)(=O)C(F)(F)F)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)OC[C@H]1O[C@](O)(c2ccc(C)c(Cc3ccc(C#C[Si](C)(C)C)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 90 °C

Procedure:
Under argon, 17.3 mg copper iodide, 31.9 mg bis-(triphenylphosphine)-palladium dichloride, 0.22 ml triethylamine and finally 0.19 ml trimethylsilylacetylene are added to a solution of 0.30 g 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl)-3-[4-(trifluoromethylsulfonyloxy)-benzyl]-4-methyl-benzene in 1.5 ml of dimethylformamide. The flask is tightly sealed and stirred at 90° C. over night. After 4 h additional 20 mg bis-(triphenylphosphine)-palladium dichloride and 0.2 ml trimethylsilylacetylene are added, and the mixture is further stirred at 90° C. for 4 h. After cooling the reaction mixture to room temperature, the solvent is removed and the residue purified by chromatography on silica gel (cyclohexane/ethyl acetate 4:1->1:2).
Reaction SMILES: [CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]([OH:18])=O)=[CH:15][C:10]=3[N:9]=[C:8]2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:30][CH2:31][NH2:32].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[OH-].[Na+]>CN(C=O)C>[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH2:30][CH2:31][NH:32][C:16]([C:14]2[CH:13]=[CH:12][C:11]3[N:7]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)[C:8]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)=[N:9][C:10]=3[CH:15]=2)=[O:18])[CH:33]=[CH:34][C:35]=1[O:36][CH3:37]
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccccn1)n2C1CCCCC1
Reactant: COc1ccc(CCN)cc1OC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CCNC(=O)c2ccc3c(c2)nc(-c2ccccn2)n3C2CCCCC2)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
1-Cyclohexyl-2-pyridin-2-yl-1H-benzoimidazole-5-carboxylic acid (0.060 g, 0.19 mmol), 3,4-dimethoxyphenethylamine (35 μL, 0.21 mmol) and TBTU (0.090 g, 0.28 mmol) were dissolved in DMF (1 mL), and DIEA (330 μL, 1.9 mmol) was added. The mixture was stirred 1 h at room temperature, when HPLC analysis indicated completion of the coupling reaction. The reaction mixture was added drop-wise with vigorous stirring to 1 N NaOH (10 mL). The precipitated product was collected by filtration, washed with water and dried. The title amide derivative was obtained as a gray solid (0.056 g, 60% yield, 98% homogeneity by HPLC).
Reaction SMILES: C(OC([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:22][CH:23]([CH:40]([CH3:42])[CH3:41])[CH:24]([OH:39])[C:25]([F:38])([F:37])[C:26](=[O:36])[NH:27][CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:21])[C:15]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[N:14][CH:13]=1)=O)C1C=CC=CC=1.C(N(CC)CC)C.Cl.C(OC(=O)CN)(C)(C)C>O1CCCC1>[NH2:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:22][CH:23]([CH:40]([CH3:42])[CH3:41])[C:24](=[O:39])[C:25]([F:38])([F:37])[C:26](=[O:36])[NH:27][CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:21])[C:15]([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)=[N:14][CH:13]=1
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ncc(NC(=O)OCc2ccccc2)c1=O)C(O)C(F)(F)C(=O)NCC(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ncc(N)c1=O)C(=O)C(F)(F)C(=O)NCC(=O)OC(C)(C)C
Reaction time: 18 h

Procedure:
2-(5-Benzyloxycarbonylamino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-[3,3-difluoro-1-isopropyl-2-hydroxy-3-[N-(tert-butoxycarbonylmethyl)carbamoyl]propyl]acetamide. To a solution of the product described at Example 1.b. (1.05 g) in tetrahydrofuran (17 mL) was added triethylamine (0.82 mL) and glycine tert-butylester hydrochloride (0.990 g). After 18 hours, additional triethylamine (0.30 mL) and glycine tert-butylester hydrochloride (0.33 g) were added. The additions were repeated after 1 day, and the reaction mixture stirred for 1 day. The mixture was evaporated and the solids were triturated with water, collected by filtration, washed (water, ether, hexane), and dried under vacuum to yield the title compound as a white powder; TLC: Rf =0.47, chloroform:methanol (97:3); m/z=672(M+1).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH2:20])[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:22]1[CH:34]=[CH:33][C:25]([CH2:26][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[CH:24][CH:23]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH:20][C:22]4[CH:23]=[CH:24][C:25]([CH2:26][N:27]5[CH2:32][CH2:31][O:30][CH2:29][CH2:28]5)=[CH:33][CH:34]=4)[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(N)nc23)cc1
Reactant: Brc1ccc(CN2CCOCC2)cc1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CS(=O)(=O)c1ccc(-c2cccn3nc(Nc4ccc(CN5CCOCC5)cc4)nc23)cc1

Procedure:
[8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(4-morpholin-4-ylmethyl-phenyl)-amine was prepared from 8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (50.0 mg, 0.173 mmol) and 4-(4-bromo-benzyl)-morpholine (55.0 mg, 0.215 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (20.0 mg, 0.0366 mmol) as the ligand in a manner analogous to Step 2d and was isolated as a yellow foam (0.006 g, 7%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.50 (d, J=6.6 Hz, 1H), 8.23 (d, J=8.3 Hz, 2H), 8.09 (d, J=8.3 Hz, 2H), 7.66 (d, J=7.4 Hz, 1H), 7.55 (d, J=8.4 Hz, 2H), 7.32 (d, J=8.2 Hz, 2H), 7.03 (t, J=6.7 Hz, 1H), 6.86 (s, 1H), 3.74-3.69 (m, 4H), 3.48 (s, 2H), 3.11 (s, 3H), 2.48-2.43 (m, 4H). MS=464 (MH)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH:16]=[CH:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[C:49]([O:53][C@@H:54]([CH3:67])[C@H:55]([NH2:66])[C:56]1[NH:60][C:59]2[CH:61]=[CH:62][C:63]([Cl:65])=[CH:64][C:58]=2[N:57]=1)([CH3:52])([CH3:51])[CH3:50].ClCl>O1CCCC1.ClCCl.C(O)C>[C:49]([O:53][C@@H:54]([CH3:67])[C@H:55]([NH:66][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([C:11]([N:13]2[CH2:17][CH:16]=[CH:15][CH2:14]2)=[O:12])=[C:2]([CH3:1])[CH:3]=1)[C:56]1[NH:60][C:59]2[CH:61]=[CH:62][C:63]([Cl:65])=[CH:64][C:58]=2[N:57]=1)([CH3:52])([CH3:50])[CH3:51]
Reactant: C[C@H](OC(C)(C)C)[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CC=CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1cc(C(=O)N[C@H](c2nc3cc(Cl)ccc3[nH]2)[C@H](C)OC(C)(C)C)ccc1C(=O)N1CC=CC1
Yield: 86 %

Procedure:
Prepared analogously to Example 1g from 3-methyl-4-(2,5-dihydropyrrol-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and (1R,2S)-2-tert-butoxy-1-(5-chloro-1H-benzimidazol-2-yl)propylamine in tetrahydrofuran. Yield: 86%; Rf value: 0.61 (silica gel: dichloromethane/ethanol=9:1); C27H31ClN4O3 (495.02); mass spectrum: (M+H)+=495/497 (chlorine isotope).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][S:12]([CH2:14][CH2:15][N:16]2[CH:20]=[CH:19][N:18]=[N:17]2)=[O:13])=[CH:7][CH:6]=1)C=C.CN1C(=O)CC(=O)N(C)C1=O>ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:16]1([CH2:15][CH2:14][S:12]([CH2:11][C:8]2[CH:7]=[CH:6][C:5]([OH:4])=[CH:10][CH:9]=2)=[O:13])[CH:20]=[CH:19][N:18]=[N:17]1
Reactant: C=CCOc1ccc(CS(=O)CCn2ccnn2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CN1C(=O)CC(=O)N(C)C1=O
Solvent: ClCCl
Product: O=S(CCn1ccnn1)Cc1ccc(O)cc1
Temperature: 50 °C
Reaction time: 5 h
Yield: 97.5 %

Procedure:
A solution of 1.00 g (3.43 mmol) 1-[2-(4-Allyloxy-phenylmethanesulfinyl)-ethyl]-1H-[1,2,3]triazole in 60 ml dichloromethane was added to a solution of 1.61 g (10.3 mmol) 1,3-dimethylbarbituric acid and 102 mg (0.09 mmol) Pd(PPh3)4 in 30 ml dichloromethane and stirred for 5 h at 50° C. The mixture was extracted with 3×50 ml sat. NaHCO3-solution and 20 ml water. Thee organic phase was discarded and the aqueous phase acidified with 2M HCl to pH=4, concentrated to volume of 50 ml and adjusted to pH=1. After five extractions with ethyl acetate, the organic extracts were combined and dried over MgSO4. After evaporation the residue was purified by chromatography on silica gel (dichloromethane/methanol 100:2) to yield 0.84 g (97%) of the title compound.