Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1.[CH:14]1[C:22]2[C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[S:19][C:18]=2[C:17]([C:27]2[CH:28]=[C:29]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35](B(O)O)[CH:34]=3)[CH:30]=[CH:31][CH:32]=2)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>C(O)C>[CH:14]1[C:22]2[C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[S:19][C:18]=2[C:17]([C:27]2[CH:28]=[C:29]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([C:2]4[CH:7]=[C:6]([C:8]5[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=5)[N:5]=[CH:4][N:3]=4)[CH:34]=3)[CH:30]=[CH:31][CH:32]=2)=[CH:16][CH:15]=1
Reactant: OB(O)c1cccc(-c2cccc(-c3cccc4c3sc3ccccc34)c2)c1
Reactant: Clc1cc(-c2ccccc2)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: c1ccc(-c2cc(-c3cccc(-c4cccc(-c5cccc6c5sc5ccccc56)c4)c3)ncn2)cc1
Temperature: 80 °C
Yield: 71 %

Procedure:
Then, 1.0 g of 4-chloro-6-phenylpyrimidine obtained in Step 1, 2.0 g of 3′-(dibenzothiophen-4-yl)-3-biphenylboronic acid, 5.3 mL of a 2M aqueous solution of potassium carbonate, 24 mL of toluene, and 3.0 mL of ethanol were put into a 100-mL three-neck flask equipped with a reflux pipe. Degasification by stirring under a reduced pressure was performed and the air in the flask was replaced with nitrogen. To this mixture, 61 mg of tetrakis(triphenylphosphine)palladium(0) (abbreviation: Pd(PPh3)4) was added and the mixture was heated at 80° C. for 7 hours to cause a reaction. An organic layer was extracted from the obtained mixture with the use of toluene and was washed with water and a saturated aqueous solution of sodium chloride. Anhydrous magnesium sulfate was added and gravity filtration was performed. After the solvent in this solution was distilled off, the obtained residue was dissolved in hot toluene and subjected to hot filtration through a filter aid in which Celite, alumina, Celite, Florisil, and Celite were stacked in this order. The solvent was distilled off and the obtained solid was recrystallized with toluene, so that 1.9 g of a white solid was obtained in a yield of 71%. Synthesis Scheme (D-2) of Step 2 is shown below.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH:7]([O:10][C:11]1[C:16]2[CH:17]=[C:18]([CH3:27])[N:19]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]=2[CH:14]=[CH:13][N:12]=1)[CH2:8][CH3:9])([CH3:4])([CH3:3])[CH3:2].[C:29]([O:33][C:34](=[O:54])[CH2:35]OC1C2C=C(C)N(CC3C=CC=CC=3)C=2C=CN=1)(C)(C)C.ICC>O1CCCC1>[C:1]([O:5][C:6](=[O:28])[CH:7]([O:10][C:11]1[C:16]2[CH:17]=[C:18]([CH3:27])[N:19]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]=2[CH:14]=[CH:13][N:12]=1)[CH2:8][CH3:9])([CH3:4])([CH3:2])[CH3:3].[CH3:29][O:33][C:34](=[O:54])[CH3:35]
Reactant: Cc1cc2c(OCC(=O)OC(C)(C)C)nccc2n1Cc1ccccc1
Agent: CCC(Oc1nccc2c1cc(C)n2Cc1ccccc1)C(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: CCI
Product: COC(C)=O
Temperature: -78 °C
Reaction time: 1 h
Yield: 23 %

Procedure:
2-(1-Benzyl-2-methyl-1H-pyrrolo[3,2-c]pyridin-4-yloxy)-butyric acid tert-butyl ester, 15: (1-Benzyl-2-methyl-1H-pyrrolo[3,2-c]pyridin-4-yloxy)-acetic acid tert-butyl ester, 14 (200 mg, 0.568 mmol) was dissolved in a dry tetrahydrofuran (10 mL) and then cooled to −78° C. To the mixture the tetrahydrofuran solution (1.0 M) of LiN(Si(CH3)3)2 (1.70 mL) was added dropwise at −78° C. The reaction mixture was stirred from −78° C. to −5° C. for 1 h and then the tetrahydrofuran solution (5 mL) of iodoethane (0.15 mL, 1.84 mmol) was added dropwise at −50° C. The mixture was stirred for 4 h from −50° C. to room temperature. The mixture was concentrated and the residue was purified by silica gel chromatography (hexane to hexane:ethyl acetate, 4:1) to afford 2-(1-benzyl-2-methyl-1H-pyrrolo[3,2-c]pyridin-4-yloxy)-butyric acid tert-butyl ester, 15 Yield: 50 mg, (23%)
Reaction SMILES: [NH2:1][C:2]([C:4]1([CH:17]([CH3:19])[CH3:18])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)=O.N1C(Cl)=NC(Cl)=NC=1Cl>CN(C)C=O.O.C(OCC)(=O)C>[C:2]([C:4]1([CH:17]([CH3:19])[CH3:18])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])[CH2:6][CH2:5]1)#[N:1]
Reactant: CC(C)C1(C(N)=O)CCN(C(=O)OC(C)(C)C)CC1
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)C1(C#N)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Yield: 99.7 %

Procedure:
To a solution of tert-butyl 4-(aminocarbonyl)-4-isopropylpiperidine-1-carboxylate (100 mg, 0.370 mmol) in dimethylformamide (2 ml) was added cyanuric chloride (34.1 mg, 0.185 mmol). After stirring over the weekend at room temperature, the mixture was diluted with 10 ml of water, and 20 ml of ethyl acetate. The phases were separated and the aqueous phase was extracted with ethyl acetate (2×15 ml). The combined organics were washed with 10 ml each of saturated sodium bicarbonate solution and brine, dried (sodium sulfate), and then concentrated to provide the title compound (93 mg, 0.369 mmol, 100% yield). Mass spectrum (ESI) 153.2.0 (M-Boc).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C@H:7]1[CH2:10][C@@H:9]([NH2:11])[CH2:8]1)=[O:6])[CH3:3].C(N(CC)CC)C.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[O:30][N:29]=[C:28]([C:31]3[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=3)[N:27]=2)=[CH:22][CH:21]=1.C([BH3-])#N.[Na+]>CC(O)=O.C1COCC1>[CH2:2]([O:4][C:5]([C@H:7]1[CH2:10][C@@H:9]([NH:11][CH2:35][C:34]2[CH:33]=[CH:32][C:31]([C:28]3[N:27]=[C:26]([C:23]4[CH:24]=[CH:25][C:20]([CH3:19])=[CH:21][CH:22]=4)[O:30][N:29]=3)=[CH:38][CH:37]=2)[CH2:8]1)=[O:6])[CH3:3]
Reactant: Cc1ccc(-c2nc(-c3ccc(C=O)cc3)no2)cc1
Reactant: CCOC(=O)[C@H]1C[C@@H](N)C1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)[C@H]1C[C@@H](NCc2ccc(-c3noc(-c4ccc(C)cc4)n3)cc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39495.4 %

Procedure:
A mixture of cis-3-amino-cyclobutanecarboxylic acid ethyl ester hydrochloride (50.7 mg, 0.282 mmol), triethylamine (0.058 mL, 0.423 mmol) and THF (2.5 mL) was stirred at room temperature for 30 minutes. 4-[5-(4-Methylphenyl)-1,2,4-oxadiazol-3-yl]benzaldehyde (74.5 mg, 0.282 mmol) and AcOH (0.50 mL) were added to the reaction mixture and stirred for 30 minutes. Sodium cyanoborohydride (35.4 g, 0.563 mmol) was added to the reaction mixture, stirred for 18 hours, quenched with sat. NaHCO3 and extracted with ethyl acetate. The organic phase was concentrated in vacuo. Purification by flash chromatography (silica, 2:8 EtOAc:hexanes) provided the title compound (43.6 g, 39.8% yield) as a solid.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][N:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:13][O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C=O)C.C(OCC)C>[CH2:15]([O:14][CH2:13][N:2]1[N:3]=[N:4][CH:5]=[N:1]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH2:15]([O:14][CH2:13][N:1]1[CH:5]=[N:4][NH:3][NH:2]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: c1nnn[nH]1
Reactant: ClCOCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C1=NNNN1COCc1ccccc1
Product: c1ccc(COCn2ncnn2)cc1
Reaction time: 4 h
Yield: 44 %
Yield: 47 %

Procedure:
A suspension of 1-H-tetrazole (2.0 g, 28.5 mmol) and potassium carbonate (5.9 g, 42.7 mmol) in DMF (30 mL) was treated with benzyl chloromethyl ether (5.36 g, 34.2 mmol), and the mixture was stirred for 4 hours. Analysis by LC/MS indicated that the reaction was not complete, so the reaction was treated with benzyl chloromethyl ether (0.5 g, 3.19 mmol) and stirred for about 16 h. After this time, the mixture was filtered, and the filtrate was concentrated in vacuo to yield a residue. The residue was diluted with diethyl ether (200 mL), washed 5× with water (50 mL), once with brine, dried over sodium sulfate, and concentrated in vacuo to yield a residue. The residue was purified over a 6×20 mm silica gel column, eluting with 20% then 30% ethyl acetate/hexanes to yield the title compound (2.39 g, 44% yield), and 1-(benzyloxymethyl)-2H-tetrazole (2.56 g, 47% yield).
Reaction SMILES: O1CCCC1.CO.[C:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]([CH2:21][CH2:22][CH2:23][C@H:24]1[C@@H:32]2[C@@H:27]([NH:28][C:29]([NH:31]2)=[O:30])[CH2:26][S:25]1)[C:18]([NH2:20])=[O:19])([O:10]C)=[O:9].[OH-].[Na+]>O>[C:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]([CH2:21][CH2:22][CH2:23][C@H:24]1[C@@H:32]2[C@@H:27]([NH:28][C:29]([NH:31]2)=[O:30])[CH2:26][S:25]1)[C:18]([NH2:20])=[O:19])([OH:10])=[O:9]
Reactant: COC(=O)CCCCCC(CCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21)C(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)C(CCCCCC(=O)O)CCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Temperature: 40 °C

Procedure:
To a mixture of 25 mL of tetrahydrofuran and 25 mL of methanol, was dissolved 5-carbomethoxypentyl-D-biotinamide (800 mg, 2.15 mmol) obtained in Production Example 5-2, followed by addition of a solution of sodium hydroxide (2.33 g, 58.3 mmol) in water (12.5 mL) dropwise at room temperature. After the addition was completed, the mixture was heated to 40° C. and reacted for 2 hours.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:19][CH3:20])[C@:4]1([CH3:18])[C@H:9]2[O:10][C@H:8]2[C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]=2[O:5]1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH:29][CH2:30][C:31]1[NH:32][CH:33]=[CH:34][N:35]=1>>[CH3:1][O:2][CH:3]([O:19][CH3:20])[C@:4]1([CH3:18])[C@@H:9]([OH:10])[C@H:8]([N:29]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[O:22][CH3:21])[CH2:30][C:31]2[NH:35][CH:34]=[CH:33][N:32]=2)[C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]=2[O:5]1
Reactant: COc1ccccc1NCc1ncc[nH]1
Reactant: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@@H]2O[C@@H]21
Product: COc1ccccc1N(Cc1ncc[nH]1)[C@@H]1c2cc([N+](=O)[O-])ccc2O[C@](C)(C(OC)OC)[C@H]1O
Yield: 82.6 %

Procedure:
The title compound (500 mg, 58%) was prepared using (2S,3S,4S)-3,4-dihydro-2-dimethoxymethyl-3,4-epoxy-2-methyl-6-nitro-2H-1-benzopyran (500 mg, 1.78 mmol) and 2-methoxyphenyl-1H-imidazol-2-ylmethylamine (253 mg, 1.25 mmol), according to the same procedure used for the preparation of example 1 above.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:14]([O:16][C:17]1[C:24]([O:25][CH2:26][CH3:27])=[C:23]([O:28][CH2:29][CH3:30])[CH:22]=[CH:21][C:18]=1[CH:19]=O)[CH3:15].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClCCl.C(O)(=O)C>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([CH2:19][C:18]2[CH:21]=[CH:22][C:23]([O:28][CH2:29][CH3:30])=[C:24]([O:25][CH2:26][CH3:27])[C:17]=2[O:16][CH2:14][CH3:15])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CCOc1ccc(C=O)c(OCC)c1OCC
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOc1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)c(OCC)c1OCC
Temperature: 20 °C
Reaction time: 12 h

Procedure:
The synthesis is carried out in argon condition. 1.1 g (5.9 mmol) of N-Boc-piperazine and 1.40 g (5.9 mmol) of 2,3,4-triethoxybenzaldehyde are mixed in 25 ml of dry dichloromethane. After dissolution 2 drops of acetic acid is added, then 2.12 g (10 mmol) of NaBH(OAc)3 is added and the mixture is stirred for 12 h at 20° C. Then 10 ml of 5% NaHCO3 aqueous solution is added dropwise with care to the reaction mixture. The organic layer is separated, washed with 5% Na2CO3 solution, dried over sodium sulfate, filtered off and concentrated in vacuum at 50÷80° C. The residue (2.2 g of yellowish oil) is used on the next step.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[CH3:15][C:16]1[O:20][C:19]([CH2:21][NH2:22])=[CH:18][CH:17]=1.Br[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1>>[CH3:15][C:16]1[O:20][C:19]([CH2:21][NH:22][C:8]2[CH:7]=[CH:6][C:5]3[C:4]([NH:1][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=2)=[CH:18][CH:17]=1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Reactant: Brc1ccccn1
Reactant: Cc1ccc(CN)o1
Product: Cc1ccc(CNc2ccc3c(Nc4ccccn4)cccc3n2)o1

Procedure:
The title compound, MS: m/e=331.4 (M+H+), was prepared in accordance with the general method of example 38 from 5-nitro-2-chloroquinoline, 5-methyl-2-furanmethanamine and 2-bromopyridine.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH2:16][CH2:15]1.[C:25]([CH2:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)#[N:26].[C:37](=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.CCOC(C)=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>[CH2:23]([S:20]([N:17]1[CH2:18][CH2:19][CH:14]([C:5]2[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=[C:2]([C:31]4[CH:32]=[CH:33][C:28]([CH2:27][CH2:25][NH:26][CH3:37])=[CH:29][CH:30]=4)[CH:3]=3)[NH:7][CH:6]=2)[CH2:15][CH2:16]1)(=[O:22])=[O:21])[CH3:24]
Reactant: O=C([O-])[O-]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reactant: N#CCc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CCNC)cc4)cc23)CC1
Temperature: 160 °C

Procedure:
To a solution of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (200 mg, 0.48 mmol) in dioxane and H2O was added was added [4-(cyanomethyl)phenyl]boronic acid (232 mg, 0.144 mmol), potassium carbonate (400 mg, 2.88 mmol), and tetrakis(triphenylphosphine)palladium (0) (30 mg, 0.048 mmol). The solution was stirred and heated in the microwave at 160° C. for 40 min. The reaction was diluted with EtOAc and H2O and filtered to obtain a yellow crystal as desired product. The solution was washed with brine and H2O and then EtOAc was concentrated. To the reside was added MeOH which precipitated the desired product and then washed again with MeOH to give 5-[4-(cyanomethyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:8]([CH2:21][OH:22])=[N:9][N:10]([CH2:12][CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[CH:11]=2)[N:5]=[C:4]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:3]=1.N1C=CN=C1.Cl[Si:33]([CH:40]([CH3:42])[CH3:41])([CH:37]([CH3:39])[CH3:38])[CH:34]([CH3:36])[CH3:35]>CN(C=O)C>[C:23]([C:4]1[CH:3]=[C:2]([NH2:1])[N:6]([C:7]2[C:8]([CH2:21][O:22][Si:33]([CH:40]([CH3:42])[CH3:41])([CH:37]([CH3:39])[CH3:38])[CH:34]([CH3:36])[CH3:35])=[N:9][N:10]([CH2:12][CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[CH:11]=2)[N:5]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: CC(C)(C)c1cc(N)n(-c2cn(CCOC3CCCCO3)nc2CO)n1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)[Si](OCc1nn(CCOC2CCCCO2)cc1-n1nc(C(C)(C)C)cc1N)(C(C)C)C(C)C
Yield: 77 %

Procedure:
A solution of Intermediate 74e (0.39 g, 1.10 mmol) in DMF (3.9 mL) was treated with imidazole (0.18 g, 2.7 mmol) then chlorotriisopropylsilane (0.28 mL, 1.3 mmol) and the mixture was stirred at RT for 22 h. The mixture was evaporated in vacuo and the residue was partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (2×). The combined organic layers were washed with saturated aqueous sodium bicarbonate solution and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-4% MeOH in DCM, to give the title compound (0.44 g, 79%). LCMS (Method 3): Rt 4.20 min, m/z 520 [MH+].
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:11][C@H:12]([CH:16]([CH3:18])[CH3:17])[C:13]([NH2:15])=[O:14])[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C.O>O1CCOCC1>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[CH2:31][CH2:30][N:29]([C:2]3[N:3]=[C:4]([NH:11][C@H:12]([CH:16]([CH3:18])[CH3:17])[C:13]([NH2:15])=[O:14])[C:5]4[S:10][CH2:9][CH2:8][C:6]=4[N:7]=3)[CH2:28][CH2:27]2)=[CH:24][CH:25]=1
Reactant: CC(C)[C@@H](Nc1nc(Cl)nc2c1SCC2)C(N)=O
Reactant: Clc1ccc(N2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: O
Product: CC(C)[C@@H](Nc1nc(N2CCN(c3ccc(Cl)cc3)CC2)nc2c1SCC2)C(N)=O
Temperature: 160 °C
Yield: 88.2 %

Procedure:
400 mg (R)-2-(2-chloro-6,7-dihydro-thieno[3,2-d]pyrimidin-4-ylamino)-3-methyl-butyramide, 750 mg 1-(4-chloro-phenyl)-piperazine and 1.2 ml diisopropylethylamine are placed in 9 ml dioxane, then heated in the microwave for 1 hour and 45 minutes at 160° C. Then water is added. The precipitate formed is suction filtered and dried. 550 mg of the product are obtained as a powder. Analytical HPLC (method B): RT=3.03 min.
Reaction SMILES: CS([O:5][C@@H:6]1[CH2:10][CH2:9][N:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[C:7]1=[O:24])(=O)=O.[Br:25][C:26]1[CH:31]=[CH:30][C:29](O)=[C:28]([F:33])[CH:27]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[Br:25][C:26]1[CH:31]=[CH:30][C:29]([O:5][C@H:6]2[CH2:10][CH2:9][N:8]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[C:7]2=[O:24])=[C:28]([F:33])[CH:27]=1
Reactant: Oc1ccc(Br)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC(N2CC[C@@H](OS(C)(=O)=O)C2=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(N2CC[C@H](Oc3ccc(Br)cc3F)C2=O)CC1
Temperature: 70 °C
Yield: 83 %

Procedure:
(R)-tert-Butyl 4-(3-(methylsulfonyloxy)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (Preparation D; 1.7 g, 4.7 mmol) was dissolved in dry DMSO (30 mL) and 4-bromo-2-fluorophenol (1.1 g, 5.6 mmol) and K2CO3 (0.78 g, 5.6 mmol) was added and the reaction heated to 70° C. under nitrogen. The reaction became purple then black. The reaction was cooled to ambient temperature after 3 hours and partitioned between water and EtOAc, extracted with EtOAc, washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified over silica gel (40% EtOAc in hexanes) to afford (S)-tert-butyl 4-(3-(4-bromo-2-fluorophenoxy)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (1.8 g, 3.9 mmol, 84% yield) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8][CH3:9])[C:3]=1[Cl:10].I([O-])(=O)(=O)=[O:12].[Na+].C(=O)([O-])[O-].[Na+].[Na+].C(Cl)(Cl)(Cl)Cl.C(#N)C.[OH2:31]>[Ru](Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([CH3:9])(=[O:12])=[O:31])[C:3]=1[Cl:10]
Reactant: O
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CSc1cccc(Br)c1Cl
Agent: Cl[Ru](Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Product: CS(=O)(=O)c1cccc(Br)c1Cl

Procedure:
To a mixture of 1-bromo-2-chloro-3-(methylthio)benzene (1.23 g, 5.2 mmol) and sodium periodate (3.3 g, 15.6 mmol) in carbon tetrachloride/acetonitrile/water (1:1:2, 30 ml) was added ruthenium trichloride (1 mg, 0.05 mol %). The resulting mixture was stirred at ambient temperature for 20 min after which aqueous sodium carbonate (10%, 50 ml) was added and the mixture was extracted with ethylacetate (3×100 ml). The combined organic phases was dried (MgSO4), filtered and evaporated to dryness to give the title compound (1.4 g). MS m/z (rel. intensity, 70 eV) 270 (M+, 66), 268 (M+, 48), 208 (65), 190 (77), 75 (bp).
Reaction SMILES: [CH3:1][C:2](=[N:4][OH:5])[CH3:3].[H-].[Na+].[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([N+]([O-])=O)[CH:11]=1.O>CN(C=O)C>[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([O:5][N:4]=[C:2]([CH3:3])[CH3:1])[CH:11]=1
Reactant: COc1ccc(C#N)c([N+](=O)[O-])c1
Reactant: CC(C)=NO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C#N)c(ON=C(C)C)c1
Reaction time: 0.5 h
Yield: 87.2 %

Procedure:
In 20 ml of DMF was dissolved acetone oxime (0.74 g), followed by sodium hydride (0.30 g). After this mixture had stirred for 30 minutes, 4-methoxy-2-nitro-benzonitrile (1.50 g) was added. After an additional 30 minutes the reaction was poured into water (500 ml) and filtered. The solid was collected and dissolved in DCM (250 ml), dried (MgSO4), and concentrated in vacuo. The resulting solid was recrystallized from ethanol to yield 1.5 g of 4-methoxy-2-[[(1-methylethylidene)amino]oxy]benzonitrile, m.p. 78°-79° C.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH2:27][C:28]#[N:29])=[CH:17][CH:16]=2)[C:7]([CH2:11][O:12][CH3:13])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].[NH:30]1C=N[N:32]=[N:31]1.CCCCCC.C(OCC)(=O)C>C(OCC)(=O)C.C(O)(C)C>[CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH2:27][C:28]3[NH:32][N:31]=[N:30][N:29]=3)=[CH:19][CH:20]=2)[C:7]([CH2:11][O:12][CH3:13])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: c1nnn[nH]1
Reactant: CCCCc1nc(Cl)c(COC)n1Cc1ccc(-c2ccccc2CC#N)cc1
Solvent: CC(C)O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCCc1nc(Cl)c(COC)n1Cc1ccc(-c2ccccc2Cc2nnn[nH]2)cc1

Procedure:
2-n-Butyl-4-chloro-1-[(2'-(cyanomethyl)biphenyl-4-yl)methyl]-5-(methoxymethyl)imidazole (5.20 g) was converted to the above tetrazole in 2 days using the procedure of Example 90, Part C. Work-up and flash chromatography over silica gel eluting with a gradient solvent system of 1:1 hexane/ethyl acetate to 1:1 ethyl acetate/isopropanol yielded 3.13 g of a light yellow solid; m.p. 149.0°-152.5°. NMR (200 MHz, CDCl3) δ 7.37-7.15 (m, 6H); 6.96 (d, 2H, J=9 Hz); 5.18 (s, 2H); 4.30 (s, 2H); 4.24 (s, 2H); 3.27 (s, 3H); 2.57 (t, 2H, J=7 Hz); 1.56 (t of t, 2H, J=7,7 Hz); 1.28 (t of q, 2H, J=7,7 Hz); 0.77 (t, 3H, J=7 Hz). Anal. Calcd. for C24H 27 ClN6O: C, 63.97, H, 6.03; Cl, 7.86. Found: C, 63.79; H, 6.04; Cl, 7.70.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[C:6]([CH3:11])[CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:12][N:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[N:15]([CH:22]([CH2:27][O:28][CH3:29])[CH2:23][C:24]([OH:26])=O)[C:14]2=[O:30])=[CH:3]1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:43][N:44]1[CH:48]=[C:47]([S:49]([NH2:52])(=[O:51])=[O:50])[N:46]=[CH:45]1.C1CCN2C(=NCCC2)CC1.Cl>O.C1COCC1>[CH3:1][N:2]1[C:10]2[C:5](=[C:6]([CH3:11])[CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:12][N:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[N:15]([CH:22]([CH2:27][O:28][CH3:29])[CH2:23][C:24]([NH:52][S:49]([C:47]3[N:46]=[CH:45][N:44]([CH3:43])[CH:48]=3)(=[O:51])=[O:50])=[O:26])[C:14]2=[O:30])=[CH:3]1
Reactant: Cn1cnc(S(N)(=O)=O)c1
Reactant: COCC(CC(=O)O)n1c(=O)n(Cc2cn(C)c3cccc(C)c23)c2ccccc21
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COCC(CC(=O)NS(=O)(=O)c1cn(C)cn1)n1c(=O)n(Cc2cn(C)c3cccc(C)c23)c2ccccc21
Temperature: 55 °C
Reaction time: 16 h
Yield: 41.7 %

Procedure:
3-[3-(1,4-Dimethyl-1H-indol-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-4-methoxy-butyric acid (30 mg, 0.074 mmol) is dissolved THF (0.70 mL) and CDI (27 mg, 0.17 mmol) is added into it at room temperature. The mixture is heated at 55° C. for 1 hr. After the mixture is cooled down to room temperature, 1-Methyl-1H-imidazole-4-sulfonic acid amide (24 mg, 0.15 mmol) is added and after 10 min, DBU (0.022 mL, 0.15 mmol) is added. The mixture is stirred for 16 hr at room temperature. 2.0 mL of 1.0 M HCl is added followed by 20 mL of water. The mixture is extracted with EtOAc (3×25 mL) and the organic layers are combined, dried and concentrated to give crude product. Purification by flash column chromatography affords 17 mg (41%) of 1-Methyl-1H-imidazole-4-sulfonic acid {3-[3-(1,4-dimethyl-1H-indol-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-4-methoxy-butyryl}-amide. LCMS (ESMS): m/z 551.25 (M+H+).