Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[Cl:16][C:17]1[CH:22]=[N:21][CH:20]=[C:19]([O:23][CH3:24])[N:18]=1.CN(C)[CH:27]=[O:28]>O1CCCC1.O.C(O)(=O)C.C1(C)C=CC=CC=1>[Cl:16][C:17]1[N:18]=[C:19]([O:23][CH3:24])[C:20]([CH:27]=[O:28])=[N:21][CH:22]=1
Reactant: CN(C)C=O
Reactant: COc1cncc(Cl)n1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: COc1nc(Cl)cnc1C=O
Temperature: -30 °C
Reaction time: 0.25 h
Yield: 77 %

Procedure:
After dissolving 11.4 ml of 2,2,6,6-tetramethylpiperidine in 100 ml of tetrahydrofuran, the solution was cooled to −30° C. Next, 24.1 ml of n-butyllithium (2.6 M, n-hexane solution) was added dropwise under a nitrogen atmosphere. After stirring for 15 minutes and cooling on ice, the mixture was stirred for 10 minutes. It was then cooled to −78° C., and a solution of 6.96 g of 2-chloro-6-methoxypyrazine in tetrahydrofuran (10 ml) was added dropwise at below −70° C. The mixture was stirred for 30 minutes, and then 6 ml of N,N-dimethylformamide was added dropwise at below −65° C. After 10 minutes, 50 ml of toluene was added to the reaction solution at below −60° C., and then after 2 minutes, a tetrahydrofuran solution (5 ml) containing 2 ml of water was added at below −65° C. After an additional 5 minutes, 60 ml of 50% aqueous acetic acid was added at once, and then after 15 minutes, 100 ml of water was added and the temperature was raised to room temperature. The reaction solution was extracted with ethyl acetate, and the organic layer was washed with water, a 1N sodium hydroxide solution and saturated brine in that order and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (6.38 g, 77% yield).
Reaction SMILES: [CH2:1]([NH:9][C:10]([C:12]1[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:24][NH2:25])=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:11])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N+:26]([C:29]1[CH:30]=[C:31]([S:35](Cl)(=[O:37])=[O:36])[CH:32]=[CH:33][CH:34]=1)([O-:28])=[O:27].C(NC(C1C(C2C=CC=CC=2C(S(C2C=CC=C([N+]([O-])=O)C=2)(=O)=O)N)=CC=CC=1)=O)CC1C=CC=CC=1>>[CH2:1]([NH:9][C:10]([C:12]1[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:24][NH:25][S:35]([C:31]2[CH:32]=[CH:33][CH:34]=[C:29]([N+:26]([O-:28])=[O:27])[CH:30]=2)(=[O:36])=[O:37])=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:11])[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: NCc1ccccc1-c1ccccc1C(=O)NCCc1ccccc1
Agent: NC(c1ccccc1-c1ccccc1C(=O)NCCc1ccccc1)S(=O)(=O)c1cccc([N+](=O)[O-])c1
Product: O=C(NCCc1ccccc1)c1ccccc1-c1ccccc1CNS(=O)(=O)c1cccc([N+](=O)[O-])c1

Procedure:
From 0.61 mmol of 2′-aminomethylbiphenyl-2-carboxylic acid phenethylamide (precursor 5a) and 3-nitrophenylsulfonyl chloride, according to the general working procedure 272 mg of 2′-(3-nitrophenylsulfonyl-aminomethyl)biphenyl-2-carboxylic acid phenethylamide were obtained; m.p. 145° C. MS (ES+): m/e=516 (M+1).
Reaction SMILES: S([O-])([O-])(=O)=O.[Na+].[Na+].[NH2:8][C:9]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:10]=1[C:11]([NH:13][CH:14]([CH:16]1[CH2:18][CH2:17]1)[CH3:15])=[O:12].[Br:24][C:25]1[CH:29]=[C:28]([C:30](=[O:39])SCC2C=CC=CC=2)[N:27]([C:40]2[C:45]([Cl:46])=[CH:44][CH:43]=[CH:42][N:41]=2)[N:26]=1.CC(C)([O-])C.[K+]>O.CS(C)=O>[Br:24][C:25]1[CH:29]=[C:28]([C:30]([NH:8][C:9]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:10]=2[C:11](=[O:12])[NH:13][CH:14]([CH:16]2[CH2:18][CH2:17]2)[CH3:15])=[O:39])[N:27]([C:40]2[C:45]([Cl:46])=[CH:44][CH:43]=[CH:42][N:41]=2)[N:26]=1
Reactant: CC(NC(=O)c1cc(Cl)ccc1N)C1CC1
Reactant: O=C(SCc1ccccc1)c1cc(Br)nn1-c1ncccc1Cl
Agent: CC(C)(C)[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(NC(=O)c1cc(Cl)ccc1NC(=O)c1cc(Br)nn1-c1ncccc1Cl)C1CC1
Reaction time: 0.08 h
Yield: 41.9 %

Procedure:
0.85 g of anhydrous sodium sulfate was added to a mixed solution comprising 0.24 g of 2-amino-5-chloro-N-(1-cyclopropylethyl)benzamide, 0.41 g of S-benzyl 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carbothioate and 5 ml of dimethyl sulfoxide at room temperature, followed by stirring for 5 minutes, and 0.14 g of potassium tert-butoxide was added, followed by reaction at room temperature for 1 hour. The reaction liquid was slowly added to water, the mixed liquid was subjected to extraction with ethyl acetate, and the organic layer was washed with a sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=9/1 to 7.5/2.5) to obtain 0.22 g of the desired product.
Reaction SMILES: [CH2:1]([N:8]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:9][CH2:10][C:11]([CH3:14])([OH:13])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22](I)[CH3:23]>C1COCC1>[CH2:15]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][CH2:10][C:11]([O:13][CH2:22][CH3:23])([CH3:14])[CH3:12])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(O)CCN(Cc1ccccc1)Cc1ccccc1
Reactant: CCI
Solvent: C1CCOC1
Product: CCOC(C)(C)CCN(Cc1ccccc1)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 11.9 %

Procedure:
Treat a 0° C. solution of 4-(dibenzylamino)-2-methylbutan-2-ol (13 g, 45.9 mmol) in THF (200 mL), under N2, portion wise with KH (30%, 6.7 g, 50.9 mmol), stir at 0° C. for 0.5 h, add ethyl iodide (8.5 g, 55 mmol) drop-wise and warm to 60° C. overnight. Cool to 0° C., quench with satd. NH4Cl and concentrate partially. Extract with EtOAc (3×), wash the combined organics with brine, dry over Na2SO4, concentrate and purify via silica gel chromatography to afford the title compound (1.7 g, 12%). 1H NMR (400 MHz, DMSO-d6): δ 7.36-7.21 (m, 10H), 3.52 (s, 4H), 3.13 (t, J=7.2 Hz, 2H), 2.40-2.36 (m, 2H), 1.68-1.64 (m, 2H), 0.99 (m, 6H), 0.83 (q, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]([NH2:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].ClCCl.Cl[CH2:17]/[CH:18]=[CH:19]\[CH2:20]Cl.CCCCCC>CCCCCC.C(OCC)(=O)C>[C:6]1([C@H:5]([N:12]2[CH2:20][CH:19]=[CH:18][CH2:17]2)[C:3]([O:2][CH3:1])=[O:4])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)[C@@H](N)c1ccccc1
Reactant: ClC/C=C\CCl
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](c1ccccc1)N1CC=CC1
Yield: 65.2 %

Procedure:
From L-phenylglycine methyl ester (808 mg, 4.89 mmol), dichloromethane (0.1 ml) and cis-1,4-dichloro-2-butene (170 mg, 1.39 mmol). Flash chromatography: silica gel, gradient neat hexane to hexane:ethyl acetate (1:2) afforded the product (197 mg, 65%) as colourless oil.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([C:8]2[CH:9]=[C:10]([C:21](O)=[O:22])[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)[CH:13]=2)=[O:7])[CH2:3]1.[F:24][C:25]([F:35])([F:34])[C:26]1[N:31]=[CH:30][C:29]([CH2:32][NH2:33])=[CH:28][CH:27]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[OH:1][CH:2]1[CH2:5][N:4]([C:6]([C:8]2[CH:9]=[C:10]([C:21]([NH:33][CH2:32][C:29]3[CH:30]=[N:31][C:26]([C:25]([F:35])([F:24])[F:34])=[CH:27][CH:28]=3)=[O:22])[CH:11]=[C:12]([C:14]3[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=3)[CH:13]=2)=[O:7])[CH2:3]1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)N3CC(O)C3)c2)cc1
Reactant: NCc1ccc(C(F)(F)F)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(C(=O)NCc3ccc(C(F)(F)F)nc3)cc(C(=O)N3CC(O)C3)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-(3-hydroxyazetidine-1-carbonyl)-4′-methylbiphenyl-3-carboxylic acid (80 mg, 0.26 mmol) in N,N-dimethylformamide (1.5 mL) were added C-(6-trifluoromethyl-pyridin-3-yl)-methylamine (70 mg, 0.40 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (200 mg, 0.53 mmol), and N,N-diisopropylethylamine (200 pt, 1.15 mmol). The reaction mixture was stirred for 16 hours at 25° C. The reaction mixture was purified by preparative HPLC to afford a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5](O)=[O:6].B.C1COCC1>C1COCC1>[NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[CH2:5][OH:6]
Reactant: Nc1cc(C(=O)O)ccc1F
Agent: B
Solvent: C1CCOC1
Product: Nc1cc(CO)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.1 %

Procedure:
3-Amino-4-fluorobenzoic acid (15 g, 97 mmol) in THF at 0° C. was treated with 1.0 M BH3.THF (50 mL), stirred overnight at room temperature, treated with an additional 130 mL 1.0 M BH3.THF, stirred 10 hours, quenched by the addition of methanol, stirred 3 hours at room temperature, solvent evaporated, the product partitioned between aqueous sodium bicarbonate/methylene chloride, the organic layer dried (sodium sulfate), filtered and solvent evaporated. The product was purified by flash chromatography over silica gel (ethyl acetate/hexane 1:1) to provide 7.0 g of the title compound.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:6][OH:7])[CH2:4][OH:5].Cl[C:9]([O:11][CH3:12])=[O:10]>ClCCl.N1C=CC=CC=1>[CH3:12][O:11][C:9]([O:1][CH2:2][CH:3]([CH2:6][OH:7])[CH2:4][OH:5])=[O:10]
Reactant: OCC(CO)CO
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)OCC(CO)CO
Temperature: 25 °C
Reaction time: 16 h
Yield: 42.1 %

Procedure:
To a solution of 2-(hydroxymethyl)-1,3-propanediol (9.4 mmol) in dichloromethane (20 mL) and pyridine (7.5 mL) at 0° C. was added methyl chloroformate (9.4 mmol) slowly. The resulting solution was warmed to room temperature and stirred for 16 h. The reaction was concentrated under reduced pressure and chromatographed by eluting with methanol-dichloromethane (1:4) to give 650 mg of 2-(methoxycarbonyloxymethyl)-1,3-propanediol.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][N:5]([CH2:7][C:8]2[CH:9]=NC(C)=N[CH:13]=2)[CH2:4][C@H:3]1[C:15]1[NH:16][C:17](=[O:30])[C:18]2[CH:23]=[N:22][N:21]([CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:19]=2[N:20]=1.C([BH3-])#N.[Na+].[F:35][C:36]1[CH:43]=CC(C=O)=C[CH:37]=1>>[F:35][C:36]1[CH:43]=[CH:13][C:8]([CH2:7][N:5]2[CH2:6][C@@H:2]([CH3:1])[C@H:3]([C:15]3[NH:16][C:17](=[O:30])[C:18]4[CH:23]=[N:22][N:21]([CH:24]5[CH2:25][CH2:26][O:27][CH2:28][CH2:29]5)[C:19]=4[N:20]=3)[CH2:4]2)=[CH:9][CH:37]=1
Reactant: Cc1ncc(CN2C[C@@H](C)[C@H](c3nc4c(cnn4C4CCOCC4)c(=O)[nH]3)C2)cn1
Reactant: O=Cc1ccc(F)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Product: C[C@@H]1CN(Cc2ccc(F)cc2)C[C@H]1c1nc2c(cnn2C2CCOCC2)c(=O)[nH]1

Procedure:
Following the procedure for the preparation of 6-{(3S,4S)-4-methyl-1-[(2-methylpyrimidin-5-yl)methyl]pyrrolidin-3-yl}-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one but substituting sodium cyanoborohydride and 4-fluorobenzaldehyde provided the title compound. 400 MHz 1H NMR (CDCl3) δ 8.02 (s, 1H), 7.36-7.33 (m, 2H), 7.05-7.01 (m, 2H), 4.82-4.77 (m, 1H), 4.14-4.09 (m, 2H), 3.79-3.76 (m, 1H), 3.62-3.54 (m, 3H), 3.34 (t, J=8.3 Hz, 1H), 2.99 (d, J=9.9 Hz, 1H), 2.85-2.83 (m, 1H), 2.60-2.55 (m, 1H), 2.45-2.30 (m, 3H), 1.99-1.82 (m, 3H), 1.20 (d, J=7.1 Hz, 3H). MS: (M+H m/z 412.1).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](Cl)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:27]3[C:22](=[N:23][CH:24]=[N:25][C:26]=3[NH2:28])[N:21]([CH:29]3[CH2:34][CH2:33][N:32]([CH:35]4[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]4)[CH2:31][CH2:30]3)[N:20]=2)=[CH:15][C:14]=1[O:42][CH3:43]>N1C=CC=CC=1>[NH2:28][C:26]1[N:25]=[CH:24][N:23]=[C:22]2[N:21]([CH:29]3[CH2:34][CH2:33][N:32]([CH:35]4[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]4)[CH2:31][CH2:30]3)[N:20]=[C:19]([C:16]3[CH:17]=[CH:18][C:13]([NH:12][C:9](=[O:10])[CH2:8][CH2:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[C:14]([O:42][CH3:43])[CH:15]=3)[C:27]=12
Reactant: COc1cc(-c2nn(C3CCN(C4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1N
Reactant: O=C(Cl)CCc1ccccc1
Solvent: c1ccncc1
Product: COc1cc(-c2nn(C3CCN(C4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1NC(=O)CCc1ccccc1
Reaction time: 5 h
Yield: 18.4 %

Procedure:
3-Phenylpropanoyl chloride (77 mg, 0.458 mmol) was added to a solution of 3-(4-amino-3-methoxyphenyl)-1-[1-(1-methylpiperidin-4-yl)-piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.229 mmol) in pyridine (1.2 mL). After 5 hours, the solvent was evaporated and the residue was purified by flash column chromatography to give N1-{4-[4-amino-1-[1-(1-methylpiperidin-4-yl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-3-phenylpropanamide (24 mg, 18%). 1H NMR (CDCl3-d) δ 1.70 (m, 2H), 1.85 (m, 2H), 2.04 (m, 4H), 2.30 (s, 3H), 2.41 (m, 5H), 2.75 (m, 2H), 2.97 (m, 2H), 3.08 (m, 4H), 3.90 (s, 3H), 4.75 (m, 1H), 5.71 (bs, 2H), 7.24 (m, 8H), 7.76 (s, 1H), 8.34 (s, 1H), 8.52 (d, J=8.12, 1H). LCMS (Finigan-Column: Pecosphere, C18, 3 um, 33×4.6 mm. Eluents: 0% B/A to 100% B/A in 4 min. (B: acetonitrile, A: 50 mM ammonia acetate buffer, PH 4.5), 3.0 mL/min.): MH+=569.5, Rt=1.65 min.
Reaction SMILES: NCCC[Si]([O:12][CH2:13][CH3:14])(OCC)OCC.Cl.[OH2:16]>>[O:16]=[CH:14][C@@H:13]([C@H:14]([C@@H:13]([C@@H:14]([CH2:13][OH:12])[OH:16])[OH:12])[OH:16])[OH:12]
Reactant: O
Reactant: CCO[Si](CCCN)(OCC)OCC
Agent: Cl
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reaction time: 3 h

Procedure:
The three wafers with porous silicon and a wafer of polished silicon introduced for comparative purposes were silanised in a cup containing 3-aminopropyltriethoxysilane (Sigma Chemical Co, St Louis, US) and 1 g of APTES in 9 ml of water, the pH value being adjusted to 3.5 with the aid of 6 M HCl. The silanisation was performed in a water bath at 75° C. for 3 h and was followed by abundant washing with water for 30 min. Careful agitation took place during each stage of the immobilisation process. Then, the wafers were placed in a solution of 2.5% glutaraldehyde (GA) (grade II, Sigma Chemical Co, St Louis, US) in 0.1 M phosphate buffer (PBS) for 2 h. The GA activation was followed by washing with PBS for 30 min. Finally, glucose oxidase (GOD) was associated with the wafers as a result of a treatment with 10 mg of glucose oxidase (EC 1.1.3.4, type X-S, Aspergillus niger) in 2 ml of PBS overnight (8 h), which was followed by washing in PBS for 1 h.
Reaction SMILES: N1C=CC=CC=1C(O)=O.[NH2:10][C:11]1[C:16]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[CH:15][CH:14]=[CH:13][N:12]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[CH3:40])[CH:34]=1>[Cu]I.CS(C)=O>[F:41][C:39]([C:35]1[CH:34]=[C:33]([CH:38]=[CH:37][CH:36]=1)[O:23][C:20]1[CH:21]=[CH:22][C:17]([C:16]2[C:11]([NH2:10])=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:18][CH:19]=1)([F:42])[CH3:40]
Reactant: Nc1ncccc1-c1ccc(O)cc1
Reactant: CC(F)(F)c1cccc(Br)c1
Agent: [Cu]I
Agent: O=C(O)c1ccccn1
Agent: O=P([O-])([O-])[O-]
Solvent: CS(C)=O
Product: CC(F)(F)c1cccc(Oc2ccc(-c3cccnc3N)cc2)c1
Temperature: 130 °C
Reaction time: 10 h
Yield: 56.9 %

Procedure:
Copper(I) iodide (102 mg) was added to a mixture of picolinic acid (66.1 mg), 4-(2-aminopyridin-3-yl)phenol (500 mg), tripotassium phosphate (1710 mg), 1-bromo-3-(1,1-difluoroethyl)benzene (712 mg) and DMSO (8 mL). The mixture was stirred at 130° C. under nitrogen for 10 hr. Activated carbon was added and the insoluble solid was removed by filtration through NH-silica gel/Celite pad (eluted with EtOAc). Silica-gel was added to the filtrate and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (NH-silica gel, eluted with EtOAc in hexane) and concentrated. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (499 mg) as pale yellow oil.
Reaction SMILES: S(O)(=O)(=O)C.[NH2:6][C:7]1[C:8]2[N:9]([C:16]([CH3:20])=[C:17]([CH3:19])[N:18]=2)[CH:10]=[C:11]([C:13]([NH2:15])=[O:14])[CH:12]=1.[CH2:21]([C:23]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31]C)[C:24]=1[CH2:25]Cl)C.C(N(C(C)C)CC)(C)C.O>CN(C)C=O.C(Cl)Cl>[CH3:19][C:17]1[N:18]=[C:8]2[C:7]([NH:6][CH2:25][C:24]3[C:27]([CH3:31])=[CH:28][CH:29]=[CH:30][C:23]=3[CH3:21])=[CH:12][C:11]([C:13]([NH2:15])=[O:14])=[CH:10][N:9]2[C:16]=1[CH3:20]
Reactant: CCc1cccc(CC)c1CCl
Reactant: Cc1nc2c(N)cc(C(N)=O)cn2c1C
Agent: CS(=O)(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(C)c1CNc1cc(C(N)=O)cn2c(C)c(C)nc12
Yield: 53.3 %

Procedure:
8-Amino-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxamide mesylate (4.0 g, 10.7 mmol), 2,6-diethylbenzylchloride (1.8 g, 9.9 mmol), diisopropylethylamin (3.0 g, 23.3 mmol) were stirred in dimethylformamide (20 ml) at 50° C. overnight and at 70° C. for 3 h. Water (60 ml) and methylene chloride were added and the organic layer was separated, dried and evaporated under reduced pressure. The residue was treated with diethyl ether and the product was filtred off to give 1.7 g (45%) of the title compound.
Reaction SMILES: [Si](O[C@H](C)[C@@H](NC1C=CC(C#N)=C(Cl)C=1C)C1OC(C2C=CC(O[Si](C(C)(C)C)(C)C)=CC=2)=NN=1)(C(C)(C)C)(C)C.[Si:42]([O:49][C:50]1[CH:83]=[CH:82][C:53]([C:54]([NH:56][NH:57][C:58](=[O:81])[C@H:59]([NH:70][C:71]2[CH:76]=[CH:75][C:74]([C:77]#[N:78])=[C:73]([Cl:79])[C:72]=2[CH3:80])[C@@H:60]([O:62][Si:63]([C:66]([CH3:69])([CH3:68])[CH3:67])([CH3:65])[CH3:64])[CH3:61])=O)=[CH:52][C:51]=1[F:84])([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>>[Si:63]([O:62][C@@H:60]([CH3:61])[C@@H:59]([NH:70][C:71]1[CH:76]=[CH:75][C:74]([C:77]#[N:78])=[C:73]([Cl:79])[C:72]=1[CH3:80])[C:58]1[O:81][C:54]([C:53]2[CH:82]=[CH:83][C:50]([O:49][Si:42]([C:45]([CH3:46])([CH3:47])[CH3:48])([CH3:43])[CH3:44])=[C:51]([F:84])[CH:52]=2)=[N:56][N:57]=1)([C:66]([CH3:69])([CH3:67])[CH3:68])([CH3:65])[CH3:64]
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(O[Si](C)(C)C(C)(C)C)c(F)c2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Agent: Cc1c(N[C@@H](c2nnc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)o2)[C@@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(O[Si](C)(C)C(C)(C)C)c(F)c3)o2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl

Procedure:
Intermediate 29e was prepared by a procedure analogous to that used for the preparation of intermediate 10c by cyclization of 4-(tert-butyldimethylsilyloxy)-N′-((2R,3S)-3-(tert-butyldimethylsilyloxy)-2-(3-chloro-4-cyano-2-methylphenylamino)butanoyl)-3-fluoro benzohydrazide (640 mg, 0.99 mmol) with PS-PPh3 (3.0 mmol/g, 661 mg, 1.98 mmol), 12 (502 mg, 1.98 mmol), and TEA (1.4 mL, 10 mmol). After column chromatography (25% EtOAc/hexanes) the title compound was isolated as a white solid (131 mg, 21%). 1H NMR (400 MHz, CDCl3, δ in ppm) 7.65 (m, 1H), 7.59 (m, 1H), 7.32 (d, J=8.6 Hz, 1H), 6.9 (t, J=8.3 Hz, 1H), 6.45 (d, J=8.8 Hz, 1H), 5.35 (d, J=8.6 Hz, 1H), 4.77 (dd, J=1.9, 8.7 Hz, 1H), 4.51 (m, 1H), 2.36 (s, 3H), 1.40 (d, J=6.1 Hz, 3H), 0.99 (s, 9H), 0.86 (s, 9H), 0.21 (s, 6H), 0.06 (s, 3H), −0.20 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:17]C)=[C:6]([S:8]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:7]=1.BrB(Br)Br.CO>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:17])=[C:6]([S:8]([N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)(=[O:9])=[O:10])[CH:7]=1
Reactant: COc1ccc(F)cc1S(=O)(=O)N1CCOCC1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: O=S(=O)(c1cc(F)ccc1O)N1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.8 %

Procedure:
To a solution of 4-(5-fluoro-2-methoxyphenylsulfonyl)morpholine (0.5 g 1.8 mmol) in CH2Cl2 (10 ml) was added dropwise a solution of tribromoborane (0.593 mg 2.36 mmol) in CH2Cl2 (20 ml) at 0° C. The mixture was stirred at room temperature for 1 h, after which methanol (10 ml) was added to quench the reaction. The solvent was evaporated under reduced pressure and ethyl acetate (30 ml) was added, washed with water and then brine, dried and concentrated into dryness to give the product (427 mg, 90% yield).
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][C:7]=1[F:13])=[O:5]>O1CCOCC1.O1CCCC1.C(OCC)(=O)C>[Br:1][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][C:7]=1[F:13])=[O:5]
Reactant: BrBr
Reactant: CC(=O)c1ccc(Br)cc1F
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C(CBr)c1ccc(Br)cc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Bromine (0.54 mL, 10.6 mmol) was added dropwise to a cold (0° C.) solution of 4-bromo-2-fluoroacetophenone (2.30 g, 10.6 mmol) in dioxane (80 mL) and tetrahydrofuran (80 mL). The mixture was stirred for 1 h at 0° C. and warmed to RT for 15 h. The mixture was diluted with ethyl acetate, washed with saturated NaHCO3 solution, 5% sodium thiosulfate solution and brine prior to drying (Na2SO4). 2-Bromo-1-(4-bromo-2-fluorophenyl)ethanone (D1) was isolated as a colorless film which solidified upon further concentration under high vacuum. This solid was dissolved into anhydrous acetonitrile (50 mL) and treated with N-Boc-L-proline (2.28 g, 10.6 mmol) and diisopropylethylamine (1.85 mL, 10.6 mmol). After being stirred for 3 h at RT, the solvent was removed in vacuo and the residue was partitioned into ethyl acetate and water. The organic phase was washed with 0.1N hydrochloric acid, saturated NaHCO3 solution and brine prior to drying (Na2SO4), filtration, and concentration. This residue was taken up in xylenes (50 mL) and treated to solid NH4OAc (4.1 g, 53.0 mmol). The mixture was heated at 140° C. for 2 hr in a thick-walled, screw-top flask before it was cooled to ambient temperature, diluted with ethyl acetate and washed with saturated NaHCO3 solution and brine prior to drying (Na2SO4) and concentration. Purification of the residue by Biotage™ flash chromatography on silica gel (65M column, preequilibration with 16% B for 1800 mL followed by gradient elution with 16% B to 16% B for 450 mL, 16% B to 50% B for 2199 ml and finally 50% B to 100% B for 2199 mL) afforded title compound (D5) (3.61 g, 83%) as a brownish/caramel-colored oil. A small portion (40 mg) of the title compound was further purified by preparative HPLC (20% B to 100% B over 14 min where B is 10 mM NH4OAc in 10:90 H2O/ACN and A is 10 mM NH4OAc in 95:5 H2O/CAN using a Phenomenex-Gemini 30×100 mm S10 column flowing at 40 mL/min) to afford pure title compound (31.8 mg) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[NH:12][C:13]([C:15]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][NH:17][N:16]=1)=O>C(O)(=O)C>[CH3:11][O:10][C:5]1[C:6]([O:8][CH3:9])=[CH:7][C:2]2[NH:1][C:13]([C:15]3[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][NH:17][N:16]=3)=[N:12][C:3]=2[CH:4]=1
Reactant: COc1cc(N)c(NC(=O)c2n[nH]cc2[N+](=O)[O-])cc1OC
Solvent: CC(=O)O
Product: COc1cc2nc(-c3n[nH]cc3[N+](=O)[O-])[nH]c2cc1OC
Temperature: 140 °C
Yield: 94 %

Procedure:
4-Nitro-1H-pyrazole-3-carboxylic acid (2-amino-4,5-dimethoxy-phenyl)-amide (2.35 g, 7.65 mmol) was dissolved in acetic acid (150 ml) and refluxed at 140° C. for 5 hours. The solution was left to cool and the solvent removed in vacuo. The resulting solid was partitioned between ethyl acetate (25 ml) and brine (25 ml). The organic layer was separated, dried (MgSO4), filtered and the solvent removed in vacuo to yield 5,6-dimethoxy-2-(4-nitro-1H-pyrazol-3-yl)-1H-benzimidazole (2.08 g, 94%).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[N:7]=[CH:8][NH:9][C:10](=O)[C:5]=2[S:4][CH:3]=1.O=P(Cl)(Cl)[Cl:14]>>[Cl:14][C:10]1[C:5]2[S:4][CH:3]=[C:2]([CH3:1])[C:6]=2[N:7]=[CH:8][N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1csc2c(=O)[nH]cnc12
Product: Cc1csc2c(Cl)ncnc12
Temperature: 110 °C
Reaction time: 2 h

Procedure:
7-Methylthieno[3,2-d]pyrimidine-4(3H)-one (1.5 g) was added to POCl3 (10 mL), and the mixture was stirred at 110° C. for 2 hours. The reaction mixture was cooled to room temperature, concentrated and diluted with DCM, and sat. NaHCO3 solution was added thereto. The aqueous layer was extracted with DCM to combine organic layers. The organic layer was dried with MgSO4 and filtered to obtain the title compound as a white solid.