Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[Br:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Br)=[CH:14][CH:13]=1>>[Br:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][O:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[CH:14][CH:13]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: O=[N+]([O-])c1cccc(O)c1
Product: O=[N+]([O-])c1cccc(OCc2ccc(Br)cc2)c1
Yield: 94.8 %

Procedure:
3-Nitro-phenol (1.00 g, 7.189 mmol) was treated with 4-bromo-benzyl bromide (1.976 g, 7.90 mmol) following the procedure of 189a providing the tile compound (2.1 g, 97%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:25]=[O:26])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=3[Cl:24])[CH2:12][CH2:13][CH2:14][CH2:15][N:7]21.[CH2:27]([Mg]Br)[CH3:28].C(OCC)C>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=4[Cl:24])[CH2:12][CH2:13][CH2:14][CH2:15][N:7]3[C:6]=2[C:5]([CH:25]([OH:26])[CH2:27][CH3:28])=[CH:4][CH:3]=1
Reactant: CC[Mg]Br
Reactant: COc1ccc(N2CCCCn3c2nc2c(Cl)ccc(C=O)c23)c(Cl)c1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCCN3c1ccc(OC)cc1Cl
Reaction time: 0.25 h
Yield: 48 %

Procedure:
To a stirred suspension of 10-chloro-1-(2-chloro-4-methoxyphenyl)-2,3,4,5-tetrahydro-1H-[1,3]diazepino[1,2-a]benzimidazole-7-carbaldehyde (267 mg, 0.684 mmol) in tetrahydrofuran (7 mL) and a solution of ethyl magnesium bromide in diethyl ether (3.0 M, 274 μL, 0.821 mmol) was added at 0° C. After 15 min, the reaction mixture was quenched with aqueous ammonium chloride, diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate, filtrated, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-40% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (137 mg, 0.325 mmol, 48%).
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][O:9][C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:17]=2[N:19]2[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]2)[N:12](CC2C=CC(OC)=CC=2)[N:11]=1>C(Cl)Cl>[CH3:8][O:9][C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:17]=2[N:19]2[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]2)[NH:12][N:11]=1
Reactant: COc1ccc(Cn2nc(OC)c3c(N4CCN(C(=O)OC(C)(C)C)CC4)c(-c4ccccc4)cnc32)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1n[nH]c2ncc(-c3ccccc3)c(N3CCNCC3)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 118.8 %

Procedure:
TFA (0.5 mL) was added to tert-butyl 4-(3-methoxy-1-(4-methoxybenzyl)-5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.098 g, 0.185 mmol) in DCM (2 mL) and stirred at room temperature for 2 hours. The reaction mixture was then concentrated to dryness. The resulting residue was dissolved in TFA (2.85 mL, 37.01 mmol) and heated at 100° C. in a sealed tube for 5 hours. The reaction mixture was again concentrated to dryness. The resulting residue was dissolved in DCM (0.5 mL), followed by the addition of HCl in ether (2 mL, 2N). The resulting solid was collected by filtration to give 3-methoxy-5-phenyl-4-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridine (0.068 g, 96%). MS APCI (+) m/z 310.1 detected.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:37]=[C:36]2[C:32]([C:33]([C:41]([OH:43])=O)=[CH:34][N:35]2[CH:38]([CH3:40])[CH3:39])=[CH:31][CH:30]=1.[NH2:44][C:45]1[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][N:46]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.O.C(OCC)(=O)C>[CH3:51][C:48]1[CH:49]=[CH:50][C:45]([NH:44][C:41]([C:33]2[C:32]3[C:36](=[CH:37][C:29]([Cl:28])=[CH:30][CH:31]=3)[N:35]([CH:38]([CH3:39])[CH3:40])[CH:34]=2)=[O:43])=[N:46][CH:47]=1
Reactant: Cc1ccc(N)nc1
Reactant: CC(C)n1cc(C(=O)O)c2ccc(Cl)cc21
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(NC(=O)c2cn(C(C)C)c3cc(Cl)ccc23)nc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 19.2 %

Procedure:
A solution of triphenylphosphine (243 mg, 0.92 mmol) in methylene chloride (3 mL) cooled to 0° C. was treated with N-bromosuccinimide (165 mg, 0.92 mmol). This solution was stirred at 0° C. for 15 min. At this time, the reaction was treated with 6-chloro-1-isopropyl-1H-indole-3-carboxylic acid (200 mg, 0.84 mmol). This solution was stirred at 0° C. for 15 min and then was allowed to warm to 25° C. where it was stirred for 30 min. The reaction was then treated with 2-amino-5-picoline (227 mg, 2.10 mmol) and was stirred at 25° C. for 18 h. At this time, the reaction was diluted with water (50 mL) and ethyl acetate (50 mL). This mixture was treated with a saturated aqueous sodium bicarbonate solution (15 mL). The organic layer was separated and was washed with a saturated aqueous sodium chloride solution (1×25 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 3/1 hexanes/ethyl acetate) afforded 6-chloro-1-isopropyl-1H-indole-3-carboxylic acid (5-methyl-pyridin-2-yl)-amide (53 mg, 19%) as a pale yellow solid: mp 132-134° C.; EI-HRMS m/e calcd for C18H18CN3O (M+) 327.1138, found 327.1135.
Reaction SMILES: C([O:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH:25]([F:27])[F:26])=[CH:20][C:19]=2[Cl:28])[CH:12]=[CH:11][N:10]=1)C1C=CC=CC=1.C(O)(C(F)(F)F)=O>>[Cl:28][C:19]1[CH:20]=[C:21]([O:24][CH:25]([F:27])[F:26])[CH:22]=[CH:23][C:18]=1[C:13]1[CH:14]([N+:15]([O-:17])=[O:16])[C:9](=[O:8])[N:10]=[CH:11][CH:12]=1
Reactant: O=[N+]([O-])c1c(-c2ccc(OC(F)F)cc2Cl)ccnc1OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C1N=CC=C(c2ccc(OC(F)F)cc2Cl)C1[N+](=O)[O-]
Yield: 92.6 %

Procedure:
2-Benzyloxy-4-(2-chloro-4-difluoromethoxy-phenyl)-3-nitro-pyridine (5.40 g, 13.3 mmol) and TFA (25 mL) were treated as in Part B of Example 113 with the exception that the crude product was isolated as 3.90 g (93%) of 4-(2-chloro-4-difluoromethoxy-phenyl)-3-nitro-3H-pyridin-2-one: MS(AP) m/z 317.0 [(M+H)+, 90], 357.9 [(M+H+CH3CN)+, 100].
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8]O)[CH:5]=[CH:4][CH:3]=1.[C:10]1(=[O:20])[NH:14][C:13](=[O:15])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][N:14]2[C:10](=[O:20])[C:11]3[C:12](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:13]2=[O:15])[CH:5]=[CH:4][CH:3]=1
Reactant: OCc1cccc(Br)n1
Reactant: O=C1NC(=O)c2ccccc21
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1Cc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.4 %

Procedure:
(6-Bromo-pyridin-2-yl)-methanol (2949 mg, 15.68 mmol), phthalimide (3000 mg, 20.39 mmol), triphenylphosphine (5348 mg, 20.39 mmol) and 1,1-(azodicarbonyl)-dipiperidine) 5144, 20.39 mmol) were dissolved In THF (150 mL) and stirred at room temperature for 4 h. The reaction mixture was cooled to 0° C. and the resulting precipitate was removed via filtration. A saturated aqueous sodium bicarbonate solution was added to the filtrate and the solution was extracted several times with ethyl acetate. The combined organic extracts were dried over magnesium sulfate and condensed under reduced pressure. The crude residue was purified by column chromatography with a gradient of 10 to 75% AcOEt/hexanes to give 2-(6-Bromo-pyridin-2-ylmethyl)-isoindole-1,3-dione as a white solid (4000 mg, 80%) MS ES (MH+ 317.2/319.1).
Reaction SMILES: [CH2:1]([O:12][C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[Li]CCCC.[CH3:23][Sn:24](Cl)([CH3:26])[CH3:25]>C1COCC1>[CH2:1]([O:12][C:13]1[S:14][C:15]([Sn:24]([CH3:26])([CH3:25])[CH3:23])=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: C[Sn](C)(C)Cl
Reactant: CCCCCCCCCCCOc1cccs1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCOc1ccc([Sn](C)(C)C)s1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A solution of 2-undecanoxy-thiophene (4.23 g, 16.6 mmol) in dry THF (80 mL) was cooled to −78° C., and a solution of n-BuLi (2.5 M, 10 mL, 25.0 mmol) was then added slowly. This mixture was stirred at −78° C. for additional 10 minutes, and then allowed to warm to room temperature and stirred at room temperature for 30 minutes, before it was cooled back to −78° C. A solution of trimethylstannyl chloride (1.0 M, 25 mL, 25.0 mmol) was added slowly. This mixture was stirred at −78° C. for 2 hours, and then allowed to warm to room temperature, and stirred at room temperature overnight. The reaction was quenched by water (20 mL), and the reaction mixture was diluted with hexane (250 mL), washed with water (100 mL×2), dried over Na2SO4, and concentrated on a rotary evaporator, leading to a slightly yellow oil (6.94 g, 100.0%), which was directly used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][CH:7]=[N:6][C:5]=2[S:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13].[H-].[Na+].CS(O[CH2:23][CH2:24][N:25]1[CH2:29][CH2:28][CH2:27][C:26]1=[O:30])(=O)=O>CN(C=O)C>[CH3:1][C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH2:23][CH2:24][N:25]3[CH2:29][CH2:28][CH2:27][C:26]3=[O:30])[CH:7]=[N:6][C:5]=2[S:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: CS(=O)(=O)OCCN1CCCC1=O
Reactant: COC(=O)c1sc2nc[nH]c(=O)c2c1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc2ncn(CCN3CCCC3=O)c(=O)c2c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.6 %

Procedure:
To a solution of methyl 5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate (0.8 g, 3.5 mmol) in DMF (10 ml) was added NaH (0.28 g, 7 mmol) followed by the addition of 2-(2-oxopyrrolidin-1-yl)ethyl methanesulfonate (0.7 g, 3.5 mmol). The mixture was then stirred overnight at RT. Reaction was quenched with water (10 ml) and mixture extracted with ethyl acetate. Ethyl acetate layer was separated, dried over anhydrous sodium sulfate and evaporated to yield 0.5 g of methyl 5-methyl-4-oxo-3-(2-(2-oxopyrrolidin-1-yl)ethyl)-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate, as an oil (yield: 42.8%).
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[N:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:26][N:25]=[N:24][N:23]=3)=[CH:14][CH:15]=2)[N:7]=[C:6]([C:27](O)=[O:28])[CH:5]=1)[CH2:2][CH3:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.CN(C=O)C.[NH2:68][C@H:69]([CH2:74][C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][C:76]=1[C:81]([F:84])([F:83])[F:82])[CH2:70][C:71]([OH:73])=[O:72].Cl>>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[N:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:23][N:24]=[N:25][N:26]=3)=[CH:14][CH:15]=2)[N:7]=[C:6]([C:27]([NH:68][C@H:69]([CH2:74][C:75]2[CH:80]=[CH:79][CH:78]=[CH:77][C:76]=2[C:81]([F:82])([F:83])[F:84])[CH2:70][C:71]([OH:73])=[O:72])=[O:28])[CH:5]=1)[CH2:2][CH3:3]
Reactant: N[C@@H](CC(=O)O)Cc1ccccc1C(F)(F)F
Reactant: CCCc1cc(C(=O)O)nn1Cc1ccc(-c2ccccc2-c2nnn[nH]2)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(C(=O)N[C@@H](CC(=O)O)Cc2ccccc2C(F)(F)F)nn1Cc1ccc(-c2ccccc2-c2nnn[nH]2)nc1
Reaction time: 0.5 h
Yield: 100 %

Procedure:
A solution of 5-propyl-1-{6-[2-(1H-tetrazol-5-yl)-phenyl]pyridin-3-ylmethyl}-1H-pyrazole-3-carboxylic acid (20 mg, 0.05 mmol), HATU (19.5 mg, 0.0514 mmol) and DIPEA (44.7 uL, 0.257 mmol) in DMF (1.59 mL, 20.5 mmol) was stirred to pre-activate the acid. After 30 minutes, (R)-3-amino-4-(2-trifluoromethylphenyl)butanoic acid.HCl (14.6 mg, 51.4 μmol)) was added. The resulting solution was stirred overnight. The mixture was concentrated, re-dissolved in water/MeCN/TFA and purified using reverse phase liquid chromatography to yield the title compound (21.1 mg; 100% purity) as a TFA salt. MS m/z: [M+H]+ calcd for C31H29F3N8O3, 619.23; found 619.6.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24][CH3:25])[N:12]2[CH2:15][CH:16]2[CH2:21][CH2:20]N(CC)CC2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4].C(OC1NC(N)=C2C(N=1)=NC(OC)=N2)CCC.[CH2:44]([N:46]1[CH2:51][CH2:50][CH:49](C(CC)CO)[CH2:48][CH2:47]1)[CH3:45]>>[CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24][CH3:25])[N:12]2[CH2:15][CH2:16][CH2:21][CH2:20][CH:49]2[CH2:50][CH2:51][N:46]([CH2:44][CH3:45])[CH2:47][CH2:48]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCC(CO)C1CCN(CC)CC1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CC3CCN(CC)CC3)c2n1
Agent: CCCCOc1nc2nc(OC)nc-2c(N)[nH]1
Product: CCCCOc1nc(N)c2nc(OC)n(CCCCC3CCN(CC)CC3)c2n1

Procedure:
Prepared similarly to Intermediate 19 from 2-(butyloxy)-8-(methyloxy)-1H-purin-6-amine and 2-(1-ethyl-4-piperidinyl)-1-butanol.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10](Br)=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][Si:15]([C:18]#[CH:19])([CH3:17])[CH3:16]>>[CH3:14][Si:15]([C:18]#[C:19][C:4]1[CH:5]=[CH:6][C:1]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:2][CH:3]=1)([CH3:17])[CH3:16]
Reactant: Brc1ccc(-c2ccccc2)nc1
Reactant: C#C[Si](C)(C)C
Product: C[Si](C)(C)C#Cc1ccc(-c2ccccn2)cc1
Yield: 88 %

Procedure:
To explain the synthesis in more detail, the Suzuki reaction between phenylboronic acid and 2,5-dibromopyridine gave 2-phenyl-5-bromopyridine in an 86% yield (see scheme 1 above). The reaction occurred preferentially on the 2 position on the pyridine ring, which is activated by the adjacent nitrogen. Reaction of 2-phenyl-5-bromopyridine with trimethylsilylacetylene under Sonogashira conditions gave the 2-phenyl-5-(trimethylsilylethynyl)pyridine (2) in an 88% yield, which could be deprotected to 2-phenyl-5-ethynylpyridine (3) in a yield of 93% using tetra-n-butylammonium hydroxide. The Diels-Alder reaction between (3) and the difluorenylcyclopentadienone (10) gave the dendronised ligand in a 48% yield, after purification by precipitation of the ligand from a dichloromethane solution by pouring the solution into ethanol. The complex was formed by the two-step procedure via the bis(chloro)-bis(iridium) dimer in a yield of 50%. This yield is no lower than those obtained from the complexation of ligands dendronised only on the phenyl ring, showing that the presence of the bulky dendron on the pyridine ring does not inhibit complexation.
Reaction SMILES: C[O:2][C:3](=[O:38])[C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([O:11][CH:12]([C:19]2[N:20]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)[N:21]=[C:22]3[C:27]=2[CH:26]=[C:25]([F:28])[C:24]([F:29])=[CH:23]3)[CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[C:6]([CH3:37])[CH:5]=1.[OH-].[Li+]>C1COCC1.CO>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([N:20]2[C:19]([CH:12]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[O:11][C:7]3[C:8]([CH3:10])=[CH:9][C:4]([C:3]([OH:38])=[O:2])=[CH:5][C:6]=3[CH3:37])=[C:27]3[C:22]([CH:23]=[C:24]([F:29])[C:25]([F:28])=[CH:26]3)=[N:21]2)=[CH:31][CH:32]=1
Reactant: COC(=O)c1cc(C)c(OC(c2c3cc(F)c(F)cc3nn2-c2ccc(Cl)cc2)C2CCCCC2)c(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(C(=O)O)cc(C)c1OC(c1c2cc(F)c(F)cc2nn1-c1ccc(Cl)cc1)C1CCCCC1

Procedure:
In analogy to the procedure described in example 7.2, [rac]-4-{[2-(4-chloro-phenyl)-5,6-difluoro-2H-indazol-3-yl]-cyclohexyl-methoxy}-3,5-dimethyl-benzoic acid methyl ester (example 33) was treated with 1 N aqueous lithium hydroxide solution in THF and MeOH to give the title compound as yellow foam. MS: m/e=523.3 [M−H−].
Reaction SMILES: [NH2:1][C:2]([C@@H:4]1[CH2:8][CH2:7][C@H:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[N:5]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:3].F[C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[C:26]#[N:27].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C.C(OCC)(=O)C>[NH2:1][C:2]([C@@H:4]1[CH2:8][CH2:7][C@H:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:24]3[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=3[C:26]#[N:27])=[CH:11][CH:10]=2)[N:5]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:3]
Reactant: CC(C)(C)OC(=O)N1[C@@H](c2ccc(O)cc2)CC[C@H]1C(N)=O
Reactant: N#Cc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1[C@@H](c2ccc(Oc3ccccc3C#N)cc2)CC[C@H]1C(N)=O
Yield: 75.3 %

Procedure:
A solution of 1,1-dimethylethyl (2S,5R)-2-(aminocarbonyl)-5-(4-hydroxyphenyl)-1-pyrrolidinecarboxylate (D13, 50 mg, 0.163 mmol), 2-fluorobenzonitrile (40 mg, 0.326 mmol) and K2CO3 (34 mg, 0.245 mmol) in DMF (1 ml) was heated under microwave irradiation for 30 min at 120° C. Then water and ethyl acetate were added to the mixture. The organic layer was washed with ice cold brine. The solution was dried over Na2SO4 and the solvent removed under reduced pressure. The crude material was purified by chromatography on silica gel using cyclohexanes/ethyl acetate (75:25) to afford the title compound (50 mg, 75%); Rf (cyclohexanes:ethyl acetate=1:1): 0.10; Rt (HPLC) 5.17 min.; MS: (ES/+) m/z: 430 [M+Na+], C23H25N3O4 requires 407.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[N:8]=[N:7][C:6]([CH2:9][O:10][CH2:11][C:12]2[NH:13][C:14]([CH3:35])=[C:15]([C:31]([O:33][CH3:34])=[O:32])[CH:16]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=3[Cl:30])[C:17]=2[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:5]1.C(N(CC)CC)C.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>ClCCl>[Cl:30][C:24]1[C:25]([Cl:29])=[CH:26][CH:27]=[CH:28][C:23]=1[CH:16]1[C:15]([C:31]([O:33][CH3:34])=[O:32])=[C:14]([CH3:35])[NH:13][C:12]([CH2:11][O:10][CH2:9][C:6]2[N:7]=[N:8][N:4]([CH2:3][CH2:2][NH:1][S:44]([CH3:43])(=[O:46])=[O:45])[N:5]=2)=[C:17]1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)C1=C(COCc2nnn(CCN)n2)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=C(COCc2nnn(CCNS(C)(=O)=O)n2)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Yield: 29.7 %

Procedure:
A solution of 2-(2-aminoethyl)-5-{[4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridin-2-yl]methoxymethyl}tetrazole (0.33 g), triethylamine (65 mg) and methanesulphonyl chloride (71 mg) in dichloromethane (15 ml) was heated under reflux for 2 hours and then evaporated. The residue was purified by chromatography on silica (6 g) using dichloromethane plus from 0 to 1% by volume of methanol as eluant. Appropriate fractions were combined and evaporated. The residual solid was recrystallized from ethyl acetate and dried to give the title compound (111 mg) as a hydrate, m.p. 245°-247° C. Found: C,46.23; H,5.02; N,13.82. C23H28Cl2N6O7S.H2O requires: C,46.26; H,5.19; N,14.08%.
Reaction SMILES: [N+:1]([C:4]1[C:5](SC#N)=[N:6][C:7]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:8][CH:9]=1)([O-:3])=[O:2].[NH2:22][CH2:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([NH:30]C(=O)OC(C)(C)C)[CH2:26][CH2:25]1>C(Cl)Cl>[NH2:30][C@H:27]1[CH2:28][CH2:29][C@H:24]([CH2:23][NH:22][C:5]2[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=[C:7]([NH:10][CH2:11][CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:6]=2)[CH2:25][CH2:26]1
Reactant: N#CSc1nc(NCCc2ccccc2)ncc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CN)CC1
Solvent: ClCCl
Product: N[C@H]1CC[C@H](CNc2nc(NCCc3ccccc3)ncc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.9 %

Procedure:
To a solution of the above (5-nitro-4-thiocyanato-pyrimidin-2-yl)-phenethyl-amine (75 mg, 0.25 mmol) in CH2Cl2 was added tert-butyl trans-4-aminomethylcyclohexylcarbamate (114 mg, 0.5 mmol). The reaction mixture was stirred at room temperature for 16 h and concentrated in vacuo. The resulting residue was then diluted with CH2Cl2 (1 mL) and TFA (0.5 mL) was added. The mixture was stirred at room temperature for 4 h and concentrated in vacuo. The resulting residue was purified by preparative LCMS to afford 36 mg (39%) of the title compound, m/z 371.6 [M+1]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.[C:7]([NH:11][C:12]([C:14]1[S:36][C:17]2[N:18]=[C:19]([S:34][CH3:35])[N:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][S:29]([CH:32]=[CH2:33])(=[O:31])=[O:30])[CH:23]=3)[C:16]=2[C:15]=1[NH2:37])=[O:13])([CH3:10])([CH3:9])[CH3:8]>>[C:7]([NH:11][C:12]([C:14]1[S:36][C:17]2[N:18]=[C:19]([S:34][CH3:35])[N:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][S:29]([CH2:32][CH2:33][N:1]4[CH2:6][CH2:5][S:4][CH2:3][CH2:2]4)(=[O:31])=[O:30])[CH:23]=3)[C:16]=2[C:15]=1[NH2:37])=[O:13])([CH3:9])([CH3:8])[CH3:10]
Reactant: C1CSCCN1
Reactant: C=CS(=O)(=O)Nc1cccc(-c2nc(SC)nc3sc(C(=O)NC(C)(C)C)c(N)c23)c1
Product: CSc1nc(-c2cccc(NS(=O)(=O)CCN3CCSCC3)c2)c2c(N)c(C(=O)NC(C)(C)C)sc2n1
Reaction time: 0.5 h

Procedure:
Reaction of thiomorpholine (184 μl) with tert-butyl 5-amino-2-methylthio-4-(3-(vinylsulfonamido)-phenyl)-thieno[2,3-d]pyrimidine-6-carboxamide (example 10, 87 mg) was performed according to the method described in example 11. The title compound was first purified by chromatography on silica gel with hept/EtOAc=3/2 (v/v) as eluent and then by HPLC using a Luna C-18 column with the following gradient: CH3CN/0.1% aq. TFA=10/90 to 90/10 (v/v) in 30 min. The title compound was then lyophilized from a mixture of 1,4dioxane and 0.1 % aq TFA.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14](O)=[O:15])=[CH:12][N:11]=[CH:10][CH:9]=2)=[C:4]([F:17])[CH:3]=1.C(Cl)(=O)C(Cl)=O.Cl.CN.[CH2:27]([N:29](CC)CC)C>ClCCl.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([NH:29][CH3:27])=[O:15])=[CH:12][N:11]=[CH:10][CH:9]=2)=[C:4]([F:17])[CH:3]=1
Reactant: O=C(O)c1cnccc1-c1ccc(Cl)cc1F
Reactant: CCN(CC)CC
Agent: CN
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CNC(=O)c1cnccc1-c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
To a solution of 4-(4-chloro-2-fluorophenyl)nicotinic acid (2 g, 7.95 mmol in dichloromethane (40 mL) cooled to 0° C. was added oxalyl chloride (2.09 mL, 23.8 mmol) followed by DMF (2 mL). The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was concentrated under reduced pressure and treated with dichloromethane (25 mL). This solution was added to a mixture of methylamine hydrochloride (5.37 g, 79 mmol) and triethylamine (11.08 mL, 79 mmol) in dichloromethane (25 mL) cooled to 0° C. The resultant mixture was stirred at room temperature for 3 h and then washed with a saturated solution of sodium bicarbonate. The organic layer was separated, dried (Na2SO4) and concentrated under reduced pressure to afford 4-(4-chloro-2-fluorophenyl)-N-methylnicotinamide (1.3 g, 4.91 mmol, 62%) as an off-white solid. LC/MS (ESI) m/e 265.1 [(M+H)+, calcd for C13H11ClFN2O 265.1]; LC/MS retention time (method C): tR=1.69 min.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[N:9]=[CH:8][C:7]([O:10][CH2:11][C:12](=[O:14])[CH3:13])=[C:6]([I:15])[CH:5]=1.Cl.O>CO>[F:3][C:4]1[N:9]=[CH:8][C:7]([O:10][CH2:11][CH:12]([OH:14])[CH3:13])=[C:6]([I:15])[CH:5]=1
Reactant: CC(=O)COc1cnc(F)cc1I
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(O)COc1cnc(F)cc1I
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.7 %

Procedure:
Add NaBH4 (35 mg, 0.94 mmol) to a solution of 1-(6-fluoro-4-iodo-pyridin-3-yloxy) propan-2-one (240 mg, 0.81 mmol) in methanol (4 mL) slowly. Stir the mixture at RT for 3 h. Add 1 N HCl and water. Extract with methylene chloride. Wash the organic layer with aqueous saturated sodium chloride. Dry over sodium sulfate. Concentrate the solution in vacuo to a yellow solid. Purify by column chromatography (hexane to 10% ethyl acetate in hexane) to afford the title compound as a light yellow solid (240 mg, 99%). MS (ES) m/z 298 [M+1]+.