Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[CH:10]([CH:12]=O)=O>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[N:8]=[CH:12][CH:10]=[N:9]2
Reactant: O=CC=O
Reactant: Nc1ccc(Br)cc1N
Solvent: CO
Product: Brc1ccc2nccnc2c1
Yield: 51 %

Procedure:
In a round bottom flask under nitrogen was combined 4-Bromo-benzene-1,2-diamine (2.01 g, 10.7 mMol), methanol (50 mL), and glyoxal (40% by wt. 3.1 mL, 26.9 mMol) and the resulting solution stirred overnight. Upon arrival the reaction was concentrated to dryness on a rotary evaporator and purified by flash column chromatography on silica gel using 5-10% ethyl acetate in dichloromethane as eluant to yield 1.14 g (50% yield) of 6-Bromo-quinoxaline as a yellow-orange solid. 1H NMR (DMSO-d6): δ=9.00 (d, 2H, J=2.8 Hz), 8.36 (d, 1H, J=2.2 Hz), 8.07 (d, 1H, J=9.0 Hz), 8.02 (dd, 1H, J=8.8, 2.1 Hz). CHN for C8H5BrN2: calc. C, 45.97; H, 2.41; N, 13.4. found C, 45.99; H 2.09; N 13.09. LC/MS (Method A), rt=1.10 mins., purity=99%, calculated mass=208, [M+H]+=209/21. HPLC (Method C): rt=7.4 mins., purity=98.52% @ 210-370 nm and 98.8% @ 322 nm.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[C:21]([C:24]([OH:26])=O)=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])[CH:5]=[CH:4][C:3]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]([F:36])([F:35])[F:34].C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)(O)O.[NH2:53][C:54]([NH2:56])=[NH:55]>CN(C)C=O.O>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[C:21]([C:24]([NH:55][C:54]([NH2:56])=[NH:53])=[O:26])=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])[CH:5]=[CH:4][C:3]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]([F:36])([F:35])[F:34]
Reactant: N=C(N)N
Reactant: Cc1cc(C(=O)N2Cc3ccc(C(=O)O)n3Cc3ccccc32)ccc1-c1ccccc1C(F)(F)F
Agent: O=C(O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)N2Cc3ccc(C(=O)NC(=N)N)n3Cc3ccccc32)ccc1-c1ccccc1C(F)(F)F
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 46.1 %

Procedure:
10-[(2-Methyl-2′-trifluoromethyl-[1,1′-biphenyl]4-yl)-carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of Example 1, Step F (0.50 g, 1.02 mmol) and 1,1′-carbonyldiimidazole (0.17 g, 1.05 mmol) were dissolved in anhydrous N,N-dimethylformamide (5 mL). After stirring for 30 minutes, guanidine carbonate (0.19 g, 1.05 mmol) was added, and the reaction was heated to 100° C. for 4 hours. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give an orange oil. Purification was achieved by preparative HPLC on a Primesphere 5 C18 (0.2×15 cm) column using a solvent gradient from 55:45:0.1 to 90:10:0.1 acetonitrile-water-trifluoroacetic acid. After removal of the acetonitrile in vacuo, the aqueous solution was neutralized with saturated aqueous sodium bicarbonate, and then extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 0.25 g of the title compound as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[CH:3]1[CH2:7][CH2:6][NH:5][C:4]1([CH3:9])[CH3:8].C(N(CC)C(C)C)(C)C.[CH3:20][C:21]([O:24][C:25]([N:27]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[N:28]([C:36]1[C:41]([F:42])=[C:40](Cl)[N:39]=[C:38]([Cl:44])[N:37]=1)[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:26])([CH3:23])[CH3:22]>CN(C=O)C>[CH3:23][C:21]([O:24][C:25]([N:27]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[N:28]([C:36]1[C:41]([F:42])=[C:40]([N:5]2[CH2:6][CH2:7][CH:3]([N:2]([CH3:10])[CH3:1])[C:4]2([CH3:9])[CH3:8])[N:39]=[C:38]([Cl:44])[N:37]=1)[C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])=[O:26])([CH3:20])[CH3:22]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)c1nc(Cl)nc(Cl)c1F
Reactant: CN(C)C1CCNC1(C)C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C1CCN(c2nc(Cl)nc(N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c2F)C1(C)C
Reaction time: 8 h
Yield: 74.7 %

Procedure:
To a solution of racemic N,N,2,2-tetramethyl-3-pyrrolidinamine (0.1466 g, 1.031 mmol) in DMF (6 mL) was added N,N-diisopropylethylamine (0.220 mL, 1.263 mmol) and tris(1,1-dimethylethyl)2-(2,6-dichloro-5-fluoro-4-pyrimidinyl)-1,1,2-hydrazinetricarboxylate (0.513 g, 1.031 mmol), and the solution was stirred overnight. The solution was partitioned between Et2O (100 mL) and water (20 mL), and the organic phase was washed with a fresh portion of water (20 mL). The combined aqueous phase was extracted with a fresh portion of Et2O (50 mL), and the combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by gradient silica gel chromatography (0% to 100% EtOAc in hexanes) to give racemic tris(1,1-dimethylethyl)2-{2-chloro-6-[3-(dimethylamino)-2,2-dimethyl-1-pyrrolidinyl]-5-fluoro-4-pyrimidinyl}-1,1,2-hydrazinetricarboxylate (0.4647 g, 75% yield) as a white foam. LCMS: (M+H)+: 603.3.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8](=[O:20])[CH2:9][CH2:10][C:11]2[CH:16]=[C:15]([CH3:17])[C:14]([OH:18])=[C:13]([CH3:19])[CH:12]=2)=[C:5]2[CH2:21][CH2:22][C:23]([CH3:26])([CH3:25])[CH2:24][C:4]=12)[CH3:2].[CH2:27]([CH:29]1[O:31][CH2:30]1)Cl>C(O)(C)C.[OH-].[Na+].C(#N)C>[CH3:19][C:13]1[CH:12]=[C:11]([CH2:10][CH2:9][C:8]([C:6]2[S:7][C:3]([CH2:1][CH3:2])=[C:4]3[CH2:24][C:23]([CH3:25])([CH3:26])[CH2:22][CH2:21][C:5]=23)=[O:20])[CH:16]=[C:15]([CH3:17])[C:14]=1[O:18][CH2:27][CH:29]1[CH2:30][O:31]1
Reactant: CCc1sc(C(=O)CCc2cc(C)c(O)c(C)c2)c2c1CC(C)(C)CC2
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CC#N
Product: CCc1sc(C(=O)CCc2cc(C)c(OCC3CO3)c(C)c2)c2c1CC(C)(C)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.6 %

Procedure:
A solution of 1-(3-ethyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-3-(4-hydroxy-3,5-dimethyl-phenyl)-propan-1-one (75 mg, 0.20 mmol) in isopropanol (4 mL) and 3 N aq. NaOH (1.7 mL) is treated with epichlorohydrine (75 mg, 0.60 mmol) and the mixture is stirred at rt for 1 h. The mixture is diluted with acetonitrile (1 mL) and separated by prep. HPLC (Phenomenex Aqua, 75×30 mm ID, 10 μm, 10-95% acetonitrile in water containing 0.5% formic acid) to give 3-(3,5-dimethyl-4-oxiranylmethoxy-phenyl)-1-(3-ethyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-propan-1-one (50 mg) as a colourless resin; LC-MS: tR=1.21 min, [M+1]=427.41.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].C(OCl)(C)(C)C.[CH3:22][S:23][CH:24]([CH3:30])[C:25](OCC)=[O:26].C(N(CC)CC)C.Cl>C(Cl)Cl>[C:4]([C:3]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:2]=1[NH:1][C:25](=[O:26])[C:24]2([CH3:30])[S:23][CH3:22])(=[O:5])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Nc1ccccc1C(=O)c1ccccc1
Reactant: CCOC(=O)C(C)SC
Agent: CC(C)(C)OCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSC1(C)C(=O)Nc2c(C(=O)c3ccccc3)cccc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A stirred solution of 3.94 g. (0.02 mole) of 2-aminobenzophenone in methylene chloride at -65°C. was treated with 2.16 g. (0.02 mole) of t-butylhypochlorite. After 15 min. 2.96 g. ethyl α-(methylthio)propionate was added dropwise and stirring continued for 1 hr. At the end of this time 2.02 g. of triethylamine (0.02 mole) was added dropwise and the reaction solution was allowed to warm to room temperature. This was followed by treatment with lN hydrochloric acid and stirred for 15 min. The methylene chloride solution was then separated and stripped under vacuum. The yellow oil residue was triturated with isopropyl ether and 3 g. of a yellow solid was filtered off (51%). Recrystallization from absolute ethanol gave a cream color solid, m.p. 135°-137°C.
Reaction SMILES: [C:1]([CH2:4][C:5]1[N:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]2=[N:7][C:6]=1[C:14]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]2[C:15]=1[CH:16]=[CH:17][C:18](=[O:26])[NH:19]2)(=[O:3])N.[OH-:27].[K+].Cl>O.C(O)C>[OH2:3].[C:1]([CH2:4][C:5]1[N:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]2=[N:7][C:6]=1[C:14]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]2[C:15]=1[CH:16]=[CH:17][C:18](=[O:26])[NH:19]2)([OH:3])=[O:27].[C:1]([CH2:4][C:5]1[N:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]2=[N:7][C:6]=1[C:14]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]2[C:15]=1[CH:16]=[CH:17][C:18](=[O:26])[NH:19]2)([OH:3])=[O:27]
Reactant: COc1ccc(-c2nc3ccccn3c2CC(N)=O)c2ccc(=O)[nH]c12
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2nc3ccccn3c2CC(=O)O)c2ccc(=O)[nH]c12
Reaction time: 8 h
Yield: 82 %

Procedure:
A mixture of 5-{3-carbamoylmethylimidazo-[1,2-a]pyridine-2-yl}-8-methoxycarbostyril (1.6 g), potassium hydroxide (2.6 g), water (3 ml) and ethanol (9 ml) was refluxed for 1 hour. After completion of reaction, water was added to the reaction mixture, which was then treated with activated carbon and adjusted to pH of about 1 by the addition of concentrated hydrochloric acid followed by allowing to stand overnight. Crystals which precipitated were collected by filtration and recrystallized from dilute hydrochloric acid to give 0.9 g of 5-{3-carboxymethylimidazo[1,2-a]pyridine-2-yl}-8-methoxycarbostyril hemihydrate.
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[C:10]([CH3:11])=[C:9]([O:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[N:8]=[CH:7][N:6]=1.[CH3:27][CH:28]([CH3:35])[CH2:29][CH2:30][CH2:31][C:32](O)=[O:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[CH:22]=[C:21]([S:23]([CH3:26])(=[O:24])=[O:25])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[N:6]=[CH:7][N:8]=[C:9]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([C:32](=[O:33])[CH2:31][CH2:30][CH2:29][CH:28]([CH3:35])[CH3:27])[CH2:15][CH2:14]2)[C:10]=1[CH3:11]
Reactant: Cc1c(Oc2ccc(S(C)(=O)=O)cc2F)ncnc1OC1CCNCC1
Reactant: CC(C)CCCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1c(Oc2ccc(S(C)(=O)=O)cc2F)ncnc1OC1CCN(C(=O)CCCC(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.1 %

Procedure:
4-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-6-(piperidin-4-yloxy)-pyrimidine (42 mg, 0.1 mmol), 5-methyl-hexanoic acid (0.12 mmol, 1.2 eq), HATU (0.12 mmol, 1.2 eq), and triethylamine (0.2 mmol, 2 eq) were dissolved in DMF (1 mL), and then stirred at room temperature for 1 hour. The crude was filtered and then purified via prep-LCMS 5-95% to provide Compound C121 as a white powder (28.2 mg, 57%). Exact mass calculated for C24H32FN3O5S 493.2, found LCMS (ESI) m/z 494.5 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[F:20][C:21]1[CH:22]=[CH:23][C:24]2[N:28]=[C:27]([CH:29]([NH2:31])[CH3:30])[N:26]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=3)[C:25]=2[CH:39]=1>C(O)CCC>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:31][CH:29]([C:27]2[N:26]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=3)[C:25]3[CH:39]=[C:21]([F:20])[CH:22]=[CH:23][C:24]=3[N:28]=2)[CH3:30])[N:5]=[CH:4][N:3]=1
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: CC(N)c1nc2ccc(F)cc2n1-c1cccc(F)c1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc(N)c1C#N)c1nc2ccc(F)cc2n1-c1cccc(F)c1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
To a microwave vessel was added 4-amino-6-chloropyrimidine-5-carbonitrile (B) (0.057 g, 0.366 mmol), DIEA (0.192 mL, 1.098 mmol), and 1-(6-fluoro-1-(3-fluorophenyl)-1H-benzo[d]imidazol-2-yl)ethanamine (0.100 g, 0.366 mmol) in n-butanol (3.66 mL). The solution was stirred at 120° C. under microwave irradiation for 2 h and then purified by column chromatography on a silica gel column using 0 to 10% gradient of MeOH in DCM as eluent to give a racemic mixture 4-amino-6-((1-(6-fluoro-1-(3-fluorophenyl)-1H-benzimidazol-2-yl)ethyl)amino)-5-pyrimidinecarbonitrile as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.54 (d, J=6.65 Hz, 3H) 5.56 (qd, J=6.91, 6.65 Hz, 1H) 6.93 (dd, J=9.00, 2.35 Hz, 1H) 7.08-7.15 (m, 1H) 7.17 (br. s., 2H) 7.31 (td, J=8.41, 2.15 Hz, 1H) 7.35-7.40 (m, 1H) 7.48 (d, J=9.59 Hz, 1H) 7.56 (td, J=8.12, 6.65 Hz, 1H) 7.69 (d, J=7.63 Hz, 1H) 7.73 (dd, J=8.80, 4.89 Hz, 1H) 7.86 (s, 1H); LC-MS (ESI) m/z 392.1 [M+H]+. The racemic mixture (0.085 g) was separated by chiral separation using SFC to give two fractions:
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[C:9](Cl)(=[O:21])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].O>O1CCCC1>[O:21]=[CH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: C1COCCN1
Reactant: CCCCCCCCCCCC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=CCCCCCCCCCCCN1CCOCC1

Procedure:
A suspension of 2.30g (57.0 mmol) of sodium hydride (60% oil dispersion) in dry tetrahydrofuran (THF) and 5.0 g (57.0 mmol) of morpholine was refluxed under nitrogen for 30 minutes. After cooling, 12.56 g (57.0 mmol) of dodecanoyl chloride in THF was added dropwise, and the mixture was refluxed 30 minutes. Water was added, and the mixture was extracted with ethyl acetate (EtOAc). The combined organic phase was dried with MgSO4, concentrated in vacuo, and purified by flash chromatography (8:1 hexane/EtOAc) to give N-(oxododecyl)morpholine, as confirmed by NMR & IR spectroscopy.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.[CH3:9][C:10]1[CH:11]=[C:12]([CH:14]=[C:15]([C:17]2[S:21][CH:20]=[N:19][CH:18]=2)[CH:16]=1)[NH2:13].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>>[F:8][C:5]1[CH:4]=[N:3][C:2]([NH:13][C:12]2[CH:14]=[C:15]([C:17]3[S:21][CH:20]=[N:19][CH:18]=3)[CH:16]=[C:10]([CH3:9])[CH:11]=2)=[N:7][CH:6]=1
Reactant: Cc1cc(N)cc(-c2cncs2)c1
Reactant: Fc1cnc(Cl)nc1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1cc(Nc2ncc(F)cn2)cc(-c2cncs2)c1
Temperature: 100 °C
Yield: 92.4 %

Procedure:
2-Chloro-5-fluoropyrimidine (0.443 ml, 3.58 mmol), 3-methyl-5-(1,3-thiazol-5-yl)aniline (682 mg, 3.58 mmol), PdOAc2 (80 mg, 0.358 mmol), Xantphos (311 mg, 0.538 mmol), and cesium carbonate (2336 mg, 7.17 mmol) were combined in a flask and degassed with Argon. Dioxane (12 mL) was added and the mixture was degassed with Argon for 5 min. The mixture was then heated to 100° C. for 2 h. The reaction was cooled to room temperature, diluted with brine and EtOAc. The layers were separated and the aqueous portion re-extracted with EtOAc. The combined organics were dried over Na2SO4, filtered and concentrated in vacuo. Purification via silica gel flash chromatography (0-40% EtOAc:CH2Cl2) afforded 5-fluoro-N-[3-methyl-5-(1,3-thiazol-5-yl)phenyl]pyrimidin-2-amine (947 mg, 92%) as a beige solid. MS ESI: [M+H]+ m/z 287. rhSYK activity=++.
Reaction SMILES: C([Si]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[C:17](F)[C:16]([N+:20]([O-:22])=[O:21])=[CH:15][C:14]=1[O:23][CH3:24])(C)C)(C)(C)C.[NH2:25][C:26]1[S:27][C:28]([C:38]([NH2:40])=[O:39])=[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=2)[N:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>O.CN(C)C=O>[Cl:37][C:33]1[CH:32]=[C:31]([C:29]2[N:30]=[C:26]([NH:25][C:17]3[CH:18]=[C:13]([O:12][CH2:11][CH2:10][CH2:9][OH:8])[C:14]([O:23][CH3:24])=[CH:15][C:16]=3[N+:20]([O-:22])=[O:21])[S:27][C:28]=2[C:38]([NH2:40])=[O:39])[CH:36]=[CH:35][CH:34]=1
Reactant: COc1cc([N+](=O)[O-])c(F)cc1OCCCO[Si](C)(C)C(C)(C)C
Reactant: NC(=O)c1sc(N)nc1-c1cccc(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc([N+](=O)[O-])c(Nc2nc(-c3cccc(Cl)c3)c(C(N)=O)s2)cc1OCCCO
Reaction time: 0.25 h
Yield: 85.3 %

Procedure:
A mixture of 0.469 g (1.31 mmole) of tert-butyl-[3-(5-fluoro-2-methoxy-4-nitro-phenoxy)-propoxy]-dimethyl-silane (IV.42), 0.331 g (1.31 mmole) of 2-amino-4-(3-chloro-phenyl)-thiazole-5-carboxylic acid amide (V.2), 1.28 g (3.93 mmole) of cesium carbonate and 5 mL of dimethylformamide was heated at 70 degrees for 3 hours. The mixture was cooled and 3 mL of 6M hydrochloric acid was added dropwise. Stirring was continued for 15 minutes. The mixture was poured into 50 mL of water, and the precipitated orange solid was collected by filtration, washed with water, and air-dried to give 0.535 g of 4-(3-chloro-phenyl)-2-[5-(3-hydroxy-propoxy)-4-methoxy-2-nitro-phenylamino]-thiazole-5-carboxylic acid amide (VI.42).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C[Al](C)C.[Br:19][C:20]1[N:25]=[CH:24][C:23]([O:26][C@H:27]2[CH2:31][CH2:30][O:29][C:28]2=[O:32])=[CH:22][CH:21]=1>C(Cl)Cl.C1(C)C=CC=CC=1>[Br:19][C:20]1[N:25]=[CH:24][C:23]([O:26][C@@H:27]([CH2:31][CH2:30][OH:29])[C:28]([NH:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)=[O:32])=[CH:22][CH:21]=1
Reactant: O=C1OCC[C@@H]1Oc1ccc(Br)nc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)[C@H](CCO)Oc2ccc(Br)nc2)CC1
Reaction time: 0.25 h

Procedure:
To a solution of tert-butyl 4-aminopiperidine-1-carboxylate (0.93 g, 4.65 mmol) in DCM (15 mL) was added dropwise 2M trimethylaluminum (2.8 mL, 5.7 mmol) in toluene. The resulting mixture was stirred for 15 minutes, and (S)-3-(6-bromopyridin-3-yloxy)dihydrofuran-2(3H)-one (1.0 g, 3.87 mmol) in DCM (10 mL) was added slowly over 5 minutes and the reaction stirred at ambient temperature for 2 hours. The reaction was slowly quenched by the addition of 5% tartaric acid (5 mL), saturated NaHCO3 (5 mL) and DCM (10 mL). The organic layer was separated, dried over MgSO4, filtered and concentrated in vacuo to provide (S)-tert-butyl 4-(2-(6-bromopyridin-3-yloxy)-4-hydroxybutanamido)piperidine-1-carboxylate. The crude material was taken on without a further purification.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[C:12]=1[C:13]#[N:14].N1C=CC=CC=1.[C:28](Cl)(=[O:30])[CH3:29]>C(Cl)Cl>[C:28]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[C:12]=1[C:13]#[N:14])(=[O:30])[CH3:29]
Reactant: CC(=O)Cl
Reactant: N#Cc1c(OCCCCCCCCO)cccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OCCCCCCCCOc1cccc([N+](=O)[O-])c1C#N
Temperature: 0 °C
Yield: 99.7 %

Procedure:
2-(8-hydroxyoctyloxy)-6-nitrobenzonitrile (804 μmol, 235 mg) (Example 214c) was dissolved in dry DCM (10 mL), cooled to 0° C., and treated successively with pyridine (3.216 mmol, 260 μL) and acetyl chloride (1.608 mmol, 114 μL). The reaction mixture was stirred and allowed to warm slowly to room temperature. When the reaction was complete, the volatiles were removed in vacuo and the crude product purified on silica gel (10% to 50% EtOAc in hexanes) to give the desired product (268 mg, 100%). MS 335 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][O:14][C:15]3[N:16]=[CH:17][C:18]([C:21]([OH:23])=O)=[N:19][CH:20]=3)=[C:11]([CH3:24])[N:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:25][C:26]([CH3:30])([CH3:29])[CH2:27][OH:28]>>[OH:28][CH2:27][C:26]([NH:25][C:21]([C:18]1[CH:17]=[N:16][C:15]([O:14][CH2:13][C:12]2[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[N:9]=[N:10][C:11]=2[CH3:24])=[CH:20][N:19]=1)=[O:23])([CH3:30])[CH3:29]
Reactant: CC(C)(N)CO
Reactant: Cc1nnn(-c2ccc(F)cc2)c1COc1cnc(C(=O)O)cn1
Product: Cc1nnn(-c2ccc(F)cc2)c1COc1cnc(C(=O)NC(C)(C)CO)cn1
Yield: 94 %

Procedure:
As described for example 80c, 5-[3-(4-fluoro-phenyl)-5-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-pyrazine-2-carboxylic acid (83 mg, 0.25 mmol), was converted, using 2-amino-2-methyl-1-propanol instead of 4-aminotetrahydropyran, to the title compound (95 mg, 94%) which was obtained as a light yellow gum. MS: m/e=401.3 [M+H]+.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:15][C:16]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][CH:38]=O)=[CH:32][C:17]=1[C:18]([NH:20][CH2:21][C:22]12[CH2:31][CH:26]3[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]3)[CH2:23]1)[CH2:29]2)=[O:19].[NH2:40][CH2:41][CH2:42][CH2:43][OH:44]>ClCCl>[Cl:15][C:16]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][CH2:38][NH:40][CH2:41][CH2:42][CH2:43][OH:44])=[CH:32][C:17]=1[C:18]([NH:20][CH2:21][C:22]12[CH2:31][CH:26]3[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]3)[CH2:23]1)[CH2:29]2)=[O:19]
Reactant: O=CCCc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Reactant: NCCCO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CCCNCCCO)ccc1Cl

Procedure:
Sodium triacetoxyborohydride (1.86 g) was added to a solution of 2-chloro-5-(3-oxopropyl)-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (1.57 g, Example 29b) and 3-amino-1-propanol (0.8 ml) in dichloromethane (150 ml). After 24 h the crude reaction mixture was purified by chromatography (eluting with 5-20% methanol in dichloromethane+1% ammonia) to give the subtitled compound as a white solid (1.05 g).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:3]=1[C:4]([NH:6][C:7]1[C:8]([C:12](O)=O)=[N:9][NH:10][CH:11]=1)=[O:5].[N:20]1([CH2:26][C:27]2[CH:28]=[C:29]([NH2:34])[C:30]([NH2:33])=[CH:31][CH:32]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:3]=1[C:4]([NH:6][C:7]1[C:8]([C:12]2[NH:33][C:30]3[CH:31]=[CH:32][C:27]([CH2:26][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:28][C:29]=3[N:34]=2)=[N:9][NH:10][CH:11]=1)=[O:5]
Reactant: Nc1ccc(CN2CCOCC2)cc1N
Reactant: O=C(O)c1n[nH]cc1NC(=O)c1c(Cl)cccc1Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(Nc1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 25.5 %

Procedure:
A mixture of 4-(2,6-dichloro-benzoylamino)-1H-pyrazole-3-carboxylic acid (75 mg, 0.25 mmol), 4-morpholin-4-ylmethyl-benzene-1,2-diamine (52 mg, 0.25 mmol), EDC (58 mg, 0.3 mmol) and HOBt (41 mg, 0.3 mmol) in DMF (4 ml) was stirred at ambient temperature for 48 hours. The mixture was partitioned between EtOAc and saturated aqueous NaHCO3 and the organic portion washed with saturated aqueous NH4Cl, dried (MgSO4) and reduced in vacuo. The residue was taken up in AcOH and heated at 100° C. for 14 hours. cooled to ambient temperature and reduced in vacuo. The residue was purified via flash column chromatography eluting with CH2Cl2-MeOH (20:1-10:1) to give 2,6-dichloro-N-[3-(5-morpholin-4-ylmethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-benzamide (30 mg) as a pink solid. (LC/MS: Rt 2.12, [M+H]+ 471.14).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[CH2:16][CH2:15][CH2:14]2>C(#N)C.O>[Br:1][C:19]1[CH:18]=[C:17]2[C:13](=[CH:12][C:11]=1[O:10][CH3:9])[CH2:14][CH2:15][CH2:16]2
Reactant: COc1ccc2c(c1)CCC2
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: O
Product: COc1cc2c(cc1Br)CCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.6 %

Procedure:
N-bromosuccinimide (1.26 g, 7.1 mmol) was added to a solution of 5-methoxyindan 124 (1.0 g, 6.7 mmol) in acetonitrile (34 mL). The resulting mixture was stirred at room temperature overnight. The mixture was diluted with water (100 mL) and extracted with dichloromethane (3×50 mL). The combined organic extracts were dried with sodium sulfate and concentrated under reduced pressure. Flash chromatography (ISCO system, silica, 0-10% ethyl acetate in hexane) provided 125 (1.53 g, 100%) as a liquid.