Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]3[CH:33]=[C:32]([NH:34][C:35]4[CH:40]=[CH:39][C:38]([CH2:41][N:42]5[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]5)=[CH:37][N:36]=4)[C:31](=[O:49])[N:30]([CH3:50])[N:29]=3)[C:18]=1[CH2:19][O:20]C(=O)C)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].O>CO>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]3[CH:33]=[C:32]([NH:34][C:35]4[CH:40]=[CH:39][C:38]([CH2:41][N:42]5[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]5)=[CH:37][N:36]=4)[C:31](=[O:49])[N:30]([CH3:50])[N:29]=3)[C:18]=1[CH2:19][OH:20])[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(CN4CCN(C)CC4)cn3)c(=O)n(C)n2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CN1CCN(Cc2ccc(Nc3cc(-c4cccc(-n5ncc6cc(C(C)(C)C)cc(F)c6c5=O)c4CO)nn(C)c3=O)nc2)CC1
Temperature: 40 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
Acetic acid 2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-{1-methyl-5-[5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-benzyl ester (4.5 g, 6.61 mmol, Eq: 1.00) and potassium carbonate (1.37 g, 9.92 mmol, Eq: 1.50) were dissolved in methanol and heated at 40° C. for 1 hour. The reaction was cooled to room temperature and water was added dropwise. The reaction was stirred at room temperature overnight. The solid that formed was filtered, washed with water, and dried in a vacuum oven over the weekend to give 3.64 g (86.2%) of an off-white crystalline solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 9.39 (s, 1H) 8.53 (s, 1H) 8.50 (d, J=2.3 Hz, 1H) 8.15 (d, J=1.9 Hz, 1H) 7.86 (d, J=1.5 Hz, 1H) 7.74 (dd, J=13.4, 1.7 Hz, 1H) 7.57-7.62 (m, 1H) 7.50-7.57 (m, 2H) 7.43-7.49 (m, 2H) 4.52-4.61 (m, 1H) 4.40 (br. s., 2H) 3.77 (s, 3H) 3.36 (s, 2H) 2.30 (br. s., 8H) 2.11 (s, 3H) 1.37 (s, 9H). MS: (M+H)+=639.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=O)[CH:2]=1.C(Cl)(=O)C(Cl)=O.[CH2:18]1[C:27]2[C:22]3[C:23](=[CH:28][CH:29]=[CH:30][C:21]=3[CH2:20][N:19]1[CH2:31][CH2:32][CH2:33][CH2:34][NH2:35])[CH:24]=[CH:25][CH:26]=2>>[CH2:18]1[C:27]2[C:22]3[C:23](=[CH:28][CH:29]=[CH:30][C:21]=3[CH2:20][N:19]1[CH2:31][CH2:32][CH2:33][CH2:34][NH:35][C:9](=[O:11])[CH:8]=[CH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH:24]=[CH:25][CH:26]=2
Reactant: O=C(O)C=Cc1cccnc1
Reactant: NCCCCN1Cc2cccc3cccc(c23)C1
Agent: O=C(Cl)C(=O)Cl
Product: O=C(C=Cc1cccnc1)NCCCCN1Cc2cccc3cccc(c23)C1

Procedure:
Batch size: 1.8 g (12.1 mmol) 3-(3-pyridyl)-acrylic acid, 4.0 g (31.5 mmol) oxalyl chloride and 2.6 g (10.8 mmol) 4-(1H,3H-benzo[de]isoquinolin-2-yl)-butylamine.
Reaction SMILES: I.[C@H:2]1([NH:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH:22][C:23](=[NH:26])SC)[CH:18]=3)[N:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>C(O)C>[C@H:2]1([NH:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH:22][C:23]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[NH:26])[CH:18]=3)[N:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: C1COCCN1
Reactant: CSC(=N)Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Agent: I
Solvent: CCO
Product: N=C(Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1)N1CCOCC1
Yield: 51.6 %

Procedure:
1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-2-methyl-isothiourea hydroiodide (345 mg, 0.72 mmol) was dissolved in 10 mL ethanol. Morpholine (350 mg, 4 mmol) was added and the reaction mixture was refluxed overnight. The solvent was evaporated and the residue was purified by column chromatography (silica gel, dichloromethane/methanol 40:1). The title compound (144 mg, 51%) was obtained as a light yellow foam; MS: m/e=388.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:22])[C:9](=[CH:13][NH:14][C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][CH:16]=1)[C:10](O)=[O:11].[CH:23]1([N:29]=[C:30]=NC2CCCCC2)CCCCC1.CNC>C(Cl)Cl.C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:22])[C:9](=[CH:13][NH:14][C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][CH:16]=1)[C:10]([N:29]([CH3:30])[CH3:23])=[O:11]
Reactant: O=C(O)C(=CNc1ccc(I)cc1)C(=O)c1ccccc1Cl
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CNC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)C(=O)C(=CNc1ccc(I)cc1)C(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.4 %

Procedure:
To a suspension of 2-chloro-α-[[(4-iodophenyl)amino]methylene]-β-oxobenzenepropanoic acid (43 mg, 0.10 mmol) in 1 mL of CH2Cl2 was added N,N′-dicyclohexylcarbodiimide (21 mg, 0.10 mmol). The mixture was cooled in an ice bath and 50 μL (0.10 mmol) of a 2M solution of dimethylamine in THF was added. The reaction mixture was stirred at rt for 16 h. The formed DCU was removed by filtration. The filtrate was washed with water and evaporated to dryness. The title compound (22 mg, 50%) was isolated by column chromatography (5% MeOH in CH2Cl2); MS 410 (M−45), 455(M+1), 477(M+Na+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][CH:12]([C:16]1[N:21]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:20](=[O:29])[C:19]2=[C:30]([Cl:33])[CH:31]=[CH:32][N:18]2[N:17]=1)[CH:13]1[CH2:15][CH2:14]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:42][C:43]1[CH:51]=[CH:50][C:46]([C:47](Cl)=[O:48])=[CH:45][CH:44]=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:34])[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH:12]([C:16]1[N:21]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:20](=[O:29])[C:19]2=[C:30]([Cl:33])[CH:31]=[CH:32][N:18]2[N:17]=1)[CH:13]1[CH2:14][CH2:15]1)[C:47](=[O:48])[C:46]1[CH:50]=[CH:51][C:43]([Cl:42])=[CH:44][CH:45]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NCCCNC(c1nn2ccc(Cl)c2c(=O)n1Cc1ccccc1)C1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCN(C(=O)c1ccc(Cl)cc1)C(c1nn2ccc(Cl)c2c(=O)n1Cc1ccccc1)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.8 %

Procedure:
(±)-(3-{[(3-Benzyl-5-chloro-4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-cyclopropyl-methyl]-amino}-propyl)-carbamic acid tert-butyl ester (Example 22H, 16 mg, 0.033 mmol) in methylene chloride (1.5 mL) was treated with triethylamine (5 μL, 0.036 mmol), and p-chlorobenzoyl chloride (6 mg, 0.034 mmol) at 0° C. and the resulting mixture was stirred at room temperature for 1 h. The mixture was diluted with methylene chloride (5 mL), washed with saturated sodium bicarbonate, dried (MgSO4) and concentrated. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate/hexanes to give the title compound (8 mg) as a clear oil: MS (ESI+) 604.2 (M++H).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[Si:33]([O:40][CH2:41][C@H:42]([NH2:50])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[I:49])([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]>C1COCC1.C(N(CC)CC)C>[Si:33]([O:40][CH2:41][C@H:42]([NH:50][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[I:1])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[I:49])([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]
Reactant: O=C(O)c1ccccc1I
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](N)c1ccccc1I
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OC[C@H](NC(=O)c1ccccc1I)c1ccccc1I
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-iodobenzoic acid (0.66 g, 2.65 mmol) in THF (90 mL) is added HOBt (0.71 g, 5.3 mmol). After the mixture is stirred at RT for 15 min, EDCl (1.0 g, 5.3 mmol) is added followed by triethylamine (1.1 mL). The mixture is stirred at RT for 20 min then (R)-2-(tert-butyldimethylsilanyloxy)-1-(2-iodophenyl)-ethylamine (Org. Lett. 6, 513 (2004)) (1.0 g, 2.65 mmol) is added and stirring is continued for 18 h. The solvent is removed under reduced pressure and water is added to the residue. The mixture is extracted with EtOAc and the organic phase is washed with brine and dried over magnesium sulfate. The solvent is removed under reduced pressure and the residue purified by flash chromatography using a gradient of 0-60% EtOAc/hexane as eluent to give the title compound as a yellow solid.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([OH:9])=[O:8])[CH:6]=1.C([O-])([O-])=O.[K+].[K+].CC1(C)COB([C:23]2[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=2)OC1>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:28][N:27]1[C:23]([C:2]2[S:3][CH:4]=[C:5]([C:7]([OH:9])=[O:8])[CH:6]=2)=[CH:24][CH:25]=[N:26]1
Reactant: O=C(O)c1csc(Br)c1
Reactant: Cn1nccc1B1OCC(C)(C)CO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1nccc1-c1cc(C(=O)O)cs1
Temperature: 80 °C

Procedure:
To a solution of 2-bromo-4-thiophenecarboxylic acid (104 mg, 0.5 mmol) in dioxane/H2O (4:1, 10 mL) was added K2CO3 (271 mg, 1.99 mmol), tetrakistriphenylphosphine Pd(0) (28.7 mg, 0.025 mmol) and 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1-methyl-1H-pyrazole (97 mg, 0.5 mmol). The reaction mixture was heated to 80° C. in a sealed tube for 12 h and was then partitioned between 6N NaOH and DCM. The pH of the aqueous phase was adjusted to ˜3 with 3M HCl and washed several times with DCM. The combined organic fractions were dried (Na2SO4), concentrated under vacuum and used directly without further purification (104 mg, quant.): LC-MS (ES) m/z=209 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:24](=[O:40])[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[O:38][N:37]=[C:36]([CH3:39])[CH:35]=2)[CH:29]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:39][C:36]1[CH:35]=[C:34]([C:30]2[CH:29]=[C:28]([C:26]3[CH2:25][C:24](=[O:40])[NH:23][C:9]4[CH:10]=[C:11]([C:19]([F:20])([F:21])[F:22])[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])=[CH:13][C:8]=4[N:7]=3)[CH:33]=[CH:32][CH:31]=2)[O:38][N:37]=1
Reactant: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cc(C)no3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cc(C)no3)c1)=N2

Procedure:
The title compound was prepared from [2-{3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionylamino}-5-(methyl-propyl-amino)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M103) (0.26 g, 0.45 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (127 mg, 61%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:14](I)[CH3:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH2:14]([O:1][C:2]1[CH:9]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])[CH3:15]
Reactant: O=Cc1ccc(C(F)(F)F)cc1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(C(F)(F)F)ccc1C=O
Temperature: 70 °C
Reaction time: 2 h
Yield: 65.4 %

Procedure:
0.80 g of 2-hydroxy-4-(trifluoromethyl)benzaldehyde was dissolved in 8 ml dimethylformamide, and 0.78 g of ethyl iodide and 0.69 g of potassium carbonate were added, and the mixture was stirred at 70° C. for 2 hours. The reaction solution was diluted with water and then extracted with ethyl acetate. The organic layer was successively washed with 1N hydrochloric acid and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was subjected to silica gel column chromatography, and from fractions eluted with hexane-ethyl acetate (5:1), 0.60 g of 2-ethoxy-4-(trifluoromethyl)benzaldehyde was obtained.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([NH:29][C:30](=[O:32])[CH3:31])([CH2:24][O:25][C:26](=[O:28])[CH3:27])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12](B2OCC(C)(C)CO2)=[CH:11][C:10]=1[Cl:23])(=[O:3])[CH3:2].[Br:33][C:34]1[CH:39]=[CH:38][C:37](I)=[C:36]([F:41])[CH:35]=1.C(=O)([O-])O.[Na+].O>COCCOC>[C:26]([O:25][CH2:24][C:6]([NH:29][C:30](=[O:32])[CH3:31])([CH2:5][O:4][C:1](=[O:3])[CH3:2])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:37]2[CH:38]=[CH:39][C:34]([Br:33])=[CH:35][C:36]=2[F:41])=[CH:11][C:10]=1[Cl:23])(=[O:28])[CH3:27]
Reactant: CC(=O)NC(CCc1ccc(B2OCC(C)(C)CO2)cc1Cl)(COC(C)=O)COC(C)=O
Reactant: Fc1cc(Br)ccc1I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(=O)NC(CCc1ccc(-c2ccc(Br)cc2F)cc1Cl)(COC(C)=O)COC(C)=O
Reaction time: 24 h
Yield: 56.1 %

Procedure:
A mixed solution of N-{1,1-bis(acetoxymethyl)-3-[2-chloro-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl]propyl}acetamide (2.05 g) of Reference Example 22, 1-bromo-3-fluoro-4-iodobenzene (1.39 g), sodium hydrogen carbonate (2.02 g) and tetrakistriphenylphosphine palladium (51 mg) in 1,2-dimethoxyethane (30 mL)-water (10 mL) was stirred at 100° C. for 9 hr. The reaction mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Pyridine (20 mL) and acetic anhydride (2 mL) were added to the residue, and the mixture was stood at room temperature for one day. Water was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (1.30 g) as white crystals.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]=[CH2:26].C([O-])([O-])=O.[K+].[K+].CC(=O)CC>O>[CH2:26]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH:17]=[CH2:16]
Reactant: Oc1ccc(-c2ccc(O)cc2)cc1
Reactant: C=CCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: C=CCCCCCCCCCOc1ccc(-c2ccc(O)cc2)cc1
Yield: 41 %

Procedure:
A mixture of 10 g (0.053 mol) of 4,4′-Dihydroxy-biphenyl, 12.52 g (0.053 mol) of 11-Bromo-1-undecene, 7.42 g (0.053 mol) of K2CO3 and 120 mL of dry butanone is refluxed for 24 h, then the reaction mixture is allowed to return to room temperature. 100 mL of water is added, then the product is filtered off, washed with water and methanol. The resulting solid is recrystallised three times from butanone to give a pure white product (7.35 g, 41% yield).
Reaction SMILES: OCCCCC[CH:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:8]1.N1CCC([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][OH:35])CC1>>[OH:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH:12]1[CH2:7][CH2:8][N:9]([C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14])[CH2:10][CH2:11]1
Reactant: O=C(OCc1ccccc1)N1CCCC(CCCCCO)C1
Reactant: OCCCCCCC1CCNCC1
Product: O=C(OCc1ccccc1)N1CCC(CCCCCCO)CC1

Procedure:
Prepared similarly to Intermediate 64 from 6-(4-piperidinyl)-1-hexanol. LCMS (System B): tRET=3.00 min; MH+ 320
Reaction SMILES: O[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][N:3]=1.P(Cl)(Cl)([Cl:17])=O.N1C2C(=CC=CC=2)C=CC=1.[OH-].[Na+]>>[Cl:17][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cnc1O
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccc2ncccc2c1
Product: O=[N+]([O-])c1cc(C(F)(F)F)cnc1Cl
Temperature: 25 °C
Yield: 85.9 %

Procedure:
A mixture of 5.22 g of 2-hydroxy-3-nitro-5-(trifluoromethyl)pyridine, 4.2 g of phosphorus oxychloride and 2.0 g of quinoline was refluxed with heating for 5.5 hours. The reaction mixture was cooled down to room temperature, then, the reaction mixture was poured into ice water. This mixture was neutralized with a sodium hydroxide aqueous solution, then, the mixture was extracted with ethyl acetate twice. The combined organic layers were washed with water and saturated saline, dried over magnesium sulfate, then, concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, to obtain 4.88 g of 2-chloro3-nitro-5-(trifluoromethyl)pyridine.
Reaction SMILES: S(Cl)(Cl)=O.[N+:5]([C:8]1[C:9]([C:13]([OH:15])=[O:14])=[N:10][NH:11][CH:12]=1)([O-:7])=[O:6].[CH3:16][CH2:17]O>>[CH2:16]([O:14][C:13]([C:9]1[C:8]([N+:5]([O-:7])=[O:6])=[CH:12][NH:11][N:10]=1)=[O:15])[CH3:17]
Reactant: O=C(O)c1n[nH]cc1[N+](=O)[O-]
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1n[nH]cc1[N+](=O)[O-]
Reaction time: 48 h
Yield: 96 %

Procedure:
Thionyl chloride (2.90 ml, 39.8 mmol) was slowly added to a mixture of 4-nitro-3-pyrazolecarboxylic acid (5.68 g, 36.2 mmol) in EtOH (100 ml) at ambient temperature and the mixture stirred for 48 h. The mixture was reduced in vacuo and dried through azeotrope with toluene to afford 4-nitro-1H-pyrazole-3-carboxylic acid ethyl ester as a white solid (6.42 g, 96%). (1H NMR (400 MHz, DMSO-d6) δ 14.4 (s, 1H), 9.0 (s, 1H), 4.4 (q, 2H), 1.3 (t, 3H)).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9](=[O:25])[CH2:10][CH2:11][CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:14][CH2:13]2)=[C:4]([O:26]C)[CH:3]=1.B(Br)(Br)Br.C(Cl)Cl.[OH-].[NH4+]>ClC(Cl)C>[NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9](=[O:25])[CH2:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:16][CH2:17]2)=[C:4]([OH:26])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)CCC1CCN(CCNS(C)(=O)=O)CC1
Agent: BrB(Br)Br
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: CS(=O)(=O)NCCN1CCC(CCC(=O)c2cc(Cl)c(N)cc2O)CC1
Reaction time: 12 h
Yield: 70.7 %

Procedure:
1-[4-Amino-5-chloro-2-methoxyphenyl]-3-{1-[2-(methylsulfonyl) aminoethyl]-piperidin-4-yl}propan-1-one (1.19 g, 2.8 mmol), prepared as in Example 11, was dissolved in dichloroethane (50 mL). Boron tribromide in methylene chloride (4 mL, 1.0 g, 4.0 mmol) was added and the mixture was stirred for approximately 12 hours. The mixture was then poured over ice and methylene chloride (150 mL) and ammonium hydroxide) were added. This bilayer mixture was stirred until a solution had formed in the methylene chloride layer. The aqueous layer was removed and combined with fresh methylene chloride (100 mL) and this bilayer mixture was stirred. The methylene chloride layers were combined and dried over potassium carbonate. Filtration and concentration gave 1-(4-amino-5-chloro-2-hydroxyphenyl)-3-{1-[2-(methylsulfonyl)aminoethyl]piperidin-4-yl}propan-1-one (0.8 g, 2.0 -mmol)
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH2:12][C:13]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:14]=1[C:15]#[N:16].O.[OH-].[Li+]>CS(C)=O>[F:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([NH:12][C:13]2[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][C:14]=2[C:15]#[N:16])[CH:7]=1
Reactant: N#Cc1cc(C(F)(F)F)ccc1N
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1cc(C(F)(F)F)ccc1Nc1cc(F)ccc1[N+](=O)[O-]
Temperature: 55 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
Combine 2,4-difluoro-1-nitro-benzene (5.36 g, 33.69 mmol), 2-amino-5-trifluoromethyl-benzonitrile (5.701 g, 30.63 mmol) and lithium hydroxide monohydrate (2.57 g, 61.25 mmol) in methyl sulfoxide (DMSO, 70 ml). Heat the resulting mixture to 55° C. for 16 hours. Cool the reaction mixture to ambient temperature, then pour into approximately 250 ml of ice water and stir for one hour. Filter the resulting mixture, wash with a large amount of water and collect the precipitate to obtain 9.53 g of the title compound (29.30 mmol, 96% yield) as a yellow amorphous solid: Mass Spectrum (m/e): 324(M−1).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH2:27][CH3:28])[CH:24]=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:15]=3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.[CH3:35][O:36][CH2:37][C:38](Cl)=[O:39]>>[CH:31]1([CH2:30][O:29][C:22]2[CH:23]=[CH:24][C:25]([CH2:27][CH3:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:34])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:38](=[O:39])[CH2:37][O:36][CH3:35])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:32][CH2:33]1
Reactant: COCC(=O)Cl
Reactant: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c1
Agent: Cl
Product: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)COC)CC4)c(C)[nH]c23)c1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-ethylphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f50) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:2][C@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[C:4]#[CH:5].[N:22]([Si](C)(C)C)=[N+:23]=[N-:24]>CN(C=O)C.CO.[Cu](I)I>[N:22]1[NH:23][N:24]=[C:4]([C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2][CH2:1][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:5]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: C#C[C@H](CCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Agent: I[Cu]I
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC[C@H](NC(=O)OC(C)(C)C)c1cn[nH]n1
Temperature: 100 °C

Procedure:
To a solution of (S)-di-tert-butyl pent-4-yne-1,3-diyldicarbamate in DMF/MeOH (3.7 mL, 1.2:1) was added azidotrimethylsilane (330 μL, 2.38 mmol) and copper iodide (15 mg, 0.079 mmol). The mixture was heated at 100° C. for 16 h, cooled to rt then filtered through celite. The filtrate was concentrated in vacuo and the crude residue was purified via silica gel chromatography (EtOAc-Heptane) to afford the title compound. LCMS: Rt=0.68 min, m/z=342.1 (M+1) Method 2m_acidic.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:25]=[CH:24][N:23]=[C:22]([C:26](O)=[O:27])[CH:21]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:29]=1.Cl.[F:31][C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[CH2:38][NH:37][CH2:36][C:35]2([CH3:43])[CH3:42].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[F:31][C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[CH2:38][N:37]([C:26]([C:22]1[N:23]=[CH:24][N:25]=[C:20]([N:17]3[CH2:18][CH2:19][CH:14]([N:10]4[CH2:9][CH2:8][C:7]5[CH:29]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=5[NH:12][C:11]4=[O:13])[CH2:15][CH2:16]3)[CH:21]=1)=[O:27])[CH2:36][C:35]2([CH3:43])[CH3:42]
Reactant: CC1(C)CNCc2ccc(F)cc21
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)O)ncn3)CC1)C(=O)N2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)N4Cc5ccc(F)cc5C(C)(C)C4)ncn3)CC1)C(=O)N2

Procedure:
60 mg (0.15 mmol) 6-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylic acid, 33 mg (0.15 mmol) 6-fluoro-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinoline hydrochloride, 66 μL (0.47 mmol) TEA and 54 mg (0.17 mmol) TBTU were stirred in 1.5 mL DMF overnight at RT. The reaction mixture was purified by HPLC. The product-containing fractions were combined and freeze-dried.