Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:28])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[NH:17][C:18]([C:20]2[S:21][C:22]([CH2:26]Br)=[CH:23][C:24]=2[Cl:25])=[O:19])=[CH:4][CH:3]=1.[NH:29]1[CH2:34][CH2:33][S:32][CH2:31][CH2:30]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:28])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[NH:17][C:18]([C:20]2[S:21][C:22]([CH2:26][N:29]3[CH2:34][CH2:33][S:32][CH2:31][CH2:30]3)=[CH:23][C:24]=2[Cl:25])=[O:19])=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(Cl)cc1)c1cc(Cl)ccc1NC(=O)c1sc(CBr)cc1Cl
Reactant: C1CSCCN1
Product: O=C(Nc1ccc(Cl)cc1)c1cc(Cl)ccc1NC(=O)c1sc(CN2CCSCC2)cc1Cl
Yield: 73.9 %

Procedure:
In a similar manner to that described in Paragraph A above, N-(4-chlorophenyl)-2-[((5-(bromomethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide (0.5 g, 1.0 mmol) was reacted with thiomorpholine (0.5 mL, 4.8 mmol). Purification by flash chromatography on silica gel afforded 0.4 g (73% yield) of N-(4-chlorophenyl)-2-[((5-((thiomorpholin-4-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide; as a pale yellow powder; NMR (CDCl3) 11.0 (s, 1), 9.0 (s, 1), 8.2 (d, 1), 7.8 (d, 2), 7.5 (d, 1), 7.4 (d, 2), 7.4 (s, 1), 7.2 (dd, 1), 3.7 (s, 2), 2.8 (m, 4), 2.7 (m, 4) ppm.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([C:11]2[S:12][C:13]([C:16]3[C:20]([CH3:21])=[C:19]([C:22]([F:25])([F:24])[F:23])[O:18][N:17]=3)=[CH:14][CH:15]=2)=[O:10])[CH2:4]1.C(N(CC)CC)C.[C:33](Cl)(=[O:35])[CH3:34]>C1COCC1>[CH3:21][C:20]1[C:16]([C:13]2[S:12][C:11]([C:9]([N:5]3[CH2:6][CH2:7][CH2:8][C@@H:3]([NH:2][C:33](=[O:35])[CH3:34])[CH2:4]3)=[O:10])=[CH:15][CH:14]=2)=[N:17][O:18][C:19]=1[C:22]([F:25])([F:24])[F:23]
Reactant: CC(=O)Cl
Reactant: Cc1c(-c2ccc(C(=O)N3CCC[C@@H](N)C3)s2)noc1C(F)(F)F
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N[C@@H]1CCCN(C(=O)c2ccc(-c3noc(C(F)(F)F)c3C)s2)C1
Reaction time: 48 h
Yield: 82.2 %

Procedure:
A suspension of ((R)-3-Amino-piperidin-1-yl)-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-methanone, hydrochloride (Example 27, 79 mg, 0.2 mmol) in THF (2 mL) was treated with triethylamine (70 μL, 0.5 mmol) followed by acetyl chloride (22 μL, 0.3 mmol). The reaction mixture was allowed to stir 48 hr, evaporated and chromatographed on silica gel with EtOAc then MeOH/EtOAc (10%) as eluant to afford product as a colorless solid (66 mg, 83%). 1H NMR (CDCl3) 1.65 (m, 2 H), 1.81 (m, 1 H), 1.95 (s, 3 H), 2.00 (obs m, 1 H), 2.33 (d, J=1.3, 3 H), 3.30 (m, 2 H), 3.98 (m, 2 H), 4.10 (br d, J=11.0, 1 H), 6.10 (br d, J=6.6, 1 H), 7.43 (d, J=4.0, 1 H), 7.49 (br s, 1 H). 13C NMR 7.9, 23.5, 30.1, 46.5, 51.0 (br), 114.8, 118.7 (q, J=271), 128.3, 129.7, 131.7, 140.1, 155.2 (J=40), 157.9, 163.3, 170.3 19F NMR −63.1. LC/MS 5.72 min, [M+1]+ 402.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11]#[CH:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17]>C(N)CCC.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>[O:8]([CH2:9][CH2:10][C:11]#[C:12][C:14]1[CH:20]=[CH:19][CH:18]=[C:16]([NH2:17])[CH:15]=1)[Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: C#CCCO[Si](C)(C)C(C)(C)C
Reactant: Nc1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCN
Product: CC(C)(C)[Si](C)(C)OCCC#Cc1cccc(N)c1

Procedure:
A mixture of 1-(t-butyldimethylsilyloxy)-3-butyne (10 mmol) and m-bromoaniline (10 mmol) in n-butylamine (50 mL) under a nitrogen atmosphere is treated with tetrakis(triphenylphosphine)palladium (0) (0.17 g) and then heated to reflux for 18 hr. After removing the solvent in vacuo, the residue is dissolved in CH2Cl2 and washed with saturated NaHCO3. The combined organic solution is dried over magnesium sulfate, filtered and evaporated to give the above described silyl protected adduct.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:42]=[CH:41][C:25]([O:26][C:27]2[CH:40]=[CH:39][C:30]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36](O)=[O:37])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C([O:46][C:47](=[O:51])[CH2:48][NH:49][CH3:50])C>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([N:49]([CH3:50])[CH2:48][C:47]([OH:46])=[O:51])=[O:37])=[CH:39][CH:40]=2)=[CH:41][CH:42]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CNC
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCCCCC(=O)O)cc2)cc1
Agent: Cl
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCCCCC(=O)N(C)CC(=O)O)cc2)cc1

Procedure:
The product from Example 234B and N-methylglycine ethyl ester hydrochloride were processed as described in Example 251A and B to provide the titled compound. 1H NMR (500 MHz, DMSO-d6) δ12.20-13.15 (br.s, 1 H), 8.94 (s, 1 H), 7.23 (m, 7 H), 7.03 (t, 1 H), 6.95 (m, 6 H), 6.82 (d, 2 H), 4.12 (s, 1 H), 4.04 (s, 2 H), 4.00 (s, 2 H), 3.94 (m, 3 H), 3.01 (s, 2 H), 2.91 (s, 3 H), 2.81 (s, 1 H), 2.40 (m, 4 H), 2.27 (t, 1 H), 1.58-1.79 (m, 4 H); MS (ESI+) m/z 660 (M+H)+.
Reaction SMILES: I[C:2]1[C:3]([O:20][CH3:21])=[CH:4][C:5]([CH:17]([CH3:19])[CH3:18])=[C:6]([CH:16]=1)[O:7][C:8]1[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1.C[Si](C)(C)[C:24]#[C:25][CH3:26].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)C>[CH:17]([C:5]1[CH:4]=[C:3]([O:20][CH3:21])[C:2]([C:24]#[C:25][CH3:26])=[CH:16][C:6]=1[O:7][C:8]1[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1)([CH3:19])[CH3:18]
Reactant: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1I
Reactant: CC#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC#Cc1cc(Oc2cnc(N)nc2N)c(C(C)C)cc1OC
Temperature: 50 °C
Reaction time: 22 h
Yield: 118.5 %

Procedure:
5-(5-Iodo-2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine (1.0 g, 2.5 mmol), bis(triphenylphosphine)palladium dichloride (290 mg, 0.25 mmol), 1-(trimethylsilyl)-1-propyne (0.44 mL, 3 mmol) and tetrabutyl ammonium fluoride (3 mL, 3 mmol) were added to 20 mL dry THF under nitrogen. The reaction mixture was stirred under nitrogen at 50° C. for 22 hours, then 150 mg of bis(triphenylphosphine)-Palladium dichloride, 0.22 mL of 1-(trimethylsilyl)-1-propyne and 1.5 mL tetrabutyl ammonium fluoride, and 0.1 mL ethanol were added to the reaction mixture. The reaction mixture was stirred under nitrogen for 18 hours at 50° C. The reaction mixture was cooled and poured into saturated aqueous NaHCO4 and extracted into EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was chromatographed on 125 g of flash silica (2%-4% MeOH/CH2Cl2) to give 925 mg of 5-(2-isopropyl-4-methoxy-5-prop-1-ynyl-phenoxy)-pyrimidine-2,4-diamine, MS (M+H)=313.
Reaction SMILES: C[O:2][C:3]([C:5]1([C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:9][C:8]2[CH:10]=[C:11]([OH:14])[CH:12]=[CH:13][C:7]=2[O:6]1)=[O:4].[Cl:19][C:20]1[CH:25]=[C:24]([CH2:26][C:27]([F:30])([F:29])[F:28])[CH:23]=[CH:22][C:21]=1[O:31][CH2:32][CH2:33][CH2:34]I>>[C:15]([C@@:5]1([C:3]([OH:2])=[O:4])[CH2:9][C:8]2[CH:10]=[C:11]([O:14][CH2:34][CH2:33][CH2:32][O:31][C:21]3[CH:22]=[CH:23][C:24]([CH2:26][C:27]([F:28])([F:29])[F:30])=[CH:25][C:20]=3[Cl:19])[CH:12]=[CH:13][C:7]=2[O:6]1)([CH3:18])([CH3:17])[CH3:16]
Reactant: COC(=O)C1(C(C)(C)C)Cc2cc(O)ccc2O1
Reactant: FC(F)(F)Cc1ccc(OCCCI)c(Cl)c1
Product: CC(C)(C)[C@@]1(C(=O)O)Cc2cc(OCCCOc3ccc(CC(F)(F)F)cc3Cl)ccc2O1

Procedure:
The title compound was prepared following the general procedure described in Example 1, Step 4, employing the chiral phenol prepared in step 1 and the iodide prepared in Example 14, Step 2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([Cl:14])=[CH:12][CH:11]=[C:10]([C:15](N(OC)C)=[O:16])[CH:9]=2)=[CH:4][CH:3]=1.CC(C[AlH]CC(C)C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([Cl:14])=[CH:12][CH:11]=[C:10]([CH:15]=[O:16])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CON(C)C(=O)c1ccc(Cl)c(-c2ccc(Cl)cc2)c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: O=Cc1ccc(Cl)c(-c2ccc(Cl)cc2)c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 87.1 %

Procedure:
4′,6-Dichloro-N-methoxy-N-methylbiphenyl-3-carboxamide (1.0 g, 3.2 mmol, 1.0 eq) was dissolved in dry THF and stirred for 10 minutes. The solution was cooled to −78° C. and DIBAL-H (1 M solution, 1.83 g, 12.9 mmol, 4 eq, 13 mL) was slowly added over 15-30 minutes. The reaction mixture was stirred for 1 h at −78° C., quenched with saturated NH4Cl solution at −78° C. and stirred for 30 minutes at ambient temperature. Water and ethyl acetate were added into the reaction mixture. The aqueous layer was separated and extracted twice with ethyl acetate. The organic layer was dried with anhydrous Na2SO4 and concentrated under vacuum to give the desired product (0.7 g, 87%). 1H NMR (400 MHz, CDCl3) δ 7.06-7.09 (d, 2H), 7.24-7.27 (d, 2H), 7.40 (s, 1H), 7.55-7.58 (d, 1H), 7.90-7.95 (m, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=3)[S:10][C:3]=12.[CH3:17][NH:18][C:19]([C:21]1[C:29]2[C:24](=[CH:25][C:26]([OH:30])=[CH:27][CH:28]=2)[N:23]([CH3:31])[CH:22]=1)=[O:20].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:17][NH:18][C:19]([C:21]1[C:29]2[C:24](=[CH:25][C:26]([O:30][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[C:9]([C:11]5[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=5)[S:10][C:3]=34)=[CH:27][CH:28]=2)[N:23]([CH3:31])[CH:22]=1)=[O:20]
Reactant: Cn1ccnc1-c1cc2nccc(Cl)c2s1
Reactant: CNC(=O)c1cn(C)c2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CNC(=O)c1cn(C)c2cc(Oc3ccnc4cc(-c5nccn5C)sc34)ccc12

Procedure:
This material was prepared by the reaction of 7-chloro-2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridine 1e with 6-hydroxy-1-methyl-1H-indole-3-carboxylic acid methylamide 21b and Cs2CO3 in a manner as previously described for example 1. 1H NMR (300 MHz, CDCl3) δ8.43 (1H, d, J=5.5 Hz), 8.05 (1H, d, J=8.7 Hz), 7.67 (1H, s), 7.61 (1H, s), 7.17 (1H, d, J=2.1 Hz), 7.13 (1H, s), 7.08 (1H, dd, J=2.1, 8.7 Hz), 7.02 (1H, s), 6.54 (1H, d, J=5.5 Hz), 3.95 (3H, s), 3.75 (3H, s), 3.01 (3H, s). LCMS (ESI+) [M+H]/z Calc'd 418, found 418. Anal. (C22H19N5O2S.0.25EtOAc) C, H, N.
Reaction SMILES: S([O:6][CH3:7])(OC)(=O)=O.[OH-].[Na+].O[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][N:12]=1.Cl>>[CH3:11][N:12]1[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:7]1=[O:6]
Reactant: COS(=O)(=O)OC
Reactant: O=[N+]([O-])c1ccc(O)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cn1cc([N+](=O)[O-])ccc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.8 %

Procedure:
To a mixture containing 20.0 ml (211.40 mmol) of dimethyl sulfate and 45 ml of 3N sodium hydroxide was added 4.00 g (28.55 mmol) of 2-hydroxy-5-nitropyridine in portions over 15 min. After complete addition, the reaction was allowed to stir at 25° C. overnight. The reaction was acidified with 1N HCl and the solids filtered, washed with ethanol and dried to afford 1.31 g (29.77%) of product.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].Br[C:8]1[CH:28]=[CH:27][C:11]([CH2:12][CH:13]2[C:22]3[C:17](=[CH:18][C:19]([O:25][CH3:26])=[C:20]([O:23][CH3:24])[CH:21]=3)[CH2:16][CH2:15][NH:14]2)=[CH:10][CH:9]=1.[OH-].[Na+].[F:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Na+].[Na+].O.O.C(O)(=O)C(O)=O>CC([O-])=O.CC([O-])=O.[Pd+2].C(Cl)Cl>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[F:31][C:32]1[CH:37]=[CH:36][C:35]([C:8]2[CH:28]=[CH:27][C:11]([CH2:12][CH:13]3[C:22]4[C:17](=[CH:18][C:19]([O:25][CH3:26])=[C:20]([O:23][CH3:24])[CH:21]=4)[CH2:16][CH2:15][NH:14]3)=[CH:10][CH:9]=2)=[CH:34][CH:33]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: COc1cc2c(cc1OC)C(Cc1ccc(Br)cc1)NCC2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C(O)C(=O)O
Solvent: ClCCl
Solvent: O
Product: COc1cc2c(cc1OC)C(Cc1ccc(-c3ccc(F)cc3)cc1)NCC2
Temperature: 25 °C

Procedure:
1-(4′-Fluoro-biphenyl-4-ylmethyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline oxalate (37) was prepared as follows: 1-(4-bromo-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline oxalate (0.452 g, 1 mmol) was added to a mixture of 20 mL CH2Cl2 and 20 ml of 1N NaOH. The reaction mixture was stirred at room temperature. After dissolving of precipitate organic phase was separated, dried over Na2SO4, filtered and evaporated. A residue was dissolved in 6 mL i-PrOH. 4-Fluoro-phenyl-boronic acid (0.153 g, 1.09 mmol) was added. The resulting solution was stirred for 30 min at room temperature. Pd(OAc)2 (1 mg, 0.0045 mmol), PPh3 (9 mg, 0.034 mmol) and 2N Na2CO3 (1 mL, 2 mmol) were added, the reaction mixture was refluxed for 6 h under Ar and evaporated. A residue was dissolved in chloroform and washed with 1N NaOH. Organic phase was dried under Na2SO4, filtered and evaporated. A residue was dissolved in MeOH, a solution of oxalic acid dihydrate (0.259 g, 2.05 mmol) was added under reflux. Oxalic acid salt was crystallized from MeOH-Et2O mixture. Yield is 0.294 g (62.9%).
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[C:30]([C:32]1[CH:37]=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][N:33]=1)#[N:31]>>[F:29][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:35]3[CH:36]=[CH:37][C:32]([C:30]#[N:31])=[N:33][CH:34]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:27])[CH3:28])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: CC1(C)OB(c2ccc(C#N)nc2)OC1(C)C
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2ccc(C#N)nc2)CC1

Procedure:
In analogy to the procedure described for the synthesis of example 6, the title compound was synthesized from (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-methanone (intermediate 1) and 2-cyanopyridine-5-boronic acid pinacol ester. The title compound was obtained in 51% yield as yellow foam. MS (m/e): 508.4 (MH+, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[C:6]([N+:16]([O-:18])=[O:17])=[CH:5][C:4]=1[NH:19]C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[C:6]([N+:16]([O-:18])=[O:17])=[CH:5][C:4]=1[NH2:19]
Reactant: COc1cc(N2CCN(C)CC2)c([N+](=O)[O-])cc1NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(N2CCN(C)CC2)c([N+](=O)[O-])cc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 59 %

Procedure:
tert-Butyl N-[2-methoxy-4-(4-methylpiperazin-1-yl)-5-nitrophenyl]carbamate (Intermediate 15, 1.4 g, 3.82 mmol) was dissolved in CH2Cl2 (20 mL) and TFA (5 mL) was then added. The mixture was stirred for 2 h at r.t. and was then concentrated in vacuo. The resulting residue was dissolved in CH3OH, absorbed onto an SCX column, washed with CH3OH and eluted with methanolic ammonia. The fractions that contained product were combined and concentrated. Purification by FCC, eluting with 1.5% 7N methanolic ammonia in CH2Cl2 gave the title compound (0.6 g, 59%) as an orange oil which crystallised on standing; 1H NMR: 2.22 (3H, s), 2.39-2.47 (4H, m), 2.87-2.97 (4H, m), 3.88 (3H, s), 4.99 (2H, s), 6.72 (1H, s), 7.20 (1H, s); m/z: ES+ MH+ 267.5.
Reaction SMILES: [NH2:1][C:2]1[C:10]([NH2:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[C:13]([C:16]1[CH:21]=[CH:20][C:19]([CH:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]2)=[CH:18][CH:17]=1)(O)=[O:14].ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[NH2:1][C:2]1[C:3]([C:4](=[O:5])[NH2:6])=[CH:7][C:8]([Cl:12])=[CH:9][C:10]=1[NH:11][C:13]([C:16]1[CH:21]=[CH:20][C:19]([CH:22]2[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:26][CH2:27]2)=[CH:18][CH:17]=1)=[O:14]
Reactant: NC(=O)c1cc(Cl)cc(N)c1N
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)O)cc2)CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)Nc3cc(Cl)cc(C(N)=O)c3N)cc2)CC1

Procedure:
A solution of 2,3-diamino-5-chlorobenzamide (0.75 g), tert-butyl 4-(4-carboxyphenyl)-piperidine-1-carboxylate (0.17 g), 1-hydroxybenzotriazole (HOBT, 0.22 g), benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP, 0.85 g) and diisopropylethylamine (DIPEA, 0.85 mL) in DMF (5 mL) was stirred for 18 hours and concentrated. The concentrate was flash chromatographed on silica gel with 10% methanol/dichloromethane.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][N:5]([CH2:9][CH2:10][CH2:11][CH2:12][O:13]C2C=C(C=CN=2)C#N)[CH2:4][CH2:3]1.CN1CCCNCC1.ClCCCCO.C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>C(O)CCC.O>[CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][N:5]([CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[CH2:4][CH2:3]1
Reactant: CN1CCCN(CCCCOc2cc(C#N)ccn2)CC1
Agent: CN1CCCNCC1
Agent: O=C([O-])[O-]
Agent: OCCCCCl
Solvent: O
Solvent: CCCCO
Product: CN1CCCN(CCCCO)CC1
Temperature: 95 °C
Reaction time: 36 h

Procedure:
2-[4-(4-Methyl-[1,4]diazepan-1-yl)-butoxy]-isonicotinonitrile. To a solution of 1-methyl-[1,4]diazepane (21.3 g, 185 mmol, 2.0 equiv) and 4-chloro-butan-1-ol (10.0 g, 92.6 mmol, 1.0 equiv) in 1-butanol (200 mL) were added K2CO3 (38.0 g, 278 mmol, 3.0 equiv) and NaI (13.9 g, 92.6 mmol, 1.0 equiv). The mixture was warmed to 95° C. and stirred for 36 h. The mixture was then cooled to rt, diluted with water, and extracted with chloroform (3×100 mL). The combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated. Purification by Method 2 afforded 9.3 g of 4-(4-methyl-[1,4]diazepan-1-yl)-butan-1-ol with a small unidentified impurity. A portion of the impure alcohol (5.0 g) was dissolved in DMF (50 mL) and cooled to 0° C. Sodium hydride (60% dispersion in oil, 1.29 g, 32.2 mmol, 1.2 equiv) was added. The mixture was warmed to rt, stirred for 1 h, and then re-cooled to 0° C. A solution of 2-chloro-isonicotinonitrile (3.72 g, 26.8 mmol, 1.0 equiv) in DMF (25 mL) was added dropwise. The mixture was stirred at rt for 18 h, then was diluted with water (25 mL) and satd. aq. NaHCO3 (100 mL), and was extracted with chloroform (3×100 mL). The combined extracts were washed with brine, dried (Na2SO4), filtered and concentrated. Purification by Method 2 afforded the title compound (1.0 g). MS (electrospray): mass calculated for C16H24N4O, 288.20; m/z found, 289.4 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.28 (dd, J=4.4 Hz, 0.8 Hz, 1H), 7.05 (dd, J=3.9, 1.1 Hz, 1H) 6.96 (s, 1H), 4.33 (t, J=6.6 Hz, 2H), 2.75-2.68 (m, 4H), 2.65-2.57 (m, 4H), 2.56-2.49 (m, 2H), 2.35 (s, 3H), 1.84-1.74 (m, 4H), 1.66-1.55 (m, 2H).
Reaction SMILES: [C:1](C1NC=CN=1)(C1NC=CN=1)=[O:2].[CH:13]1([CH2:19][CH2:20][C:21]([NH:23][CH:24]2[C:25](=[N:41][OH:42])[NH:26][C:27]3[CH:40]=[CH:39][CH:38]=[CH:37][C:28]=3[C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[N:30]2)=[O:22])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>C1COCC1>[CH:13]1([CH2:19][CH2:20][C:21]([NH:23][CH:24]2[N:30]=[C:29]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:28]3[CH:37]=[CH:38][CH:39]=[CH:40][C:27]=3[N:26]3[C:1](=[O:2])[O:42][N:41]=[C:25]23)=[O:22])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: O=C(CCC1CCCCC1)NC1N=C(c2ccccc2)c2ccccc2NC1=NO
Solvent: C1CCOC1
Product: O=C(CCC1CCCCC1)NC1N=C(c2ccccc2)c2ccccc2-n2c1noc2=O

Procedure:
Carbonyl diimidazole (35 mg, 0.21 mmol) was added to a solution of (Z)-3-cyclohexyl-N-(2,3-dihydro-2-hydroxyimino-5-phenyl-1H-1,4-benzodiazepin-3-yl)propanamide (80 mg, 0.2 mmol) in THF (15 mL) and the mixture was heated under reflux for 1 h. The solvent was evaporated under reduced pressure and the residue was triturated with ethanol (6 mL). The solid was collected and dried in vacuo to give 3-cyclohexyl-N-{1-oxo-6-phenyl-1H ,4H-[1,2,4}oxadiazolo[4,3-a][1,4]benzodiazepin-4-yl}propanamide as a solid, m.p. 226° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=1)=[CH:10][CH:9]=2)=[O:5])C.Br[C:26]1[CH:37]=[CH:36][C:29]([O:30][C:31]([CH3:35])([CH3:34])[CH2:32][OH:33])=[CH:28][CH:27]=1>>[C:21]([C:18]1[CH:19]=[CH:20][C:15]([C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[N:7]([C:26]2[CH:37]=[CH:36][C:29]([O:30][C:31]([CH3:35])([CH3:34])[CH2:32][OH:33])=[CH:28][CH:27]=2)[C:6]([C:4]([OH:3])=[O:5])=[CH:14]3)=[CH:16][CH:17]=1)([CH3:23])([CH3:22])[CH3:24]
Reactant: CC(C)(CO)Oc1ccc(Br)cc1
Reactant: CCOC(=O)c1cc2cc(-c3ccc(C(C)(C)C)cc3)ccc2[nH]1
Product: CC(C)(CO)Oc1ccc(-n2c(C(=O)O)cc3cc(-c4ccc(C(C)(C)C)cc4)ccc32)cc1

Procedure:
The title compound was prepared in accordance with Example 1 using 5-(4-tert-butylphenyl)indole-2-carboxylic acid ethyl ester and 2-(4-bromophenoxy)-2-methylpropan-1-ol.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([NH:18][C@@H:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C@@H:20]1[NH:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=2)[N:29]=[C:28]([NH:38]CC2C=CC(OC)=CC=2)[N:27]=1)=[N:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N+]1([O-])CCOCC1.O>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[C:14]([O:13][C:11]([NH:10][C:9]([NH:18][C@@H:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C@@H:20]1[NH:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=2)[N:29]=[C:28]([NH2:38])[N:27]=1)=[N:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[O:12])([CH3:15])([CH3:16])[CH3:17]
Reactant: COc1ccc(CNc2nc(N[C@H]3CCCC[C@H]3NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c3cc(OC)ccc3n2)cc1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Solvent: O
Product: COc1ccc2nc(N)nc(N[C@H]3CCCC[C@H]3NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c2c1
Reaction time: 9 h
Yield: 66.2 %

Procedure:
A solution of 1.76 g of (1R,2S)-N-[N,N′-bis(tert-butoxycarbonyl)]amidino-2-[2-(4-methoxybenzylamino)-6-methoxyquinazolin-4-yl]aminocyclohexylamine in 80 mL of methylene chloride was combined with 3.17 g of N-methylmorpholine-N-oxide and 95 mg of tetrapropylammonium perruthenate, and stirred for 9 hours. The reaction solution was combined with water, extracted with methylene chloride, and dried. After the solvent was distilled off, the residue was purified by column chromatography on silica gel (chloroform:methanol 10:1) to obtain 0.95 g of the desirable compound.