Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[F:8][C:9]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:10]=1[O:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:19]=[C:20]3[CH2:31][CH2:30][NH:29][CH:28]([CH3:32])[C:21]3=[N:22][C:23]=2[NH:24][CH:25]([CH3:27])[CH3:26])[CH2:14][CH2:13]1.[CH3:38][N:39]([CH3:43])[C:40](Cl)=[O:41].CCN(C(C)C)C(C)C>C(Cl)Cl>[F:8][C:9]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:10]=1[O:11][CH:12]1[CH2:13][CH2:14][N:15]([C:18]2[N:19]=[C:20]3[CH2:31][CH2:30][N:29]([C:40]([N:39]([CH3:43])[CH3:38])=[O:41])[CH:28]([CH3:32])[C:21]3=[N:22][C:23]=2[NH:24][CH:25]([CH3:27])[CH3:26])[CH2:16][CH2:17]1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: CN(C)C(=O)Cl
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCNC2C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCN(C(=O)N(C)C)C2C

Procedure:
A solution of 2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-isopropyl-5-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (15 mg, 0.028 mmol), dimethylcarbamic chloride (6.1 mg, 0.056 mmol), and DIPEA (10.9 mg, 0.085 mmol) in DCM (282 μL) was stirred at room temperature overnight. Purification by HPLC Method A afforded the title compound as a TFA salt (6.1 mg) as an off-white film. 1H NMR (500 MHz, methanol-d4) δ ppm 1.26 (dd, J=9.3, 6.4 Hz, 6H), 1.50 (d, J=6.8 Hz, 3H), 1.89-1.98 (m, 2H), 2.12 (dq, J=13.2, 3.6 Hz, 2H), 2.55-2.64 (m, 1H), 2.88 (s, 6H), 2.94-3.03 (m, 3H), 3.34-3.41 (m, 3H), 3.72-3.82 (m, 1H), 4.14 (quin, J=6.5 Hz, 1H), 4.45 (dt, J=7.4, 3.8 Hz, 1H), 4.67 (q, J=6.8 Hz, 1H), 6.83-6.91 (m, 1H), 6.98 (ddd, J=11.4, 8.4, 3.2 Hz, 1H), 7.17 (td, J=9.3, 5.4 Hz, 1H); ESI-MS m/z [M+H]+ 489.90.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[N+:13]([C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=1[S:25](Cl)(=[O:27])=[O:26])([O-:15])=[O:14].N1C=CC=CC=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[N+:13]([C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=1[S:25]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:11][CH:12]=1)(=[O:27])=[O:26])([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)c([N+](=O)[O-])c1
Reactant: COC(=O)c1ccc(CN)cc1
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc(CNS(=O)(=O)c2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cc1
Reaction time: 2 h

Procedure:
A solution of methyl 4-(aminomethyl)benzoate (1.00 g, 4.96 mmol), 2,4-dinitrobenzenesulfonyl chloride (1.39 g, 5.21 mmol), DCM (16.5 mL) and pyridine (481 uL, 5.95 mmol) was treated with Hunig's base (2.17 mL, 12.4 mmol) and stirred for 2 h. The reaction was concentrated, taken into EtOAc and washed with 2M aq. HCl 2×, water, brine, dried (MgSO4) and concentrated to afford a brown oil used crude in the next reaction. MS: cal'd 396 (MH+), exp 396 (MH+).
Reaction SMILES: [C@@H:1]1([N:9]2[CH:13]=[C:12](I)[CH:11]=[C:10]2[N+:15]([O-:17])=[O:16])[O:6][C@H:5]([CH2:7][OH:8])[C@@H:3]([OH:4])[CH2:2]1.C(N(CC)CC)C.[CH2:25]([NH:28][C:29](=[O:33])[CH:30]([Cl:32])[Cl:31])[C:26]#[CH:27]>CN(C=O)C.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.[Cu]I>[C@@H:1]1([N:9]2[CH:13]=[C:12]([C:27]#[C:26][CH2:25][NH:28][C:29](=[O:33])[CH:30]([Cl:32])[Cl:31])[CH:11]=[C:10]2[N+:15]([O-:17])=[O:16])[O:6][C@H:5]([CH2:7][OH:8])[C@@H:3]([OH:4])[CH2:2]1
Reactant: C#CCNC(=O)C(Cl)Cl
Reactant: O=[N+]([O-])c1cc(I)cn1[C@H]1C[C@H](O)[C@@H](CO)O1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NCC#Cc1cc([N+](=O)[O-])n([C@H]2C[C@H](O)[C@@H](CO)O2)c1)C(Cl)Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 80.8 %

Procedure:
1-(2-Deoxy-β-D-ribofuranosyl)-4-iodo-2-nitropyrrole (Compound 1) (354 mg, 1.0 mmol), Pd(PPh3)4 (58 mg, 0.05 mmol), CuI (30 mg, 0.16 mmol) and triethylamine (209 μl, 1.5 mmol) were dissolved in DMF (3.5 ml), followed by addition of a 1 M DMF solution of N-(2-propynyl)-dichloroacetamide (1.5 ml, 1.5 mmol). After stirring at room temperature for 12 hours, the reaction mixture was partitioned between ethyl acetate and water, and the organic layer was washed three times with water. After drying over anhydrous sodium sulfate, the organic layer was concentrated and purified on a silica gel column (CH2Cl2:MeOH, 20:1, v/v) and by HPLC (34%-35% CH3CN, 12 minutes) to give Compound 3 (317 mg, 81%).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[N+:27]([O-])=O)=[CH:17][CH:16]=3)[CH:9]=2)[N:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>ClC1C=CC=CC=1Cl>[CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=2)[O:14][C:15]2[CH:20]=[CH:19][C:18]3[C:21]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[NH:27][C:17]=3[CH:16]=2)[N:3]=1
Reactant: Cc1cc(C)n(-c2cccc(Oc3ccc(-c4ccccc4[N+](=O)[O-])cc3)c2)n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Clc1ccccc1Cl
Product: Cc1cc(C)n(-c2cccc(Oc3ccc4c(c3)[nH]c3ccccc34)c2)n1
Yield: 91.2 %

Procedure:
A solution of 3,5-dimethyl-1-(3-(2′-nitrobiphenyl-4-yloxy)phenyl)-1H-pyrazole 3 (2.19 g, 5.68 mmol, 1.0 eq) and PPh3 (4.47 g, 17.04 mmol, 3.0 eq) in 1,2-dichlorobenzene (30 mL) was refluxed (175-185° C.) for 24 hours, then cooled, and the solvent was removed by distillation under high vacuum. The residue was purified through column chromatography on silica gel using hexane/ethyl acetate (10:1-5:1) as an eluent to obtain the desired product as a white solid (1.83 g in 92% yield). 1H NMR (DMSO-d6, 400 MHz): δ 2.11 (s, 3H), 2.28 (s, 3H), 6.02 (s, 1H), 6.92 (dd, J=8.4, 2.0 Hz, 1H), 7.05 (dd, J=8.4, 2.4 Hz, 1H), 7.10 (t, J=2.0 Hz, 1H), 7.13-7.16 (m, 2H), 7.22-7.25 (m, 1H), 7.32-7.36 (m, 1H), 7.46 (d, J=8.0, 1H), 7.47 (t, J=8.4 Hz, 1H), 8.07 (d, J=7.2 Hz, 1H), 8.12 (d, J=8.4 Hz, 1H), 11.25 (s, 1H). 13C NMR (DMSO-d6, 100 MHz): δ 12.30, 13.24, 101.46, 107.52, 110.92, 111.10, 113.37, 116.43, 118.09, 118.87, 119.12, 119.88, 121.50, 122.23, 125.23, 130.36, 139.24, 140.17, 140.68, 140.99, 148.10, 154.44, 158.21.
Reaction SMILES: [CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)=[CH:16][N:17]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH:25]([CH2:27][C:28](O)=[O:29])=[CH2:26].C1(N=C=NC2CCCCC2)CCCCC1>N1(C2C=CN=CC=2)CCCC1.ClCCl>[CH2:1]([C:7]1[CH:8]=[CH:9][C:10]([C:13]2[S:14][C:15]([C:18]3[CH:19]=[CH:20][C:21]([O:24][C:28]([CH2:27][CH:25]=[CH2:26])=[O:29])=[CH:22][CH:23]=3)=[CH:16][N:17]=2)=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1ccc(-c2ncc(-c3ccc(O)cc3)s2)cc1
Reactant: C=CCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Product: C=CCC(=O)Oc1ccc(-c2cnc(-c3ccc(CCCCCC)cc3)s2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 80.3 %

Procedure:
30 ml of dichloromethane was added to 2.0 g (5.93 mM) of 2-(4-hexylphenyl)-5-(4-hydroxyphenyl)-1,3-thiazole and 0.52 g (6.16 mM) of vinylacetic acid, followed by stirring at room temperature to the mixture, 1.21 g (5.86 mM) of N,N'-dicyclohexylcarbodiimide (DCC) and 0.02 g of 4-pyrrolidinopyridine were added, followed by stirring for 5 hours at room temperature. The resultant dicyclohexylurea was recovered by filtration, followed by washing with dichloromethane to be added to the filtrate. The resultant dichloromethane solution was condensed into a solid under reduced pressure, followed by purification by silica gel column chromatography (eluent: toluene) and recrystallization from a mixture solvent of ethanol/ethyl acetate to obtain 1.93 g of 2-(4-hexylphenyl)-5-(4-allylcarbonyloxyphenyl)-1,3-thiazole (Yield: 81.1%).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:18][C:17]3[CH:19]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:21]=[C:22]([Cl:23])[C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[NH:28]1[CH2:31][CH2:30][CH2:29]1>C(#N)C>[Cl:23][C:22]1[C:16]2[O:15][CH2:14][C@H:13]([CH2:12][N:28]3[CH2:31][CH2:30][CH2:29]3)[O:18][C:17]=2[CH:19]=[C:20]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3c(Cl)cc(S(C)(=O)=O)cc3O2)cc1
Reactant: C1CNC1
Solvent: CC#N
Product: CS(=O)(=O)c1cc(Cl)c2c(c1)O[C@@H](CN1CCC1)CO2

Procedure:
Preparation according to Example 57 using [(2R)-5-chloro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.027 g, 0.062 mmol), azetidine (0.1 ml), ACN (3 ml). MS m/z (rel. intensity, 70 eV) 317 (M+, 1), 85 (3), 71 (5), 70 (bp), 68 (2), 63 (3).
Reaction SMILES: [N+:1]([C:4]1[CH:20]=[CH:19][C:7]2[NH:8][C:9](=[O:18])/[C:10](=[CH:12]/[C:13]3[NH:14][CH:15]=[CH:16][CH:17]=3)/[S:11][C:6]=2[CH:5]=1)([O-])=O.O.NN>[Ni].C(O)C>[NH2:1][C:4]1[CH:20]=[CH:19][C:7]2[NH:8][C:9](=[O:18])/[C:10](=[CH:12]/[C:13]3[NH:14][CH:15]=[CH:16][CH:17]=3)/[S:11][C:6]=2[CH:5]=1
Reactant: O=C1Nc2ccc([N+](=O)[O-])cc2S/C1=C\c1ccc[nH]1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Product: Nc1ccc2c(c1)S/C(=C\c1ccc[nH]1)C(=O)N2

Procedure:
A catalytic amount of Raney nickel was added portionwise with stirring to a mixture of (Z)-7-nitro-2-[(pyrrol-2-yl)methylene]-2H-1,4-benzothiazin-3(4H)-one (Example 5) (0.43 g, 1.5 mmol) and hydrazine hydrate (98%) (0.8 ml) in ethanol (20 ml). The reaction mixture heated under reflux for 5.5 hours, then filtered and the solvent removed in vacuo. The product was purified by silica gel chromatography using a gradient of (98:2) to (95:5) toluene:ethanol as the mobile phase.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([O:9][CH3:10])[CH:3]=1.[Br:11][C:12]1[C:13](F)=[CH:14][C:15]([F:22])=[C:16]([CH:21]=1)[C:17]([O:19][CH3:20])=[O:18]>>[Br:11][C:12]1[C:13]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[O:9][CH3:10])=[CH:14][C:15]([F:22])=[C:16]([CH:21]=1)[C:17]([O:19][CH3:20])=[O:18]
Reactant: COc1cc(Cl)ccc1O
Reactant: COC(=O)c1cc(Br)c(F)cc1F
Product: COC(=O)c1cc(Br)c(Oc2ccc(Cl)cc2OC)cc1F
Yield: 41.5 %

Procedure:
Prepared according to Preparation 3 with 4-chloro-2-methoxyphenol (0.13 mL, 1.07 mmol) and methyl 5-bromo-2,4-difluorobenzoate (Preparation 18, 255 mg, 1.02 mmol) at room temperature for 18 hours. The crude product was purified by silica gel chromatography eluting with 5% EtOAc in Heptane to afford the title compound as a white solid (0.165 g).
Reaction SMILES: C[O:2][C:3]([C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[O:6]1)[CH2:12]2)=[O:4].[OH-].[Na+].Cl>CO.O>[C:5]12([C:3]([OH:4])=[O:2])[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[O:6]1)[CH2:12]2
Reactant: COC(=O)C12CC3CC(CC(C3)O1)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C12CC3CC(CC(C3)O1)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.6 %

Procedure:
To a solution of Example 54A (2.5 g, 12.6 mmol) in methanol/water (1:1, 100 mL), 5 N aqueous NaOH (3.8 mL, 19 mmol) was added. The mixture was stirred at room temperature for 3 hours and then extracted with dichloromethane to remove un-reacted starting material. The aqueous layer was acidified (pH˜2) with 6 N aqueous HCl and then extracted with dichloromethane. The combined acidic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure to afford 1.92 g of the title compound. MS (ESI+) m/z 183 (M+H)+
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20]C)=[O:19])=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>CC(O)=O>[N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([CH2:17][C:18]([OH:20])=[O:19])=[CH:15][CH:16]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)Cc1ccc(OCCCN2CCCCC2)cc1
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)Cc1ccc(OCCCN2CCCCC2)cc1
Temperature: 80 °C

Procedure:
To a stirring mixture of methyl 2-(4-(3-(piperidin-1-yl)propoxy)phenyl)acetate (570 mg) in HOAc (5 mL) was added 6N HCl (10 mL). The reaction mixture was warmed to 80° C. for 2 h. The crude product mixture was concentrated under reduced pressure and directly taken to the next reaction without further purification. Method[1], MS(ESI) 278.1 [M+H], Retention time=0.666 min.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]3[CH:19]=[C:20]([O:23][C:24]4[CH:29]=[C:28](Cl)[N:27]=[CH:26][N:25]=4)[CH:21]=[CH:22][C:13]2=3)=[O:11])[CH:6]=[CH:7][CH:8]=1.[CH3:33][NH2:34]>C1COCC1>[F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]3[CH:19]=[C:20]([O:23][C:24]4[CH:29]=[C:28]([NH:34][CH3:33])[N:27]=[CH:26][N:25]=4)[CH:21]=[CH:22][C:13]2=3)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: CN
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)N1CCCCc2cc(Oc3cc(Cl)ncn3)ccc21
Solvent: C1CCOC1
Product: CNc1cc(Oc2ccc3c(c2)CCCCN3C(=O)Nc2cccc(C(F)(F)F)c2)ncn1

Procedure:
A solution of 0.23 g (0.50 mMol) of 7-(6-chloro-pyrimidin-4-yloxy)-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide in 5 ml THF and 2 ml MeNH2 (2 M in THF) is kept at rt in a sealed vessel for 15 h. Then SiO2 is added and the mixture concentrated in vacuo. The resulting powder is put on top of a chromatography column (SiO2; hexane/EtOAc 95:5) and the title compound eluated with hexane/EtOAc 95:5→75:25→2:8: MS: [M+1]+=458; Anal.: C,H,N,F.
Reaction SMILES: [CH:1]1([N:7]2[C:11]([NH2:12])=[C:10]([C:13]([NH2:15])=[O:14])[C:9]([CH3:16])=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:17]1[CH:22]=[CH:21][C:20]([CH:23]=O)=[CH:19][CH:18]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH:1]1([N:7]2[C:11]3=[N:12][C:23]([C:20]4[CH:21]=[CH:22][N:17]=[CH:18][CH:19]=4)=[N:15][C:13](=[O:14])[C:10]3=[C:9]([CH3:16])[NH:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=Cc1ccncc1
Reactant: Cc1nn(C2CCCCC2)c(N)c1C(N)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1[nH]n(C2CCCCC2)c2nc(-c3ccncc3)nc(=O)c1-2
Yield: 31.7 %

Procedure:
1-Cyclohexyl-3-methyl-5-amino-1H-pyrazole-4-carboxamide (1.2 g, 5.4 mmol), 4-pyridinecarboxaldehyde (0.87 g, 8.1 mmol), toluene (125 ml) and p-toluenesulfonic acid monohydrate were combined and heated to reflux for 24 hours. The solvent was removed in vacuo and the residue was poured into water (450 ml). The obtained precipitate was collected by filtration, recrystallized from isopropanol (200 ml) and dried for 24 hours in high vacuum to afford 0.53 g (32%) of 1-cyclohexyl-3-methyl-6-(4-pyridyl)-pyrazolo[3,4-d]pyrimidin-4-one as a cream colored solid, m.p. 292°-293° C.
Reaction SMILES: C1C2C(COC([NH:18][C@H:19]([C:23]([N:25]([CH3:42])[C@@H:26]([C@@H:38]([CH3:41])[CH2:39][CH3:40])[C@H:27]([O:36][CH3:37])[CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:24])[CH:20]([CH3:22])[CH3:21])=O)C3C(=CC=CC=3)C=2C=CC=1.C(NCC)C>O1CCCC1.CC1CCCO1>[CH3:37][O:36][C@@H:27]([C@@H:26]([N:25]([CH3:42])[C:23](=[O:24])[C@H:19]([CH:20]([CH3:22])[CH3:21])[NH2:18])[C@@H:38]([CH3:41])[CH2:39][CH3:40])[CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:33])[CH3:34])=[O:30]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)OC(C)(C)C)OC)N(C)C(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Solvent: C1CCOC1
Solvent: CCNCC
Solvent: CC1CCCO1
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)OC(C)(C)C)OC)N(C)C(=O)[C@@H](N)C(C)C
Reaction time: 6 h

Procedure:
To a solution of #5 (26 g, 42 mmol, 1 eq.) in tetrahydrofuran (260 mL, 0.16 M) was added diethylamine (22 mL) over 30 minutes. The reaction was stirred for about 6 hours and the suspension was then filtered through Celite and washed with additional tetrahydrofuran (25 mL). The filtrate was concentrated in vacuo to provide a pale yellow oil, which was redissolved in 2-methyltetrahydrofuran (50 mL) and concentrated again to ensure complete removal of diethylamine. The crude oil of #6 (>15.25 g) was taken into the next step without further purification.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[CH2:20]([N:22]([CH2:31][CH3:32])[CH2:23][CH2:24][CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[CH3:21]>C(OCC)(=O)C>[CH2:31]([N:22]([CH2:20][CH3:21])[CH2:23][CH2:24][CH:25]1[CH2:26][CH2:27][N:28]([C:2]([N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[NH:7][C:6]3[CH:16]=[CH:17][CH:18]=[N:19][C:5]2=3)=[O:3])[CH2:29][CH2:30]1)[CH3:32]
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Reactant: CCN(CC)CCC1CCNCC1
Solvent: CCOC(C)=O
Product: CCN(CC)CCC1CCN(C(=O)N2c3ccccc3C(=O)Nc3cccnc32)CC1
Yield: 34 %

Procedure:
Prepared analogously to Example 4 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 4-[2-(diethylamino)ethyl]piperidine in a yield of 34% of theory. Colourless crystals, m.p. 154° C. (ethyl acetate).
Reaction SMILES: [CH3:1][CH2:2][N:3]1[C:9]2[N:10]=[C:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[N:12]=[CH:13][C:8]=2[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4]1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[S:33])=[CH:27][CH:26]=1>>[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]([N:17]2[CH2:18][CH2:19][N:14]([C:11]3[N:12]=[CH:13][C:8]4[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4][N:3]([CH2:2][CH3:1])[C:9]=4[N:10]=3)[CH2:15][CH2:16]2)=[S:33])=[CH:27][CH:26]=1
Reactant: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCNCC3)nc21
Reactant: COc1ccc(N=C=S)cc1
Product: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCN(C(=S)Nc4ccc(OC)cc4)CC3)nc21

Procedure:
Pipemidic acid (30 mg, 0.0989 mmol) and 4-methoxyphenyl isothiocyanate (13.7 μL, 0.0989 mmol) were used. Purification on silica yielded compound 24 in Table 1, below (37 mg, 80%). 1H NMR (300 MHz, CDCl3) δ 9.33 (s, 1H), 8.67 (s, 1H), 7.30 (s, 1H), 7.15 (d, J=8.76 Hz, 2H), 6.90 (d, J=8.82 Hz, 2H), 4.34 (q, J=7.10 Hz, 2H), 4.25-3.92 (m, 8H), 3.81 (s, 3H), 1.49 (t, J=7.12 Hz, 3H) ppm.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[F-].[Cs+]>O1CCOCC1>[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=2)=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Product: FC(F)(F)c1ccc(-c2ccc(OCc3ccccc3)cc2)nc1
Temperature: 105 °C

Procedure:
A mixture of 2-chloro-5-trifluoromethylpyridine (1.81 g, 10 mmol), 4-benzyloxyphenyl boronic acid (2.74 g, 12 mmol) and CsF (5.32 g, 35 mmol) in dioxane (40 mL) is degassed and filled with nitrogen. PdCl2 (dppf) (200 mg) is added under nitrogen, the reaction mixture is heated at 105° C. overnight. The mixture is cooled to room temperature, diluted with ethyl acetate (100 mL), filtered through a pad of Celite. The filtrate is concentrated and the residue is purified by column chromatography on silica gel giving the title compound (2.55 g, 77.4%).
Reaction SMILES: [CH:1]1([CH:4]([OH:18])[CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=2[O:16][CH3:17])[CH2:3][CH2:2]1.C(=O)=O.CC(O)C>>[CH:1]1([C@@H:4]([OH:18])[CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=2[O:16][CH3:17])[CH2:3][CH2:2]1
Reactant: COc1cc([N+](=O)[O-])ccc1OCC(O)C1CC1
Agent: O=C=O
Solvent: CC(C)O
Product: COc1cc([N+](=O)[O-])ccc1OC[C@H](O)C1CC1

Procedure:
Racemic 1-cyclopropyl-2-(2-methoxy-4-nitrophenoxy)ethanol (45.1 g, mmol) in 2/1 MeCN/1-PrOH (451 mL) was resolved by chiral chromatography resolution using a CHIRALPAK® AD-H (3×25 cm, 5 μm) column under the Chiral-SFC conditions. The chromatographic conditions employed an 85/15 mixture of CO2/i-PrOH as the mobile solvent with a flow rate of 130 mL/min at 35° C. with the BPR pressure maintained at 100 bar and detector wavelength at 234 nM. Each 0.7 mL injection required a run time of 7 min. The chiral purity of the R enantiomer was determined to be greater than 99.9% at 234 nm based on SFC/UV area % using analytical SFC conditions. Concentration of the resultant eluant under vacuum using a rotary evaporator yielded (R)-1-cyclopropyl-2-(2-methoxy-4-nitrophenoxy)ethanol as yellow oil. Subsequent dissolution in 150 ml EtOH and reconcentration yielded the title compound in the form of a yellow oil which solidified to form a light yellow solid (20.9 g) upon drying under high vacuum overnight. M.P. 77° C. 1H NMR (400 MHz, CDCl3): δ ppm 0.30-0.37 (m, 1H), 0.42-0.50 (m, 1H), 0.55-0.69 (m, 2H), 0.97-1.08 (m, 1H), 2.40-2.70 (bs, 1H), 3.41 (ddd, J=8.3, 8.3, 2.7 Hz, 1H), 3.93 (s, 3H), 4.10 (dd, J=9.3, 8.0 Hz, 1H), 4.23 (dd, J=9.3, 2.7 Hz, 1H), 6.95 (d, J=8.8 Hz, 1H), 7.74 (d, J=2.2 Hz, 1H), 7.89 (dd, J=8.8, 2.2 Hz, 1H). 13C NMR (100 MHz, CDCl3) ppm 153.7, 149.2, 141.7, 117.6, 111.5, 106.7, 74.4, 73.5, 56.2, 13.4, 2.7, 2.0. HPLC: 6.26 min retention time, 98.7% API; ZORBAX® column SB C18 4.6×75 mm; flow rate 2.5 ml/min; Gradient solvent system: from 100% A:0% B to 0% A:100% B for 8 min (Solvent A: 10% MeOH−90% H2O=0.2% H3PO4; Solvent B: 90% MeOH−10% H2O+0.2% H3PO4) Detection at 220 nm. LC/MS: m/e=254.3 (M+H).
Reaction SMILES: C([O:4][C:5](=[O:83])[CH2:6][C@H:7]([OH:82])[C@H:8]([NH:16][C:17](=[O:81])[C@H:18]([NH:40][C:41](=[O:80])[C@H:42]([NH:50][C:51](=[O:79])[CH2:52][C@H:53]([OH:78])/[CH:54]=[CH:55]/[CH2:56][CH2:57][S:58][C:59]([C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=1)([C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH2:19][S:20][C:21]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)C=C.N1CCOCC1>CO.C(Cl)Cl.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>[OH:82][C@H:7]([C@H:8]([NH:16][C:17](=[O:81])[C@H:18]([NH:40][C:41](=[O:80])[C@H:42]([NH:50][C:51](=[O:79])[CH2:52][C@H:53]([OH:78])/[CH:54]=[CH:55]/[CH2:56][CH2:57][S:58][C:59]([C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)([C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=1)[C:60]1[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=1)[CH2:43][C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)[CH2:19][S:20][C:21]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:6][C:5]([OH:83])=[O:4]
Reactant: C=CCOC(=O)C[C@H](O)[C@@H](Cc1ccccc1)NC(=O)[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)[C@@H](Cc1ccccc1)NC(=O)C[C@H](O)/C=C/CCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: C1COCCN1
Solvent: ClCCl
Product: O=C(O)C[C@H](O)[C@@H](Cc1ccccc1)NC(=O)[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)[C@@H](Cc1ccccc1)NC(=O)C[C@H](O)/C=C/CCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 3 h
Yield: 70.7 %

Procedure:
To a solution of 4E (210 mg, 0.184 mmol), Pd(PPh3)4 (21 mg, 0.018 mmol) in dry methanol/CH2Cl2 (5:1, 6 mL) under argon was added morpholine (32 μL, 0.37 mmol) which was allowed to stir for 3 h. The reaction mixture was concentrated in vacuo, CH2Cl2 (20 mL) was then added before washing with 1M HCl (15 mL), sat. sodium hydrogen carbonate (15 mL), sat. brine (15 mL), dried over MgSO4 and concentrated in vacuo. Purification was then carried out by column chromatography on silica gel (6-10% MeOH/CH2Cl2) to give 5E (140 mg, 0.13 mmol, 69%).