Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[F:15][C:16]([F:26])([F:25])[O:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:24][C:21]2[CH:22]=[CH:23][C:18]([O:17][C:16]([F:15])([F:25])[F:26])=[CH:19][CH:20]=2)=[C:3]([C:11]([F:14])([F:13])[F:12])[CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)c(C(F)(F)F)c1
Reactant: Oc1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=[N+]([O-])c1ccc(Oc2ccc(OC(F)(F)F)cc2)c(C(F)(F)F)c1
Temperature: 95 °C
Yield: 92.8 %

Procedure:
A mixed solution composed of 44.3 g of 1-chloro-4-nitro-2-trifluoromethylbenzene, 98 mL of N,N-dimethylacetamide, 35 g of 4-trifluoromethoxyphenol, and 20.4 g of potassium carbonate was stirred with heating at 90 to 100° C. for 3 hr. This reaction solution was concentrated under the reduced pressure. Ethyl acetate was then added to and dissolved in the residue, and the solution was washed with brine. The solution was then concentrated under the reduced pressure. n-Hexane was added to the residue, and the precipitated crystals were collected by filtration to give 66.9 g of 4-nitro-1-(4-trifluoromethoxyphenoxy)-2-trifluoromethylbenzene (yield 92.7%).
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[C:4](Cl)=[O:5])[CH3:2].[NH:9]1[CH:13]=[N:12][C:11]([S:14]([CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)(=[O:16])=[O:15])=[N:10]1.Cl>N1C=CC=CC=1.ClCCl>[CH:18]1([CH2:17][S:14]([C:11]2[N:12]=[CH:13][N:9]([C:4]([N:3]([CH2:7][CH3:8])[CH2:1][CH3:2])=[O:5])[N:10]=2)(=[O:16])=[O:15])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: CCN(CC)C(=O)Cl
Reactant: O=S(=O)(CC1CCCCC1)c1nc[nH]n1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCN(CC)C(=O)n1cnc(S(=O)(=O)CC2CCCCC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.7 %

Procedure:
Diethylcarbamoyl chloride (1.2 ml; 9.4 mmol) was added to cyclohexylmethyl 1,2,4-triazol-3-yl sulfone (2.0 g; 8.7 mmol) in dry pyridine (10 ml) under dry nitrogen, and the solution stirred at room temperature overnight. The resulting mixture was poured into 2M hydrochloric acid (40 ml) at 2° C. and the cloudy solution extracted into ethyl acetate (3×60 ml). The extracts were combined, dried (Na2SO4), filtered and evaporated, to afford a colorless oil which was dissolved in 95% dichloromethane, 5% acetonitrile, and the solution filtered through silica. Evaporation afforded 3-(cyclohexylmethylsulfonyl)-N,N-diethyl-1,2,4-triazole-1-carboxamide (2.82 g; 98%) as white crystals, m.p. 40°-46° C. (Found, C: 51.04; H: 7.39; N: 17.01; S: 9.81. C14H24N4O3S requires C: 51.20; H: 7.37; N: 17.06; S: 9.76%). NMR - d(CDCl3 ; 90 MHz) 0.80-2.30 (17H, m), 3.31 (2H, d, J=6.1 Hz), 3.61 (4H, m) and 8.92 (1H, s).
Reaction SMILES: O.[NH2:2][NH2:3].[N:4]1([C:10](SC)=[C:11]([C:14]#[N:15])[C:12]#[N:13])[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1>CO>[NH2:13][C:12]1[NH:3][N:2]=[C:10]([N:4]2[CH2:9][CH2:8][O:7][CH2:6][CH2:5]2)[C:11]=1[C:14]#[N:15]
Reactant: CSC(=C(C#N)C#N)N1CCOCC1
Reactant: NN
Solvent: O
Solvent: CO
Product: N#Cc1c(N2CCOCC2)n[nH]c1N
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
2.78 ml (56 mmol) of hydrazine hydrate are added to a slurry of 9.8 9 (46.8 mmol) of 3-(morpholin-4-yl)-3methylsulfanyl-2-cyanoacrylonitrile in 60 ml of methanol and heated to boiling, with the solid dissolving. After 3.5 hours, the reaction mixture is cooled to RT, concentrated by evaporation and recrystallised from ≈70 ml of boiling ethanol, yielding 5-amino-3-(morpholin-4-yl)-1H-pyrazole-4-carbonitrile: m.p. 199-201° C.; TLC: Rf=0.19 (ethyl acetate/toluene=3 3:1).
Reaction SMILES: [C:1]([C:4]1([C:7]([NH:9][C:10]2[CH:40]=[CH:39][C:13]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]#[C:25][CH:26]5[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]5)[S:23][C:16]=34)=[C:12]([F:41])[CH:11]=2)=[O:8])[CH2:6][CH2:5]1)(=[O:3])[NH2:2].F[C:43]([F:48])(F)[C:44](O)=O>>[F:41][C:12]1[CH:11]=[C:10]([N:9]([C:4]2[CH:5]=[CH:6][C:43]([F:48])=[CH:44][CH:1]=2)[C:7]([C:4]2([C:1]([NH2:2])=[O:3])[CH2:6][CH2:5]2)=[O:8])[CH:40]=[CH:39][C:13]=1[O:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]2[CH:21]=[C:22]([C:24]#[C:25][CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[S:23][C:16]=12
Reactant: CC(C)(C)OC(=O)N1CCC(C#Cc2cc3nccc(Oc4ccc(NC(=O)C5(C(N)=O)CC5)cc4F)c3s2)CC1
Reactant: O=C(O)C(F)(F)F
Product: NC(=O)C1(C(=O)N(c2ccc(F)cc2)c2ccc(Oc3ccnc4cc(C#CC5CCNCC5)sc34)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 117.6 %

Procedure:
A mixture of tert-butyl 4-(2-(7-(4-(1-(carbamoyl)cyclopropanecarboxamido)-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)ethynyl)piperidine-1-carboxylate (Example 124, Step B, 20 mg, 0.0297 mmol) and 2,2,2-trifluoroacetic acid (339 mg, 2.97 mmol) were stirred at room temperature for 30 minutes. The reaction was concentrated in vacuo, using toluene to azeotrope (3×5 mL). The residue was partioned between EtOAc (5 mL) and 1:1 water/saturated aqueous NaHCO3 (5 mL). The phases were separated and the aqueous phase was re-extracted with EtOAc (2×5 mL). The combined organic phases were washed with brine (5 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The product was purified by preparative TLC (0.5 mm thickness, Rf=0.22), eluting with 10% MeOH (containing 7N NH3) in CHCl3. The product was obtained as a beige powder (10 mg, 55%). HPLC: 93% purity (220 nm); LRMS (APCI+): 94% purity, 220 nm, m/z 573 (M+1) detected; 1H NMR (400 MHz, CDCl3) δ 10.07 (s, 1H), 8.47 (d, J=6 Hz, 1H), 8.30 (s, 1H), 7.76 (m, 1H), 7.52 (s, 1H), 7.44 (m, 2H), 7.24 (m, 2H), 7.06 (t, J=9 Hz, 2H), 6.51 (d, J=6 Hz, 1H), 3.12 (m, 3H), 2.79 (m, 3H), 2.00 (m, 2H), 1.80 (m, 4H), 1.62 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([O:21][C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=2)[CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18](=[S:20])[NH2:19])=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[K].Cl[CH:34]([CH:40]=O)[C:35]([O:37][CH2:38][CH3:39])=[O:36].C(O)(=O)C.CN(C)C(=O)C>O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([O:21][C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=2)[CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18]1[S:20][C:34]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:40][N:19]=1)=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Cl)C=O
Reactant: CS(=O)(=O)c1ccc(Oc2cc(OCc3ccccc3)c3[nH]c(C(N)=S)cc3c2)cc1
Agent: [K]
Solvent: CC(=O)O
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCOC(=O)c1cnc(-c2cc3cc(Oc4ccc(S(C)(=O)=O)cc4)cc(OCc4ccccc4)c3[nH]2)s1
Temperature: 100 °C
Reaction time: 4 h
Yield: 71.3 %

Procedure:
A mixture of 7-(benzyloxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carbothioamide (280 mg), ethyl 2-chloro-3-oxopropanoate potassium salt (234 mg), acetic acid (0.5 mL) and N,N-dimethylacetamide (5 mL) was stirred at 100° C. for 4 h. Ethyl 2-chloro-3-oxopropanoate potassium salt (234 mg) and acetic acid (0.5 mL) were added again, and the mixture was stirred at 100° C. for 3 h. Furthermore, ethyl 2-chloro-3-oxopropanoate potassium salt (234 mg) and acetic acid (0.5 mL) were added and the mixture was stirred at 100° C. for 7 h. Water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=5/95 to 50/50, volume ratio) to give the title compound (242 mg, crude yield 71%) as a yellow solid. MS 549 (MH+).
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:21]=[C:22]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]4)[CH:23]=[CH:24][CH:25]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[CH2:36]([S:44][C:45]1[CH:46]=[C:47](B(O)O)[CH:48]=[CH:49][CH:50]=1)[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[C:10]1[N:11]=[C:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([C:47]3[CH:48]=[CH:49][CH:50]=[C:45]([S:44][CH2:36][CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH:46]=3)=[CH:35][CH:34]=2)[N:8]([C:20]2[CH:21]=[C:22]([N:26]3[S:30](=[O:31])(=[O:32])[NH:29][C:28](=[O:33])[CH2:27]3)[CH:23]=[CH:24][CH:25]=2)[CH:9]=1
Reactant: OB(O)c1cccc(SCCc2ccccc2)c1
Reactant: O=C1CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)c2)S(=O)(=O)N1
Product: O=C1CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4cccc(SCCc5ccccc5)c4)cc3)c2)S(=O)(=O)N1

Procedure:
5-{3-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (119 mg, 0.2 mmol) was treated as described in general procedure G using 3-(phenethylsulfanyl)phenylboronic acid (104 mg, 0.4 mmol, prepared according to general procedure I) to give 5-{3-[4-(2,4-dichloro-phenyl)-2-(3′-phenethylsulfanyl-biphenyl-4-ylmethyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C1([O:24][C:25](=O)[NH:26][CH2:27][CH:28]2[CH2:33][CH2:32][C:31]([N:40]([CH3:42])[CH3:41])([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:30][CH2:29]2)C=CC=CC=1>O1CCOCC1>[CH3:41][N:40]([CH3:42])[C:31]1([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:32][CH2:33][CH:28]([CH2:27][NH:26][C:25]([N:15]2[CH2:16][CH2:17][CH:12]([C:6]3[C:5]4[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=4)[NH:8][CH:7]=3)[CH2:13][CH2:14]2)=[O:24])[CH2:29][CH2:30]1
Reactant: COc1ccc2[nH]cc(C3CCNCC3)c2c1
Reactant: CN(C)C1(c2ccccc2)CCC(CNC(=O)Oc2ccccc2)CC1
Solvent: C1COCCO1
Product: COc1ccc2[nH]cc(C3CCN(C(=O)NCC4CCC(c5ccccc5)(N(C)C)CC4)CC3)c2c1
Yield: 30.1 %

Procedure:
In each case 5-methoxy-3-piperidine-4-yl-1H-indole (169.3 mg, 0.735 mmole) in dioxane (4.5 ml) and the diastereoisomer mixture of (4-dimethylamino-4-phenylcyclohexylmethyl)-carbamic acid phenyl ester (259.0 mg, 0.735 mmole) were dissolved in two microwave reaction vessels. The reaction mixture was treated with microwave radiation as follows: experiment 1 (150° C., 52 minutes) and experiment 2 (200° C., 2 minutes). In each experiment the reaction mixture was worked up by distilling off the solvent in vacuo. The respective residue contained, apart from phenol, also the two diastereomers of 4-(5-methoxy-1H-indol-3-yl)piperidine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexylmethyl)-amide. The diastereoisomers were separated and purified by flash chromatography on silica gel (30 g and 40 g). Methanol/EE (1:1, ca. 600 ml) was used as eluent. The non-polar diastereoisomer of 4-(5-methoxy-1H-indol-3-yl)piperidine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexylmethyl)-amide [experiment 1 (116 mg, m.p. 106°-107° C., 32%) and experiment 2 (89 mg, m.p. 110°-112° C., 25%)], and the polar diastereoisomer of 4-(5-methoxy-1H-indol-3-yl)piperidine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexylmethyl)-amide [experiment 1 (108 mg, m.p. 98°-100° C., 30%) and experiment 2 (92 mg, m.p. 92°-97° C., 26%)] were thereby obtained in pure form.
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:10][CH:11]([CH3:13])[CH3:12])[C:7]([OH:9])=O)(=[O:3])[CH3:2].ClC(OCC)=O.[NH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>O1CCCC1.C(N(CC)CC)C>[C:1]([S:4][CH2:5][CH:6]([CH2:10][CH:11]([CH3:13])[CH3:12])[C:7]([NH:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[O:9])(=[O:3])[CH3:2]
Reactant: NCCN1CCOCC1
Reactant: CC(=O)SCC(CC(C)C)C(=O)O
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)SCC(CC(C)C)C(=O)NCCN1CCOCC1
Temperature: -5 °C
Reaction time: 0.33 h
Yield: 51.6 %

Procedure:
2-[(Acetylthio)methyl]-4-methylpentanoic acid (2.0 g) is dissolved in 40 ml of tetrahydrofuran (THF) and 1.0 g of triethylamine. This solution is cooled to -5° C. and ethyl chloroformate in 5 ml of THF is added dropwise. The reaction mixture is stirred at -5° C. for 20 minutes and then N-(2-aminoethyl)morpholine [1.3 g] in 20 ml of THF is added dropwise. It is stirred at 20° C. for 4 hours and stored at 0° C. for about 16 hours. Triethylamine hydrochloride is filtered off and the filtrate is concentrated in vacuo. This residue is dissolved in ether and washed once with aqueous NaHCO3 and twice with water. The ether is dried with MgSO4, filtered and concentrated in vacuo to yield 1.6 g of material. This is purified by dissolving 0.6 g in 2 ml of ether and placing it on top of a pad of alumina (activity II 10 g). The column is washed through with 250 ml of ether which is concentrated in vacuo. Product crystallizes and is washed with 1:5 ether-pentane. The remainder of the crude is seeded with a small crystal and then washed with 1:5 ether-pentane. Total yield is 1.0 g of the title compound, melting point 54°-59° C.
Reaction SMILES: [Br:1][C:2]1[CH:30]=[C:29]([CH3:31])[C:5]([C:6]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:18][CH2:17][CH2:16][C@H:15]3[CH2:19][O:20]C(=O)C3C=CC=CC=3)[CH2:10][CH2:9]2)=[O:7])=[C:4]([CH3:32])[CH:3]=1.[OH-].[Li+]>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[C:4]([CH3:32])[C:5]([C:6]([N:8]2[CH2:9][CH2:10][CH:11]([N:14]3[CH2:18][CH2:17][CH2:16][C@H:15]3[CH2:19][OH:20])[CH2:12][CH2:13]2)=[O:7])=[C:29]([CH3:31])[CH:30]=1
Reactant: Cc1cc(Br)cc(C)c1C(=O)N1CCC(N2CCC[C@H]2COC(=O)c2ccccc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(Br)cc(C)c1C(=O)N1CCC(N2CCC[C@H]2CO)CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 68.4 %

Procedure:
To a solution of 2.20 g (4.4 mmol) of benzoic acid (S)-1-[1-(4-bromo-2,6-dimethyl-benzoyl)-piperidin-4-yl]-pyrrolidin-2-ylmethyl ester in 120 ml of THF/MeOH (1:1) was added 11.0 ml (11.0 mmol) of lithium hydroxide solution (1 molar in water) drop by drop and the reaction mixture was then heated up to 50° C. After 2 hours, the solvents were evaporated and the residue poured into crashed ice and extracted twice with CH2Cl2; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 1:0 to 9:1) to give 1.19 g (68%) of the title compound as light yellow oil. MS: 395.2 (MH+, 1 Br).
Reaction SMILES: [C:1]([C:4]1[CH:24]=[CH:23][C:7]2[N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:12]=3)[CH:9]=[N:10][C:6]=2[CH:5]=1)(=O)[CH3:2].Cl.[CH2:26]([O:28][NH2:29])[CH3:27]>C(O)C>[CH2:26]([O:28][N:29]=[C:1]([C:4]1[CH:24]=[CH:23][C:7]2[N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:12]=3)[CH:9]=[N:10][C:6]=2[CH:5]=1)[CH3:2])[CH3:27]
Reactant: CC(=O)c1ccc2c(c1)ncn2-c1cccc(-c2cccnc2)c1
Reactant: CCON
Agent: Cl
Solvent: CCO
Product: CCON=C(C)c1ccc2c(c1)ncn2-c1cccc(-c2cccnc2)c1
Temperature: 70 °C

Procedure:
32a from Example 5 (5 g, 15.97 mmol) is suspended in absolute ethanol (50 ml) and heated to 70° C. O-Ethyl hydroxylamine hydrochloride (2.4 g, 24.61 mmol) is added and the mixture is heated to reflux for 1.5 hours. After cooling the solvent is removed by evaporation, and the residue is stirred with aqueous sodium hydroxide (50 ml, 1 M). The crude product is filtered off. Column-chromatographic workup on silica gel using a mixture of ethyl acetate and ethanol (9:1) as the eluent affords pure 33a. Yield: 3.7 g (65%). Mp 105-106° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14]Cl)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[NH2:21][C:22]1[C:27]([Br:28])=[CH:26][C:25]([O:29][CH2:30][CH2:31][CH2:32][NH:33][CH3:34])=[CH:24][C:23]=1[Br:35]>C(N(CC)CC)C>[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][N:33]([CH3:34])[CH2:32][CH2:31][CH2:30][O:29][C:25]3[CH:24]=[C:23]([Br:35])[C:22]([NH2:21])=[C:27]([Br:28])[CH:26]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Reactant: CNCCCOc1cc(Br)c(N)c(Br)c1
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)CCCOc1cc(Br)c(N)c(Br)c1)CC2

Procedure:
The title compound is prepared from [3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-1-chloropropane, N-[3-(4-amino-3,5-dibromo-phenyloxy)-propyl]-methylamine and triethylamine analogously to Example 6.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C@H:4]([NH:12][CH2:13][CH2:14][NH:15]C(OC(C)(C)C)=O)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:23])[C@H:4]([NH:12][CH2:13][CH2:14][NH2:15])[CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)[C@@H](Cc1ccccc1)NCCNC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@@H](Cc1ccccc1)NCCN
Temperature: 25 °C
Reaction time: 1 h
Yield: 125.3 %

Procedure:
(2R)-2-(2-(tert-Butoxycarbonylamino)ethylamino)-3-phenylpropionic acid methyl ester (1.32 g; 4.094 mmol) was dissolved in methylene chloride (10 ml) and trifluoroacetic acid (10 ml) was added. The reaction mixture was stirred for 1 hour at room temperature. The solvent was evaporated in vacuo and the residue was dissolved in methylene chloride (5 ml) and evaporated in vacuo. Methylene chloride (5 ml) was added and evaporated in vacuo to afford 1.14 g of (2R)-2-(2-aminoethylamino)-3-phenylpropionic acid methyl ester as a trifluoroacetate salt.
Reaction SMILES: [N:1]1([C:6]2[CH:18]=[CH:17][C:9]([O:10][C@@H:11]3[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[CH2:20][C:21]1[CH:29]=[CH:28][C:24]2[O:25][CH2:26][O:27][C:23]=2[CH:22]=1.C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>CN(C=O)C.C(OCC)(=O)C.CO>[N:1]1([C:6]2[CH:18]=[CH:17][C:9]([O:10][C@@H:11]3[CH2:16][CH2:15][CH2:14][N:13]([CH2:20][C:21]4[CH:29]=[CH:28][C:24]5[O:25][CH2:26][O:27][C:23]=5[CH:22]=4)[CH2:12]3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1cn(-c2ccc(O[C@@H]3CCCNC3)cc2)cn1
Reactant: ClCc1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: c1cn(-c2ccc(O[C@@H]3CCCN(Cc4ccc5c(c4)OCO5)C3)cc2)cn1
Temperature: 50 °C

Procedure:
(3R)-3-[4-(Imidazol-1-yl)phenoxy]piperidine (150 mg, 0.61 mmol) was dissolved in DMF (2 mL) and was added to a solution of 5-chloromethyl-1,3-benzodioxole (0.16 ml in 50% methylene chloride, 1.0 eq.) in DMF, followed by the addition of K2CO3 (2.5 eq.) and NaI (0.1 eq.). The resulting mixture was heated at 50° C. for 1 hour. The solvent was evaporated and flash column chromatography on silical gel with 3% methanol in methylene chloride gave a crude product (112 mg). Additional flash chromatography with 3% methanol in ethyl acetate afforded (3R)-3-[4-(imidazol-1-yl)phenoxy]-1-[(1,3-benzodioxol-5-yl)methy]piperidine (70 mg), 1H NMR (CDCl3) 7.75 (s, 1), 7.30 (d, 2), 7.20 (d, 2), 7.00 (d, 2), 6.85 (s, 1), 6.75 (d, 2), 5.90 (s, 2), 4.40 (m, 1), 3.50 (s, 2), 3.00 (m, 1), 2.70 (m, 1), 2.20 (m, 3), 1.85 (m, 1), 1.50 (m, 2) ppm.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=3)[NH2:23])[CH2:14][CH2:13]2)[N:3]=1.[C:27]([O:31][C:32]([N:34]1[CH2:40][CH2:39][CH2:38][C@H:35]1[CH:36]=O)=[O:33])([CH3:30])([CH3:29])[CH3:28].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([NH:23][CH2:36][CH:35]4[CH2:38][CH2:39][CH2:40][N:34]4[C:32]([O:31][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:33])[CH:24]=[CH:25][CH:26]=3)[CH2:16][CH2:17]2)[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: Cc1ccc2c(N3CCN(CCc4cccc(NCC5CCCN5C(=O)OC(C)(C)C)c4)CC3)cccc2n1
Reaction time: 24 h
Yield: 39.8 %

Procedure:
3-{2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6, 115 mg) and N-(tert-butoxycarbonyl)-L-prolinal (1.2 equiv., 79 mg) were stirred in methanol (2 mL) until the mixture became a clear solution. Then, sodium triacetoxyborohydride (1.2 eq., 85 mg) was added. After 24 h the reaction mixture was loaded onto an ion-exchange cartridge (SCX-2) and eluted with methanol followed by ammonia/methanol (1M). The combined basic fractions were concentrated in vacuo and purified by column chromatography (SPE cartridge, silica) using DCM-methanol (95:5) as eluent to afford the title compound (70 mg, 40% yield).
Reaction SMILES: S(Cl)(Cl)=O.[NH:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]([OH:16])=[O:15])=[CH:13][C:8]=2[N:7]=[CH:6]1.[CH3:17]O>>[NH:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]([O:16][CH3:17])=[O:15])=[CH:13][C:8]=2[N:7]=[CH:6]1
Reactant: CO
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc2[nH]cnc2c1
Temperature: 0 °C
Yield: 90 %

Procedure:
Thionyl chloride (10 mL) was added dropwise to a solution of 1H-benzo[d]imidazole-5-carboxylic acid (4.8 g, 30 mmol) in MeOH (150 mL) cooled to 0° C. The reaction mixture was heated at reflux for 18 h, and then solvent (about 2/3) was concentrated under reduced pressure. After cooling, a yellow solid was precipitated from the solution and was filtered to afford 4 g (90%) of methyl 1H-benzo[d]imidazole-5-carboxylate (20): MS (ESI) m/z=177 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:24]2[O:23][C:10]3[C:11](=[O:22])[N:12]([C@@H:14]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:15]([OH:17])=O)[CH2:13][C:9]=3[CH2:8][C:7]=2[C:6]([O:25][CH3:26])=[CH:5][CH:4]=1.CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[NH2:58][C:59]1[CH:64]=[CH:63][C:62]([Cl:65])=[CH:61][N:60]=1>O1CCCC1.O>[Cl:65][C:62]1[CH:63]=[CH:64][C:59]([NH:58][C:15](=[O:17])[C@@H:14]([N:12]2[CH2:13][C:9]3[CH2:8][C:7]4[C:6]([O:25][CH3:26])=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:24]=4[O:23][C:10]=3[C:11]2=[O:22])[CH2:18][CH:19]([CH3:21])[CH3:20])=[N:60][CH:61]=1
Reactant: COc1ccc(OC)c2c1CC1=C(O2)C(=O)N([C@@H](CC(C)C)C(=O)O)C1
Reactant: Nc1ccc(Cl)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: O
Product: COc1ccc(OC)c2c1CC1=C(O2)C(=O)N([C@@H](CC(C)C)C(=O)Nc2ccc(Cl)cn2)C1
Temperature: 90 °C
Yield: 18.5 %

Procedure:
A solution of (S)-2-(5,8-dimethoxy-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-4-methyl-pentanoic acid (100 mg, 0.24 mmol), in tetrahydrofuran (10 mL) was treated with N-methylmorpholine (760 mg, 0.69 mmol), 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate (HATU) (263 mg, 0.69 mmol) and commercially available 2-amino-5-chloropyridine (42 mg, 0.33 mmol). The mixture was heated in a sealed tube was heated for 16 hours at 90° C. The reaction mixture was diluted with water and extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue, upon silica gel flash chromatography using hexane-ethyl acetate gradient elution, afforded (S)-2-(5,8-dimethoxy-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-4-methyl-pentanoic acid (5-chloro-pyridin-2-yl)-amide (21 mg, 16.2%), as an off white solid. 1H NMR (DMSO-d6) δ: 11.09 (br. s., 1H), 8.40 (br. s., 1H), 8.05 (d, J=8.8 Hz, 1H), 7.90 (d, J=8.8 Hz, 1H), 6.91 (d, J=8.8 Hz, 1H), 6.66 (d, J=8.8 Hz, 1H), 5.05 (br. s., 1H), 4.38 (d, J=19.1 Hz, 1H), 4.03 (d, J=18.6 Hz, 1H), 3.76 (s, 6H), 3.55 (br. s., 2H), 1.82 (br. s., 1H), 1.67 (br. s., 1H), 1.45 (br. s., 1H), 0.93 (t, J=6.1 Hz, 6H).