Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]2[N:11]([C:17]([CH3:21])=[C:18]([CH3:20])[N:19]=2)[CH:12]=[C:13]([CH2:15][OH:16])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:24]I>CN(C)C=O>[CH2:1]([O:8][C:9]1[C:10]2[N:11]([C:17]([CH3:21])=[C:18]([CH3:20])[N:19]=2)[CH:12]=[C:13]([CH2:15][O:16][CH3:24])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc2c(OCc3ccccc3)cc(CO)cn2c1C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCc1cc(OCc2ccccc2)c2nc(C)c(C)n2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of 1.2 g of 8-benzyloxy-6-hydroxymethyl-2,3-dimethylimidazo[1,2-a]pyridine in 12 ml of dimethylformamide is treated with 0.36 g of 60% strength sodium hydride in paraffin under an inert gas atmosphere, stirred for 30 minutes at room temperature until the evolution of gas is complete, and then treated at room temperature with 0.56 ml of methyl iodide. After a reaction time of one hour, it is poured onto 100 ml of ice water and extracted 3 times with 100 ml of ethyl acetate each time. The organic phases are combined and washed with water. The solvent is stripped off in vacuo and the oily residue is chromatographed on silica gel (eluent: methylene chloride/methanol=100/1). 0.34 g of the title compound of melting point 107° C. (diethyl ether) is obtained.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:8]1[CH:9]=[N:10][CH:11]=[C:12]([Cl:16])[C:13]=1[CH:14]=[O:15].[S:17]1[CH:21]=[CH:20][N:19]=[C:18]1[SH:22]>C1COCC1>[Cl:16][C:12]1[CH:11]=[N:10][CH:9]=[C:8]([S:22][C:18]2[S:17][CH:21]=[CH:20][N:19]=2)[C:13]=1[CH2:14][OH:15]
Reactant: O=Cc1c(Cl)cncc1Cl
Reactant: Sc1nccs1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: OCc1c(Cl)cncc1Sc1nccs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Cs2CO3 (0.22 g, 0.68 mmol) was added to a solution of 3,5-dichloro-pyridine-4-carbaldehyde (0.10 g, 0.57 mmol) and thiazole-2-thiol (0.10 g, 0.85 mmol) in THF (10 mL). After stirring at room temperature overnight, the solvent was removed in vacuo and saturated aqueous NaCl solution (20 mL) and EA (40 mL) were added to the reaction mixture. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo and the residue was used in the following step without further purification. The aldehyde group in 3-chloro-5-(thiazol-2-ylsulfanyl)-pyridine-4-carbaldehyde was reduced as described for the synthesis of (3,5-dichloro-pyridin-4-yl)-methanol to give [3-chloro-5-(thiazol-2-ylsulfanyl)-pyridin-4-yl]-methanol which was used in the following step without further purification. Conversion of [3-chloro-5-(thiazol-2-ylsulfanyl)-pyridin-4-yl]-methanol into 3-chloro-4-chloromethyl-5-(thiazol-2-ylsulfanyl)-pyridine according to the synthesis of 3,5-dichloro-4-chloromethyl-pyridine and subsequent reaction with 2-methyl-4-(1-methyl-1H-imidazol-2-yl)-quinolin-8-ol according to the synthesis of 8-(3,5-dichloro-pyridin-4-ylmethoxy)-4-imidazol-1-yl-2-methylquinoline yielded the title compound as the TFA salt. MS (m/z): 480.2 [M+H+].
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[N:6][CH:7]=1.[Si:17]([C:21]#[CH:22])([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C>O1CCOCC1.CCOC(C)=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.[Cu]I>[O:14]1[CH2:15][CH2:16][N:11]([CH2:10][CH2:9][NH:8][C:5]2[CH:4]=[CH:3][C:2]([C:22]#[C:21][Si:17]([CH3:20])([CH3:19])[CH3:18])=[CH:7][N:6]=2)[CH2:12][CH2:13]1
Reactant: C#C[Si](C)(C)C
Reactant: Ic1ccc(NCCN2CCOCC2)nc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C[Si](C)(C)C#Cc1ccc(NCCN2CCOCC2)nc1
Temperature: 80 °C

Procedure:
5-Iodo-N-(2-morpholinoethyl)pyridin-2-amine (0.82 g, 2.46 mmol), TMS acetylene (1.70 mL, 12.3 mmol), and triethylamine (0.69 mL, 4.92 mmol) were dissolved in dioxane (20 mL) and with nitrogen for about 15 min. Tetrakis(triphenylphosphine)palladium (142 mg, 0.12 mmol) and copper (I) iodide (47 mg, 0.25 mmol) were added before the reaction mixture was heated to 80° C. for 3.5 h. The reaction mixture was diluted with 100 mL EtOAc, washed with 50 mL saturated, aqueous NaHCO3, and dried over anhydrous Na2SO4. After purification by chromatography, the title compound was obtained. MS (ES+): 304 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH:42](=O)[CH2:43][CH3:44].C(O)(=O)C.C(=O)(O)[O-].[Na+]>CN1CCCC1=O.C(Cl)Cl>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:15][C:16]1[CH:17]=[CH:18][C:19]([N:22]2[CH2:23][CH2:24][N:25]([CH2:42][CH2:43][CH3:44])[CH2:26][CH2:27]2)=[CH:20][CH:21]=1
Reactant: CCC=O
Reactant: O=C1NC(=O)c2ccc(I)cc2/C1=C/Nc1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCN1CCN(c2ccc(N/C=C3\C(=O)NC(=O)c4ccc(I)cc43)cc2)CC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 69.7 %

Procedure:
(4Z)-6-Iodo-4-{[(4-piperazin-1-ylphenyl)amino]methylene}isoquinoline-1,3(2H,4H)-dione (47.4 mg, 0.1 mmol) is dissolved in N-methylpyrrolidinone (1 mL) and methylene chloride (0.3 mL), followed by addition of sodium triacetoxyborohydride (244 mg, 1.15 mmol), propionaldehyde (0.186 mL, 2.6 mmol) and acetic acid (0.15 mL, 2.6 mmol). After stirring at room temperature for 40 min, methylene chloride and saturated sodium bicarbonate solution were added. The organic layer is separated and dried to give 36 mg (70%) of the title compound as a yellow solid. MS (ESI) m/z 517 (M+H)+1.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][CH2:7][CH2:8][C:4]2([C:9]([O:11][CH3:12])=[O:10])[CH2:3][NH:2]1.CCN(C(C)C)C(C)C.[Br:22][C:23]1[CH:24]=[N:25][C:26](Cl)=[N:27][CH:28]=1>CCO>[Br:22][C:23]1[CH:24]=[N:25][C:26]([N:2]2[CH2:3][C:4]3([C:9]([O:11][CH3:12])=[O:10])[CH2:8][CH2:7][CH2:6][CH:5]3[CH2:1]2)=[N:27][CH:28]=1
Reactant: Clc1ncc(Br)cn1
Reactant: COC(=O)C12CCCC1CNC2
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C12CCCC1CN(c1ncc(Br)cn1)C2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 45.7 %

Procedure:
To the solution of methyl octahydrocyclopenta[c]pyrrole-3a-carboxylate (1.0 g, 5.91 mmol) in EtOH (10.0 mL) was added DIPEA (2.80 mL, 16.12 mmol) at rt and the mixture stirred at rt for 10 min followed by addition of 5-bromo-2-chloropyrimidine (1.10 g, 5.37 mmol). The reaction was heated up to 70° C. for 2 h. After completion (by TLC), solvent was evaporated and the crude residue purified over 100-200 M silica-gel using 7.0% EtOAc:hexane to obtain the desired product as a white solid (0.80 g, 45%). MS: 326.19 [M+H]+.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[Si:7]([O:14][C@H:15]1[C:20](=[CH2:21])[C@H:19]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH2:18][C:17](CO)([OH:30])[CH2:16]1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]>CO.[Cl-].[Na+].O>[Si:7]([O:14][C@H:15]1[C:20](=[CH2:21])[C@H:19]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH2:18][C:17](=[O:30])[CH2:16]1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: C=C1[C@H](O[Si](C)(C)C(C)(C)C)CC(O)(CO)C[C@H]1O[Si](C)(C)C(C)(C)C
Agent: [Cl-]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CO
Product: C=C1[C@H](O[Si](C)(C)C(C)(C)C)CC(=O)C[C@H]1O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Sodium periodate saturated water (2.2 mL) was added to a solution of the diol 4 (146 mg, 0.36 mmol) in methanol (9 mL) at 0° C. The solution was stirred at 0° C. for 1 h, poured into brine and extracted with ether and benzene. The organic extracts were combined, washed with brine, dried (MgSO4) and evaporated. An oily residue was dissolved in hexane (1 mL) and applied on a silica Sep-Pak cartridge. Pure 4-methylenecyclohexanone derivative 5 (110 mg, 82%) was eluted with hexane/ethyl acetate (95:5) as a colorless oil: 1H NMR (CDCl3) δ 0.050 and 0.069 (6H and 6H, each s, 4×SiCH3), 0.881 (18H, s, 2×Si-t-Bu), 2.45 (2H, ddd, J=14.2, 6.9, 1.4 Hz), 2.64 (2H, ddd, J=14.2, 4.6, 1.4 Hz), 4.69 (2H, dd, J=6.9, 4.6 Hz), 5.16 (2H, s); MS m/z (relative intensity) no M+, 355 (M+-Me, 3), 313 (M+-t-Bu, 100), 73 (76).
Reaction SMILES: [CH2:1]1[O:4][CH:2]1[CH3:3].[CH2:5]([NH2:8])[CH2:6][NH2:7]>C(O)C.CCOCC>[OH:4][CH:2]([CH3:3])[CH2:1][NH:7][CH2:6][CH2:5][NH:8][CH2:1][CH:2]([OH:4])[CH3:3]
Reactant: CC1CO1
Reactant: NCCN
Solvent: CCO
Solvent: CCOCC
Product: CC(O)CNCCNCC(C)O
Temperature: 20 °C
Yield: 28.5 %

Procedure:
(IV-a): Propylene oxide (142.4 g, 2.4 mol) was added dropwise over a period of 11 hours to a solution of ethylenediamine (71.9 g, 1.2 mol) in 25 mL absolute ethanol and 10 mL of nitrogen purged distilled water at 90° C. After addition, the reaction was maintained for an additional hour, then cooled to room temperature (about 20° C.). The reaction solution was concentrated by rotary evaporation to give a milky white suspension which, upon dissolution in anhydrous ether, produced a white precipitate of N,N'-bis(2-hydroxypropyl)ethylenediamine in 28.5 percent yield. The product was crystallized from methanol/ethanol [m.p. 132° C., IR(Nujol): 3250(OH); NMR(MeOHd4): δ3.8(m,2H); 2.6(t,8H); 1.2(d,6H)].
Reaction SMILES: C([N:8]1[CH2:12][C@H:11]([N:13]2[CH2:18][C:17]([F:20])([F:19])[CH2:16][CH2:15][C:14]2=[O:21])[C@@H:10]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[F:20][C:17]1([F:19])[CH2:18][N:13]([C@H:11]2[CH2:12][NH:8][CH2:9][C@@H:10]2[NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:26])[CH3:27])[C:14](=[O:21])[CH2:15][CH2:16]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CN(Cc2ccccc2)C[C@@H]1N1CC(F)(F)CCC1=O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1CNC[C@@H]1N1CC(F)(F)CCC1=O
Yield: 4175.2 %

Procedure:
To a solution of the product of Step 9 (2 g, 0.06 mmol) in methanol was added excess ammonium formate and 10% Pd/C. The reaction mixture was heated under reflux overnight. After filtering, the solution was evaporated and residue was purified on silica gel (10% methanol/chloroform) to obtain the title product (800 mg). 1H NMR (400 MHz, CDCl3) δ 5.25 (1H,s), 4.7 (1H, m), 3.45 (1H, m), 3.25 (1H, m), 3.04 (m) 2.9 (1H, m), 2.5 (6H, m), 1.80 (4H, m), 1.45 (9H, s). MS m/z 284 (MH+).
Reaction SMILES: [C:1]1([CH:9]=[CH:8][CH:7]=[C:5]([OH:6])[C:3]=1[OH:4])[OH:2].[Cl:10][CH2:11][C:12](O)=[O:13].P(Cl)(Cl)(Cl)=O>>[CH:8]1[C:9]([C:12]([CH2:11][Cl:10])=[O:13])=[C:1]([OH:2])[C:3]([OH:4])=[C:5]([OH:6])[CH:7]=1
Reactant: Oc1cccc(O)c1O
Reactant: O=C(O)CCl
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(CCl)c1ccc(O)c(O)c1O

Procedure:
Pyrogallol is reacted with chloroacetic acid in the presence of phosphorus oxychloride to form ω-chloro-2,3,4-trihydroxyacetophenone,
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[S:21][C:20]3[CH:22]=[CH:23][C:24]([C:26](O)=[O:27])=[CH:25][C:19]=3[CH:18]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:29].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[CH3:47][NH:48][CH3:49]>C(Cl)Cl.CCN(CC)CC>[CH3:47][N:48]([CH3:49])[C:26]([C:24]1[CH:23]=[CH:22][C:20]2[S:21][C:17]([C:12]([C:9]3[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3](=[O:30])[C:2]([CH3:32])([CH3:31])[CH3:1])=[C:7]([CH3:29])[CH:8]=3)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:18][C:19]=2[CH:25]=1)=[O:27]
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc2cc(C(=O)O)ccc2s1
Reactant: CNC
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc2cc(C(=O)N(C)C)ccc2s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 41 %

Procedure:
A solution of 2-{1-[4-(3,3-dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzo[b]thiophene-5-carboxylic acid (210 mg, 0.464 mmol) in CH2Cl2 (5.0 mL) is treated with Et3N (1.0 mL), HOBT (94 mg, 0.70 mmol), and EDC (134 mg, 0.70 mmol). The mixture is stirred for 10 min at RT, and dimethylamine (1.0 mL, 2.0 M in THF) is added. The reaction mixture is stirred for 18 h, loaded onto a silica gel column, and eluted with 65% EtOAc/Hex to afford the title compound (90 mg, 41%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[C@H:7]([N:11]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[S:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH2:8][CH2:9]O)([CH3:4])([CH3:3])[CH3:2].[I:36]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1>ClCCl.CO>[C:1]([O:5][C:6](=[O:35])[C@H:7]([N:11]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[S:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH2:8][CH2:9][I:36])([CH3:4])([CH3:3])[CH3:2]
Reactant: II
Reactant: CC(C)(C)OC(=O)[C@@H](CCO)N(C(=O)OC(C)(C)C)S(=O)(=O)c1ccc(-c2ccc(Cl)cc2)cc1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)[C@@H](CCI)N(C(=O)OC(C)(C)C)S(=O)(=O)c1ccc(-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.4 %

Procedure:
A solution of the title E compound, (2R)-[t-butoxycarbonyl(4′-chlorobiphenyl-4-sulfonyl)amino]4-hydroxybutyric acid t-butyl ester (2.0 g, 9.58 mmol) in 50 mL dichloromethane is sequentially treated with iodine (2.88 g, 14.37 mmol), triphenylphosphine (3.72 g, 14.37 mmol) and imidazole (0.97 g, 14.37 mmol) at RT. After 2 h, 20 mL of methanol are added and the reaction mixture is stirred at RT for 30 min further. The solvent is evaporated and the product is purified by chomatography on silica gel (eluant; 1/19—EtOAc/hexane) to afford 2.46 g (78%) of (2R)-[t-butyloxycarbonyl(4′-chlorobiphenyl-4-sulfonyl)amino]-4-iodobutyric acid t-butyl ester.
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:19]([NH:21][NH:22][CH2:23][CH:24]([CH3:26])[CH3:25])=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.Cl[C:38]([O:40][CH3:41])=[O:39]>ClCCl.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:19]([NH:21][N:22]([CH2:23][CH:24]([CH3:25])[CH3:26])[C:38]([O:40][CH3:41])=[O:39])=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)CNNC(=O)[C@H](CC(C)C)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Reactant: COC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)N(CC(C)C)NC(=O)[C@H](CC(C)C)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
0.50 g of (E)-2(R)-[1(S)-(tertbutoxycarbonyl)-4-phenyl-3-butenyl]-2′-isobutyl-4-methylvalerohydrazide and 0.12 ml of pyridine were dissolved in 10 ml of dichloromethane and cooled to 0° C. under nitrogen. 0.12 ml of methyl chloroformate and a few crystals of 4-dimethylaminopyridine were added in succession and the mixture was left to come to room temperature and then stirred for 1 hour. The mixture was diluted with dichloromethane and then washed in succession with 5% aqueous sodium hydrogen carbonate solution, water, 2M aqueous hydrochloric acid and water and then dried over magnesium sulphate. The solvent was evaporated to give 0.54 g of methyl (E)-3-[2(R)-[1(S)-(tertbutoxycarbonyl)-4-phenyl-3-butenyl]-4-methylvaleryl]-2-isobutylcarbazate in the form of a white foam.
Reaction SMILES: C([O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)(=O)C=C.[Cl-].[Al+3].[Cl-].[Cl-].[Cl-].[Na+].Cl>>[F:12][C:9]1[CH:8]=[CH:7][C:6]([OH:5])=[C:11]2[C:10]=1[CH2:8][CH2:7][C:6]2=[O:5]
Reactant: C=CC(=O)Oc1ccc(F)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C1CCc2c(F)ccc(O)c21
Temperature: 80 °C
Reaction time: 2 h
Yield: 95.8 %

Procedure:
4-Fluorophenyl acrylate (12.0 g) was added to a mixture of aluminum chloride (33.7 g) and sodium chloride (14.8 g), and the mixture was stirred at 80° C. for 2 hours and then at 160° C. for 1 hour. After completion of the reaction, ice-water and concentrated hydrochloric acid were added, and the reaction mixture was extracted with chloroform. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography. From the eluate of hexane-ethyl acetate (9:1), 4-fluoro-7-hydroxy-1-indanone (5.75 g) was obtained as a pale yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH2:15])[CH:6]=[C:7]([O:12][CH3:13])[C:8]=1[CH:9]([CH3:11])[CH3:10].Br[C:17]1[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=1[F:24]>>[F:23][C:22]1[CH:21]=[CH:20][CH:19]=[C:18]([F:24])[C:17]=1[CH:15]=[CH:14][C:5]1[CH:6]=[C:7]([O:12][CH3:13])[C:8]([CH:9]([CH3:11])[CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: C=Cc1cc(OC)c(C(C)C)c(OC)c1
Reactant: Fc1cccc(F)c1Br
Product: COc1cc(C=Cc2c(F)cccc2F)cc(OC)c1C(C)C

Procedure:
This compound was synthesized from (3,5-dimethoxy-4-i-propylphenyl)ethene and 1-bromo-2,6-diflurobenzene quantitatively in the same procedure as described in preparation of 31B. 1HNMR (CDCl3, ppm): δ 1.32 (d, J=7.1 Hz, 6H), 3.62 (qint, J=7.1 Hz, 1H), 3.90 (s, 6H), 6.73 (s, 2H), 6.8-7.2 (m, 4H), 7.41 (d, J=16.6 Hz, 1H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:11]([CH3:16])([CH3:15])[CH2:10][CH2:9][C:8]([CH3:18])([CH3:17])[C:7]=2[CH:6]=1)=O.[OH:19][CH:20]1[CH2:25][CH2:24][N:23]([C:26](=[S:28])[NH2:27])[CH2:22][CH2:21]1>>[CH3:15][C:11]1([CH3:16])[CH2:10][CH2:9][C:8]([CH3:17])([CH3:18])[C:7]2[CH:6]=[C:5]([C:3]3[N:27]=[C:26]([N:23]4[CH2:24][CH2:25][CH:20]([OH:19])[CH2:21][CH2:22]4)[S:28][CH:2]=3)[CH:14]=[CH:13][C:12]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)CBr)ccc21
Reactant: NC(=S)N1CCC(O)CC1
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCC(O)CC4)n3)ccc21

Procedure:
The preparation was carried out as already described starting from 397 mg (0.94 mmol) of 2-bromo-1-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)ethanone and 100 mg (0.62 mmol) of 4-hydroxypiperidine-1-carbothioic acid amide from step a. The product was purified by means of preparative HPLC and is in the form of the hydrochloride.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[F:28][C:29]([F:36])([F:35])[CH2:30][CH2:31][C:32](O)=[O:33]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:32](=[O:33])[CH2:31][CH2:30][C:29]([F:36])([F:35])[F:28])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: O=C(O)CCC(F)(F)F
Agent: Cl
Product: O=C(CCC(F)(F)F)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1

Procedure:
The title compound, white solid (106 mg, 93%), MS (ISP) m/z=455.3 [(M+H)+], mp 204.5° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and 4,4,4-trifluoro-butanoic acid.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:12]2[NH:11][N:10]=[CH:9][C:8]=2[C:7]2[CH2:13][N:14]([CH2:23][C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[C:15](=[O:22])[C@H:16]([CH2:18][C:19](O)=[O:20])[CH2:17][C:6]=2[CH:5]=1.Cl.[F:31][C:32]1[CH:33]=[CH:34][CH:35]=[C:36]2[C:41]=1[NH:40][C:39](=[O:42])[N:38]([CH:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)[CH2:37]2.ClC1C2NN=CC=2C2CN(CC(C)(C)C)C(=O)[C@H](CC(=O)N3CCC(N4CC5C(=CC=CC=5)NC4=O)CC3)CC=2C=1>>[Cl:3][C:4]1[C:12]2[NH:11][N:10]=[CH:9][C:8]=2[C:7]2[CH2:13][N:14]([CH2:23][C:24]3[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=3)[C:15](=[O:22])[C@H:16]([CH2:18][C:19]([N:46]3[CH2:45][CH2:44][CH:43]([N:38]4[CH2:37][C:36]5[C:41](=[C:32]([F:31])[CH:33]=[CH:34][CH:35]=5)[NH:40][C:39]4=[O:42])[CH2:48][CH2:47]3)=[O:20])[CH2:17][C:6]=2[CH:5]=1
Reactant: O=C1Nc2c(F)cccc2CN1C1CCNCC1
Reactant: O=C(O)C[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(Cc2ccncc2)C1=O
Agent: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ncc23)C[C@@H](CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C1=O
Agent: Cl
Product: O=C(C[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(Cc2ccncc2)C1=O)N1CCC(N2Cc3cccc(F)c3NC2=O)CC1
Yield: 16 %

Procedure:
(S)-2-(4-Chloro-8-oxo-9-(pyridin-4-ylmethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetic acid dihydrochloride (100 mg, 0.2 mmol) and 8-fluoro-3-(piperidin-4-yl)-3,4-dihydroquinazolin-2(1H)-one hydrochloride (61 mg, 0.2 mmol) were reacted in a manner analogous to the preparation of 4-Chloro-9-(2,2-dimethyl-propyl)-7-(S)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one. Title compound was obtained as white solid in 16% yield. MS m/e (M+H)+=616.2. 1H NMR (500 MHz, DMSO-D6): δ=13.46 (s, 1H), 9.23 (d, J=6.41, 1H), 8.31 (m, 2H), 8.24 (d, J=6.10, 1H), 7.22 (s, 1H), 7.13 (dd, J1=9.46, J2=4.88, 2H), 7.05 (m, 1H), 6.91 (m, 1H), 6.85 (s, 1H), 5.40 (d, J=17.09, 1H), 4.66 (m, 3H), 4.54 (d, J=11.90, 1H), 4.41 (m, 1H), 4.36 (s, 1H), 4.28 (d, J=4.58, 1H), 4.10 (d, J=12.51, 1H), 4.00 (m, 1H), 3.17 (m, 2H), 3.04 (m, 1H), 2.94 (m, 1H), 2.62 (d, J=11.29, 1H), 2.43 (m, 1H), 1.83 (m, 1H), 1.62 (m, 3H).
Reaction SMILES: Br.[NH2:2][C:3]1[CH:4]=[CH:5][C:6](/[C:11](/[C:19]2[CH:24]=[CH:23][C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:21][CH:20]=2)=[CH:12]/[C@@H:13]2[NH:17][C:16](=[O:18])[CH2:15][CH2:14]2)=[N:7][C:8]=1[O:9]C.O>O1CCOCC1>[NH2:2][C:3]1[C:8](=[O:9])[NH:7][C:6](/[C:11](/[C:19]2[CH:20]=[CH:21][C:22]([C:25]([CH3:27])([CH3:26])[CH3:28])=[CH:23][CH:24]=2)=[CH:12]/[C@H:13]2[CH2:14][CH2:15][C:16](=[O:18])[NH:17]2)=[CH:5][CH:4]=1
Reactant: COc1nc(/C(=C/[C@H]2CCC(=O)N2)c2ccc(C(C)(C)C)cc2)ccc1N
Agent: Br
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)c1ccc(/C(=C\[C@H]2CCC(=O)N2)c2ccc(N)c(=O)[nH]2)cc1
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 41.6 %

Procedure:
48% hydrobromic acid (0.5 mL) was added to a solution of (5R)-5-[(E)-2-(5-amino-6-methoxypyridin-2-yl)-2-(4-tert-butylphenyl)ethenyl]pyrrolidin-2-one (20 mg) in 1,4-dioxane (1 mL), and the mixture was stirred at 65° C. for 30 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=10:0→4:1) and crystallized from chloroform-ethyl acetate to give the title compound as a light brown powder (8 mg, 44%).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[NH2:18][CH:19]([CH2:23][CH:24]1[CH2:27][CH2:26][CH2:25]1)[C:20]([NH2:22])=[O:21]>>[C:20]([CH:19]([NH:18][C:15]([C:7]1[CH:6]=[N:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])[CH2:23][CH:24]1[CH2:27][CH2:26][CH2:25]1)(=[O:21])[NH2:22]
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Reactant: NC(=O)C(N)CC1CCC1
Product: NC(=O)C(CC1CCC1)NC(=O)c1cnc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 69, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g, 50 mg, 0.21 mmol) and 2-amino-3-cyclobutyl-propionamide (52.5 mg, 0.26 mmol) as starting materials and isolated (30 mg, 39.4%) as white solid; LC-MS (UV peak area, ESI) 99.04%%, 357.4 (M−H)'.