Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1/[CH:8]=[N:9]/[NH:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1.CN[C@@H]1CCCC[C@H]1NC.C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1.[Cl-].[NH4+].[Cu]I>[F:17][C:14]1[CH:15]=[CH:16][C:11]([N:10]2[C:2]3[CH:7]=[CH:6][N:5]=[CH:4][C:3]=3[CH:8]=[N:9]2)=[CH:12][CH:13]=1
Reactant: Fc1ccc(N/N=C/c2cnccc2Br)cc1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Product: Fc1ccc(-n2ncc3cnccc32)cc1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
A mixture of N-[1-(4-bromopyridin-3-yl)-meth-(E)-ylidene]-N′-(4-fluorophenyl)-hydrazine (3.0 g, 0.010 mol), CuI (97 mg, 0.51 mmol), trans-N,N′-dimethylcyclohexane-1,2-diamine (595 μL, 3.77 mmol), and K2CO3 (2.8 g, 0.020 mol) in NMP (100 mL) was warmed at 120° C. After stifling overnight, the mixture was diluted with aqueous ammonium chloride (400 mL) and the resulting solid collected by filtration. The solid was dissolved in EtOAc, and the aqueous layer was extracted with EtOAc. The combined organics layers were dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography to afford 1-(4-fluorophenyl)-1H-pyrazolo[4,3-c]pyridine as an orange solid.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4]1[C:9]([OH:10])=[C:8]([C:11]([CH3:13])=[O:12])[CH:7]=[CH:6][C:5]=1[OH:14].Br[CH2:16][CH2:17][CH:18]([Br:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CC(C)=O>[Br:20][CH:18]([CH3:19])[CH2:17][CH2:16][O:14][C:5]1[CH:6]=[CH:7][C:8]([C:11](=[O:12])[CH3:13])=[C:9]([OH:10])[C:4]=1[CH2:3][CH2:2][CH3:1]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: CC(Br)CCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CC(C)=O
Product: CCCc1c(OCCC(C)Br)ccc(C(C)=O)c1O
Yield: 29.1 %

Procedure:
A mixture of 5.0 g of 2,4-dihydroxy-3-propylacetophenone, 11.1 g of 1,3-dibromobutane, 6.0 g of potassium carbonate and 50 mg of tetra-n-butylammonium bromide in 130 ml of acetone was refluxed overnight. After cooling, the insoluble matter was filtered off, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=8:1) to give 2.47 g of 1-[4-(3-bromobutoxy)-2-hydroxy-3-propylphenyl]ethanone. Melting point 53°-55° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[S:11]([CH3:14])(=[O:13])=[O:12].[Cl:15][C:16]1[CH:33]=[CH:32][C:19]2[N:20]([CH2:25][CH2:26][CH2:27][S:28]([CH3:31])(=[O:30])=[O:29])[C:21]([CH2:23]Cl)=[N:22][C:18]=2[CH:17]=1>>[Cl:15][C:16]1[CH:33]=[CH:32][C:19]2[N:20]([CH2:25][CH2:26][CH2:27][S:28]([CH3:31])(=[O:29])=[O:30])[C:21]([CH2:23][N:7]3[C:8]4[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=4)[C:5]([S:11]([CH3:14])(=[O:12])=[O:13])=[CH:6]3)=[N:22][C:18]=2[CH:17]=1
Reactant: CS(=O)(=O)CCCn1c(CCl)nc2cc(Cl)ccc21
Reactant: CS(=O)(=O)c1c[nH]c2ccc(F)cc12
Product: CS(=O)(=O)CCCn1c(Cn2cc(S(C)(=O)=O)c3cc(F)ccc32)nc2cc(Cl)ccc21

Procedure:
The title compound was prepared in analogy to Example 1-2 by using 5-fluoro-3-(methylsulfonyl)-1H-indole and 5-chloro-2-(chloromethyl)-1-(3-(methylsulfonyl)propyl)-1H-benzo[d]imidazole instead of 3-(methylsulfonyl)-1H-indole and 5-chloro-2-(chloromethyl)-1-(3-(methylsulfonyl)propyl)-1H-benzo[d]imidazole.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH:14]([C:16]2[CH:21]=[C:20]([F:22])[C:19]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:18][C:17]=2[F:31])O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:32]C(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH:14]([C:16]2[CH:21]=[C:20]([F:22])[C:19]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:18][C:17]=2[F:31])[Br:32])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](C(O)c2cc(F)c(OCc3ccccc3)cc2F)C1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCO[C@H](C(Br)c2cc(F)c(OCc3ccccc3)cc2F)C1
Reaction time: 1 h

Procedure:
To a solution of 7.5 g of ((S)-2-[(4-benzyloxy-2,5-difluoro-phenyl)-hydroxy-methyl]-morpholine-4-carboxylic acid tert-butyl ester in dichloromethane (90 ml) was added with cooling (0-5° C.) tetrabromomethane (12.5 g) and afterwards triphenylphosphine (13.5 g) in small portions. Stirring continued for 1 hour at room temperature before the mixture was added dropwise to diethyl ether (600 mL). Solids were removed by filtration and the filtrate was concentrated in vacuo. The residue was then purified by column chromatography (heptane-ethyl acetate (3:1)/silica gel) to give 5.6 g of the title compound.
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:13][CH2:12][CH2:11][CH:10]1[C:14]1[S:15][C:16]2[CH2:25][C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:17]=2[N:18]=1)=O)(C)(C)C.[ClH:26]>C(OCC)(=O)C>[ClH:26].[ClH:26].[NH2:8][CH:9]1[CH2:13][CH2:12][CH2:11][CH:10]1[C:14]1[S:15][C:16]2[CH2:25][C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:17]=2[N:18]=1
Reactant: CC(C)(C)OC(=O)NC1CCCC1c1nc2c(s1)Cc1ccccc1-2
Agent: Cl
Solvent: CCOC(C)=O
Product: NC1CCCC1c1nc2c(s1)Cc1ccccc1-2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In 6 ml of ethyl acetate, 155 mg of 2-[2-(tert-butoxycarbonylamino)cyclopentyl]-8H-indeno[1,2-d]thiazole was dissolved. Then, 15 ml of a 4N solution of hydrogen chloride in ethyl acetate was added, followed by stirring at room temperature for one hour. The crystals precipitated were collected by filtration, and the crystals were recrystallized from ethyl acetate-methanol, whereby 39 mg of 2-(2-aminocyclopentyl)-8H-indeno[1,2-d]thiazole dihydrochloride was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][N:20]([CH2:23][C:24]3[S:28][C:27](Br)=[N:26][CH:25]=3)[CH2:19][CH2:18]2)=[O:14])[CH:3]=1.[N:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[OH:36].CN[C@@H]1CCCC[C@H]1NC.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[Cu]I>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][N:20]([CH2:23][C:24]3[S:28][C:27]([N:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]4=[O:36])=[N:26][CH:25]=3)[CH2:19][CH2:18]2)=[O:14])[CH:3]=1
Reactant: CCOc1nc(C(=O)NCC2CCN(Cc3cnc(Br)s3)CC2)cc(N)c1C#N
Reactant: Oc1ccccn1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCOc1nc(C(=O)NCC2CCN(Cc3cnc(-n4ccccc4=O)s3)CC2)cc(N)c1C#N
Temperature: 110 °C
Yield: 35.6 %

Procedure:
The compound prepared in Example 336 (30 mg), pyridin-2-ol (0.0124 g), copper(I) iodide (0.0068 g), trans-N1,N2-dimethylcyclohexane-1,2-diamine (0.0113 mL), and potassium carbonate (0.0173 g) were combined in N,N-dimethylformamide (0.5 mL). The reaction mixture was purged with argon for 5 minutes and then heated at 110° C. for 4 hours. The reaction mixture was diluted with ethyl acetate (15 mL) and passed through a plug of silica gel, eluting with ethyl acetate. The eluent was concentrated and the residue was purified by column chromatography on silica gel (ethyl acetate:methanol=19:1) to obtain the title compound (11 mg) having the following physical data.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:21])[CH2:9][N:10]([CH2:18][CH2:19]O)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][C:3]=1[Cl:22].C(N(CC)CC)C.CS(Cl)(=O)=O>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:21][CH2:19][CH2:18][N:10]([C:11]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:17])[CH2:9]2)=[CH:4][C:3]=1[Cl:22]
Reactant: CC(C)(C)OC(=O)N(CCO)CC(O)c1ccc(Br)c(Cl)c1
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(Br)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.9 %

Procedure:
To a stirred solution of tert-butyl (RS)-2-(4-bromo-3-chlorophenyl)-2-hydroxyethyl(2-hydroxyethyl)carbamate (12.7 g) and triethylamine (6.72 ml) in THF (150 ml) at 0-5° C. was added dropwise methanesulfonyl chloride (2.76 ml). The reaction mixture was then stirred at room temperature for 1 hour to afford a white suspension. The reaction mixture was then filtered to remove triethylamine hydrochloride, washing the filter with THF (20 ml). The filtrate was cooled to 0-5° C. and potassium 2-methyl-2-butoxide (28.4 ml, 1.7 M solution in toluene) was added. The reaction mixture was stirred at room temperature for 30 min and then poured into EtOAc and extracted sequentially with dilute aq. HCl, water and saturated brine. The organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel; gradient: 0% to 50% EtOAc in hexanes) to afford tert-butyl (RS)-2-(4-bromo-3-chlorophenyl)morpholine-4-carboxylate (9.32 g, 77%) as a yellow oil. MS (ISP): 324.0 ([{81Br37Cl}M+H—C4H8]+), 321.9 ([{79Br37Cl/81Br35Cl}M+H—C4H8]+), 319.8 ([{79Br35Cl}M+H—C4H8]+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]([N:12]2[CH2:18][CH2:17][C:16](=[O:19])[N:15]([CH2:20][CH2:21]O)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.CS([Cl:34])(=O)=O.O>ClCCl>[Cl:34][CH2:21][CH2:20][N:15]1[C:16](=[O:19])[CH2:17][CH2:18][N:12]([C:10](=[O:11])/[CH:9]=[CH:8]/[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH2:13][CH2:14]1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(/C=C/c1cccc(Cl)c1)N1CCC(=O)N(CCO)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(/C=C/c1cccc(Cl)c1)N1CCC(=O)N(CCCl)CC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 102.2 %

Procedure:
To an ice-cooled solution of 2.13 g (3.50 mmol) of 1-[(E)-3-(3-chloro-phenyl)-acryloyl]-4-(2-hydroxy-ethyl)-[1,4]diazepan-5-one and 0.73 ml (5.25 mmol) of Et3N in 35 ml of dichloromethane were added 0.29 ml (3.68 mmol) of methanesulfonyl chloride under stirring within 5 min keeping the temperatue at 0° C. The reaction was stirred at room temperature for 1 h 45 min. Water was added and after 5 min, the reaction was then partitioned between ether and aqueous saturated NaHCO3. The water phase was extracted again with ether (2×), the organic phases were washed with aqueous 10% NaCl, dried (Na2SO4) and concentrated to yield 1.22 g (87%) of the title compound as yellow viscous oil. MS: 341.0 (MH+, 2Cl).
Reaction SMILES: Cl[C:2]1[N:27]=[CH:26][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH2:19][C:20]([F:23])([F:22])[F:21])[N:17]=[C:16]([CH2:24][OH:25])[N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.Cl.[CH3:29][NH:30][CH3:31]>>[CH3:29][N:30]([CH3:31])[C:2]1[N:27]=[CH:26][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH2:19][C:20]([F:23])([F:22])[F:21])[N:17]=[C:16]([CH2:24][OH:25])[N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1
Reactant: OCc1nc(-c2cn3c(n2)-c2cnc(Cl)cc2OCC3)n(CC(F)(F)F)n1
Reactant: CNC
Agent: Cl
Product: CN(C)c1cc2c(cn1)-c1nc(-c3nc(CO)nn3CC(F)(F)F)cn1CCO2

Procedure:
(5-(9-chloro-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-2-yl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3-yl)methanol 387 was reacted with dimethylamine-HCl to give 394 (11 mg) as a colorless solid. LCMS: 410.1. 1H NMR (400 MHz, DMSO) δ 9.06 (s, 1H), 7.94 (s, 1H), 6.13 (s, 1H), 5.84 (q, J=8.9 Hz, 2H), 5.32 (t, J=6.1 Hz, 1H), 4.50 (m,4H), 4.45 (d, J=6.0 Hz, 2H), 3.05 (s, 6H)
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:18][CH3:19])[C:4]2[C:9]([C:10](=[O:16])[C:11]=1[C:12]([NH:14][CH3:15])=[O:13])=[CH:8][CH:7]=[C:6](Cl)[N:5]=2.[CH3:20][O:21][CH2:22][C:23]([CH3:27])([OH:26])[C:24]#[CH:25]>CN(C=O)C.CCN(CC)CC.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[NH2:1][C:2]1[N:3]([CH2:18][CH3:19])[C:4]2[C:9]([C:10](=[O:16])[C:11]=1[C:12]([NH:14][CH3:15])=[O:13])=[CH:8][CH:7]=[C:6]([C:25]#[C:24][C:23]([OH:26])([CH3:27])[CH2:22][O:21][CH3:20])[N:5]=2
Reactant: CCn1c(N)c(C(=O)NC)c(=O)c2ccc(Cl)nc21
Reactant: C#CC(C)(O)COC
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCn1c(N)c(C(=O)NC)c(=O)c2ccc(C#CC(C)(O)COC)nc21

Procedure:
A suspension of 3 g (10.69 mmol) of 2-amino-7-chloro-1-ethyl-N-methyl-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxamide in 20 ml of a DMF/Et3N mixture (V/V; 1/1) is placed in an 80 ml microwave tube. This suspension is sparged with argon for 10 minutes and then 1.83 g of (±)-1-methoxy-2-methyl-3-butyn-2-ol (16.03 mmol), 0.081 g of CuI (0.43 mmol) and 0.375 g of bis(triphenylphosphine) palladium(II)dichloride (0.53 mmol) are successively added.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[C:10]2[CH:9]=[C:8]3[NH:11][C:12]([CH2:14][CH2:15][C:16]4[CH:17]=[C:18]([NH:22]C(=O)C)[CH:19]=[CH:20][CH:21]=4)=[N:13][C:7]3=[CH:6][C:5]=2[N:4]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:3]1=[O:31]>CC(O)C.Cl>[NH2:22][C:18]1[CH:17]=[C:16]([CH2:15][CH2:14][C:12]2[NH:11][C:8]3=[CH:9][C:10]4[C:2]([CH3:32])([CH3:1])[C:3](=[O:31])[N:4]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:5]=4[CH:6]=[C:7]3[N:13]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: CCCCCN1C(=O)C(C)(C)c2cc3[nH]c(CCc4cccc(NC(C)=O)c4)nc3cc21
Agent: Cl
Solvent: CC(C)O
Product: CCCCCN1C(=O)C(C)(C)c2cc3[nH]c(CCc4cccc(N)c4)nc3cc21

Procedure:
A solution of N-{3-[2-(7,7-dimethyl-6-oxo-5-pentyl-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-ethyl]-phenyl}-acetamide (70 mg) in 2-propanol (1 ml) and hydrochloric acid (6 M; 1 ml) is heated under reflux for 3.5 h. Afterwards the mixture is concentrated in vacuo and the residual aqueous layer is neutralized with saturated NaHCO3 solution. The desired compound is obtained by an aqueous work-up (47 mg).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:12]2[CH:13]=[N:14][N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:23](=[O:25])[CH3:24])[CH2:19][CH2:18]3)[CH:16]=2)=[C:6]2[CH:10]=[C:9](Cl)[O:8][C:7]=12.[O:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]1[N:32]1[C:40]2[C:35](=[CH:36][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:38][CH:39]=2)[C:34]([C:50]#[N:51])=[N:33]1>>[C:23]([N:20]1[CH2:21][CH2:22][CH:17]([N:15]2[CH:16]=[C:12]([C:5]3[CH:4]=[N:3][C:2]([NH2:1])=[C:7]4[O:8][C:9]([C:37]5[CH:36]=[C:35]6[C:40](=[CH:39][CH:38]=5)[N:32]([CH:27]5[CH2:28][CH2:29][CH2:30][CH2:31][O:26]5)[N:33]=[C:34]6[C:50]#[N:51])=[CH:10][C:6]=34)[CH:13]=[N:14]2)[CH2:18][CH2:19]1)(=[O:25])[CH3:24]
Reactant: CC1(C)OB(c2ccc3c(c2)c(C#N)nn3C2CCCCO2)OC1(C)C
Reactant: CC(=O)N1CCC(n2cc(-c3cnc(N)c4oc(Cl)cc34)cn2)CC1
Product: CC(=O)N1CCC(n2cc(-c3cnc(N)c4oc(-c5ccc6c(c5)c(C#N)nn6C5CCCCO5)cc34)cn2)CC1
Yield: 65 %

Procedure:
The title compound was prepared in 65% yield from 1-{4-[4-(7-amino-2-chlorofuro[2,3-c]pyridin-4-yl)-1H-pyrazol-1-yl]piperidin-1-yl}ethanone and 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole-3-carbonitrile by a procedure analogous to Example 87. 1H NMR (400 MHz, CDCl3): δ 8.39 (s, 1 H), 8.07-7.92 (m, 2 H), 7.90-7.80 (m, 2 H), 7.72 (s, 1 H), 7.19 (s, 1 H), 5.87 (dd, J=2.9, 8.2 Hz, 1 H), 4.97 (s, 2 H), 4.87-4.68 (m, 1 H), 4.60-4.28 (m, 1 H), 4.11-3.87 (m, 2 H), 3.88-3.68 (m, 1 H), 3.39-3.16 (m, 1 H), 2.95-2.69 (m, 1 H), 2.61-2.43 (m, 1 H), 2.31 (br. s, 2 H), 2.23-2.12 (m, 4 H), 2.12-1.96 (m, 2 H), 1.93-1.62 (m, 4 H); MS (ESI): 551.19 [M+H]+; HPLC tR=2.62 min (ZQ3, polar—4 min).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([OH:9])=O.[F:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=1>>[F:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH:16][C:7]([C:3]2[S:4][CH:5]=[CH:6][C:2]=2[CH3:1])=[O:9])=[CH:13][CH:12]=1
Reactant: NCc1ccc(F)cc1
Reactant: Cc1ccsc1C(=O)O
Product: Cc1ccsc1C(=O)NCc1ccc(F)cc1
Yield: 94 %

Procedure:
Following the procedure as described in Preparation 18, making variations only as required to use 3-methylthiophene-2-carboxylic acid in place of 3-methylfuran-2-carboxylic acid to react with 4-fluorobenzylamine in place of benzylamine, N-(4-fluorobenzyl)-3-methylthiophene-2-carboxamide was obtained as a colorless solid in 94% yield: 1H NMR (300 MHz, CDCl3) δ 7.37-7.26 (m, 3H), 7.08-7.00 (m, 2H), 6.90 (d, J=5.0 Hz, 1H), 6.09 (br s, 1H), 4.57 (d, J=5.8 Hz, 2H), 2.52 (s, 3H); MS (ES+) m/z 250.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH3:9])[N:3]=1.Br[CH2:11][C:12](=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14]>C(O)C>[CH3:9][C:4]1[N:3]2[CH:11]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:1]=[C:2]2[CH:7]=[C:6]([CH3:8])[N:5]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: Cc1cc(N)nc(C)n1
Solvent: CCO
Product: CCOC(=O)c1cn2c(C)nc(C)cc2n1
Yield: 8.1 %

Procedure:
4-Amino-2,6-dimethylpyrimidine (16.24 mmol, 2 g) was mixed with ethanol (30 ml) and stirred well. Ethyl bromopyruvate (20.30 mmol, 3.96 g) was added in small portions. The resulting mixture was refluxed for 5.5 h and stirred at RT overnight. The solvent was evaporated, DCM was added and washed with Na2HCO3. The organic phase was dried, filtered and evaporated. The crude product was purified by flash chromatography and trituration from EtOAc/heptane, respectively. 0.287 g of the title product was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.33 (t, 3H), 2.42 (d, 3H), 2.80 (s, 3H), 4.33 (q, 2H), 7.32 (s, 1H), 8.50 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([C:28]([N:30]2[CH:38]3[CH:33]([CH2:34][CH2:35][CH2:36][CH2:37]3)[CH2:32][CH2:31]2)=[O:29])[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:22]4[CH:23]=[C:24]([C:28]([N:30]5[CH:38]6[CH:33]([CH2:34][CH2:35][CH2:36][CH2:37]6)[CH2:32][CH2:31]5)=[O:29])[N:25]=[CH:26][N:27]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: O=C(c1cc(Cl)ncn1)N1CCC2CCCCC21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)N4CCC5CCCCC54)ncn3)CC1)C(=O)N2

Procedure:
705 mg (2.56 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 680 mg (2.56 mmol) (6-chloro-pyrimidin-4-yl)-(octahydro-indol-1-yl)-methanone and 0.871 mL (5 mmol) DIPEA were stirred in 10 mL DMF for 2 h at RT. The reaction mixture was purified by HPLC. The product-containing fractions were combined and the ACN was eliminated by rotary evaporation. The aqueous phase was made alkaline with 4M NaOH and extracted with EtOAc. The organic phase was dried, filtered and the filtrate was concentrated to dryness by rotary evaporation. The residue was crystallised from a mixture of MeOH and diethyl ether and the solid was suction filtered and dried.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C@@H:4](/[CH:5]=[C:6](/[F:14])\[C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[C@H:3]1[C:15]([OH:17])=[O:16].[C:19]([C@@H:21](O)[C:22]1[CH:27]=[CH:26][C:25]([F:28])=[C:24]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:23]=1)#[N:20]>>[CH3:1][C:2]1([CH3:18])[C@@H:4](/[CH:5]=[C:6](/[F:14])\[C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:11])[CH3:12])[C@H:3]1[C:15]([O:17][C@H:21]([C:19]#[N:20])[C:22]1[CH:27]=[CH:26][C:25]([F:28])=[C:24]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:23]=1)=[O:16]
Reactant: CC(C)(C)OC(=O)/C(F)=C\[C@H]1[C@@H](C(=O)O)C1(C)C
Reactant: N#C[C@@H](O)c1ccc(F)c(Oc2ccccc2)c1
Product: CC(C)(C)OC(=O)/C(F)=C\[C@H]1[C@@H](C(=O)O[C@H](C#N)c2ccc(F)c(Oc3ccccc3)c2)C1(C)C

Procedure:
Using the procedure of Step B of Example 43, (1R,cis,E) 2,2-dimethyl-3-[2-fluoro-3-oxo-3-(1,1-dimethyl-ethoxy)-1-propenyl]-cyclopropane carboxylic acid and (S)α-cyano-3-phenoxy-4-fluoro-benzyl alcohol were reacted to obtain (S)α-cyano-3-phenoxy-4-fluoro-benzyl (1R,cis,E) 2,2-dimethyl-3-[2-fluoro-3-oxo-3-(1,1-dimethyl-ethoxy)-1-propenyl]-cyclopropanecarboxylate melting at 122° C. and having a specific rotation of [α]D20 =+61°±2.5° (c=0.35% in chloroform).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:4]=1[CH2:5][N:6]([C:21]1[S:25][N:24]=[CH:23][N:22]=1)[S:7]([C:10]1[C:19]([F:20])=[CH:18][C:13]2[NH:14][C:15](=[O:17])[O:16][C:12]=2[CH:11]=1)(=[O:9])=[O:8].C(P(CCCC)CCCC)CCC.CCOC(/N=N/C(OCC)=O)=O.[I:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=1[C@@H:64](O)[CH3:65]>C1COCC1>[CH3:1][O:2][C:3]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:4]=1[CH2:5][N:6]([C:21]1[S:25][N:24]=[CH:23][N:22]=1)[S:7]([C:10]1[C:19]([F:20])=[CH:18][C:13]2[N:14]([C@@H:64]([C:59]3[CH:60]=[CH:61][CH:62]=[CH:63][C:58]=3[I:57])[CH3:65])[C:15](=[O:17])[O:16][C:12]=2[CH:11]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc3oc(=O)[nH]c3cc2F)c(OC)c1
Reactant: C[C@H](O)c1ccccc1I
Agent: CCCCP(CCCC)CCCC
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc3oc(=O)n([C@H](C)c4ccccc4I)c3cc2F)c(OC)c1
Reaction time: 24 h

Procedure:
Added N-(2,4-dimethoxybenzyl)-5-fluoro-2-oxo-N-(1,2,4-thiadiazol-5-yl)-2,3-dihydrobenzo[d]oxazole-6-sulfonamide (11-3, 2 g, 4.29 mmol) to THF (21.44 ml). Added tri-n-butylphosphine (2.116 ml, 8.58 mmol) and DEAD (1.358 ml, 8.58 mmol) and cooled to 0° C. Was a clear orange solution. Added (S)-1-(2-iodophenyl)ethanol (16-2, 1.064 g, 4.29 mmol). After 24 h at 0° C., concentrated in vacuo, dissolved in 5 mL DCM and purified by normal-phase HPLC (80 g ISCO column, 0-50% EtOAc:Hex) to give 32-1 as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[N:11]=[C:10]([O:12][CH3:13])[C:9]([NH:14][C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=3)[CH2:19][CH2:18]2)=[O:16])=[CH:8][C:4]=1[C:5](O)=[O:6])[CH3:2].[CH:35]1[C:48]2[C:39](=[N:40][C:41]3[C:46]([C:47]=2[NH:49][C:50]2[CH:51]=[C:52]([NH:58][C:59](=[O:63])[CH:60]([NH2:62])[CH3:61])[CH:53]=[C:54]([CH2:56][OH:57])[CH:55]=2)=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH:38]=[CH:37][CH:36]=1>>[CH:45]1[C:46]2[C:41](=[N:40][C:39]3[C:48]([C:47]=2[NH:49][C:50]2[CH:51]=[C:52]([NH:58][C:59]([CH:60]([NH:62][C:5]([C:4]4[CH:8]=[C:9]([NH:14][C:15]([N:17]5[CH2:22][CH2:21][N:20]([C:23]6[CH:24]=[C:25]([O:33][CH3:34])[C:26]([O:31][CH3:32])=[C:27]([O:29][CH3:30])[CH:28]=6)[CH2:19][CH2:18]5)=[O:16])[C:10]([O:12][CH3:13])=[N:11][C:3]=4[CH2:1][CH3:2])=[O:6])[CH3:61])=[O:63])[CH:53]=[C:54]([CH2:56][OH:57])[CH:55]=2)=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:42]=[CH:43][CH:44]=1
Reactant: CC(N)C(=O)Nc1cc(CO)cc(Nc2c3ccccc3nc3ccccc23)c1
Reactant: CCc1nc(OC)c(NC(=O)N2CCN(c3cc(OC)c(OC)c(OC)c3)CC2)cc1C(=O)O
Product: CCc1nc(OC)c(NC(=O)N2CCN(c3cc(OC)c(OC)c(OC)c3)CC2)cc1C(=O)NC(C)C(=O)Nc1cc(CO)cc(Nc2c3ccccc3nc3ccccc23)c1
Yield: 44.3 %

Procedure:
The same reaction procedure to the example 1 were carried out using 2-ethyl-5-{[4-(3,4,5-trimethoxyphenyl)-piperazine-1-carbonyl]-amino}-6-methoxy-nicotinic acid and N-[3-(acridine-9-yl-amino)-5-hydroxymethyl-phenyl]-2-aminopropaneamide to give the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[C:28]2[CH2:27][CH2:26][CH2:25][C:24](=[O:29])[C:23]=2[CH:22]=[CH:21][C:20]=1[CH2:30][CH:31]=[CH2:32].[H][H]>[Pd].C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:33])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[C:28]2[CH2:27][CH2:26][CH2:25][C:24](=[O:29])[C:23]=2[CH:22]=[CH:21][C:20]=1[CH2:30][CH2:31][CH3:32]
Reactant: C=CCc1ccc2c(c1OCCCCCOc1ccccc1/C=C/C(=O)OC)CCCC2=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCc1ccc2c(c1OCCCCCOc1ccccc1CCC(=O)OC)CCCC2=O
Yield: 77.7 %

Procedure:
A mixture of 1.72 g (3.84 mmol) of (E)-3-[2-[5-[(5-oxo-2-(2-propenyl)-5,6,7,8-tetrahydro-1-naphthalenyl)oxy]pentyloxy]phenyl]-2-propenoic acid methyl ester from the preceding experiment, 0.1 g of 10% palladium of carbon, and 50 mL of ethyl acetate was stirred in an atmosphere of hydrogen until gas uptake ceased. The catalyst was filtered with suction on a pad of Celite and the filter cake was washed thoroughly with ethyl acetate. Concentration of the combined filtrate and washes under reduced pressure gave a yellow oil which was chromatographed on 50 g of silica gel. Elution with 4:1 hexane-ether afforded 1.35 g (78%) of 2-[5-[(5-oxo-2-propyl-5,6,7,8-tetrahydro-1-naphthalenyl)oxy]pentyloxy]benzenepropanoic acid methyl ester as a pale-yellow oil.