Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].[OH-].[K+:10].O=[C:12]([CH3:19])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].O>C(OC(C)C)(=O)C>[K+:10].[CH2:17]([O:16][C:14](=[O:15])[CH:13]=[C:12]([NH:1][C@H:2]([C:6]([O-:8])=[O:7])[CH:3]([CH3:5])[CH3:4])[CH3:19])[CH3:18]
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(C)[C@H](N)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)OC(C)C
Solvent: O
Product: CCOC(=O)C=C(C)N[C@H](C(=O)[O-])C(C)C

Procedure:
L-Valine (117.2 g, 1.0 mol), KOH (85%, 66.0 g, 1 mol) and ethyl 3-oxobutanoate (140.2 mL, 1.1 mol) are dissolved in isopropyl acetate (1 L). The reaction mixture is heated to reflux using a Dean-Stark apparatus. 32 mL water are isolated during 1.75 h. A small quantity of precipitate is formed. 500 mL are distilled off.
Reaction SMILES: Cl[CH2:2]/[CH:3]=[CH:4]/[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[I-:12].[Na+].CCCCCC>CC(C)=O>[CH:6]1([CH2:5]/[CH:4]=[CH:3]/[CH2:2][I:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: ClC/C=C/CC1CCCCC1
Reactant: [I-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CC(C)=O
Product: IC/C=C/CC1CCCCC1
Reaction time: 8 h
Yield: 76 %

Procedure:
The chloride (B) (38.6 g) was added to a solution of sodium iodide (55.7 g) in acetone (1 litre) and the solution was allowed to stand overnight. Hexane (500 ml) was added and the precipitated solid was removed by filtration. The filtrate was concentrated and the residue partitioned between water (500 ml) and hexane (500 ml). The organic phase was separated, washed with saturated sodium thiosulphate solution (500 ml) and saturated sodium chloride solution (2×500 ml), and dried (MgSO4). The solvent was removed by evaporation and the residual liquid distilled under vacuum to give (2E)-4-cyclohexyl-1-iodobut-2-ene (C) as a dark liquid (44.9 g), b.p. 80°-85° C. at 0.15 mm Hg; NMR: 0.8-1.8(complex m, 11H), 1.9(t, 2H), 3.9(m, 2H), 5.7(m, 2H). (iii) A 1.6M solution of butyllithium in hexane (93.9 ml) was added dropwise over 30 minutes to a stirred solution of diisopropylamine (21.9 ml) in dry tetrahydrofuran (THF) (200 ml) at 0° C. under an atmosphere of argon. The temperature was maintained at 0° C. for 30 minutes and then the solution was cooled to -40° C. A solution of (4S)-4-benzyl-3-(3-methylbutyryl)oxazolidin-2-one (31.3 g) (obtained as described in Tetrahedron. 1987, 44, 5525) in dry THF (70 ml) was added dropwise over 30 minutes. The solution was kept at -40° C. for 30 minutes and then the temperature was allowed to rise to 0° C. A solution of iodide (C) (39.0 g) in dry THF (75 ml) was added dropwise over 30 minutes, and then the solution was stirred at 0° C. for 1 hour. Saturated sodium chloride solution (250 ml) was added and the mixture was extracted with ether (3×250 ml). The extracts were washed with saturated sodium chloride solution (2×250 ml) and dried (MgSO4). The solvent was removed by evaporation and the residue was purified by flash chromatography, eluting with ethyl acetate/hexane (8:92 v/v), to give (4s)-4-benzyl-3-[(2S,4E)-6-cyclohexyl-2-isopropylhex-4-enoyl]oxazolidin-2-one (A) (34.5 g) as a clear oil; NMR: 0.8 -1.2(complex m, 12H), 1.6(m, 6H), 1.85(t, 1H), 2.0(m, 2H), 2.35(m, 2H), 2.6(m, 1H), 3.3(dt, 1H), 3.8(m, 1H), 4.1(d, 1H), 4.7(m, 1H), 5.4(m, 2H), 7.3(m, 5H); mass spectrum (+ve FAB), 398 (M+H+); 22 [α]436 +45.8 (c, 1.04, CHCl3). ##STR1##
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:14][C:15]([CH:17]2[CH2:21][CH2:20][C:19](=[O:22])[N:18]2[CH:23]2[CH2:28][CH2:27][N:26]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([CH3:37])[CH:31]=3)[CH2:25][CH2:24]2)=[O:16])[CH:5]=[C:6]([C:8]2[N:12]([CH3:13])[N:11]=[N:10][N:9]=2)[CH:7]=1.C(N(CC)CC)C.CN([CH:48]=[O:49])C.[CH3:50][OH:51]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:50][O:51][C:48](=[O:49])[C:2]1[CH:7]=[C:6]([C:8]2[N:12]([CH3:13])[N:11]=[N:10][N:9]=2)[CH:5]=[C:4]([NH:14][C:15]([CH:17]2[CH2:21][CH2:20][C:19](=[O:22])[N:18]2[CH:23]2[CH2:28][CH2:27][N:26]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([CH3:37])[CH:31]=3)[CH2:25][CH2:24]2)=[O:16])[CH:3]=1
Reactant: Cc1cc(CN2CCC(N3C(=O)CCC3C(=O)Nc3cc(Br)cc(-c4nnnn4C)c3)CC2)ccc1Cl
Reactant: CN(C)C=O
Reactant: CO
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(NC(=O)C2CCC(=O)N2C2CCN(Cc3ccc(Cl)c(C)c3)CC2)cc(-c2nnnn2C)c1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
To a solution of 1-[1-(4-Chloro-3-methyl-benzyl)-piperidin-4-yl]-5-oxo-pyrrolidine-2-carboxylic acid [3-bromo-5-(1-methyl-1H-tetrazol-5-yl)-phenyl]-amide (400 mg) in MeOH (20 ml) was added triethylamine (140 μl), DMF (5 ml), and [1,1′-bis(diphenylphosphino)-ferrocen]palladium (II) chloride (50 mg) and the reaction stirred for 2 d at 80° C. under a 3 bar CO atmosphere. The reaction mixture was filtered and the filtrate concentrated in vacuum. The residue was partitioned between water and EtOAc and the organic layer was then separated, dried and concentrated in vacuum. The residue was purified by flash chromatography (DCM: MeOH 100:0 to 95:5 gradient) to give the title compound (400 mg). Rf=0.37 (95:5 DCM:MeOH).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=O.C1C=CC=CC=1.[N+:18](C)([O-:20])=[O:19].[CH2:22](N)CCC>C(O)(=O)C>[N+:18]([C:5]([C:4]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:2]([F:1])[CH:3]=1)=[CH2:22])([O-:20])=[O:19]
Reactant: CCCCN
Reactant: COc1ccc(C=O)cc1F
Reactant: C[N+](=O)[O-]
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: C=C(c1ccc(OC)c(F)c1)[N+](=O)[O-]

Procedure:
After a mixture of 9.8 g of 3-fluoro-4-methoxybenzaldehyde, benzene, nitromethane, n-butylamine and acetic acid is refluxed, the reaction mixture is extracted with toluene. The extract is condensed, and the residue is recrystallized from a mixture of acetic acid and n-hexane. 10 g of α-nitro-3-fluoro-4-methoxystyrene are obtained.
Reaction SMILES: [C:1]1([CH2:7][C@@H:8]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:9]([O:11][C@@H:12]2[CH:17]3[CH2:18][CH2:19][N:14]([CH2:15][CH2:16]3)[CH2:13]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:27][CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:30]>>[Br-:27].[O:30]=[C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:28][N+:14]12[CH2:15][CH2:16][CH:17]([CH2:18][CH2:19]1)[C@@H:12]([O:11][C:9](=[O:10])[C@H:8]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:13]2
Reactant: O=C(O[C@H]1CN2CCC1CC2)[C@@H](Cc1ccccc1)Nc1ccccc1
Reactant: O=C(CBr)c1ccccc1
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)[C@@H](Cc1ccccc1)Nc1ccccc1)C2)c1ccccc1
Product: [Br-]
Yield: 98.1 %

Procedure:
To a solution of (R)—((R)-quinuclidin-3-yl) 3-phenyl-2-(phenylamino)propanoate (Diastereoisomer 1 of C22) (50.0 mg, 0.14 mmol), is added 2-bromo-1-phenylethanone (28.4 mg, 0.14 mmol) and the mixture reacted in a closed vessel under MW irradiation for 1 hour at 100° C. (LC-MS monitoring: complete conversion). Solvent is removed under reduced pressure and residue is triturated with EtOAc to obtain the title compound as a white solid (75.5 mg, 98% yield, bromide salt, single diastereoisomer).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([OH:16])=O)=[N:10][N:11]([CH3:13])[CH:12]=2)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[F:50][C:51]1[C:66]([F:67])=[CH:65][C:54]2[NH:55][C:56]([CH2:58][CH:59]3[CH2:64][CH2:63][CH2:62][CH2:61][NH:60]3)=[N:57][C:53]=2[CH:52]=1>CN(C=O)C.C(OCC)C>[F:50][C:51]1[C:66]([F:67])=[CH:65][C:54]2[NH:55][C:56]([CH2:58][CH:59]3[CH2:64][CH2:63][CH2:62][CH2:61][N:60]3[C:14]([C:9]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[CH:12][N:11]([CH3:13])[N:10]=3)=[O:16])=[N:57][C:53]=2[CH:52]=1
Reactant: Cn1cc(-c2ccc(F)cc2)c(C(=O)O)n1
Reactant: Fc1cc2nc(CC3CCCCN3)[nH]c2cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(-c2ccc(F)cc2)c(C(=O)N2CCCCC2Cc2nc3cc(F)c(F)cc3[nH]2)n1
Reaction time: 16 h
Yield: 57 %

Procedure:
A solution of 4-(4-fluoro-phenyl)-1-methyl-1H-pyrazole-3-carboxylic acid (73 mg, 0.33 mmol), HATU (124 mg, 0.33 mmol) and N,N-diisopropylethylamine (0.35 ml) in DMF (6 ml) was stirred at room temperature under argon for 0.5 h. The mixture was then treated with (RS)-5,6-difluoro-2-piperidin-2-ylmethyl-1H-benzoimidazole.2HCl, D20 (105 mg, 0.33 mmol) and stirring, under argon was continued for 16 h. The reaction mixture was diluted with diethyl ether and washed with water (3×), dried (MgSO4) and the solvent removed in vacuo. Chromatography (silica gel, ethyl acetate) afforded the title compound (88 mg, 57%).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].[H][H].[Cl:19][C:20]1[CH:25]=[N:24][CH:23]=[C:22](Cl)[N:21]=1>CN(C=O)C>[Cl:19][C:20]1[N:21]=[C:22]([O:14][CH:11]2[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]2)[CH:23]=[N:24][CH:25]=1
Reactant: Clc1cncc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cncc(Cl)n2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 1-boc-4-hydroxypiperidine (3.80 g, 18.9 mmol) in DMF (76 mL) at 0° C. was added sodium hydride (60% mineral oil dispersion; 0.906 g, 22.7 mmol). Once hydrogen evolution had ceased, 2,6-dichloropyrazine (2.81 g, 18.9 mmol) was added and the reaction mixture was allowed to warm to ambient temperature. After 1 h, the reaction mixture was quenched with brine (100 mL) and extracted with EtOAc (2×100 mL). The combined organics were dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by silica gel chromatography (EtOAc/Hexanes gradient) to afford tert-butyl 4-[(6-chloropyrazin-2-yl)oxy]piperidine-1-carboxylate as a yellow solid. LRMS (ESI) calculated for C14H20ClN3O3 336.1; found [M+Na]+, 336.1.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[CH:20][C:21]([F:35])=[C:22]4[C:26]=3[N:25]([CH3:27])[CH:24]=[C:23]4[CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].[OH-].[Na+].Cl>O1CCCC1.C(O)(C)C.O>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[CH:20][C:21]([F:35])=[C:22]4[C:26]=3[N:25]([CH3:27])[CH:24]=[C:23]4[CH2:28][CH2:29][C:30]([OH:32])=[O:31])[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2]
Reactant: CCOC(=O)CCc1cn(C)c2c(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)ccc(F)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)O
Product: CC(C)Oc1ccc(-c2nc(-c3ccc(F)c4c(CCC(=O)O)cn(C)c34)no2)cc1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.1 %

Procedure:
To a solution of ethyl 3-[7-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-4-fluoro-1-methyl-1H-indol-3-yl]propanoate (D130) (349 mg) in tetrahydrofuran (THF) (10 mL), Isopropanol (5 mL) and water (2 mL), was added sodium hydroxide (293 mg). The reaction mixture was stirred at room temperature overnight. LCMS showed the reaction was complete. The reaction mixture was neutralized with 2 M HCl till pH ˜6.0. After removing part of organic solvent, the residue was purified by MDAP to give 3-[7-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-4-fluoro-1-methyl-1H-indol-3-yl]propanoic acid (E96) (204 mg). δH (DMSO-d6, 400 MHz): 1.38 (6H, d), 2.61 (2H, t), 3.04 (2H, t), 3.63 (3H, s), 4.95-5.01 (1H, m), 6.96 (1H, dd), 7.23 (1H, s), 7.43 (1H, dd), 7.55 (1H, d), 8.42 (1H, dd), 8.53 (1H, d), 12.15 (1H, s); δF (DMSO-d6, 376 MHz): −120.5; MS (ES): C24H21FN4O4 requires 448; found 449.2 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH:5]=[C:6]1[CH2:9][CH2:8][CH2:7]1)[CH3:2].[N+:11]([CH3:14])([O-:13])=[O:12].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:10])[CH2:5][C:6]1([CH2:14][N+:11]([O-:13])=[O:12])[CH2:9][CH2:8][CH2:7]1)[CH3:2]
Reactant: CCOC(=O)C=C1CCC1
Reactant: C[N+](=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CC1(C[N+](=O)[O-])CCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.1 %

Procedure:
The unsaturated ester (2) (5.79 g, 41.4 mmol) was dissolved in tetrahydrofuran (20 mL) and stirred at 70° C. with nitromethane (4.67 mL, 86.4 mmol) and tetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 55 mL, 55.0 mmol). After 18 hours, the mixture was cooled to room temperature, diluted with ethyl acetate (150 mL), and washed with 2N HCl (60 mL) followed by brine (100 mL). The organic phase was collected, dried (MgSO4), and the solvent removed in vacuo. The residue was purified by flash chromatography (silica, ethyl acetate:heptane 1:1) to give 4.34 g (52%) of a clear oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)=[N:10][C:9]=2[C:20]([NH:22][C:23]2[S:24][CH:25]=[CH:26][N:27]=2)=[O:21])=[CH:4][CH:3]=1.[CH3:28][N:29]([CH3:34])[CH2:30][CH2:31][CH2:32]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:32][CH2:31][CH2:30][N:29]([CH3:34])[CH3:28])=[CH:15][CH:14]=3)=[N:10][C:9]=2[C:20]([NH:22][C:23]2[S:24][CH:25]=[CH:26][N:27]=2)=[O:21])=[CH:4][CH:3]=1
Reactant: O=C(Nc1nccs1)c1nc(-c2ccc(O)cc2)[nH]c1-c1ccc(F)cc1
Reactant: CN(C)CCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CN(C)CCCOc1ccc(-c2nc(C(=O)Nc3nccs3)c(-c3ccc(F)cc3)[nH]2)cc1

Procedure:
5-(4-Fluorophenyl)-2-(4-hydroxyphenyl)-N-(2-thiazolyl)-imidazole-4-carboxamide, 3-dimethylaminopropanol, triphenyl-phosphine and diethyl azodicarboxylate are reacted and treated in the same manner as in Example 24 to give 5-(4-fluorophenyl)-2-(4-(3-dimethylaminopropyloxy)phenyl)-N-(2-thiazolyl)imidazole-4-carboxamide.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:7]([C:10]1[CH:11]=[C:12]([CH:21]=[CH:22][C:23]=1Cl)[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14])([O-:9])=[O:8].Cl.N1CCCCC1>>[N+:7]([C:10]1[CH:11]=[C:12]([CH:21]=[CH:22][C:23]=1[N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14])([O-:9])=[O:8]
Reactant: O=C(c1ccccc1)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: C1CCNCC1
Agent: Cl
Product: O=C(c1ccccc1)c1ccc(N2CCCCC2)c([N+](=O)[O-])c1
Reaction time: 0.07 h

Procedure:
15 ml. of piperidine are added at once to 13 g. of 3-nitro-4-chloro-benzophenone under stirring. Due to the highly exothermic reaction the mixture warms to 98° to 100 °C within 4 to 5 minutes, thereafter piperidine hydrochloride starts to separate from the homogeneous reaction mixture. The mixture is stirred for 10 minutes at 98° to 100 °C, thereafter cooled, the product is triturated with 30 ml. of n-hexane, and filtered. The crystalline substance is washed on the filter with 2×30 ml. of n-hexane, suctioned well, and suspended several times in distilled water to remove piperidine hydrochloride. The obtained product is dried until constant weight. 15.5 g. of crystalline 3-nitro-4-piperidino-benzophenone are obtained; m.p.: 77°C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([F:8])[C:5]2[O:9][C:10]3[C:15]([C@@:16]4([CH2:21][CH2:20][O:19][C:18]([NH2:22])=[N:17]4)[C:4]=2[CH:3]=1)=[CH:14][C:13]([NH2:23])=[CH:12][CH:11]=3.[O:24]1[CH2:29][CH2:28][CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH2:25]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1.O.C(C1C(C(C)(C)C)=C([Pd]Cl)C=CC=1NC)(C)(C)C>[O:24]1[CH2:29][CH2:28][CH:27]=[C:26]([C:2]2[N:7]=[C:6]([F:8])[C:5]3[O:9][C:10]4[C:15]([C@@:16]5([CH2:21][CH2:20][O:19][C:18]([NH2:22])=[N:17]5)[C:4]=3[CH:3]=2)=[CH:14][C:13]([NH2:23])=[CH:12][CH:11]=4)[CH2:25]1
Reactant: CC1(C)OB(C2=CCCOC2)OC1(C)C
Reactant: NC1=N[C@@]2(CCO1)c1cc(N)ccc1Oc1c2cc(Cl)nc1F
Agent: CNc1ccc([Pd]Cl)c(C(C)(C)C)c1C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: NC1=N[C@@]2(CCO1)c1cc(N)ccc1Oc1c2cc(C2=CCCOC2)nc1F
Yield: 71.6 %

Procedure:
A mixture of (S)-3-chloro-1-fluoro-5′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazine]-2′,7-diamine (0.354 g, 1.058 mmol), 2-(5,6-dihydro-2H-pyran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.667 g, 3.17 mmol), 1,1-bis[(di-t-butyl-p-methylaminophenyl]palladium(ii) chloride (0.037 g, 0.053 mmol) and potassium phosphate tribasic (0.673 g, 3.17 mmol) in dioxane/water (42 mL) was heated in microwave at 130° C. for 40 min. The mixture was poured into water and extracted with EtOAc. The combined organics were dried over Na2SO4, filtered, concentrated and chromatographed on silica gel using 0-5% 2M NH3 MeOH/DCM to afford (S)-3-(5,6-dihydro-2H-pyran-3-yl)-1-fluoro-5′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazine]-2′,7-diamine (0.29 g, 0.758 mmol, 72% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[OH-].[Na+].[H][H].[C:17](OC(=O)C)(=[O:19])[CH3:18]>[Ni].O>[C:17]([NH:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH2:6][CH2:7]1)(=[O:19])[CH3:18]
Reactant: Nc1ccc(CCC(=O)O)cc1
Reactant: [H][H]
Reactant: CC(=O)OC(C)=O
Agent: [Ni]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)N[C@H]1CC[C@H](CCC(=O)O)CC1
Temperature: 0 °C
Reaction time: 0.58 h

Procedure:
A mixture of 397 g of 3-(4-amino-phenyl)propionic acid, 125 g of NaOH and 160 g of Raney nickel in 5.71 of water is hydrogenated at 170° C. and 100 bar until no further hydrogen is taken up (30 hours). After filtration and washing the residue with water, 6.31 of a colourless solution are obtained as the filtrate, which is combined with a solution of 129 g of NaOH in 400 ml of water, after which 454 ml of acetic anhydride are added dropwise thereto within 35 minutes. After 5 hours the precipitate is filtered off, the filtrate is adjusted to pH 4 by the addition of concentrated hydrochloric acid and stirred for 3 hours at 0° C. It is then suction filtered, washed with 250 ml of ice water and dried at 70° C. In this way, 216 g of 3-(trans-4-acetylaminocyclohexyl)propionic acid are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[C:14]([OH:16])=O)[CH3:2].[CH2:17]([O:19][C:20]([C:22]1([NH2:31])[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23]1)=[O:21])[CH3:18].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:17]([O:19][C:20]([C:22]1([NH:31][C:14]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:12]=[CH:13][C:4]=2[O:3][CH2:1][CH3:2])=[O:16])[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23]1)=[O:21])[CH3:18]
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Reactant: CCOc1ccc2ccccc2c1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(NC(=O)c2c(OCC)ccc3ccccc23)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.2 %

Procedure:
To a solution of 2-ethoxy-naphthalene-1-carboxylic acid (335 mg, 1.55 mmol), 2-amino-indan-2-carboxylic acid ethyl ester (318 mg, 1.55 mmol), HATU (886 mg, 2.33 mmol) in anhydrous DMF (8 mL) is added DIPEA (385 μL, 2.33 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (40 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (115 g silica gel, gradient elution: 5-50% EtOAc in heptane) to give a pure product (45) as white solid (420 mg, 67%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][C:13]2[C:21]3[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=3)[NH:15][C:14]=2[CH3:23])[CH:7]=1)[CH3:2].Br[C:26]1[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=1>>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][C:13]2[C:21]3[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=3)[N:15]([C:26]3[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=3)[C:14]=2[CH3:23])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Reactant: Cn1cc(Br)cn1
Product: CCOC(=O)Cc1cccc(Sc2c(C)n(-c3cnn(C)c3)c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 42, Step 4, using the following starting materials: [3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-phenyl]-acetic acid ethyl ester and 4-bromo-1-methylpyrazole.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:13]([O:15]CC)=[CH2:14])=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.C1C(=O)N([Br:25])C(=O)C1.Br.OS([O-])=O.[Na+]>CC#N.O.C(OCC)(=O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:13](=[O:14])[CH2:15][Br:25])=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1
Reactant: C=C(OCC)c1cc(=O)oc2cc(Br)ccc12
Reactant: O=C1CCC(=O)N1Br
Agent: Br
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(CBr)c1cc(=O)oc2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of vinyl ether from Step 1 (1.02 g) in CH3CN:H2O 4:1 (25 mL) were successively added NBS (0.82 g) and concentrated HBr (20 μL). After being stirred at r.t. for 4 h. The reaction mixture was treated with 5% aqueous NaHSO3 (1 mL). Ethyl acetate was then added and the organic phase was washed with saturated aqueous NaHCO3, H2O and brine, dried (MgSO4) and evaporated. Flash chromatography of the residue (silica gel; hexane/EtOAc (85:15)) afforded the title compound as a white solid.
Reaction SMILES: [C:1]1([C:9]([CH2:11][C:12]2[CH:19]=[CH:18][C:15]([O:16]C)=[CH:14][CH:13]=2)=[O:10])[CH:8]=[CH:7][C:4]([O:5]C)=[CH:3][CH:2]=1.Cl.N1C=CC=CC=1>O>[OH:5][C:4]1[CH:7]=[CH:8][C:1]([C:9]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([OH:16])=[CH:18][CH:19]=2)=[O:10])=[CH:2][CH:3]=1
Reactant: COc1ccc(CC(=O)c2ccc(OC)cc2)cc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: O=C(Cc1ccc(O)cc1)c1ccc(O)cc1
Temperature: 200 °C
Yield: 85.4 %

Procedure:
Desoxyanisoin (5.00 g, 19.5 mmol) and pyridine hydrochloride (9.02 g, 78.0 mmol) were added to a round-bottom flask equipped with a condenser. The mixture was refluxed for 5 h at 200° C., cooled to room temperature, and poured into water. The precipitate was filtered and recrystallized from acetic acid to give 3.8 g (85% yield) of a pale yellow crystalline solid. 1H NMR (DMSO-d4, 300 MHz, ppm): 10.35 (s, 1H, HO—Ar—CO), 9.28 (s, 1H, HO—Ar—CH2), 7.91 (d, 2H, J=8.7 Hz, Ar—H), 7.04 (d, 2H, J=8.5 Hz, Ar—H), 6.84 (d, 2H, J=8.7 Hz, Ar—H), 6.68 (d, 2H, J=8.5 Hz, Ar—H), 4.11 (s, 2H, Ar—CO—CH2—Ar). 13C NMR (DMSO-d6, 75 MHz, ppm): 196.5, 162.3, 156.2, 131.3, 130.7, 128.1, 125.9, 115.5, 115.4, 43.7.