Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:12]([OH:14])=O)[CH2:10][OH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:15][C:16]1[CH:25]=[C:24]2[C:19]([C:20]([CH3:27])=[CH:21][C:22](=[O:26])[O:23]2)=[CH:18][CH:17]=1.OC1C2N=NNC=2C=CC=1.C1(N=C=NC2CCCCC2)CCCCC1.C(NC1CCCCC1)(NC1CCCCC1)=O>C(Cl)Cl>[C:4]([O:3][C:1]([NH:8][CH:9]([CH2:10][OH:11])[C:12]([NH:15][C:16]1[CH:25]=[C:24]2[C:19]([C:20]([CH3:27])=[CH:21][C:22](=[O:26])[O:23]2)=[CH:18][CH:17]=1)=[O:14])=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: Cc1cc(=O)oc2cc(N)ccc12
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(NC1CCCCC1)NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Product: Cc1cc(=O)oc2cc(NC(=O)C(CO)NC(=O)OC(C)(C)C)ccc12
Reaction time: 0.5 h

Procedure:
Briefly, 1.1 mmol N-BOC-L-Serine (Fluka) is dissolved in 2 ml methylene chloride. Then 1.1 mmol 7-Amino-4-methylcoumarin and 1.2 mmol hydroxybenztriazole are added with stirring. Over a period of 30 minutes, a solution of 1.3 mmol dicyclohexyl carbodiimide in 1.4 ml methylene chloride is added dropwise. The reaction is stirred at room temperature for 20 hours, during which time a precipitate of dicyclohexylurea forms. The precipitate is removed by filtration and washed with methylene chloride. The combined solutions (filtrates) are evaporated under reduced pressure and the residue chromatographed over silica gel with methylene chloride--ethylacetate as the eluent yielding 2-((tert-butoxy)carbonylamino)-3-hydroxy-N-(4-methyl-2-oxo(2H-chromen-7-yl))propanamide.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([CH2:10][O:11][CH3:12])=[CH:4][C:3]=1[O:13][CH3:14].CCCCCC.C[O:22][B:23]([O:26]C)[O:24]C.Cl>O1CCCC1.C1(C)C=CC=CC=1>[CH3:14][O:13][C:3]1[CH:4]=[C:5]([CH2:10][O:11][CH3:12])[CH:6]=[C:7]([O:8][CH3:9])[C:2]=1[O:22][B:23]([OH:26])[OH:24]
Reactant: COCc1cc(OC)c(Br)c(OC)c1
Reactant: COB(OC)OC
Agent: Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: COCc1cc(OC)c(OB(O)O)c(OC)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66.9 %

Procedure:
Under cooling in an dry ice-acetone bath in nitrogen flow, to a solution of 2-bromo-1,3-dimethoxy-5-(methoxymethyl)benzene (20.0 g, 76.6 mmol) in tetrahydrofuran (200 mL) was added a solution (50.9 mL, 80.4 mmol) of 1.58Mn-butyllithiumin hexane, and the reaction mixture was stirred for 30 minute. Then, to the reaction mixture was added a solution of trimethoxyborane (8.75 g, 84.2 mmol) in tetrahydrofuran (20 mL), and the reaction temperature was raised up to 0° C. under stirring. To the reaction mixture was added 1N hydrochloric acid (200 mL), and the reaction mixture was stirred for 30 minutes at room temperature. After the reaction, to the reaction mixture was added toluene (200 mL) and an organic layer was separated, then, the remaining aqueous layer was further extracted with toluene (100 mL). Combined organic layers were washed with water (100 mL), and the solvent was concentrated under reduced pressure. The resulting residue was dissolved in t-butyl methyl ether (75 mL), the reaction mixture was stirred for 30 minutes. Then, to this was added heptane (223 mL), and the mixture was further stirred for 2 hours. A precipitate was filtrated, and the precipitate was washed with a t-butyl methyl ether-heptane mixed solution (1:3, 3.75 mL), and dried at 40° C. for 24 hours to obtain 12.4 g of a title compound (yield: 71.8%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[C:10]([CH:11]([CH3:13])[CH3:12])[C:3]=12.[H-].[Na+].F[C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([N+:25]([O-:27])=[O:26])[CH:18]=1.O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([N+:25]([O-:27])=[O:26])[CH:18]=3)[N:9]=[C:10]([CH:11]([CH3:13])[CH3:12])[C:3]=12
Reactant: CC(C)c1n[nH]c2nccc(Cl)c12
Reactant: N#Cc1ccc(F)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1nn(-c2ccc(C#N)c([N+](=O)[O-])c2)c2nccc(Cl)c12
Reaction time: 0.5 h
Yield: 85 %

Procedure:
Compound (6b) (0.335 g) was dissolved in DMF (8.6 mL), and sodium hydride (0.097 g, a 55% dispersion in paraffin liquid) was added to the resulting solution at 0° C., followed by stirring for 30 min. Then, 4-fluoro-2-nitrobenzonitrile was added to the reaction solution, followed by stirring at 60° C. for 30 min. Water was added to the reaction solution, and the precipitate was collected by filtration and washed by sprinkling water to obtain 4-{4-chloro-3-isopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl}-2-nitrobenzonitrile (0.5 g, 85%). 4-{4-Chloro-3-isopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl}-2-nitrobenzonitrile (0.35 g) and ammonium chloride (0.35 g) were dissolved in a solvent mixture of THF (3 mL), methanol (3 mL), and water (3 mL). Iron (0.57 g) was added to the resulting solution, followed by stirring at 70° C. for 1 hr. Insoluble matters were filtered by celite, and the solvent was distilled away. The precipitate was washed with water and was collected by filtration to obtain compound (106a) (0.32 g, 95%) as a white solid.
Reaction SMILES: [CH:1]1[N:5]=[CH:4][N:3]([C:6](N2C=NC=C2)=[S:7])[CH:2]=1.[N:13]1([C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]([F:30])([F:29])[F:28])=[O:20])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(N(CC)CC)C>ClCCl>[N:3]1([C:6]([N:16]2[CH2:17][CH2:18][N:13]([C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:28])([F:30])[F:29])=[O:20])[CH2:14][CH2:15]2)=[S:7])[CH:2]=[CH:1][N:5]=[CH:4]1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccccc1C(F)(F)F)N1CCN(C(=S)n2ccnc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
1,1-Thiocarbonyldiimidazole (2.14 g, 11.4 mmol) was added to the mixture of piperazin-1-yl-(2-trifluoromethylphenyl)methanone (3.36 g, 11.40 mmol) and triethyl amine (1.75 mL, 12.5 mmol) in 50 mL of dichloromethane at 0° C. The mixture was warmed up to room temperature and then stirred at room temperature overnight. The reaction mixture was washed with brine (2×15 mL), dried over anhydrous Na2SO4, concentrated to give the light yellow foam. The crude compound was triturated by anhydrous ether to afford [4-(imidazole-1-carbothioyl)piperazin-1-yl]-(2-trifluoromethylphenyl)methanone as a white solid in 96% yield (4.40 g).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:9]2[CH:10]=[N:11][C:12]([NH2:26])=[C:13]([O:14][C@@H:15]([C:17]3[C:22]([Cl:23])=[CH:21][CH:20]=[C:19]([F:24])[C:18]=3[Cl:25])[CH3:16])[C:8]=2[O:7][CH:6]=1)=[O:4]>Cl>[NH2:26][C:12]1[N:11]=[CH:10][C:9]2[C:5]([C:3]([OH:4])=[O:2])=[CH:6][O:7][C:8]=2[C:13]=1[O:14][C@@H:15]([C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[C:19]([F:24])[C:18]=1[Cl:25])[CH3:16]
Reactant: COC(=O)c1coc2c(O[C@H](C)c3c(Cl)ccc(F)c3Cl)c(N)ncc12
Agent: Cl
Product: C[C@@H](Oc1c(N)ncc2c(C(=O)O)coc12)c1c(Cl)ccc(F)c1Cl
Temperature: 100 °C

Procedure:
A suspension of 6-amino-7-[(R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]furo[3,2-c]pyridine-3-carboxylic acid methyl ester (140 mg, 0.35 mmol) in 1N aq. HCl (5 mL) was heated at 100° C. for 7 h. The mixture was cooled to rt, and the off-white solid was collected by filtration to give the title compound. LC-MS (ES+): 384.96/386.96 [MH+]. 1H NMR (CD3OD, 400 MHz): δ 1.95 (d, J=6.6 Hz, 3H), 6.70 (q, J=6.6 Hz, 1H), 7.26 (m, 1H), 7.44 (dd, J=9.1, 4.8 Hz, 1H), 8.20 (s, 1H), 8.43 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[C:16]3[C:17]4([CH2:20][O:21][C:15]=3[CH:14]=[CH:13][CH:12]=2)[CH2:19][CH2:18]4)=[N:8][CH:9]=1)([O-])=O.O.[Cl-].[NH4+]>O1CCCC1>[C:17]12([C:16]3[C:11]([O:10][C:7]4[N:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=4)=[CH:12][CH:13]=[CH:14][C:15]=3[O:21][CH2:20]1)[CH2:19][CH2:18]2
Reactant: O=[N+]([O-])c1ccc(Oc2cccc3c2C2(CC2)CO3)nc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(Oc2cccc3c2C2(CC2)CO3)nc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96 %

Procedure:
To a solution of 5-nitro-2-(spiro[1-benzofuran-3,1′-cyclopropan]-4-yloxy)pyridine (Reference Intermediate 215, 99 mg) in tetrahydrofuran (5 ml)/water (2.5 ml) iron (97 mg, 1.741 mmol) and then ammonium chloride (93 mg, 1.741 mmol) were added and the reaction mixture was stirred for 4 hours at room temperature. The catalyst was filtered off and the residue was diluted with an aqueous saturated solution of NaHCO3 (5 ml) and extracted with ethyl acetate (3×10 ml). The organic layer was dried over sodium sulphate, filtered and evaporated and the residue was purified by flash chromatography (Biotage system) on silica gel using a 10 g SNAP column and cyclohexane/ethyl acetate 8:2 to cyclohexane/ethyl acetate 1:1 as eluents affording the title compound as a light yellow solid (85 mg).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:18][N:17]=[C:16]([C:19]3[CH:24]=[C:23]([C:25](=[O:37])[NH:26][CH2:27][C:28]4[CH:33]=[CH:32][C:31]([F:34])=[C:30]([O:35][CH3:36])[CH:29]=4)[N:22]=[C:21]([CH3:38])[N:20]=3)[CH2:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:39]>O1CCOCC1>[ClH:39].[F:34][C:31]1[CH:32]=[CH:33][C:28]([CH2:27][NH:26][C:25]([C:23]2[CH:24]=[C:19]([C:16]3[CH2:15][CH:14]([CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[O:18][N:17]=3)[N:20]=[C:21]([CH3:38])[N:22]=2)=[O:37])=[CH:29][C:30]=1[O:35][CH3:36]
Reactant: COc1cc(CNC(=O)c2cc(C3=NOC(C4CCN(C(=O)OC(C)(C)C)CC4)C3)nc(C)n2)ccc1F
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc(CNC(=O)c2cc(C3=NOC(C4CCNCC4)C3)nc(C)n2)ccc1F
Yield: 82 %

Procedure:
Tert-butyl-4-(3-(6-(4-fluoro-3-methoxybenzylcarbamoyl)-2-methylpyrimidin-4-yl)-4,5-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.3 g, 0.569 mmol, G.1.18) was dissolved in 4N 1,4-dioxane.HCl (5 mL) and stirred at RT for about 1 h. Excess solvent was removed in vacuo and the crude material was triturated with ether (2×10 mL) to afford N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5-(piperidin-4-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide hydrochloride as a white solid 0.2 g (82%). LC/MS (Table 1, method e) Rt=2.53 min; MS m/z 428.3 (M+H)+.
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[C:15]([O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])=[O:16])=O)(C)(C)C.Cl.C(OCC)(=O)C>C(OCC)(=O)C>[NH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[C:15]([O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])=[O:16]
Reactant: CC(C)(C)OC(=O)NC1CCCCC1C(=O)OCC[Si](C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOC(=O)C1CCCCC1N
Temperature: 25 °C
Reaction time: 6 h
Yield: 115.1 %

Procedure:
To a solution of 2.82 g of 2-(trimethylsilyl)ethyl(1RS,2SR)-2-[(t-butoxycarbonyl)amino]cyclohexanecarboxylate in 10 ml of ethyl acetate, were added 20 ml of 4 M hydrogen chloride/ethyl acetate under ice-cooling, followed by stirring at room temperature for 6 hours. The reaction solution was evaporated to obtain 2.30 g of 2-(trimethylsilyl)ethyl(1RS,2SR)-2-aminocyclohexanecarboxylate as a colorless amorphous substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([F:20])[CH:14]=3)=[CH:11][C:10]([C:21]([O:23]CC)=[O:22])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.ClC1C=C(N2C(C3C=C(F)C=C(Cl)C=3)=CC(C(O)=O)=N2)C=CC=1F>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([F:20])[CH:14]=3)=[CH:11][C:10]([C:21]([OH:23])=[O:22])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(-c2cc(C)cc(F)c2)n(-c2cccc(Cl)c2)n1
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccc(F)c(Cl)c2)n1
Product: Cc1cc(F)cc(-c2cc(C(=O)O)nn2-c2cccc(Cl)c2)c1
Reaction time: 6 h

Procedure:
The preparation of the title compound takes place starting from the compound of Example 58A in analogy to the synthesis of the compound of Example 71A but with stiffing for 6 hours. 1.64 g (100% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:11][CH2:12][CH2:13][CH2:14]Br)=[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:6]1(=[O:23])=[O:22])([CH3:4])([CH3:3])[CH3:2].[F:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:11][CH2:12][CH2:13][CH2:14][O:31][C:28]2[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=2)=[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:6]1(=[O:23])=[O:22])([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1ccc(F)cc1
Reactant: CC(C)(C)N1C(=O)C(NCCCBr)=C(c2ccccc2)S1(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)N1C(=O)C(NCCCOc2ccc(F)cc2)=C(c2ccccc2)S1(=O)=O
Temperature: 120 °C
Yield: 31 %

Procedure:
The title compound was prepared as described for Example 5 from 2-tert-butyl-4-[(3-bromopropyl)amino]-5-phenylisothiazol-3(2H)-one 1,1-dioxide and 4-fluorophenol using 3 equivalents of K2CO3 and with heating at 80° C. for 15 mins, 100° C. for 1 h and 120° C. for 1 h. The reaction mixture was evaporated to dryness and the residue was purified by silica gel column chromatography (Horizons Biotage) using 12-20% EtOAc in petroleum ether 40-60° C. as eluent to give the title compound (0.007 g, 31%). 1H NMR (500 MHz CDCl3): δ 7.54-7.50 (m, 2H), 7.45-7.40 (m, 3H), 7.00-6.96 (m, 2H), 6.82-6.78 (m, 2H), 5.76 (t, 1H), 3.86 (t, 2H), 3.11-3.02 (m, 2H), 1.88-1.80 (m, 2H), 1.75 (s, 9H); 13C NMR (125 MHz CDCl3): δ 159.8, 158., 154.7, 156.7, 135.3, 131.8, 129.7, 128.8, 125.3, 116.2, 160.0, 115.6, 115.5, 107.2, 66.7, 61.7, 42.5, 28.9, 27.8; Mass Spectrum: M+H+ 433.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH:9]=[CH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:25])C=1.O.S([O-])(O)=O.[Na+]>ClCCl>[C:1]1([CH:7]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:8][CH:9]2[O:25][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCC(c1ccccc1)c1ccccc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: c1ccc(C(CC2CO2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.52 g of 4,4-diphenylbut-1-ene in 25 mL of dichloromethane at 0° C. was added 0.75 g of 50-60% by wt of m-chloroperbenzoic acid. The mixture was stirred at room temperature overnight, then heated at reflux for 1 hr. Water, 1 mL, and 0.25 g of sodium hydrogen sulfite were added to destroy the excess oxidizing agent. The organic layer was washed with water and dilute sodium hydrogen carbonate solution, dried, then concentrated in vacuo to give 0.5 g of 4,4-diphenylbut-1-ene oxide which is characterized by:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][C@H:13]3[CH2:18][CH2:17][C@H:16]([NH:19][C:20](=[O:22])[CH3:21])[CH2:15][CH2:14]3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH2:23]([OH:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[H-].[Na+]>CC(N(C)C)=O>[CH2:23]([O:30][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][C@H:13]3[CH2:18][CH2:17][C@H:16]([NH:19][C:20](=[O:22])[CH3:21])[CH2:15][CH2:14]3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: OCc1ccccc1
Reactant: CC(=O)N[C@H]1CC[C@H](Oc2ccc3c(Cl)nccc3c2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(=O)N[C@H]1CC[C@H](Oc2ccc3c(OCc4ccccc4)nccc3c2)CC1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
975 mg (3.06 mmol) of N-[4-(1-chloro-isoquinolin-6-yloxy)-cyclohexyl]-acetamide (18) were dissolved in 20 ml of dimethyl acetamide and 992 mg (9.17 mmol) of benzyl alcohol were added. After addition of 367 mg (9.17 mmol) of sodium hydride (60%), the reaction mixture was stirred for 3 h at room temperature and for 1 h at 80° C. Then, the solvent was removed in vacuo, the residue was dissolved in dichloromethane and washed three times with water. The organic layer was dried with magnesium sulfate and evaporated. Final purification by preparative HPLC yielded 680 mg of the title compound. Rt=1.75 min (Method B). Detected mass: 391.2 (M+H+).
Reaction SMILES: C([Li])CCC.C(OCC)C.Br[C:12]1[CH:13]=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2.CN(OC)[C:24](=[O:28])[CH2:25][CH2:26][CH3:27]>C1COCC1>[N:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[C:12]([C:24](=[O:28])[CH2:25][CH2:26][CH3:27])[CH:13]=1
Reactant: CCCC(=O)N(C)OC
Reactant: Brc1cnc2ccccc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCC(=O)c1cnc2ccccc2c1
Temperature: 0 °C
Yield: 58.1 %

Procedure:
In a dry 3-necked flask under argon at -50° C., n-butyl lithium (0.0025M, 0.021 ml) was added to 150 ml diethylether. Then 4.16 grams 3-bromoquinoline in 2 ml THF was added dropwise while stirring and maintaining the temperature at -60° C. to -55° C. The solution was stirred for 30 minutes, and 2.3 grams N-methyl-N-methoxybutanamide were then added dropwise at -50° C. and the solution was stirred an additional 30 minutes. The solution was then allowed to warm to 0° C. and stirred for one hour. The reaction was quenched with a saturated solution of ammonium chloride and the THF layer separated, washed with brine, separated, and dried over magnesium sulfate. Filtration through diatomaceous earth, followed by concentration and subsequent thin layer chromatography (35% ethylacetate/65% CH2Cl2) gave a total yield of 2.03 g (51%) of the title compound.
Reaction SMILES: C([O:8][C:9](=[O:32])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:31])[C@@H:16]1[CH2:20][CH2:19][CH2:18][N:17]1[C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])C1C=CC=CC=1>C1COCC1.[Pd]>[CH2:24]([NH:23][C:21]([N:17]1[CH2:18][CH2:19][CH2:20][C@H:16]1[C:15]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:10]1[C:9]([OH:32])=[O:8])=[O:31])=[O:22])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)NCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C(O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
Palladium-black (0.87 g) was added to a solution of N-(benzylaminocarbonyl)-L-prolyl-L-proline benzyl ester (43.55 g) in THF (400 ml), and the mixture was stirred at room temperature overnight under a hydrogen atmosphere. The reaction mixture was filtered and concentrated to give the title compound (34.5 g).
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[CH2:25]([O:24][C:22]([N:20]=[C:16]([N:7]1[CH2:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH2:8]1)[O:17][CH2:18][CH3:19])=[O:23])[CH3:26]
Reactant: CCOC(=O)Cl
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Product: CCOC(=O)N=C(OCC)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and ethyl chloroformate, there is obtained ethyl N-ethoxycarbonyl-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as an oil, mass spectrum m/e: M+ 338 (14), 309 (19), 293 (12), 263 (78), 194 (100);
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[O:11])=[CH:4][CH:3]=1.C(OCC)(=O)CC(OCC)=O.CC(C)([O-])C.[K+]>O1CCOCC1.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].ClCCl>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C@H:8]([C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[O:11])=[C:20]([CH3:26])[CH:21]=1
Reactant: Cc1cc(C(=O)C[C@@H](c2ccc(Br)cc2)c2ccc(Cl)cc2C)ccn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCOC(=O)CC(=O)OCC
Product: Cc1cc(C(=O)C[C@@H](c2ccccc2)c2ccc(Cl)cc2C)ccn1
Temperature: 80 °C
Yield: 79.1 %

Procedure:
A mixture of (S)-3-(4-bromophenyl)-3-(4-chloro-2-methylphenyl)-1-(2-methylpyridin-4-yl)propan-1-one (example 282, step 1; 200 mg, 466 μmol) diethyl malonate (112 mg, 700 μmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (19 mg, 23 mmol) and potassium tert-butoxide (157 mg, 1.4 mmol) in 1,4-dioxane (4 mL) was heated at 80° C. for 5 h, then partitioned between sat. aq. ammonium chloride solution and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and evaporated. Chromatography (SiO2; heptane-ethyl acetate gradient) produced the title compound (129 mg, 79%). Light yellow oil, MS (ESI+): m/z=350.2 ([M+H]+).
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]([F:44])([F:43])[C:5]1[CH:6]=[C:7]([C:15]([CH3:42])([CH3:41])[C:16]([N:18]([C:20]2[CH:21]=[N:22][C:23]([N:34]3[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]3)=[CH:24][C:25]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH:32]=[O:33])[CH3:19])=[O:17])[CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1>CO.[Cl-].[Na+].O>[F:44][C:4]([F:3])([F:43])[C:5]1[CH:6]=[C:7]([C:15]([CH3:42])([CH3:41])[C:16]([N:18]([C:20]2[CH:21]=[N:22][C:23]([N:34]3[CH2:35][CH2:36][N:37]([CH3:40])[CH2:38][CH2:39]3)=[CH:24][C:25]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH2:32][OH:33])[CH3:19])=[O:17])[CH:8]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:10]=1
Reactant: CN1CCN(c2cc(-c3ccccc3C=O)c(N(C)C(=O)C(C)(C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cn2)CC1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN1CCN(c2cc(-c3ccccc3CO)c(N(C)C(=O)C(C)(C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cn2)CC1
Reaction time: 0.5 h
Yield: 68.2 %

Procedure:
To a mixture of 15 mg (0.41 mmol) sodium borohydride in 2 ml methanol were added at 0° C. 200 mg (0.338 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-formyl-phenyl)-6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide. After stirring at 0° C. for 1 h 1 ml brine was added at 0° C. The mixture was stirred for 30 min. Methanol was distilled off and the residue was diluted with 20 ml ethyl acetate and washed with 20 ml brine. The organic layer was dried over sodium sulfate, concentrated and purified by flash chromatography to give 137 mg (68%) of the title compound as a light brown solid.
Reaction SMILES: C([O:4][C:5]([C:7]1([NH:10][C:11]([C:13]2[N:17]3[C@@:18]([CH2:31][C:32]4[CH:37]=[CH:36][C:35]([Br:38])=[CH:34][CH:33]=4)([CH3:30])[C:19](=[O:29])[N:20]([C:21]4[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=4)[C:16]3=[N:15][CH:14]=2)=[O:12])[CH2:9][CH2:8]1)=[O:6])C=C.N1CCOCC1>C1COCC1.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>[Br:38][C:35]1[CH:36]=[CH:37][C:32]([CH2:31][C@@:18]2([CH3:30])[N:17]3[C:13]([C:11]([NH:10][C:7]4([C:5]([OH:6])=[O:4])[CH2:8][CH2:9]4)=[O:12])=[CH:14][N:15]=[C:16]3[N:20]([C:21]3[CH:22]=[C:23]([Cl:28])[CH:24]=[C:25]([Cl:27])[CH:26]=3)[C:19]2=[O:29])=[CH:33][CH:34]=1
Reactant: C=CCOC(=O)C1(NC(=O)c2cnc3n2[C@](C)(Cc2ccc(Br)cc2)C(=O)N3c2cc(Cl)cc(Cl)c2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: C1COCCN1
Product: C[C@@]1(Cc2ccc(Br)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)NC3(C(=O)O)CC3)n21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1-{[(R)-5-(4-bromo-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-cyclopropanecarboxylic acid allyl ester (200 mg, 0.32 mmol) and morpholine (0.282 mL, 3.24 mmol) in 2 mL of THF was added Pd(Ph3P)4 (19 mg, 0.016 mmol). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was then diluted with 30 mL of EtOAc and washed with 10 mL each of 10% HCl solution, water, and brine, dried over Na2SO4, filtered, and concentrated. The residue was applied to a SiliaBond Carbonate preloaded cartridge (2 g, 0.7 mmol/g, Silicycle). The column was eluted with 30 mL of 10% MeOH in CH2Cl2 followed by 200 mL of 0.1:1:9 TFA/MeOH/CH2Cl2 to furnish 142 mg 76%) of the title compound as a colorless foam, m/z 579.4 [M+1]+.