Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][NH:11][C:10](=[O:13])[CH2:9]2)=[CH:4][C:3]=1[I:14].C(N(CC)CC)C.[C:22](=O)([O:28]C(C)(C)C)[O:23][C:24]([CH3:27])([CH3:26])[CH3:25].Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:24]([O:23][C:22]([N:11]1[CH2:12][C@@H:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([I:14])[CH:4]=2)[CH2:9][C:10]1=[O:13])=[O:28])([CH3:27])([CH3:26])[CH3:25]
Reactant: O=C1C[C@H](c2ccc(Cl)c(I)c2)CN1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@@H](c2ccc(Cl)c(I)c2)CC1=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 79.8 %

Procedure:
To (4R)-4-(4-chloro-3-iodophenyl)pyrrolidin-2-one (17.4 g, 54.4 mmol) was added 50 mL DCM. The solution was cooled to 0° C. Triethylamine (9.1 mL, 65.25 mmol) was added followed by di-tert butyl carbonate (13.1 g, 59.04 mmol) in 60 mL of DCM. A catalytic amount of DMAP was added, the mixture warmed to room temperature, and then stirred overnight at room temperature. A 5% solution of HCl (50 mL) was added and the organic phase separated. The DCM layers were then washed with brine and evaporated to give the title compound (43a) as a yellowish solid (18.3 g, 80% yield). 1H-NMR (400 MHz, CD3OD): δ 7.83-7.84 d, J=2 Hz, 1H), 7.35-7.46 (m, 1H), 7.31-7.33 (m, 1H), 4.11-4.15 (m, 1H), 3.62-3.67 (m, 2H), 3.45-3.61 (m, 1H), 2.80-2.84 (m, 1H), 2.69-2.74 (m, 1H) 1.52 (s, 9H); MS (ESI) m/z 443.86 (M+Na)+.
Reaction SMILES: C([C@H:3]([S:7]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[N:9][C:10]([C:12]1[CH:13]=[N:14][CH:15]=[C:16]([C:18]#[C:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=2)[CH:17]=1)=[O:11])=[O:8])[C:4]([O-:6])=O)C.[CH2:33]([N:35]([CH2:39][CH3:40])[CH2:36][CH2:37][NH2:38])[CH3:34]>CO>[CH2:33]([N:35]([CH2:39][CH3:40])[CH2:36][CH2:37][NH:38][C:4](=[O:6])[CH2:3][S@:7](=[O:8])([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[N:9][C:10](=[O:11])[C:12]1[CH:17]=[C:16]([C:18]#[C:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=2)[CH:15]=[N:14][CH:13]=1)[CH3:34]
Reactant: CCN(CC)CCN
Reactant: CC[C@@H](C(=O)[O-])S(=O)(=NC(=O)c1cncc(C#Cc2cccc(O)c2)c1)c1ccccc1
Solvent: CO
Product: CCN(CC)CCNC(=O)C[S@@](=O)(=NC(=O)c1cncc(C#Cc2cccc(O)c2)c1)c1ccccc1
Temperature: 30 °C
Yield: 60.3 %

Procedure:
(S)-Ethyl[N-({5-[(3-hydroxyphenyl)ethynyl]pyridin-3-yl}carbonyl)-S-phenylsulfonimidoyl]acetate (73 mg, 0.16 mmol) in anhydrous MeOH (1.5 mL) was added N,N-diethylethylenediamine (0.12 mL, 0.84 mmol) dropwise. The reaction mixture was heated at 30° C. for 4 hours. The reaction mixture was evaporated and the residue was partitioned between EtOAc and saturated aqueous NaHCO3. The organic layer was washed once with brine, dried (anhydrous Na2SO4), concentrated. The residue was purified by chromatography (silica gel, 50:1 CHCl3:MeOH to 10:1 CHCl3:MeOH). The product containing fractions were concentrated to give the title compound as a foamy solid (50 mg, 59%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:17]#[N:18])=[C:6]([NH:8][C:9](=O)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=1.[OH-:19].[Na+].OO.Cl>O>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5]([C:17](=[O:19])[NH:18][C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N:8]2)=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: N#Cc1ccc(Cl)cc1NC(=O)c1ccccc1
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: O
Product: O=c1[nH]c(-c2ccccc2)nc2cc(Cl)ccc12
Temperature: 80 °C
Reaction time: 24 h

Procedure:
To a suspension of N-(5-chloro-2-cyanophenyl)benzamide (150 mg, 0.58 mmol) in H2O (5 mL) was added in sequence NaOH (100 mg, 2.5 mmol) and H2O2 (30% in H2O, 0.25 mL, 2.2 mmol). The reaction was heated to 80° C. for 24 h then cooled to it and stirred at it for 1 d. Aq HCl (2 M, 6 mL) was added forming a thick precipitate that was collected by a filtration. The filter cake was washed with H2O several times affording the title compound as a creamy-white solid; MS (ES+): m/z 257.1 (100) [MH+]; HPLC: tR=3.34 min (OpenLynx, polar—5 min).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Br[C:36]1[C:47]([CH3:48])=[CH:46][C:39]([O:40][C@H:41]2[CH2:45][CH2:44][O:43][CH2:42]2)=[CH:38][C:37]=1[CH3:49]>>[CH3:49][C:37]1[CH:38]=[C:39]([O:40][C@H:41]2[CH2:45][CH2:44][O:43][CH2:42]2)[CH:46]=[C:47]([CH3:48])[C:36]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[C:10]2[C:6]=1[CH2:7][CH2:8][C@H:9]2[O:11][C:12]1[CH:25]=[CH:24][C:15]2[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=2[CH:13]=1
Reactant: Cc1cc(O[C@H]2CCOC2)cc(C)c1Br
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(O[C@H]6CCOC6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate and (S)-3-(4-bromo-3,5-dimethylphenoxy)tetrahydrofuran following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 4): tR=1.89 min; Mass spectrum (ESI+): m/z=555 [M+Na]+.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]([F:14])([F:13])[F:12])=[CH:6][CH:5]=1)=[O:3].[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](OC)=[O:24])=[CH:18][CH:17]=1.[H-].[Na+]>C1COCC1>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](=[O:24])[CH2:1][C:2]([C:4]2[CH:5]=[CH:6][C:7]([O:10][C:11]([F:12])([F:13])[F:14])=[CH:8][CH:9]=2)=[O:3])=[CH:18][CH:17]=1
Reactant: CC(=O)c1ccc(OC(F)(F)F)cc1
Reactant: COC(=O)Cc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(CC(=O)c1ccc(OC(F)(F)F)cc1)Cc1ccc(Br)cc1

Procedure:
A solution of 5.40 g 4-trifluoromethoxyacetophenone and 7.57 g methyl 4-bromophenylacetate in 60 mL anhydrous THF was treated with 1.59 g 60% NaH for 60 hours. After removing the solvent under reduced pressure, the reaction mixture was diluted with 250 mL ether and washed with 250 mL 0.2 M HCl, 2×100 mL 5% NaHCO3 and 100 mL saturated brine, dried over anhydrous Na2SO4, and evaporated to give a crude product. It was purified on silica gel using 0-25% EtOAc in hexanes to give title compound as red oil. 1H NMR (CDCl3, 500 MHz) δ 7.86˜7.89 (m, 2H), 7.48˜7.51 (m, 2H), 7.27 (d, J=7 Hz, 2H), 7.17˜7.19 (m, 2H), 6.07 (s, 1H), 3.70 (s, 2H).
Reaction SMILES: [CH3:1]/[C:2](=[CH:8]\[C:9]1[CH:14]=[C:13]([F:15])[C:12](F)=[C:11]([F:17])[CH:10]=1)/[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:18]1([OH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:15][C:13]1[CH:14]=[C:9](/[CH:8]=[C:2](\[CH3:1])/[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:10]=[C:11]([F:17])[C:12]=1[O:24][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Oc1ccccc1
Reactant: CCOC(=O)/C(C)=C/c1cc(F)c(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)/C(C)=C/c1cc(F)c(Oc2ccccc2)c(F)c1
Reaction time: 3 h
Yield: 88.8 %

Procedure:
To a solution of (E)-ethyl 2-methyl-3-(3,4,5-trifluorophenyl)acrylate (Intermediate 41.1, 6.0 g, 24.56 mmol) in dry DMF (25 mL) under N2 was added phenol (2.774 g, 29.5 mmol) and K2CO3 (10.2 g, 73.68 mmol). The resulting solution was brought to 120° C. and stirred for 3 hours at which point TLC indicated complete conversion. The solvent was removed by rotary evaporation and the resulting residue brought up in EtOAc (200 mL) and washed with water (2×200 mL), 1N NaOH (2×200 mL) and brine (200 mL). The organic layer was dried over Na2SO4 and concentrated to yield 6.94 g (89%) of the title compound as tan crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:20][O:21][C:22]1[C:27]2[O:28][C:29]3[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][C:30]=3[C:26]=2[C:25]([C:38](Cl)=[O:39])=[CH:24][CH:23]=1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH2:8][C:38]([C:25]1[C:26]2[C:30]3[CH:31]=[C:32]([N+:35]([O-:37])=[O:36])[CH:33]=[CH:34][C:29]=3[O:28][C:27]=2[C:22]([O:21][CH3:20])=[CH:23][CH:24]=1)=[O:39]
Reactant: Cc1c(Cl)cncc1Cl
Reactant: COc1ccc(C(=O)Cl)c2c1oc1ccc([N+](=O)[O-])cc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)c2c1oc1ccc([N+](=O)[O-])cc12
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 32.3 %

Procedure:
A solution of 3,5-dichloro-4-methyl-pyridine (0.593 g, 3.66 mmoles) in tetrahydrofuran (200 mL) is cooled to −60° C. under nitrogen atmosphere. A 1M solution of lithium bis(trimethylsilyl) amide (4.4 mL, 4.4 mmoles) is added dropwise and the resulting mixture is stirred at −60° C. for 30 minutes. A solution of 4-methoxy-8-nitro-dibenzofuran-1-carbonyl chloride (3a) (0.75 g, 2.44 mmoles) in dry tetrahydrofuran (20 mL) is added dropwise, maintaining the temperature below −60° C. After stirring for 15 minutes at −60° C., the mixture is stirred at room temperature for 3.5 hours. The mixture is then quenched with a saturated NH4Cl solution (20 mL); the product precipitated as a solid which is recovered by filtration and washed with methanol to yield 340 mg of the title compound.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:24]=[CH:23][C:9]([NH:10][CH:11]=[C:12]([C:18]([O:20]CC)=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:8]([I:25])[CH:7]=1)(=[O:3])[CH3:2]>O(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:4][CH2:5][C:6]1[CH:24]=[C:23]2[C:9](=[C:8]([I:25])[CH:7]=1)[N:10]=[CH:11][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:18]2[OH:20])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(=CNc1ccc(COC(C)=O)cc1I)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2c(I)cc(COC(C)=O)cc2c1O
Temperature: 25 °C
Yield: 62.2 %

Procedure:
A solution of diethyl 2-({4-[(acetyloxy)methyl]-2-iodoanilino}methylene)malonate (1.75 g) in Ph2O (20 mL) is heated at 250° C. for 40 min. The reaction is cooled to room temperature and diluted with hexanes. The resulting solid is collected and dried. The crude solid is adsorbed onto silica and chromatographed (Biotage flash 40S, gradient from CH2Cl2 to 2% MeOH/CH2Cl2). Product containing fractions are combined and concentrated to yield 0.98 g (62%) of ethyl 6-[(acetyloxy)methyl]-4-hydroxy-8-iodo-3-quinolinecarboxylate, m.p. 119-123° C.
Reaction SMILES: [C:1]([C:3]1[N:7]([CH3:8])[N:6]=[C:5]([C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])[C:4]=1[C:16]([F:19])([F:18])[F:17])#N.[OH-:20].[Na+].Cl.[OH2:23]>>[CH3:8][N:7]1[C:3]([C:1]([OH:23])=[O:20])=[C:4]([C:16]([F:19])([F:18])[F:17])[C:5]([C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])=[N:6]1
Reactant: Cn1nc(C(F)(F)C(F)(F)F)c(C(F)(F)F)c1C#N
Reactant: [OH-]
Reactant: O
Agent: Cl
Agent: [Na+]
Product: Cn1nc(C(F)(F)C(F)(F)F)c(C(F)(F)F)c1C(=O)O
Temperature: 100 °C
Reaction time: 8 h

Procedure:
11.0 g (37.5 mmol) of 5-cyano-1-methyl-3-pentafluoroethyl-4-trifluoromethyl-1H-pyrazole, 22 ml of 50% strength sodium hydroxide solution and 7.0 ml of distilled water are heated in an oil bath until the solid has dissolved. The reaction mixture is then stirred overnight (oil bath temperature 100° C.). After cooling, the reaction mixture is poured onto a mixture of 150 ml of concentrated hydrochloric acid and 150 ml of ice. The mixture is afterstirred for 30 minutes and the solid is filtered off. The solid is washed with a small amount of water and then dried in an oil pump vacuum. This gives 11.2 g (95%) of 1-methyl-3-pentafluoroethyl-4-trifluoromethyl-1H-pyrazole-5-carboxylic acid as a white solid.00
Reaction SMILES: [CH:1](Br)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH:22]([C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1)[N:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][CH2:31][OH:32])[CH2:25][CH2:24]1>O>[C:2]1([CH:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:32][CH2:31][CH2:30][CH2:29][N:26]2[CH2:25][CH2:24][N:23]([CH:22]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[Cl:15])[C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[CH2:28][CH2:27]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: OCCCN1CCN(C(c2ccc(F)cc2)c2ccccc2Cl)CC1
Solvent: O
Product: Fc1ccc(C(c2ccccc2Cl)N2CCN(CCCOC(c3ccccc3)c3ccccc3)CC2)cc1

Procedure:
A mixture containing 7.4 g of benzhydryl bromide and 21.8 g of 4-[(2-chlorophenyl)-(4-fluorophenyl)methyl]-1-(3-hydroxypropyl)piperazine is heated at 160° to 170° C. under nitrogen gas for 30 minutes, then cooled to 90° to 100° C. and poured into water. The aqueous phase is extracted with benzene, washed with water, thebenzene solution is dried over anhydrous potassium carbonate and then evaporated under reduced pressure. The residue is purified by chromatography on a Kieselgel column by using a 4:1 mixture of benzene andchloroform as eluant. The thus-obtained product is recrystallized from n-hexane to give the aimed product, m.p.: 98°-99° C.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=O)[N:5]1[C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[N:17][C:18]([O:24][CH3:25])=[CH:19][CH:20]=2)[N:15]=1.[CH3:26][C:27](=[O:32])[CH2:28][CH2:29][CH2:30][CH3:31].O>CN(C)C=O>[CH3:25][O:24][C:18]1[N:17]=[C:16]2[C:21]([CH:22]=[CH:23][C:14]([N:5]3[CH:6]([CH2:26][C:27](=[O:32])[CH2:28][CH2:29][CH2:30][CH3:31])[C:7]4[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:4]3=[O:3])=[N:15]2)=[CH:20][CH:19]=1
Reactant: CCCCC(C)=O
Reactant: COc1ccc2ccc(N3C(=O)c4ccccc4C3O)nc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCC(=O)CC1c2ccccc2C(=O)N1c1ccc2ccc(OC)nc2n1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 28.4 %

Procedure:
An oily suspension (50% by weight; 3.1 g) of sodium hydride is added in small portions at a temperature in the region of -5° C. to a solution, maintained under a nitrogen atmosphere, of 3-hydroxy-2-(7-methoxy-1,8-naphthyridin-2-yl)-1-isoindolinone (10 g) in anhydrous dimethylformamide (195 cc), and the suspension obtained is stirred for 30 minutes at a temperature in the region of -5° C. A solution of 2-hexanone (6.5 g) in anhydrous dimethylformamide (5 cc) is then added and stirring is continued for 8 hours at a temperature in the region of 0° C. and then for 16 hours at a temperature in the region of 20° C. The reaction mixture is then poured into water (1.5 litres). The solid obtained is separated by filtration, washed with water and dried in the air. After recrystallization in ethanol, 2-(7-methoxy-1,8-naphthyridin-2-yl)-3-(2-oxohexyl)-1-isoindolinone (3.6 g), m.p. 161° C., is obtained.
Reaction SMILES: [CH:1]1([C:6]([OH:8])=[O:7])[CH2:5][CH:4]=[CH:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN(C=O)C>[CH:1]1([C:6]([O:8][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:7])[CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: O=C(O)C1CC=CC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)C1CC=CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of cyclopent-3-ene-1-carboxylic acid (9.63 g, 85.88 mmol) in 143 mL of degassed DMF was added potassium carbonate (14.24 g, 103.06 mmol) and benzyl bromide (11.24 mL, 94.47 mmol). The mixture was stirred for 2 hours at ambient temperature, and then poured into 150 mL of water and extracted with ethyl acetate. The extracts were washed with water and brine, and dried over sodium sulfate. Filtration and concentration under vacuum afforded benzyl cyclopent-3-ene-1-carboxylate as an oil.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[O:15][CH2:16][CH2:17][CH2:18][CH3:19].[Cl:20][C:21]1[N:22]=[C:23]([C:28](O)=[O:29])[NH:24][C:25]=1[CH2:26][CH3:27].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>ClCCl.CC(N(C)C)=O>[CH2:16]([O:15][C@H:3]1[C@@H:2]([NH:1][C:28]([C:23]2[NH:24][C:25]([CH2:26][CH3:27])=[C:21]([Cl:20])[N:22]=2)=[O:29])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4]1)[CH2:17][CH2:18][CH3:19]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: CCCCO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: CCCCO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Yield: 117.1 %

Procedure:
The same operation as in Example (106d) was performed using tert-butyl cis(±)-4-amino-3-butoxypiperidine-1-carboxylate obtained in Example (119d) (1.26 g, 4.6 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (85% content, 1.03 g, 5 mmol), WSC hydrochloride (2.88 g, 15 mmol), HOBt (1.01 g, 7.5 mmol), DMA (15 mL) and dichloromethane (15 mL). The resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/4, 2/3, 3/2, 4/1) to obtain 2.31 g of the title compound as a colorless solid (100%).
Reaction SMILES: [NH2:1][C:2](=[N:30][OH:31])[CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([Cl:29])[C:15]=3[NH:19][C:20](=[O:28])[CH2:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[N:10]=2)[CH2:5][CH2:4]1.N1C=CC=CC=1.C(C(CCCC)[CH2:41][O:42]C(Cl)=O)C>ClCCl>[Cl:29][C:14]1[C:15]([NH:19][C:20](=[O:28])[CH2:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([N:6]1[CH2:7][CH2:8][CH:3]([C:2]3[NH:1][C:41](=[O:42])[O:31][N:30]=3)[CH2:4][CH2:5]1)[CH:18]=[CH:17]2
Reactant: CCCCC(CC)COC(=O)Cl
Reactant: NC(=NO)C1CCN(c2ccc3c(NC(=O)CC4CCCCC4)c(Cl)ccc3n2)CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(N3CCC(c4noc(=O)[nH]4)CC3)ccc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of N-[2-[4[amino(hydroxyimino)methyl]-1-piperidinyl]-6-chloro-5-quinolinyl]-cyclohexaneacetamide (example 102(a)) (0.1 g) and pyridine (0.02 mL) in dichloromethane (5 mL) at 0° C. was added 2-ethylhexylchloroformate (0.064 mL). After 10 minutes the reaction was allowed to warm to room temperature and was then stirred for 2 hours. The solvent was removed under vacuum and the resulting solid was transferred to a 10 mL microwave vial with isohexane (3 mL) and heated within a microwave at 140° C. for 20 minutes. The reaction mixture was filtered and the solid was taken up in boiling methanol (20 mL) and purified by Varian NH2 cartridge (methanol (50 mL) and then acetic acid:methanol 10:90 as eluant) to afford the title product (0.042 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:16][C@@:13]3([O:15][CH2:14]3)[CH2:12][CH2:11][CH2:10]2)[C:5]([F:17])=[CH:4][N:3]=1.[C-:18]#[N:19].[Na+].Cl([O-])(=O)(=O)=O.[Li+].CCOC(C)=O>CC#N>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:10][CH2:11][CH2:12][C@:13]([CH2:14][C:18]#[N:19])([OH:15])[CH2:16]2)[C:5]([F:17])=[CH:4][N:3]=1
Reactant: [C-]#N
Reactant: Fc1cnc(Cl)nc1NC1CCC[C@@]2(CO2)C1
Agent: [Li+]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: N#CC[C@]1(O)CCC[C@H](Nc2nc(Cl)ncc2F)C1
Temperature: 100 °C

Procedure:
A suspension of 2-chloro-5-fluoro-N-[(3S)-1-oxaspiro[2.5]octan-7-yl]pyrimidin-4-amine, 49c, (0.50 g, 1.94 mmol), NaCN (0.11 g, 2.33 mmol) and lithium perchlorate (0.25 g, 2.33 mmol) in CH3CN was heated at 100° C. in a pressure tube for 3 h. The mixture was diluted into EtOAc and the organic phase was washed with aqueous saturated NaHCO3 solution, dried with MgSO4, filtered and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel chromatography (EtOAc/hexanes) afforded the desired product: 1H NMR (300.0 MHz, CDCl3) δ 7.78 (d, J=2.7 Hz, 1H), 4.85 (d, J=6.6 Hz, 1H), 4.28 (qn, J=4.0 Hz, 1H), 2.45 (s, 2H), 2.16 (d, J=13.0 Hz, 1H), 2.05 (d, J=11.7 Hz, 1H), 1.80-1.71 (m, 3H), 1.46-1.28 (m, 2H) and 1.17-1.06 (m, 1H) ppm; LCMS RT=2.15 (M+H) 285.34.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[F:27])=[CH:14][CH:15]=1)=[O:5])C.[NH2:28][C:29]1[N:34]=[CH:33][C:32]([CH2:35][N:36]2[CH2:41][CH2:40][NH:39][C:38](=[O:42])[CH2:37]2)=[CH:31][CH:30]=1.C[Al](C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.CO.C(Cl)Cl>[O:42]=[C:38]1[NH:39][CH2:40][CH2:41][N:36]([CH2:35][C:32]2[CH:31]=[CH:30][C:29]([NH:28][C:4]([C:6]3[C:7]4[N:8]=[CH:9][CH:10]=[N:11][C:12]=4[C:13]([C:16]4[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=4[F:27])=[CH:14][CH:15]=3)=[O:5])=[N:34][CH:33]=2)[CH2:37]1
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2F)c2nccnc12
Reactant: Nc1ccc(CN2CCNC(=O)C2)cn1
Agent: C[Al](C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1cc(OC)c(F)c(-c2ccc(C(=O)Nc3ccc(CN4CCNC(=O)C4)cn3)c3nccnc23)c1F
Temperature: 80 °C
Reaction time: 7 h

Procedure:
The title compound was prepared in analogy to the procedure described in Example 115 but using 8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 124.1), 4-(6-amino-pyridin-3-ylmethyl)-piperazin-2-one (Step 103.1), 1.5 equiv of trimethyl aluminum, stirring the reaction mixture for 7 h at 80° C. and pouring it onto a saturated aqueous solution of NaHCO3 and DCM. The title compound: ESI-MS: 535.1 [M+H]+; tR=3.50 min (System 1); TLC: Rf=0.16 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C(N(CC)CC)C.[N+:17]([C:20]1[CH:21]=[C:22]([CH:29]=[CH:30][CH:31]=1)[O:23][CH2:24][CH2:25][CH2:26][CH2:27][NH2:28])([O-:19])=[O:18]>C(#N)C.C(OCC)(=O)C>[Br:1][C:2]1[C:3]([NH:28][CH2:27][CH2:26][CH2:25][CH2:24][O:23][C:22]2[CH:29]=[CH:30][CH:31]=[C:20]([N+:17]([O-:19])=[O:18])[CH:21]=2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: NCCCCOc1cccc([N+](=O)[O-])c1
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cccc(OCCCCNc2nc(Cl)ncc2Br)c1
Reaction time: 12 h

Procedure:
A solution of 2.28 g (10 mmol) of 5-bromo-2,4-dichloro-pyrimidine and 1.4 ml of triethylamine (10 mmol) in 32 ml of acetonitrile is mixed at 4° C. while being stirred with a solution of 2.1 g (10 mmol) of 4-(3-nitro-phenoxy)-butylamine in 5 ml of acetonitrile. After 12 hours, it is diluted with ethyl acetate and filtered. The filtrate is concentrated by evaporation in a rotary evaporator, and the remaining residue is purified by chromatography (hexane/ethyl acetate 1:1, Flashmaster II). 2.7 g (7 mmol, corresponding to 70% of theory) of the product is obtained.