Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:9]#N)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:11][O:12]C(=O)C1C=CC=CC=1.S(=O)(=O)(O)[OH:22].CO>O.C(Cl)(=O)C>[CH3:11][O:12][C:9](=[O:22])[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:8]
Reactant: COC(=O)c1ccccc1
Reactant: N#CC(=O)c1ccccc1
Reactant: O=S(=O)(O)O
Solvent: CO
Solvent: O
Solvent: CC(=O)Cl
Product: COC(=O)C(=O)c1ccccc1
Reaction time: 1 h
Yield: 194.2 %

Procedure:
A mixture of 393 g (3 mol) of benzoyl cyanide, 20.3 g (0.26 mol) of acetyl chloride and 202 g of benzoic acid methyl ester was added dropwise, at 22° C., to 450 g (4.6 mol) of concentrated sulphuric acid. The mixture was subsequently stirred for one hour and 72 g (4 mol) of water were then added at 22° C. in the course of about 20 minutes. The mixture was then stirred for a further 3 hours at 22° C. 304 g (9.5 mols) of methanol were added to the reaction mixture and the mixture was stirred for 3 hours at about 70° C. After cooling, the reaction mixture was diluted with 390 g of water. The organic phase was separated off and washed successively with 160 g of water, 160 g of sodium bicarbonate solution and 160 g of water. The combined aqueous phases were extracted twice with 30 ml of toluene each time. The organic phases were combined, and concentrated by distilling off the solvent. Distillation of the residue gave 473 g (96% of theory) of phenylglyoxylic acid methyl ester, which had a boiling point of 136° C./12 mm Hg and a purity of 99% (determined by gas chromatography).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([NH2:8])[CH:7]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][C:18]=1[C:27]([F:30])([F:29])[F:28]>N1C=CC=CC=1>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:8][C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:24])=[O:25])=[CH:19][C:18]=1[C:27]([F:30])([F:28])[F:29]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: Nc1cc(Cl)ccc1Oc1ccccc1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cc(Cl)ccc1Oc1ccccc1)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-chloro-2-phenoxy-phenylamine (75 mg, 0.34 mmol) in anhydrous pyridine (0.5 mL) was added drop wise a solution of 4-chloro-3-trifluoromethyl-benzenesulfonyl chloride (95 mg, 0.341 mmol) in pyridine (0.5 mL). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was separated by preparative HPLC using acetonitrile-water solvent mixture and pure product fractions were lyophilized to provide pure product as a solid. 1H NMR (400 MHz, CDCl3) δ 8.04 (d, J=2.0 Hz, 1 H), 7.80 (dd, J=8.4, 2.0 Hz, 1 H), 7.70 (d, J=2.4 Hz, 1 H), 7.51 (d, J=8.4 Hz, 1 H), 7.27-7.23 (m, 2 H), 7.14-7.10 (m, 1 H), 7.05-7.02 (m, 2 H), 6.66 (d, J=8.4 Hz, 1 H), 6.60-6.56 (m, 2 H). MS m/z: 484.0 (M+Na).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([NH:25]S(C)(=O)=O)[CH:23]=4)[N:18]([CH2:30][C:31]([OH:33])=[O:32])[C:17]=3[CH3:34])=[CH:11][CH:12]=[N:13]2)=[CH:8][CH:7]=1.C(N(CC)CC)C.O>ClCCl>[C:1]([NH:25][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[N:18]([CH2:30][C:31]([OH:33])=[O:32])[C:17]([CH3:34])=[C:16]2[C:10]1[C:9]2[C:14](=[CH:15][C:6]([Cl:5])=[CH:7][CH:8]=2)[N:13]=[CH:12][CH:11]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: Cc1c(-c2ccnc3cc(Cl)ccc23)c2cc(NS(C)(=O)=O)ccc2n1CC(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)Nc1ccc2c(c1)c(-c1ccnc3cc(Cl)ccc13)c(C)n2CC(=O)O
Temperature: 20 °C
Reaction time: 1 h

Procedure:
Acetyl chloride (60 μl) was added to a solution of the product from Example 46 step a) and triethylamine (0.13 ml) in dichloromethane (3 ml) at 0° C. and stirred at 20° C. for 1 hour. Water was added and the mixture was extracted with dichloromethane. The organic extracts were dried (MgSO4), evaporated and purified by chromatography (silica, ethyl acetate as eluent) to give the sub-title compound (290 mg). M.p. 281-4° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]2=[N:14][C:15]([CH3:22])=[CH:16][C:17]([NH:18][CH2:19][CH2:20]Cl)=[C:12]2[N:11]=[C:10]1[CH3:23].[CH:24]1([NH2:29])[CH2:28][CH2:27][CH2:26][CH2:25]1>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]2=[N:14][C:15]([CH3:22])=[CH:16][C:17]([NH:18][CH2:19][CH2:20][NH:29][CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[C:12]2[N:11]=[C:10]1[CH3:23]
Reactant: NC1CCCC1
Reactant: Cc1cc(NCCCl)c2nc(C)n(-c3ccc(Cl)cc3Cl)c2n1
Solvent: CN1CCCC1=O
Product: Cc1cc(NCCNC2CCCC2)c2nc(C)n(-c3ccc(Cl)cc3Cl)c2n1

Procedure:
Heat a solution of [3-(2,4-dichlorophenyl)-2,5-dimethylimidazolo[5,4-b]pyridin-7-yl](2-chloroethyl)amine (0.08 g, 0.22 mmol), and cyclopentyl amine (0.2 mL g, 0.22 mmol) in dry NMP (3 mL) at 80° C. for 20 h. Pour the cooled mixture onto water (30 mL) and extract twice with EtOAc (50 mL). Wash the combined extracts with brine (50 mL), dry, and evaporate in vacuo. Purify by preparative TLC (10% MeOH in CH2Cl2) to obtain the title compound as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2(O)[C:15]3=[N:16][CH:17]=[CH:18][CH:19]=[C:14]3[O:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.[Cl:23][CH2:24][C:25]#[N:26].C(O)(=[O:29])C.OS(O)(=O)=O>O.CCOC(C)=O>[Cl:23][CH2:24][C:25]([NH:26][C:10]1([C:7]2[CH:8]=[CH:9][C:4]([O:3][C:2]([F:22])([F:21])[F:1])=[CH:5][CH:6]=2)[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[O:13][CH2:12][CH2:11]1)=[O:29]
Reactant: N#CCCl
Reactant: CC(=O)O
Reactant: OC1(c2ccc(OC(F)(F)F)cc2)CCOc2cccnc21
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(CCl)NC1(c2ccc(OC(F)(F)F)cc2)CCOc2cccnc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred mixture of 4-(4-(trifluoromethoxy)phenyl)-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-ol (3 g. 9.6 mmol, Intermediate 3) and 2-chloroacetonitrile (7.2 mL, 128.5 mmol) at 0° C., were added acetic acid (8.68 mL) and conc. H2SO4 (9.45 mL). The ice bath was then removed, and the reaction was stirred at room temperature for 12 h. The progress of reaction was monitored by TLC (50% EtOAc in petroleum ether). The reaction was diluted with H2O (20 mL) and EtOAc (40 mL) and quenched slowly with saturated NaHCO3 (125 mL). The organic layer was separated and the aqueous layer extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (50 mL), dried over MgSO4, and concentrated to give the product as a residue. Purification by column chromatography (60-120 mesh silica, 0-50% EtOAc in hexanes) gives the title compound as a white solid. MS (ESI pos. ion) m/z: 387.0 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14]OS(C)(=O)=O)[O:11][C:10]2=[O:20])[CH:5]=[CH:6][C:7]=1[I:8].[N-:21]=[N+:22]=[N-:23].[Na+].O.CCOC(C)=O>CN(C=O)C>[N:21]([CH2:14][C@@H:12]1[O:11][C:10](=[O:20])[N:9]([C:4]2[CH:5]=[CH:6][C:7]([I:8])=[C:2]([F:1])[CH:3]=2)[CH2:13]1)=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Temperature: 72.5 °C
Yield: 99 %

Procedure:
A solution of (5R)-methanesulfonic acid 3-(3-fluoro-4-iodophenyl)-2-oxo-oxazolidin-5-ylmethyl ester (1020, 14.0 g, 33.7 mmol) in anhydrous DMF (50 mL) was treated with sodium azide (NaN3, 4.4 g, 67.5 mmol, 2.0 equiv) at 25° C., and the resulting mixture was subsequently warmed up to 70-75° C. for 4 h. When TLC and HPLC/MS showed that the reaction was complete, the reaction mixture was cooled down to room temperature before being treated with H2O (100 mL) and EtOAc (100 mL). The two layers were then separated, and the aqueous layer was extracted with EtOAc (2×50 mL). The combined organic extracts were then washed with water (2×50 mL) and saturated aqueous NaCl solution (50 mL), dried over MgSO4, and concentrated in vacuo. The residue was further dried in vacuo to afford the crude, (5R)-5-azidomethyl-3-(3-fluoro-4-iodophenyl)-oxazolidin-2-one (1023, 12.08 g, 12.2 g theoretical, 99%) as white powders. For 1023: 1H NMR (300 MHz, DMSO-d6) δ 3.67-3.81 (m, 3H), 4.14 (t, 1H, J=5.4 Hz), 4.88-4.94 (m, 1H), 7.22 (dd, 1H, J=2.4, 8.7 Hz), 7.56 (dd, 1H, J=2.4, 8.7 Hz), 7.84 (dd, 1H, J=7.5, 8.7 Hz); LCMS C10H8FIN4O2, LCMS (EI) m/e 363 (M++H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=[O:8].S(=O)(=O)(O)O.[CH2:15](O)[CH3:16]>>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([O:9][CH2:15][CH3:16])=[O:8]
Reactant: CCO
Reactant: O=C(O)c1cnccn1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cnccn1

Procedure:
To a solution of pyrazine-2-carboxylic acid (100 g) in ethanol (EtOH, 1000 ml) was added conc. sulfuric acid (45 ml) at room temperature. After refluxing for 8 hours, the reaction mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate (AcOEt, 1500 ml) and water (H2O, 1000 ml), and sodium hydrogencarbonate (NaHCO3) was added to adjust the pH of the mixture to 8. The aqueous layer was extracted with AcOEt (1000 ml), and the combined organic layer was washed with brine and dried over magnesium sulfate (MgSO4). The solution was concentrated in vacuo, and the residue was crystallized from hexane (1000 ml) to give 111.2 g of ethyl pyrazine-2-carboxylate,
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[C:10]1([OH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[Cs+].[Cs+].C1(C(O)=O)C2C(=CC=CC=2)C=CC=1>C(OCC)(=O)C.C1(C)C=CC=CC=1>[O:16]([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Oc1ccccc1
Reactant: N#Cc1ccc(Br)cc1
Agent: O=C(O)c1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: N#Cc1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
4-Bromobenzonitrile (2.5 mmol), phenol (3.5 or 5.0 mmol), Cs2CO3 (3.5 or 5.0 mmol), (CuOTf)2 PhH (0.0625 mmol, 5.0 mol % Cu), ethyl acetate (0.125 mmol, 5.0 mol %), 1-naphthoic acid (3.5 mmol), molecular sieves (625 mg) and toluene (1.5 mL) were added to an oven-dried test tube which was then sealed with a septum, purged with argon, and heated to 110 C. under argon until the aryl halide was consumed as determined by GC analysis. Upon cooling at room temperature, dichloromethane was added and the solvent was removed by filtration. The remaining molecular sieves were stirred with another portion of dichloromethane for 1 h at room temperature, and the solvent was removed by filtration. The combined organic phases were washed with 5% aqueous NaOH. The aqueous layer was then extracted three times with dichloromethane and the combined organic layers were washed with brine. The organic layer was dried over Mg2SO4 and concentrated under vacuum to give the crude product. Purification by flash column chromatography (3% EtOAc/hexane) gave the analytically pure product as a clear oil (405 mg, 86% yield). 1H NMR (300 MHz, CDCl3) δ 7.57 (d, J=8.7 Hz, 2 H), 7.40 (t, J=7.9 Hz, 2 H), 7.22 (t, J=7.6 Hz, 1 H), 7.05 (d, J=7.9 Hz, 2 H), 6.98 (d, J=8.8 Hz, 2 H); 13C NMR (75 MHz, CDCl3) δ 154.6, 133.9, 130.0, 124.9, 120.2, 118.6, 117.7, 105.6; IR (neat): 3068, 2226, 1586, 1483, 1245, 1165 cm−1.
Reaction SMILES: [NH2:1][CH2:2][C:3]([O:5]C(C)(C)C)=[O:4].N1C=CC=CC=1.[Br:16][CH2:17][C:18](Br)=[O:19].Cl>C(Cl)Cl>[Br:16][CH2:17][C:18]([NH:1][CH2:2][C:3]([OH:5])=[O:4])=[O:19]
Reactant: CC(C)(C)OC(=O)CN
Reactant: O=C(Br)CBr
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(O)CNC(=O)CBr
Reaction time: 3 h
Yield: 153.1 %

Procedure:
To a solution of 4 g (0.02 mol) of t-butyl glycinate and 4 ml of pyridine in 100 ml of methylene dichloride at 0° under nitrogen was added a solution of 2.01 ml (0.024 mol) of bromoacetyl bromide in 10 ml of methylene dichloride. After the addition, the mixture was stirred for 3 hrs and poured into 1 N aqueous hydrochloride. The organic layer was separated and then washed successively with 1 N HCl, water and brine. After drying over anhydrous sodium sulfate, the mixture was evaporated to dryness in vacuo to yield 6 g of a light brown product, which upon recrystallization from hexane-ethyl acetate, yielded a product with mp 90°-91°.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]([OH:10])=O)=[CH:6][C:5]([CH3:11])=[N:4]1)[CH3:2].O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:23][C:24]1[CH:25]=[C:26]([CH:43]=[CH:44][C:45]=1[CH3:46])[O:27][C:28]1[CH:29]=[CH:30][C:31]2[N:32]([N:34]=[C:35]([NH:37][C:38]([CH:40]3[CH2:42][CH2:41]3)=[O:39])[N:36]=2)[CH:33]=1>CN(C)C=O.CN(C)C(=O)C>[CH:40]1([C:38]([NH:37][C:35]2[N:36]=[C:31]3[CH:30]=[CH:29][C:28]([O:27][C:26]4[CH:43]=[CH:44][C:45]([CH3:46])=[C:24]([NH:23][C:8]([C:7]5[N:3]([CH2:1][CH3:2])[N:4]=[C:5]([CH3:11])[CH:6]=5)=[O:10])[CH:25]=4)=[CH:33][N:32]3[N:34]=2)=[O:39])[CH2:41][CH2:42]1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)cc1N
Reactant: CCn1nc(C)cc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCn1nc(C)cc1C(=O)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)ccc1C
Yield: 53.8 %

Procedure:
In the same manner as in Example 18-4 and using 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (572 mg, 3.71 mmol), tetrahydrofuran (10 mL), oxalyl chloride (536 μL, 6.17 mmol), N-[6-(3-amino-4-methylphenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (200 mg, 0.619 mmol), N,N-dimethylformamide (1 drop) and N,N-dimethylacetamide (10 mL) as starting materials, the title compound (153 mg, 54%) was obtained as a pale-yellow solid.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[CH2:5][S:4][C:3]1=[S:8].[OH:9][C:10]1[CH:11]=[C:12]([CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[C:17]=1[OH:18])[CH:13]=O.N1CCCCC1>C(O)(=O)C>[OH:9][C:10]1[CH:11]=[C:12]([CH:13]=[C:5]2[S:4][C:3](=[S:8])[N:2]([CH3:1])[C:6]2=[O:7])[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[C:17]=1[OH:18]
Reactant: CN1C(=O)CSC1=S
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: CN1C(=O)C(=Cc2cc(O)c(O)c([N+](=O)[O-])c2)SC1=S
Temperature: 100 °C

Procedure:
A solution containing 0.74 g (0,005 mol) of 3-methyl -2-thioxothiazolidin-4-one, 0.92 g (0.005 mol) of 3,4-dihydroxy-5-nitrobenzaldehyde, 0.05 ml of piperidine in 10 ml of acetic acid was heated for 8 h at 100° C. The product was filtered and washed with 2-propanol. Yield 0.87 g (56%), mp 274°-276° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:18][CH2:19][C:20]#[N:21].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[C:19]([CH2:20][NH:21][C:10]([CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:12])#[N:18]
Reactant: N#CCN
Reactant: CC(C)CC(NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)CC(NC(=O)OC(C)(C)C)C(=O)NCC#N
Reaction time: 2 h

Procedure:
A solution comprised of 2-tert-butoxycarbonylamino-4-methylvaleric acid (5 g, 30 mmol) in DMF (20 mL) was cooled in an ice bath and then aminoacetonitrile hydrochloride (3 g, 30 mmol), PyBOP® (11.25 g, 21 mmol) and triethylamine (6 mL, 60 mmol) were added sequentially to the solution. The mixture was stirred for 2 hours and then concentrated under vacuum. The residue was partitioned between ethyl acetate (50 mL) and saturated sodium bicarbonate (40 mL). The organic layer was separated, washed with water, 1M hydrochloric acid (20 mL), water and brine, dried (MgSO4) and concentrated under reduced pressure. Product was purified from the residue using a plug of silica with ethyl acetate as the eluant to provide tert-butyl 1-cyanomethylcarbamoyl-3-methylbutylcarbamate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14](O)=[O:15])=[CH:12][N:11]=[CH:10][C:9]=2[F:17])=[C:4]([F:18])[CH:3]=1.C1C=CC2N(O)N=[N:25][C:23]=2C=1.C(Cl)CCl.Cl.CN.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([NH:25][CH3:23])=[O:15])=[CH:12][N:11]=[CH:10][C:9]=2[F:17])=[C:4]([F:18])[CH:3]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1cncc(F)c1-c1ccc(Cl)cc1F
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CNC(=O)c1cncc(F)c1-c1ccc(Cl)cc1F
Reaction time: 0.08 h
Yield: 63 %

Procedure:
To the solution of 4-(4-chloro-2-fluorophenyl)-5-fluoronicotinic acid (530 mg, 1.966 mmol) in DMF (5 mL) cooled at 0° C., was added HOBT (602 mg, 3.93 mmol) and EDC (565 mg, 2.95 mmol), then the mixture was stirred for 5 min. Methylamine hydrochloride (531 mg, 7.86 mmol) and DIEA (1.030 mL, 5.90 mmol) were added and the resultant mixture was stirred at RT for 12 h. Ice-cold water was added to the reaction and the solid obtained was collected by vacuum filtration. The solid so obtained was washed with water (50 mL) and air dried to afford 4-(4-chloro-2-fluorophenyl)-5-fluoro-N-methylnicotinamide (350 mg, 1.238 mmol, 63% yield) as an orange oil. LC/MS (ESI) m/e 282.9 [(M+H)+, calcd for C13H10ClF2N2O 283.0]; LC/MS retention time (method D): tR=0.83 min.
Reaction SMILES: [NH2:1][CH:2]1[CH:8]=[CH:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:3]1=[O:19].[C:20]([S:23][C@@H:24]([C@@H:28]([CH3:31])[CH2:29][CH3:30])[C:25](O)=[O:26])(=[O:22])[CH3:21]>>[C:20]([S:23][C@@H:24]([C@@H:28]([CH3:31])[CH2:29][CH3:30])[C:25]([NH:1][CH:2]1[CH:8]=[CH:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:3]1=[O:19])=[O:26])(=[O:22])[CH3:21]
Reactant: CC[C@H](C)[C@H](SC(C)=O)C(=O)O
Reactant: CCOC(=O)CN1C(=O)C(N)C=Cc2ccccc21
Product: CCOC(=O)CN1C(=O)C(NC(=O)[C@@H](SC(C)=O)[C@@H](C)CC)C=Cc2ccccc21
Yield: 48.6 %

Procedure:
0.525 g (2 mmol) of 3-amino-1-ethoxycarbonylmethyl-1H-[1]benzazepin-2-one and 0.418 g (2.2 mmol) of (2S,3S)-2-acetylthio-3-methylvaleric acid were reacted in the same manner as that of Example A-2. Thus, 0.42 g of the title compound was obtained as a colorless amorphous product. Yield 48%.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH:46]=O)[CH:41]=5)[C:36]([F:39])=[CH:37][CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[NH:50]1[CH2:55][CH2:54][CH:53]([OH:56])[CH2:52][CH2:51]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH2:46][N:50]6[CH2:55][CH2:54][CH:53]([OH:56])[CH2:52][CH2:51]6)[CH:41]=5)[C:36]([F:39])=[CH:37][CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: OC1CCNCC1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(C=O)c3)c2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(CN4CCC(O)CC4)c3)c2)c1
Reaction time: 2 h
Yield: 71.3 %

Procedure:
To a solution of N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(6-fluoro-3′-formyl-3-biphenylyl)methyl]-1,3-benzenedicarboxamide (0.133 g, 0.2 mmol) in DCM (3 mL) was added 4-piperidinol (0.021 g, 0.210 mmol), NaBH(OAc)3 (0.051 g, 0.240 mmol). This mixture was stirred at room temperature for 15 h at which time more 4-piperidinol (0.004 g, 0.04 mmol) was added and stirring continued for 2 h. Then more NaBH(OAc)3 (0.025 g, 0.1 mmol) was added and the mixture was stirred for an additional 2 h. The reaction mixture was filtered, concentrated, and purified using a Gilson HPLC (with 0.1% TFA). The fraction was concentrated and basified with an amine cartridge to afford 0.1067 g of the title compound. LC-MS m/z 748 (M+H)+; 1H NMR (400 MHz, CD3OD) δ ppm 1.40 (t, J=7.65 Hz, 3 H) 1.49 (t, J=7.15 Hz, 3 H) 1.62-1.83 (m, 1 H) 1.83-2.01 (m, 4 H) 2.05-2.27 (m, 3 H) 3.08 (t, J=12.05 Hz, 1 H) 3.16 (q, J=7.36 Hz, 2 H) 3.32-3.41 (m, 2 H) 3.53 (d, J=12.30 Hz, 1 H) 3.62-3.72 (m, 2 H) 3.76-4.10 (m, 3 H) 4.31-4.51 (m, 5 H) 4.61 (s, 2 H) 4.72 (s, 2 H) 7.18 (dd, J=10.67, 8.41 Hz, 1 H) 7.38-7.46 (m, 1 H) 7.50-7.63 (m, 4 H) 7.65-7.76 (m, 2 H) 8.01-8.09 (m, 2 H) 8.29 (s, 1 H) 8.40 (t, J=1.63 Hz, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[C:12](=O)([O-])[O-].[Cs+].[Cs+].CI.O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(O)cc1Br
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])c(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
To a solution of 3-bromo-4-nitrophenol (4.1 g) in N,N-dimethylformamide (40 ml) were sequentially added cesium carbonate (9.2 g) and methyl iodide (1.5 ml), and the solution was stirred overnight at room temperature. Water was added thereto, the solution was stirred, extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide 2-bromo-4-methoxy-1-nitrobenzene (4.1 g). Synthesized from 7-benzyloxy-3-bromo-1,2-dihydronaphthalene and 2-bromo-4-methoxy-1-nitrobenzene according to an analogous synthetic method to Preparation Example 107, 7-benzyloxy-3-(5-methoxy-2-nitrophenyl)-1,2-dihydronaphthalene (3.4 g) was used according to an analogous synthetic method to Example 30 to provide the title compound (1.6 g).
Reaction SMILES: Cl.[I:2][C:3]1[CH:4]=[C:5]([NH2:12])[CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[CH:8]2.[N-:13]([C:16]#[N:17])[C:14]#[N:15].[Na+]>CN(C)C=O>[C:14]([N:13]=[C:16]([NH2:17])[NH:12][C:5]1[CH:6]=[C:7]2[C:11](=[C:3]([I:2])[CH:4]=1)[NH:10][CH:9]=[CH:8]2)#[N:15]
Reactant: Nc1cc(I)c2[nH]ccc2c1
Reactant: N#C[N-]C#N
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CN=C(N)Nc1cc(I)c2[nH]ccc2c1
Temperature: 50 °C
Reaction time: 2.5 h

Procedure:
A solution of 7-iodo-1H-indol-5-ylamine hydrochloride IV (24.6 g, 83.7 mmol) in N,N-dimethylformamide (400 mL) at 25° C. was treated with sodium dicyanamide (18.6 g, 209 mmol). The reaction mixture was warmed to 50° C. for 2 h, concentrated in vacuo, and the residue treated with water (500 mL). The resulting mixture was allowed to stand at 25° C. for 2.5 h during which time a yellow precipitate formed. The precipitate was collected by filtration and washed with water to afford N″-cyano-N-(7-iodo-1H-indol-5-yl)guanidine V (22.59 g, 83%) as a light yellow solid: 1H NMR (DMSO-d6, 300 MHz) δ 11.02 (broad s, 1H), 8.89 (broad s, 1H), 7.46 (d, J=1.83 Hz, 1H), 7.37 (d, J=1.83 Hz, 1H), 7.35 (t, J=2.56 Hz, 1H), 6.85 (broad s, 2H), 6.56 (dd, J1=1.83 Hz, J2=3.10 Hz, 1H).
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([OH:3])=[O:2].[F:12][C:13]([F:21])([C:17]([F:20])([F:19])[F:18])[CH:14](O)[CH3:15].C(Cl)CCl.CCCCCC>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH:8]([C:7]1[CH:10]=[CH:11][C:4]([C:1]([O:3][CH:14]([C:13]([F:21])([F:12])[C:17]([F:20])([F:19])[F:18])[CH3:15])=[O:2])=[CH:5][CH:6]=1)=[O:9]
Reactant: CC(O)C(F)(F)C(F)(F)F
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: CN(C)c1ccncc1
Solvent: CCCCCC
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(OC(=O)c1ccc(C=O)cc1)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 36 h
Yield: 67 %

Procedure:
A mixture of 4-carboxybenzaldehyde (21.9 g, 145.9 mmol), 3,3,4,4,4-pentafluoro-2-butanol (24.1 g, 146.9 mmol), EDC (33.5 g, 174.8 mmol) and DMAP (18.1 g, 148.1 mmol) was dissolved in DMF (60 ml) at rt. It was stirred for 36 h at rt. Hexane was added, it was washed with 1 N HCl, sat NaHCO3 and brine. The aqueous layers were extracted three times with hexane. It was dried over Na2SO4, filtered, concentrated, and the residue was purified by silica gel chromatography (ethyl acetate:hexane 1:10) to yield the desired aldehyde as a yellow oil (67%).