Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@H:3]([N:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N+:15]([O-:17])=[O:16])[C:6]1=[O:18])[CH3:4].[C:19](OC(=O)C)(=[O:21])[CH3:20].C(N(CC)CC)C.C(Cl)Cl>CNC1(NC)C=CN=CC1>[C:19]([O:1][CH2:2][C@H:3]([N:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N+:15]([O-:17])=[O:16])[C:6]1=[O:18])[CH3:4])(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@H](CO)n1ccc2c([N+](=O)[O-])cccc2c1=O
Agent: CNC1(NC)C=CN=CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OC[C@@H](C)n1ccc2c([N+](=O)[O-])cccc2c1=O
Yield: 99.1 %

Procedure:
(R)-2-(1-hydroxypropan-2-yl)-5-nitroisoquinolin-1(2H)-one (19 g, 0.073 mol), acetic anhydride (10 g, 0.1 mol), triethylamine (30 g, 0.3 mol), 4,4-dimethylaminopyridine (200 mg, 0.002 mol) and methylene chloride (500 mL, 8 mol) were stirred at room temperature overnight. The solvents were removed under reduced pressure and the residue was purified flash chromatography to afford the title compound as a yellow oil (21 g, 100% yield).
Reaction SMILES: [NH2:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@H:3]1[OH:11].[C:12]([OH:21])(=[O:20])[C@@H:13]([C@H:15]([C:17]([OH:19])=[O:18])[OH:16])[OH:14]>CO.CN(C=O)C>[NH2:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@H:3]1[OH:11].[CH3:13][OH:14].[C:17]([C@@H:15]([C@H:13]([C:12]([OH:21])=[O:20])[OH:14])[OH:16])([OH:19])=[O:18]
Reactant: N[C@@H]1c2ccccc2C[C@@H]1O
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: CO
Solvent: CN(C)C=O
Product: N[C@H]1c2ccccc2C[C@H]1O
Temperature: 20 °C
Reaction time: 1 h

Procedure:
Racemic cis-1-amino-2-indanol (66.6 g, water wet, content 81.1%) was dissolved in 180 ml of methanol with 10 ml of DMF at reflux. Then 65 g of (R,R)-tartaric acid dissolved in 200 ml of methanol were added. Stirring of the mixture was continued for one hour at reflux and then it was cooled down again to 20° C. and isolation by filtration was effected. The solid was washed twice with 120 ml of methanol. After drying, 54.8 g of (1S,2R)-1-amino-2-indanol-(R,R)-tartrate methanol solvate were obtained with an e.e. of 97.0%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]([C:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[S:26][CH:25]=1)[C:20]([O:22][CH3:23])=[O:21]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]([C:24]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[S:26][CH:25]=2)[C:20]([O:22][CH3:23])=[O:21])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: COC(=O)C(N)c1csc2ccccc12
Product: COC(=O)C(NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)c1csc2ccccc12

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl 2-amino-2-(benzothiophen-3-yl)acetate (prepared from 2-amino-2-(benzothiophen-3-yl)acetic acid [CAS 95834-94-9] using General Procedure H), the title compound was prepared as a solid (mp=185-186° C.).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:15])[N:12](C)[N:13]=2)=[CH:4][CH:3]=1.[C:16]([O-])([O-])=O.[K+].[K+].Br[CH2:23][CH2:24][CH2:25][N:26]1[C:30](=[O:31])[C:29]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:28]2[C:27]1=[O:36]>CN(C=O)C>[C:30]1(=[O:31])[N:26]([CH2:25][CH2:24][CH2:23][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:9]([CH3:16])[CH2:10][C:11](=[O:15])[NH:12][N:13]=3)=[CH:4][CH:3]=2)[C:27](=[O:36])[C:28]2=[CH:35][CH:34]=[CH:33][CH:32]=[C:29]12
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: O=C([O-])[O-]
Reactant: CN1N=C(c2ccc(O)cc2)CCC1=O
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1CC(=O)NN=C1c1ccc(OCCCN2C(=O)c3ccccc3C2=O)cc1
Yield: 104 %

Procedure:
A mixture of 500 mg (2.45 mmol) of 6-(4-hydroxyphenyl)-methyl-4,5-dihydro-3(2H)-pyridazinone (prepared by the method described in Eur. Pat. Appl. EP 178,189 A2), 373 mg (2.70 mmol) of powdered anhydrous K2CO3, and 790 mg (2.95 mmol) of N-(3-bromopropyl)phthalimide in 10 ml of DMF is heated at 100° C. for 2 hrs. The DMF is removed under vacuum, the residue is taken up in 125 ml of EtOAc and 100 ml of water, the organic phase washed once with 75 ml of water, died (MgSO4), and the solvent removed to give 0.997 g of 6-[4-(3-phthalimidopropyloxy)phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone as a white solid. Yield, 99%.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=[O:11])[NH:6]2.[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25](O)=[O:26])[C:20]2=[O:28])=[CH:15][CH:14]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(#N)C.CN(C=O)C>[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([NH:1][C:2]3[CH:10]=[CH:9][CH:8]=[C:7]4[C:3]=3[CH2:4][C:5](=[O:11])[NH:6]4)=[O:26])[C:20]2=[O:28])=[CH:15][CH:14]=1
Reactant: Nc1cccc2c1CC(=O)N2
Reactant: O=C(O)c1cccn(-c2ccc(F)cc2)c1=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1Cc2c(cccc2NC(=O)c2cccn(-c3ccc(F)cc3)c2=O)N1

Procedure:
4-aminooxindole (80 mg, 0.54 mmol) was made to react to 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (125.5 mg, 0.54 mmol) in the presence of O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU, 250 mg, 0.78 mmol) and triethylamine (TEA, 0.23 mL, 1.62 mmol) in a mixture of dry DMF and acetonitrile (1:3, 6 mL) under rt for 14 hours. Resultant solid was collected by filter, washed by methanol, water and ether, and dried to give 1-(4-fluorophenyl)-2-oxo-N-(2-oxoindolin-4-yl)-1,2-dihydropyridine-3-carboxamide: YD: 56%; mp: 293-295° C. 1H-NMR (400 MHz, DMSO-d6): 11.77 (s, 1H), 10.41 (s, 1H), 8.58 (dd, J=7.6, 2 Hz, 1H), 8.10 (dd, J=6.6, 2 Hz, 1H), 7.77 (d, J=8.4 Hz, 1H), 7.59 (m, 2H), 7.41 (d, J=8.8 Hz, 2H), 7.17 (dd, J=8, 7.6 Hz, 1H), 6.71 (dd, 7.6, 6.6 Hz, 1H), 6.68 (d, J=7.6 Hz, 1H), 3.36 (s, 2H). (C20H14N3O3F. 0.3; H2O) C, H, N.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[F:28][C:29]([F:46])([F:45])[C:30]1[CH:35]=[CH:34][C:33]([C:36]2[C:37]([C:42](Cl)=[O:43])=[CH:38][CH:39]=[CH:40][CH:41]=2)=[CH:32][CH:31]=1>C(Cl)Cl>[C:1]1([CH2:7][N:8]2[CH2:9][CH2:10][N:11]([C:14]3[CH:15]=[CH:16][C:17]([NH:20][C:42]([C:37]4[C:36]([C:33]5[CH:34]=[CH:35][C:30]([C:29]([F:28])([F:45])[F:46])=[CH:31][CH:32]=5)=[CH:41][CH:40]=[CH:39][CH:38]=4)=[O:43])=[CH:18][CH:19]=3)[CH2:12][CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: Nc1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(N2CCN(Cc3ccccc3)CC2)cc1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90.6 %

Procedure:
A mixture of 4-[4-(phenylmethyl)-1-piperazinyl]-benzenamine (0.3 mol) and triethylamine (0.36 mol) in DCM (1500 ml) was stirred at room temperature for 15 minutes. 4′-(Trifluoromethyl)-[1,1′-biphenyl]-2-carbonyl chloride (0.36 mol) was added dropwise over 30 minutes. The mixture was stirred at room temperature for 3 hours and then washed twice with water, then washed with a saturated NaCl solution. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was stirred in DIPE (800 ml). The precipitate was filtered off, washed twice with DIPE and dried in vacuo at 50° C., yielding 140.2 g of N-[4-[4-(phenylmethyl)-1-piperazinyl]phenyl]-4′-(trifluoromethyl)-[1,1′-biphenyl]-2-carboxamide (intermediate 1, mp. 180° C.).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH:11]2[CH2:12][CH2:13][CH:7]1[CH2:8][CH:9]([N:14]1[CH2:19][CH2:18][C:17]3([C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]3)[CH2:16][CH2:15]1)[CH2:10]2)=[O:5])[CH3:2].FC(F)(F)C(O)=O>ClCCl.C(#N)C>[N:14]1([CH:9]2[CH2:10][CH:11]3[N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:7]([CH2:13][CH2:12]3)[CH2:8]2)[CH2:19][CH2:18][C:17]2([C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22][NH:21][CH2:20]2)[CH2:16][CH2:15]1
Reactant: CCOC(=O)N1C2CCC1CC(N1CCC3(CC1)CN(C(=O)OC(C)(C)C)Cc1ccccc13)C2
Solvent: CC#N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)N1C2CCC1CC(N1CCC3(CC1)CNCc1ccccc13)C2
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 88.3 %

Procedure:
The crude tert-butyl 1′-(8-(ethoxycarbonyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H -spiro[isoquinoline-4,4′-piperidine]-2(3H)-carboxylate 5b (3.641 g) was dissolved in dichloromethane (10 mL) and treated with trifluoroacetic acid (10 mL). The reaction was stirred at room temperature for 45 min, then concentrated under reduced pressure. The oil obtained was re-dissolved in acetonitrile, re-concentrated under reduced pressure, treated with 2 N NaOH (25 mL) and extracted with dichloromethane (2×50 mL). The combined extracts were washed with saturated NaHCO3, saturated brine, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to afford 2.55 g crude ethyl 3-(2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate 5c as a pale yellow oil, which solidified upon standing overnight at room temperature. LC/MS m/z [M+H]+ 384.2 retention time 1.34 min (10-99% CH3CN—H2O gradient, with 0.05% TFA, 5 min). 1H-NMR (400 MHz, CDCl3) δ 7.60 (d, J=8.0 Hz, 1H), 7.29 (t, J=7.3 Hz, 1H), 7.19 (t, J=7.4 Hz, 1H), 7.07 (d, J=7.5 Hz, 1H), 6.06 (br s, 2H), 4.37 (br s, 2H), 4.25 (s, 2H), 4.12 (q, J=7.1 Hz, 2H), 3.47 (m, 3H), 3.24 (m, 2H), 2.93 (m, 2H), 2.53 (m, 2H), 1.96 (m, 8H), 1.71 (m, 2H), 1.26 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][O:6][C:7]1[CH:22]=[CH:21][C:10]([C:11]([O:13]CC2C=CC=CC=2)=[O:12])=[CH:9][CH:8]=1)=[O:4]>CO.C(OCC)(=O)C>[CH3:1][O:2][C:3]([CH2:5][O:6][C:7]1[CH:22]=[CH:21][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1)=[O:4]
Reactant: COC(=O)COc1ccc(C(=O)OCc2ccccc2)cc1
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)COc1ccc(C(=O)O)cc1

Procedure:
5 g of benzyl 4-(methoxycarbonylmethyloxy)benzoate were dissolved in methanol/ethyl acetate and hydrogenated in the presence of 600 mg of catalyst (Pd/C, 10% strength). After flushing with inert gas, the catalyst was filtered off and the filtrate was concentrated in vacuo. The residue was triturated with diisopropyl ether/heptane (9/1) and filtered off with suction. Yield: 3.3 g.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:42])[C@H:15]([CH2:19][S:20]([N:23]1[CH2:28][CH2:27][N:26]([C:29]2[N:34]=[CH:33][C:32]([C:35]3[CH:40]=C[C:38](F)=[CH:37][CH:36]=3)=[CH:31][N:30]=2)[CH2:25][CH2:24]1)(=[O:22])=[O:21])[CH:16]([CH3:18])[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.Cl.[N:46]1(C2N=CC(C3C=NC=CC=3)=CN=2)CCNCC1.C([C@@H]1COC(=O)N1C(=O)[C@H](CS(Cl)(=O)=O)C(C)C)C1C=CC=CC=1>>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:42])[C@H:15]([CH2:19][S:20]([N:23]1[CH2:24][CH2:25][N:26]([C:29]2[N:30]=[CH:31][C:32]([C:35]3[CH:40]=[N:46][CH:38]=[CH:37][CH:36]=3)=[CH:33][N:34]=2)[CH2:27][CH2:28]1)(=[O:22])=[O:21])[CH:16]([CH3:18])[CH3:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(F)cc3)cn2)CC1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: c1cncc(-c2cnc(N3CCNCC3)nc2)c1
Agent: CC(C)[C@@H](CS(=O)(=O)Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: Cl
Product: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3cccnc3)cn2)CC1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Yield: 82 %

Procedure:
Prepared according to the method for the preparation of 4-(R)-benzyl-3-(2-(R)-{4-[5-(4-fluorophenyl)pyrimidin-2-yl]piperazine-1-sulfonylmethyl}-3-methyl-butyryl)oxazolidin-2-one, from 2-piperazin-1-yl-5-pyridin-3-ylpyrimidine, trihydrochloride (0.292 g) and 4-(R)-benzyl-3-(2-(R)-chlorosulfonylmethyl-3-methylbutyryl)oxazolidin-2-one (0.343 g), to yield the title compound as a yellow solid (0.393 g, 82%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6](Cl)=[O:7])#[N:2].[NH3:16].C(OCC)(=O)C.CCCCCC>C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6]([NH2:16])=[O:7])#[N:2]
Reactant: N#Cc1cc(C(=O)Cl)cc(C(F)(F)F)c1
Reactant: N
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: N#Cc1cc(C(N)=O)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
In 1-neck 250 mL round-bottomed flask, 3-cyano-5-(trifluoromethyl)benzoyl chloride (3.0 g, 1.0 eq.) was dissolved in THF (30 mL, 10 V) at 0° C. Ammonia gas was added and the reaction mixture was stirred for 1-2 h at 0° C. The progress of the reaction was followed by TLC analysis on silica gel with ethyl acetate:hexane (5:5) as mobile phase and visualization with UV, SM Rf=0.10 and Product Rf=0.25. Reaction mixture was quenched into the ice-water slurry (100 mL) and extracted in the ethyl acetate (100 mL×3). Organic layer was washed with brine solution (100 mL) followed by drying using anhydrous sodium sulphate. Organic layer was concentrated under reduced pressure to afford 2.5 g of crude compound as white solid, yield (88%). This crude 3-cyano-5-(trifluoromethyl)benzamide was directly used for next step without purification; Mass: (ES−) 212.95 (M−1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]([CH3:28])([CH3:27])[N:5]1[C:11]2[CH:12]=[CH:13][C:14]([F:16])=[CH:15][C:10]=2[C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])=[N:8][CH:7]([CH2:24][CH3:25])[C:6]1=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:31].N1C=CC=CC=1>C(Cl)Cl.O>[CH3:1][O:2][C:3](=[O:29])[C:4]([CH3:28])([CH3:27])[N:5]1[C:11]2[CH:12]=[CH:13][C:14]([F:16])=[CH:15][C:10]=2[C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])=[N:8][CH:7]([CH2:24][CH3:25])[C:6]1=[S:31]
Reactant: CCC1N=C(c2ccccc2Cl)c2cc(F)ccc2N(C(C)(C)C(=O)OC)C1=O
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC1N=C(c2ccccc2Cl)c2cc(F)ccc2N(C(C)(C)C(=O)OC)C1=S

Procedure:
A mixture of 0.01 mole of 7-fluoro-5-(o-chlorophenyl)-2,3-dihydro-α,α-dimethyl-3-ethyl-2-oxo-1H-1,4-benzodiazepin-1-acetic acid methyl ester, 0.0105 mole of phosphorus pentasulfide and 100 ml. of pyridine is heated under reflux for 24 hours. The mixture is evaporated and the residue thus obtained is dissolved in methylene chloride-water. The organic layer is separated, washed with saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate and evaporated. The residue thus obtained is chromatographed on silica gel and eluted to give 7-fluoro-α,α-dimethyl-3-ethyl-5-(o-chlorophenyl)-2,3-dihydro-2-thioxo-1H-1,4-benzodiazepin-1-acetic acid methyl ester.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].ClCCl.C([O-])(O)=O.[Na+].Cl.[CH2:23]([O:30][NH2:31])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C)C=O.O1CCCC1>[C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:31][O:30][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:11])=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: NOCc1ccccc1
Reactant: CC(=O)Oc1ccc(C(=O)O)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)Oc1ccc(C(=O)NOCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.2 %

Procedure:
To a suspension of 4-(acetyloxy)benzoic acid (17) (10.0 g, 55.5 mmol) in dichloromethane (200 ml) oxalyl chloride (15 ml, 172 mmol) and dimethylformamide (0.1 ml) were added. The reaction mixture was stirred at ambient temperature for 30 minutes and at reflux temperature for 1 hour. The volatiles were evaporated in vacuo, the residue was dissolved in benzene (100 ml) and the solvent was evaporated again. The procedure was repeated several times until the poignant smell disappeared after drying in vacuo. The viscous oil was dissolved in tetrahydrofuran (100 ml) and this solution slowly over 10 minutes was added to a prearranged mixture consisting of saturated NaHCO3 solution (100 ml), solid NaHCO3 (11 g), O-benzylhydroxylamine hydrochloride (9.90 g, 62 mmol), and tetrahydrofuran (150 ml). The resulting mixture was stirred at ambient temperature for 1 hour and the volume of the reaction mixture was decreased ca. twice by evaporating the mixture on vacuum rotary evaporator. The residue was extracted with ethyl acetate (3×100 ml), the combined organic extracts were successively washed with 2N HCl (100 ml), water (100 ml), brine (100 ml), and dried (Na2SO4). The solvents were evaporated and the residue was crystallized from toluene to give the title compound (14.275 g, 90%) as white crystals, m.p. 120-122° C. 1H NMR (CDCl3, HMDSO) δ: 2.30 (3H, s); 5.02 (2H, s); 7.14 (2H, d, J=8.6 Hz); 7.26-7.54 (5H, m); 7.69 (2H, d, J=8.6 Hz); 8.56 (1H, br s).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][NH:5][C:4]2=[N:8][CH:9]=[CH:10][C:3]=12.[C:11]1([SH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)CCC>[C:11]1([S:17][C:2]2[C:3]3[CH:10]=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Sc1ccccc1
Reactant: Clc1nc[nH]c2nccc1-2
Solvent: CCCCO
Product: c1ccc(Sc2ncnc3[nH]ccc23)cc1
Temperature: 140 °C
Yield: 91.6 %

Procedure:
To a solution of 4-chloro-1H-pyrrolo[2,3-d]pyrimidine (1.69 g, 11.0 mmol) and TEA (4.60 mL, 33.0 mmol) in 1-butanol (25.0 mL) was added benzenethiol (3.39 mL, 33.0 mmol), and the mixture was refluxed at 140° C. overnight. The reaction was then cooled to rt and concentrated in vacuo. The off-white solid was purified by silica gel chromatography eluting with a gradient of 0 to 35% EtOAc in DCM to afford the product (2.29 g, 92%). LC/MS: Rt=1.55 min, ES+ 228 (FA standard).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)[N:6]=[CH:5]2.[OH:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:33]=[CH:32][C:28]([C:29]([O-])=[O:30])=[CH:27][CH:26]=2)[CH2:21][CH2:20]1>>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([N:7]2[C:8]3[C:4](=[CH:3][C:2]([NH:1][C:29](=[O:30])[C:28]4[CH:27]=[CH:26][C:25]([N:22]5[CH2:23][CH2:24][CH:19]([OH:18])[CH2:20][CH2:21]5)=[CH:33][CH:32]=4)=[CH:10][CH:9]=3)[CH:5]=[N:6]2)=[CH:12][CH:13]=1
Reactant: O=C([O-])c1ccc(N2CCC(O)CC2)cc1
Reactant: Nc1ccc(-n2ncc3cc(N)ccc32)cc1
Product: Nc1ccc(-n2ncc3cc(NC(=O)c4ccc(N5CCC(O)CC5)cc4)ccc32)cc1

Procedure:
Compound 515 was prepared according to the procedure described in Scheme IV from 5-amino-1-(4-aminophenyl)indazole and 4-(4-hydroxypiperidin-1-yl)benzoate. [M+H]+ calcd for C25H25N5O2: 428.20; found: 427.93.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH2:10][NH:11][CH3:12])[CH:3]=[CH:2]1.Cl.Cl.[CH3:15][N:16]1[CH2:22][C:21]2[CH:23]=[C:24](/[CH:27]=[CH:28]/[C:29]([OH:31])=O)[CH:25]=[N:26][C:20]=2[NH:19][C:18](=[O:32])[CH2:17]1.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH2:10][N:11]([CH3:12])[C:29](=[O:31])/[CH:28]=[CH:27]/[C:24]2[CH:25]=[N:26][C:20]3[NH:19][C:18](=[O:32])[CH2:17][N:16]([CH3:15])[CH2:22][C:21]=3[CH:23]=2)[CH:3]=[CH:2]1
Reactant: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Reactant: CNCc1cccc2cc[nH]c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CC(=O)Nc2ncc(/C=C/C(=O)N(C)Cc3cccc4cc[nH]c34)cc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.6 %

Procedure:
To a solution of (1H-indol-7-ylmethyl)methylamine (103 mg, 0.6 mmol), (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid dihydrochloride (160 mg, 0.5 mmol), HOBt (81 mg, 0.5 mmol) and diisopropylethylamine (0.41 mL, 2 mmol) in DMF (12 mL) was added EDC hydrochloride (114 mg, 0.6 mmol). The mixture was stirred overnight at room temperature. Water (75 mL) was added and the solution stirred for 1 hr. The precipitate was collected by filtration and triturated with hexanes to afford (E)-N-(1H-indol-7-ylmethyl)-N-methyl-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylamide (155 mg, 79%) as a white solid and as a mixture of amide rotomers. 1H NMR (300 MHz, DMSO-d6) δ 10.78-11.23 (m, 1H), 10.34-10.30 (m, 1H), 8.54-8.45 (m, 1H), 8.14-8.00 (m, 1H), 7.64-7.27 (m, 4H), 6.99-6.75 (m, 2H), 6.47-6.45 (m, 1H), 5.10-4.82 (2×s, 2H), 3.79-3.71 (2×s, 2H), 3.42-3.38 (m, 2H), 3.15-2.95 (2×s, 3H), 2.36-2.31 (2×s, 3H); ESI MS m/z 390 [C22H23N5O2+H]+
Reaction SMILES: O[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=[O:9])[CH:3]=1.C(Cl)(C([Cl:15])=O)=O>CCOC(C)=O.CN(C=O)C>[Cl:15][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=[O:9])[CH:3]=1
Reactant: O=C(O)c1cc(O)ncn1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(O)c1cc(Cl)ncn1
Temperature: 75 °C
Reaction time: 3 h
Yield: 92.9 %

Procedure:
To a solution of 6-hydroxypyrimidine-4-carboxylic acid (6.0 g, 42.8 mmol) in EtOAc (90 mL) was added (COCl)2 (12 mL) dropwise, followed by a few drops of DMF. The mixture was stirred at 75° C. for 3 h, and then at 25° C. for 16 h. The solvent was evaporated to give the crude 6-chloropyrimidine-4-carboxylic acid (6.3 g, yield: 92.9%). 1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 6.88 (s, 1H).
Reaction SMILES: FC1C(I)=C(C(N2[C@@H:14]3[CH2:15]C[C@H]2[C@H:12]([NH:17][C:18]2N=CC(C(F)(F)F)=CN=2)[CH2:13]3)=O)C=CC=1.I[C:30]1[C:35]([CH3:36])=[CH:34][CH:33]=[CH:32][C:31]=1[C:37]([N:39]1[C@@H:43]2[CH2:44][CH2:45][C@H:40]1[C@H:41]([NH:46][C:47]1[N:52]=[CH:51][C:50]([C:53]([F:56])([F:55])[F:54])=[CH:49][N:48]=1)[CH2:42]2)=[O:38].C([Sn](CCCC)(CCCC)C1OC=CN=1)CCC.C([Sn](CCCC)(CCCC)C1C=CC=CN=1)CCC>>[CH3:36][C:35]1[C:30]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:18][N:17]=2)=[C:31]([C:37]([N:39]2[C@@H:43]3[CH2:44][CH2:45][C@H:40]2[C@H:41]([NH:46][C:47]2[N:52]=[CH:51][C:50]([C:53]([F:56])([F:55])[F:54])=[CH:49][N:48]=2)[CH2:42]3)=[O:38])[CH:32]=[CH:33][CH:34]=1
Reactant: Cc1cccc(C(=O)N2[C@@H]3CC[C@H]2[C@H](Nc2ncc(C(F)(F)F)cn2)C3)c1I
Reactant: O=C(c1cccc(F)c1I)N1[C@@H]2CC[C@H]1[C@H](Nc1ncc(C(F)(F)F)cn1)C2
Agent: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: CCCC[Sn](CCCC)(CCCC)c1ncco1
Product: Cc1cccc(C(=O)N2[C@@H]3CC[C@H]2[C@H](Nc2ncc(C(F)(F)F)cn2)C3)c1-c1ccccn1

Procedure:
Prepared analogous to Example 284 substituting title compound of Example 277 with title compound of Example 276 and 2-(tributylstannyl)oxazole with 2-(tributylstannyl)pyridine. MS (ESI) mass calcd. for: C24H22F3N5O, 453.2 m/z found 454.2 [M+H]+. 1H NMR (400 MHz, Chloroform-d) 8.72-8.66 (m, 1H), 8.45 (s, 0.5H), 8.39 (s, 1.5H), 7.86-7.75 (m, 1H), 7.52-7.44 (m, 1H), 7.38-7.20 (m, 4.2H), 7.18-7.12 (m, 0.8H), 4.72-4.65 (m, 0.8H), 4.49-4.45 (m, 0.2H), 4.32 (s, 0.8H), 4.03-3.95 (m, 1H), 3.88-3.83 (m, 0.2H), 2.26 (s, 2.2H), 2.23 (s, 0.8H), 2.16 (dd, J=12.8, 7.9 Hz, 0.8H), 1.98-1.08 (m, 5.2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:4]=1[CH:5]=O.[NH:13]1[CH2:19][C:17](=[O:18])[NH:16][C:14]1=[O:15].C(CN)O>O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:4]=1[CH:5]=[C:19]1[NH:13][C:14](=[O:15])[NH:16][C:17]1=[O:18]
Reactant: O=C1CNC(=O)N1
Reactant: COc1ccc(OC)c(C=O)c1
Solvent: NCCO
Solvent: O
Product: COc1ccc(OC)c(C=C2NC(=O)NC2=O)c1

Procedure:
A mixture of 2,5-dimethoxybenzaldehyde (2.504 g.) and hydantoin (1.507 g., 1 molar ratio) in water (15 ml) was heated to 70°. To this 2 layer liquid was added monoethanolamine (1.38 g., 1.5 molar ratio). The mixture was heated 4 hours at 90°-92° (bath temperature) with magnetic stirring. The title compound was isolated in the usual manner and obtained as a yellow solid (3.288 g.), m.p. 250°-252°. Crystallization from dioxane (86% recovery) gave m.p. 251°-252°.