Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C([Li])CCC.[C:11]([C:14]1[O:18][CH:17]=[N:16][C:15]=1[CH3:19])(=[O:13])[CH3:12].C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:19][C:15]1[N:16]=[CH:17][O:18][C:14]=1[C:11]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)([OH:13])[CH3:12]
Reactant: CC(=O)c1ocnc1C
Reactant: c1ccsc1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ncoc1C(C)(O)c1cccs1
Temperature: -40 °C
Reaction time: 1 h

Procedure:
Thiophene (3.36 g) in dry tetrahydrofuran (20 ml) was stirred and cooled to -40° C. under a dry nitrogen atmosphere and n-butyllithium (2.5M solution in hexane, 16 ml) was added dropwise. The mixture was allowed to warm to -20° C. and then after 1 hour was cooled to -70° C. 5-Acetyl-4-methyloxazole (5 g) in dry tetrahydrofuran (15 ml) was added dropwise. After a further 1 hour the mixture was allowed to warm the room temperature and was stirred for a further 2 hours. Aqueous sodium hydrogen carbonate was added and the mixture was extracted with diethylether. The material thus obtained was purified by flaon chromatography to give the title compound. M.p. 84°-85° C.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:29])[N:4]([C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=2[F:28])[C:22](O)=[O:23])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].C[N:31]1CCOCC1.ClC1N=C(OC)N=C(OC)N=1.[NH4+].[OH-]>O.O1CCCC1>[Br:1][C:2]1[C:3](=[O:29])[N:4]([C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=2[F:28])[C:22]([NH2:31])=[O:23])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: CN1CCOCC1
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1cc(C(=O)O)ccc1F
Agent: COc1nc(Cl)nc(OC)n1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1cc(C(N)=O)ccc1F
Reaction time: 0.5 h
Yield: 65 %

Procedure:
A 250 mL round bottomed flask equipped with stirbar and nitrogen inlet was charged with 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-fluorobenzoic acid (3.65 g, 7.8 mmol), 4-methylmorpholine (2.6 mL, 23.4 mmol), 2-chloro-4,6-dimethoxy-1,3,5-triazine (1.64 g, 9.36 mmol) and tetrahydrofuran (40 mL). After stirring the mixture for 30 min at 250 C, NH4OH (20.0 mL) was added. The mixture was stirred for 30 min and diluted with water. The product precipitated from solution. The precipitated was filtered and washed with water and diethyl ether to give the title compound (2.37 g, 65%) as a white solid. 1H NMR (400 MHz, (CD3)2SO) δ 7.9 (d, J=7.3 Hz, 1H), 7.61 (q, J=8.6 and 6.7 Hz, 1H), 7.5 (m, 2H), 7.3 (t, J=9.6 Hz, 1H), 7.15 (t, J=8.7 Hz, 1H), 6.7 (s, 1H), 5.36 (s, 2H), 2 (s, 3H) ppm. ES-HRMS m/z 469.0172 (M+H calcd for C20H15BrF3N2O3 requires 469.0195).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1.[P:14]([O-:19])([O:17][CH3:18])[O:15][CH3:16]>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([P:14]([O:17][CH3:18])([O:15][CH3:16])=[O:19])([OH:12])[CH3:11])=[CH:6][CH:5]=1
Reactant: COP([O-])OC
Reactant: COC(=O)c1ccc(C(C)=O)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(C)(O)P(=O)(OC)OC)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-acetyl-benzoic acid methyl ester (1.0 g, 5.61 mmol) in THF (5.6 mL) was cooled to 0° C. and dimethyl phosphite (0.7 g, 6.17 mmol) and N,N,N′N′-tetramethyl-guanidine (0.07 g, 0.56 mmol) were added dropwise. The reaction mixture was warmed to ambient temperature and stirred for 30 minutes. The reaction mixture was diluted with EtOAc and washed with 1N aqueous HCl (2×), brine, then dried (MgSO4) and concentrated in vacuo. The residue was purified by MPLC (Isocratic CH2Cl2 for 6 CV then 0-7.5% MeOH in CH2Cl2) to afford the title compound: MS: cal'd 289 (MH+), exp 289 (MH+)
Reaction SMILES: CN(C)C=O.[CH3:6][C:7]1[C:8]([N+:14]([O-:16])=[O:15])=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:24][C:25]([F:28])([F:27])[F:26]>CCOCC.O>[N+:14]([C:8]1[C:9]([O:13][CH2:24][C:25]([F:28])([F:27])[F:26])=[CH:10][CH:11]=[CH:12][C:7]=1[CH3:6])([O-:16])=[O:15]
Reactant: FC(F)(F)CI
Reactant: Cc1cccc(O)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cc1cccc(OCC(F)(F)F)c1[N+](=O)[O-]

Procedure:
To 50 ml of dimethylformamide containing 7.65 g (50 mmol) of 3-methyl-2-nitrophenol, 13.6 g (100 mmol) of potassium carbonate and 12.6 g (60 mmol) of 1-iodo-2,2,2-trifluoroethane were added, and the mixture was heated at 120° to 130° C. under agitation for 2 hours. Water and ether were added to the reaction mixture, and thereafter, the ether layer was concentrated to obtain 11.2 g of 2-nitro-3-(2,2,2-trifluoroethoxy)toluene as an oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH:11]([N:12]2[C:16]([CH:17]=[O:18])=[CH:15][N:14]=[CH:13]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:19])[O:3]1.[CH3:21][Mg]Br.C(OCCCC)CCC.CC(C)=O>C1COCC1.O>[OH:18][CH:17]([C:16]1[N:12]([CH:11]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4](=[O:19])[O:3][C:2]2([CH3:20])[CH3:1])[CH:13]=[N:14][CH:15]=1)[CH3:21]
Reactant: C[Mg]Br
Reactant: CC1(C)OC(=O)c2ccccc2C1n1cncc1C=O
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCOCCCC
Product: CC(O)c1cncn1C1c2ccccc2C(=O)OC1(C)C
Temperature: 25 °C

Procedure:
To a solution of 3-(3,3-dimethyl-1-oxo-isochroman-4-yl)-3H-imidazole-4-carbaldehyde (0.500 g, 1.852 mmol) (Example 9a) in THF (20 mL) at −78° C. is added 1M methyl magnesium bromide in dibutyl ether (2.41 mL, 2.41 mmol). The reaction mixture is stirred at −78° C. for 3 h, whereupon acetone (2 mL) is added. The mixture is allowed to warm to ambient temperature and then poured into water (50 mL). The mixture is extracted with ethyl acetate. The combined organic phase is washed with water, dried over Na2SO4 and concentrated in vacuo. The residue is purified by silica gel chromatography (gradient methanol in dichloromethane, 1% to 5%) to give 4-[5-(1-hydroxy-ethyl)-imidazol-1-yl]-3,3-dimethyl-isochroman-1-one as a white solid. Resolution of all four stereoisomers of the title compound is achieved by chiral HPLC. Stereoisomer A is separated with a ChiralPak IA column using an 85:15 heptane-isopropanol mobile phase. The remaining three stereoisomers are resolved with a ChiralPak AD using an 85:15 heptane-ethanol mobile phase to give stereoisomer B (tr=61.4 min), stereoisomer C (tr=76.7 min) and stereoisomer D (tr=94.9 min)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([C@H:12]([CH:17]([CH3:19])C)C(OC)=O)[CH2:5]2.BrC1C=CC([C:25]([O:27][CH3:28])=[O:26])=C(CBr)C=1.Cl.NCCCC(OC)=O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH2:12][CH2:17][CH2:19][C:25]([O:27][CH3:28])=[O:26])[CH2:5]2
Reactant: COC(=O)c1ccc(Br)cc1CBr
Reactant: COC(=O)[C@@H](C(C)C)N1Cc2cc(Br)ccc2C1=O
Agent: COC(=O)CCCN
Agent: Cl
Product: COC(=O)CCCN1Cc2cc(Br)ccc2C1=O

Procedure:
The compound of example 374 was prepared analogous to compound of example 359 by reaction of the compound of example 358 and methyl 4-aminobutanoate hydrochloride.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[S:6]([N:16]1[CH2:20]C2=C[S:22][CH:23]=[C:18]2[CH2:17]1)([C:9]1[CH:15]=[CH:14][C:12]([CH3:13])=[CH:11][CH:10]=1)(=[O:8])=[O:7].ICC>CCCCCC.O1CCCC1>[CH2:3]([C:2]1[S:22][CH:23]=[C:18]2[CH2:17][N:16]([S:6]([C:9]3[CH:10]=[CH:11][C:12]([CH3:13])=[CH:14][CH:15]=3)(=[O:8])=[O:7])[CH2:20][C:1]=12)[CH3:4]
Reactant: [Li]CCCC
Reactant: Cc1ccc(S(=O)(=O)N2Cc3cscc3C2)cc1
Solvent: CCI
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCc1scc2c1CN(S(=O)(=O)c1ccc(C)cc1)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.75 ml of a 1.6M solution of n-butyllithium in hexane are added, at -70° C., to a solution of 1.4 g of 5-tosyl-5,6-dihydro-4H-thieno[3,4-c]pyrrole in 15 ml of dry tetrahydrofuran. 0.51 ml of iodoethane is then added and the mixture is stirred at room temperature for 2 h and the solution is then poured into 100 ml of ice-cold water. The solid formed is filtered off, washed with hexane and recrystallized from ethanol. 0.16 g of product is obtained. Melting point: 117°-120° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[NH2:7].[CH2:8]([O:15][C:16](=[O:24])[NH:17][CH:18]([CH3:23])[C:19](=O)[CH2:20]Br)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CCO>[CH2:8]([O:15][C:16](=[O:24])[NH:17][CH:18]([C:19]1[N:7]=[C:2]2[N:3]=[CH:4][CH:5]=[CH:6][N:1]2[CH:20]=1)[CH3:23])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Nc1ncccn1
Reactant: CC(NC(=O)OCc1ccccc1)C(=O)CBr
Solvent: CCO
Product: CC(NC(=O)OCc1ccccc1)c1cn2cccnc2n1
Temperature: 25 °C

Procedure:
A mixture of pyrimidin-2-ylamine (3 gm, 31.5 mmol) and (3-bromo-1-methyl-2-oxopropyl)-carbamic acid benzyl ester (9.4 gm, 31.54 mmol) in EtOH (20 mL) was heated to reflux overnight. After completion, the reaction mixture was cooled to rt and EtOH was removed in vacuo. The residue was dissolved in EtOAc and washed with satd. sodium bicarbonate solution. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography using silica gel (100-200 mesh) and 0-5% MeOH in DCM to provide (1-imidazo[1,2-a]pyrimidin-2-yl-ethyl)-carbamic acid benzyl ester: LC-MS (ESI) m/z 297.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[C:18]([CH3:19])=[N:17][N:16]([CH3:20])[C:10]=2[N:11]=[C:12](S)[CH2:13][N:14]=1.[CH2:21]([NH2:24])[C:22]#[CH:23]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[C:18]([CH3:19])=[N:17][N:16]([CH3:20])[C:10]=2[N:11]=[C:12]([NH:24][CH2:21][C:22]#[CH:23])[CH2:13][N:14]=1
Reactant: C#CCN
Reactant: Cc1nn(C)c2c1C(c1ccccc1F)=NCC(S)=N2
Solvent: C1CCOC1
Product: C#CCNC1=Nc2c(c(C)nn2C)C(c2ccccc2F)=NC1

Procedure:
A mixture of 3.0 g. of 4-(2-fluorophenyl)-1,6-dihydro-1,3-dimethylpyrazolo[3,4-e][1,4]diazepine-7-thiol (prepared as disclosed in U.S. Pat. No. 3,770,762), 1.8 g. of 2-propynylamine and 50 ml. of tetrahydrofuran is heated at reflux for 2 hours, then evaporated at reduced pressure to give a residue of 4-(2-fluorophenyl)-1,6-dihydro-1,3-dimethyl7-(2-propynylamino)pyrazolo[3,4-e][1,4]diazepine; m.p. 202°-204° C. (dec.) after trituration with ether, filtration and drying.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([N:8]([CH3:22])[C:9](=[O:21])[C:10]([C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([Cl:20])[CH:14]=2)([CH3:12])[CH3:11])=[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])[CH:3]=1.[OH:30][C@H:31]1[CH2:35][NH:34][C@H:33]([CH2:36][OH:37])[CH2:32]1.CS(C)=O>C([O-])(O)=O.[Na+]>[Cl:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:4]1[CH:3]=[C:2]([N:34]2[CH2:35][C@H:31]([OH:30])[CH2:32][C@H:33]2[CH2:36][OH:37])[N:7]=[CH:6][C:5]=1[N:8]([CH3:22])[C:9](=[O:21])[C:10]([C:13]1[CH:14]=[C:15]([Cl:20])[CH:16]=[C:17]([Cl:19])[CH:18]=1)([CH3:12])[CH3:11]
Reactant: CN(C(=O)C(C)(C)c1cc(Cl)cc(Cl)c1)c1cnc(Cl)cc1-c1ccccc1Cl
Reactant: OC[C@@H]1C[C@@H](O)CN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: CN(C(=O)C(C)(C)c1cc(Cl)cc(Cl)c1)c1cnc(N2C[C@H](O)C[C@H]2CO)cc1-c1ccccc1Cl
Temperature: 13 °C
Reaction time: 9 h
Yield: 28.5 %

Procedure:
To a solution of 0.15 g (0.32 mmol) N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-dichloro-phenyl)-N-methyl-isobutyramide and 0.25 g (2.13 mmol) (2S,4R)-4-hydroxy-2-hydroxymethyl-pyrrolidine in 2 ml dimethyl sulfoxide 0.2 g (1.55 mmol) Na2CO3 was added and the solution was stirred at 13° C. for 9 h After cooling to ambient temperature, the solution was poured into 20 ml 0.5 N NaHCO3-solution and extracted three times with 30 ml CH2Cl2. The combined organic layers were dried (Na2SO4), filtered and evaporated. The residue was purified by flash-chromatography (SiO2, CH2Cl2/ethyl acetate 1:2) to give 0.05 g (31%) of the title compound as a white foam. MS m/e (%): 548.3 (M+H+, 100).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28](=[O:41])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[N:39][CH:38]=[CH:37][N:36]=2)[CH:30]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28](=[O:41])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[N:39][CH:38]=[CH:37][N:36]=2)[CH:30]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cnccn2)c1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cnccn3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J20) (290 mg, 1.0 mmol) and 3-oxo-3-(3-pyrazin-2-yl-phenyl)-propionic acid tert-butyl ester (Example K14) (298 mg, 1.0 mmol) according to the general procedure M. Obtained as a white foam (350 mg, 68%).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:13]=[CH:12][C:11]2[NH:10][C:9](=[O:14])[N:8]3[CH2:15][CH2:16][CH2:17][N:18]=[C:7]3[C:6]=2[CH:5]=1.[CH2:21](Br)[CH:22]=[CH2:23]>>[F:20][C:2]([F:1])([F:19])[O:3][C:4]1[CH:13]=[CH:12][C:11]2[N:10]([CH2:23][CH:22]=[CH2:21])[C:9](=[O:14])[N:8]3[CH2:15][CH2:16][CH2:17][N:18]=[C:7]3[C:6]=2[CH:5]=1
Reactant: C=CCBr
Reactant: O=C1Nc2ccc(OC(F)(F)F)cc2C2=NCCCN12
Product: C=CCN1C(=O)N2CCCN=C2c2cc(OC(F)(F)F)ccc21

Procedure:
Preparation analogously to Example 29 from 10-trifluoromethoxy-6-oxo-2,3,4,5,6,7-hexahydropyrimido-[1,2-c]-quinazoline and allyl bromide.
Reaction SMILES: [OH-].[Na+].O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[OH:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=1[N:23]1[N+:27]([O-])=[C:26]2[CH:29]=[CH:30][CH:31]=[CH:32][C:25]2=[N:24]1.S(=O)(=O)(O)O>C1C2C(=O)C3C(=CC=CC=3)C=2C=CC=1.O.CO>[OH:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=1[N:23]1[N:27]=[C:26]2[CH:29]=[CH:30][CH:31]=[CH:32][C:25]2=[N:24]1
Reactant: Cc1ccc(O)c(-n2nc3ccccc3[n+]2[O-])c1
Agent: O=C1c2ccccc2-c2ccccc21
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CO
Product: Cc1ccc(O)c(-n2nc3ccccc3n2)c1
Yield: 92.8 %

Procedure:
Example 5 of U.S. Pat. No. 4,835,284 is duplicated. Water (70 ml), 97% sodium hydroxide 5.2 g, 2-nitro-2'-hydroxy-5'-methylazobenzene (12.9 g) and toluene (10 ml) are mixed and heated to 60° C. After stirring, hydroquinone (0.6 g) is added and glucose (5.0 g) is added to the mixture over one hour at 40° to 45° C. The mixture is further stirred for two hours, and the azobenzene disappears. The reaction liquor is neutralized with 62% sulfuric acid 5.8 g, and is cooled to 20° C. to precipitate a crystal. The crystal thus precipitated is separated by filtration to obtain a wet product 12 g of 2-(2'-hydroxy-5'-methylphenyl)benzotriazole-N-oxide (dry weight: 10.8 g, yield 90.0%, and melting point: 138° C. to 140° C.). To the wet product (12 g) thus obtained, are added methanol (60 ml), water (30 ml), 97% sodium hydroxide (13.0 g) and 9-fluorenone (0.5 g), and glucose (5.5 g) is further added to the mixture over one hour while stirring at 50° to 55° C. The mixture is reacted while stirring at 75° C. (boiling point) for 5 hours. As a result, the N-oxide disappears. The reaction liquor is neutralized with 62% sulfuric acid 19.8 g to pH 8 to precipitate a crystal. The precipitated crystal is separated by filtration, and the separated crystal is fully washed with water and further with methanol. The washed crystal is then dried, thus obtaining 9.4 g of 2-(2'-hydroxy-5'-methylphenyl)benzotriazole having a melting point of 128° to 130° C. at the yield of 92.8%. One can see that the reaction using an aromatic ketone takes over 9 hours to complete. Two catalysts are also required.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([CH2:13][CH2:14][CH2:15][N:16]3[CH2:20][CH2:19][CH2:18][C:17]3=[O:21])[C:9]2=[O:12])=[CH:4][C:3]=1[N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:34])[CH2:24][CH2:23]1.CN(C)C=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH:73]1([C:76]2[O:77][CH:78]=[C:79]([C:81](O)=[O:82])[N:80]=2)[CH2:75][CH2:74]1>O.C(OCC)(=O)C>[O:12]=[C:9]1[C:10]2[C:5](=[CH:4][C:3]([N:22]3[CH2:23][CH2:24][N:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[CH3:34])[CH2:26][CH2:27]3)=[C:2]([NH:1][C:81]([C:79]3[N:80]=[C:76]([CH:73]4[CH2:75][CH2:74]4)[O:77][CH:78]=3)=[O:82])[CH:11]=2)[CH2:6][CH2:7][N:8]1[CH2:13][CH2:14][CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][C:17]1=[O:21]
Reactant: O=C(O)c1coc(C2CC2)n1
Reactant: Cc1ccccc1N1CCN(c2cc3c(cc2N)C(=O)N(CCCN2CCCC2=O)CC3)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccccc1N1CCN(c2cc3c(cc2NC(=O)c2coc(C4CC4)n2)C(=O)N(CCCN2CCCC2=O)CC3)CC1
Temperature: 25 °C
Yield: 10 %

Procedure:
In a 40 ml scintillation vial equipped with a magnetic stir bar and fitted with a nitrogen inlet, the 7-amino-2-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-6-(4-o-tolyl-piperazin-1-yl)-3,4-dihydro-2H-isoquinolin-1-one 10d (48.10 mg, 0.10 mmol) was taken up in clean, dry N,N-dimethylformamide (2.00 ml, 25.83 mmol) and the mixture was stirred at room temperature and under an inert nitrogen atmosphere until all solids were in solution. To this was added the HATU (47.50 mg, 0.12 mmol) followed by the N,N-diisopropylethylamine (0.04 ml, 0.23 mmol) and the mixture was stirred until all solids were in solution. The reaction mixture was allowed to stir for 15 min and then the 2-cyclopropyl-oxazole-4-carboxylic acid 1h (20.70 mg, 0.14 mmol) was added in one portion. The reaction was then allowed to stir overnight at room temperature. The reaction was diluted with 10 ml of water and 10 ml of ethyl acetate. The layers were separated and the product was extracted from the aqueous with ethyl acetate (3×15 ml). The organic phases were combined, washed with brine (1×25 ml) and then with saturated lithium chloride aqueous solution (2×15 ml). The organic solution was then dried over Na2SO4; the solution was then decanted and the solvent was removed under reduced pressure. The product was purified using silica gel column chromatography, eluting with a gradient of 100% dichloromethane to 7.5% MeOH in dichloromethane. A secondary purification was undertaken using reverse-phase prep HPLC, eluting a gradient of 30% MeOH in water to 100% MeOH over a five minute period. The product, 2-cyclopropyl-oxazole-4-carboxylic acid [1-oxo-2-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-6-(4-o-tolyl-piperazin-1-yl)-1,2,3,4-tetrahydro-isoquinolin-7-yl]-amide 10e (6.10 mg, 0.01 mmol), was isolated as a slightly off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([S:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:15])=[CH:10][N:9]2[CH:22]=1)=[O:4].FC(F)(F)C(OO)=[O:26].FC(F)(F)C(OC(=O)C(F)(F)F)=O.OO>C(Cl)Cl>[CH3:1][O:2][C:3]([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([S:14]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)(=[O:26])=[O:15])=[CH:10][N:9]2[CH:22]=1)=[O:4]
Reactant: COC(=O)Nc1cn2cc(S(=O)c3ccccc3)ccc2n1
Reactant: O=C(OO)C(F)(F)F
Agent: OO
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)Nc1cn2cc(S(=O)(=O)c3ccccc3)ccc2n1

Procedure:
Portionwise, with cooling, 0.500 g. (0.0015 mole) of 2(methoxycarbonylamino)-6-(phenylsulfinyl) imidazo [1,2-a] pyridine is added to 5 ml. of a methylene chloride solution of trifluoroperacetic acid prepared from 415 μl. trifluoroacetic anhydride and 65 μl. of 90% hydrogen peroxide. The solution is heated at reflux for 20 hours. The cooled reaction mixture is washed with 10 ml. of a saturated aqueous sodium bicarbonate solution, the organic layer is separated and chromatographed on silica gel. Elution with 50% ethyl acetate-methylene chloride yields 2-(methoxycarbonylamino) 6-(phenylsulfonyl) imidazo [1,2-a] pyridine, m.p. 300° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.[CH3:11][CH:12]1[C:17](=[O:18])[CH2:16][CH2:15][CH2:14][C:13]1=O.S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[Cl:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[N:9]1[C:17](=[O:18])[CH2:16][CH2:15][CH2:14][C:13]1=[C:12]2[CH3:11]
Reactant: NNc1ccc(Cl)cc1
Reactant: CC1C(=O)CCCC1=O
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: Cc1c2n(c3ccc(Cl)cc13)C(=O)CCC2
Reaction time: 4 h
Yield: 158 %

Procedure:
To a suspension of p-chlorophenylhydrazine hydrochloride (8.52 g) in toluene (100 ml) were added 2-methylcyclohexane-1,3-dione (5.0 g) and 40% sulfuric acid (40 ml), and the mixture was stirred at 80°-85° C. for 4 hours. After cooling, the organic layer was separated. The aqueous layer was extracted with toluene. The organic layers were combined and washed with aqueous sodium bicarbonate, water, and brine. After dried over sodium sulfate, the organic layer was evaporated. The residue was recrystallized from methanol to give 2-chloro-8,9-dihydro-10-methylpyrido[1,2-a]indol-6(7H)-one (14.63 g).
Reaction SMILES: Cl.Br[CH:3]([CH2:6][NH:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]#[N:5].N(CCO)(CCO)CCO>>[C:4]([CH:3]1[CH2:6][N:7]1[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])#[N:5]
Reactant: CCOC(=O)CNCC(Br)C#N
Agent: Cl
Solvent: OCCN(CCO)CCO
Product: CCOC(=O)CN1CC1C#N
Yield: 34 %

Procedure:
reaction of 2-bromo-3-(carbethoxymethylamino)-propionitrile hydrochloride (prepared by reacting 2,3-dibromopropionitrile with glycine ethyl ester; m.p. 70°-75° C.) with triethanolamine gives ethyl 2-cyano-1-aziridineacetate; b.p.0.1 : 88°-90° C.; yield 34% of theory;
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15][CH2:16][CH2:17][NH2:18])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:19]=[C:20]1[NH:29][C:28](=S)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21]1>CN(C)C=O>[O:19]=[C:20]1[N:29]=[C:28]([NH:18][CH2:17][CH2:16][CH2:15][O:14][C:10]2[CH:9]=[C:8]([CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:13]=[CH:12][N:11]=2)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21]1
Reactant: O=c1[nH]c(=S)c2ccccc2[nH]1
Reactant: NCCCOc1cc(CN2CCCCC2)ccn1
Solvent: CN(C)C=O
Product: O=c1nc(NCCCOc2cc(CN3CCCCC3)ccn2)c2ccccc2[nH]1

Procedure:
3-[4-(Piperidinomethyl)pyrid-2-yloxy]propylamine (2.03 g) and 2-oxo-4-thiono-1,2,3,4-tetrahydroquinazoline (1.24 g) were stirred in dimethylformamide (5 ml) at ambient temperature for 5 days. The reaction mixture was filtered to afford a solid that was washed with cold dimethylformamide and diethyl ether to yield the title product (1.25 g), m.p. 189°-192° C. (recrystallised from isopropanol).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4](C#N)[C:5]2[CH:6]=[CH:7][N:8]([C:11]3[N:12]([CH2:22][CH3:23])[C:13](=[O:21])[NH:14][C:15](=[O:20])[C:16]=3[CH:17]([CH3:19])[CH3:18])[C:9]=2[CH:10]=1.N1C2C(=CC=CC=2)C=C1>>[CH2:22]([N:12]1[C:11]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[CH:2][CH:10]=3)[CH:6]=[CH:7]2)=[C:16]([CH:17]([CH3:18])[CH3:19])[C:15](=[O:20])[NH:14][C:13]1=[O:21])[CH3:23]
Reactant: CCn1c(-n2ccc3c(C#N)cc(Cl)cc32)c(C(C)C)c(=O)[nH]c1=O
Agent: c1ccc2[nH]ccc2c1
Product: CCn1c(-n2ccc3ccccc32)c(C(C)C)c(=O)[nH]c1=O

Procedure:
This compound was made by a procedure similar to that used to prepare 6-chloro-1-(3-ethyl-5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidin-4-yl)-1H-indole-4-carbonitrile (90), except that 1H-indole was used instead of 6-chloro-1H-indole-4-carbonitrile. LC-MS shows 298.2 (M+1). 1H NMR (300 MHz, CDCl3): δ 8.32 (br, 1H), 7.72 (d, 1H), 7.25 (m, 2H), 7.19 (m, 1H), 6.80 (m, 1H), 3.50 (m, 1H), 3.18 (m, 1H), 1.97 (m, 1H), 1.17 (dd, 6H), 1.03 (t, 3H).