Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:7]=[C:8]([C:13]2[N:17]=[C:16]([C:18]3[S:19][CH:20]=[CH:21][C:22]=3[Cl:23])[O:15][N:14]=2)[CH:9]=[CH:10][C:11]=1[Cl:12].[C-:24]#[N:25].[K+].C(=O)([O-])[O-].[Na+].[Na+]>S(=O)(=O)(O)O.O.C(OCC)(=O)C>[Cl:23][C:22]1[CH:21]=[CH:20][S:19][C:18]=1[C:16]1[O:15][N:14]=[C:13]([C:8]2[CH:9]=[CH:10][C:11]([Cl:12])=[C:6]([C:24]#[N:25])[CH:7]=2)[N:17]=1
Reactant: Nc1cc(-c2noc(-c3sccc3Cl)n2)ccc1Cl
Reactant: [C-]#N
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1cc(-c2noc(-c3sccc3Cl)n2)ccc1Cl
Reaction time: 1.25 h
Yield: 22 %

Procedure:
A solution of sodium nitrite (76.8 mg, 1.11 mmol) and water (650 μL) was added dropwise to a stirred suspension of 3-(3-amino-4-chloro-phenyl)-5-(3-chlorothiophen-2-yl)-[1,2,4]-oxadiazole (335 mg, 1.07 mmol) in sulfuric acid (3.0 mL), water (8 mL) and some crushed ice in an ice bath. The solution was stirred for 1.25 h and then was poured into a solution of cuprous cyanide (152 mg, 1.70 mmol), potassium cyanide (231 mg, 3.55 mmol) and water (8 mL) in an ice bath. The solution was stirred for 10 min, then ethyl acetate (50 mL) was added, followed by sodium carbonate to bring the solution to pH 7, and the solution was equilibrated to room temperature. The ethyl acetate layer was concentrated by rotary evaporation and the product was purified by column chromatography to yield 75.7 mg (22%) of the title compound as a light yellow solid. 1H NMR (CDCl3): 8.49 (d, J=2.20 Hz, 1H), 8.33 (dd, J1=8.52 Hz, J2=2.20 Hz, 1H), 7.67 (m, 2H), 7.16 (d, J=5.50 Hz, 1H).
Reaction SMILES: [CH:1]1[C:6]([CH:7]=O)=[CH:5][C:4]2[O:9][CH2:10][O:11][C:3]=2[CH:2]=1.[C:12]([O:19][CH3:20])(=[O:18])[CH2:13][C:14]([O:16][CH3:17])=[O:15].O>C1C=CC=CC=1.C(O)(=O)C.N1CCCCC1>[CH3:17][O:16][C:14](=[O:15])[C:13](=[CH:7][C:6]1[CH:1]=[CH:2][C:3]2[O:11][CH2:10][O:9][C:4]=2[CH:5]=1)[C:12]([O:19][CH3:20])=[O:18]
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: COC(=O)CC(=O)OC
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)C(=Cc1ccc2c(c1)OCO2)C(=O)OC
Yield: 84.8 %

Procedure:
A mixture of piperonal (15.0 g, 0.1 mol), dimethyl malonate (13.4 g, 0.1 mol), acetic acid (0.32 g, 5.3 mmol) and piperidine (0.43 g, 5.0 mmol) in benzene (200 ml) was stired and refluxed for 6 h with azeotropic distillation of H2O. The solvent was then removed at reduced pressure and the residue dissolved in ethyl acetate (100 ml). This solution was then extracted with 5% HCl (1X, 50 ml), then 5% Na2 CO3 (1X, 50 ml) followed by extraction with saturated aqueous NaCl (1x, 50 ml). The organic layer was dried (MgSO4), filtered and the solvent removed at reduced pressure to give a clear light oil (22.4 g) which solidified in part on standing. The oil was removed (by pipet) and the residual solid (18.3 g) recrystallized from ethanol (1X) to give 14.6 g (55%) of (a) as a crystalline white solid; mp 77°-74°.
Reaction SMILES: [BH4-].[Na+].[Cl-].[Li+].[CH2:5]([N:12]1[CH2:16][C@H:15]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:14][C@H:13]1[C:25](OC)=[O:26])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl.[OH-].[Na+].[Cl-].[Na+]>O1CCCC1.C(O)C>[CH2:5]([N:12]1[CH2:16][C@H:15]([O:17][Si:18]([C:21]([CH3:22])([CH3:23])[CH3:24])([CH3:20])[CH3:19])[CH2:14][C@H:13]1[CH2:25][OH:26])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1Cc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CO)N(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.9 %

Procedure:
To a suspension of sodium borohydride (16.2 g) and lithium chloride (18.1 g) in tetrahydrofuran (190 ml) were dropwise added (2S,4R)-1-benzyl-2-methoxycarbonyl-4-(t-butyldimethylsilyloxy)pyrrolidine (74.8 g) in tetrahydrofuran (190 ml), and ethanol (750 ml) under ice-cooling. The mixture was stirred at ambient temperature for 2 hours. The reaction mixture was cooled with dry ice-acetone bath and poured into ice-water. The mixture was adjusted to pH 6 with 1N hydrochloric acid and stirred for 10 minutes. The mixture was adjusted to pH 9~10 with 1N sodium hydroxide, and saturated with sodium chloride. After being extracted with ethyl acetate and tetrahydrofuran (1:1) three times, the organic layer was dried over anhydrous magnesium sulfate and evaporated in vacuo. To the residue was added chloroform. The chloroform layer was again dried over anhydrous magnesium sulfate, and evaporated in vacuo to give (2S,4R)-1-benzyl-2-hydroxymethyl-4-(t-butyldimethylsilyloxy)pyrrolidine (70.10 g).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:19][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:10]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: O=[N+]([O-])c1cc2c(NCc3ccccc3)nc(Cl)nc2s1
Product: O=[N+]([O-])c1cc2c(NCc3ccccc3)nc(-n3ccnc3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-6-nitro-4-benzylamino-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-6-nitro-4-benzylamino-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:9][CH:10]=2)[C:5]1=O.O.[NH2:19][CH2:20][C@H:21]([OH:23])[CH3:22]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:13]([C:8]1[CH:7]=[C:6]2[C:11]([CH2:12][C:4]3[CH:3]=[CH:2][N:19]([CH2:20][C@H:21]([OH:23])[CH3:22])[C:5]=32)=[CH:10][CH:9]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: C[C@@H](O)CN
Reactant: CC(C)(C)c1ccc2c(c1)C(=O)C(CC=O)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: C[C@@H](O)Cn1ccc2c1-c1cc(C(C)(C)C)ccc1C2
Reaction time: 0.75 h
Yield: 70.6 %

Procedure:
A solution of 2.3 g of (RS)-2-(2-oxoethyl)-6-tert-butyl-1-indanone and 80 mg of p-toluenesulfonic acid in 70 ml of anhydrous toluene was heated on a water separator. A solution of 3.0 g of (R)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 45 minutes, during which time the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate toluene 1:1). 1.9 g (70%) of (R)-1-(7-tert-butyl-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a brown oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:11]2[N:12]=[CH:13][N:14]([C:16]([N:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH3:19])=[O:17])[CH:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10])#[N:2].C([Sn](CCCC)=O)CCC.[N:36]([Si](C)(C)C)=[N+:37]=[N-:38]>C1(C)C=CC=CC=1>[CH:20]1([N:18]([CH3:19])[C:16]([N:14]2[CH:15]=[C:11]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([C:1]4[N:36]=[N:37][NH:38][N:2]=4)[CH:4]=3)[N:12]=[CH:13]2)=[O:17])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: COc1ccc(-c2cn(C(=O)N(C)C3CCCCC3)cn2)cc1C#N
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: COc1ccc(-c2cn(C(=O)N(C)C3CCCCC3)cn2)cc1-c1nn[nH]n1
Temperature: 25 °C
Yield: 57 %

Procedure:
A mixture of 4-(3-cyano-4-methoxyphenyl)-N-cyclohexyl-N-methyl-1H-imidazole-1-carboxamide (305 mg, 0.901 mmol), dibutylstannanone (28.0 mg, 0.113 mmol) and azidotrimethylsilane (0.239 ml, 1.803 mmol) was heated in toluene (8 mL) at 115° C. for 20 h. The mixture was then cooled to room temperature and evaporated to dryness. The crude product was chromatographed over silica using a mixture of dichlormethane/methanol (95:5). After evaporation of the homogenous fractions, the residual product was triturated with diethyl ether, filtered and dried to give the product as off-white crystals, (196 mg, 54%).
Reaction SMILES: C(OC([N:8]1[CH2:12][C:11](=[CH:13][C:14]#[N:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=O)(C)(C)C.[CH2:19]([N:21]1[C:33]2[CH:32]=[CH:31][C:30]([NH2:34])=[CH:29][C:28]=2[C:27]2[C:22]1=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH3:20]>>[C:14]([CH:13]=[C:11]1[CH2:12][NH:8][C@H:9]([C:16]([NH:34][C:30]2[CH:31]=[CH:32][C:33]3[N:21]([CH2:19][CH3:20])[C:22]4[C:27]([C:28]=3[CH:29]=2)=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:18])[CH2:10]1)#[N:15]
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Reactant: CC(C)(C)OC(=O)N1CC(=CC#N)C[C@H]1C(=O)O
Product: CCn1c2ccccc2c2cc(NC(=O)[C@@H]3CC(=CC#N)CN3)ccc21

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(cyanomethylene)-2-pyrrolidinecarboxylic acid, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in 36% purity by LC/MS. MS(ESI+): m/z=345.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[O:38]1[CH2:42][CH2:41][O:40][CH:39]1[CH2:43][NH2:44]>>[O:38]1[CH2:42][CH2:41][O:40][CH:39]1[CH2:43][NH:44][C:21]1[N:20]=[C:19]([O:18][C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:29]=[C:30]([N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)[CH:31]=[C:2]([F:1])[CH:3]=3)=[CH:9][CH:10]=2)[CH:24]=[CH:23][N:22]=1
Reactant: NCC1OCCO1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Product: O=C(Nc1ccc(Oc2ccnc(NCC3OCCO3)n2)c2ccccc12)c1cc(F)cc(N2CCOCC2)c1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and C-[1,3]dioxolan-2-yl-methylamine according to conditions described in general procedure C. Mp: 122-124° C.; 1H NMR (400 MHz, DMSO-d6) δ 3.25-3.30 (m, 6 H), 3.73-3.83 (m, 8 H), 4.19 (bs, 1 H), 6.36 (bs, 1 H), 7.04 (d, J=12.0 Hz, 1 H), 7.26-7.31 (m, 2 H), 7.38-7.61 (m, 5 H), 7.83 (d, J=8.8 Hz, 1 H), 7.99 (d, J=9.2 Hz, 1 H), 8.20 (s, 1 H), 10.46 (s, 1 H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[C:10](=[O:12])[NH:9][CH2:8]2)#[CH:2].Cl[C:14]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][N:17]=[C:16]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]3)=[CH:27][CH:26]=2)[N:15]=1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CO>[O:12]=[C:10]1[C:11]2[C:7](=[CH:6][CH:5]=[CH:4][C:3]=2[C:1]#[C:2][C:18]2[C:19]([C:20]([F:22])([F:21])[F:23])=[CH:14][N:15]=[C:16]([NH:24][C:25]3[CH:26]=[CH:27][C:28]([N:31]4[CH2:32][CH2:33][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:35][CH2:36]4)=[CH:29][CH:30]=3)[N:17]=2)[CH2:8][NH:9]1
Reactant: C#Cc1cccc2c1C(=O)NC2
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc(C(F)(F)F)c(C#Cc4cccc5c4C(=O)NC5)n3)cc2)CC1
Temperature: 120 °C
Yield: 66.4 %

Procedure:
To a nitrogen de-gassed solution of 7-ethynylisoindolin-1-one (161) (0.074 g, 0.47 mmol) and tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate (I3) (0.180 g, 0.393 mmol), in dry DMF (7 mL) were added triethylamine (0.219 mL, 1.57 mmol) followed by triphenylphosphine (0.015 g, 0.059 mmol), trans-dichlorobis(triphenylphosphine)palladium(II) (0.028 g, 0.039 mmol) and CuI (0.011 g, 0.059 mmol). The reaction mixture was heated under microwave irradiation at 120° C. for 20 minutes and then concentrated to dryness in vacuo and purified by silica gel chromatography (Biotage Isolera, 40 g Si cartridge, 0-100% EtOAc in petroleum benzine 40-60° C., then 0-5% methanol in EtOAc) to give the title compound (I62) (0.151 g, 66% yield) as an orange gum; 1H NMR (400 MHz, d6-DMSO) δ 10.32 (s, 1H), 8.77 (s, 1H), 8.72 (s, 1H), 7.75-7.67 (m, 2H), 7.67-7.64 (m, 1H), 7.60-7.56 (m, 2H).), 6.95 (d, J=9.1 Hz, 2H), 4.40 (s, 2H), 3.51-3.42 (m, 4H), 3.11-3.00 (m, 4H), 1.42 (s, 9H). LCMS Method C: rt 6.23 min, m/z 579.2 [M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[S:65][CH:66]=[C:67]([C:69]([O:71][CH2:72][CH3:73])=[O:70])[N:68]=1>>[CH2:72]([O:71][C:69]([C:67]1[N:68]=[C:64]([NH:63][C:30]([C@@H:20]2[NH:19][C@@H:18]([CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C@:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[C@H:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])[S:65][CH:66]=1)=[O:70])[CH3:73]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: CCOC(=O)c1csc(N)n1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1csc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2cccc(Cl)c2F)n1

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.3 g, 0.52 mmol), was reacted with diisopropylethylamine (0.34 g, 2.6 mmol), diphenylphosphinic chloride (0.25 g, 1 mmol), then reacted with ethyl 2-aminothiazole-4-carboxylate (Oakwood) (0.13 g, 0.78 mmol) to give rac-2-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-thiazole-4-carboxylic acid ethyl ester as a off white solid (Yield 0.1 g, 31%).
Reaction SMILES: Cl.C(N1CCCC2(C3C(=CC=CC=3)CN2)C1=O)CC.Cl.[CH2:21]([N:24]1[CH2:29][CH2:28][CH2:27][C:26]2([C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31](=[O:38])[NH:30]2)[CH2:25]1)[CH2:22][CH3:23]>>[CH2:21]([N:24]1[CH2:29][CH:28]=[CH:27][C:26]2([C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31](=[O:38])[NH:30]2)[CH2:25]1)[CH2:22][CH3:23]
Reactant: CCCN1CCCC2(C1)NC(=O)c1ccccc12
Agent: CCCN1CCCC2(NCc3ccccc32)C1=O
Agent: Cl
Product: CCCN1CC=CC2(C1)NC(=O)c1ccccc12
Yield: 14.6 %

Procedure:
1′-Propylspiro[isoindoline-3,3′-piperidin]-one hydrochloride. The compound from STEP B (6.60 g) was cyclised according to the general Heck procedure described in EXAMPLE 1 to give an oil which was chromatographed on silica gel with ethyl acetate/n-heptane as the eluent to give 830 mg 1′-propylspiro-[isoindoline-3,3′-1,2,3,6-tetrahydropyridin]-1-one as an oil. This compound was hydrogenated as described in EXAMPLE 1 yielding the free base of the title compound as white crystals. The title compound was also prepared from cyclization of the STEP C compound followed by hydrogenation-debenzylation plus propylation. 13C NMR (CDCl3): δ 169.44, 150.10, 131.77, 131.58, 128.51, 124.14, 121.56, 62.74, 60.87, 60.26, 53.24, 34.88, 23.34, 19.00. 11.82; MS(TSP+) m/z: 245 (M+H+, 100); MS(CI, NH3): 245 (M+H+, 100), 180 (3). MP: 110-112°.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6](=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:7]([OH:9])=O)(=[O:3])[CH3:2].S(Cl)(Cl)=O.[F:18][C:19]([F:28])([F:27])[C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1.C(N(CC)CC)C>ClCCl>[F:18][C:19]([F:27])([F:28])[C:20]1[CH:21]=[CH:22][C:23]([NH:24][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[O:4][C:1](=[O:3])[CH3:2])=[CH:25][CH:26]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CC(=O)Oc1ccccc1C(=O)O
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(=O)Oc1ccccc1C(=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
Acetylsalicyclic acid (10 g, 55 mmol) was added to thionyl chloride (8.1 ml, 110 mmol) and the suspension refluxed to complete dissolution of the acid. The yellow solution was then cooled at room temperature and thionyl chloride evaporated under reduced pressure. Crude acyl chloride was dissolved in chloroform and the solvent removed under reduced pressure to give a reddish oil. This procedure was repeated three times. The oil was dissolved in dichloromethane (100 ml) and the resulting solution slowly added at 0° C. to a solution of 4-trifluoromethylaniline (6.3 ml, 50 mmol) and triethylamine (23 ml, 166 mmol) in dichloromethane (100 ml). The mixture was stirred overnight at room temperature then the organic solution was washed successively with 1N HCl (2×200 ml), 1N NaOH (200 ml) and water (200 ml). The organic phase was dried with anhydrous sodium sulphate and evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel (eluent n-hexane-ethyl acetate 8:2) giving 13 g (80%) of pure N-(4-trifluoromethylphenyl)-2-acetoxy-benzamide as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[C:11]([OH:20])[C:10]([C:21]([OH:23])=[O:22])=[N:9]1.C(N(CC)C(C)C)(C)C.[C:33](OC(=O)C)(=[O:35])[CH3:34]>C(Cl)Cl>[C:33]([O:20][C:11]1[C:10]([C:21]([OH:23])=[O:22])=[N:9][N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)(=[O:35])[CH3:34]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1nn(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)c1O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Oc1c(C(=O)O)nn(-c2ccccc2Cl)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-(2-Chlorophenyl)-5-(4-chlorophenyl)-4-hydroxy-1H-pyrazole-3-carboxylic acid I-6c (572.0 g, 1.64 mol) was combined with 8 liters of methylene chloride to give an off-white suspension. N,N-Diisopropylethylamine (427.9 g, 3.29 mol) was added over 15 minutes while keeping the temperature between 20–25° C. A clear yellow solution resulted. Acetic anhydride (334.5 g, 3.24 mol) was added over 5 minutes keeping the temperature between 20–25° C. The reaction was stirred at room temperature for 16 hours. The crude reaction solution was washed twice with 4 liters portions of 0.5 M citric acid and once with 4 liters of brine. The crude solution was concentrated in vacuo to a total volume of 1 liter. This milky suspension was then added to 4 liters of hexanes causing the desired product to precipitate instantly. The solids were granulated for 30 minutes and then collected by filtration. The filtercake was rinsed with 3 liters of hexanes and then air-dried for 16 hours. The isolated product was then further dried at 60° C. and 8 mm for 2 hours. 4-Acetoxy-1-(2-chlorophenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylic acid I-6d (601.6 g, 94%) was isolated as a powdery, off-white solid.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[NH:12][CH:13]=[C:14]([C:15]([OH:17])=O)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[NH:3]1.[OH:18][CH2:19][CH2:20][CH2:21][NH2:22]>>[OH:18][CH2:19][CH2:20][CH2:21][NH:22][C:15]([C:14]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[NH:3][C:2](=[O:1])[C:11]=2[NH:12][CH:13]=1)=[O:17]
Reactant: O=C(O)c1c[nH]c2c(=O)[nH]c3ccccc3c12
Reactant: NCCCO
Product: O=C(NCCCO)c1c[nH]c2c(=O)[nH]c3ccccc3c12
Yield: 8.5 %

Procedure:
This compound is prepared according to synthesis 79 from 75 mg (0.33 mmol) of 4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid (synthesis 75) and 28 μL (0.36 mmol) of 3-hydroxy-propylamine. The aqueous phase is evaporated, the residue is taken up in methanol and then filtered. The filtrate is evaporated and the residue is purified by preparative LCMS to give 8 mg (9%) of N-(3-hydroxy-propyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxamide in the form of a white solid.
Reaction SMILES: [N:1]1([CH2:6][C:7]2N3C=C(C)C=CC3=[N:9][C:8]=2C2C=CC(C)=CC=2)C=CN=C1.Cl.[Cl:25][C:26]1[CH:27]=[C:28]([Cl:44])[C:29]2[N:30]([C:32]([CH2:42]Cl)=[C:33]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)[N:34]=2)[CH:31]=1.N1C=CC=N1>>[N:9]1([CH2:42][C:32]2[N:30]3[CH:31]=[C:26]([Cl:25])[CH:27]=[C:28]([Cl:44])[C:29]3=[N:34][C:33]=2[C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=2)[CH:8]=[CH:7][CH:6]=[N:1]1
Reactant: Cc1ccc(-c2nc3c(Cl)cc(Cl)cn3c2CCl)cc1
Reactant: Cc1ccc(-c2nc3ccc(C)cn3c2Cn2ccnc2)cc1
Agent: Cl
Agent: c1cn[nH]c1
Product: Cc1ccc(-c2nc3c(Cl)cc(Cl)cn3c2Cn2cccn2)cc1

Procedure:
The title compound was prepared according to Method A and the experimentals described for compound 1 from 6,8-dichloro-3-(chloromethyl)-2-p-tolylimidazo[1,2-a]pyridine hydrochloride and 1H-pyrazole. m/e+ 357 for C18H15Cl2N4 [M+H]+; 1H-NMR (300 MHz, CDCl3) δ 8.28 (d, J=2.1 Hz, 1H), 7.67 (d, J=7.8 Hz, 2H), 7.60 (d, J=1.5 Hz, 1H), 7.35 (d, J=7.8 Hz, 2H), 7.30 (m, 2H), 6.31 (t, J=2.7 Hz, 1H), 5.71 (s, 2H), 2.44 (s, 3H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[N:15][C:14]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][C@@H:18]3[CH3:23])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[O:24]1[CH2:27][C:26](=O)[CH2:25]1.[BH3-]C#N.[Na+]>CO.[Cl-].[Zn+2].[Cl-]>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[N:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH:26]4[CH2:27][O:24][CH2:25]4)[CH2:19][C@@H:18]3[CH3:23])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: O=C1COC1
Reactant: C[C@H]1CNCCN1c1cnc(Nc2cc(Br)cn(C)c2=O)cn1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: C[C@H]1CN(C2COC2)CCN1c1cnc(Nc2cc(Br)cn(C)c2=O)cn1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 69.3 %

Procedure:
A mixture of 230e (2.0 g, 5.3 mmol), oxetan-3-one (763 mg, 10.6 mmol), NaBH3CN (835 mg, 13.3 mmol), and zinc chloride (1.8 g, 13.3 mmol) in methanol (60 mL) was stirred at 50° C. for 30 min. The mixture was concentrated under reduced pressure. To the residue was added water and the resulting mixture was extracted with dichloromethane three times. The combined organic layer was then concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (50:1 to 20:1) to afford 230f as a yellow oil (1.6 g, 70%). MS: [M+H]+ 437.2.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][C:9]([O:15][C:16]1[C:21]([Cl:22])=[CH:20][C:19]([N+:23]([O-])=O)=[CH:18][C:17]=1[Cl:26])=[CH:8]2)=[O:4].[NH4+].[Cl-]>CCO.C1COCC1.O.[Fe]>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][C:9]([O:15][C:16]1[C:17]([Cl:26])=[CH:18][C:19]([NH2:23])=[CH:20][C:21]=1[Cl:22])=[CH:8]2)=[O:4]
Reactant: COC(=O)c1ccc2ncc(Oc3c(Cl)cc([N+](=O)[O-])cc3Cl)cc2c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: COC(=O)c1ccc2ncc(Oc3c(Cl)cc(N)cc3Cl)cc2c1
Yield: 110.1 %

Procedure:
To a solution of 3-(2,6-dichloro-4-nitro-phenoxy)-quinoline-6-carboxylic acid methyl ester (95) (0.93 mmol) and NH4Cl (283 mg, 5.3 mmol) in EtOH/THF/water (8 mL/16 mL/1 mL) was added iron powder (296 mg, 5.3 mmol). The reaction mixture was refluxed for 4 h. Insoluble materials were removed by Celite pad, which was washed by THF, acetone and then EtOH. The filtrate was concentrated, and sat NaHCO3 was added and extracted twice with AcOEt. Organic layer was washed by brine, dried over anhydrous MgSO4, and concentrated to afford compound 96 (372 mg, over weight). 1H NMR (300 MHz, DMSO-d6) δ 3.89 (3H, s), 5.75 (2H, s), 6.76 (2H, s), 7.73 (1H, d, J=2.9 Hz), 8.09 (2H, s), 8.67 (1H, s), 8.94 (1H, d, J=2.9 Hz).