Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[In+3].[Cl-].[Cl-].FC(F)(F)C(O)=O.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19](O)[CH:20]2[CH2:22][CH:21]2[C:23]#[N:24])=[C:15]([F:26])[CH:14]=1.[F:27][C:28]1[CH:29]=[C:30]2[C:34](=[C:35]([CH2:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH:36]=1)[NH:33][CH:32]=[CH:31]2>ClCCl>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([C:31]2[C:30]3[C:34](=[C:35]([CH2:37][S:38]([CH3:41])(=[O:39])=[O:40])[CH:36]=[C:28]([F:27])[CH:29]=3)[NH:33][CH:32]=2)[CH:20]2[CH2:22][CH:21]2[C:23]#[N:24])=[C:15]([F:26])[CH:14]=1
Reactant: CS(=O)(=O)Cc1cc(F)cc2cc[nH]c12
Reactant: N#CC1CC1C(O)c1ccc(Cl)cc1F
Agent: [Cl-]
Agent: [In+3]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)Cc1cc(F)cc2c(C(c3ccc(Cl)cc3F)C3CC3C#N)c[nH]c12

Procedure:
471 mg (2.13 mmol) of indium(III) chloride and 0.25 ml (3.19 mmol) of trifluoroacetic acid were added to 400 mg (1.77 mmol) of the compound from Example 165A and 483 mg (2.13 mmol) of the compound from Example 87A under argon in 18 ml of dichloromethane, and the mixture was heated under reflux for 3 days. It was concentrated and the residue was taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) and another RP18 separation with acetonitrile/water 55:45 to result in 131 mg (17% of theory) of diastereomer 1 and 127 mg (17% of theory) of diastereomer 2 of the title compound.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([O:9]C)=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=1.[Cl:17]N1C(=O)CCC1=O.[OH-].[Na+]>O1CCCC1>[Cl:17][C:12]1[CH:13]=[N:14][N:15]([CH3:16])[C:11]=1[C:3]1[CH:4]=[C:5]([C:7]([OH:9])=[O:8])[O:6][C:2]=1[CH3:1]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1cc(-c2ccnn2C)c(C)o1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1oc(C(=O)O)cc1-c1c(Cl)cnn1C
Reaction time: 12 h
Yield: 83.8 %

Procedure:
A solution of methyl 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylate (300 mg, 1.36 mmol) and N-chlorosuccinimide (182 mg, 1.36 mmol) in tetrahydrofuran (6.7 ml) was stirred in a sealed tube for 1 h at 70° C. 6N sodium hydroxide (3.4 ml, 20.4 mmol) was added in one portion and the solution stirred an additional 12 h. The reaction mixture was then partitioned between H2O-DCM and the pH of the aqueous phase was adjusted to ˜4 and washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and used directly without further purification yielding 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxylic acid (275 mg, 1.14 mmol, 84% yield) as a orange oil: LCMS (ES) m/e 241, 243 (M, M+2)+.
Reaction SMILES: [CH2:1]([C:5]1([CH2:31][CH2:32][CH2:33][CH3:34])[C:14]2[C:9](=[CH:10][C:11]([F:15])=[CH:12][CH:13]=2)[C:8]([OH:16])=[C:7]([C:17]2[NH:22][C:21]3[CH:23]=[CH:24][C:25](I)=[CH:26][C:20]=3[S:19](=[O:29])(=[O:28])[N:18]=2)[C:6]1=[O:30])[CH2:2][CH2:3][CH3:4].[C:35]([NH2:39])(=[O:38])[CH:36]=[CH2:37].C(N(CC)CC)C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([C:5]1([CH2:31][CH2:32][CH2:33][CH3:34])[C:14]2[C:9](=[CH:10][C:11]([F:15])=[CH:12][CH:13]=2)[C:8]([OH:16])=[C:7]([C:17]2[NH:22][C:21]3[CH:23]=[CH:24][C:25](/[CH:37]=[CH:36]/[C:35]([NH2:39])=[O:38])=[CH:26][C:20]=3[S:19](=[O:29])(=[O:28])[N:18]=2)[C:6]1=[O:30])[CH2:2][CH2:3][CH3:4]
Reactant: C=CC(N)=O
Reactant: CCCCC1(CCCC)C(=O)C(C2=NS(=O)(=O)c3cc(I)ccc3N2)=C(O)c2cc(F)ccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCC1(CCCC)C(=O)C(C2=NS(=O)(=O)c3cc(/C=C/C(N)=O)ccc3N2)=C(O)c2cc(F)ccc21
Temperature: 100 °C
Yield: 55.6 %

Procedure:
A solution of the compound of Example 20B (65 mg, 0.11 mmol), acrylamide (9 mg, 0.12 mmol), triethylamine (45 μL, 0.33 mmol), and palladium (II) acetate (1.2 mg, 0.005 mmol) in N,N-dimethylformamide (1.5 mL) in a resealable pressure tube was degassed by evacuation and purging with nitrogen. The pressure tube was sealed and warmed at 100° C. for 1 h. The solution was cooled and diluted with ethyl acetate and water. The mixture was acidified by addition of citric acid solution (1 M, 2 mL). The organic layer was extracted with water (2×) and with saturated NaCl solution. Drying (Na2SO4) and concentration in vacuo afforded a solid, which was purified by flash chromatography eluting with methanol in dichloromethane. These procedures afforded the title compound (33 mg, 56%) as a light amber solid.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](O)=[O:8])([CH3:3])[CH3:2].O=S(Cl)[Cl:15]>>[CH:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([Cl:15])=[O:8])([CH3:3])[CH3:2]
Reactant: CC(C)c1cccc(C(=O)O)c1
Reactant: O=S(Cl)Cl
Product: CC(C)c1cccc(C(=O)Cl)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
A mixture of 3-isopropyl-benzoic acid (5.00 g, 30.4 mmol) in SOCl2 (50 ml) was stirred at 100° C. for 2 h. The reaction mixture was concentrated to give 3-isopropyl-benzoyl chloride (5.00 g, 91%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([CH2:14][NH2:15])[CH2:12][C@H:11]2[C@@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20](O)=[O:21]>>[C:1]([O:5][C:6]([N:8]1[C@H:13]([CH2:14][NH:15][C:20](=[O:21])[C:19]2[CH:23]=[CH:24][CH:25]=[C:17]([Br:16])[CH:18]=2)[CH2:12][C@H:11]2[C@@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1[C@H](CN)C[C@@H]2C[C@@H]21
Reactant: O=C(O)c1cccc(Br)c1
Product: CC(C)(C)OC(=O)N1[C@H](CNC(=O)c2cccc(Br)c2)C[C@@H]2C[C@@H]21

Procedure:
prepared by reaction of (1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester with 3-bromo-benzoic acid. LC-MS (acidic): tR=1.08 min; [M+H]+=394.9.
Reaction SMILES: Cl[N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([SH:17])=[CH:13][CH:12]=1.C(N(CC)CC)C>C1C=CC=CC=1>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([S:17][N:2]2[C:6](=[O:7])[CH2:5][CH2:4][C:3]2=[O:8])=[CH:13][CH:12]=1
Reactant: COc1ccc(S)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COc1ccc(SN2C(=O)CCC2=O)cc1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
A mixture of 17.1 g. (128 mmole) of N-chlorosuccinimide and 700 ml. of benzene is treated with 15 g. (107 mmole) of p-methoxythiophenol dissolved in 125 ml. of benzene. After 75 minutes, the resulting orange solution is cooled to 15° and 13.0 g. (128 mmole) of triethylamine in 125 ml. of benzene is added over a period of 25 minutes. The cooling bath is removed and the reaction is stirred at room temperature for an additional 45 minutes. The reaction mixture is then filtered and the organic solution is rinsed with three 200 ml. portions of water, 200 ml. of brine and dried (MgSO4). Removal of the solvents in vacuo gives 27.0 g. of crude product. Recrystallization from chloroform-hexane gives 21.2 g. of
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][C:24]([NH2:26])=[O:25])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.[CH3:28][O:29][C:30]1[N:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>>[CH3:28][O:29][C:30]1[N:35]=[CH:34][C:33]([C:2]2[CH:3]=[CH:4][C:5]([C@@H:8]([N:10]3[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][C:24]([NH2:26])=[O:25])([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[O:12][C:11]3=[O:27])[CH3:9])=[CH:6][CH:7]=2)=[CH:32][CH:31]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCC(N)=O)(c2ccccc2)OC1=O
Reactant: COc1ccc(B(O)O)cn1
Product: COc1ccc(-c2ccc([C@H](C)N3CC[C@](CCC(N)=O)(c4ccccc4)OC3=O)cc2)cn1

Procedure:
The title compound was prepared from 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanamide and 6-methoxypyridine-3-boronic acid following a procedure analogous to that described in Example 64. LC-MS Method 3 tR=1.106 min, m/z=460.2; 1H NMR (CD3OD) 1.54 (m, 3H), 1.95 (m, 1H), 2.16-2.29 (m, 4H), 2.40 (m, 2H), 2.44 (m, 1H), 3.10 (m, 1H), 3.99 (s, 3H), 5.56 (m, 1H), 6.94 (m, 1H), 7.03 (m, 2H), 7.28-7.39 (m, 8H), 7.93 (m, 1H), 8.28 (m, 1H).
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[N:8][C:9]([O:12][CH2:13][C:14]2[C:15]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[CH:10][CH:11]=1)=[O:5])C.[F:26][C:27]([F:31])([F:30])[CH2:28][NH2:29]>>[F:26][C:27]([F:31])([F:30])[CH2:28][NH:29][C:4]([C:6]1[N:7]=[N:8][C:9]([O:12][CH2:13][C:14]2[C:15]([C:20]3[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=3)=[N:16][O:17][C:18]=2[CH3:19])=[CH:10][CH:11]=1)=[O:5]
Reactant: NCC(F)(F)F
Reactant: CCOC(=O)c1ccc(OCc2c(-c3ccncc3)noc2C)nn1
Product: Cc1onc(-c2ccncc2)c1COc1ccc(C(=O)NCC(F)(F)F)nn1
Yield: 66 %

Procedure:
As described for example 67e, 6-(5-methyl-3-pyridin-4-yl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid ethyl ester (100 mg, 0.29 mmol) was converted, using 2,2,2-trifluoroethylamine instead of aminomethylcyclopropane, to the title compound (76 mg, 66%) which was obtained as a white solid. MS: m/e=394.1 [M+H]+.
Reaction SMILES: C(C1C=C(NC(=O)CCCC2C=CC([B:25]([OH:27])[OH:26])=CC=2)C=CC=1S(CC)(=O)=O)#N.Br[C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][CH2:38][C:39]([NH:41][C:42]2[CH:43]=[CH:44][C:45]([S:58]([CH:61]([CH3:63])[CH3:62])(=[O:60])=[O:59])=[C:46]([CH:57]=2)[CH2:47][N:48]([CH3:56])[C:49](=[O:55])[O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:40])=[C:32]([CH2:64][CH3:65])[CH:31]=1.CC1(C)COB(B2OCC(C)(C)CO2)OC1>>[C:51]([O:50][C:49]([N:48]([CH2:47][C:46]1[CH:57]=[C:42]([NH:41][C:39](=[O:40])[CH2:38][CH2:37][CH2:36][C:33]2[CH:34]=[CH:35][C:30]([B:25]([OH:27])[OH:26])=[CH:31][C:32]=2[CH2:64][CH3:65])[CH:43]=[CH:44][C:45]=1[S:58]([CH:61]([CH3:63])[CH3:62])(=[O:60])=[O:59])[CH3:56])=[O:55])([CH3:54])([CH3:53])[CH3:52]
Reactant: CCS(=O)(=O)c1ccc(NC(=O)CCCc2ccc(B(O)O)cc2)cc1C#N
Reactant: CCc1cc(Br)ccc1CCCC(=O)Nc1ccc(S(=O)(=O)C(C)C)c(CN(C)C(=O)OC(C)(C)C)c1
Agent: CC1(C)COB(B2OCC(C)(C)CO2)OC1
Product: CCc1cc(B(O)O)ccc1CCCC(=O)Nc1ccc(S(=O)(=O)C(C)C)c(CN(C)C(=O)OC(C)(C)C)c1
Yield: 67 %

Procedure:
Using a procedure analogous to that described for the preparation of 6D, 21C (0.513 g, 0.86 mmol) was coupled to 5,5,5′,5′-tetramethyl-[2,2′]bi[[1,3,2]dioxaborinanyl] (0.215 g, 0.952 mmol) and hydrolyzed to give boronic acid 21D (0.278 g, 67%). MS (ESI) m/z 561.48 (M+H)+.
Reaction SMILES: [Cl-].[C:2]([O:6][C:7](=[O:10])[CH2:8][Zn+])([CH3:5])([CH3:4])[CH3:3].Br[C:12]1[CH:13]=[CH:14][C:15]([F:18])=[N:16][CH:17]=1.O>C1COCC1.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[F:18][C:15]1[N:16]=[CH:17][C:12]([CH2:8][C:7]([O:6][C:2]([CH3:5])([CH3:4])[CH3:3])=[O:10])=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)C[Zn+]
Reactant: Fc1ccc(Br)cn1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Cc1ccc(F)nc1
Temperature: 65 °C
Reaction time: 1.5 h
Yield: 40.5 %

Procedure:
(2-tert-Butoxy-2-oxoethyl)zinc(II) chloride (0.5M in ethyl ether) (Rieke Metals, Inc., Lincoln, Nebr.; 73.9 mL, 36.9 mmol) was added to a mixture of 5-bromo-2-fluoropyridine (Acros, Morris Plains, N.J.; 2.92 mL, 28.4 mmol) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (Aldrich, St. Louis, Mo.; 0.201 g, 0.284 mmol) in THF (150 mL) and the resulting yellow solution was stirred at 65° C. for 1.5 h in a flask fitted with an air-cooled reflux condenser. Water (200 μL) was added to the reaction, and the resulting mixture was concentrated onto silica gel and chromatographically purified (silica gel, 0 to 30% EtOAc/hexanes) to provide tert-butyl 2-(6-fluoropyridin-3-yl)acetate (2.43 g, 11.50 mmol, 40.5% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 7.74 (td, J=8.0, 2.5 Hz, 1H), 6.90 (dd, J=8.4, 2.9 Hz, 1H), 3.52 (s, 2H), 1.44 (s, 9H). m/z (ESI, +ve) 212.1 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:22]=[C:21]([CH:23]4[CH2:25][CH2:24]4)[N:20]([CH3:26])[C:19]=3[CH:27]=2)[C:11](=[O:28])[CH:10]=1)C1C=CC=CC=1.C1(OC)C=CC=CC=1>C(O)(C(F)(F)F)=O>[CH:23]1([C:21]2[N:20]([CH3:26])[C:19]3[CH:27]=[C:15]([N:12]4[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][C:11]4=[O:28])[CH:16]=[CH:17][C:18]=3[N:22]=2)[CH2:24][CH2:25]1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4ccccc4)cc3=O)cc21
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cc21
Temperature: 130 °C
Yield: 122.3 %

Procedure:
To a stirred solution of 4-(benzyloxy)-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (840 mg) in TFA (21 ml) was added anisole (7 ml), and the reaction mixture was heated at 130° C. for 4 h. The mixture was cooled and concentrated in vacuo. The residue was triturated with Et2O to give the title compound (778 mg) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[N:10][C:11]([O:16][CH3:17])=[C:12]([O:14][CH3:15])[CH:13]=2)[N:5]=[C:4]2[CH2:18][N:19]([C:22]3[CH:23]=[N:24][N:25]([CH2:27][C:28]([F:31])([F:30])[F:29])[CH:26]=3)[C:20](=[O:21])[C:3]=12.C(=O)([O-])[O-].[Na+].[Na+].[CH2:38](OB(OCC)OCC)[CH3:39].C1COCC1>C1(C)C=CC=CC=1>[CH3:15][O:14][C:12]1[CH:13]=[C:8]([C:6]2[N:5]=[C:4]3[CH2:18][N:19]([C:22]4[CH:23]=[N:24][N:25]([CH2:27][C:28]([F:31])([F:30])[F:29])[CH:26]=4)[C:20](=[O:21])[C:3]3=[C:2]([CH2:38][CH3:39])[CH:7]=2)[CH:9]=[N:10][C:11]=1[O:16][CH3:17]
Reactant: CCOB(OCC)OCC
Reactant: COc1cc(-c2cc(Cl)c3c(n2)CN(c2cnn(CC(F)(F)F)c2)C3=O)cnc1OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCc1cc(-c2cnc(OC)c(OC)c2)nc2c1C(=O)N(c1cnn(CC(F)(F)F)c1)C2
Temperature: 80 °C

Procedure:
As shown in step 10-iii Scheme 10, 4-Chloro-2-(5,6-dimethoxypyridin-3-yl)-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (Compound 82, 75 mg, 0.165 mmol and a degassed solution of 2M aqueous sodium carbonate (826 uL, 1.65 mmol] were suspended in 10 mL of toluene. The reaction mixture was purged with nitrogen for 5 minutes and tetrakistriphenylphosphine palladium(0) (38 mg, 0.033 mmol] was added, followed by the addition of 2 M triethylborate solution in THF (992 μL, 1.0 mmol). The reaction vessel was sealed and heated for 14 hours at 80° C. The reaction mixture was cooled and the volatiles removed under reduced pressure. The residue was dissolved in EtOAc/DCM 1:1 and filtered. The filtrate was concentrated under reduced pressure. The product was purified by preparative thin layer chromatography produced 2-(5,6-dimethoxypyridin-3-yl)-4-ethyl-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (Compound 182, 1.1 mg): ESMS (M+1) 448.
Reaction SMILES: [CH3:1][CH:2]1[S:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[C:12]2=[N:19]C1C=CC=CC=1.Cl.[C:27]([C:31]1[CH:36]=[CH:35][C:34]([NH:37]N)=[CH:33][CH:32]=1)([CH3:30])([CH3:29])[CH3:28]>>[CH3:30][C:27]([C:31]1[CH:32]=[CH:33][C:34]([NH:37][N:19]=[C:12]2[C:11]3[C:15](=[CH:16][CH:17]=[C:9]([C:3]4[CH:2]([CH3:1])[S:7][C:6](=[O:8])[NH:5][N:4]=4)[CH:10]=3)[NH:14][C:13]2=[O:18])=[CH:35][CH:36]=1)([CH3:28])[CH3:29]
Reactant: CC(C)(C)c1ccc(NN)cc1
Reactant: CC1SC(=O)NN=C1c1ccc2c(c1)C(=Nc1ccccc1)C(=O)N2
Agent: Cl
Product: CC1SC(=O)NN=C1c1ccc2c(c1)C(=NNc1ccc(C(C)(C)C)cc1)C(=O)N2
Yield: 83 %

Procedure:
Starting from 1,3-dihydro-5-(3,6-dihydro-6-methyl-2-oxo -2H-1,3,4-thiadiazin-5-yl)-3-phenylimino-2H-indol-2-one, and 4t-butyl phenylhydrazine hydrochloride and following the method described in Example 21, the desired compound was obtained.
Reaction SMILES: C([Li])CCC.[CH2:6]([O:12][CH:13]1[NH:17][C:16](=[O:18])[CH2:15][CH2:14]1)[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CCCCCC.O1CCCC1>[C:19]([N:17]1[CH:13]([O:12][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:14][CH2:15][C:16]1=[O:18])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCCCCCOC1CCC(=O)N1
Reactant: O=C(Cl)c1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCCOC1CCC(=O)N1C(=O)c1ccccc1
Reaction time: 0.33 h

Procedure:
16 cm3 of a 1.6M solution of butyllithium in hexane is added at -70° C. to 4.5 g of 5-n-hexyloxy pyrrolidin-2-one in solution in 130 cm3 of anhydrous tetrahydrofuran. Agitation is carried out for 20 minutes at -70° C. and under the same conditions a solution of 3.4 g of benzoyl chloride in 20 cm3 of tetrahydrofuran is added. After allowing to return to ambient temperature and concentration under reduced pressure, the residue is chromatographed on silica (eluent: toluene-ethyl acetate 8-2). 3.3 g of the product sought is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].S([O-])(OC)(=O)=O.ClCCCl.[C-:22]#[N:23].[Na+]>O>[C:22]([C:4]1[C:3]([O:2][CH3:1])=[C:8]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:6][N:5]=1)#[N:23]
Reactant: [C-]#N
Reactant: COc1cnccc1[N+](=O)[O-]
Agent: COS(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: COc1c([N+](=O)[O-])ccnc1C#N
Temperature: 70 °C
Reaction time: 4 h
Yield: 53 %

Procedure:
A mixture of 12.5 g (12.5 moles) of the N-oxide of 3-methoxy-4-nitropyridine, 7.72 mL (1.1 eq.) of methyl sulphate and 70 mL of 1,2-dichloroethane is heated at 70° C. for 2.5 hours. It is allowed to cool and 70 mL of water are added. It is cooled in a salt and ice bath and, in portions, 7.55 g (2.1 moles) of sodium cyanide are added, controlling the temperature so as not to exceed 10° C. After 4 hours stirring, the reaction mixture is extracted with ethyl ether, the organic phase is washed with water, concentrated and the residue chromatographed (ethyl acetate/dichloromethane). There is obtained 7.06 g of a yellow oil (yield 53%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[I:9](O)(=O)(=O)=O.S(=O)(=O)(O)O.II>C(O)(=O)C.O>[I:9][C:7]1[C:2]([CH3:1])=[CH:3][C:4]([NH2:8])=[N:5][CH:6]=1
Reactant: Cc1ccnc(N)c1
Reactant: [O-][I+3]([O-])([O-])O
Agent: II
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(N)ncc1I
Temperature: 80 °C
Yield: 389.6 %

Procedure:
To a stirred solution of 4-methyl-pyridin-2-ylamine (30 g, 278 mmol, 1 eq) in acetic acid (167 mL) was added periodic acid (12.7 g, 55.6 mmol, 0.2 eq) followed by addition of sulphuric acid (4.8 mL, 90.8 mmol, 0.34 eq), water (33.3 mL) and iodine (28.7 g, 111.1 mmol, 0.4 eq) at room temperature. Resulting reaction mixture was heated at 80° C. for 6 hours. After complete consumption of starting material, reaction mixture was cooled and poured into sodium thiosulfate solution (200 mL), reddish oil was settled down at the bottom. Reaction mixture was decanted from reddish oil and filtrate was basified with 50% sodium hydroxide solution (100 mL), yellow colored solid was formed. Resulting solid was extracted with diethyl ether (2×200 mL) and dried over sodium sulfate. Organic layer was concentrated under reduced pressure to afford brown semi solid (60 g, crude). Crude was purified by column chromatography using silica gel (100-200 mesh). Desired compound was eluted at 15% EtOAc in hexane to get title compound as faint brown solid (50.7 g, 78%). 1H NMR (400 MHz, CDCl3) δ: 2.27 (s, 3H), 4.46 (bs, 2H), 6.44 (s, 1H), 8.24 (s, 1H).
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.CC[N:17](CC)CC.ClC(OCC(C)C)=O.[NH4+].[OH-]>C1COCC1>[O:1]1[C:5]([C:6]2[CH:14]=[CH:13][C:9]([C:10]([NH2:17])=[O:11])=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1
Reactant: CCN(CC)CC
Reactant: O=C(O)c1ccc(-c2cnco2)cc1
Agent: CC(C)COC(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)c1ccc(-c2cnco2)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 48.7 %

Procedure:
A mixture of 4-(5-oxazolyl)benzoic acid (1.0 g, 5.46 mmol) and Et3N (552 mg, 5.46 mmol) in 25 mL of THF was cooled to 0° C. and ClCOOi-Bu (745 mg, 5.46 mmol) was added dropwise. After the addition was over, the reaction mixture was stirred for additional 5 min and then aq NH4OH (0.63 mL of 28% solution, 10.46 mmol) was added. After overnight stirring, the solvent was evaporated, the residue was taken up in water and basified to pH 9. The precipitated solid was filtered, washed with water and dried over P2O5 in a vacuum desiccator to provide 500 mg (48%) of the 4-(5-oxazolyl)-benzamide: 1H NMR (DMSO-d6) δ 8.50 (s, 1H), 8.20–7.80 (m, 5H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]2[C:11]([O:13][C:14](=[O:15])[C:2]=12)=O.[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[F:23]>>[F:16][C:17]1[C:18]([F:23])=[CH:19][C:20]2[C:14](=[O:15])[C:2]3[C:3](=[CH:4][C:5]4[C:10]([CH:1]=3)=[CH:9][CH:8]=[CH:7][CH:6]=4)[C:11](=[O:13])[C:21]=2[CH:22]=1
Reactant: Fc1ccccc1F
Reactant: O=C1OC(=O)c2cc3ccccc3cc21
Product: O=C1c2cc(F)c(F)cc2C(=O)c2cc3ccccc3cc21

Procedure:
Using the same procedure and naphthalene-2,3-dicarboxylic anhydride and 1,2-difluorobenzene gives 2,3-difluoronaphthacene-5,12-dione.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:19]=[CH:18][C:13]3[O:14][CH2:15][CH2:16][O:17][C:12]=3[CH:11]=2)[C:5]([C:20]#[N:21])=[C:4](SC2C=CC=CC=2)[N:3]=1.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:35][NH2:36]>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:19]=[CH:18][C:13]3[O:14][CH2:15][CH2:16][O:17][C:12]=3[CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([NH:36][CH2:35][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=2)[N:3]=1
Reactant: NCc1ccccn1
Reactant: N#Cc1c(N)nc(Sc2ccccc2)c(C#N)c1-c1ccc2c(c1)OCCO2
Solvent: CN(C)C=O
Product: N#Cc1c(N)nc(NCc2ccccn2)c(C#N)c1-c1ccc2c(c1)OCCO2
Temperature: 100 °C
Reaction time: 3 h

Procedure:
100 mg (0.26 mmol) of 2-amino-4-(2,3-dihydro-1,4-benzodioxin-6-yl)-6-(phenyl-sulfanyl)-3,5-pyridinedicarbonitrile and 56 mg (0.52 mmol) of 2-picolylamine in 8 ml of DMF are heated at 100° C. After 3 hours, another 224 mg (2.08 mmol) of 2-picolylamine are added, and the mixture is heated at 100° C. for another 4 hours. After dilution with water, the mixture is extracted three times with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The evaporation residue is purified by preparative HPLC on reversed-phase silica gel.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C@@H:5]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][OH:7].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:26][S:27]([O:7][CH2:6][C@H:5]([NH:8][C:9]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:18])[CH2:4][CH2:3][CH2:2][O:1][S:27]([CH3:26])(=[O:29])=[O:28])(=[O:29])=[O:28]
Reactant: O=C(N[C@@H](CO)CCCO)OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCC[C@H](COS(C)(=O)=O)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of benzyl (1R)-4-hydroxy-1-(hydroxymethyl)butylcarbamate (1.5 g) in DCM (60 ml) was treated with triethylamine (3.3 ml) and stirred at room temperature for 10 min. Methanesulphonyl chloride (1.34 ml) was then added dropwise and the resultant mixture stirred at 0° C. for 75 min. Sodium bicarbonate solution was added and the reaction mixture allowed to reach room temperature over 1 h. The organic layer was separated, washed with brine, dried (over magnesium sulphate) and concentrated under reduced pressure to give a yellow oil. The oil was purified using Biotage™ chromatography (eluting with hexane:ethyl acetate 1:2, 1:3) to give the title compound (1.924 g) as a yellow oil