Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[C:27](=[O:28])[CH2:26][NH:25][CH2:24]4)=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38].O>O1CCCC1>[CH3:1][C:2]1[C:3]([N:9]2[CH2:10][CH2:11][N:12]([C:15]([C:17]3[CH:18]=[CH:19][C:20]([N:23]4[C:27](=[O:28])[CH2:26][N:25]([S:37]([CH3:36])(=[O:39])=[O:38])[CH2:24]4)=[CH:21][CH:22]=3)=[O:16])[CH2:13][CH2:14]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(N4CNCC4=O)cc3)CC2)c(C)c1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CN(S(C)(=O)=O)CC4=O)cc3)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}imidazolidin-4-one (48 mg) described in Example 635 and triethylamine (0.12 mL) was dissolved in tetrahydrofuran (1 mL), and methanesulfonyl chloride (15 μL) was added under ice-cooling. After stirring at room temperature for 8 hr, water was added to the reaction mixture, and the mixture was extracted with chloroform. The solvent was evaporated, and the residue was purified by column chromatography (ethyl acetate:hexane) to give the title compound (34 mg).
Reaction SMILES: [CH:1]1([C:5]2[C:14](I)=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([CH3:16])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:17][N:18](C=O)C>[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:17]([C:14]1[C:5]([CH:1]2[CH2:4][CH2:3][CH2:2]2)=[CH:6][C:7]([CH3:16])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])#[N:18]
Reactant: COC(=O)c1cc(I)c(C2CCC2)cc1C
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COC(=O)c1cc(C#N)c(C2CCC2)cc1C
Temperature: 100 °C

Procedure:
A mixture of methyl 4-cyclobutyl-5-iodo-2-methylbenzoate (compound 152.3, 4.17 g, 12.64 mmol), Zn(CN)2 (2.96 g, 25.21 mmol) and Pd(PPh3)4 (0.73 g, 0.63 mmol) in DMF (30 ml) was degassed and the flask was filled with argon through a balloon. The mixture was heated at 100° C. under argon overnight. After cooling to ambient temperature, the mixture was quenched with saturated aq. FeSO4 (20 ml) and diluted with EtOAc (200 ml). The greenish solid was removed by filtration through celite. The filtrate was partitioned between water and EtOAc. The EtOAc layer was washed with brine, dried (Na2SO4), and concentrated. The residue was purified using column (silica gel) chromatography (hexanes:EtOAc 30:1 to 20:1). Yield: 2.55 g, white solid, 88%. 1H NMR (400 MHz, Chloroform-d) δ 8.16 (s, 1H), 7.28 (s, 1H), 3.90 (s, 3H), 3.86-3.82 (m, 1H), 2.68 (s, 3H), 2.55-2.45 (m, 2H), 2.27-2.04 (m, 3H), 1.89-1.87 (m, 1H).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]1.C(N(CC)CC)C.Cl[CH2:33][CH2:34][S:35](Cl)(=[O:37])=[O:36]>C1COCC1.C(OCC)(=O)C>[Cl:17][C:12]1[CH:11]=[C:10]([C@@H:9]2[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4][C@H:3]2[CH2:2][NH:1][S:35]([CH:34]=[CH2:33])(=[O:37])=[O:36])[CH:15]=[CH:14][C:13]=1[Cl:16]
Reactant: O=S(=O)(Cl)CCCl
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CN)C1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C=CS(=O)(=O)NC[C@@H]1CN(C(=O)OC(C)(C)C)CCO[C@H]1c1ccc(Cl)c(Cl)c1
Reaction time: 8 h

Procedure:
To a solution of tert-butyl (6R,7R)-6-(aminomethyl)-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (633 mg) in THF (10 mL) were added triethylamine (0.705 mL) and 2-chloroethanesulfonyl chloride (0.213 mL) at 0° C., and the mixture was gradually warmed from 0° C. to room temperature, and stirred overnight. The reaction mixture was diluted with ethyl acetate. The diluted solution was washed with distilled water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (0.965 g).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:19]([O:21][C:22](=[O:31])[CH:23]=[C:24]1[CH2:28][CH2:27][C:26]([CH3:30])([CH3:29])[CH2:25]1)[CH3:20].[N+:32]([CH3:35])([O-:34])=[O:33]>C1COCC1.C(OCC)(=O)C>[CH2:19]([O:21][C:22](=[O:31])[CH2:23][C:24]1([CH2:35][N+:32]([O-:34])=[O:33])[CH2:28][CH2:27][C:26]([CH3:30])([CH3:29])[CH2:25]1)[CH3:20]
Reactant: C[N+](=O)[O-]
Reactant: CCOC(=O)C=C1CCC(C)(C)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1(C[N+](=O)[O-])CCC(C)(C)C1
Temperature: 70 °C
Reaction time: 19 h
Yield: 40.8 %

Procedure:
Tetrabutylammonium fluoride (5.75 mL of a 1 M solution in THF, 5.75 mmol) was added to a solution of the ester 2 (697 mg, 3.83 mmol) and nitromethane (467 mg, 7.66 mmol) in THF (20 mL) and the mixture heated to 70° C. After 19 hours, nitromethane (233 mg, 1.9 mmol) and tetrabutylammonium fluoride (1.9 mL of a 1 M solution in THF, 1.9 mmol) were added and reflux continued for 7 hours, whereupon the solution was cooled to room temperature, diluted with ethyl acetate (40 mL), and washed with 2N HCl (20 mL) then brine (20 mL). The organic phase was dried (MgSO4) and concentrated. The crude product was flash chromatographed (9:1 hexane/ethyl acetate) to give the nitro ester 3 (380 mg, 41%) as an oil.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[F:26][C:27]1[CH:28]=[C:29]([NH:38][C:39]([C@H:41]2[C:50]3[C:45](=[CH:46][C:47]([CH2:51][O:52][CH3:53])=[CH:48][CH:49]=3)[CH2:44][CH2:43][NH:42]2)=[O:40])[CH:30]=[C:31]2[C:35]=1[C:34]([CH3:37])([CH3:36])[CH2:33][CH2:32]2.[C:54]([O:58][C:59](=[O:68])[CH2:60][C@@H:61]1[CH2:64][C@H:63]([C:65](O)=[O:66])[CH2:62]1)([CH3:57])([CH3:56])[CH3:55].CCN(C(C)C)C(C)C>O.CN(C=O)C>[F:26][C:27]1[CH:28]=[C:29]([NH:38][C:39]([C@H:41]2[C:50]3[C:45](=[CH:46][C:47]([CH2:51][O:52][CH3:53])=[CH:48][CH:49]=3)[CH2:44][CH2:43][N:42]2[C:65]([C@@H:63]2[CH2:62][C@H:61]([CH2:60][C:59]([O:58][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:68])[CH2:64]2)=[O:66])=[O:40])[CH:30]=[C:31]2[C:35]=1[C:34]([CH3:37])([CH3:36])[CH2:33][CH2:32]2
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](C(=O)O)C1
Reactant: COCc1ccc2c(c1)CCN[C@H]2C(=O)Nc1cc(F)c2c(c1)CCC2(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COCc1ccc2c(c1)CCN(C(=O)[C@H]1C[C@@H](CC(=O)OC(C)(C)C)C1)[C@H]2C(=O)Nc1cc(F)c2c(c1)CCC2(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of HATU (100 mg, 0.26 mmol), (R)—N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-6-(methoxymethyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide hydrochloride (100 mg, 0.24 mmol), cis-3-(2-(tert-butoxy)-2-oxoethyl)cyclobutanecarboxylic acid (56.3 mg, 0.26 mmol), DIEA (0.094 mL, 0.53 mmol) and DMF (2 mL) was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 3→50% ethyl acetate/hexane) to give tert-butyl 2-(cis-3-((R)-1-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-6-(methoxymethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclobutyl)acetate (130 mg, 0.225 mmol, 94%) as a colorless oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[N:16][C:17]=4[NH2:19])[N:12]([CH3:20])[N:11]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH3:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][C:29](O)=[O:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:20][N:12]1[C:13]2=[N:14][CH:15]=[N:16][C:17]([NH2:19])=[C:18]2[C:10]([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[N:1]([C:29](=[O:30])[CH2:28][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[CH3:21])[CH2:2][CH2:3]3)=[N:11]1
Reactant: Cn1nc(-c2ccc3c(c2)CCN3)c2c(N)ncnc21
Reactant: Cc1ccccc1CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccccc1CC(=O)N1CCc2cc(-c3nn(C)c4ncnc(N)c34)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial with cap, to the solution of 3-(2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine.2HCl (70 mg, 0.206 mmol), (2-methylphenyl)acetic acid (31.0 mg, 0.206 mmol), HATU (78 mg, 0.206 mmol) in DMF (2 mL) was added Hunig's base (0.144 mL, 0.825 mmol). The mixture was stirred at room temperature for overnight. LCMS showed the reaction was completed. The reaction was poured into water, white solid formed. The white solid was filtered, dried to give the product.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([S:13][C:14]2[CH:15]=[C:16]([C:28]3[NH:29][CH:30]=[CH:31][CH:32]=3)[C:17]3[C:18](=[O:27])[NH:19][C:20]4[C:25]=3[C:24]=2[C:23]([F:26])=[CH:22][CH:21]=4)[CH2:9]1)=O)(C)(C)C.O>C(O)(C(F)(F)F)=O.C(Cl)Cl>[F:26][C:23]1[C:24]2[C:25]3[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:27])[C:17]=3[C:16]([C:28]1[NH:29][CH:30]=[CH:31][CH:32]=1)=[CH:15][C:14]=2[S:13][C@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Sc2cc(-c3ccc[nH]3)c3c4c(ccc(F)c24)NC3=O)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C1Nc2ccc(F)c3c(S[C@H]4CCNC4)cc(-c4ccc[nH]4)c1c23

Procedure:
(S)-3-[6-Fluoro-2-oxo-3-(1H-pyrrol-2-yl)-1,2-dihydro-benzo[cd]indol-5-ylsulfanyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (from Example 56 above) (54 mg, 0.12 mmol) was dissolved at 0° C. in a 50% TFA in CH2Cl2 solution (6 mL) that contained H2O (0.3 mL). After 2 hours the reaction mixture was partitioned between ethyl acetate and aqueous 1 N NaOH. The pH of the aqueous layer was adjusted to 14. The aqueous layer was extracted twice with ethyl acetate and the combined organic layer was washed with H2O, dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by a precipitation out of THF with excess of pentane to give 6-fluoro-5-[(S)-(pyrrolidin-3-ylsulfanyl)]-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one as a yellow solid. (Yield 41 mg; 97%).
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]1[O:8][CH2:7][CH2:6][O:5]1.[C-:9]#[N:10].[K+]>CN(C)C=O.C1OCCOCCOCCOCCOCCOC1>[C:9]([CH2:2][CH2:3][CH:4]1[O:8][CH2:7][CH2:6][O:5]1)#[N:10]
Reactant: BrCCC1OCCO1
Reactant: [C-]#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCCC1OCCO1
Temperature: 23 °C
Reaction time: 72 h
Yield: 55.9 %

Procedure:
A mixture of 2-(2-bromoethyl)-1,3-dioxolane (8.14 g, 45 mmol), potassium cyanide (5.85 g, 90 mmol), and 18-crown-6 (30 mg) in 30 mL of dimethylformamide was stirred for 72 hours at 23° C. The reaction mixture was filtered, diluted with 70 mL of dichloromethane and washed twice with 10 mL of water. The organic phase was dried over magnesium sulfate and distilled under vacuum to yield 3.2 g of 2-(2-cyanoethyl)-1,3-dioxolane. This was stirred in 20 mL of 1M HCl for 40 hours. The mixture was neutralized with sodium bicarbonate and extracted with 100 mL of dichloromethane. The dichloromethane extract was dried over magnesium sulfate and evaporated to yield 2.5 g of the desired aldehyde as an oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[N:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1.Cl.[C:25](O)(=[O:29])[C@H:26]([CH3:28])[OH:27].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>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[C:5]2[N:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:25](=[O:29])[CH:26]([OH:27])[CH3:28])[CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2nc(CN3CCNCC3)sc2n1
Reactant: C[C@H](O)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(O)C(=O)N1CCN(Cc2nc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Reaction time: 8 h

Procedure:
A mixture of 5-chloro-7-morpholin-4-yl-2-piperazin-1-ylmethyl-thiazolo[5,4-d]pyrimidine with HCl salt (1 g, 2.6 mmol), L-(+)-lactic acid (460 mg, 5.1 mmol), HATU (1.9 g, 5.1 mmol) and N,N-diisopropylethylamine (1.4 mL, 7.8 mmol) in 8 mL of DMF was stirred overnight. The mixture was diluted with ethyl acetate, and washed with saturated sodium bicarbonate aqueous solution and brine. The organic layer was dried over magnesium sulfate, filtered and evaporated to yield the crude 1-[4-(5-Chloro-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidin-2-ylmethyl)-piperazin-1-yl]-2-hydroxy-propan-1-one (900 mg).
Reaction SMILES: [CH:1]1([C:4]([C:6]2[C:7](Cl)=[N:8][CH:9]=[N:10][C:11]=2[Cl:12])=O)[CH2:3][CH2:2]1.[NH2:14][NH2:15]>C1COCC1>[Cl:12][C:11]1[N:10]=[CH:9][N:8]=[C:7]2[NH:14][N:15]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[C:6]=12
Reactant: NN
Reactant: O=C(c1c(Cl)ncnc1Cl)C1CC1
Solvent: C1CCOC1
Product: Clc1ncnc2[nH]nc(C3CC3)c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.4 %

Procedure:
A mixture of Cyclopropyl-(4,6-dichloro-pyrimidin-5-yl)-methanone (0.75 g, 3.5 mmol), anhydrous hydrazine (0.13 mL, 4.1 mmol) and THF (35 mL) was stirred at room temperature for 4 hours. The reaction was partitioned between water and EtOAc. The organic layer was washed with brine, dried and passed through a short silica gel pad to give 4-Chloro-3-cyclopropyl-1H-pyrazolo[3,4-d]pyrimidine (0.50 g, 74%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 11.87 (s, 1H), 8.80 (s, 1H), 2.55 (m, 1H), 1.15 (m, 2H), 1.14 (m, 2H).
Reaction SMILES: Br[CH:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[Cl:16])[C:9](=[O:17])[C:8]2[C:7]([Cl:18])=[CH:6][CH:5]=[CH:4][C:3]1=2.C(=O)([O-])[O-].[Ca+2].[CH2:24]([OH:28])[CH:25]([CH3:27])[CH3:26].O>C1COCC1>[CH2:24]([O:28][CH:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[Cl:16])[C:9](=[O:17])[C:8]2[C:7]([Cl:18])=[CH:6][CH:5]=[CH:4][C:3]1=2)[CH:25]([CH3:27])[CH3:26]
Reactant: O=C1c2cccc(Cl)c2C(Br)c2cccc(Cl)c21
Reactant: CC(C)CO
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)COC1c2cccc(Cl)c2C(=O)c2cccc(Cl)c21

Procedure:
To a solution of compound (6) (2.0 mmol) and anhydrous calcium carbonate (0.5 g) in dry THF (20 ml) was added dropwise a solution of an appropriate iso-butanol (10 ml) in dry THF (10 ml) under N2. The reaction mixture was refluxed for 3 hours. Water (250 ml) was added and then extracted with dichloromethane. The combined organic extracts were washed with water, dried (MgSO4), and concentrated. The resulting precipitate was collected by filtration, washed with water and further purified by crystallization (CH3CN).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[Br:12][C:13]1[N:14]=[CH:15][C:16]([NH2:19])=[N:17][CH:18]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Br:12][C:13]1[N:14]=[CH:15][C:16]([NH:19][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[N:17][CH:18]=1
Reactant: Nc1cnc(Br)cn1
Reactant: COc1ccc(B(O)O)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc(Nc2cnc(Br)cn2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 10.4 %

Procedure:
Into a 50 mL roundbottom flask, was placed 4-methoxyphenylboronic acid (5.4 g, 35.54 mmol). To this was added 5-bromo-pyrazin-2-ylamine (3 g, 17.24 mmol). Cu(OaC)2 (3.45 g, 19.06 mmol) was added, followed by addition of a solution of DMAP (4.2 g, 34.43 mmol) in CH2Cl2 (20 mL). The resulting solution was stirred at room temperature for 12 hours. The reaction progress was monitored by thin layer chromatography (TLC) (ethyl acetate/petroleum ether=1:2). When the reaction was complete, the mixture was filtered, then concentrated under vacuum. The residue was dissolved in ethyl acetate (EtOAc), then washed with water. The organic layer was dried over Na2SO4, then filtered and concentrated. The crude product was purified by silica gel chromatography (SGC) eluting with ethyl acetate/petroleum ether (1:5, v/v) to provide (5-bromo-pyrazin-2-yl)-(4-methoxy-phenyl)-amine (i) (500 mg, yield 10%) as a yellow solid.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH:20]=[C:21]([F:23])[CH:22]=1)[C:7]([C:9]1[CH:18]=[C:17]([CH3:19])[C:12]2[NH:13][C:14](=[O:16])[O:15][C:11]=2[CH:10]=1)=[O:8].I[CH3:25]>CN(C=O)C>[F:3][C:4]1[CH:5]=[C:6]([CH:20]=[C:21]([F:23])[CH:22]=1)[C:7]([C:9]1[CH:18]=[C:17]([CH3:19])[C:12]2[N:13]([CH3:25])[C:14](=[O:16])[O:15][C:11]=2[CH:10]=1)=[O:8]
Reactant: Cc1cc(C(=O)c2cc(F)cc(F)c2)cc2oc(=O)[nH]c12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)c2cc(F)cc(F)c2)cc2oc(=O)n(C)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.349 g (8.00 mmol) sodium hydride (55%, suspension in mineral oil) were added at RT to 2.20 g (7.61 mmol) 6-(3,5-difluoro-benzoyl)-4-methyl-3H-benzoxazol-2-one in 10 mL DMF. The reaction mixture was stirred for 30 min at RT. Then 0.634 mL (10.0 mmol) iodomethane were added and the mixture was stirred for 1 h at RT. Then another 0.1 mL iodomethane were added and the mixture was stirred further at RT. After the addition of ice water the mixture was extracted with EtOAc. The organic phase was washed with water, dried on sodium sulphate and evaporated down i. vac. The residue was purified by flash chromatography. The fractions containing the product were combined, evaporated down and dried i. vac.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH2:19][C:18]([CH2:25][C:26]([O:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:27])([C:20](=O)[CH:21]=[N+]=[N-])[O:17][N:16]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C[OH:41].C1[CH2:46][O:45]CC1>C([O-])(=O)C1C=CC=CC=1.[Ag+]>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH2:19][C:18]([CH2:25][C:26]([O:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:27])([CH2:20][C:21]([O:45][CH3:46])=[O:41])[O:17][N:16]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: CO
Reactant: CCCCOC(=O)CC1(C(=O)C=[N+]=[N-])CC(c2cccc(OCc3ccccc3)c2)=NO1
Agent: [Ag+]
Agent: O=C([O-])c1ccccc1
Solvent: CCN(CC)CC
Product: CCCCOC(=O)CC1(CC(=O)OC)CC(c2cccc(OCc3ccccc3)c2)=NO1
Reaction time: 0.33 h

Procedure:
Silver benzoate (0.393 g) was added to a mixture of butyl (3-(3-(benzyloxy)phenyl)-5-(diazoacetyl)-4,5-dihydro-1,2-oxazol-5-yl)acetate (1.87 g), triethylamine (1.496 mL), methanol (40 mL), and THF (20 mL) at 50 C, and the obtained mixture was stirred at 50 C for 20 minutes. The precipitate was filtered off, and then, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (0.919 g).
Reaction SMILES: [CH2:1]=O.Cl.[CH3:4][NH:5][CH3:6].[CH3:7][N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1>[OH-].[Na+]>[CH3:4][N:5]([CH2:1][C:9]1[N:8]([CH3:7])[CH:12]=[CH:11][CH:10]=1)[CH3:6]
Reactant: CNC
Reactant: C=O
Reactant: Cn1cccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CN(C)Cc1cccn1C
Yield: 86.2 %

Procedure:
A mixture of 35% aqueous formaldehyde solution (20.8 ml, 264.3 mmol) and dimethylamine hydrochloride (22.70 g, 278.4 mmol) was added to 1-methylpyrrole (21.42 g, 264.1 mmol) with stirring under ice-cooling over a 90-minute interval, and then the resulting mixture was stirred at room temperature for 6 hours. After stirring, 10% aqueous sodium hydroxide solution (150 ml) was added to the reaction mixture, and the reaction mixture was extracted with ether. The extract was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After filtration, the solvent was removed in vacuo, and the residue was purified by chromatography on a silica gel column using a mixed solvent of dichloromethane and methanol (10:1) as the eluent to afford 2-(N,N-dimethylaminomethyl)-1-methylpyrrole (31.47 g, yield: 86%).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:18]=[CH:17][C:8]2[CH:9]=[C:10]([C:14](O)=[O:15])[C:11](=[O:13])[O:12][C:7]=2[C:6]=1[O:19][C:20](=[O:22])[CH3:21])(=[O:3])[CH3:2].S(Cl)([Cl:25])=O>CN(C)C=O.C1C=CC=CC=1>[C:1]([O:4][C:5]1[CH:18]=[CH:17][C:8]2[CH:9]=[C:10]([C:14]([Cl:25])=[O:15])[C:11](=[O:13])[O:12][C:7]=2[C:6]=1[O:19][C:20](=[O:22])[CH3:21])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc2cc(C(=O)O)c(=O)oc2c1OC(C)=O
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc2cc(C(=O)Cl)c(=O)oc2c1OC(C)=O

Procedure:
A mixture of 7,8-diacetoxy-2-oxo-2H-1-benzopyran-3-carboxylic acid (612 mg), thionyl chloride (0.5 mL), dimethylformamide (one drop), and benzene (40 mL) was refluxed for 1 hour and then concentrated to about 10 mL. Hexane (20 mL) was added and the separated precipitates were filtered off, followed by vacuum drying, to yield 7,8-diacetoxy-2-oxo-2H-1-benzopyran-3-carbonyl chloride (600 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][NH:7][C:6]2=[O:13])#[N:2].Br[CH2:15][C:16](=[O:32])[CH2:17][C@H:18]1[C@H:23]([O:24][CH3:25])[CH2:22][CH2:21][CH2:20][N:19]1[C:26]([O:28][CH2:29][CH:30]=[CH2:31])=[O:27]>>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][N:7]([CH2:15][C:16](=[O:32])[CH2:17][C@H:18]1[C@H:23]([O:24][CH3:25])[CH2:22][CH2:21][CH2:20][N:19]1[C:26]([O:28][CH2:29][CH:30]=[CH2:31])=[O:27])[C:6]2=[O:13])#[N:2]
Reactant: N#Cc1ccc2nc[nH]c(=O)c2c1
Reactant: C=CCOC(=O)N1CCC[C@@H](OC)[C@@H]1CC(=O)CBr
Product: C=CCOC(=O)N1CCC[C@@H](OC)[C@@H]1CC(=O)Cn1cnc2ccc(C#N)cc2c1=O
Yield: 49 %

Procedure:
By the method of Example 4, 6-cyanoquinazolin-4(3H)-one and allyl trans-2-(3-bromo-2-oxopropyl)-3-methoxypiperidine-1-carboxylate were converted to title compound in 49% yield; 1H--NMR(CDCl3) 1.2-1.9 (m, 4H), 2.9 (d, 2H), 2.9-3.5 (m, 4H), 4.6-6.2 (m, 5H), 5.2 (s, 2H), 7.8-8.6 (m, 4H).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:8]2[N:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6](=[O:13])[O:5][C:4]1=[O:14].Br[CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19]>CC(N(C)C)=O>[CH3:19][CH:18]([CH3:20])[CH2:17][CH2:16][N:3]1[C:8]2[N:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6](=[O:13])[O:5][C:4]1=[O:14]
Reactant: O=c1[nH]c2ncccc2c(=O)o1
Reactant: CC(C)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(C)CCn1c(=O)oc(=O)c2cccnc21
Reaction time: 0.5 h
Yield: 50.9 %

Procedure:
A suspension of sodium hydride (95%, 0.048 g, 2.0 mmol) in dimethylacetamide (2 mL) at 20° C. under nitrogen was reacted with the product of Example 1A (0.3 g, 1.83 mmol). The reaction mixture was stirred for ½ hour then treated with 1-bromo-3-methylbutane (0.3 g, 2.0 mmol) and stirred for an additional 16 hours. The reaction was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated under vacuum. The crude product was purified by flash column chromatography on silica gel eluting with hexanes and ethyl acetate (3:1) to give the title compound as a white solid (0.218 g, 51%). MS (ESI−) m/z 233 (M−H)−. 1H NMR (300 MHz, DMSO-d6) δ 0.93 (s, 3H), 0.96 (s, 3H), 1.55 (m, 2H), 1.66 (m, 1H), 4.14 (t, J=7.72 Hz, 2H), 7.37 (dd, J=7.91, 4.96 Hz, 1H), 8.38 (dd, J=7.72, 1.84 Hz, 1H), 8.78 (dd, J=4.78, 1.84 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[N:6]=1.[CH:11]1([N+:17]#[C-:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[CH:19](=O)[CH3:20]>Cl(O)(=O)(=O)=O>[CH:11]1([NH:17][C:18]2[N:6]3[C:2]([S:3][CH:4]=[C:5]3[CH2:7][C:8]([OH:10])=[O:9])=[N:1][C:19]=2[CH3:20])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: Nc1nc(CC(=O)O)cs1
Reactant: [C-]#[N+]C1CCCCC1
Reactant: CC=O
Agent: [O-][Cl+3]([O-])([O-])O
Product: Cc1nc2scc(CC(=O)O)n2c1NC1CCCCC1

Procedure:
Compound 17 was prepared in accordance with the general synthesis instructions from 1.0 ml (0.1 mmol) (2-aminothiazol-4-yl)acetic acid solution (0.1 M, MC), 0.575 ml (0.115 mmol) cyclohexylisonitrile solution (0.2 M, MC), 0.500 ml (0.15 mmol) acetaldehyde solution (0.3 M, MC) and 10 μl perchloric acid (w=20%) in a substance library.