Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:3][CH:4]1[C:16](=[O:17])[N:6]2[C:7]([C:13]([OH:15])=[O:14])=[C:8]([CH3:12])[CH2:9][S:10](=[O:11])[C@H:5]12)=[O:2].[CH3:18][Si:19]([CH3:29])([CH3:28])N1CCCCCC1=O.NS(O)(=O)=O.[Br:35]N1C(=O)CCC1=O>ClCCl>[Br:35][CH2:12][C:8]1[CH2:9][S:10](=[O:11])[C@@H:5]2[CH:4]([NH:3][CH:1]=[O:2])[C:16](=[O:17])[N:6]2[C:7]=1[C:13]([O:15][Si:19]([CH3:29])([CH3:28])[CH3:18])=[O:14]
Reactant: CC1=C(C(=O)O)N2C(=O)C(NC=O)[C@H]2S(=O)C1
Reactant: O=C1CCC(=O)N1Br
Reactant: C[Si](C)(C)N1CCCCCC1=O
Agent: NS(=O)(=O)O
Solvent: ClCCl
Product: C[Si](C)(C)OC(=O)C1=C(CBr)CS(=O)[C@@H]2C(NC=O)C(=O)N12
Yield: 62 %

Procedure:
A suspension of 357.6 mg (1.39 mmoles) of 7-formamido-3-methyl-3-cephem-4-carboxylic acid-1-oxide in 40 ml of dichloromethane was heated to reflux and 359 mg (1.94 mmoles) of N-trimethylsilylcaprolactam were added thereto to obtain a clear, colorless solution within 3 minutes. This was cooled in an ice-bath and 100 mg (1.02 mmoles) of amidosulfonic acid were added. Bromination was carried out in half an hour using 301.3 mg (1.69 mmoles) of N-bromosuccinimide as the brominating agent to obtain a 62% yield of trimethylsilyl 3-bromomethyl-7-formamido-3-cephem-4-carboxylate-1-oxide.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3]([NH2:5])=[O:4].C(Cl)(=O)[C:9](Cl)=[O:10].[NH2:14][C:15]1[N:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]([CH:31]3[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]3)=[O:30])[CH:23]=2)=[CH:17][CH:16]=1.O>ClCCCl.C1COCC1>[CH3:37][N:34]1[CH2:35][CH2:36][CH:31]([C:29]([NH:28][C:24]2[CH:23]=[C:22]([O:21][C:18]3[CH:19]=[N:20][C:15]([NH:14][C:9]([NH:5][C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1])=[O:10])=[CH:16][CH:17]=3)[CH:27]=[CH:26][N:25]=2)=[O:30])[CH2:32][CH2:33]1
Reactant: CC(C)(C)C(N)=O
Reactant: O=C(Cl)C(=O)Cl
Reactant: CN1CCC(C(=O)Nc2cc(Oc3ccc(N)nc3)ccn2)CC1
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CN1CCC(C(=O)Nc2cc(Oc3ccc(NC(=O)NC(=O)C(C)(C)C)nc3)ccn2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28 %

Procedure:
A solution of 2,2,2-trimethylacetamide (0.042 g, 0.412 mmol) in DCE (2 mL) was treated with oxalyl chloride (0.036 mL, 0.412 mmol), stirred at RT for 0.5 h, then heated at 75° C. for 1 h. The mixture was cooled to RT, added to a mixture of Example A8 (0.09 g, 0.275 mmol) and TEA (0.1 mL) in THF (2 mL) and stirred at RT for 1.5 h. The mixture was treated with water, extracted with EtOAc (3×) and the combined organics were dried over Na2SO4 and concentrated to dryness. The material was layered with EtOAc, allowed to stand overnight and the resulting solid collected via filtration to afford 1-methyl-N-(4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)piperidine-4-carboxamide (35 mg, 27%) as a peach-colored solid. 1H NMR (400 MHz, DMSO-d6): δ 11.24 (s, 1H), 10.52 (s, 1H), 10.50 (s, 1H), 8.25 (d, J=2.9 Hz, 1H), 8.20 (d, J=5.7 Hz, 1H), 8.10 (d, J=9.0 Hz, 1H), 7.74 (dd, J=9.0, 2.9 Hz, 1H), 7.65 (d, J=2.4 Hz, 1H), 6.73 (dd, J=5.7, 2.4 Hz, 1H), 2.77 (m, 2H), 2.38 (m, 1H), 2.13 (s, 3H), 1.82 (m, 2H), 1.66 (m, 2H), 1.55 (m, 2H), 1.22 (s, 9H); MS (ESI) m/z: 455.3 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:41])[C:5]([CH3:40])([CH3:39])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([N+]#[C-])(S(C1C=CC(C)=CC=1)(=O)=O)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([CH3:26])([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH3:2].Cl.[OH2:43]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:41])[C:5]([CH3:40])([CH3:39])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12](=[O:43])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([CH3:26])([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH3:2]
Reactant: [C-]#[N+]C(CCCCCCC(C)(C)C(=O)OCC)(CCCCCCC(C)(C)C(=O)OCC)S(=O)(=O)c1ccc(C)cc1
Reactant: O
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)CCCCCCC(=O)CCCCCCC(C)(C)C(=O)OCC
Temperature: 25 °C
Reaction time: 1.33 h
Yield: 40 %

Procedure:
To a solution of 9-isocyano-2,2,16,16-tetramethyl-9-(toluene-4-sulfonyl)-heptadecanedioic acid diethyl ester (12.0 g, 20.3 mmol) in methylene chloride (200 mL) was added concd HCl (47 mL). The reaction mixture was stirred for 80 min at room temperature. The mixture was diluted with water (200 mL), the layers were separated, and the aqueous layer was extracted with methylene chloride (3×70 mL). The combined organic layers were washed with saturated NaHCO3 solution (3×40 mL) and brine (50 mL). The solution was dried over MgSO4, and concentrated in vacuo to yield the crude product (7.52 g). Purification by column chromatography (silica gel, ethyl acetate/hexanes=1/9) gave 2,2,16,16-tetramethyl-9-oxoheptadecanedioic acid diethyl ester (3.5 g, 40%) as a colorless oil. 1H NMR (300 MHz, CDCl3/TMS): δ (ppm): 4.14 (q, J=7.1 Hz, 4H), 2.41 (t, J=7.0 Hz, 4H), 1.66-1.35 (m, 20H), 1.25 (t, J=7.1 Hz, 6H), 1.17 (s, 12H). 13C NMR (75 MHz, CDCl3/TMS): δ (ppm): 211.24, 177.89, 60.01, 42.69, 42.07, 40.64, 29.86, 29.07, 25.13, 24.73, 23.74, 14.24. HRMS (LSIMS, gly): Calcd for C25H47O5 (MH+): 427.3423, found: 427.3430.
Reaction SMILES: [CH2:1]1[O:24][C:23]2[CH:22]=[CH:21][C:5]([CH2:6][CH:7]3[C:16]4[C:11](=[C:12]([O:19][CH3:20])[CH:13]=[CH:14][C:15]=4[O:17][CH3:18])[CH2:10][CH2:9][NH:8]3)=[CH:4][C:3]=2[O:2]1.Br[CH2:26][C:27](Br)=[O:28].[NH2:30][CH2:31][C:32]1[NH:33][C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=1>>[CH2:1]1[O:24][C:23]2[CH:22]=[CH:21][C:5]([CH2:6][CH:7]3[C:16]4[C:11](=[C:12]([O:19][CH3:20])[CH:13]=[CH:14][C:15]=4[O:17][CH3:18])[CH2:10][CH2:9][N:8]3[CH2:26][C:27]([NH:30][CH2:31][C:32]3[NH:33][C:34]4[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=4[N:36]=3)=[O:28])=[CH:4][C:3]=2[O:2]1
Reactant: O=C(Br)CBr
Reactant: COc1ccc(OC)c2c1CCNC2Cc1ccc2c(c1)OCO2
Reactant: NCc1nc2ccccc2[nH]1
Product: COc1ccc(OC)c2c1CCN(CC(=O)NCc1nc3ccccc3[nH]1)C2Cc1ccc2c(c1)OCO2

Procedure:
prepared by reaction of 1-(3,4-Methylenedioxy-benzyl)5,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 2-(aminomethyl)-benzimidazole
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:14][C:13]([NH:15][C:16]([N:18]3[CH:22]=[CH:21]N=C3)=[O:17])=[N:12][C:11]=2[CH3:23])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.NCC[C:34]([NH:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35].O>CN(C)C=O>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[S:14][C:13]([NH:15][C:16](=[O:17])[NH:18][CH2:22][CH2:21][C:34]([NH:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[N:12][C:11]=2[CH3:23])=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)NC(=O)CCN
Reactant: CC(=O)c1ccc(-c2sc(NC(=O)n3ccnc3)nc2C)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(-c2sc(NC(=O)NCCC(=O)NC(C)(C)C)nc2C)cc1
Reaction time: 1.5 h

Procedure:
Imidazole-1-carboxylic acid [5-(4-acetyl-phenyl)-4-methyl-thiazol-2-yl]-amide (0.455 g, 1.40 mmol) is dissolved in dimethylformamide (10 ml) and treated with triethylamine (0.21 ml, 1.47 mmol) and 3-Amino-N-tert-butyl-propionamide (0.266 g, 1.47 mmol). The reaction mixture is stirred for 1.5 hours, then water (200 ml) added and the resulting suspension filtered. The solid is washed with water and dried under high vacuum to afford the titled product as a pale yellow solid. [M+H] 403.34
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][CH2:22][CH2:21][N:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2OC)[C:19]1=[O:33])=[O:16])[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N[C@H:42]1CCCCN(C2C=CC=CC=2C)C1=O>>[CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:15](=[O:16])[NH:17][C@H:18]1[CH2:24][CH2:23][CH2:22][CH2:21][N:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:42])[C:19]1=[O:33])[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccccc1N1CCCC[C@H](NC(=O)[C@H](CC[C@H](Cc2ccccc2)C(=O)O)Cc2ccccc2)C1=O
Reactant: Cc1ccccc1N1CCCC[C@H](N)C1=O
Product: Cc1ccccc1N1CCCC[C@H](NC(=O)[C@H](CC[C@H](Cc2ccccc2)C(=O)O)Cc2ccccc2)C1=O

Procedure:
(2R,5R)-2,5-Dibenzyl-6-oxo-6-((S)-2-oxo-1-o-tolylazepan-3-ylamino)hexanoic acid (65 mg, 0.12 mmol) was synthesized as described for the preparation of Intermediate 70 using (S)-3-amino-1-o-tolylazepan-2-one. Anal. Calcd. for C33H38N2O4 m/z 526.4. found: 527.4 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.37-6.84 (m, 16H), 4.84-4.72 (m, 1H), 4.01-3.78 (m, 1H), 3.51 and 3.28 (dd, J=15.0, 4.8 Hz, 1H), 3.04-2.81 (m, 2H), 2.79-2.61 (m, 3H), 2.50-2.37 (m, 1H), 2.18 (s, 1H), 2.13 (s, 2H), 2.03-1.44 (m, 10H).
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:28][C:29]1[CH:30]=[C:31]([C:42]2[CH:49]=[CH:48][C:45]([CH:46]=O)=[CH:44][CH:43]=2)[S:32][C:33]=1[C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1.CC([O-])(C)C.[K+].O>C(Cl)(Cl)Cl.C1COCC1>[Br:28][C:29]1[CH:30]=[C:31]([C:42]2[CH:49]=[CH:48][C:45](/[CH:46]=[CH:2]/[C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)=[CH:44][CH:43]=2)[S:32][C:33]=1[C:34]1[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=1
Reactant: c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: COc1ccc(-c2sc(-c3ccc(C=O)cc3)cc2Br)cc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2sc(-c3ccc(/C=C/c4ccccc4)cc3)cc2Br)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 47 %

Procedure:
A mixture of benzyltriphenylphosphonium bromide (23.7 g, 54.7 mmol) and (62) (17 g, 45.5 mmol) was dispersed in chloroform (300 mL) and stirred at RT under argon atmosphere for 15 min. A solution of t-BuOK (10.3 g, 91 mmol) in anhydrous THF (80 mL) was added dropwise. The reaction mixture was stirred at RT for 3 h. Then water was added, followed by extraction with chloroform. The combined extracts were dried over anhydrous MgSO4 and solvent evaporated to half of its initial volume by rotary evaporation; the resulting light yellow precipitation was filtered and dried (9.63 g; 47% yield).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])[C:5]([NH2:18])=[CH:4][CH:3]=1.Cl[S:20]([C:23]1[CH:27]=[CH:26][S:25][C:24]=1[C:28]([O:30][CH3:31])=[O:29])(=[O:22])=[O:21]>>[F:8][C:7]1[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])=[C:5]([NH:18][S:20]([C:23]2[CH:27]=[CH:26][S:25][C:24]=2[C:28]([O:30][CH3:31])=[O:29])(=[O:21])=[O:22])[CH:4]=[CH:3][C:2]=1[F:1]
Reactant: COC(=O)c1sccc1S(=O)(=O)Cl
Reactant: Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F
Product: COC(=O)c1sccc1S(=O)(=O)Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F

Procedure:
According to the general procedure B, 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene 1,2-diamine was reacted with methyl 3-(chlorosulfonyl)thiophene-2-carboxylate to obtain the title compound. 1H NMR (300 MHz, CDCl3): δ 8.58 (s, 1H), 7.43 (dd, J=5.1& 10.8 Hz, 2H), 7.35 (dd, J=1.8 & 10.2 Hz, 1H), 7.31 (ddd, J=2.1, 4.2 & 9.3 Hz, 1H), 7.04 (m, 2H), 5.88 (dt, J=2.7, 8.7 & 17.4 Hz, 1H), 5.65 (br s, 1H), 3.85 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH:12]([CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([C:21]([O-:23])=[O:22])[CH2:17][CH2:16]3)[O:11][C:10]2=[O:24])=[CH:5][CH:4]=1)#[N:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH:12]([CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([C:21]([OH:23])=[O:22])[CH2:17][CH2:16]3)[O:11][C:10]2=[O:24])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(N2CC(CN3CCC(C(=O)[O-])CC3)OC2=O)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(N2CC(CN3CCC(C(=O)O)CC3)OC2=O)cc1
Reaction time: 0.08 h

Procedure:
1 g of tert-butyl (1-(3-(4-cyanophenyl)-2-oxo-5-oxazolidinylmethyl)piperidine-4-carboxylate is dissolved in 12 ml of dichloromethane, and 12 ml of trifluoroacetic acid are then added; the mixture is left to stand for 5 min., concentrated by evaporation and worked up in the customary manner; 1-(3-(4-cyanophenyl)-2-oxo-5-oxazolidinylmethyl)piperidine-4-carboxylic acid, FAB 330, is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]([C:7]1[CH:12]=[CH:11][C:10](SC)=[CH:9][CH:8]=1)=[O:6])[CH3:2].O[O:17][S:18]([O-:20])=O.[K+].[CH3:22]O>O>[CH2:1]([O:3][C:4](=[O:15])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([S:18]([CH3:22])(=[O:20])=[O:17])=[CH:9][CH:8]=1)=[O:6])[CH3:2]
Reactant: O=S([O-])OO
Reactant: CO
Reactant: CCOC(=O)C(=O)c1ccc(SC)cc1
Agent: [K+]
Solvent: O
Product: CCOC(=O)C(=O)c1ccc(S(C)(=O)=O)cc1
Reaction time: 16 h
Yield: 21 %

Procedure:
(4-Methylsulfanyl-phenyl)-oxo-acetic acid ethyl ester (1.09 g, 4.86 mmol) and oxone (8.96 g, 14.6 mmol) were combined in a mixture of water (2.2 mL) and methanol (22 mL) and stirred for 16 h. The volatiles were evaporated in vacuo and the residue was treated with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic phases were dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 33% ethyl acetate/hexanes) to afford (4-methanesulfonyl-phenyl)-oxo-acetic acid ethyl ester as a white solid (261 mg, 21%): H1-NMR (400 MHz, CDCl3) δ=1.46 (3H, t, J=7.1 Hz), 3.10 (3H, s), 4.48 (2H, q, J=7.1 Hz), 8.09 (2H, m), 8.23 (2H, m).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C1C=CC=CC=1.[CH:18]([C:20]([CH3:22])=[O:21])=[CH2:19]>C(N(CC)CC)C>[O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][C:3]1([CH2:19][CH2:18][C:20](=[O:21])[CH3:22])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)C1CCCC1=O
Reactant: C=CC(C)=O
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCOC(=O)C1(CCC(C)=O)CCCC1=O

Procedure:
(B.) A mixture of 102.0 g of ethyl 2-oxocyclopentanecarboxylate, 300 ml of benzene, 67 ml of methyl vinyl ketone and 20 ml of triethylamine was allowed to stir magnetically at reflux for 2.5 hours. Concentration followed by Claisen distillation gave 128 g of product.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)#N.N1CCNCC1.[OH2:21].[OH-:22].[NH4+].[S:24](=[O:28])(=[O:27])([OH:26])[OH:25]>>[S:24](=[O:26])(=[O:25])([OH:28])[OH:27].[N:9]1([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:1]([OH:22])=[O:21])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1
Reactant: [OH-]
Reactant: O
Reactant: N#Cc1ccccc1N1CCNCC1
Agent: C1CNCCN1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Product: O=C(O)c1ccccc1N1CCNCC1
Temperature: 100 °C

Procedure:
1-(2-Cyanophenyl)piperazine (2.00 g, 10.68 mmol) was suspended in 10 mL of concentrated sulfuric acid. The piperazine slowly dissolved as the reaction mixture was heated to 100° C. After heating the reaction for 2 hr, the reaction was cooled to room temperature. 10 mL of water was added and the reaction was heated to 100° C. for another 4 hr. After cooling to room temperature, the reaction mixture was poured into 200 mL of ice water. The aqueous mixture was neutralized with ammonium hydroxide and the mixture was concentrated under vacuum. The product was extracted from the inorganic salts by washing with 25% methanol in tetrahydrofuran. The crude material was used in the next step without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]#[C:12][C:13]2[NH:21][C:20]3[C:19](=[O:22])[NH:18][C:17](=[O:23])[N:16]([CH2:24][CH3:25])[C:15]=3[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:26](N(CC)CC)C.COS(OC)(=O)=O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]#[C:12][C:13]2[N:21]([CH3:26])[C:20]3[C:19](=[O:22])[NH:18][C:17](=[O:23])[N:16]([CH2:24][CH3:25])[C:15]=3[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCn1c(=O)[nH]c(=O)c2[nH]c(C#Cc3ccc(OC)c(OC)c3)nc21
Reactant: CCN(CC)CC
Solvent: COS(=O)(=O)OC
Solvent: CN(C)C=O
Product: CCn1c(=O)[nH]c(=O)c2c1nc(C#Cc1ccc(OC)c(OC)c1)n2C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 8-(3,4-dimethoxyphenylethynyl)-3-ethyl-3,7-dihydro-purine-2,6-dione (1.52 g, 4.4 mmol) in 10 ml of dimethylformamide (DMF) was added triethylamine (3 ml, 20 mmol) and dimethylsulfate (0.65 ml, 7 mmol). The mixture was stirred at room temperature for 0.5 h. The product was precipitated by addind water (40 ml), filtered under reduced pressure, washed with water and dried at 70° C. (310 mg, 20%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[C:10](#[N:13])[CH2:11][CH3:12].CC(C)([O-])C.[K+].C(O)(C)(C)C>O1CCCC1>[NH2:7][C:6]([C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=1)=[C:11]([CH3:12])[C:10]#[N:13]
Reactant: CCC#N
Reactant: N#Cc1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: CC(C#N)=C(N)c1ccc(Cl)cc1
Reaction time: 24 h
Yield: 49.5 %

Procedure:
In a 2 L round bottom flask (fitted with rubber septum, nitrogen blanket and stir bar) combine 4-chlorobenzonitrile (60.0 g, 1.00 equiv, 432 mmol), propionitrile (61.2 mL, 2.00 equiv, 864 mmol), tetrahydrofuran (43.2 mL) and 1.0 M potassium t-butoxide in t-butanol (tert-butyl alcohol, potassium derivative, 475 mL, 1.10 equiv; 475 mmol); and stir for 24 h. Quench with aqueous NaHCO3 and extract with ethyl acetate. Wash the organic phase 2 times with brine, dry (K2CO3), filter, and concentrate to dryness. Purify by flash chromatography on silica, eluting with 15:85 to 50:50 ethyl acetate/hexane, to afford 3-amino-3-(4-chlorophenyl)-2-methylacrylonitrile (as an uncharacterized E-/Z-mixture). Yield: 49.5%. LCMS: 193.0 (m+1).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]3[CH:12]=[N:13][CH:14]=[C:15]([C:18]=3[NH:19][C:20]3[C:21]([CH3:29])=[C:22]4[C:26](=[CH:27][CH:28]=3)[NH:25][CH:24]=[CH:23]4)[C:16]#[N:17])=[CH:8][C:7]=2[CH:30]=1)=O.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CN1C(=O)CCC1>[CH3:29][C:21]1[C:20]([NH:19][C:18]2[C:15]([C:16]#[N:17])=[CH:14][N:13]=[CH:12][C:11]=2[C:9]2[O:10][C:6]3[CH:5]=[CH:4][C:3]([CH2:1][N:35]4[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]4)=[CH:30][C:7]=3[CH:8]=2)=[CH:28][CH:27]=[C:26]2[C:22]=1[CH:23]=[CH:24][NH:25]2
Reactant: CN1CCNCC1
Reactant: Cc1c(Nc2c(C#N)cncc2-c2cc3cc(C=O)ccc3o2)ccc2[nH]ccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: Cc1c(Nc2c(C#N)cncc2-c2cc3cc(CN4CCN(C)CC4)ccc3o2)ccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.6 %

Procedure:
To a solution of 5-(5-formyl-1-benzofuran-2-yl)-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile (800 mg, 2.04 mmol) in a mixture of CH2Cl2 (40 mL) and NMP (5 mL) at room temperature under nitrogen was added N-methylpiperazine (613 mg, 6.12 mmol) followed by glacial acetic acid (674 mg, 11.22 mmol) and the reaction mixture was stirred at room temperature for 1 h. Sodium triacetoxyborohydride (2.38 g, 11.22 mmol) was added to the reaction mixture and the reaction was stirred at room temperature for 5 h. The reaction mixture was partitioned between CH2Cl2 and aqueous 1N HCl. The aqueous layer was washed with CH2Cl2 and treated with aqueous 1N NaOH whereupon solids precipitated. The solids were collected and dissolved in CH2Cl2. The solution was washed with water thrice and brine, dried over sodium sulfate, and concentrated and the residue was purified by column chromatography (MeOH/CH2Cl2, 6% to 7.5%) to give 560 mg (58%) of 4-[(4-methyl-1H-indol-5-yl)amino]-5-{5-[(4-methylpiperazin-1-yl)methyl]-1-benzofuran-2-yl}nicotinonitrile as a yellow solid. HPLC retention time: 5.9 min.(g); melting range: 162-165° C. (decom.); and HRMS: 477.24093.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:10])[CH3:9].[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][N:23]([C:26]2[N:31]=[C:30]3[N:32]([CH3:39])[C:33]4[CH2:38][CH2:37][NH:36][CH2:35][C:34]=4[C:29]3=[CH:28][CH:27]=2)[C:22](=[O:40])[CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:8]([N:36]1[CH2:37][CH2:38][C:33]2[N:32]([CH3:39])[C:30]3[C:29]([C:34]=2[CH2:35]1)=[CH:28][CH:27]=[C:26]([N:23]1[CH:24]=[CH:25][C:20]([O:19][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:21][C:22]1=[O:40])[N:31]=3)(=[O:10])[CH3:9]
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)nc31)CNCC2
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCc2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)nc3n2C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.6 %

Procedure:
Triethylamine (33 μL, 0.24 mmol), DMAP (5.8 mg, 0.048 mmol) and acetyl chloride (25 μL, 0.36 mmol) were added to a solution of 4-(benzyloxy)-1-(9-methyl-5,7,8,9-tetrahydro-6H-pyrido[3′,4′:4,5]pyrrolo[2,3-b]pyridin-2-yl)pyridin-2(1H)-one (93 mg, 0.24 mmol) in CH2Cl2 (14 mL) and the resulting solution was stirred at ambient temperature for 2 h under N2. The resulting solution was concentrated to dryness under reduced pressure. Flash chromatography (12 g ISCO column, CH2Cl2/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 2 column volumes, increased to 0:100 over 20 column volumes and held for 5 column volumes) gave the title compound (86 mg, 83%) as an off-white powder and a mixture of rotomers: mp 206-208° C.; 1H NMR (500 MHz, DMSO-d6) δ 8.01 (t, J=8.5 Hz, 1H), 7.80 (dd, J=7.5, 2.5 Hz, 1H), 7.49-7.36 (m, 5H), 7.33-7.26 (m, 1H), 6.15 (dd, J=8.0, 3.0 Hz, 1H), 5.98 (d, J=2.5 Hz, 1H), 5.16 (s, 2H), 4.71-4.66 (m, 2H), 3.90-3.81 (m, 2H), 3.67 (m, 3H), 3.00-2.86 (m, 2H), 2.16-2.10 (m, 3H); ESI MS m/z 429 [M+H]; HPLC (Method A)>99% (AUC), tR=18.2 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[F:15][CH2:16][CH2:17]I.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.C(OCC)(=O)C>[F:15][CH2:16][CH2:17][N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1
Reactant: FCCI
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC1(C)OB(c2cnn(CCF)c2)OC1(C)C
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.05 g, 0.2 mmol), 1-fluoro-2-iodoethane (0.049 g, 0.28 mmol, SynQuest Labs, Cat. No. 1100-k-18), and cesium carbonate (250 mg, 0.77 mmol) in acetonitrile (1.0 mL) in a sealed reaction vial was heated at 90° C. with stirring overnight. After cooling it was diluted with ethyl acetate. Then the organic solution was washed with water, brine; dried over Na2SO4. After filtration the filtrate was concentrated to yield 19 mg of the product which was directly used in the next step reaction without further purification.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([NH:8][CH2:9][C:10]2[C:11]([CH3:25])=[CH:12][C:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[N:14][C:15]=2[CH3:16])=[O:7])[CH:3]=[N:2]1.Br[CH2:27][C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][C:32]([Cl:38])=[CH:33][CH:34]=2)[N:29]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O.C(OCC)(=O)C.O>[Cl:38][C:32]1[CH:31]=[C:30]2[C:35]([CH:36]=[CH:37][C:28]([CH2:27][N:1]3[CH:5]=[C:4]([C:6]([NH:8][CH2:9][C:10]4[C:11]([CH3:25])=[CH:12][C:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[N:14][C:15]=4[CH3:16])=[O:7])[CH:3]=[N:2]3)=[N:29]2)=[CH:34][CH:33]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CNC(=O)c1cn[nH]c1
Reactant: Clc1ccc2ccc(CBr)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CNC(=O)c1cnn(Cc2ccc3ccc(Cl)cc3n2)c1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
To a solution of tert-butyl (5-((1H-pyrazole-4-carboxamido)methyl)-4,6-dimethylpyridin-2-yl)carbamate (100 mg, 0.290 mmol) in acetone (2.5 ml) were added 2-(bromomethyl)-7-chloroquinoline (74.3 mg, 0.290 mmol) and K2CO3 (200 mg, 1.448 mmol). Reaction mixture was stirred for 5 h at 50° C. Reaction mixture was diluted with ethyl acetate and water. Phases were separated and organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated to afford the title compound. HPLC (Method G) Rt=1.736 min, MS (Method V) [M+H]+=521.3.