Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([S:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:4][N:3]=1.[Cl:15][CH:16]([C:22]([CH3:24])=O)[C:17](OCC)=[O:18]>C(O)(=O)C>[CH2:8]([S:7][C:5]1[N:6]=[C:2]2[N:1]=[C:22]([CH3:24])[C:16]([Cl:15])=[C:17]([OH:18])[N:3]2[N:4]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Nc1n[nH]c(SCc2ccccc2)n1
Reactant: CCOC(=O)C(Cl)C(C)=O
Solvent: CC(=O)O
Product: Cc1nc2nc(SCc3ccccc3)nn2c(O)c1Cl
Temperature: 25 °C
Yield: 60 %

Procedure:
A solution of 16 g (77 mmol) of 3-amino-5-benzylthio-1,2,4-triazole and 10.6 g (77 mmol) of ethyl 2-chloroacetoacetate in 150 ml of glacial acetic acid was heated at 100° C. for 17 hours. Upon cooling to room temperature the solid which separated was collected by filtration. The filtrate was diluted with ice water to separate an additional quantity of solid. The solids were combined and dried to yield 14.0 g (60% of the desired product as a solid, m.p. 258°-260° C. IR and 1H NMR were in agreement with the assigned structure.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:13][C:14]2[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][N:17]=[C:16]([NH:24][C:25]3[CH:39]=[CH:38][C:28]([CH2:29][P:30](=[O:37])([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33])=[CH:27][CH:26]=3)[N:15]=2)=[C:6]2[C:10]=1[CH2:9][N:8]([CH3:11])[C:7]2=[O:12].[CH2:40]([N:42]([CH2:59][CH3:60])[CH2:43][CH2:44][N:45]1[CH:49]=[C:48](B2OC(C)(C)C(C)(C)O2)[CH:47]=[N:46]1)[CH3:41]>>[CH2:59]([N:42]([CH2:40][CH3:41])[CH2:43][CH2:44][N:45]1[CH:49]=[C:48]([C:2]2[CH:3]=[CH:4][C:5]([NH:13][C:14]3[C:19]([C:20]([F:23])([F:21])[F:22])=[CH:18][N:17]=[C:16]([NH:24][C:25]4[CH:26]=[CH:27][C:28]([CH2:29][P:30](=[O:37])([O:31][CH2:32][CH3:33])[O:34][CH2:35][CH3:36])=[CH:38][CH:39]=4)[N:15]=3)=[C:6]3[C:10]=2[CH2:9][N:8]([CH3:11])[C:7]3=[O:12])[CH:47]=[N:46]1)[CH3:60]
Reactant: CCN(CC)CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)c4c3C(=O)N(C)C4)n2)cc1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCN(CC)CC)c4)c4c3C(=O)N(C)C4)n2)cc1)OCC

Procedure:
The title compound was prepared according to the procedure of Example 97 using diethyl [4-({4-[(7-bromo-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzyl]phosphonate and N,N-diethyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]ethanamine (Compound 175A). MS (ES+): m/z 715.47 (100) [MH+]; HPLC: tR=0.75 min (UPLC, purity).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[CH2:10][C:11](=[O:13])[CH3:12].[C:14](O)(=O)C.N1CCCCC1.C=O>CC#N>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[C:10](=[CH2:14])[C:11](=[O:13])[CH3:12]
Reactant: CC(=O)Cc1c(F)ccc(F)c1F
Reactant: CC(=O)O
Agent: C=O
Solvent: CC#N
Solvent: C1CCNCC1
Product: C=C(C(C)=O)c1c(F)ccc(F)c1F
Temperature: 70 °C
Yield: 205 %

Procedure:
A solution of 18 (3.5 g, 18.6 mmol), acetic acid (0.34 ml, 5.58 mmol), piperidine (0.37 ml, 3.72 mmol), formaldehyde (6.0 g, 37% aqueous solution) in MeCN (20 mL) was heated over weekend. The conversion was about 60%. Reaction was heated to 70° C. overnight. The mixture was concentrated and extracted with MTBE and HCl (0.5N). The organic layer was washed with aqueous K2CO3 (0.5N) and water, in turns. The organic layer was concentrated. The product was isolated by chromatography column (hexane and EtOAc), yielding 31 (2.29 g, 61.5%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][C:15]3[N:19]4[CH:20]=[C:21]([C:24](O)=[O:25])[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[C:27]([O:31][C:32](=[O:38])[N:33]([CH2:35][CH2:36][NH2:37])[CH3:34])([CH3:30])([CH3:29])[CH3:28].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][C:15]3[N:19]4[CH:20]=[C:21]([C:24]([NH:37][CH2:36][CH2:35][N:33]([CH3:34])[C:32](=[O:38])[O:31][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: CN(CCN)C(=O)OC(C)(C)C
Reactant: COc1ccc2c(OCc3nnc4ccc(C(=O)O)cn34)ccnc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc2c(OCc3nnc4ccc(C(=O)NCCN(C)C(=O)OC(C)(C)C)cn34)ccnc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
3-((7-Methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxylic acid (0.072 g, 0.21 mmol) was dissolved in DMF (1.5 mL) then added N-(2-aminoethyl)-N-methyl carbamic acid tert-butyl ester (0.054 ml, 0.31 mmol), 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.12 g, 0.31 mmol) and triethylamine (0.043 ml, 0.31 mmol). The reaction mixture was stirred at room temperature overnight then concentrated under vacuum. The sample was purified by flash chromatography eluting with 6% 7N ammonia in methanol/dichloromethane to afford tert-butyl 2-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamido)ethyl(methyl)carbamate (0.097 g, 93% yield) as a pale yellow solid.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]2[C@@H:3]1[S:4][C@@:5]([N:23]1[CH2:27][CH2:26][N:25]([NH2:28])[C:24]1=[O:29])([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)=[O:11])[CH2:6]2.Cl.[O-:31][C:32]#[N:33].[Na+].C(=O)([O-])O.[Na+]>O.CO>[NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]2[C@@H:3]1[S:4][C@:5]([C:10]([O:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=1)=[O:11])([N:23]1[CH2:27][CH2:26][N:25]([NH:28][C:32]([NH2:33])=[O:31])[C:24]1=[O:29])[CH2:6]2
Reactant: N[C@@H]1C(=O)N2C[C@@](C(=O)OCc3ccc([N+](=O)[O-])cc3)(N3CCN(N)C3=O)S[C@H]12
Reactant: N#C[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: NC(=O)NN1CCN([C@]2(C(=O)OCc3ccc([N+](=O)[O-])cc3)CN3C(=O)[C@@H](N)[C@H]3S2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.9 %

Procedure:
In a mixed solvent consisting of 30 ml of water and 30 ml of methanol was suspended 5.00 g of (3R,5R,6R)-6-amino-3-(3-amino-2-oxoimidazolidin-1-yl)-3-(p-nitrobenzyloxycarbonyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane. To suspension was added 2.96 ml of concentrated hydrochloric acid with water cooling. To the resulting solution was added 1.36 g of sodium cyanate in 10 minutes, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was filtered. To the filtrate were added 50 ml of ethyl acetate and 50 ml of water. The aqueous layer was separated. The organic layer was extracted three times each with 30 ml of water. The extracts were combined with the aqueous layer obtained previously. The combined aqueous solution was adjusted to pH 6.9 with sodium hydrogencarbonate. The solvent was removed by distillation under reduced pressure. The residue was dehydrated by four times of azeotropy with ethanol. To the resulting residue was added a mixed solvent consisting of 50 ml of methylene chloride and 10 ml of methanol. The insolubles were removed by filtration. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (eluant: chloroform/methanol=10/1 to 5/1) to obtain 4.29 g (yield: 77.9%) of (3R,5R,6R)-6-amino-3-(p-nitrobenzyloxycarbonyl)-7-oxo-3-(2-oxo-3-ureidoimidazolidin-1-yl)-4-thia-1-azabicyclo[3.2.0]heptane.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:15].[C:16](OC(=O)C)(=[O:18])[CH3:17].[H][H]>[Pd].C(O)(=O)C>[C:16]([NH:12][C:9]1[CH:10]=[CH:11][C:2]([CH3:1])=[C:3]2[C:8]=1[C:7](=[O:15])[CH2:6][CH2:5][CH2:4]2)(=[O:18])[CH3:17]
Reactant: Cc1ccc([N+](=O)[O-])c2c1CCCC2=O
Reactant: CC(=O)OC(C)=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(C)c2c1C(=O)CCC2

Procedure:
The compound prepared in (5) above (2.5 gm) was dissolved into a mixed-solvent of 50 ml of acetic acid and 50 ml of acetic anhydride. The mixture was catalytically hydrogenated for 1 hour in a hydrogen stream with the addition of 800 mg of 10% palladium-on-carbon. After removing the catalyst by filtration, the reaction mixture was concentrated. The residue was subjected to silica gel column chromatography using chloroform as an eluant to obtain fractions containing the target compound. The fractions were concentrated to produce 2.22 gm of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:19]=[C:18]([F:20])[C:6]([CH2:7][N:8]([CH3:17])[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[C:5]([F:21])[CH:4]=1)#[N:2].[NH2:22][OH:23]>C(O)C>[F:21][C:5]1[CH:4]=[C:3]([C:1](=[N:22][OH:23])[NH2:2])[CH:19]=[C:18]([F:20])[C:6]=1[CH2:7][N:8]([CH3:17])[CH2:9][C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11]
Reactant: CN(CC(=O)OC(C)(C)C)Cc1c(F)cc(C#N)cc1F
Reactant: NO
Solvent: CCO
Product: CN(CC(=O)OC(C)(C)C)Cc1c(F)cc(C(N)=NO)cc1F

Procedure:
A solution of tert-butyl 2-((4-cyano-2,6-difluorobenzyl)(methyl)amino)acetate (0.281 g, 0.95 mmol) and 50% aqueous hydroxylamine (0.32 mL) in ethanol (1.3 mL) was heated at 75° C. for 18 hours. The solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water, and then the organic phase was passed through a hydrophobic frit. The solvent was evaporated in vacuo to afford the title compound. 1H NMR (CDCl3, 400 MHz) δ 7.22-7.13 (2H, m), 4.81 (2H, br s), 3.91 (2H, s), 3.20 (2H, s), 2.40 (3H, s), 1.48 (9H, s).
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].[CH3:38][NH:39][CH2:40][C:41]#[CH:42]>>[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]([N:39]([CH3:38])[CH2:40][C:41]#[CH:42])[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Reactant: C#CCNC
Product: C#CCN(C)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and N-methylprop-2-ynylamine according to conditions described in general procedure C. Mp: 97-98° C.; 1H NMR (400 MHz, DMSO-d6) δ 2.88 (s, 3 H), 3.26-3.33 (m, 5H), 3.77 (t, J=4.8 Hz, 4H), 4.24 (s, 2H), 6.32 (d, J=5.5 Hz, 1H), 7.06 (d, J=14.3 Hz, 1H), 7.26 (d, J=8.8 Hz, 1H), 7.45-7.64 (m, 5H), 7.85-7.87 (m, 1H), 8.01 (d, J=8.0 Hz, 1H), 8.32 (d, J=5.5 Hz, 1H), 10.49 (s, 1H).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N-]C(C)C)(C)C.[Li+].C([Li])CCC.CCCCCC.C(NC(C)C)(C)C.[O:45]1[CH2:50][CH2:49][CH:48]([CH2:51][CH:52]=[O:53])[CH2:47][CH2:46]1>O1CCCC1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[CH:52]([OH:53])[CH2:51][CH:48]2[CH2:49][CH2:50][O:45][CH2:46][CH2:47]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=CCC1CCOCC1
Reactant: O=S(=O)(c1ccccc1)n1ccc2cccnc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1c(C(O)CC2CCOCC2)cc2cccnc21
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 57.4 %

Procedure:
To a suspension of 1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridine (5.0 g, 19.4 mmol) in dry tetrahydrofuran (125 mL) at −78° C. was added freshly prepared lithium diisopropylamide [prepared by adding 1.6 M n-butyllithium in n-hexane (18 mL, 29 mmol) to a 0° C. solution of diisopropylamine (4.4 mL, 31 mmol) in dry tetrahydrofuran (17 mL)] dropwise. The mixture was stirred at −78° C. for 5 min and then treated with (tetrahydro-pyran-4-yl)-acetaldehyde (3.7 g, 29 mmol) dropwise. The resulting mixture was stirred at −78° C. for 1 h and quenched with brine. The mixture was extracted with ethyl acetate (2×150 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (QingDao silica gel, 200-300 mesh, 50% ethyl acetate/hexanes) afforded 1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-(tetrahydro-pyran-4-yl)-ethanol as a colorless oil (4.3 g, 57%): LC/MS m/e calcd for C20H22N2O4S [M+H]+ 387.47, observed 387.1.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:20])[N:10]([C@H:12]1[CH2:17][CH2:16][C@H:15]([CH:18]=O)[CH2:14][CH2:13]1)[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br-].[Br:22][CH2:23][CH2:24][CH2:25][CH2:26][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>CC(O)(CC)C>[CH2:1]([O:8][C:9](=[O:20])[N:10]([CH:12]1[CH2:17][CH2:16][CH:15]([CH:18]=[CH:26][CH2:25][CH2:24][CH2:23][Br:22])[CH2:14][CH2:13]1)[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CN(C(=O)OCc1ccccc1)[C@H]1CC[C@H](C=O)CC1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CCC(C)(C)O
Product: CN(C(=O)OCc1ccccc1)C1CCC(C=CCCCBr)CC1
Temperature: 25 °C

Procedure:
A solution of 126.5 g (459.4 mmol) of trans-(4-Formyl-cyclohexyl)-methyl-carbamic acid benzyl ester in 1.27 l 2-methyl-2-butanol was treated with 263.6 g (551.3 mmol) (4-bromobutyl)triphenylphosphonium bromide and 254 g (1838 mmol) of K2CO3 and was heated at reflux for 3.5 h. The reaction was cooled (RT), filtered and evaporated. The residue was suspended in hexane (1.8 l, first at RT then at 0° C.) and filtered. Purification by column chromatography on silica gel (hexane/EtOAc 4:1) gave 149.9 g (83%) of trans-(1 E/Z)-[4-(5-Bromo-pent-1-enyl)-cyclohexyl]-methyl-carbamic acid benzyl ester, MS: 293 (M, 1Br).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]3[C:11]4([CH2:21][O:22][C:8]3=[CH:7][C:5]=2[N:6]=1)[C:19]1[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=1)[NH:13][C:12]4=[O:20].Br[CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27].BrCC1CCCCO1.N1C2C(=CC=CC=2)C2(C3=CC4SC=NC=4C=C3OC2)C1=O>>[CH3:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]3[C:11]4([CH2:21][O:22][C:8]3=[CH:7][C:5]=2[N:6]=1)[C:19]1[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=1)[N:13]([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:12]4=[O:20]
Reactant: Cc1nc2cc3c(cc2s1)C1(CO3)C(=O)Nc2ccccc21
Reactant: CC(C)CCBr
Agent: BrCC1CCCCO1
Agent: O=C1Nc2ccccc2C12COc1cc3ncsc3cc12
Product: Cc1nc2cc3c(cc2s1)C1(CO3)C(=O)N(CCC(C)C)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2-methylspiro[furo[2,3-f][1,3]benzothiazole-7,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, and 1-bromo-3-methylbutane to replace 2-(bromomethyl)tetrahydro-2H-pyran, methylbutyl)spiro[furo[2,3-f][1,3]benzothiazole-7,3′-indol]-2′(1′H)-one was obtained (71%) as a colorless solid: mp 137-138° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ7.60 (d, J=8.6 Hz, 1H), 7.32-7.27 (m, 1H), 7.13-7.08 (m, 1H), 7.03-6.92 (m, 3H), 5.03 (d, J=8.8 Hz, 1H), 4.78 (d, J=8.8 Hz, 1H), 4.12-4.01 (m, 1H), 3.71-3.60 (m, 1H), 2.56 (s, 3H), 1.93-1.61 (m, 3H), 1.06-1.00 (m, 6H); 13C NMR (75 MHz, CDCl3) δ176.8, 169.3, 160.4, 149.4, 142.8, 132.9, 129.1, 128.7, 123.6, 122.8, 122.2, 120.4, 108.6, 108.4, 81.1, 58.2, 39.2, 36.1, 26.0, 23.0, 22.5, 20.3; MS (ES+) m/z 378.5 (M+1).
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[C:10]([F:13])[CH:11]=2)[NH:6][C:5]=1[CH3:14])#[N:2].[CH2:15]([Br:24])[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:17]>C(#N)C>[BrH:24].[C:1]([CH2:3][C:4]1[C:12]2[C:7]([N:8]([CH2:15][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:17])[CH:9]=[C:10]([F:13])[CH:11]=2)=[N:6][C:5]=1[CH3:14])#[N:2]
Reactant: Cc1[nH]c2ncc(F)cc2c1CC#N
Reactant: O=C(CBr)c1ccccc1
Solvent: CC#N
Product: Br
Product: Cc1nc2n(CC(=O)c3ccccc3)cc(F)cc-2c1CC#N
Yield: 89.3 %

Procedure:
A mixture of 3- (cyanomethyl)-5-fluoro-2-methylpyrrolo [2,3-b]pyridine (0.28 g, 1.5 mmol) and phenacyl bromide 0.32 g, 1.6 mmol) in acetonitrile (5 ml) was refluxed under argon for 3 h, during which time the initial solution was transformed into a suspension. Then the suspension was cooled in an ice bath, filtered and washed with diethyl ether (2×2 ml). The crystalline product was purified by recrystallization from hot acetonitrile to give 0.52 g (90% ) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7]2[O:12][C:11](=[O:13])[C:10]3[CH:14]=[C:15]([Br:19])[CH:16]=[C:17]([Br:18])[C:9]=3[N:8]=2)[N:4]([C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[N:3]=1.[CH3:27][NH:28][NH2:29].O1CCCC1>O>[Br:1][C:2]1[CH:6]=[C:5]([C:7]([NH:8][C:9]2[C:17]([Br:18])=[CH:16][C:15]([Br:19])=[CH:14][C:10]=2[C:11]([N:28]([CH3:27])[NH2:29])=[O:13])=[O:12])[N:4]([C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[N:3]=1
Reactant: O=c1oc(-c2cc(Br)nn2-c2ncccc2Cl)nc2c(Br)cc(Br)cc12
Reactant: CNN
Solvent: C1CCOC1
Solvent: O
Product: CN(N)C(=O)c1cc(Br)cc(Br)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A mixture of 1.0 g of 2-[3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6,8-dibromo-4H-3,1-benzoxazine-4-one, 0.28 ml of methylhydrazine and 16 ml of tetrahydrofuran was stirred at room temperature for 19 hours. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel chromatography to obtain 0.97 g of 3-bromo-N-[4,6-dibromo-2-(N-methylhydrazinocarbonyl)phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide of the formula:
Reaction SMILES: [C:1]([N:3]=[C:4]1[NH:9][CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:6]([CH3:24])[NH:5]1)#[N:2].Cl[C:26]([O:28][CH2:29][CH3:30])=[O:27]>O1CCCC1.N1C=CC=CC=1>[C:1]([N:3]=[C:4]1[NH:5][C:6]([CH3:24])=[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)[N:9]1[C:26]([O:28][CH2:29][CH3:30])=[O:27])#[N:2]
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)C1=C(C)NC(=NC#N)NC1c1cccc([N+](=O)[O-])c1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCOC(=O)C1=C(C)NC(=NC#N)N(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 13 h
Yield: 84.7 %

Procedure:
A suspension of 1,2,3,4-tetrahydro-2-cyanoimino-6-methyl-4-(3-nitrophenyl)-5-pyrimidinecarboxylic acid, ethyl ester (565 mg, 1.72 mmoles) in dry tetrahydrofuran (70 ml) and pyridine (2.0 ml) was cooled to 0° C. and treated with ethyl chloroformate (0.17 ml, 2.24 mmoles) dropwise under argon. After the addition was completed, the cooling bath was removed and the reaction was allowed to stir at room temperature for 13 hours. Dry dimethylformamide (2.0 ml) was added and the reaction suspension became a homogeneous solution. It was then treated with triethylamine (0.5 ml) followed by ethyl chloroformate (0.1 ml). The reaction was allowed to stir at room temperature for 1 hour and then diluted with ethyl acetate. It was washed with 1N hydrochloric acid, water, sodium bicarbonate solution and brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated. The residue was purified by flash chromatography (10% ethyl acetate in dichloromethane) to provide a light yellow foam (585 mg). This material was combined with another batch of the same product and was crystallized from isopropyl ether-dichloromethane to yield the title compound, melting point 173.5°-175° C.
Reaction SMILES: [F:1][C:2]1[C:8]([CH3:9])=[CH:7][C:5]([NH2:6])=[C:4](I)[CH:3]=1.[CH3:11][Si:12]([C:15]#[CH:16])([CH3:14])[CH3:13]>C(N(CC)CC)C.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>[F:1][C:2]1[C:8]([CH3:9])=[CH:7][C:5]([NH2:6])=[C:4]([C:16]#[C:15][Si:12]([CH3:14])([CH3:13])[CH3:11])[CH:3]=1
Reactant: Cc1cc(N)c(I)cc1F
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: Cc1cc(N)c(C#C[Si](C)(C)C)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
Into a mixture of 4-fluoro-2-iodo-5-methylaniline (12.0 g, 47.8 mmol, plus ca. 10% of the undesired isomer), PdCl2(PPh3)2 (1.68 g, 2.39 mmol) and copper(I) iodide (0.455 g, 2.39 mmol) in triethylamine (125 mL) at 0° C. was added trimethylsilylacetylene (5.15 g, 52.6 mmol) dropwise. The mixture was warmed to room temperature and stirred overnight. The solvent was evaporated and the residue was dissolved in ethyl ether and filtered. The filtrate was evaporated and purified via flash chromatography with 5-35% ethyl acetate in hexane to give 4-fluoro-5-methyl-2-((trimethylsilyl)ethynyl)aniline (10.3 g, 97%), which contained ˜10% of the undesired isomer (4-fluoro-3-methyl-2-((trimethylsilyl)ethynyl)aniline).
Reaction SMILES: [C:1]([C:9]1[S:13][C:12]([CH2:14][N:15](C)[C:16](=O)OC(C)(C)C)=[CH:11][C:10]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)(=O)C.[ClH:36]>C(OCC)(=O)C>[ClH:36].[CH3:16][NH:15][CH2:14][C:12]1[S:13][C:9]([C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:8])=[C:10]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:11]=1
Reactant: CN(Cc1cc(-c2ccccc2)c(C(=O)c2ccccc2)s1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CNCc1cc(-c2ccccc2)c(C(=O)c2ccccc2)s1
Reaction time: 1 h
Yield: 57 %

Procedure:
tert-Butyl [(5-benzoyl-4-phenyl-2-thienyl)methyl]methylcarbamate (236 mg) was dissolved in ethyl acetate (3 mL), and a 4 mol/L hydrogen chloride-ethyl acetate solution (3 mL) was added at room temperature. After stirring for 1 hr, the reaction mixture was concentrated under reduced pressure. The residue was recrystallized from a mixed solvent of ethyl acetate and ethanol to give the title compound as colorless crystals (yield 114 mg, yield 57%).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[S:9]1[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10]1.C([O-])([O-])=O.[K+].[K+]>CCCCCC>[ClH:1].[Cl:1][C:13]1[S:9][CH:10]=[C:11]([CH2:14][NH2:15])[CH:12]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: N#Cc1ccsc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Product: Cl
Product: NCc1csc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-chlorosuccinimide (1.0 eq, 12.2 g) in hexane (100 mL) were added thiophene-3-carbonitrile (10 g, 91.6 mmol) and 70% HClO4 (1 mol %, 0.1 mL). The reaction mixture was stirred overnight at room temperature and subsequently K2CO3 was added. Removal of the solids and the volatiles afforded the crude product as a yellow oil. (This was a mixture of starting material: desired product: wrong isomer: dichlorinated 48%:26%:19%:6%.) Purification twice by column chromatography afforded 5-chlorothiophene-3-carbonitrile (1.71 g, 13%) as a yellow oil.
Reaction SMILES: [CH:1]1[C:6]([C:7]([CH2:9]Br)=O)=[CH:5][CH:4]=[C:3]([Br:11])[CH:2]=1.[CH2:12]([O:14][C:15](=[O:20])[CH2:16][C:17](=[S:19])[NH2:18])[CH3:13]>C(O)C>[CH2:12]([O:14][C:15](=[O:20])[CH2:16][C:17]1[S:19][CH:9]=[C:7]([C:6]2[CH:5]=[CH:4][C:3]([Br:11])=[CH:2][CH:1]=2)[N:18]=1)[CH3:13]
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: CCOC(=O)CC(N)=S
Solvent: CCO
Product: CCOC(=O)Cc1nc(-c2ccc(Br)cc2)cs1

Procedure:
A mixture of p-α-dibromoacetophenone (13.9 g, 0.05 mole) and 2-thiocarbamoylacetic acid ethyl ester in ethanol (65 ml) was heated under reflux for 21/2 hours. On cooling, there was obtained the title compound (12.2 g) mp 189°-191° C. (dec). An analytical sample recrystallization from ethanol had mp 191°-193° C.