Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([Cl:11])[C:3]=1Cl.[OH-].[Na+].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]#[N:24])=[CH:18][CH:17]=1.Cl>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.O1CCCC1>[Cl:11][C:4]1[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=[C:2]([Cl:1])[C:3]=1[CH:22]([C:19]1[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][CH:18]=1)[C:23]#[N:24]
Reactant: N#CCc1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)c(Cl)c1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: N#CC(c1ccc(Cl)cc1)c1c(Cl)cc([N+](=O)[O-])cc1Cl
Reaction time: 4 h
Yield: 93.3 %

Procedure:
To a stirred mixture of 45.3 parts of 1,2,3-trichloro-5-nitrobenzene, 300 parts of a sodium hydroxide solution 50%, 5 parts of N,N,N-triethylbenzenemethanaminium chloride and 360 parts of tetrahydrofuran was added dropwise, during a 5 minutes period, a solution of 33.3 parts of 4-chlorobenzeneacetonitrile in 90 parts of tetrahydrofuran. Upon completion, stirring was continued for 4 hours at 50° C. The reaction mixture was poured into 1500 parts of crushed ice and acidified with concentrate hydrochloric acid. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was stirred in 2,2'-oxybispropane. The product was filtered off and dried, yielding 63.8 parts (93.3%) of 2,6-dichloro-α-(4-chlorophenyl)-4-nitrobenzeneacetonitrile (intermediate 3).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:28])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3([CH3:27])[CH2:26][CH2:25]3)[C:5]2=[CH:4][CH:3]=1.[CH3:29][O:30][CH:31]([Si:33]([CH3:36])([CH3:35])[CH3:34])[CH3:32].[CH2:37](Br)[CH:38]=[CH2:39].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[CH2:39]([N:12]1[C:13](=[O:23])[CH2:14][CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)[C:10]2([C:5]3[C:6](=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=3)[NH:8][C:9]2=[O:28])[CH:11]1[C:24]1([CH3:27])[CH2:25][CH2:26]1)[CH:38]=[CH2:37].[CH3:29][O:30][CH:31]([Si:33]([CH3:36])([CH3:35])[CH3:34])[CH3:32]
Reactant: CC1(C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Br)ccc23)CC1
Reactant: C=CCBr
Agent: COC(C)[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCN1C(=O)CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Br)ccc32)C1C1(C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.7 %

Procedure:
To a solution of racemic (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-2′-(1-methyl cyclopropyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (200 mg, 0.34 mmol) and allyl bromide (1.2 g, 10 mmol) in DMF (15 mL) was added Cs2CO3 (4 g, 12.1 mmol). The mixture was stirred at room temperature for 2 h, then poured into water (100 mL), extracted with ethyl acetate for 3 times. The organic layer was washed with water, dried over Na2SO4, concentrated to give crude product as a light yellow solid (210 mg).
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]=[CH:9][N:8]([CH:11]3[CH2:14][CH2:13][CH2:12]3)[C:4]=2[N:5]=[N:6][CH:7]=1.[CH2:15]([S:17]([C:20]1[CH:25]=[CH:24][C:23]([C:26]2[C:31]([F:32])=[CH:30][CH:29]=[C:28](B3OC(C)(C)C(C)(C)O3)[CH:27]=2)=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH3:16]>>[CH:11]1([N:8]2[C:4]3[N:5]=[N:6][CH:7]=[C:2]([C:28]4[CH:27]=[C:26]([C:23]5[CH:24]=[CH:25][C:20]([S:17]([CH2:15][CH3:16])(=[O:18])=[O:19])=[CH:21][CH:22]=5)[C:31]([F:32])=[CH:30][CH:29]=4)[C:3]=3[N:10]=[CH:9]2)[CH2:14][CH2:13][CH2:12]1
Reactant: CCS(=O)(=O)c1ccc(-c2cc(B3OC(C)(C)C(C)(C)O3)ccc2F)cc1
Reactant: Clc1cnnc2c1ncn2C1CCC1
Product: CCS(=O)(=O)c1ccc(-c2cc(-c3cnnc4c3ncn4C3CCC3)ccc2F)cc1
Yield: 10 %

Procedure:
Prepared according to the method described for Example 26 using 4-chloro-7-cyclobutyl-7H-imidazo[4,5-c]pyridazine (Preparation 99) and 2-(4′-ethylsulfonyl-6-fluorobiphenyl-3-yl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (Preparation 48) to afford the title compound as an off white solid in 10% yield, 10 mg.
Reaction SMILES: [N+:1](/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([O-:3])=[O:2].[C:12]([O:19][CH3:20])(=[O:18])[CH2:13][C:14]([O:16][CH3:17])=[O:15]>C1(C)C=CC=CC=1>[CH3:17][O:16][C:14]([CH:13]([C@H:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:4][N+:1]([O-:3])=[O:2])[C:12]([O:19][CH3:20])=[O:18])=[O:15]
Reactant: O=[N+]([O-])/C=C/c1ccccc1
Reactant: COC(=O)CC(=O)OC
Solvent: Cc1ccccc1
Product: COC(=O)C(C(=O)OC)[C@@H](C[N+](=O)[O-])c1ccccc1
Temperature: 0 °C
Reaction time: 60 h

Procedure:
[(S,S)-N-(2,4,6-triisopropylbenzenesulfonyl)-1,2-diphenylethylenediamine](hexamethylbenzene)ruthenium (14.8 mg, 0.02 mmol, S/C=50), trans-β-nitrostyrene (149 mg, 1.0 mmol), dimethyl malonate (114 μl, 1.0 mmol) and toluene (1 ml) were added into Schlenk (20 ml) under an argon atmosphere, and stirred at 0° C. for 60 hours. 1HNMR determination of the solution showed that the yield of the product was 99%. The reaction solution was purified by flash column chromatography (hexane/acetone=80/20, SiO2), and the optical purity was measured by HPLC (CHIRALPACK AD manufactured by Daicel Co., Ltd., hexane:2-propanol=90:10, flow rate 0.5 ml/min, detection by 210 nm), resulting to 91% ee.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([S:16][CH3:17])[N:11]=2)=[CH:4][CH:3]=1.OC1O[N:21]=[N+:22]2[C:27]=1[CH:26]=[CH:25][O:24][CH2:23]2>C1(C)C=C(C)C=C(C)C=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:10]3[CH:15]=[CH:14][N:13]=[C:12]([S:16][CH3:17])[N:11]=3)=[C:27]3[N:22]([CH2:23][O:24][CH2:25][CH2:26]3)[N:21]=2)=[CH:4][CH:3]=1
Reactant: CSc1nccc(C#Cc2ccc(F)cc2)n1
Reactant: Oc1on[n+]2c1C=COC2
Solvent: Cc1cc(C)cc(C)c1
Product: CSc1nccc(-c2c(-c3ccc(F)cc3)nn3c2CCOC3)n1
Temperature: 160 °C

Procedure:
A mixture of 4-[2-(4-fluorophenyl)ethynyl]-2-(methylthio)pyrimidine (i.e. the product of Example 1, Step A) (1.26 g, 5.16 mmol) and 3-hydroxy-7H-[1,2,3]oxadiazolo[3,4-c][1,3]oxazin-8-ium inner salt (i.e. the product of Step C) (0.99 g, 6.96 mmol) in mesitylene (20 mL) was heated at 160° C. for 24 h. The reaction mixture was concentrated under reduced pressure, and the residual oil was purified by medium pressure liquid chromatography using 0-100% ethyl acetate in hexanes as eluant to give 290 mg of the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[S:8](=[O:15])(=[O:14])[CH2:9][CH2:10][S:11](=[O:13])(=[O:12])[C:6]=2[CH:5]=[CH:4][C:3]=1[C:16](O)=[O:17].[CH2:19]([N:21]1[C:25]([OH:26])=[CH:24][CH:23]=[N:22]1)[CH3:20].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C.C(=O)(O)[O-].[Na+]>[CH2:19]([N:21]1[C:25]([OH:26])=[C:24]([C:16]([C:3]2[CH:4]=[CH:5][C:6]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][S:8](=[O:15])(=[O:14])[C:7]=3[C:2]=2[CH3:1])=[O:17])[CH:23]=[N:22]1)[CH3:20]
Reactant: Cc1c(C(=O)O)ccc2c1S(=O)(=O)CCS2(=O)=O
Reactant: CCn1nccc1O
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCn1ncc(C(=O)c2ccc3c(c2C)S(=O)(=O)CCS3(=O)=O)c1O
Temperature: 20 °C
Reaction time: 1 h

Procedure:
5.0 g (0.017 mol) of 8-methyl-2,3-dihydro-1,1,4,4-tetraoxobenz[1,4]dithiin-7-carboxylic acid were dissolved in 50 ml of acetonitrile, and 1.93 g (0.017 mol) of 1-ethyl-5-hydroxypyrazole and 3.56 g (0.017 mol) of N,N-dicyclohexylcarbodiimide were added. The reaction mixture was stirred at 20° C. for one hour and then taken up in 100 ml of 2% sodium bicarbonate solution, the precipitate that formed was filtered off with suction and the filtrate was dried and concentrated. The remaining white solid (5.8 g) was subsequently dissolved in 15 ml of dioxane, 4.2 g (0.03 mol) of potassium carbonate were added and the mixture was heated under reflux for 3 hours. After cooling, water was added, the mixture was washed with ethyl acetate, the aqueous phase was adjusted to pH 3 using 2N hydrochloric acid and the precipitate was filtered off with suction, washed with water and dried.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:14][CH2:13][C@H:12](/[C:15](=[C:20](\[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)/[C:21]([O:23][CH3:24])=[O:22])/[C:16]([O:18][CH3:19])=[O:17])[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:40][CH2:41][NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46]>CN(C=O)C.O>[C:45]([O:44][C:43]([NH:42][CH2:41][CH2:40][O:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:25]/[C:20](=[C:15](\[C@H:12]2[CH2:13][CH2:14][C@@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:10][CH2:11]2)/[C:16]([O:18][CH3:19])=[O:17])/[C:21]([O:23][CH3:24])=[O:22])=[CH:31][CH:30]=1)=[O:49])([CH3:48])([CH3:47])[CH3:46]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: COC(=O)/C(Cc1ccc(O)cc1)=C(\C(=O)OC)[C@H]1CC[C@@H](O[Si](C)(C)C(C)(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)/C(Cc1ccc(OCCNC(=O)OC(C)(C)C)cc1)=C(\C(=O)OC)[C@H]1CC[C@@H](O[Si](C)(C)C(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 19 h

Procedure:
A suspension of dimethyl 2-(cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)-3-(4-hydroxybenzyl)maleate (35 mg, 0.075 mmol) and cesium carbonate (27 mg, 0.083 mmol) in DMF (1.2 ml) was cooled to 0° C., a solution of tert-butyl (2-bromoethyl)carbamate (20 mg, 0.091 mmol) in DMF (0.5 ml) was added dropwise, and the mixture was stirred at room temperature for 19 hr. The reaction mixture was diluted with water and was extracted with ethyl acetate, the organic layer was washed with saturated brine and was dried over anhydrous sodium sulfate, and the filtrate was removed by distillation under reduced pressure. The residue was chromatographed on silica gel column (hexane:ethyl acetate=8:2) to give the title compound as an oil (20 mg, yield 43%).
Reaction SMILES: [Br-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)Cl.[CH3:24][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[C:34]=1[N:33]=[C:32]([C:35]1[S:36][CH:37]=[CH:38][CH:39]=1)[CH:31]=[C:30]2[C:40]([OH:42])=O.[NH2:43][C:44]1[O:45][C:46]([C:49]2[O:50][CH:51]=[CH:52][CH:53]=2)=[N:47][N:48]=1>N1C=CC=CC=1>[O:50]1[CH:51]=[CH:52][CH:53]=[C:49]1[C:46]1[O:45][C:44]([NH:43][C:40]([C:30]2[C:29]3[C:34](=[C:25]([CH3:24])[CH:26]=[CH:27][CH:28]=3)[N:33]=[C:32]([C:35]3[S:36][CH:37]=[CH:38][CH:39]=3)[CH:31]=2)=[O:42])=[N:48][N:47]=1
Reactant: Nc1nnc(-c2ccco2)o1
Reactant: Cc1cccc2c(C(=O)O)cc(-c3cccs3)nc12
Agent: [Br-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cccc2c(C(=O)Nc3nnc(-c4ccco4)o3)cc(-c3cccs3)nc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 12.5 %

Procedure:
Triphenylphosphine bromide (352 mg, 0.80 mmol) was added to a methylene chloride (1 mL) solution of commercially available 8-methyl-2-(2-thienyl)-4-quinolinecarboxylic acid (108 mg, 0.40 mmol), and the mixture was stirred at room temperature for 1 hour. The reaction solution was added to a pyridine (3 mL) solution of 2-amino-5-(2-furyl)-1,3,4-oxadiazole (90.7 mg, 0.60 mmol), and the mixture was stirred at room temperature for 2 hours and then heated with stirring overnight at 60° C. The reaction solution was concentrated. After that, to the residue, water was added, and the deposited solid was collected by filtration, washed with water, dried, and then purified by preparative HPLC to obtain the title compound (22 mg, 0.05 mmol).
Reaction SMILES: [CH3:1][N:2]([C@@H:10]1[CH2:14][C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@@H:12]([CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([N:28]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=3)=[O:33])[CH2:29][CH:30]=[CH2:31])[CH2:24][CH2:23]2)[CH2:11]1)C(OC(C)(C)C)=O.[CH:45]1([C:51](Cl)=[O:52])[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1>>[CH3:1][N:2]([C@@H:10]1[CH2:14][C@H:13]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@@H:12]([CH2:21][N:22]2[CH2:23][CH2:24][CH:25]([N:28]([C:32]([O:34][CH2:35][C:36]3[CH:37]=[CH:38][C:39]([N+:42]([O-:44])=[O:43])=[CH:40][CH:41]=3)=[O:33])[CH2:29][CH:30]=[CH2:31])[CH2:26][CH2:27]2)[CH2:11]1)[C:51]([CH:45]1[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1)=[O:52]
Reactant: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@H](N(C)C(=O)OC(C)(C)C)C[C@@H]2c2ccccc2)CC1
Reactant: O=C(Cl)C1CCCCC1
Product: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@H](N(C)C(=O)C3CCCCC3)C[C@@H]2c2ccccc2)CC1

Procedure:
Using essentially the same procedure as in Example 16, Step A and B but substituting 1-(R)-(N-(methyl)-N-(t-butoxycarbonyl)amino)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopentane from Example 29, Step H in Step A and cyclohexanoyl chloride in Step B, the title compound was prepared.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]3[N:14]=[CH:15][CH:16]=[C:12]3[N:11]=[C:10]([NH:17][C:18](=[O:29])[C:19]3[CH:24]=[CH:23][C:22]([C:25]([OH:28])([CH3:27])[CH3:26])=[CH:21][CH:20]=3)[CH:9]=2)[CH2:3]1.F[C:31](F)(F)[C:32]([O-])=[O:33].C(Cl)(=O)C.O>N1C=CC=CC=1>[C:32]([NH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]3[N:14]=[CH:15][CH:16]=[C:12]3[N:11]=[C:10]([NH:17][C:18](=[O:29])[C:19]3[CH:24]=[CH:23][C:22]([C:25]([OH:28])([CH3:26])[CH3:27])=[CH:21][CH:20]=3)[CH:9]=2)[CH2:3]1)(=[O:33])[CH3:31]
Reactant: O=C([O-])C(F)(F)F
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc(N3CCC[C@H](N)C3)n3nccc3n2)cc1
Solvent: O
Solvent: CC(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)N[C@H]1CCCN(c2cc(NC(=O)c3ccc(C(C)(C)O)cc3)nc3ccnn23)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33 %

Procedure:
As crude product mixture of (S)—N-(7-(3-aminopiperidin-1-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (Compound 305, Example 319), trifluoroacetate salt (50 mg, 0.054 mmol) was dissolved in pyridine (2 ml). At 0° C. acetyl chloride (0.013 ml, 0.18 mmol) was added and the mixture was stirred for 2 hours at room temperature. Afterwards an additional amount of acetyl chloride (0.008 ml) was added to drive the reaction to completion. Water (2 ml) was then added to quench the reaction. The mixture was concentrated in vacuo, and the crude product was purified by preparatory HPLC (25-60% MeCN/H2O gradient+0.01% TFA). Lyophilization of the collected fractions gave the titled compound (50 mg, 33%) as a white powder. 1H NMR (400 MHz, DMSO-d6) δ=10.91 (s, 1H), 8.09 (d, J=2.3 Hz, 1H), 8.03-7.95 (m, 3H), 7.64-7.57 (m, 2H), 7.38 (s, 1H), 6.36 (d, J=2.3 Hz, 1H), 4.13 (br. s., 2H), 3.87 (br. s., 1H), 3.22-3.13 (m, 1H), 3.08 (dd, J=9.5, 11.5 Hz, 1H), 2.00-1.86 (m, 2H), 1.82 (s, 2H), 1.76 (br. s., 1H), 1.52 (br. s., 1H), 1.46 (s, 5H); ESI-MS: m/z 437.5 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[N:8]=[CH:9][CH:10]=[C:5]2[C:4](=[O:11])[N:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>N1C=CC=CC=1>[NH:1]([C:2]1[N:7]=[C:6]2[N:8]=[CH:9][CH:10]=[C:5]2[C:4](=[O:11])[N:3]=1)[C:12]([CH3:13])=[O:14]
Reactant: NC1=NC(=O)C2=CC=NC2=N1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)NC1=NC(=O)C2=CC=NC2=N1
Reaction time: 2 h
Yield: 64.9 %

Procedure:
2-Aminopyrrolo(2,3-d)pyrimidin-4-one (3.0 g) and acetic anhydride (10 g) are suspended in pyridine (50 ml) and the reaction is conducted under reflux for 24 hours. The solvent and excess reagent are distilled off under reduced pressure and, on an ice bath, 5% (W/V) alcoholic ammonia (20 ml) is added to the residue. The mixture is stirred for 2 hours. The resulting crystalline precipitate is collected by filtration and washed with dilute hydrochloric acid and water to give the above-identified compound (2.5 g).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]=1[N+:12]([O-:14])=[O:13])(=[O:3])[CH3:2].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:7][C:6]=1[N+:12]([O-:14])=[O:13])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(O)cc1[N+](=O)[O-]
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)Nc1ccc(OCc2ccccc2)cc1[N+](=O)[O-]

Procedure:
2.94 G. of 1-acetamido-4-hydroxy-2-nitrobenzene, 5.13 g. of benzyl bromide and 4.2 g. anhydrous potassium carbonate are refluxed overnight in acetone with stirring, evaporated to dryness, the excess benzyl bromide removed under vacuum, water added and the product extracted with dichloromethane to give 1-acetamido-4-benzyloxy-2-nitrobenzene.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])/[CH:7]=[CH:8]/[C:9]1[CH:13]=[CH:12][NH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[S:25][C:24]([S:26](Cl)(=[O:28])=[O:27])=[CH:23][CH:22]=1>>[C:1]([O:5][C:6](=[O:14])/[CH:7]=[CH:8]/[C:9]1[CH:13]=[CH:12][N:11]([S:26]([C:24]2[S:25][C:21]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][N:15]=3)=[CH:22][CH:23]=2)(=[O:27])=[O:28])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)/C=C/c1cc[nH]c1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccn2)s1
Product: CC(C)(C)OC(=O)/C=C/c1ccn(S(=O)(=O)c2ccc(-c3ccccn3)s2)c1

Procedure:
Starting from (E)-3-(1H-pyrrol-3-yl)-acrylic acid tert-butyl ester (compound D1) and art-known 5-pyridin-2-yl-thiophene-2-sulfonylchloride the title compound can be obtained analogously or similarly as described for compound C1.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].N1CCCC1.[CH2:18]([N:20]1[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]1)[CH3:19]>C(O)C>[CH2:18]([N:20]1[CH2:21][CH:22]=[C:23]([C:7]2[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[NH:9][CH:8]=2)[CH2:24][CH2:25]1)[CH3:19]
Reactant: CCN1CCC(=O)CC1
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Solvent: C1CCNC1
Solvent: CCO
Product: CCN1CC=C(c2c[nH]c3ccc([N+](=O)[O-])cc23)CC1
Yield: 41.8 %

Procedure:
A solution of 5-nitroindole (38) (0.5 g, 3.083 mmol) in dry ethanol (15 mL) was treated with pyrrolidine (0.65 mL, 9.250 mmol), N-ethyl-4-piperidone (0.8 mL, 6.167 mmol) at room temperature and the resulting solution was refluxed for 3 days. The reaction was brought to room temperature and solvent was evaporated. The crude was purified by column chromatography (2 M NH3 in methanol: CH2Cl2, 5:95), and washed with ether (3×10 mL) to obtain compound 60 (0.35 g, 42%) as a solid. mp 188-190° C.; 1H NMR (DMSO-d6) δ: 1.07 (t, 3H, J=7.2 Hz), 2.41-2.50 (m, 4H), 2.63 (t, 2H, J=5.1 Hz), 3.10-3.15 (m, 2H), 6.18 (s, 1H), 7.55 (d, 1H, J=9.0 Hz), 7.65 (s, 1H), 8.01 (dd, 1H, J=2.1, 9.0 Hz), 8.69 (d, 1H, J=2.1 Hz), 11.86 (s, 1H)— ESI-MS m/z (%): 272 (M+, 100).
Reaction SMILES: [C:1]([C:3]1[CH:7]=[N:6][NH:5][C:4]=1[NH2:8])#[N:2].CN(C)[CH:11]=[CH:12][C:13]([C:15]1[CH:16]=[C:17]([N:21]([CH2:26][CH3:27])[S:22]([CH3:25])(=[O:24])=[O:23])[CH:18]=[CH:19][CH:20]=1)=O.C(OCC)(=O)C>C(O)(=O)C>[C:1]([C:3]1[CH:7]=[N:6][N:5]2[C:13]([C:15]3[CH:16]=[C:17]([N:21]([CH2:26][CH3:27])[S:22]([CH3:25])(=[O:24])=[O:23])[CH:18]=[CH:19][CH:20]=3)=[CH:12][CH:11]=[N:8][C:4]=12)#[N:2]
Reactant: CCN(c1cccc(C(=O)C=CN(C)C)c1)S(C)(=O)=O
Reactant: N#Cc1cn[nH]c1N
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCN(c1cccc(-c2ccnc3c(C#N)cnn23)c1)S(C)(=O)=O
Yield: 52.1 %

Procedure:
A mixture of 0.196 g (1.82 mmol) of 4-cyano-2H-pyrazol-3-ylamine and 0.54 g (1.82 mmol) of N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-ethyl-methanesulfonamide in 10 ml of glacial acetic acid was refluxed for 8 hours and then the solvent was removed by reduced pressure distillation. To the resulting residue were added 10 ml of dichloromethane and 10 ml of saturated sodium bicarbonate solution. The two layers were separated, and the aqueous layer was washed with 10 ml of dichloromethane. The organic layers were washed with 10 ml of water and dried over magnesium sulfate. The dichloromethane layer was evaporated to dryness to yield an oil which, in the presence of ethyl acetate, gave 324 mg of N-[3-(3-cyano-pyrazolo[1,5-a]pyrimidin-7-yl)-phenyl]-N-ethyl-methanesulfonamide as a yellow solid (yield 52.4%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1I.C[O:11][C:12](=O)[C:13]1[CH:18]=[C:17]([O:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:16]=[CH:15][C:14]=1B1OC(C)(C)C(C)(C)O1>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[C:3]=1[C:14]1[CH:15]=[CH:16][C:17]([O:19][CH2:20][CH2:21][N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)=[CH:18][C:13]=1[C:12](=[O:11])[NH:8]2
Reactant: COC(=O)c1cc(OCCN2CCOCC2)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: Nc1nccc(Cl)c1I
Product: O=c1[nH]c2nccc(Cl)c2c2ccc(OCCN3CCOCC3)cc12
Yield: 6.4 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 1 using 4-chloro-3-iodopyridin-2-amine (65 mg, 0.26 mmol) and 5-(2-morpholin-4-yl-ethoxy)-2-(4,4,5,5-tetramethyl[1,3,2]-dioxaborolan-2-yl)-benzoic acid methyl ester (110 mg, 0.28 mmol) to provide 222 (6 mg, 6% yield) as a white solid. LC-MS (M+H=360, obsd.=360).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C@@H:4]([NH:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[CH2:5][CH2:6][S:7][CH3:8].I([O-])(=O)(=O)=[O:22].[Na+]>CO.O>[CH3:1][O:2][C:3](=[O:20])[C@@H:4]([NH:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[CH2:5][CH2:6][S:7]([CH3:8])=[O:22]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: COC(=O)[C@H](CCSC)NC(=O)OCc1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)[C@H](CCS(C)=O)NC(=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
Sulfide 59 (5.40 g, 18.2 mmol) was dissolved in methanol (60 mL). This was cooled in ice and a solution of sodium metaperiodate (4.08 g, 1.05 equiv) in water (25 mL) was added dropwise over 10 mins. This was stirred in ice for 1 h and then at rt for a further 2 h. The resultant white precipitate was removed by filtration under vacuum, the residue washed with methanol and the filtrate concentrated in vacuo. The resultant colourless oil was partitioned between DCM and water. The aqueous phase was extracted twice more with DCM, methanol added to the combined organic extracts to obtain an homogenous solution and this was dried (MgSO4), filtered and concentrated in vacuo to afford a yellow oil, 5.69 g, 100%. This was obtained as a 1:1 mixture of diastereoisomers.
Reaction SMILES: [NH:1]([C:8]1[N:9]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[CH:14][C:13](/[CH:19]=[CH:20]/[C:21]([OH:23])=[O:22])=[C:12]([CH3:24])[N:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)=O.N>CO.[Pd]>[NH:1]([C:8]1[N:9]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:10]2[N:11]=[C:12]([CH3:24])[C:13]([CH:19]=[CH:20][C:21]([OH:23])=[O:22])=[CH:14][C:15]=2[C:16](=[O:18])[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc2c(cc1/C=C/C(=O)O)c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Agent: [Pd]
Agent: N
Solvent: CO
Solvent: O=CO
Product: Cc1nc2c(cc1C=CC(=O)O)c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Yield: 86.8 %

Procedure:
To a stirred suspension of 2-anilino-6-[(E)-3-hydroxy-3-oxo-1-propenyl]-7-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one (40.0 mg, 0.100 mmol) in MeOH (2.0 mL), was added Pd/C (5.3 mg, 10% weight on carbon) under an argon atmosphere, followed by the addition of ammonia formate (19.0 mg, 0.30 mmol) in a single portion. The reaction mixture was heated at reflux for 2 h, cooled and filtered. The filtrate was diluted with water (10 mL) and extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was washed with water and dried in vacuo to afford 3-(7-anilino-2-methyl-5-oxo-8-phenyl-5,8-dihydro-1,8-naphthyridin-3-yl)propenoic acid (34.5 mg, 86%): LCMS RT: 2.31 min, MH+: 400.4, Rf=0.61 (4:1 EtOAc:MeOH).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[Br:12][C:13]1[CH:14]=[C:15]([CH3:22])[C:16]([F:21])=[C:17]([CH2:19][OH:20])[CH:18]=1>ClCCl>[Br:12][C:13]1[CH:14]=[C:15]([CH3:22])[C:16]([F:21])=[C:17]([CH:18]=1)[CH:19]=[O:20]
Reactant: Cc1cc(Br)cc(CO)c1F
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Cc1cc(Br)cc(C=O)c1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of pyridinium chlorochromate (3.77 g, 17.1 mmol) and silica gel in 25 ml dichloromethane was added a solution of (5-bromo-2-fluoro-3-methylphenyl)methanol in 25 mL dichloromethane. The reaction was stirred for 30 minutes at room temperature. Added additional silica gel and concentrated to adsorb reaction products onto the silica gel. Flash chromatographed (80 g silica, 5-10% ethyl acetate/hexanes gradient) to yield 2.1 g of 5-bromo-2-fluoro-3-methylbenzaldehyde as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 2.31 (d, J=2.15 Hz, 3 H) 7.42-7.63 (m, 1 H) 7.77 (dd, J=5.46, 2.34 Hz, 1 H) 10.27 (s, 1 H).