Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][O:7][C:6]2[CH:10]=[CH:11][C:12]([C:15]3[N:20]4[N:21]=[C:22]([C:24]5[CH:25]=[C:26]([C:30]6[CH:35]=[CH:34][CH:33]=[C:32]([OH:36])[CH:31]=6)[CH:27]=[CH:28][CH:29]=5)[CH:23]=[C:19]4[N:18]=[C:17]([CH3:37])[C:16]=3[C@H:38]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[C:39]([O:41][CH3:42])=[O:40])=[C:13]([Cl:14])[C:5]1=2)[CH:2]=[CH2:3].C([O-])([O-])=O.[K+].[K+].Br[CH2:55][CH:56]=[CH2:57].O>CN(C=O)C>[CH2:1]([N:4]1[CH2:9][CH2:8][O:7][C:6]2[CH:10]=[CH:11][C:12]([C:15]3[N:20]4[N:21]=[C:22]([C:24]5[CH:25]=[C:26]([C:30]6[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH2:57][CH:56]=[CH2:55])[CH:31]=6)[CH:27]=[CH:28][CH:29]=5)[CH:23]=[C:19]4[N:18]=[C:17]([CH3:37])[C:16]=3[C@H:38]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[C:39]([O:41][CH3:42])=[O:40])=[C:13]([Cl:14])[C:5]1=2)[CH:2]=[CH2:3]
Reactant: C=CCBr
Reactant: C=CCN1CCOc2ccc(-c3c([C@H](OC(C)(C)C)C(=O)OC)c(C)nc4cc(-c5cccc(-c6cccc(O)c6)c5)nn34)c(Cl)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1cccc(-c2cccc(-c3cc4nc(C)c([C@H](OC(C)(C)C)C(=O)OC)c(-c5ccc6c(c5Cl)N(CC=C)CCO6)n4n3)c2)c1
Temperature: 50 °C
Yield: 42 %

Procedure:
To a solution of (2S)-methyl 2-(7-(4-allyl-5-chloro-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-(3′-hydroxy-[1,1′-biphenyl]-3-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (90 mg, 0.138 mmol) in DMF (2 mL) was added K2CO3 (38.1 mg, 0.276 mmol) followed by 3-bromoprop-1-ene (0.017 mL, 0.207 mmol) and the resulting mixture was heated at 50° C. for 16 h. After cooling to room temperature, water was added and the mixture was extracted with ether (50 mL), washed with brine, dried (Na2SO4), filtered and concentrated. Crude was then purified by biotage (5-30% EtOAc/hexane) to afford (2S)-methyl 2-(7-(4-allyl-5-chloro-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-(3′-(allyloxy)-[1,1′-biphenyl]-3-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (40 mg, 0.058 mmol, 41.9% yield) as white solid. 28 mg of starting material was also recovered. 1H NMR (500 MHz, CDCl3) δ: 8.05 (t, J=1.6 Hz, 1H), 7.84 (dt, J=7.7, 1.4 Hz, 1H), 7.57-7.53 (m, 1H), 7.45 (t, J=7.6 Hz, 1H), 7.37 (t, J=7.9 Hz, 1H), 7.23-7.20 (m, 1H), 7.19-7.16 (m, 1H), 7.03-6.97 (m, 2H), 6.96-6.92 (m, 2H), 6.17-6.00 (m, 2H), 5.50-5.44 (m, 1H), 5.39-5.29 (m, 3H), 5.25 (dd, J=10.2, 1.6 Hz, 1H), 5.09 (s, 1H), 4.62 (dt, J=5.3, 1.4 Hz, 2H), 4.27 (t, J=4.4 Hz, 2H), 3.67 (s, 3H), 3.27-3.17 (m, 2H), 2.86 (s, 3H), 1.19 (s, 9H). LCMS (M+H)=693.4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:22][C:23]#[N:24])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)(=[O:11])=[O:10])=[C:4]([C:25](=[O:33])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:32])[CH:3]=1.C([Sn](=O)CCCC)CCC.[N:44]([Si](C)(C)C)=[N+:45]=[N-:46]>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:22][C:23]2[NH:46][N:45]=[N:44][N:24]=2)[S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)(=[O:11])=[O:10])=[C:4]([C:25](=[O:33])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:32])[CH:3]=1
Reactant: COc1ccc(S(=O)(=O)N(CC#N)c2ccc(Cl)cc2C(=O)c2ccccc2Cl)cc1OC
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)N(Cc2nnn[nH]2)c2ccc(Cl)cc2C(=O)c2ccccc2Cl)cc1OC

Procedure:
To 1 g of N-[4-chloro-2-(2-chlorobenzoyl)phenyl]-N-(cyanomethyl)-3,4-dimethoxybenzenesulfonamide dissolved in 20 ml of THF are successively added 0.3 g of dibutyltin oxide and 2.6 ml of azidotrimethylsilane, and the mixture is refluxed for 18 hours. The reaction medium is taken up in ethyl acetate and washed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is purified by filtration on silica H, eluting with dichloromethane, to give 0.95 g of the expected product.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([CH:8]=[CH:9][C:10]#[N:11])=[CH:6][CH:5]=1)(O)=[O:2].S(Cl)([Cl:16])=O.C1(C)C=CC=CC=1>CN(C)C=O>[Cl:16][C:1]([C:4]1[CH:13]=[CH:12][C:7]([CH:8]=[CH:9][C:10]#[N:11])=[CH:6][CH:5]=1)=[O:2]
Reactant: N#CC=Cc1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: N#CC=Cc1ccc(C(=O)Cl)cc1
Yield: 48.4 %

Procedure:
14.3 g (83 mmols) of 4-carboxycinnamonitrile, 11.9 g (100 mmols) of thionyl chloride, 100 ml of toluene and 0.18 ml of N,N-dimethylformamide are boiled under reflux for 15 minutes and then evaporated. Recrystallising the residue twice from carbon tetrachloride gives 7.7 g (48% of theory) of 4-chloroformylcinnamonitrile in the form of yellow crystals; melting point 161.0° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10]OS(C)(=O)=O.[C-:16]#[N:17].[K+].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][C:16]#[N:17]
Reactant: [C-]#N
Reactant: CS(=O)(=O)OCCCc1ccccc1Br
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCCCc1ccccc1Br
Temperature: 60 °C
Reaction time: 16 h
Yield: 91.5 %

Procedure:
Methanesulfonyl chloride (7.7 mL, 97 mmol) in 100 mL dry THF is added to a solution of 3-(2-bromo-phenyl)-propan-1-ol (17.4 g, 80.9 mmol) and triethyl amine (14.7 g, 146 mmol) in 200 mL dry THF at 0° C. under an argon atmosphere. Water is added and the mixture is extracted with ethyl acetate. The organic phase is washed with brine, dried with MgSO4 and concentrated in vacuo to give 23 g (97%) methanesulfonic acid 3-(2-bromo-phenyl)-propyl ester as an oil. Methanesulfonic acid 3-(2-bromo-phenyl)-propyl ester (23 g, 78 mmol) in 300 mL dry DMF is added to a suspension of potassium cyanide (15.3 g, 235 mmol) in dry DMF. The reaction mixture is stirred at 60° C. for 16 hours. Water is added and the mixture is extracted with ethyl acetate (3 times). The organic phase is washed with brine (twice), dried with MgSO4 and concentrated in vacuo. The residue is placed on a plug of silica gel and eluted with ethyl acetate/heptane (1:4) and concentrated in vacuo to give 16.0 g 4-(2-bromo-phenyl)-butyronitrile (91%) as an oil. 300 mL concentrated HCl is added to 4-(2-bromo-phenyl)-butyronitrile (16.0 g, 71 mmol) in 150 mL acetic acid. The reaction mixture is stirred at 60° C. for 16 hours. The reaction mixture concentrated in vacuo partly and is poured into water. The mixture is extracted with ethyl acetate (3 times). The organic phase is washed with brine (twice), dried with MgSO4 and concentrated in vacuo to give the title compound as a crystalline material.
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[C:6](=[N:7][C:8](SC)=[N:9][CH:10]=2)[N:5]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=1)[CH:2]=[CH2:3].[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][N:33]([CH2:36][C:37]([N:39]([CH3:41])[CH3:40])=[O:38])[CH2:32][CH2:31]2)=[CH:26][CH:25]=1>>[CH3:40][N:39]([CH3:41])[C:37](=[O:38])[CH2:36][N:33]1[CH2:32][CH2:31][N:30]([C:27]2[CH:28]=[CH:29][C:24]([NH:23][C:8]3[N:7]=[C:6]4[N:5]([C:16]5[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=5)[N:4]([CH2:1][C:2]#[CH:3])[C:12](=[O:13])[C:11]4=[CH:10][N:9]=3)=[CH:25][CH:26]=2)[CH2:35][CH2:34]1
Reactant: C=CCn1c(=O)c2cnc(SC)nc2n1-c1cccc(C)n1
Reactant: CN(C)C(=O)CN1CCN(c2ccc(N)cc2)CC1
Product: C#CCn1c(=O)c2cnc(Nc3ccc(N4CCN(CC(=O)N(C)C)CC4)cc3)nc2n1-c1cccc(C)n1

Procedure:
34.3 mg of the entitled compound was obtained as a yellow solid in the same manner as in Example 113-1 to 113-2, for which, however, 2-allyl-1-(6-methylpyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one was used in place of 2-allyl-1-[6-(1-hydroxy-1-methylethyl)-2-pyridinyl]-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one used in Example 113-1, and 2-[4-(4-aminophenyl)piperazin-1-yl]-N,N-dimethylacetamide was used in place of 4-(4-methylpiperazin-1-yl)aniline used in Example 113-2.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]([N:11]1[C:15](=[O:16])[CH2:14][CH2:13][C:12]1=[O:17])=[O:10])[CH2:2][CH2:3][CH3:4].[CH2:18]([OH:25])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24]>>[OH:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][O:25][C:12]([CH2:13][CH2:14][C:15]([NH:11][C:9](=[O:10])[O:8][CH2:7][CH2:6][O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[O:16])=[O:17]
Reactant: CCCCOCCOC(=O)N1C(=O)CCC1=O
Reactant: OCCCCCCO
Product: CCCCOCCOC(=O)NC(=O)CCC(=O)OCCCCCCO

Procedure:
According to the same manner as described in Example 1 except for reacting N-butoxyethyloxycarbonylsuccinimide with 1,6-hexanediol under conditions shown in Table 20, butoxyethyl N-{3-(6-hydroxyhexyloxycarbonyl)propionyl)carbamate was obtained. Characteristics and identified structure of the resulting compound are shown in Table 17.
Reaction SMILES: [OH:1][C@@H:2]([CH3:13])[CH2:3][N:4]1[CH:8]=[C:7]([C:9]([OH:11])=O)[N:6]=[C:5]1[CH3:12].[NH2:14][C@@H:15]([CH3:32])[CH2:16][N:17]1[CH:21]=[CH:20][C:19]([C:22]2[CH:29]=[C:28]([F:30])[C:25]([C:26]#[N:27])=[C:24]([Cl:31])[CH:23]=2)=[N:18]1.CN(C=O)C>C(Cl)Cl>[Cl:31][C:24]1[CH:23]=[C:22]([C:19]2[CH:20]=[CH:21][N:17]([CH2:16][C@@H:15]([NH:14][C:9]([C:7]3[N:6]=[C:5]([CH3:12])[N:4]([CH2:3][C@@H:2]([OH:1])[CH3:13])[CH:8]=3)=[O:11])[CH3:32])[N:18]=2)[CH:29]=[C:28]([F:30])[C:25]=1[C:26]#[N:27]
Reactant: Cc1nc(C(=O)O)cn1C[C@H](C)O
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nc(C(=O)N[C@@H](C)Cn2ccc(-c3cc(F)c(C#N)c(Cl)c3)n2)cn1C[C@H](C)O
Yield: 13.7 %

Procedure:
The title compound was prepared using the procedure described in Example 3(h) starting from (S)-1-(2-hydroxypropyl)-2-methyl-1H-imidazole-4-carboxylic acid (0.608 mmol, 112 mg) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (0.507 mmol, 141 mg) using DMF (2 ml) as the solvent. After the reaction had stopped, DCM was added and the reaction mixture was evaporated. The residue was purified by flash chromatography. The purified product was dissolved in a mixture of MeOH/DCM and washed twice with 1M NaHCO3. The organic phase was dried, filtered and evaporated. The product was further purified by trituration from diethyl ether, filtered and dried with vacuum. 31 mg of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.01-1.08 (m, 6H), 2.33 (s, 3H), 3.68-3.91 (m, 3H), 4.22-4.48 (m, 3H), 4.91 (d, 1H), 7.02 (d, 1H), 7.47 (s, 1H), 7.86 (d, 1H), 7.94 (d, 1H), 8.01 (s, 1H), 8.06 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[C:12]#[N:13])=[CH:6][C:5](Br)=[CH:4][N:3]=1.[C:19]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)([OH:21])=[O:20].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>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.O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:25]2[CH:26]=[CH:27][C:22]([C:19]([OH:21])=[O:20])=[CH:23][CH:24]=2)=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[C:12]#[N:13]
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: N#Cc1ccccc1COc1cc(Br)cnc1N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccccc1COc1cc(-c2ccc(C(=O)O)cc2)cnc1N
Temperature: 85.5 °C
Reaction time: 0.5 h
Yield: 83.2 %

Procedure:
2-(2-Amino-5-bromo-pyridin-3-yloxymethyl)-benzonitrile (9.0 g, 29.6 mmol), 4-carboxybenzeneboronic acid (5.4 g, 32.5 mmol), tetrakis(triphenylphosphine)palladium(0) (1.1 g, 1.0 mmol), anhydrous potassium carbonate (13.8 g, 70.0 mmol), dimethylformamide (72 mL) and water (36 mL) were charged to a 250 mL three neck round bottom flask equipped with a thermometer, a reflux condenser and magnetic stirring. The mixture was purged with nitrogen and gradually heated from 81 to 90° C. over a period of 2 hr. Thin layer chromatography (ethyl acetate:hexane:acetic acid 4:6:0.5) showed a trace of starting material at Rf 0.7, product at Rf 0.4 and an impurity at Rf 0.5. The mixture was cooled to 45° C. The sticky solids were collected by vacuum filtration, washed with 30 mL of ethanol:water 1:1 and discarded. The filtrate was diluted with 432 mL of water and 8 mL of 9 N potassium hydroxide solution (to pH 12-13), cooled in an ice bath and stirred for 30 minutes. The solids were collected by vacuum filtration and washed with 20 mL of water. The solids were discarded. The filtrate was cooled in an ice bath acidified with acetic acid to pH 7.5 using a pH meter. The solids were collected by vacuum filtration, washed with 20 mL water and dried under vacuum to give 8.5 g (83% yield) of 4-[6-amino-5-(2-cyano-benzyloxy)-pyridin-3-yl]-benzoic acid as a very dark solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH2:17][CH3:18])[C:12]([C:19]3[O:23][N:22]=[C:21]([CH2:24][CH2:25]O)[CH:20]=3)=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:27]1(=[O:37])[NH:31][C:30](=[O:32])[C:29]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:28]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH2:17][CH3:18])[C:12]([C:19]3[O:23][N:22]=[C:21]([CH2:24][CH2:25][N:31]4[C:27](=[O:37])[C:28]5[C:29](=[CH:33][CH:34]=[CH:35][CH:36]=5)[C:30]4=[O:32])[CH:20]=3)=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCCNc1nc(Nc2cccc(F)c2)ncc1-c1cc(CCO)no1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCCNc1nc(Nc2cccc(F)c2)ncc1-c1cc(CCN2C(=O)c3ccccc3C2=O)no1
Reaction time: 0.58 h
Yield: 123.4 %

Procedure:
To a solution of 2-(5-(2-((3-fluorophenyl)amino)-4-(propylamino)pyrimidin-5-yl)isoxazol-3-yl)ethanol (S5, 5.3 mg), phthalimide (10.9 mg) and triphenylphosphine (19.4 mg) in tetrahydrofuran (1 mL), a 1.9 mol/L solution of diisopropyl azodicarboxylate in toluene (39 μL) was added under ice cooling, and the mixture was stirred at the same temperature for 35 minutes, and then stirred at room temperature for 2 hours and 30 minutes. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent, 84 to 35% hexane in ethyl acetate) to obtain 2-(2-(5-(2-((3-fluorophenyl)amino)-4-(propylamino)pyrimidin-5-yl)isoxazol-3-yl)ethyl)isoindoline-1,3-dione (S6, 8.9 mg) as white solid.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11]#[N:12].F[C:14]1[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16][C:15]=1[N+:22]([O-:24])=[O:23].[H-].[Na+]>C1COCC1>[F:21][C:17]1[C:18]([F:20])=[CH:19][C:14]([NH:1][C:2]2[S:6][C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=3[C:3]=2[C:11]#[N:12])=[C:15]([N+:22]([O-:24])=[O:23])[CH:16]=1
Reactant: N#Cc1c(N)sc2ccccc12
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1c(Nc2cc(F)c(F)cc2[N+](=O)[O-])sc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.8 %

Procedure:
Combine 2-amino-benzo[b]thiophene-3-carbonitrile (3.93 g, 22.6 mmol), 2,4,5-trifluoro-nitrobenzene (4.0 g, 22.6 mmol) in 30 mL of THF, add sodium hydride (3.54 g, 88.5 mmol)) portionwise at 0˜5° C., after addition, the reaction stir overnight at RT, Pour the rection on ice water (200 mL), extract with dichloromethane (3×50 mL), the combined organic layer wash with water and brine, dry over Na2SO4. Concentrate down to a residue, purify by chromatography, gradient hexanes to hexane:CH2Cl2: EtOAc=5:5:0.5, obtain red orange solid 1.71 g as the title compound. 1H NMR (300 MHz, DMSO-d6): δ 10.34 (br, 1H), 8.41-8.35 (m, 1H), 7.96-7.94 (m, 1H), 7.85-7.79 (m, 1H), 7.64-7.61 (m, 1H), 7.52-7.49 (m, 1H), 7.42-7.36 (m, 1H).
Reaction SMILES: BrCBr.Cl[Si](C)(C)C.[C:9]([O:13][C:14]([N:16]1[CH2:19][CH:18](I)[CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].[Cl:21][C:22]1[CH:27]=[C:26](I)[CH:25]=[CH:24][N:23]=1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>CN(C=O)C.[Zn]>[Cl:21][C:22]1[N:23]=[CH:24][C:25]([CH:18]2[CH2:19][N:16]([C:14]([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:15])[CH2:17]2)=[CH:26][CH:27]=1
Reactant: Clc1cc(I)ccn1
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: BrCBr
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(c2ccc(Cl)nc2)C1
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 57.1 %

Procedure:
A 250-mL round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with zinc (2.54 g, 38.9 mmol), DMF (32 mL), and dibromomethane (736 mg, 4.24 mmol). After stirring at 70° C. for 10 min, the reaction mixture was cooled to room temperature, and chlorotrimethylsilane (423 mg, 3.89 mmol) was added. The resulting mixture was stirred at room temperature for 30 min, and a solution of 1-(tert-butoxycarbonyl)-3-iodoazetidine (9.31 g, 38.9 mmol) in DMF (32 mL) was added. After stirring at 40° C. for 1 h, a solution of 2-chloro-4-iodo-pyridine (10.0 g, 35.3 mmol) in DMF (16 mL) was added, followed by a solution of (dibenzylideneacetone)dipalladium(0) (1.62 g, 1.77 mmol) and tri(2-furyl)-phosphine (820 mg, 3.53 mmol) in DMF (16 mL). After stirring at 70° C. for 16, the reaction mixture was partitioned between saturated aqueous ammonium chloride (200 mL) and diethyl ether (200 mL). The layers were separated, and the aqueous phase was extracted with diethyl ether (200 mL). The organic extracts were combined, dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford a 54% yield (5.42 g) of 117a as a yellow oil: 1H NMR (500 MHz, CDCl3) δ 8.29 (d, 1H, J=2.5 Hz), 7.70 (dd, 1H, J=8.5, 2.5 Hz), 7.35 (d, 1H, J=8.5 Hz), 4.37 (t, 2H, J=8.5 Hz), 3.91 (dd, 2H, J=8.5, 4.5 Hz), 3.73 (m, 1H), 1.46 (s, 9H); MS (ESI+) m/z 269.0 (M+H).
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[S:8][C:9]3[CH:15]=[C:14]([O:16][S:17]([C:20]4[CH:25]=[CH:24][C:23](F)=[CH:22][CH:21]=4)(=[O:19])=[O:18])[CH:13]=[CH:12][C:10]=3[N:11]=2)=[O:5])[CH2:3][CH2:2]1.[CH:27]([N:30]([CH:34]([CH3:36])[CH3:35])[CH2:31][CH2:32][NH2:33])([CH3:29])[CH3:28]>CN1C(=O)CCC1>[CH:1]1([C:4]([NH:6][C:7]2[S:8][C:9]3[CH:15]=[C:14]([O:16][S:17]([C:20]4[CH:25]=[CH:24][C:23]([NH:33][CH2:32][CH2:31][N:30]([CH:34]([CH3:36])[CH3:35])[CH:27]([CH3:29])[CH3:28])=[CH:22][CH:21]=4)(=[O:19])=[O:18])[CH:13]=[CH:12][C:10]=3[N:11]=2)=[O:5])[CH2:3][CH2:2]1
Reactant: CC(C)N(CCN)C(C)C
Reactant: O=C(Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2s1)C1CC1
Solvent: CN1CCCC1=O
Product: CC(C)N(CCNc1ccc(S(=O)(=O)Oc2ccc3nc(NC(=O)C4CC4)sc3c2)cc1)C(C)C

Procedure:
A solution of 4-fluorobenzenesulfonic 2-(cyclopropanecarbonylamino)benzo-thiazol-6-yl ester (example 7) (100 mg, 255 μmol) and N,N-diisopropyl-ethane-1,2-diamine (147 mg, 1.02 mmol) in 2 ml of NMP is heated at 110° C. by microwave for 10 minutes. The crude reaction product is purified by preparative LC/MS (basic medium (pH 9)) to give after freeze-drying 66 mg of 4-(2-hydroxy-2-methylpropylamino)benzenesulfonic 2-(cyclopropanecarbonyl-amino)benzothiazol-6-yl ester (beige-colored solid).
Reaction SMILES: [CH3:1][NH2:2].Cl.[N:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][S:12](Cl)(=[O:14])=[O:13])=[CH:6][CH:5]=1.C(=O)([O-])O.[Na+]>CO.O>[CH3:1][NH:2][S:12]([CH2:11][CH2:10][C:7]1[CH:8]=[CH:9][N:4]=[CH:5][CH:6]=1)(=[O:14])=[O:13]
Reactant: O=S(=O)(Cl)CCc1ccncc1
Reactant: CN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CNS(=O)(=O)CCc1ccncc1
Temperature: 25 °C

Procedure:
To 50 ml of a 40% solution of methylamine in methanol was added 3.0 g of 2-(pyridin-4-yl)ethanesulfonyl chloride hydrochloride as such (i.e., as a solid). After stirring for a while at room temperature, a solution of 2.1 g of sodium hydrogencarbonate in 15 ml of water was carefully added thereto. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluted with dichloromethane/methanol) to thereby give 1.3 g of the title compound as brownish white scaly crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([Cl:12])[C:6]=2[C:13]([OH:15])=O.S(Cl)([Cl:18])=O>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([Cl:12])[C:6]=2[C:13]([Cl:18])=[O:15]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1c(Cl)ccc2cc(Cl)cnc12
Product: O=C(Cl)c1c(Cl)ccc2cc(Cl)cnc12
Yield: 95.7 %

Procedure:
3,7-Dichloro-8-quinolinecarboxylic acid(20 g, 82 mmol) was added to thionyl chloride(80 ml), and the mixture refluxed for 3 hours and concentrated under reduced pressure to afford the desired product(20.6 g, yield=95.7%) as a light brown solid.
Reaction SMILES: Br[CH2:2][C:3]1[S:7][CH:6]=[N:5][C:4]=1[CH2:8][CH3:9].[SH:10][C:11]1[N:16]=[C:15]([OH:17])[CH:14]=[C:13]([C:18]([F:21])([F:20])[F:19])[N:12]=1.C(N(CC)CC)C>C(O)C>[CH2:8]([C:4]1[N:5]=[CH:6][S:7][C:3]=1[CH2:2][S:10][C:11]1[N:16]=[C:15]([OH:17])[CH:14]=[C:13]([C:18]([F:21])([F:19])[F:20])[N:12]=1)[CH3:9]
Reactant: CCc1ncsc1CBr
Reactant: Oc1cc(C(F)(F)F)nc(S)n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCc1ncsc1CSc1nc(O)cc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.8 %

Procedure:
A mixture of 5-(bromomethyl)-4-ethyl-1,3-thiazole (5.2 mmol), 2-sulfanyl-6-(trifluoromethyl)pyrimidin-4-ol (700 mg, 3.6 mmol), and triethylamine (1.5 mL, 11 mmol) in absolute ethanol (40 mL) was stirred at room temperature overnight. The mixture was evaporated. The residue was treated with diethyl ether (100 mL). The solid material was removed by filtration. The filtrate was recovered and evaporated. The crude product was purified by flash chromatography (0-4% MeOH/CH2Cl2), affording the title compound (900 mg, 78% yield); 1H NMR (500 MHz, DMSO-d6): δ 1.19 (t, 2H, J=7.5 Hz), 2.76 (m, 2H, J=7.5 Hz), 4.65 (s, 2H), 6.65 (s, 1H), 8.88 (s, 1H); M+ 322.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[C:8]2[C:20]3[N:19]4[CH:21]=[CH:22][N:23]=[C:18]4[C:17](=[O:24])[NH:16][C:15]=3[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=3)[CH:2]=1.CN(C)C=O>[Pd].C(O)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH:8]2[C:20]3[N:19]4[CH:21]=[CH:22][N:23]=[C:18]4[C:17](=[O:24])[NH:16][C:15]=3[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=3)[CH:2]=1
Reactant: O=c1[nH]c2c3ccccc3c(=Cc3cccnc3)c2n2ccnc12
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=c1[nH]c2c(n3ccnc13)C(Cc1cccnc1)c1ccccc1-2
Yield: 37.8 %

Procedure:
The procedure is performed as in Example 21, but starting with 1 g of 10-(3-pyridylmethylene)-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one, 150 ml of dimethylformamide, 5 ml of acetic acid and 0.1 g of 10% palladium on charcoal. 0.38 g of 10-(3-pyridylmethyl)-5H,10H-imidazo[1,2-a]indeno-[1,2-e]pyrazin-4-one is obtained, in the form of an off-white solid melting above 260° C. (Analysis % calculated C: 72.60, H: 4.49, N: 17.82, O: 5.09, % found C: 72.3, H: 4.8, N: 17.8, O: 5.4).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([S:12](Cl)(=[O:14])=[O:13])=[CH:9]2)=[CH:4][CH:3]=1.[CH2:16]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCN(CC)CC>C1COCC1>[CH2:24]([N:23]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[S:12]([C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][C:2]([Br:1])=[CH:3][CH:4]=2)[CH:9]=1)(=[O:14])=[O:13])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=S(=O)(Cl)c1ccc2ccc(Br)cc2c1
Reactant: c1ccc(CNCc2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccc2ccc(Br)cc2c1)N(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 92 %

Procedure:
A mixture of 207 (1.50 g, 4.92 mmol), dibenzylamine (1.45 g, 7.38 mmol), and Et3N (0.75 g, 7.38 mmol) in THF (15 mL) was stirred at room temperature for 48 h. The solvents were evaporated under reduced pressure and the residue was extracted with EtOAc. The EtOAc extracts were washed with water and brine, then dried and evaporated. The residue was purified by chromatography on silica gel eluting with petroleum ether/EtOAc (95:5 then 1:1) to give N,N-dibenzyl-7-bromo-2-naphthalenesulfonamide (208) (2.11 g, 92%). A sample was recrystallised from petroleum ether/EtOAc as colorless crystals: mp 127-129° C.; 1H NMR (CDCl3) δ 8.25 (d, J=1.4 Hz, 1H), 8.05 (d, J=1.6 Hz, 1H), 7.91 (d, J=8.7 Hz, 1H), 7.79 (dd, J1=8.6, 1.8 Hz, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.71 (dd, J=8.8, 1.9 Hz, 1H), 7.22-7.15 (m, 6H), 7.09-7.04 (m, 4H), 4.39 (s, 4H); 13C NMR δ 138.9, 135.4, 133.3, 133.0, 132.1, 131.2, 129.4, 129.3, 128.6, 128.5, 127.8, 127.3, 123.0, 121.6, 50.6. Anal. (C24H20BrNO2S. 1/10Bn2NH) C, H, N.