Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([NH:16][C:17]3[CH:48]=[CH:47][C:20]([O:21][C:22]4[CH:27]=[CH:26][N:25]=[C:24]([N:28]([C:38]([O:40]C5C=CC=CC=5)=O)C(=O)OC5C=CC=CC=5)[CH:23]=4)=[CH:19][CH:18]=3)=[O:15])[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.Cl.Cl.Cl.[CH3:52][N:53]([CH3:64])[CH:54]1[CH2:57][N:56]([CH:58]2[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]2)[CH2:55]1.C(N(CC)CC)C.O>CN(C)C=O>[CH3:52][N:53]([CH3:64])[CH:54]1[CH2:55][N:56]([CH:58]2[CH2:63][CH2:62][N:61]([C:38]([NH:28][C:24]3[CH:23]=[C:22]([O:21][C:20]4[CH:19]=[CH:18][C:17]([NH:16][C:14]([C:11]5([C:9]([NH:8][C:5]6[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=6)=[O:10])[CH2:13][CH2:12]5)=[O:15])=[CH:48][CH:47]=4)[CH:27]=[CH:26][N:25]=3)=[O:40])[CH2:60][CH2:59]2)[CH2:57]1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2)ccn1
Reactant: CN(C)C1CN(C2CCNCC2)C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C1CN(C2CCN(C(=O)Nc3cc(Oc4ccc(NC(=O)C5(C(=O)Nc6ccc(F)cc6)CC5)cc4)ccn3)CC2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 24.8 %

Procedure:
To a solution of phenyl N-[4-(4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-phenoxycarbonylcarbamate (50.0 mg) in N,N-dimethylformamide (2.0 ml) were added N,N-dimethyl-N-[1-(piperidin-4-yl)azetidin-3-yl]amine trihydrochloride (90.5 mg), triethylamine (0.129 ml) and water (0.10 ml), followed by stirring at room temperature for 12 hr. The reaction mixture was partitioned between ethyl acetate and a 1N aqueous solution of sodium hydroxide. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (Fuji Silysia NH, ethyl acetate, then ethyl acetate:methanol=20:1). Fractions containing the target compound were concentrated. To the residue was added diethyl ether:hexane=1:3, and the precipitate was collected by filtration. This was washed with hexane and dried under aeration to provide the titled compound as white powder (11.8 mg, 24.8%).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[Cl:5][C:6]1[CH:11]=[C:10]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2F)(=[O:14])=[O:13])[CH:9]=[CH:8][C:7]=1[NH:22][C:23](=[O:31])[C@:24]([OH:30])([CH3:29])[C:25]([F:28])([F:27])[F:26].[Cl-].[NH4+]>CN1C(=O)CCC1>[Cl:5][C:6]1[CH:11]=[C:10]([S:12]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=2[NH:4][CH2:3][CH2:1][OH:2])(=[O:14])=[O:13])[CH:9]=[CH:8][C:7]=1[NH:22][C:23](=[O:31])[C@:24]([OH:30])([CH3:29])[C:25]([F:28])([F:27])[F:26]
Reactant: NCCO
Reactant: C[C@@](O)(C(=O)Nc1ccc(S(=O)(=O)c2ccccc2F)cc1Cl)C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN1CCCC1=O
Product: C[C@@](O)(C(=O)Nc1ccc(S(=O)(=O)c2ccccc2NCCO)cc1Cl)C(F)(F)F
Temperature: 120 °C

Procedure:
Ethanolamine (0.014 ml) was added to a solution of (R)-N-[2-chloro-4-(2-fluoro-phenylsulphonyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Method 63) (0.10 g) in NMP (1.5 ml) and the solution was heated at 120° C. for 18 hours then cooled. Saturated aqueous ammonium chloride solution (10 ml) was added and the mixture was extracted with ethyl acetate (2×20 ml). The organic extracts were combined, washed with brine and dried. Volatile material was removed by evaporation and the residue was purified by chromatography on a silica gel Mega Bond Elut column eluting with 0-50% ethyl acetate/hexane to give the title compound (0.074 g) as a solid. Mp 68-70° C.; NMR (CDCl3): 1.75 (s, 3H), 3.3 (q, 2H), 3.90 (m, 2H), 3.95 (brs, 1H), 6.50 (brt, 1H), 6.70 (d, 1H) 6.80 (m, 1H), 7.4 (m, 1H), 7.85 (m, 2H), 8.00 (d, 1H), 8.55 (d, 1H), 9.25 (brs, 1H); MS (ESP−): 465; EA: found: C, 46.6; H, 4.0; N, 5.8%; C18H18ClF3N2O5S requires: C, 46.31; H, 3.89; N, 6.00%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:8]([CH:18]=O)=[CH:7]2.Cl.CN.C[CH2:24][N:25](C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[NH2:45][C:46]1[N:51]=[C:50](Cl)[CH:49]=[C:48]([CH3:53])[N:47]=1>C(Cl)Cl.C1COCC1>[CH3:24][N:25]([CH2:18][C:8]1[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:10][C:11]2[C:6]([CH:7]=1)=[CH:5][CH:4]=[CH:3][C:2]=2[CH3:1])[C:50]1[CH:49]=[C:48]([CH3:53])[N:47]=[C:46]([NH2:45])[N:51]=1
Reactant: Cc1cc(Cl)nc(N)n1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1cccc2cc(C=O)c(-c3ccccc3)nc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CN
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cc(N(C)Cc2cc3cccc(C)c3nc2-c2ccccc2)nc(N)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 20.3 %

Procedure:
A mixture of 8-methyl-2-phenylquinoline-3-carboxaldehyde (100 mg, 0.4 mmol), methylamine hydrochloride (120 mg, 1.8 mmol) and DIPEA (230 mg, 1.8 mmol) in DCM (20 mL) was treated with titanium(IV) n-propoxide (228 mg, 0.8 mmol). The reaction mixture was stirred at r.t. for 18 h. The solvent was removed in vacuo and the residue dissolved in THF (20 mL) before triacetoxyborohydride (170 mg, 0.8 mmol) was added. The reaction mixture was stirred at r.t. for 2 h, the solvent removed in vacuo and the residue partitioned between DCM (100 mL) and water (30 mL). The organic layer was separated, dried (MgSO4) and the solvent removed in vacuo. The residue was dissolved in NMP (2 mL) and to this solution was added DIPEA (230 mg, 1.8 mmol) and 2-amino-4-chloro-6-methylpyrimidine (57 mg, 0.4 mmol). The mixture was heated in a microwave at 220° C. for 2 h. Purification by preparative HPLC (Method 1) gave the title compound as an off-white solid (30 mg, 20%). δH (CDCl3) 7.82 (s, 1H), 7.62-7.70 (m, 2H), 7.61 (d, J 7.9 Hz, 1H), 7.46-7.55 (m, 5H), 5.75 (s, 1H), 4.93 (s, 2H), 4.67 (s, 2H), 2.93 (s, 3H), 2.82 (s, 3H), 2.22 (s, 3H). LCMS (ES+) 370.2 (M+H)+, RT 2.36 minutes (Method 3).
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([C:13]2[C:14](=[O:23])[N:15]([CH3:22])[N:16]=[C:17]([CH3:21])[C:18]=2[O:19][CH3:20])[CH:5]=1.C([O-])(O)=O.[Na+].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>C(Cl)Cl>[CH3:20][O:19][C:18]1[C:17]([CH3:21])=[N:16][N:15]([CH3:22])[C:14](=[O:23])[C:13]=1[N:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([Cl:3])=[C:5]1[Br:1]
Reactant: COc1c(C)nn(C)c(=O)c1-n1cc(Cl)c2ccccc21
Reactant: BrBr
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1c(C)nn(C)c(=O)c1-n1c(Br)c(Cl)c2ccccc21
Yield: 49.7 %

Procedure:
Part of a solution of bromine (200 mg, 1.25 mmol) in DCM (4 mL) is added dropwise, slowly, to a solution of 4-(3-chloroindol-1-yl)-5-methoxy-2,6-dimethyl-pyridazin-3-one (184 mg, 0.606 mmol) in DCM (2 mL) at 0° C. The bromine decolourised as it was added and addition was continued cautiously until an orange colour just persisted. NaHCO3 (0.5 g saturated solution in water) is added cautiously, followed by sufficient sodium metabisulphite to decolorise the excess bromine. The resulting reaction mixture was extracted with DCM (3×60 mL) and the combined DCM layers were filtered through MgSO4 and concentrated in vacuo. The resulting yellow gum was purified by flash chromatography (combiflash, 0 to 30% DCM/EtOAc) to yield the desired pro duct 5-methoxy-2,6-dimethyl-4-(2-bromo-3-chloroindol-1-yl)pyridazin-3-one (115 mg, 0.301 mmol, 50% Yield) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[S:4][C:3]=1/[CH:8]=[CH:9]/[C:10](N(C)C)=O.[N+]([O-])(O)=O.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH2:29])=[NH:28])=[CH:22][C:21]=1[CH2:30][OH:31]>CC#N>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]2[N:29]=[C:8]([C:3]3[S:4][C:5]([CH3:7])=[N:6][C:2]=3[CH3:1])[CH:9]=[CH:10][N:28]=2)=[CH:22][C:21]=1[CH2:30][OH:31]
Reactant: Cc1nc(C)c(/C=C/C(=O)N(C)C)s1
Reactant: N=C(N)Nc1ccc(Cl)c(CO)c1
Solvent: CC#N
Solvent: O=[N+]([O-])O
Product: Cc1nc(C)c(-c2ccnc(Nc3ccc(Cl)c(CO)c3)n2)s1

Procedure:
By condensation of 3-dimethylamino-1-(2,4-dimethyl-thiazol-5-yl)-propenone and N-(4-chloro-3-hydroxymethyl-phenyl)-guanidine nitrate. Yellow solid. Mp 245-246° C. Anal. RP-HPLC: tR=14.6 min (10-70% MeCN, purity >95%). 1H-NMR (DMSO-D6) δ: 2.62 (s, 3H, CH3), 2.63 (s, 3H, CH3), 4.53 (d, 2H, J=5.5 Hz, CH2), 5.34 (m, 1H, OH), 7.08 (d, 1H, J=5.5 Hz, pyrimidinyl-H), 7.29 (m, 1H, Ph-H), 7.73 (m, 1H, Ph-H), 7.94 (s, 1H, Ph-H), 8.51 (d, 1H, J=5.5 Hz, pyrimidinyl-H), 9.78 (s, 1H, NH). MS (ESI+) m/z 347.11 [M+H]+ (C16H15ClN4OS requires 346.84).
Reaction SMILES: [CH3:1][N:2]1[CH:6]([C:7]([O:9]C(C)(C)C)=[O:8])[CH2:5][N:4]([C:14]2[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=2)[C:3]1=[O:21].[C:22]([OH:28])([C:24]([F:27])([F:26])[F:25])=[O:23].C(Cl)Cl>>[OH:28][C:22]([C:24]([F:27])([F:26])[F:25])=[O:23].[CH3:1][N:2]1[CH:6]([C:7]([OH:9])=[O:8])[CH2:5][N:4]([C:14]2[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=2)[C:3]1=[O:21]
Reactant: Cc1cccnc1N1CC(C(=O)OC(C)(C)C)N(C)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccnc1N1CC(C(=O)O)N(C)C1=O

Procedure:
A solution of 1,1-dimethylethyl 3-methyl-2-oxo-4-imidazolidinecarboxylate (600 mg, 3 mmol) (prepared as described in step (iii) of Example 13, starting from (4S)-2-oxo-3-{[(phenylmethyl)oxy]carbonyl}-4-imidazolidinecarboxylic acid) and 2-bromo-3-methylpyridine (515 mg, 3 mmol) in 1,4-dioxane (20 ml) was treated with cesium carbonate (1464 mg, 4.5 mmol), Xantphos™ (130 mg, 0.225 mmol) and tris(dibenzylideneacetone)dipalladium(0) (68.6 mg, 0.075 mmol) and the mixture was heated under reflux under argon for 18 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined, washed with water and brine and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with 0-100% ethyl acetate in isohexane to give 1,1-dimethylethyl 3-methyl-1-(3-methyl-2-pyridinyl)-2-oxo-4-imidazolidinecarboxylate (700 mg, 80%). LC/MS [M+H]+=292. (ii) A solution of 1,1-dimethylethyl 3-methyl-1-(3-methyl-2-pyridinyl)-2-oxo-4-imidazolidinecarboxylate (700 mg, 2.4 mmol) in TFA/DCM (1:2, 12 ml) was stirred at room temperature for 6 hours. The solution was evaporated and the residue was co-evaporated with toluene and dried to give 3-methyl-1-(3-methyl-2-pyridinyl)-2-oxo-4-imidazolidinecarboxylic acid TFA salt (assume ˜2.4 mmol) which was used in the next step. LC/MS [M+H]+=236.
Reaction SMILES: [C:1]([O:13][CH3:14])(=[O:12])[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH2:15](O)CO>>[CH2:15]=[CH:6][C:5]1[CH:4]=[CH:3][CH:2]=[CH:11][CH:10]=1.[C:6]1(=[O:7])[O:8][CH2:9][CH2:14][O:13][C:1](=[O:12])[C:2]2[CH:11]=[CH:10][C:5]1=[CH:4][CH:3]=2
Reactant: COC(=O)c1ccc(C(=O)OC)cc1
Reactant: OCCO
Product: C=Cc1ccccc1
Product: O=C1OCCOC(=O)c2ccc1cc2
Temperature: 190 °C

Procedure:
Dimethyl terephthalate is recrystallized from dried ethanol. 30 g (0.154 mol) of the dimethyl terephthalate and 30 ml of TCB are added to a 250 ml three-neck round bottom flask fitted with a nitrogen stream inlet and outlet, a magnet stirrer, a dropping funnel, and a condenser, and heated to about 190° C. 20 g of hydroxy-terminated polystyrene, 70 ml of TCB, and 2 ml of catalyst solution (titanium butoxide, magnesium acetate, methanol, and butanediol solution) are introduced dropwise into the reactor over 3 hours. After refluxing for one and one-half hours and confirming the absence of hydroxy-terminated polystyrene by thin layer chromotography analysis, the reactor is cooled to below 190° C., and 10.54 g (0.170 mol) of ethylene glycol is added. The contents are kept refluxing at about 214° C. for 10 hours while maintaining a nitrogen stream purge. The reaction mixture is thereafter cooled, and the crude styrene-ethylene terephthalate product precipitated in excess methanol before being dried in a vacuum oven for 24 hours. The crude condensation product is finally extracted with cyclohexane for 12 hours to remove unreacted or chain unextended polystyrene.
Reaction SMILES: FC(F)(F)[C:3]1([C:7]([OH:9])=O)[CH2:6][CH2:5][CH2:4]1.O=S(Cl)Cl.[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C@:23]([C:32]2[CH:37]=[C:36]([O:38][C:39]([F:44])([F:43])[CH:40]([F:42])[F:41])[CH:35]=[C:34]([F:45])[CH:33]=2)([NH2:31])[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:21][CH:22]=1>ClCCCl>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]([NH:31][C:7]([CH:3]2[CH2:4][CH2:5][CH2:6]2)=[O:9])([C:32]2[CH:37]=[C:36]([O:38][C:39]([F:43])([F:44])[CH:40]([F:42])[F:41])[CH:35]=[C:34]([F:45])[CH:33]=2)[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:21][CH:22]=1
Reactant: N[C@@](Cc1ccccc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(Cl)cn1
Reactant: O=C(O)C1(C(F)(F)F)CCC1
Solvent: O=S(Cl)Cl
Solvent: ClCCCl
Product: O=C(NC(Cc1ccccc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(Cl)cn1)C1CCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 22 %

Procedure:
To a solution of 1-trifluoromethylcyclobutyl carboxylic acid (22.7 mg, 0.135 mmol) in DCE (1 mL) was added SOCl2 (16 mg, 0.135 mmol) and the resulting mixture was heated at reflux for 2 h. The reaction mixture was allowed to cool down to room temperature and TEA was added (31 μL, 0.23 mmol), followed by the addition of (S)-1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethanamine (20 mg, 0.045 mmol). The reaction was stirred at room temperature for 18 h, concentrated and the residue purified by preparative HPLC Shimadzu-AXIA column, 30×100 mm eluting with 30-100% MeOH (90% in H2O, 0.1% TFA) gradient over 12 min with flow rate 40 mL/min and UV detection at 220 nm to give N-(1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)cyclobutanecarboxamide (5.2 mg, 22% yield). LCMS: RT=2.14 min [M+H] 525.2 (LCMS Method 2.); NMR: 400 MHz 1H (CDCl3) 8.29 ppm, 1H, s; 8.13 ppm, 1H, s; 7.68 ppm, 1H, m; 7.11 ppm, 6H, m; 6.87 ppm, 1H, m; 6.57 ppm, 2H, m; 5.87 ppm, 1H, t, J=53 Hz; 4.45 ppm, 1H, dd, J=12.8, 3.6 Hz; 3.51 ppm, 1H, dd, J=12.8, 3.6 Hz; 3.09 ppm, 1H, m; 2.20 ppm, 4H, m; 1.94 ppm, 2H, m.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[CH:10]=[C:11]([S:16]([N:19]([C:21]2[S:25][C:24]3[CH2:26][CH2:27][CH2:28][CH2:29][C:23]=3[C:22]=2[C:30]([O:32]C(C)(C)C)=[O:31])[CH3:20])(=[O:18])=[O:17])[CH:12]=[CH:13][C:14]=1[Cl:15]>C(Cl)Cl>[Cl:8][C:9]1[CH:10]=[C:11]([S:16]([N:19]([C:21]2[S:25][C:24]3[CH2:26][CH2:27][CH2:28][CH2:29][C:23]=3[C:22]=2[C:30]([OH:32])=[O:31])[CH3:20])(=[O:17])=[O:18])[CH:12]=[CH:13][C:14]=1[Cl:15]
Reactant: CN(c1sc2c(c1C(=O)OC(C)(C)C)CCCC2)S(=O)(=O)c1ccc(Cl)c(Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(c1sc2c(c1C(=O)O)CCCC2)S(=O)(=O)c1ccc(Cl)c(Cl)c1
Reaction time: 1 h

Procedure:
TFA (30 ml, 404 mmol) was added to a solution of tert-butyl 2-(3,4-dichloro-N-methylphenylsulfonamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (8.00 g, 16.8 mmol) in DCM (100 ml), and stirring was carried out for 1 h at room temperature. The reaction mixture was concentrated, and the TFA that remained was removed with toluene, DCM and diethyl ether. The residue was washed twice with diisopropyl ether.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[F:7][C:8]1[N:13]=[C:12]([O:14][CH3:15])[C:11](B(O)O)=[CH:10][CH:9]=1.Cl[C:20]1[C:29]2[C:24](=[CH:25][C:26]([S:30]([NH:33][C:34]3[CH:39]=[CH:38][N:37]=[CH:36][N:35]=3)(=[O:32])=[O:31])=[CH:27][CH:28]=2)[CH:23]=[CH:22][N:21]=1>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.O1CCOCC1>[F:7][C:8]1[N:13]=[C:12]([O:14][CH3:15])[C:11]([C:20]2[C:29]3[C:24](=[CH:25][C:26]([S:30]([NH:33][C:34]4[CH:39]=[CH:38][N:37]=[CH:36][N:35]=4)(=[O:31])=[O:32])=[CH:27][CH:28]=3)[CH:23]=[CH:22][N:21]=2)=[CH:10][CH:9]=1
Reactant: O=S(=O)(Nc1ccncn1)c1ccc2c(Cl)nccc2c1
Reactant: COc1nc(F)ccc1B(O)O
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: [Na+]
Solvent: C1COCCO1
Product: COc1nc(F)ccc1-c1nccc2cc(S(=O)(=O)Nc3ccncn3)ccc12
Yield: 40 %

Procedure:
To a microwave vial containing Na2CO3 (1.216 ml, 2.432 mmol), (6-fluoro-2-methoxypyridin-3-yl)boronic acid (0.166 g, 0.973 mmol) and 1-chloro-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (0.26 g, 0.811 mmol) and Dioxane (4.05 ml) was added tetrakis(triphenylphosphine)palladium (0.094 g, 0.081 mmol) and purged with nitrogen and irradiated at 100° C. for 30 min. The reaction mixture was diluted with DMSO to dissolve the observed yellow ppt. Purification was done on reverse phase HPLC with 0.1% NH4OH in ACN and water as mobile phase to obtain 1-(6-fluoro-2-methoxypyridin-3-yl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (133.2 mg, 0.324 mmol, 39.9% yield) as yellow solid; m/z (ESI) 412.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[N+:16]([O-])=O)[O:5][CH2:6][CH2:7][N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1>[Pd].CO>[F:1][C:2]1[CH:3]=[C:4]([O:5][CH2:6][CH2:7][N:8]2[CH2:9][CH2:10][CH2:11][CH2:12]2)[CH:13]=[CH:14][C:15]=1[NH2:16]
Reactant: O=[N+]([O-])c1ccc(OCCN2CCCC2)cc1F
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(OCCN2CCCC2)cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of 1-[2-(3-fluoro-4-nitro-phenoxy)-ethyl]-pyrrolidine (1.96 g, 7.7 mmol) and 10% palladium on carbon (0.2 g) in MeOH (40 mL) is stirred for 0.5 h at RT, under a hydrogen atmosphere. The reaction mixture is filtered through a pad of celite and concentrated to provide the title compound. ESI-MS: 225.1 [MH]; tR=0.95 min (system 1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:9]=1.[H-].[Na+].Cl.[CH3:22][N:23]([CH2:25][CH2:26]Cl)[CH3:24].Cl>O1CCOCC1.C(O)C>[CH3:22][N:23]([CH2:25][CH2:26][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[C:10]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:9]=1)[CH3:24]
Reactant: CN(C)CCCl
Reactant: Oc1ccccc1-c1nc(-c2ccccc2)no1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: C1COCCO1
Product: CN(C)CCOc1ccccc1-c1nc(-c2ccccc2)no1
Temperature: 27.5 °C
Reaction time: 0.25 h

Procedure:
2.38 g of 5-(2-hydroxyphenyl)-3-phenyl-1,2,4-oxadiazole are dissolved in 100 ml of anhydrous dioxane and stirred with 0.3 g of 80% sodium hydride suspension in oil for 15 minutes at 25-30° C. To this solution is added 60 ml of anhydrous dioxane, the resulting mixture is combined with 2.88 g of 2-(N,N-dimethylamino)ethylchloride hydrochloride and 0.6 g of 80% sodium hydride suspension in oil. This solution is also stirred for 15 minutes at 25-30° C. The combined solutions are refluxed for 8 hours, left to stand overnight and evaporated down in vacuo. The residue is mixed with water and 20 ml of 1N sodium hydroxide solution and extracted with ethyl acetate. The organic phase is dried over sodium sulphate, the solvent evaporated in vacuo and the residue chromatographed on silica gel with ethyl acetate/isopropanol (70:30, mixed with 2.5% of a 25% ammonia solution). The base thus obtained is dissolved in anhydrous ethanol, acidified with ethereal HCl and precipitated with diethyl ether. The residue is recrystallised from anhydrous ethanol and diethylether. Yield: 2.2 g (64% of theory). m.p.: 186-187° C.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-])=O)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5].O.NN>[Fe](Cl)(Cl)Cl.CO>[CH3:18][N:2]([CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH2:15])[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:1]
Reactant: CN(C)CC(=O)N1CCc2ccc([N+](=O)[O-])cc21
Agent: Cl[Fe](Cl)Cl
Agent: NN
Solvent: O
Solvent: CO
Product: CN(C)CC(=O)N1CCc2ccc(N)cc21
Temperature: 65 °C
Yield: 80.2 %

Procedure:
A suspension of N,N-dimethyl-2-(6-nitro-2,3-dihydro-1 H-indol-1-yl)-2-oxoethanamine (13.6 g, 54.6 mmol), hydrazine hydrate (21.42 mL, 436 mmol), iron (III) chloride (1.768 g, 10.91 mmol), activated carbon (15 g), and methanol (100 mL) was maintained at 65° C. for 12 hours, cooled, and filtered through celite (rinsed with additional methanol). Filtrates were concentrated, redissolved in ethyl acetate, and washed twice with saturated aqueous sodium chloride and sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered, and concentrated to afford 1-[(dimethylamino)acetyl]-2,3-dihydro-1H-indol-6-amine (9.6 g, 80% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.44 (d, J=1.40 Hz, 1 H), 6.83 (d, J=8.03 Hz, 1 H), 6.20 (dd, J=7.93, 2.11 Hz, 1 H), 4.94 (s, 2 H), 4.06 (t, J=8.43 Hz, 2 H), 3.14 (s, 2 H), 2.91 (t, J=8.33 Hz, 2 H), 2.25 (s, 6 H).
Reaction SMILES: [C:1]([CH:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]1[N:14]=[C:13]([C:15](=O)[CH2:16]Br)[CH:12]=[CH:11][CH:10]=1)([OH:3])=[O:2].[CH2:19]([O:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[O:31][CH2:32][CH3:33])[C:25]([NH2:27])=[S:26])[CH3:20]>>[CH2:19]([O:21][C:22]1[CH:23]=[C:24]([C:25]2[S:26][CH:16]=[C:15]([C:13]3[CH:12]=[CH:11][CH:10]=[C:9]([N:5]4[CH2:6][CH2:7][CH2:8][CH:4]4[C:1]([OH:3])=[O:2])[N:14]=3)[N:27]=2)[CH:28]=[CH:29][C:30]=1[O:31][CH2:32][CH3:33])[CH3:20]
Reactant: O=C(CBr)c1cccc(N2CCCC2C(=O)O)n1
Reactant: CCOc1ccc(C(N)=S)cc1OCC
Product: CCOc1ccc(-c2nc(-c3cccc(N4CCCC4C(=O)O)n3)cs2)cc1OCC

Procedure:
A reaction was conducted in the same manner as in Example 1, by using 6-(2-carboxy-1-pyrrolidinyl)-2-(α-bromoacetyl)pyridine and 3,4-diethoxythiobenzamide, to obtain 2-(3,4-diethoxyphenyl)-4-[6-(2-carboxy-1-pyrrolidinyl)-2-pyridyl]thiazole.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O.Cl[CH2:15][C:16]([O:18][C:19](=O)[CH2:20]Cl)=O.O1C=CC=C1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([C:16]1[O:18][CH:19]=[CH:20][CH:15]=1)=[O:12])=[O:13]
Reactant: O=C(CCl)OC(=O)CCl
Reactant: COC(=O)CCCCCCC(=O)O
Solvent: Cc1ccccc1
Solvent: c1ccoc1
Product: COC(=O)CCCCCCC(=O)c1ccco1
Temperature: 50 °C
Reaction time: 6 h
Yield: 92.3 %

Procedure:
In 50 ml of toluene were dissolved 9.41 g (0.05 mole) of suberic acid monomethyl ester and 9.83 g (0.0575 mole) of monochloroacetic anhydride. To the resulting solution were added 4.43 g (0.065 mole) of furan and 0.71 g of boron trifluoride-diethyl ether complex and the resulting mixture was then stirred at 50° C. for 6 hours. After completion of the reaction, the reaction solution was cooled and washed successively with of water, 5% aqueous sodium carbonate solution and water. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure and the resulting concentrated residue was purified by silica gel-filled column chromatography to obtain 11 g of 2-(7-methoxycarbonyl-1-oxoheptyl)furan.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].C(O)(=O)CC.N(OS(=O)(=O)O)=O.[CH:24]([O:26][C:27](=[O:40])[CH2:28][CH2:29][CH2:30][N:31]([CH2:38][CH3:39])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[CH2:25].S(=O)(=O)(O)[NH2:42]>CO.C(O)(=O)C>[CH:24]([O:26][C:27](=[O:40])[CH2:28][CH2:29][CH2:30][N:31]([C:32]1[CH:37]=[CH:36][C:35]([N:42]=[N:4][C:3]2[CH:5]=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:2]=2[Cl:1])=[CH:34][CH:33]=1)[CH2:38][CH3:39])=[CH2:25]
Reactant: C=COC(=O)CCCN(CC)c1ccccc1
Reactant: NS(=O)(=O)O
Reactant: Nc1ccc([N+](=O)[O-])cc1Cl
Agent: O=NOS(=O)(=O)O
Solvent: CC(=O)O
Solvent: CO
Solvent: CCC(=O)O
Product: C=COC(=O)CCCN(CC)c1ccc(N=Nc2ccc([N+](=O)[O-])cc2Cl)cc1
Temperature: 5 °C
Reaction time: 2 h

Procedure:
5.2 parts of 2-chloro-4-nitroaniline, 20 parts of propionic acid and 30 parts of acetic acid were charged and cooled to 5° C. 11.4 parts of 40% (w/w) nitrosyl sulfuric acid were added, whilst the temperature was held below 10° C. The diazotization mixture was stirred for a further 2 hrs at 5-10° C. To a separate vessel were charged 7.0 parts of 4-(ethyl-phenyl-amino)-butyric acid vinyl ester, 100 parts of methanol, 1 part sulfamic acid and 100 parts of ice. With stirring, the diazotization mixture was slowly added followed by a further 300 parts of ice. The reaction mixture was stirred over night and the product was isolated by filtration, washed with water and dried to yield 10.4 parts of 4-{[4-(2-chloro-4-nitrophenylazo)-phenyl]-ethyl-amino}-butyric acid vinyl ester. λmax=509 nm (DMF).