Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1.[O:22]=[C:23]1[CH:28]=[C:27]([CH2:29][CH2:30][NH:31][C:32](=[O:48])[C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)[CH:26]=[CH:25][NH:24]1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([NH:11][C:4]2[C:5]3[N:10]=[CH:9][S:8][C:6]=3[N:7]=[C:2]([C:36]3[CH:37]=[CH:38][C:33]([C:32]([NH:31][CH2:30][CH2:29][C:27]4[CH:26]=[CH:25][NH:24][C:23](=[O:22])[CH:28]=4)=[O:48])=[CH:34][CH:35]=3)[N:3]=2)[CH:17]=[CH:16][C:15]=1[O:18][CH3:19]
Reactant: CC1(C)OB(c2ccc(C(=O)NCCc3cc[nH]c(=O)c3)cc2)OC1(C)C
Reactant: COc1ccc(Nc2nc(Cl)nc3scnc23)cc1OC
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
Solvent: O
Product: COc1ccc(Nc2nc(-c3ccc(C(=O)NCCc4cc[nH]c(=O)c4)cc3)nc3scnc23)cc1OC
Yield: 9.2 %

Procedure:
Under N2 atmosphere, 5-chloro-N-(3,4-dimethoxyphenyl)thiazolo[5,4-d]pyrimidin-7-amine (100 mg, 0.31 mmol), N-(2-(2-oxo-1,2-dihydropyridin-4-yl)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (140 mg, 0.38 mmol), Pd(PPh3)4 (20 mg, 0.017 mmol) was added in 20 mL of 1,4-dioxane. Na2CO3 (100 mg, 0.94 mmol) in 3 mL of water was added and then the mixture was stirred at reflux for 18 hours. The solvent was removed under reduce pressure and the residue was purified by silica gel chromatography, eluting with DCM/MeOH (20/1) to give 4-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)-N-(2-(2-oxo-1,2-dihydropyridin-4-yl)ethyl)benzamide (15 mg, 9%) as a yellow sold. 1H NMR (300 MHz, DMSO): δ 11.34 (s, 1H), 10.15 (s, 1H), 9.38 (s, 1H), 8.67-8.65 (m, 1H), 8.45 (s, 1H), 8.43 (s, 1H), 7.95-7.81 (m, 3H), 7.51-7.47 (m, 1H), 7.26 (d, 1H, J=6.6 Hz), 7.01 (d, 1H, J=8.7 Hz), 6.15 (s, 1H), 6.08 (d, 1H, J=6.6 Hz), 3.83 (s, 3H), 3.78 (s, 3H), 3.50-3.48 (m, 2H), 2.72-2.65 (m, 2H). LC-MS: 528.9 [M+H]+, tR=1.35 min. HPLC: 98.40% at 214 nm, 99.86% at 254 nm, tR=5.18 min.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][S:7][C:8]1[N:13]=[CH:12][C:11](N)=[CH:10][CH:9]=1.N([O-])=[O:16].[Na+].C(=O)(O)[O-].[Na+]>O>[CH3:6][S:7][C:8]1[N:13]=[CH:12][C:11]([OH:16])=[CH:10][CH:9]=1
Reactant: CSc1ccc(N)cn1
Reactant: O=N[O-]
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CSc1ccc(O)cn1
Reaction time: 0.5 h
Yield: 60 %

Procedure:
A solution of 5.5 ml of concentrated sulfuric acid and 8 ml of water is added to 1.9 g (13.55 mM) of 6-(methylthio)-3-pyridinamine. The reaction medium is brought to −6° C. and a solution of 1.59 g (23.03 mM) of sodium nitrite in 3 ml of water is added dropwise without exceeding 0° C. The mixture is stirred for 1 hour 30 min between 0° C. and −4° C. and then refluxed for 1 hour. The cooled reaction medium is poured in the presence of sodium bicarbonate and the mixture is then extracted with ethyl acetate. The organic phase is concentrated under reduced pressure and the residue is then chromatographed on silica gel (dichloromethane/ethyl acetate, 90/10; v/v) to give the expected product in the form of a white powder with a yield of 60%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=S)[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1.[NH2:20][CH2:21][C:22]([OH:24])=[O:23].C(=O)([O-])[O-].[Na+].[Na+].Cl>O.C(O)C>[C:22]([CH2:21][NH:20][C:10]1[CH2:9][N:8]=[C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:6]2[CH:19]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[N:11]=1)([OH:24])=[O:23]
Reactant: S=C1CN=C(c2ccccc2)c2cc(Cl)ccc2N1
Reactant: NCC(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(O)CNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Yield: 77.5 %

Procedure:
A suspension of 3.5 g of 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-thione, 5.5 g of glycine, 5.5 g of sodium carbonate, 100 ml of ethanol and 30 ml of water was refluxed with stirring for an hour and the mixture was poured into water. The pH of the solution was adjusted to 4 by addition of 2N hydrochloric acid and was extracted with chloroform. The mixture was filtered and the filtrate was dried over magneesium sulfate and evaporated to dryness. The gummy residue was crystallized by trituration with methanol and the mixture was filtered. The recovered solid was crystallized from ethanol to obtain 3.1 g (77% yield) of 2-carboxymethylamino-7-chloro-5-phenyl-3H-1,4-benzodiazepine melting at 215-220° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[C:16]2[CH:17]=[CH:18][C:19]4[N+:23]([O-])=[C:22]([C:25]5[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=5)[NH:21][C:20]=4[CH:31]=2)[CH:13]=[CH:12][O:11]3)=[CH:4][CH:3]=1.O.O.[Sn](Cl)Cl.C([O-])(O)=O.[Na+].N([O-])=O.[Na+]>O.CCO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[C:16]2[CH:17]=[CH:18][C:19]4[N:23]=[C:22]([C:25]5[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=5)[NH:21][C:20]=4[CH:31]=2)[CH:13]=[CH:12][O:11]3)=[CH:4][CH:3]=1
Reactant: [O-][n+]1c(-c2ccncc2)[nH]c2cc(-c3c(-c4ccc(F)cc4)nc4occn34)ccc21
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: O=N[O-]
Solvent: CCO
Solvent: O
Product: Fc1ccc(-c2nc3occn3c2-c2ccc3nc(-c4ccncc4)[nH]c3c2)cc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 67.7 %

Procedure:
A mixture of 6-[6-(4-fluorophenyl)-imidazo[2,1-b]oxazol-5-yl]-2-pyridin-4-yl-1H-benzoimidazole 3-oxide (0.26 g, 0.56 mmol), tin(II) chloride dihydrate (0.64 g, 2.8 mmol) and EtOH (5.5 mL) was heated at about 70° C. for about 18 h. The reaction was poured over ice then the pH was adjusted to 8 with saturated aqueous NaHCO3 and filtered to remove tin salts. The filter cake was stirred with EtOAc (3×30 mL) then filtered. Each organic filtrate was then used to extract the initial aqueous filtrate. The combined organic layers were washed with brine, dried over Na2SO4, decanted, and concentrated. To the crude material was added 6 M HCl in water (0.94 mL; VWR). The reaction was cooled to about 0° C. and then NaNO2 (0.058 g, 0.85 mmol) in water (0.53 mL) was added dropwise. After about 2 h, no reaction was seen by LC-MS. The reaction was filtered, washing with water, and dried in the vacuum oven at 55-65° C. to give the title compound (0.15 g, 64%): LC/MS (Table 1, Method b) Rt, =1.82 min; MS m/z: 396.2 (M+H)+.
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[CH:12]=[C:11]([OH:13])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7].[C:14](OC(=O)C)(=[O:16])[CH3:15].Cl>O>[F:3][C:4]1[CH:12]=[C:11]([O:13][C:14](=[O:16])[CH3:15])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1ccc(O)cc1F
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(=O)Oc1ccc(C(=O)O)c(F)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 62.4 %

Procedure:
In a 100 ml-reaction vessel, 12.1 g (1.83×10-1M) of potassium hydroxide and 50 ml of water were placed, followed by cooling to 0° C. To the mixture, 12.0 g (7.69×10-2M) of 2-fluoro-4-hydroxybenzoic acid was added and dissolved therein. To the solution, 7.9 g (7.74×10-2M) of acetic anhydride was added dropwise in 30 minutes at 0° C., followed by stirring for 2 hours. After stirring, the reaction mixture was acidified with 6N-hydrochloric acid to precipitate a crystal. The crystal was recovered by filtration, followed by washing with water and drying to obtain 9.5 g of 2-fluoro-4-acetoxybenzoic acid (Yield: 62.4%).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].O=P(Cl)(Cl)[Cl:26]>>[Cl:26][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnc2ccc(Oc3ccccc3)cc2c1O
Product: CCOC(=O)c1cnc2ccc(Oc3ccccc3)cc2c1Cl

Procedure:
Prepared as in Example 1b from ethyl 4-hydroxy-6-phenoxyquinoline-3-carboxylate (Example 8c) and POCl3 as a tan solid (96%). 1H NMR (400 MHz, DMSO-d6) δ 1.36 (t, J=8.0 Hz, 3H), 4.40 (q, J=8.0 Hz, 2H), 7.23 (d, J=8.0 Hz, 2H), 7.29 (t, J=8.0 Hz, 1H), 7.50 (t, J=8.0 Hz, 2H), 7.63 (d, J=4.0 Hz, 1H), 7.76 (dd, J=8.0 Hz, 1H), 8.21 (d, J=8.0 Hz, 1H), 9.06 (s, 1H). MS 328, 330 (MH+).
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([CH2:34][CH2:35]CS([O-])(=O)=O)[CH2:19][CH2:18][N:17]([C:20](=[O:33])[C:21]3[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=3)[CH2:16]2)=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.Cl.[C:42]1([C:48]2([C:54]([NH2:56])=[O:55])[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]2)[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([CH2:34][CH2:35][N:51]3[CH2:50][CH2:49][C:48]([C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=4)([C:54]([NH2:56])=[O:55])[CH2:53][CH2:52]3)[CH2:19][CH2:18][N:17]([C:20](=[O:33])[C:21]3[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=3)[CH2:16]2)=[CH:11][CH:10]=1
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(O[Si](C)(C)C(C)(C)C)cc3)C2)cc(OC)c1OC
Agent: Cl
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3ccc(O)cc3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 3.3 using 2-[3-[4-(tert-butyldimethylsilyloxy)-phenyl]-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (8 mmol) and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride (12 mmol). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[C:6]([OH:8])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:52][C:53]1[CH:64]=[CH:63][C:56]2[NH:57][C:58]([CH:60]([NH2:62])[CH3:61])=[N:59][C:55]=2[CH:54]=1.ClCl>O1CCCC1.C(Cl)Cl.C(O)C>[Cl:52][C:53]1[CH:64]=[CH:63][C:56]2[NH:57][C:58]([CH:60]([NH:62][C:6](=[O:8])[C:5]3[CH:9]=[CH:10][C:11]([C:12]([N:14]4[CH2:18][CH2:17][CH2:16][CH2:15]4)=[O:13])=[C:3]([C:2]([F:1])([F:20])[F:19])[CH:4]=3)[CH3:61])=[N:59][C:55]=2[CH:54]=1
Reactant: O=C(O)c1ccc(C(=O)N2CCCC2)c(C(F)(F)F)c1
Reactant: CC(N)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: ClCCl
Product: CC(NC(=O)c1ccc(C(=O)N2CCCC2)c(C(F)(F)F)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1g from 3-trifluoromethyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine and rac.-1-(5-chloro-1H-benzimidazol-2-yl)ethylamine in tetrahydrofuran. Yield: quantitative; Rf value: 0.50 (silica gel; methylene chloride/ethanol=9:1); C22H20ClF3N4O2 (464.88); mass spectrum: (M−H)-=463/465 (chlorine isotope).
Reaction SMILES: [CH2:1]1[CH2:10][N:9]([C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14](O)=[O:15])[CH2:8][C:7]2[CH:6]=[N:5][C:4]3[CH:20]=[CH:21][CH:22]=[CH:23][C:3]=3[C:2]1=2.[CH2:24]([C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][CH:32]=1)[NH2:29])[CH3:25]>>[CH2:1]1[CH2:10][N:9]([C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14]([NH:29][C:28]2[CH:30]=[CH:31][CH:32]=[C:26]([CH2:24][CH3:25])[CH:27]=2)=[O:15])[CH2:8][C:7]2[CH:6]=[N:5][C:4]3[CH:20]=[CH:21][CH:22]=[CH:23][C:3]=3[C:2]1=2
Reactant: CCc1cccc(N)c1
Reactant: O=C(O)c1cccc(N2CCc3c(cnc4ccccc34)C2)c1
Product: CCc1cccc(NC(=O)c2cccc(N3CCc4c(cnc5ccccc45)C3)c2)c1
Yield: 52.8 %

Procedure:
In a manner similar to Example 3, 3-(1,4-dihydrobenzo[c]-2,7-naphthyridin-3(2H)-yl)benzoic acid (0.20 mmol, 61 mg) and 3-ethylaniline (0.30 mmol, 0.037 mL) were reacted to give the title compound as an off-white solid (43 mg, 53%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([NH2:18])[C:7]=1[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].[H-].[Na+].[CH3:21][O:22][C:23]1[CH:28]=[C:27]([O:29][CH3:30])[N:26]=[C:25](S(C)(=O)=O)[N:24]=1.Cl.[Cl-].[Na+]>O1CCCC1>[Cl:1][C:2]1[C:7]([C:8]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:9])=[C:6]([NH:18][C:25]2[N:26]=[C:27]([O:29][CH3:30])[CH:28]=[C:23]([O:22][CH3:21])[N:24]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: Nc1cccc(Cl)c1C(=O)OCc1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: COc1cc(OC)nc(Nc2cccc(Cl)c2C(=O)OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 50 %

Procedure:
Under a nitrogen atmosphere a solution of 5.2 grams (0.020 mole) of phenylmethyl 6-chloroanthranilate in 150 mL of tetrahydrofuran was stirred, and 0.8 gram (0.02 mole) of 60% sodium hydride in mineral was added in one portion. Upon completion of addition, the reaction mixture was stirred for 5 minutes, and the reaction mixture temperature was slowly brought to 50° C. After this time 4.3 grams (0.020 mole) of 4,6-dimethoxy-2-methylsulfonylpyrimidine (prepared as in Example 1, Steps A-C) was added in one portion. Upon completion of - addition, the reaction mixture was warmed to reflux where it was stirred for about 18 hours. The reaction mixture was cooled to ambient temperature and was poured into a solution of 50 mL of 3N hydrochloric acid and 200 mL of an aqueous solution saturated with sodium chloride. The mixture was extracted with three 250 mL portions of diethyl ether. The combined extracts were washed with one 250 mL portion of an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil. The oil was adsorbed onto silica gel and was subjected to column chromatography on silica gel. Elution was accomplished with 20% ethyl acetate in hexane. The appropriate fractions were combined and concentrated under reduced pressure to yield 4.0 grams of phenylmethyl 6-chloro-2-(4,6-dimethoxypyrimidin-2-ylamino)benzoate. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1Cl)=[CH:9][CH:8]=[CH:7][CH:6]=2.[OH2:13]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:4][CH2:3][CH:2]([OH:13])[CH3:11])=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: O
Reactant: Clc1c(Br)cnc2ccccc12
Product: CC(O)CNc1c(Br)cnc2ccccc12
Temperature: 150 °C

Procedure:
A mixture of 3 g of 3-bromo-4-chloro-quinoline and 10 g of aminopropanol-2 was heated to 150° C. for 20 minutes. The mixture was cooled and poured into 120 ml of water and the product was extracted with 100 ml of ether. The ether layer was dried over sodium sulfate, the solvent removed by evaporation and the residue recrystallized from ether/hexane. The yield was 2.6 g, mp 82°-83° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:10][CH:11]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-])=O)[CH:13]=2)[CH3:9])[CH:5]=[CH:6][CH:7]=1.[BH4-].[Na+]>O.O.O.O.O.O.[Ni](Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:10][CH:11]([C:21]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)[C:12]2[CH:13]=[C:14]([NH2:18])[CH:15]=[CH:16][CH:17]=2)[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C(NC(C)c2cccc(Cl)c2)c2cccc([N+](=O)[O-])c2)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: COc1ccc(C(NC(C)c2cccc(Cl)c2)c2cccc(N)c2)cc1
Yield: 89.5 %

Procedure:
Following a similar procedure to that described in Example (1b), 2.60 g of N-[1-(3-chlorophenyl)ethyl]-N-[(4-methoxyphenyl)-(3-nitrophenyl)methyl]amine [prepared as described in step (a) above], 3.11 g of nickel chloride hexahydrate and 1.04 g of sodium borohydride were reacted, to obtain 2.15 g of the title compound as a yellow oil.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:30])([CH3:29])[O:6][C@@H:7]1[CH2:23][C:22]2[C@@:10]([CH3:28])([C@@H:11]3[C@@H:19]([CH2:20][CH:21]=2)[C@H:18]2[C@@:14]([CH3:27])([C@@H:15]([C:24](=[O:26])[CH3:25])[CH2:16][CH2:17]2)[CH2:13][CH2:12]3)[CH2:9][CH2:8]1)([CH3:4])[CH3:3].Br[CH2:32][CH2:33][CH2:34][C:35]([CH3:37])=[CH2:36].[I-].[I-].[Sm+2]>>[CH3:4][C:2]([Si:5]([CH3:30])([CH3:29])[O:6][C@@H:7]1[CH2:23][C:22]2[C@@:10]([CH3:28])([C@@H:11]3[C@@H:19]([CH2:20][CH:21]=2)[C@H:18]2[C@@:14]([CH3:27])([C@@H:15]([C@@:24]([OH:26])([CH2:32][CH2:33][CH2:34][C:35]([CH3:37])=[CH2:36])[CH3:25])[CH2:16][CH2:17]2)[CH2:13][CH2:12]3)[CH2:9][CH2:8]1)([CH3:1])[CH3:3]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: C=C(C)CCCBr
Agent: [I-]
Agent: [Sm+2]
Product: C=C(C)CCC[C@](C)(O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@]4(C)[C@H]3CC[C@@]21C
Yield: 70.7 %

Procedure:
The coupling reaction of the protected pregnenolone 1 (500.0 mg, 1.16 mmol) with 5-bromo-2-methyl-1-pentene 9 (199.0 mg, 1.22 mmol) in the presence of samarium diiodide was performed under similar condition as described for the preparation of 2 to afford the 20S-hydroxy steroid 10 (419.0 mg, 0.82 mmol, 71%) as a white powder.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[CH:21]=[CH:20][C:19]4[C:15](=[CH:16][N:17]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[N:18]=4)[CH:14]=3)[OH:12])=[CH:9][N:10]=2)[N:7]=1.[CH3:30][N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1.C([O-])([O-])=O.[Na+].[Na+]>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.COCCOC>[CH3:30][N:31]1[CH:35]=[C:34]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([CH:11]([C:13]4[CH:21]=[CH:20][C:19]5[C:15](=[CH:16][N:17]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:28])([CH3:29])[CH3:27])[N:18]=5)[CH:14]=4)[OH:12])=[CH:9][N:10]=3)[N:7]=2)[CH:33]=[N:32]1
Reactant: C[Si](C)(C)CCOCn1cc2cc(C(O)c3cnc4ccc(Cl)nn34)ccc2n1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cn1cc(-c2ccc3ncc(C(O)c4ccc5nn(COCC[Si](C)(C)C)cc5c4)n3n2)cn1

Procedure:
(rac)-(6-Chloro-imidazo[1,2-b]pyridazin-3-yl)-[2-(2-trimethylsilanyl-ethoxymethyl)-2H-indazol-5-yl]-methanol (Stage 150.3, 134 mg, 0.296 mmol) was charged into a microwave vial together with DME (2 mL), 1-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H -pyrazole (173 mg, 0.815 mmol), followed by 2 M Na2CO3 (0.300 mL) and PdCl2(PPh3)2 (20 mg). The RM was submitted to microwave irradiation at 150° C. for 30 min. After filtration and evaporation of the solvent, the residue was taken into EtOAc and washed with saturated aqueous sodium carbonate. The aqueous phase was again extracted 3 times with EtOAc. Combined organic layers were washed with brine and dried on Na2SO4. After evaporation of the solvent the crude was purified by flash chromatography (CombiFlash® Companion System®, with 12 g RediSep® silica gel column, DCM/MeOH=100:0->92:8) to afford the title compound (tR 1.17 min (conditions 2), MH+=476)
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][CH3:19])[CH:12]=2)[CH2:7][CH2:6]1)=[O:4].[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([N:8]2[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][N:24]3[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]3)[CH2:6][CH2:7]2)=[CH:12][C:13]=1[O:18][CH3:19]
Reactant: COc1cc(N2CCN(C(=O)CCl)CC2)ccc1Cl
Reactant: CN1CCNCC1
Product: COc1cc(N2CCN(C(=O)CN3CCN(C)CC3)CC2)ccc1Cl

Procedure:
In a 4 mL vial was added 2-chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone (1) (200 mg, 0.66 mmol, 1.0 equiv) and 1-methylpiperazine (725 μL, 6.60 mmol, 10.00 equiv). A stir bar was placed in the vial and the vial was then capped. The resultant mixture stirred at 60° C. overnight. The crude product was purified by reversed phase HPLC (acetonitrile —H2O with 0.1% TFA as the eluent) to yield 1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-(4-methyl-piperazin-1-yl)-ethanone (25): HPLC retention time, 0.32 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using 1 ml/min flow rate, a 2.5 minute gradient of 20% to 100% B with a 1.1 minute wash at 100% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile); MS (ES) M+H expected, 367.5, found, 367.9.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:26]1[CH:27]=[C:28]([O:32][CH3:33])[CH:29]=[CH:30][CH:31]=1>>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=3)=[O:5])[N:7]=[CH:8]2)[CH:12]=1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3Cl)c2)cn1
Reactant: COc1cccc(Br)c1
Product: COc1cccc(C(=O)c2cn(-c3cccc(-c4ccccc4Cl)c3)cn2)c1

Procedure:
This compound is prepared by method C using compound 12e and 3-bromoanisole
Reaction SMILES: [CH3:1][NH:2][CH3:3].[C:4]([NH:8][S:9]([C:12]1[CH:13]=[C:14]([S:18](Cl)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1)(=[O:11])=[O:10])([CH3:7])([CH3:6])[CH3:5].O>C(OCC)(=O)C>[CH3:1][N:2]([CH3:3])[S:18]([C:14]1[CH:13]=[C:12]([S:9]([NH:8][C:4]([CH3:7])([CH3:6])[CH3:5])(=[O:11])=[O:10])[CH:17]=[CH:16][CH:15]=1)(=[O:20])=[O:19]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(S(=O)(=O)Cl)c1
Reactant: CNC
Solvent: O
Solvent: CCOC(C)=O
Product: CN(C)S(=O)(=O)c1cccc(S(=O)(=O)NC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dimethylamine gas was allowed to bubble for 3 minutes into a solution of 1.8 grams (7 mmole) of 3-tert-butylsulfamoyl-benzenesulfonyl chloride in ethyl acetate. Water was added and the mixture was stirred at room temperature for 1 hour. The ethyl acetate layer was separated, dried over magnesium sulfate and concentrated in vacuo to a solid which was triturated with hexane/isopropyl ether to give 1.59 grams of the titled compound. m.p. 100-102° C.
Reaction SMILES: C(O)(=O)CC(O)=[O:4].[C:8]([OH:16])(=[O:15])[CH:9]([CH2:11][C:12]([OH:14])=[O:13])[OH:10].C(O)(=O)/C=C\C(O)=O.[C:25]([OH:37])(=[O:36])[CH2:26][C:27]([CH2:32][C:33]([OH:35])=[O:34])([C:29]([OH:31])=[O:30])[OH:28]>>[C:8]([OH:16])(=[O:15])[CH:9]([CH:11]([C:12]([OH:14])=[O:13])[OH:4])[OH:10].[C:25]([OH:37])(=[O:36])[CH2:26][C:27]([CH2:32][C:33]([OH:35])=[O:34])([C:29]([OH:31])=[O:30])[OH:28]
Reactant: O=C(O)CC(O)C(=O)O
Reactant: O=C(O)CC(=O)O
Agent: O=C(O)/C=C\C(=O)O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Product: O=C(O)C(O)C(O)C(=O)O

Procedure:
Aged (and brittle) carboxylated cellulose, malonic acid, malic acid and maleic acid each was separately reacted with ZnO to produce adhesive material followed by formation of hard cement in a way similar to that with citric acid. One sample of tartaric acid, however, did not yield a "stringy" adhesive mass like with citric acid but it was found that this sample of tartaric acid was somewhat slow to wet in spite of being very soluble. In general it appears that polycarboxylic acids that are readily (quickly) soluble, considerably soluble and quickly wet show reaction with ZnO as does citric acid.