Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[C:15]([S:16]([Cl:19])(=[O:18])=[O:17])[C:9]=3[CH:8]=[CH:7][C:6]=2[N:5]([C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])[CH2:4]1.[N+:26]([O-])([O-:28])=[O:27].[K+]>OS(O)(=O)=O>[Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[C:15]([S:16]([Cl:19])(=[O:18])=[O:17])[C:9]=3[C:8]([N+:26]([O-:28])=[O:27])=[CH:7][C:6]=2[N:5]([C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])[CH2:4]1
Reactant: O=C(N1CC(CCl)c2c1ccc1c(S(=O)(=O)Cl)cccc21)C(F)(F)F
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=C(N1CC(CCl)c2c1cc([N+](=O)[O-])c1c(S(=O)(=O)Cl)cccc21)C(F)(F)F
Reaction time: 0.5 h
Yield: 23.3 %

Procedure:
The 6-sulfonyl chloride 114(750 mg, 1.9 mmol) was dissolved in conc. H2SO4 (20 mL), the solution was cooled in an ice bath, and a solution of KNO3 (195 mg, 1.95 mmol) in H2SO4 (5 mL) was added slowly. The mixture was vigorously for 30 min, quenched with cold water, and extracted with EtOAc (3×50 mL). The extracts were dried and concentrated under reduced pressure, and the resulting solid was separated by column chromatography on silica gel. Elution with EtOAc/petroleum ether (from 1:4 to 1:1) gave 1-(chloromethyl)-5-nitro-3-(trifluoroacetyl)-1,2-dihydro-3H-benzo[e]indole-6-sulfonyl chloride (115) (202 mg, 59%, based on consumption of starting material): mp (EtOAc/petroleum ether) 169° C. (dec.); 1H NMR [(CD3)2SO] δ 8.63 (s, 1H), 8.22 (dd, J=7.6, 0.9 Hz, 1H), 8.13 (dd, J=8.4 Hz, 1H), 7.71 (dd, J=7.8, 7.8 Hz, 1H), 4.66-4.56 (m, 2H), 4.49-4.43 (m, 1H), 4.17-4.02 (m, 2H); 13C NMR δ 153.4 (q, JC-F 37.4 Hz), 149.2, 145.2, 137.7, 131.4, 130.5, 129.9, 127.7, 124.9, 118.6, 115.6 (q, JC-F 288 Hz) 114.3, 52.6, 47.5, 41.4. Anal. (C15H9Cl2F3N2O5S) C, H, N. 114 (457 mg, 61%) was also recovered.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[NH:6][C:5](=[O:10])[C:4]=1[CH2:11][NH:12][C:13]([C:15]1[C:23]2[C:18](=[N:19][C:20]([N:24]3[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]3)=[CH:21][CH:22]=2)[N:17]([CH:37]([CH3:41])[CH2:38][O:39][CH3:40])[C:16]=1[CH3:42])=[O:14].Cl>CO>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[NH:6][C:5](=[O:10])[C:4]=1[CH2:11][NH:12][C:13]([C:15]1[C:23]2[C:18](=[N:19][C:20]([N:24]3[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]3)=[CH:21][CH:22]=2)[N:17]([CH:37]([CH3:41])[CH2:38][O:39][CH3:40])[C:16]=1[CH3:42])=[O:14]
Reactant: COCC(C)n1c(C)c(C(=O)NCc2c(OC)cc(C)[nH]c2=O)c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)nc21
Agent: Cl
Solvent: CO
Product: COCC(C)n1c(C)c(C(=O)NCc2c(OC)cc(C)[nH]c2=O)c2ccc(N3CCNCC3)nc21
Reaction time: 2 h
Yield: 24.7 %

Procedure:
To tert-butyl 4-(3-(((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-1-(1-methoxypropan-2-yl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-6-yl)piperazine-1-carboxylate (crude, used directly from last step), was added saturated hydrochloride solution in methanol (5 ml) at 0° C. The reaction mixture was allowed to room temperature and stirred for 2 hours. The reaction mixture was concentrated and purified by preparative HPLC (Mobile phase A: water with 0.05% ammonia solution; Mobile phase B: MeCN; column temperature: 30° C. Gradient: 30-60% B 10 min) to give a N-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-(1-methoxypropan-2-yl)-2-methyl-6-(piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (23 mg, 24.7%, two steps.). LRMS (M+H) m/z: calcd 482.26. found 483. 1H NMR (400 MHz, CDCl3) δ: 1.59-1.62 (d, J=7.2 Hz, 3H), 2.21 (s, 3H), 2.71 (s, 3H), 2.96-3.01 (m, 4H), 3.23 (s, 3H), 3.40-3.43 (m, 4H), 3.81-3.88 (m, 4H), 4.10-4.14 (m, 1H), 4.61-4.63 (d, J=5.6 Hz, 2H), 5.91 (s, 1H), 6.41-6.44 (d, J=8.8 Hz, 1H), 7.41-7.45 (m, 1H), 7.90-7.93 (d, J=8.8 Hz, 1H).
Reaction SMILES: [O:1]=[C:2]1[CH:11]2[CH2:12][CH2:13]O[C:10]2=[C:9]2[C:4]([C:5]([O:15][CH3:16])=[CH:6][CH:7]=[CH:8]2)=[N:3]1.[F:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[C:20]([CH3:25])[CH:19]=1>C(O)COCCO.O>[CH3:25][C:20]1[CH:19]=[C:18]([F:17])[CH:24]=[CH:23][C:21]=1[N:22]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([O:15][CH3:16])[C:4]=3[NH:3][C:2](=[O:1])[C:11]=2[CH2:12][CH2:13]1
Reactant: COc1cccc2c1=NC(=O)C1CCOC=21
Reactant: Cc1cc(F)ccc1N
Solvent: O
Solvent: OCCOCCO
Product: COc1cccc2c3c(c(=O)[nH]c12)CCN3c1ccc(F)cc1C
Temperature: 250 °C
Yield: 78.9 %

Procedure:
4-Oxo-6-methoxy-2,3-dihydrofuro[3,2-c]quinoline (217 mg, 1.0 mmol) was dissolved in 10 ml of diethylene glycol in a pressure tube and (278 μl, 2.5 mmol) of 4-fluor-2-methylaniline (278 μl, 2.5 mmol) was added under nitrogen. The reaction mixture was heated at 250° C. for 15 hours. The reaction mixture was diluted with 20 ml of salt water and the aqueous layer was extracted with methylene chloride (15 ml×3). After washing with water (15 ml×3), the organic layer was dried by anhydrous magnesium sulfate and filtered, and concentrated under reduced pressure. The residue was purified with ethyl acetate as eluent according to silica gel chromatography to obtain 256 mg of desired compound as solid in 79% of yield.
Reaction SMILES: O.[NH2:2][NH2:3].F[C:5]1[C:12]([I:13])=[C:11]([CH3:14])[CH:10]=[CH:9][C:6]=1[C:7]#[N:8].O>C(O)C>[I:13][C:12]1[C:11]([CH3:14])=[CH:10][CH:9]=[C:6]2[C:5]=1[NH:3][N:2]=[C:7]2[NH2:8]
Reactant: Cc1ccc(C#N)c(F)c1I
Reactant: NN
Solvent: O
Solvent: CCO
Product: Cc1ccc2c(N)n[nH]c2c1I
Temperature: 100 °C
Reaction time: 8 h
Yield: 87.7 %

Procedure:
A solution of hydrazine monohydrate (0.56 mL, 11.6 mmol) and 2-fluoro-3-iodo-4-methylbenzonitrile (WO2006094187, 1.00 g, 3.8 mmol) in ethanol (7 mL) was stirred and heated to 100° C. in a sealed tube. After stirring overnight, the mixture was cooled and water was added. The resultant precipitate was filtered, washed with water and hexanes, and then dried in vacuo to give the title compound (0.91 g, 87%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:5]([O:7][C:8](=O)[C:3]=12)=[O:6].C([NH2:15])=O>O>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:3]=1[C:8](=[O:7])[NH:15][C:5]2=[O:6]
Reactant: NC=O
Reactant: O=C1OC(=O)c2c(Cl)cccc21
Solvent: O
Product: O=C1NC(=O)c2c(Cl)cccc21
Temperature: 125 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
A mixture of 3-chlorophthalic acid anhydride (9 g, 49.2 mmol) and formamide (100 mL) was heated to 125 ° C. and stirred for 3 h. Water (300 mL) was then added and the mixture was cooled to room temperature. The mixture was filtered and the resulting white solid was washed with water and dried to give 4-chloro-1H-isoindole-1,3(2H)-dione (7.7 g, 86% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[NH:28][C:27](=O)[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)[CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>O=P(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([N:12]2[CH2:13][CH2:14][N:15]([CH2:18][C:19]3[N:28]=[C:27]([N:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)[CH2:16][CH2:17]2)(=[O:11])=[O:10])=[CH:7][CH:8]=1
Reactant: C1CCNCC1
Reactant: COc1ccc(S(=O)(=O)N2CCN(Cc3nc4ccccc4c(=O)[nH]3)CC2)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(S(=O)(=O)N2CCN(Cc3nc(N4CCCCC4)c4ccccc4n3)CC2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-[4-(4-Methoxy-benzenesulfonyl)-piperazin-1-ylmethyl]-3H-quinazolin-4-one (83 mg, 0.2 mmol) in POCl3 (1 mL) was heated to 90° C. for 2 hours. Then the excess POCl3 was removed in vacuo. The residue was dissolved in toluene (5 mL) and then the solvent was removed in vacuo. This step was repeated twice more. The residue was then dissolved in THF (1 mL) and piperidine (197 μL, 2 mmol) was added. The reaction was stirred at room temperature for 1 day. The reaction mixture was partitioned between dichloromethane and water. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by HPLC. 1H NMR (400 MHz, CDCl3) δ 7.92 (m, 3H), 7.67 (m, 3H), 7.03 (d, J=8.8 Hz, 2H), 4.70 (s, 2H), 4.12 (s, 4H), 3.90 (s, 3H), 3.45 (m, 8H), 1.88 (m, 6H); HPLC ret. time 2.61 min, 10-99% CH3CN, 5 min run; ESI-MS m/z 482.0 (M+1)+.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][C:8]([S:39][C:40]([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([CH3:38])[CH2:9][NH:10][CH2:11][CH2:12][NH:13][CH2:14][C:15]([S:18][C:19]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:17])[CH3:16].Br[CH2:60][CH2:61][CH2:62][CH2:63][C:64]([O:66][CH2:67][CH3:68])=[O:65]>CC#N>[CH3:38][C:8]([S:39][C:40]([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)([C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)([CH3:7])[CH2:9][N:10]([CH2:11][CH2:12][NH:13][CH2:14][C:15]([S:18][C:19]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)([CH3:16])[CH3:17])[CH2:60][CH2:61][CH2:62][CH2:63][C:64]([O:66][CH2:67][CH3:68])=[O:65]
Reactant: CCOC(=O)CCCCBr
Reactant: CC(C)(CNCCNCC(C)(C)SC(c1ccccc1)(c1ccccc1)c1ccccc1)SC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CCCCN(CCNCC(C)(C)SC(c1ccccc1)(c1ccccc1)c1ccccc1)CC(C)(C)SC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 65.7 %

Procedure:
K2CO3 (1.92 g, 13.9 mmol, 100 mol %) was added to N,N′-bis(2-methyl-2-triphenylmethylthiopropyl)ethylenediamine (10.03 g, 13.9 mmol) in CH3CN (60 mL), followed by ethyl 5-bromovalerate (3.30 mL, 20.8 mmol, 150 mol %). The reaction was heated at reflux under argon overnight. The solution was then concentrated to a paste and partitioned between 0.25 M KOH (100 mL) and ethyl acetate (100 mL). The aqueous layer was extracted with ethyl acetate (1×50 mL) and the combined ethyl acetate layers were washed with 50 mL water and NaCl solution (2×50 mL), dried with Na2SO4 and concentrated to an orange oil. Purification by flash chromatography (300 g flash silica, 100% CHCl3 to 5% MeOH/CHCl3) gave pure title compound (7.75 g, 66% yield). FABMS analysis yielded an (MH+) of 849 (compared with a calculated molecular weight of 849.24 for the compound C55H64N2O2S2).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[N:5][C:6]([N:9]2[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[N:10]2)=[CH:7][N:8]=1.C(N(CC)CC)C.[C:31](OC(=O)C)(=[O:33])[CH3:32].C(=O)([O-])O.[Na+]>ClCCl>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([NH:16][C:4]2[C:3]([CH2:2][NH:1][C:31](=[O:33])[CH3:32])=[N:8][CH:7]=[C:6]([N:9]3[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[N:10]3)[N:5]=2)=[CH:22][CH:21]=1
Reactant: Cc1cc(C)n(-c2cnc(CN)c(Nc3ccc(Cl)cc3)n2)n1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCc1ncc(-n2nc(C)cc2C)nc1Nc1ccc(Cl)cc1
Reaction time: 0.75 h
Yield: 65.2 %

Procedure:
[3-Aminomethyl-6-(3,5-dimethyl-pyrazol-1-yl)-pyrazin-2-yl ]-(4-chloro-phenyl)-amine (40 mg, 0.12 mmol), triethylamine (19 μL, 0.13 mmol) and dichloromethane (2 mL) was cooled on an ice bath. Acetic anhydride (12 μM, 0.12 mmol) was added and the mixture was stirred for 45 min. Aqueous sodium hydrogen carbonate was added and the aqueous phase was extracted with ethyl acetate (3×). The combined organic phases were dried over sodium sulphate, filtrated and concentrated in vacuo. The crude product was purified by flash chromatography (dichloromethane/methanol as eluent) to give N-[3-(4-chloro-phenylamino)-5-(3,5-dimethyl -pyrazol-1-yl)-pyrazin-2-ylmethyl]-acetamide (29 mg, 64%) as a white solid. Mp. 228-230° C. LC-ESI-HRMS of [M+H]+ shows 371.1404 Da. Calc. 371.138712 Da, dev. 4.5 ppm
Reaction SMILES: C(O[C:4](=[O:15])[CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:6]([CH3:8])=O)C.[CH3:16][CH:17]([NH:26][NH2:27])[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1>C(O)C>[CH3:8][C:6]1[NH:27][N:26]([CH:17]([CH3:16])[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)[C:4](=[O:15])[C:5]=1[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(NN)c1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)C(C(C)=O)c1ccccc1
Solvent: CCO
Product: Cc1[nH]n(C(C)c2ccc(Cl)c(Cl)c2)c(=O)c1-c1ccccc1

Procedure:
20.6 g of α-phenylacetoacetic acid ethyl ester were added dropwise under nitrogen to a solution of 20.5 g (0.1 mol) of α-methyl-3,4-dichlorobenzylhydrazine in 20 ml of absolute ethanol, during which the temperature of the reaction mixture rose to 55° C. After heating the reaction solution for 2 hours under reflux, the reaction product crystallized out on cooling the reaction mixture. The crystals were filtered off, rinsed with ether and recrystallized from an ethanol/dimethyl formamide mixture.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=O)=[CH:5][CH:4]=1.[H-].[Na+].O1C2C=CC(C(C3C=C(OC)C=C(OC)C=3)=[CH:32][C:33]#[N:34])=CC=2OCC1>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:32][C:33]#[N:34])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)c2ccc(OC)cc2)cc1
Reactant: COc1cc(OC)cc(C(=CC#N)c2ccc3c(c2)OCCO3)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(C(=CC#N)c2ccc(OC)cc2)cc1
Yield: 69 %

Procedure:
Bis-(4-methoxy-phenyl)-methanone (2.42 g, 10 mmol), cyano-methylphosphonic acid diethyl ester (1.6 ml, 10 mmol) in anhydrous THF (10 ml), and sodium hydride (0.48 g, 10 mmol) were treated in the same manner as described above for the synthesis of 3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3-(3,5-dimethoxyphenyl)acrylonitrile. The crude material was purified by flash column chromatography to give 3,3-bis-(4-methoxy-phenyl)-acrylonitrile as a solid (1.84 g, 69%): 1H NMR (CDCl3) δ 7.39 (d, J=8.7 Hz, 1H, Ar), 7.25 (d, J=8.7 Hz, 1H, Ar), 6.95 (d,j=8.7 Hz, 1H, Ar), 6.88 (d, J=8.7 Hz, 1H, Ar), 5.54 (s, 1H, CH), 3.86, 3.83 (2s, 6H, CH3); 13C NMR (CDCl3) δ 162.3, 161.4, 160.9, 131.7, 131.3, 130.1, 129.5, 118.7, 113.9, 113.8, 91.5, 55.4, 55.3; Anal. Calcd. For C17H15NO2: C, 76.94; H, 5.70; N, 5.27. Found: C, 76.83; H, 5.64; N, 5.17.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH:5]([CH2:31][CH3:32])[CH2:6][CH2:7][N:8]1[C:28](=[S:29])[N:11]2[C:12]3[CH:13]=[C:14]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=4)[O:15][C:16]=3[CH:17]=[C:10]2[C:9]1=[O:30])C>FC(F)(F)C(O)=O.O>[CH2:31]([CH:5]([CH2:6][CH2:7][N:8]1[C:28](=[S:29])[N:11]2[C:12]3[CH:13]=[C:14]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=4)[O:15][C:16]=3[CH:17]=[C:10]2[C:9]1=[O:30])[C:4]([OH:33])=[O:3])[CH3:32]
Reactant: CCOC(=O)C(CC)CCN1C(=O)c2cc3oc(-c4cccc(C(F)(F)F)c4)cc3n2C1=S
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCC(CCN1C(=O)c2cc3oc(-c4cccc(C(F)(F)F)c4)cc3n2C1=S)C(=O)O
Temperature: 70 °C

Procedure:
Compound 25 (100 mg, 0.22 mmol, prepared as described hereinabove) was dissolved in a mixture of trifluoroacetic acid and water (4:1; 3 ml) and the solution was heated to 70° C. for 7 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][N:10]([CH2:12]N(C)C)[CH3:11]>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH2:9][N:10]([CH3:12])[CH3:11])[CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: CN(C)CN(C)C
Solvent: C1COCCO1
Product: CN(C)Cc1cc(Cl)ccc1O

Procedure:
A solution of 4-chlorophenol (25.72 g), N,N,N',N'-tetramethyldiaminomethane (27.2 ml) and 1,4-dioxane (250 ml) was heated on a steam bath for 16 hours. The mixture was evaporated to dryness and the residue was dissolved in 2M hydrochloric acid, washed with dichloromethane, basified with concentrated sodium hydroxide solution and extracted with dichloromethane to give an oil which was distilled to give 4-chloro-2-(dimethylaminomethyl)phenol, b.p. 90°-97° C. at 0.26 mbar.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][N:3]=[C:2]1[N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][C:7]1=[O:15].[CH:16](=O)[C:17]1[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[OH:19].N1CCCCC1>C1C=CC=CC=1>[S:1]1[CH2:5][CH2:4][N:3]=[C:2]1[N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[CH:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[OH:19])[C:7]1=[O:15]
Reactant: O=C1Cc2ccccc2N1C1=NCCS1
Reactant: O=Cc1ccccc1O
Solvent: c1ccccc1
Solvent: C1CCNCC1
Product: O=C1C(=Cc2ccccc2O)c2ccccc2N1C1=NCCS1
Yield: 64.1 %

Procedure:
To a warmed solution of 1-(2-thiazolin-2-yl)-indolin-2-one (prepared as described in Example 3A; 2.0 g; 9.2 mmole) and salicylaldehyde (1.6 g; 12.9 mmole) in dry benzene (100 ml) is added a small amount of piperidine (0.6 ml). The resultant mixture is heated at reflux temperature for 2 hours. The reaction mixture is extracted with dilute HCl solution (5 ml of concentrated HCl in 120 ml of water) twice. The acidic layers are combined and treated with saturated NaHCO3 solution until pH paper indicates it is slightly basic. The precipitate is collected by filtration and washed well with water. This crude material is recrystallized from acetone/hexane (treated with charcoal) to give 1.9 g of the product: m.p. 195.5°-197° C.
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)[CH:5]=1.O1CCOCC1.C(=O)([O-])[O-].[K+].[K+].[NH2:32][C:33]([C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1)=[O:34]>O>[C:33]([C:35]1[CH:40]=[C:39]([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:2])=[O:19])=[CH:13][CH:14]=2)[CH:38]=[CH:37][CH:36]=1)(=[O:34])[NH2:32]
Reactant: NC(=O)c1cccc(B(O)O)c1
Reactant: COC(=O)c1cccc(COc2ccc(I)cc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: NC(=O)c1cccc(-c2ccc(OCc3cccc(C(=O)O)c3)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A first stock solution was prepared consisting of 3-(4-iodo-phenoxymethyl)-benzoic acid methyl ester (of Intermediate 1; 1.11 g, 3 mmol), bis(tri-cyclohexyl-phosphine)palladium (available from Strem Chemicals, Inc., Newburyport, Mass.; 105 mg, 0.16 mmol), and dioxane (approximately 62 mL). A second stock solution was prepared consisting of potassium carbonate (1.245 g, 9 mmol) and water (approximately 6.2 mL). The solutions were sonicated and degassed by bubbling nitrogen gas through them. 4 mL of the first stock solution and 0.4 mL of the second stock solution were added to a reaction vial containing (3-aminocarbonylphenyl)boronic acid (available from Apollo Scientific Ltd., Stockport, UK; 99 mg, 0.6 mmol). The mixture was heated in a microwave oven at 170 degrees for 25 min and then passed through a silica gel column (1 g of silica), and washed with dioxane (1 mL) and dimethylacetamide (1 mL). 2 M potassium hydroxide solution (0.4 mL) was added. The mixture was stirred at room temperature overnight, and then 1 M HCl (0.8 mL) was added and the solvents were removed in the Genevac. Aqueous methanol (50%; approximately 2 mL) was added, then the vial was centrifuged and the solvent was removed. This process was repeated to give 3-(3′-carbamoyl-biphenyl-4-yloxymethyl)-benzoic acid. Mass spectrum MH+=348.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]([CH2:20][CH2:21][OH:22])([CH2:17][CH2:18][OH:19])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N+]1([O-])CCOCC1>C(Cl)Cl.C(#N)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]2([CH2:17][C:18](=[O:19])[O:22][CH2:21][CH2:20]2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCC(CCO)(CCO)CC1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Solvent: ClCCl
Product: O=C1CC2(CCO1)CCN(C(=O)OCc1ccccc1)CC2

Procedure:
9-benzyloxycarbonyl-2-oxo-3-oxa-9-azaspiro[5.5]undecane is prepared by reaction of 1-benzyloxycarbonyl-4,4-bis-(2-hydroxyethyl)piperidine with 4-methylmorpholine-N-oxide in methylene chloride/acetonitrile in the presence of tetrapropylammonium perruthenate and pulverized molecular sieve.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]([N:11]1[CH2:16][C@H:15]([CH3:17])[N:14]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH2:13][C@H:12]1[CH3:26])=[O:10])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][CH2:8][C:9]([N:11]1[CH2:16][C@H:15]([CH3:17])[N:14]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[CH2:13][C@H:12]1[CH3:26])=[O:10]
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)CNC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)CN
Temperature: 25 °C
Reaction time: 2 h
Yield: 112.4 %

Procedure:
To a solution of {2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethyl}-carbamic acid tert-butyl ester (1.45 g, 3.28 mmol) in dichloromethane (38 mL) was added trifluoroacetic acid (20 mL). The reaction was stirred at ambient temperature for two hours. The reaction was diluted with dichloromethane and washed with 1N sodium hydroxide. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated to the give the title compound (1.03 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9]>N([O-])=O.[Na+].O.Cl>[CH3:7][C:2]1[CH:3]=[C:4]([CH3:5])[N:1]([C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=2[OH:9])[N:1]=1
Reactant: Nc1cc(F)ccc1O
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cc(C)n(-c2cc(F)ccc2O)n1
Reaction time: 0.5 h
Yield: 25.4 %

Procedure:
To 100 mg of 2-amino-4-fluorophenol was added 0.8 ml of 5N-hydrochloric acid, and a solution in which 65 mg of sodium nitrite was dissolved in 0.2 ml of water was added dropwise at 0° C., and stirred for 30 minutes. Then, a solution in which 249 mg of stannous chloride was dissolved in 0.46 ml of 5N-hydrochloric acid, was added dropwise at 0° C., and stirred at 0° C. for 30 minutes and then at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and 2.5 ml of ethanol and 81 μl of acetyl acetone were added, followed by heating at reflux for 4 hours. To the reaction mixture was added 50 ml of water, neutralized with a saturated solution of sodium hydrogen carbonate, and extracted with 50 ml of ethyl acetate. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure and purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1) to yield 20.6 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[S:10][CH:9]2C#N)=O)=[CH:4][CH:3]=1.F[B-](F)(F)F.[H+].[C:27]([C:33]([O:35][CH3:36])=[O:34])#[C:28][C:29]([O:31][CH3:32])=[O:30]>ClCCl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]2[N:8]3[C:9]([S:10][C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=43)=[C:28]([C:29]([O:31][CH3:32])=[O:30])[C:27]=2[C:33]([O:35][CH3:36])=[O:34])=[CH:19][CH:20]=1
Reactant: N#CC1Sc2ccccc2N1C(=O)c1ccc(Cl)cc1
Reactant: COC(=O)C#CC(=O)OC
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1c(C(=O)OC)c2sc3ccccc3n2c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3-(4-chlorobenzoyl)-2,3-dihydrobenzo[d]thiazole-2-carbonitrile (9.12 g, 30.0 mmol) in dichloromethane (50 mL) was added dropwise 9 mL of tetrafluoroboric acid (HBF4). The solution was stirred for 3 h at room temperature. The brown precipitates appeared were collected by filtration and the filter cake was washed with ether. The solid salt was added to a solution of dimethyl acetylenedicarboxylate (12.7 g, 90.0 mmol) in DMF (40 mL) and then warmed at 35° C. for 14 h. The reaction mixture was concentrated in vacuo and the residue was crystallized from methanol to give dimethyl 1-(4-chlorophenyl)benzo[d]pyrrolo[2,1-b]thiazole-2,3-dicarboxylate, 2.5 g (21%); mp 172-173° C. 1H NMR (DMSO-d6) δ 3.64 (3H, s, COOMe), 3.83 (3H, s, COOMe), 6.85-6.87 (1H, m, ArH), 7.30-7.42 (2H, m, ArH), 7.60-7.66 (4H, m, 4×ArH), 8.04-8.06 (1H, m, ArH). Anal. Calcd. for (C20H14ClNO4S.0.5H2O): C, 58.75; H, 3.70; N, 3.43; S, 7.84. Found: C, 58.76; H, 3.45; N, 3.59; S, 7.73.