Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C:9]1([CH2:13][CH:14]([OH:17])CO)[CH2:12][CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1COCC1.CC(O)(C)C.O.I([O-])(=O)(=O)=O.[Na+].CCOC(C)=O.CCCCCC>O>[Si:1]([O:8][C:9]1([CH2:13][CH:14]=[O:17])[CH2:10][CH2:11][CH2:12]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC1(CC(O)CO)CCC1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OC1(CC=O)CCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96.4 %

Procedure:
To a 2 L round bottomed flask was added 3-(1-(tert-butyldimethylsilyloxy)cyclobutyl)propane-1,2-diol (80.0 g, 307 mmol) and THF/t-BuOH/H2O (1:1:2, 2 L). Sodium periodate (120.15 g, 562 mmol) was added and the reaction was stirred at RT. After addition the solution became yellow and thickened. The stirrer was adjusted to maintain stirring. After 1.5 h, the reaction is complete as monitored by TLC (10% EtOAc/Hexane). 300 mL H2O was added to the reaction and the aqueous solution was extracted with ether (3×600 mL). The combined organics were dried over MgSO4 and carefully concentrated in vacuo (Note: volatile product). The oil was re-dissolved in 200 mL of benzene and azeotroped to remove any excess t-BuOH. The crude oil was adsorbed onto a plug of silica gel and chromatographed through a glass column, eluting with 3% EtOAc in hexane, to provide a golden oil after concentrating in vacuo (Note: volatile product). The oil was dissolved in 200 mL of benzene and concentrated in vacuo. The mixture was further concentrated to remove excess benzene to give 2-(1-(tert-butyldimethylsilyloxy)cyclobutyl)acetaldehyde (67.5 g, 296 mmol, 96.2% yield). The title compound yielded contained some benzene and was carried forward without further purification.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.[C:6]([O:10][C:11]([NH:13][CH2:14][CH2:15]CO)=[O:12])([CH3:9])([CH3:8])[CH3:7]>C(#N)C.O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:6]([O:10][C:11]([NH:13][CH2:14][CH2:15][CH2:1][Br:5])=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)NCCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCBr
Reaction time: 15 h
Yield: 76.9 %

Procedure:
25 g of carbon tetrabromide in solution in 50 ml of acetonitrile were slowly added at a temperature between 20° and 25° C. to a solution of 9 g of the product of Step A in 120 ml of tetrahydrofuran and 19.7 g of triphenyl phosphine. After stirring for 15 hours, the insoluble part was filtered off and the filtrate was concentrated to dryness under reduced pressure. The 45 g of residue were chromatographed on silica (eluant: hexane-ethyl acetate (8-2)) to obtain 9.4 g of the expected product melting at 40° C.
Reaction SMILES: [Na].[CH2:2]([OH:7])[CH2:3][CH2:4][CH2:5][OH:6].Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>>[CH2:21]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:7])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH3:9]
Reactant: CCCCCCCCCCCCCBr
Reactant: OCCCCO
Agent: [Na]
Product: CCCCCCCCCCCCCOCCCCO
Temperature: 150 °C
Reaction time: 5 h

Procedure:
2.3 g. Sodium are dissolved by warming in 44 ml. butane-1,4-diol, 38 ml. 1-bromotridecane are added thereto and the reaction mixture is stirred for 5 hours at a bath temperature of 150° C. After cooling, extraction is carried out with a mixture of diethyl ether-ligroin (1:2 v/v), the extract is evaporated and the residue is purified on a silica gel column by elution with ligroin which is subsequently replaced by diethyl ether-ligroin (1:1 v/v). The desired fractions are collected and evaporated. 19.4 g. (71% of theory) of thin layer chromatographically uniform 4-tridecyloxybutanol are thus obtained; m.p. 26°-29° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([NH2:10])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[Br:11]Br.O>C(O)(=O)C>[Br:11][C:6]1[C:5]2[S:1][CH:2]=[N:3][C:4]=2[CH:9]=[CH:8][C:7]=1[NH2:10]
Reactant: BrBr
Reactant: Nc1ccc2ncsc2c1
Solvent: O
Solvent: CC(=O)O
Product: Nc1ccc2ncsc2c1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
To a solution of benzothiazol-6-ylamine (6.4 g, 42.6 mmol) in glacial acetic acid (40 mL) was added bromine (2.18 mL) in glacial acetic acid (10 mL) dropwise. The reaction mixture was stirred at RT for 1 h. Water (160 mL) was added to the reaction mixture and the solid formed was extracted with ethyl acetate (3×40 mL). The combined organic fractions were washed with saturated aqueous sodium bicarbonate solution (200 mL), water (100 mL), and brine (20 mL), dried over anhydrous sodium sulfate, and concentrated. Purification of the residue by column chromatography (20% ethyl acetate:hexanes) afforded 6.5 g (67%) of the title compound as a yellow solid. 1H NMR (300 MHz, CDCl3): δ 4.31 (br. s, 2H), 7.02 (d, J=8.4 Hz, 1H), 7.92 (d, J=8.4 Hz, 1H), 8.80 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:19])([CH3:18])[CH3:17])=[CH:12][C:11]=2[F:20])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Br[C:22]1[N:27]=[C:26]([CH:28]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:29]([OH:31])[CH3:30])[CH:25]=[CH:24][CH:23]=1>>[F:20][C:11]1[CH:12]=[C:13]([C:16]([OH:19])([CH3:17])[CH3:18])[CH:14]=[CH:15][C:10]=1[C:4]1[S:3][C:2]([NH:1][C:22]2[CH:23]=[CH:24][CH:25]=[C:26]([CH:28]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH:29]([OH:31])[CH3:30])[N:27]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: CC(O)C(c1cccc(Br)n1)N1CCOCC1
Product: CC(O)C(c1cccc(Nc2sc(-c3ccc(C(C)(C)O)cc3F)cc2C(N)=O)n1)N1CCOCC1

Procedure:
The title compound was prepared as described in Example 1 using 2-amino-5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (150 mg, 0.510 mmol) and 1-(6-bromopyridin-2-yl)-1-morpholin-4-ylpropan-2-ol (168 mg, 0.510 mmol) as starting materials. 1H NMR (600 MHz, d6-DMSO): δ 11.96 (s, 1H), 7.84 (s, 1H), 7.81 (s, 1H), 7.66 (t, 1H), 7.54 (m, 1H), 7.36 (s, 1H), 7.32 (d, 1H), 7.31 (s, 1H), 7.95 (d, 1H), 6.78 (d, 1H), 5.13 (s, 1H), 4.55 (m, 1H), 4.18 (s, 1H), 3.54 (m, 4H), 3.31 (d, 1H), 2.61 (m, 2H), 2.33 (m, 2H), 1.40 (s, 6H), 0.89 (d, 3H). Calc'd for C26H32FN4O4S [M+H]+: 515. found 515.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:16])[N:5]([CH2:12][C:13]([OH:15])=O)[C:6]2=[O:11].[N:17]1([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:16])[N:5]([CH2:12][C:13]([N:20]1[CH2:19][CH2:18][N:17]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][CH2:21]1)=[O:15])[C:6]2=[O:11]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Nc1cccc2c1C(=O)N(CC(=O)O)C2=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)CN2C(=O)c3cccc(N)c3C2=O)CC1

Procedure:
2 g (9.08 mmol) of (4-amino-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetic acid, 1.692 g (9.08 mmol) of tert-butyl 1-piperazinecarboxylate, 1.916 g (10 mmol) of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride, 1.35 g (10 mmol) of 1-hydroxy-1H-benzotriazole and 3.8 ml (27 mmol) of triethylamine are stirred in 200 ml of dichloromethane at RT overnight. The reaction mixture is then washed with sat. aqu. NaHCO3 solution, dried over MgSO4, filtered and concentrated. The crude product (3.05 g) can be used without further purification for the next step or, if required, be chromatographed on silica gel (CH2Cl2/EtOH=1/0 to 2/1+0.1% conc. aqueous ammonia solution) for purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[CH2:12][CH2:13][C:14]([OH:16])=[O:15].[OH-].[K+].Cl>O.C(O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: O=C(O)CCCl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CCOc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 25 %

Procedure:
A mixture of 4-nitrophenol (14.0 g., 0.10 mol), 3-chloropropionic acid (10.8 g., 0.10 mol) and potassium hydroxide (11.2 g., 0.20 mol) in water and ethanol is heated at reflux temperature for 2 hours, cooled to ambient temperature, acidified with concentrated HCl to pH˜1, and extracted with ethyl acetate. The organic phase is washed with a saturated aqueous solution of sodium bicarbonate. The aqueous bicarbonate phase is acidified with concentrated hydrochloric acid, and extracted with ethyl acetate. The final ethyl acetate extract is washed with brine, dried over MgSO4 and concentrated in vacuo. The resultant residue is crystallized from ethyl ether and hexane to afford the title compound as an off-white crystalline solid, 5.3 g (25% yield), mp 117-118° C., identified by NMR and mass spectral analyses.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][NH:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17])=[O:8])C>CO.O.Cl>[F:17][C:11]1[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]=1[N:9]1[CH:4]=[CH:5][NH:6][C:7]1=[O:8]
Reactant: CCOC(CNC(=O)Nc1ccc(F)cc1F)OCC
Agent: Cl
Solvent: O
Solvent: CO
Product: O=c1[nH]ccn1-c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 72 h
Yield: 89.4 %

Procedure:
This urea (37.5 g) was dissolved in a mixture of 560 mL of methanol and 280 ml of water, and 300 ml of 0.48M hydrochloric acid was added thereto and the resulting mixture was stirred for three days at room temperature. The reaction solution was concentrated under reduced pressure. The crystals thus separated out were washed with a mixture of water and methanol (5:1) to give 22.8 g of 1-(2,4-difluorophenyl)-2(1H,3H)-imidazolone as a colorless powder.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Mg].[CH:12](=[O:14])[CH3:13].[NH4+].[Cl-]>C(OCC)C>[C:1]1([CH2:7][CH2:8][CH2:9][CH:12]([OH:14])[CH3:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCCCc1ccccc1
Reactant: CC=O
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(O)CCCc1ccccc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
In one portion, 3.6 ml (4.72 g, 23.7 mmol) of 3-phenylpropyl bromide are added to a suspension of 5.2 g (213 mmol) of magnesium in 30 ml of diethyl ether. A further 30 ml (39.3 g, 197 mmol) of 3-phenylpropyl bromide are added dropwise at such a rate that constant reflux is maintained. After the addition has ended, the mixture is diluted with 100 ml of diethyl ether and refluxed for 30 min. The mixture is diluted with a further 80 ml of diethyl ether and cooled to −78° C. A solution, of a temperature of 0° C., of 19 ml of acetaldehyde in 50 ml of ether is added dropwise, and the reaction mixture is stirred at −78° C. for 2 hours and warmed to room temperature. 50 ml of saturated NH4Cl solution are added and the organic phase is extracted with 1N HCl and saturated NaHCO3 solution and dried over Na2SO4. Removal of the solvent gives 33.4 g (95%) of a slightly yellow oil.
Reaction SMILES: [CH3:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][CH2:5][CH2:4][NH:3]1.Cl[C:14]1[CH:23]=[C:22]([Cl:24])[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([CH3:25])[CH:20]=2)[N:15]=1>>[Cl:24][C:22]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([CH3:25])[CH:20]=2)[N:15]=[C:14]([N:3]2[CH:2]([CH3:1])[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[S:6][CH2:5][CH2:4]2)[CH:23]=1
Reactant: Cc1ccc2nc(Cl)cc(Cl)c2c1
Reactant: CC1NCCSc2ccccc21
Product: Cc1ccc2nc(N3CCSc4ccccc4C3C)cc(Cl)c2c1
Temperature: 170 °C
Reaction time: 5 h
Yield: 28.3 %

Procedure:
A mixture of 5-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine (1.0 g, 5.58 mmol) and 2,4-dichloro-6-methylquinoline (1.7 g, 8.02 mmol) was heated with stirring in a 2 mL of microwave process vial for 5 hours at 170° C. under microwave irradiation. The solvent was removed by concentration in vacuo. The residue was purified by flash column chromatography to give 560 mg of the mixture of 5-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine and 4-(4-chloro-6-methylquinolin-2-yl)-5-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23](Br)[CH:22]=2)[CH:18]=[CH:19][CH:20]=1.CC([O-])(C)C.[Na+]>C1(C)C(C)=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[Br:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:22]=[CH:23][CH:24]=[C:25]([N:12]3[C:11]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=4[C:5]4[C:13]3=[CH:1][CH:2]=[CH:3][CH:4]=4)[CH:26]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: Brc1cccc(-c2cccc(Br)c2)c1
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1C
Product: Brc1cccc(-c2cccc(-n3c4ccccc4c4ccccc43)c2)c1
Yield: 54.7 %

Procedure:
9H-carbazole (10 g, 59.8 mmol) and 3,3′-dibromo-1,1′-biphenyl (41.1 g, 132 mmol) were dissolved in xylene (100 ml). Sodium 2-methylpropan-2-olate (8.62 g, 90 mmol), Tris(dibenzylideneacetone)dipalladium(0) (Pd2dba3) (0.548 g, 0.598 mmol) and 1,1′-bis(diphenylphosphanyl) ferrocene (dppf) (0.663 g, 1.196 mmol) were then added into the mixture. The reaction mixture was degassed with nitrogen for 30 minutes, and heated to reflux for 48 h. The crude mixture was filtered through a pad of Celite® and washed with DCM. The solvents were evaporated under vacuum and the material was purified via column chromatography using hexane and DCM (95/5). After the excess of dibromobiphenyl came out, the polarity was increased gradually to 30% DCM in hexane. The compound 9-(3′-bromo-[1,1′-biphenyl]-3-yl)-9H-carbazole (13.02 g, 32.7 mmol, 54.7% yield) was afforded as white solids.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[NH2:8][C:9]1[C:14]([CH3:15])=[CH:13][N:12]=[C:11]([Cl:16])[N:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[Cl:16][C:11]1[N:10]=[C:9]([NH:8][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[C:14]([CH3:15])=[CH:13][N:12]=1
Reactant: Cc1cnc(Cl)nc1N
Reactant: Brc1cccnc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1cnc(Cl)nc1Nc1cccnc1
Yield: 57.1 %

Procedure:
A mixture of 3-bromopyridine (379 mg, 2.4 mmol), 4-amino-2-chloro-5-methylpyrimidine (287 mg, 2.0 mmol), Pd2(dba)3 (18 mg, 0.02 mmol), xantphos (23 mg, 0.04 mmol) and cesium carbonate (975 mg, 3.0 mmol) in dioxane (15 mL) was heated under refluxed for 1 h under argon. The solvent was removed and the residue on purification by HPLC gave an intermediate, 2-chloro-5-methyl-N-(pyridin-3-yl)pyrimidin-4-amine as yellow solid (252 mg, 57%). For second Buckwald, a mixture of 2-chloro-5-methyl-N-(pyridin-3-yl)pyrimidin-4-amine (80 mg, 0.36 mmol), 4-(2-(pyrrolidin-1-yl)ethoxy)benzenamine (74 mg, 0.34 mmol), Pd2(dba)3 (3.2 mg, 0.003 mmol), xantphos (4.2 mg, 0.007 mmol) and cesium carbonate (234 mg, 0.72 mmol) in dioxane (5 mL) was heated under refluxed for 1 h under argon. The crude reaction mixture on purification using HPLC gave the title compound as light brown solid (28 mg, 20%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[C:12]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]([N:32]4[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]4)=[O:31])=[CH:26][CH:25]=3)[C:13]3[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([N+:20]([O-])=O)[CH:14]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[H][H]>C(O)(=O)C.[Ni]>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[C:12]([NH:23][C:24]3[CH:25]=[CH:26][C:27]([C:30]([N:32]4[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]4)=[O:31])=[CH:28][CH:29]=3)[C:13]3[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([NH2:20])[CH:14]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: CN1CCN(C(=O)c2ccc(NC(=C3C(=O)Nc4cc(Cl)ccc43)c3ccc(N)c([N+](=O)[O-])c3)cc2)CC1
Agent: [Ni]
Solvent: CC(=O)O
Product: CN1CCN(C(=O)c2ccc(NC(=C3C(=O)Nc4cc(Cl)ccc43)c3ccc(N)c(N)c3)cc2)CC1
Reaction time: 4 h

Procedure:
0.746 g of 6-chloro-3-{1-[4-(4-methyl-1-piperazinyl-carbonyl)phenylamino]-1-(4-amino-3-nitrophenyl)methylene}-2-indolinone are hydrogenated in 30 ml acetic acid with the addition of 0.60 g Raney nickel under 50 psi of hydrogen pressure for 4 hours. After the addition of another 0.30 g of Raney nickel hydrogenation is continued under the same conditions for a further 4 hours, then the catalyst is removed by suction filtering. The residue obtained from the filtrate by distilling off the solvent is dissolved in water, the solution is made alkaline with soda solution. The crude product precipitated is suction filtered, washed with water, dried, dissolved in 70 ml of dichloromethane/methanol/ammonia solution=70:30:3 and filtered through a layer of silica gel. The filtrate is concentrated by evaporation, the residue is stirred with 5 ml of ethyl acetate, suction filtered and dried at 80° C.
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([CH2:15][N:16]3[CH:20]=[C:19]([N+:21]([O-])=O)[CH:18]=[N:17]3)[CH:10]=2)[O:8][CH2:7][CH2:6][O:5]1.[NH4+].[Cl-]>CCO.O.[Fe]>[CH3:3][C:4]1([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([CH2:15][N:16]3[CH:20]=[C:19]([NH2:21])[CH:18]=[N:17]3)[CH:10]=2)[O:8][CH2:7][CH2:6][O:5]1
Reactant: CC1(c2ccnc(Cn3cc([N+](=O)[O-])cn3)c2)OCCO1
Agent: [Fe]
Agent: N#N
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: CC1(c2ccnc(Cn3cc(N)cn3)c2)OCCO1
Temperature: 75 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a mixture of 4-(2-methyl-[1,3]dioxolan-2-yl)-2-(4-nitro-pyrazol-1-ylmethyl)-pyridine (174 mg, 0.60 mmol), iron powder (101 mg, 1.80 mmol) and NH4Cl (162 mg, 3.00 mmol) in a mixture of EtOH (4.0 mL) and water (2.0 mL) was stirred at 75° C. for 1 h. The reaction mixture was filtered while hot and the filter cake rinsed with EtOH. The filtrate was concentrated under reduced pressure and the residue partitioned between CH2Cl2 (10 mL) and aq. 1M NaOH (10 mL). The aq. layer was extracted with CH2Cl2 (2×10 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvent removed under reduced pressure to give the title compound as a red oil. LC-MS-conditions 02: tR=0.55 min, [M+H]+=261.39.
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:14]([S:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:13]([CH3:22])[N:12]=[C:11]1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:25]CCOCCOC.C[O-].[Na+]>CO>[CH2:1]([O:8][CH2:9][N:10]1[C:14]([S:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:13]([CH3:22])[N:12]=[C:11]1[OH:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(Br)n(COCc2ccccc2)c1Sc1ccccc1
Reactant: COCCOCCOC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1nc(O)n(COCc2ccccc2)c1Sc1ccccc1

Procedure:
To a mixture of 15 mg of 1-benzyloxymethyl-2-bromo-4-methyl-5-phenylthioimidazole (I-20) (0.04 mmol), obtained in Example 20, and 3 ml of 2-methoxyethyl ether is added 1 ml of 1M sodium methoxide solution in methanol, and the resultant mixture is heated at 130° C. for 5 hours. After evaporating the 2-methoxyethyl ether, the residue is chromatographed on a column of silica gel, eluting with 3% methanol/methylene chloride. The crude product is recrystallized from ethyl acetate/isopropyl ether to give 9 mg of the product (I-28). Yield, 71%; mp. 147°-148° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[CH:7]=[C:8]([C:14](=O)[CH3:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])([O-:3])=[O:2].[NH2:20][C:21]1[NH:25][N:24]=[N:23][N:22]=1>C(O)C>[CH2:12]([O:11][C:9]([C:8]1[CH:7]([C:6]2[CH:17]=[CH:18][CH:19]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:22]2[N:23]=[N:24][N:25]=[C:21]2[NH:20][C:14]=1[CH3:15])=[O:10])[CH3:13]
Reactant: Nc1nnn[nH]1
Reactant: CCOC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(C)=O
Solvent: CCO
Product: CCOC(=O)C1=C(C)Nc2nnnn2C1c1cccc([N+](=O)[O-])c1
Yield: 61.3 %

Procedure:
To 50 ml of ethanol are added 2.6 g of ethyl 3-nitro-α-acetylcinnamate and 0.9 g of 5-aminotetrazole, and then heated under reflux for 16 hours. On cooling, 2 g of 6-ethoxycarbonyl-5-methyl-7-(3-nitrophenyl)-4,7-dihydrotetrazolo[1,5-a]pyrimidine, melting at 210°-212° C., is obtained.
Reaction SMILES: [Cl:1][CH2:2][CH:3]([OH:23])[CH2:4][C:5]1[C:14]2[O:15][C:16]([C:20]([OH:22])=[O:21])=[CH:17][C:18](=[O:19])[C:13]=2[CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH2:9][CH2:10]2.C(=O)(O)[O-].[Na+:28]>O>[Cl:1][CH2:2][CH:3]([OH:23])[CH2:4][C:5]1[C:14]2[O:15][C:16]([C:20]([O-:22])=[O:21])=[CH:17][C:18](=[O:19])[C:13]=2[CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH2:9][CH2:10]2.[Na+:28]
Reactant: O=C(O)c1cc(=O)c2cc3c(c(CC(O)CCl)c2o1)CCCC3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=C([O-])c1cc(=O)c2cc3c(c(CC(O)CCl)c2o1)CCCC3

Procedure:
To a suspension of the acid from step (a) (1.474 g) in water (30 ml) was added sodium bicarbonate (0.368 g) and the resulting solution was freeze-dried. The solid obtained was dried in vacuo to give the required salt, 1.4 g (89%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[Br:14]N1C(=O)CCC1=O.O.C(OCC)C>CC1CCCO1>[Br:14][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:11]2[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][C:7]=2[CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cccc2c1OC(C)(C)C2
Solvent: O
Solvent: CC1CCCO1
Solvent: CCOCC
Product: COc1cc(Br)cc2c1OC(C)(C)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
56 g 7-methoxy-2,2-dimethyl-2,3-dihydro-1-benzofuran are dissolved in 200 ml 2-methyltetrahydrofuran, 58 g N-bromosuccinimide are added portion wise, while keeping the temperature of the reaction mixture below 50° C., and the reaction is stirred for one hour at RT. Water and diethyl ether are added to the reaction mixture, the phases are separated, the organic phase is washed with 1 M aqueous sodium carbonate solution, dried over MgSO4, and the solvent is removed under reduced pressure. The resulting crude product is purified by distillation under vacuum yielding 5-bromo-7-methoxy-2,2-dimethyl-2,3-dihydro-1-benzofuran.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:14]([O:23][CH3:24])(=[O:22])[C:15]1[C:16](=[CH:18][CH:19]=[CH:20][CH:21]=1)[NH2:17].N1C=CC=CC=1.O>C(Cl)Cl>[CH3:24][O:23][C:14](=[O:22])[C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH:17][S:10]([C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[O:12])=[O:11]
Reactant: COC(=O)c1ccccc1N
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccccc1NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-Nitrobenzenesulfonyl chloride (2.22 g, 10 mmol) is added to a solution of methyl anthranilate (1.51 g, 10 mmol) in 20 mL of DCM at RT, followed by slow addition of pyridine (0.97 mL, 12 mmol). The reaction is stirred 16 h at RT. Water (1 mL) is added. After 1 h, the mixture is partitioned between DCM (40 mL) and water (30 mL). The organic phase is washed with water (30 mL) and brine (30 mL), dried over anhydrous magnesium sulfate and concentrated under vacuum to an orange solid. The solid is redissolved in DCM (30 mL), and hexane (100 mL) is added. The solution is concentrated to approximately 60 mL at which point an orange solid rapidly precipitated. The solid is collected by filtration and dried under vacuum to give 2-(4-nitro-benzenesulfonylamino)-benzoic acid methyl ester.