Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][CH2:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([CH2:15][NH:16][C:17]3[N:26]=[C:25]([N:27]([CH3:29])[CH3:28])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]=3)[CH2:11][CH2:10]2)=[C:4]([O:32][C:33]([F:36])([F:35])[F:34])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:43]1(B(O)O)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.[ClH:52]>C1(C)C=CC=CC=1.CCOC(C)=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.CO>[ClH:52].[ClH:52].[CH3:28][N:27]([CH3:29])[C:25]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[C:17]([NH:16][CH2:15][C@H:12]2[CH2:13][CH2:14][C@H:9]([CH2:8][NH:7][CH2:6][C:5]3[CH:30]=[CH:31][C:2]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)=[CH:3][C:4]=3[O:32][C:33]([F:36])([F:35])[F:34])[CH2:10][CH2:11]2)[N:26]=1
Reactant: OB(O)c1ccccc1
Reactant: CN(C)c1nc(NC[C@H]2CC[C@H](CNCc3ccc(Br)cc3OC(F)(F)F)CC2)nc2ccccc12
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CN(C)c1nc(NC[C@H]2CC[C@H](CNCc3ccc(-c4ccccc4)cc3OC(F)(F)F)CC2)nc2ccccc12
Temperature: 130 °C
Reaction time: 12 h

Procedure:
To a solution of trans-N2-{4-[(4-bromo-2-trifluoromethoxy-benzylamino)-methyl]-cyclohexylmethyl}-N4,N4-dimethyl-quinazoline-2,4-diamine obtained in step B of example 15 (300 mg, 0.529 mol) in toluene (6.6 mL) were added MeOH (2.2 mL), 2 M aqueous K2CO3 (2.2 mL), phenylboronic acid (77 mg, 0.635 mmol), and tetrakis (triphenylphosphine) palladium (61 mg, 0.053 mmol). The reaction mixture was stirred at 130° C. for 12 hr. The mixture was poured into water, and the aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated and, purified by flash chromatography (NH-silica gel, 33% CHCl3 in hexane and silica gel, 9% MeOH in CHCl3) to give pale yellow oil. To a solution of above oil in EtOAc (2 mL) was added 4 M hydrogen chloride in EtOAc (0.1 mL). The mixture was stirred at ambient temperature for 20 min and concentrated. A solution of the residue in Et2O (2 mL) was stirred at ambient temperature for 30 min. The precipitate was collected by filtration, washed with Et2O, and dried under reduced pressure to give trans-N4,N4-dimethyl-N2-(4-{[(3-trifluoromethoxy-biphenyl-4-ylmethyl)-amino]-methyl}-cyclohexylmethyl)-quinazoline-2,4-diamine dihydrochloride (70 mg, 21%) as a white solid.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[CH:13]=[C:12]([F:14])[C:11]([F:15])=[CH:10][C:6]=2[C:7]([OH:9])=O)[CH2:3][CH2:2]1.[C:16]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:19])[NH:17][NH2:18].C(N=C=NCCCN(C)C)C>ClCCl>[C:21]([O:20][C:16]([NH:17][NH:18][C:7](=[O:9])[C:6]1[CH:10]=[C:11]([F:15])[C:12]([F:14])=[CH:13][C:5]=1[NH:4][CH:1]1[CH2:2][CH2:3]1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: O=C(O)c1cc(F)c(F)cc1NC1CC1
Reactant: CC(C)(C)OC(=O)NN
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NNC(=O)c1cc(F)c(F)cc1NC1CC1
Reaction time: 16 h
Yield: 81.4 %

Procedure:
To a solution of 2-cyclopropylamino-4,5-difluorobenzoic acid (Example 5) (1.32 g, 6.19 mmol) and tert-butyl carbazate (1.30 g, 9.75 mmol) in dichloromethane (30 mL) is added 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (1.87 g, 9.75 mmol). After 16 hours, the reaction mixture is diluted with dichloromethane and washed with saturated NaHCO3, water, and brine. The organic layer is dried over MgSO4 and filtered. The filtrate is concentrated under vacuum and purified via flash column chromatography (1:2 ethyl acetate/hexanes) to afford N2-(2-cyclopropylamino-4,5-difluorobenzoyl)hydrazinecarboxylic acid tert-butyl ester as a solid (1.65 g). MS EI: m/z 328 (M+).
Reaction SMILES: [H-].[Na+].[CH2:3]([CH2:13][NH2:14])[CH2:4][C:5]([NH2:12])([C:9]([OH:11])=[O:10])[CH:6]([F:8])[F:7].O.[ClH:16]>C1COCC1>[OH2:10].[ClH:16].[F:7][CH:6]([F:8])[C@@:5]([C:9]([OH:11])=[O:10])([CH2:4][CH2:3][CH2:13][NH2:14])[NH2:12]
Reactant: NCCCC(N)(C(=O)O)C(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: NCCC[C@](N)(C(=O)O)C(F)F
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Into a dry 100 ml three necked RB flask equipped with a stirrer, gas inlet and outlet arrangement methyl-2,5-di[1-(3,4-chlorophenyl) methylidene amino] pentanoate (2.0 g) and sodium hydride (0.21 g) in dry THF (20 ml) were added. The resulting suspension was stirred at 50° C. under a nitrogen atmosphere for 2 hrs. The reaction mixture was then cooled to 5° C. and the nitrogen inlet was replaced with chlorodifluoromethane gas tube. The gas was passed for about 45 mts. The reaction was stirred at RT and allowed to stand overnight. The reaction mixture was worked up by quenching with water and the pH was adjusted to 2 with aqueous HCl. The reaction mixture was extracted with MDC twice. The water layer was concentrated and taken up in methanol and chilled. The crystallized inorganic material was removed. The filtrate was concentrated and the residue taken up in 6N HCl and hydrolyzed. The resulting aqueous layer was evaporated. The crude product was dissolved in ethanol, chilled again to remove any inorganic material and further purified by water-acetone to give a product with a melting point (mp) 223–225° C. with spectral data such as NMR matching with material obtained in Example 8.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[C:9]1([CH2:15][CH2:16][OH:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[H-].[Na+]>CN1CCCC1=O>[Cl:1][C:2]1[N:3]=[N:4][C:5]([O:17][CH2:16][CH2:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: OCCc1ccccc1
Reactant: Clc1ccc(Cl)nn1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Clc1ccc(OCCc2ccccc2)nn1

Procedure:
3,6-Dichloropyridazine (1.0 g, 6.712 mmol), 2-phenylethanol (820 mg, 6.712 mmol) and sodium hydride (60 percent suspension in oil, 268 mg, 6.712 mmol) were stirred in 25 ml of N-methylpyrrolidin-2-one at room temperature for 30 minutes. After concentrating, water and ethyl acetate were added, and the organic phase was removed, concentrated and purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 878 mg (56%), M+H+: 235.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)=[C:11]3[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:38](OC(=O)C)(=[O:40])[CH3:39]>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[C:38]([NH:30][S:27]([C:24]1[CH:25]=[CH:26][C:21]([C:20]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[N:9][N:10]3[CH:15]=[C:14]([C:16]([F:17])([F:19])[F:18])[CH:13]=[CH:12][C:11]=23)=[CH:22][CH:23]=1)(=[O:29])=[O:28])(=[O:40])[CH3:39]
Reactant: CC(=O)OC(C)=O
Reactant: NS(=O)(=O)c1ccc(-c2c(-c3ccc(F)cc3)nn3cc(C(F)(F)F)ccc23)cc1
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)NS(=O)(=O)c1ccc(-c2c(-c3ccc(F)cc3)nn3cc(C(F)(F)F)ccc23)cc1
Yield: 29.9 %

Procedure:
A solution of 4-[2-(4-fluoro-phenyl)-6-trifluoromethyl-pyrazolo[1,5-a]pyridin-3-yl]benzenesulphonamide (0.185 g 0.42 mmol), triethylamine (0.4 ml), 4-dimethylaminopyridine (0.024 g 0.18 mmol) and acetic anhydride (0.12 ml 1.2 mmol) in chloroform (10 ml) was stirred at room temperature for 4 hr. The reaction mixture was washed with 2M hydrochloric acid (10 ml), M Na2CO3 (5 ml) and water (10 ml). Drying (MgSO4) and removal of solvent gave the title compound as a white solid (0.06 g 31%).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]([C:24]3[N:29]=[C:28]([C:30]4[CH:35]=[CH:34][C:33]([C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:32][CH:31]=4)[N:27]=[C:26]([C:40]4[CH:45]=[CH:44][C:43]([C:46]([CH3:49])([CH3:48])[CH3:47])=[CH:42][CH:41]=4)[N:25]=3)[CH:12]=[C:13](B3OC(C)(C)C(C)(C)O3)[CH:14]=2)O1.Br[C:52]1[C:65]2[C:56](=[C:57]3[C:62](=[CH:63][CH:64]=2)[CH:61]=[CH:60][CH:59]=[N:58]3)[N:55]=[CH:54][CH:53]=1.[Cl-].[Li+].C(=O)([O-])[O-].[Na+].[Na+]>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.C(O)C.C1(C)C=CC=CC=1>[N:55]1[C:56]2[C:65](=[CH:64][CH:63]=[C:62]3[C:57]=2[N:58]=[CH:59][CH:60]=[CH:61]3)[C:52]([C:13]2[CH:12]=[C:11]([C:24]3[N:25]=[C:26]([C:40]4[CH:41]=[CH:42][C:43]([C:46]([CH3:47])([CH3:48])[CH3:49])=[CH:44][CH:45]=4)[N:27]=[C:28]([C:30]4[CH:31]=[CH:32][C:33]([C:36]([CH3:39])([CH3:37])[CH3:38])=[CH:34][CH:35]=4)[N:29]=3)[CH:10]=[C:9]([C:61]3[C:62]4[C:57](=[C:56]5[C:65](=[CH:64][CH:63]=4)[CH:52]=[CH:53][CH:54]=[N:55]5)[N:58]=[CH:59][CH:60]=3)[CH:14]=2)=[CH:53][CH:54]=1
Reactant: CC(C)(C)c1ccc(-c2nc(-c3ccc(C(C)(C)C)cc3)nc(-c3cc(B4OC(C)(C)C(C)(C)O4)cc(B4OC(C)(C)C(C)(C)O4)c3)n2)cc1
Reactant: Brc1ccnc2c1ccc1cccnc12
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: [Cl-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(C)(C)c1ccc(-c2nc(-c3ccc(C(C)(C)C)cc3)nc(-c3cc(-c4ccnc5c4ccc4cccnc45)cc(-c4ccnc5c4ccc4cccnc45)c3)n2)cc1
Temperature: 100 °C
Reaction time: 88 h

Procedure:
In a stream of argon, 168 mg of 2-[3,5-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-4,6-bis(4-tert-butylphenyl)-1,3,5-triazine, 155 mg of 4-bromo-1,10-phenanthroline, 32 mg of lithium chloride and 23 mg of tetrakis(triphenylphosphine)palladium were suspended in a toluene (6.0 mL)/ethanol (1.5 mL) mixed solvent. 1.0 mL of a 2.0M aqueous sodium carbonate solution was added in the obtained suspension, and the mixture was stirred at 100° C. for 88 hours. Then the reaction mixture was left to be cooled to room temperature, and distilled under a reduced pressure to remove low-boiling point ingredients. Water was added to the residue to give a crude product. The crude product was collected by filtration, and evaporated to dryness under a reduced pressure. The dried crude product was recrystallized from a dichloromethane/hexane mixed solvent to give 169 mg of target 2-[3,5-bis(1,10-phenanthrolin-4-yl)phenyl]-4,6-bis(4-tert-butylphenyl)-1,3,5-triazine as a white solid (yield, 87%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([S:12](Cl)(=[O:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[NH3:16]>C(Cl)Cl>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([S:12](=[O:14])(=[O:13])[NH2:16])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: N
Reactant: O=S(=O)(Cl)c1cccc2c(Cl)nccc12
Solvent: ClCCl
Product: NS(=O)(=O)c1cccc2c(Cl)nccc12

Procedure:
A solution of 1-chloro-5-chlorosulphonylisoquinoline (613 mg, 2.34 mmol) in methylene chloride saturated with ammonia gas (20 mL) was stirred at RT for 18 h, concentrated in vacuo to a white solid and purified by column chromatography upon silica gel (preabsorbed) using EtOAc-hexanes (1:1) as eluant to give 1-chloro-5-sulphamoylisoquinoline as a white solid (206 mg, 0.85 mmol).
Reaction SMILES: [C:1]([N:5]1[C:14]2[C:9](=[CH:10][C:11]([O:18][CH3:19])=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[CH2:8][CH2:7][CH2:6]1)(=[O:4])[CH:2]=[CH2:3].[CH3:20][NH:21][CH3:22]>CO>[CH3:20][N:21]([CH3:22])[CH2:3][CH2:2][C:1]([N:5]1[C:14]2[C:9](=[CH:10][C:11]([O:18][CH3:19])=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: CNC
Reactant: C=CC(=O)N1CCCc2cc(OC)c([N+](=O)[O-])cc21
Solvent: CO
Product: COc1cc2c(cc1[N+](=O)[O-])N(C(=O)CCN(C)C)CCC2
Temperature: 65 °C

Procedure:
1-acryloyl-6-(methyloxy)-7-nitro-1,2,3,4-tetrahydroquinoline (crude from previous reaction, assumed 0.91 mmol) was dissolved in methanol (5 mL), treated with excess dimethyl amine (5.0 mL, 10 mmol, 2 M in THF, Aldrich), and the reaction heated in a sealed tube at 65° C. for 16 h. The mixture was cooled, concentrated, and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous layer was separated and then back-extracted with dichloromethane. The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated to give N,N-dimethyl-3-[6-(methyloxy)-7-nitro-3,4-dihydro-1(2H)-quinolinyl]-3-oxo-1-propanamine which was taken directly to the next step without determination of yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.83-1.94 (m, 2 H), 2.18 (bs, 6 H), 2.56-2.71 (m, 4 H), 2.80 (t, J=6.4 Hz, 2 H), 3.71 (t, J=6.0 Hz, 2 H), 3.90 (s, 3 H), 7.20 (s, 1 H), 8.27 (very broad singlet due to amide rotomers, 1 H); ESIMS (M+H)+=308.
Reaction SMILES: [Cl:1]/[C:2](=[CH:12]/[CH2:13][C:14]1[CH:19]=[C:18]([O:20]C)[C:17]([Cl:22])=[CH:16][C:15]=1[O:23]C)/[CH2:3][C:4]1[CH:5]=[C:6]([OH:11])[CH:7]=[C:8]([OH:10])[CH:9]=1.B(Br)(Br)Br>C(Cl)Cl.[Al]>[Cl:1]/[C:2](=[CH:12]/[CH2:13][C:14]1[CH:19]=[C:18]([OH:20])[C:17]([Cl:22])=[CH:16][C:15]=1[OH:23])/[CH2:3][C:4]1[CH:5]=[C:6]([OH:11])[CH:7]=[C:8]([OH:10])[CH:9]=1
Reactant: COc1cc(C/C=C(/Cl)Cc2cc(O)cc(O)c2)c(OC)cc1Cl
Agent: BrB(Br)Br
Agent: [Al]
Solvent: ClCCl
Product: Oc1cc(O)cc(C/C(Cl)=C\Cc2cc(O)c(Cl)cc2O)c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 100.3 %

Procedure:
A stirred solution of 13 (0.0500 g, 0.135 mmol, 1 equiv) in CH2Cl2 (7 mL) was enclosed in aluminum foil and cooled 0° C. To the stirred solution was added dropwise BBr3 (1 M in CH2Cl2; 0.677 mL, 0.677 mmol, 5 equiv). The resulting solution was allowed to slowly warm to room temperature and stir for 18 h. The reaction mixture was quenched with a saturated aqueous solution of NaHCO3 (8 mL) and allowed to stir at room temperature for an additional hour. The solution was acidified with HCl, extracted with EtOAc (×2) and the combined organic layers were dried (MgSO4), filtered, and concentrated under reduced pressure. The crude product was purified by chromatography on SiO2 (chloroform/acetone, 3:1) to give 0.0462 g (96% yield) of 14 as a slight yellow film. An analytically pure sample was obtained via SFC chromatography using the semi-prep (250×10 mm) silica column (RT=4.68 min, 8 mL/min, 25% methanol, 220 nm detection): Rf 0.15 (acetone/chloroform, 2:8); IR (neat) 3343, 1692, 1599, 1495, 1417, 1329, 1184, 1143, 1005, 822 cm−1; 1H NMR (600 MHz (CD3)2CO) δ 8.17 (bs, 4 H), 6.86 (s, 1 H), 6.84 (s, 1 H), 6.29 (d, 2 H, J=2.4 Hz), 6.32 (t, 1 H, J=7.8 Hz), 3.69 (s, 2 H), 3.47 (d, 2 H, J=7.8 Hz); 13C NMR (150 MHz, CDCl3) δ 159.5, 149.0, 146.9, 140.5, 133.7, 128.0, 127.0, 118.5, 118.5, 116.7, 108.0, 101.8, 40.2, 29.5; HRMS (ES−) [2M-H]− m/z calcd for C32H27O8Cl4 679.0460, found 679.0482.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[NH:9]C(=O)O[C:12](=[O:13])[C:7]=2[CH:6]=[CH:5][CH:4]=1.[Br:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1>CN(C=O)C>[NH2:9][C:8]1[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=1[C:12]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([Br:15])=[CH:17][CH:18]=1)=[O:13]
Reactant: COc1cccc2c(=O)oc(=O)[nH]c12
Reactant: Nc1ccc(Br)cc1
Solvent: CN(C)C=O
Product: COc1cccc(C(=O)Nc2ccc(Br)cc2)c1N

Procedure:
A solution of 8-methoxy-1H-benzo[d][1,3]oxazine-2,4-dione (1.50 g, 7.70 mmol) and 4-bromoaniline (1.40 g, 8.10 mmol) in anhydrous DMF (10 mL) was stirred at 115° C. for 16 hours under nitrogen. DMF was removed and the residue was mixed with water (100 mL) and ethyl acetate (150 mL). The organic phase was separated and washed with brine (50 mL). The solvent was removed and the residue was purified by column chromatography (SiO2, hexane/ethyl acetate=1:1) to give 2-amino-N-(4-bromo-phenyl)-3-methoxy-benzamide. Yield: 1.49 g (60%).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([NH:7][NH:8][C:9]([N:11]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[O:14][C:13]2[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:12]1=2)=[O:10])=[O:6].[CH3:27][N:28]=[C:29]=[O:30]>>[CH3:27][NH:28][C:29]([NH:2][CH2:3][CH2:4][C:5]([NH:7][NH:8][C:9]([N:11]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[O:14][C:13]2[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:12]1=2)=[O:10])=[O:6])=[O:30]
Reactant: NCCC(=O)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reactant: CN=C=O
Agent: Cl
Product: CNC(=O)NCCC(=O)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21

Procedure:
8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[3-[[(methylamino)carbonyl]amino]-1-oxopropyl]hydrazide (12) was prepared from 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-(3-amino-1-oxopropyl)hydrazide, monohydrochloride (9), prepared as described above in Example 9, and methylisocyanate, in the manner described in Example 10 above, on a one mmol scale to yield 0.17 g (40%) of product. Analysis calculated for C19H20N5O4C1 0.4 H2O (M.W. 425.06): C, 53.69; H, 4.93; N, 16.48; Cl, 8.34. Found: C, 53.96; H, 4.87; N, 16.06; Cl, 8.46.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][CH:5]=[C:6](Cl)[C:7]=1[Cl:8].Cl.[CH2:11]([O:13][C:14](=[O:17])[CH2:15][NH2:16])[CH3:12].C(N(C(C)C)CC)(C)C>C(O)C>[Cl:8][C:7]1[C:6]([NH:16][CH2:15][C:14]([O:13][CH2:11][CH3:12])=[O:17])=[CH:5][N:4]=[N:3][C:2]=1[Cl:1]
Reactant: Clc1cnnc(Cl)c1Cl
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CNc1cnnc(Cl)c1Cl
Yield: 30.8 %

Procedure:
A solution of 3,4,5-trichloropyridazine (300 mg), glycine ethyl ester hydrochloride (228 mg) and diisopropylethyl amine (844 μL) in ethanol was stirred for 3 hours under reflux. After the reaction was completed, the mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate: hexane=1:9 to 1:1) to give 126 mg (31% yield) of the title compound as a pale pink amorphous.
Reaction SMILES: C(OC([N:11]1[CH2:15][CH:14]([C:16]2[C:24]3[C:19](=[CH:20][C:21]([F:25])=[CH:22][CH:23]=3)[NH:18][CH:17]=2)[CH:13]2[N:26]([C:29](=[O:45])[CH:30]([NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[CH2:27][CH2:28][CH:12]12)=O)C1C=CC=CC=1>CO>[C:41]([O:40][C:38](=[O:39])[NH:37][CH:30]([CH:31]1[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]1)[C:29]([N:26]1[CH2:27][CH2:28][CH:12]2[NH:11][CH2:15][CH:14]([C:16]3[C:24]4[C:19](=[CH:20][C:21]([F:25])=[CH:22][CH:23]=4)[NH:18][CH:17]=3)[CH:13]12)=[O:45])([CH3:44])([CH3:42])[CH3:43]
Reactant: CC(C)(C)OC(=O)NC(C(=O)N1CCC2C1C(c1c[nH]c3cc(F)ccc13)CN2C(=O)OCc1ccccc1)C1CCCCC1
Solvent: CO
Product: CC(C)(C)OC(=O)NC(C(=O)N1CCC2NCC(c3c[nH]c4cc(F)ccc34)C21)C1CCCCC1
Reaction time: 2 h
Yield: 94.6 %

Procedure:
A 500 mL Parr bottle was charged with crude 48 (1.5 g, 2.4 mmol) and 10% Pd-on-carbon (300 mg) in reagent grade MeOH (20 mL). The mixture was pressurized to 50 PSI H2 (344.7 KPa) then shaken for 2 h. The catalyst was removed by filtration through diatomaceous earth (Celite®) and the solids were washed with MeOH and EtOAc. The filtrate was concentrated in vacuo to afford 1.1 g of 49 which was used without further purification. 1H NMR (300 MHz, CDCl3): δ9.03 (s, 1H), 8.16 (dd, J=5.4 Hz, 8.4 Hz, 1H), 7.57 (s, 1H), 7.00 (d, J=8.7 Hz, 1H), 6.93 (t, J=8.7 Hz, 1H), 5.30 (d, J=8.7 Hz, 1H), 4.76 (m, 1H), 4.30-4.20 (m, 4H), 3.89 (m, 2H), 3.55 (m, 1H), 3.48 (s, 3H), 2.73-2.69 (m, 1H), 2.05-1.99 (m, 1H), 1.74-1.65 (m, 8H), 1.43 (s, 9H), 1.26-1.06 (m, 2H) ppm. Mass spectrum, m/z [485.3] (M+H)+.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:14][O:15][CH:16]([O:19][CH3:20])[CH2:17][NH2:18]>C1C=CC=CC=1>[CH3:14][O:15][CH:16]([O:19][CH3:20])[CH2:17][NH:18][C:1](=[O:3])[CH3:2]
Reactant: COC(CN)OC
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: COC(CNC(C)=O)OC

Procedure:
A solution of 32 g (313 mmol) of acetic anhydride in 200 ml of benzene is added, drop by drop, to a suspension, stirred and heated to reflux, of 40 g (290 mmol) of potassium carbonate and 30 g (285 mmol) of aminoacetaldehyde dimethyl acetal in 200 ml of benzene. Reflux is maintained for 30 min., then the mixture is cooled and filtered, the precipitate is washed with benzene, the filtrate is evaporated and the residual oil is treated with vegetable charcoal in 300 ml of diethyl ether. After filtration and evaporation, 36.8 g (250 mmol) of product are obtained. n25D =1.4450.
Reaction SMILES: [CH:1]1([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15]O)=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.S(Cl)([Cl:25])=O>O>[CH:1]1([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][Cl:25])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: OCCc1ccc(C2CCCCCC2)cc1
Solvent: O
Solvent: c1ccncc1
Product: ClCCc1ccc(C2CCCCCC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
73.6 g of β-(p-cycloheptyl-phenyl)-ethanol are mixed with 31.6 ml of absolute pyridine. 29.5 ml of thionyl chloride are added dropwise to this mixture, whilst cooling with ice. Thereafter, the reaction mixture is slowly heated to 100°-110° C and kept at this temperature for 2 hours. The reaction solution is again cooled to room temperature, 69 ml of water are added, and the whole is extracted with a mixture of ether and chloroform. The organic phase is washed twice with 2 N sodium carbonate solution, three times with 2 N hydrochloric acid and finally once with 2 N sodium carbonate solution, dried over sodium sulphate, filtered and evaporated. The residue, a brown oil, is distilled in a high vacuum. Hereupon, β-(p-cycloheptyl-phenyl)-ethyl chloride is obtained as a light yellow oil of boiling point 130°-5° C/0.2 mm Hg.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH:12]([NH2:15])([CH3:14])[CH3:13]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:15][CH:12]([CH3:14])[CH3:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(C)N
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: ClCCl
Product: CC(C)NS(=O)(=O)c1ccc(Br)cc1
Yield: 27.7 %

Procedure:
According to general procedure C, 4-Bromobenzene sulfonyl chloride (0.40 g, 1.56 mmol) and isopropylamine (0.33 mL, 3.90 mmol) were stirred together with dry dichloromethane (5 mL) for 16 hours. 4-bromo-N-isopropylbenzenesulfonamide (0.12 g, 28%) was provided after purification. MS (ESI) m/z 278. HPLC purity 100.0% at 210-370 nm, 8.7 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[C:11]1([C:17]2[N:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1>C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.O>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:20]1[CH:19]=[CH:18][C:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:22][CH:21]=1)([O-:10])=[O:9]
Reactant: OB(O)c1ccc(-c2ccccc2)nc1
Reactant: O=[N+]([O-])c1ccccc1I
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccccc1-c1ccc(-c2ccccc2)nc1
Temperature: 25 °C
Yield: 65.7 %

Procedure:
2-Iodo-1-nitrobenzene (6.88 g, 27.64 mmol), 6-phenyl-3-pyridinylboronic acid (5.5 g, 27.64 mmol), potassium phosphate (17.6 g, 82.91 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (0.451 g, 0.522 mmol) and Pd2(bda)3 (0.119 g, 0.55 mmol) were to toluene (150 mL) and water (12 mL). Nitrogen was bubbled through the solution for 30 minutes and then the solution was refluxed for overnight in an atmosphere of nitrogen. The reaction was then allowed to cool to room temperature and the organic phase was separated from the aqueous phase. The aqueous phase was extracted with ethylacetate and the organic fractions were combined and dried over sodium sulfate and the solvent removed under vacuum. The product was chromatographed using silica gel with ethylacetate and hexanes as the eluent. The solvent was removed to give 5.02 g of the title compound.