Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=CC2N(O)N=[N:7]C=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[C:24]([O:28][C:29]([N:31]([CH2:35][C:36]1[CH:41]=[CH:40][C:39]([NH:42][C:43]2[N:48]=[C:47]([CH2:49][CH2:50][C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=3[CH2:57][C:58]([OH:60])=O)[C:46]([C:61]([F:64])([F:63])[F:62])=[CH:45][N:44]=2)=[CH:38][CH:37]=1)[CH2:32][CH2:33][OH:34])=[O:30])([CH3:27])([CH3:26])[CH3:25].CCN(CC)CC.C(=O)([O-])[O-].[NH4+].[NH4+].C([O-])(O)=O.[Na+]>CN(C=O)C>[NH2:7][C:58](=[O:60])[CH2:57][C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][C:51]=1[CH2:50][CH2:49][C:47]1[C:46]([C:61]([F:64])([F:62])[F:63])=[CH:45][N:44]=[C:43]([NH:42][C:39]2[CH:40]=[CH:41][C:36]([CH2:35][N:31]([CH2:32][CH2:33][OH:34])[C:29](=[O:30])[O:28][C:24]([CH3:26])([CH3:25])[CH3:27])=[CH:37][CH:38]=2)[N:48]=1
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N(CCO)Cc1ccc(Nc2ncc(C(F)(F)F)c(CCc3ccccc3CC(=O)O)n2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N(CCO)Cc1ccc(Nc2ncc(C(F)(F)F)c(CCc3ccccc3CC(N)=O)n2)cc1
Temperature: 40 °C
Reaction time: 22 h

Procedure:
HOBt (0.119 g, 0.879 mmol) and EDCl.HCl (0.169 g, 0.879 mmol) were added to a solution of 2-(2-(2-(2-((4-(((tert-butoxycarbonyl)(2-hydroxyethyl)amino)methyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetic acid (A74) (0.421 g, 0.733 mmol) and Et3N (0.408 mL, 0.297 mmol) in DMF (10 mL). After 10 minutes ammonium carbonate (1.34 g, 14.65 mmol) was added and the resulting mixture was stirred at 40° C. for 22 hours. Saturated aqueous saturated NaHCO3 solution (25 mL) was added the resulting mixture extracted with EtOAc (3×15 mL). The combined organic fractions were dried (Na2SO4), filtered and evaporated in vacuo. The residue was adsorbed onto silica gel then purified using column chromatography (CombiFlash Rf, 24 g SiO2 cartridge, 40-100% EtOAc in cyclohexane) to give the title compound A75 as a white solid (0.301 g, 76%); 1H NMR (300 MHz, CDCl3) δ 8.56 (s, 1H), 7.61-7.58 (m, 3H), 7.30-7.26 (m, 6H), 5.48 (brs, 2H), 4.49 (brs, 2H), 3.74 (brs, 4H), 3.42 (brs, 2H), 3.15-3.12 (m, 4H), 1.50 (s, 9H). LCMS-B: rt 7.344 min; m/z 574 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:10]=2[N:11]=[C:12](SC)[N:13]=1.[NH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[CH2:31]([O:30][C:28](=[O:29])[CH2:27][NH:26][C:12]1[N:13]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:9]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:10]=2[N:11]=1)[CH3:32]
Reactant: CCOC(=O)CN
Reactant: CCC(CC)n1c(=O)ccc2c(-c3ccccc3Cl)nc(SC)nc21
Product: CCOC(=O)CNc1nc(-c2ccccc2Cl)c2ccc(=O)n(C(CC)CC)c2n1

Procedure:
The product of Example 44, and ethyl glycinate were reacted by the procedure of Example 60 to afford the title compound [4-(2-chloro-phenyl)-8-(1-ethyl-propyl)-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-acetic acid ethyl ester. LC MS (m/e)=429 (MH+). Rt=2.49 min
Reaction SMILES: Br[C:2]1[C:7]([Br:8])=[C:6]([Cl:9])[C:5]([Br:10])=[C:4](Br)[C:3]=1[OH:12].[H][H]>[OH-].[K+].CO.[Ni]>[Br:8][C:7]1[CH:2]=[C:3]([OH:12])[CH:4]=[C:5]([Br:10])[C:6]=1[Cl:9]
Reactant: Oc1c(Br)c(Br)c(Cl)c(Br)c1Br
Reactant: [H][H]
Agent: [Ni]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Oc1cc(Br)c(Cl)c(Br)c1
Yield: 61 %

Procedure:
8.9 g of 2,3,5,6-tetrabromo-4-chlorophenol are dissolved in a mixture of 40 ml of 1 N methanolic KOH and 60 ml of methanol and then 4 g of Raney nickel are added to the solution. Hydrogenation is carried out with hydrogen in a shaking apparatus for 41/2 hours under normal pressure at 20° C. The uptake of hydrogen is 98% of theory. The catalyst is removed by filtration and the filtrate is concentrated. The residue is recrystallised twice from cyclohexane, affording 3.5 g of 3,5-dibromo-4-chlorophenol in the form of colourless crystals with a melting point of 121° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH2:11]([N:18]1[CH2:23][CH2:22][CH:21]([NH:24][CH3:25])[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH2:11]([N:18]1[CH2:23][CH2:22][CH:21]([N:24]([CH3:25])[C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:20][CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CNC1CCN(Cc2ccccc2)CC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CN(c1ccc([N+](=O)[O-])cc1)C1CCN(Cc2ccccc2)CC1
Temperature: 100 °C
Yield: 95.4 %

Procedure:
A mixture of 1-fluoro-4-nitrobenzene (12.24 mmol, 1.726 g), 1-benzyl-N-methylpiperidin-4-amine (12.24 mmol, 2.5 g) and potassium carbonate (12.24 mmol, 1.691 g) was heated at 100° C. using an oil bath for 48 hours. The reaction mixture was allowed to cool to room temperature, diluted with dichloromethane and filtered. The filtrate was concentrated under vacuum to give the intermediate 1-benzyl-N-methyl-N-(4-nitrophenyl)piperidin-4-amine (3.8 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[C:11]([NH2:20])=[N:12][C:13]([NH2:19])=[N:14]3)[CH2:3][CH2:2]1.[C:21]1([CH3:30])[C:22]([C:27](Cl)=[O:28])=[CH:23][CH:24]=[CH:25][CH:26]=1>>[NH2:19][C:13]1[N:12]=[C:11]([NH2:20])[C:10]2[C:15](=[CH:16][CH:17]=[CH:18][C:9]=2[O:8][CH2:7][CH:4]2[CH2:5][CH2:6][N:1]([C:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[CH3:30])=[O:28])[CH2:2][CH2:3]2)[N:14]=1
Reactant: Nc1nc(N)c2c(OCC3CCNCC3)cccc2n1
Reactant: Cc1ccccc1C(=O)Cl
Product: Cc1ccccc1C(=O)N1CCC(COc2cccc3nc(N)nc(N)c23)CC1
Yield: 70 %

Procedure:
The amidation of 5-(piperidin-4-ylmethoxy)quinazoline-2,4-diamine (50 mg; 0.18 mmol) was carried out using o-toluoyl chloride (57 mg; 0.37 mmol) via Method AA to yield 101 mg. (70% yield). 1HNMR (400 MHz, DMSO-d6) δ 7.35 (t, J=8.4 Hz, 1H), 7.25 (m, 6H), 6.76 (d, J=8.0 Hz, 1H), 6.54 (d, J=8.0 Hz, 1H), 5.94 (br s, 2H), 4.59 (br d, J=13.2 Hz, 1H), 4.03 (d, J=6.0 Hz, 2H), 3.3 (m, 1H), 3.04 (t, J=11.6 Hz, 1H), 2.88 (t, J=12.0 Hz, 1H), 2.23 (m, 4H), 1.89 (br d, J=13.2 Hz, 1H), 1.69 (m, 1H), 1.24 (m, 2H). MS m/z (ESI) 392 (M+H)+.
Reaction SMILES: [C:1]1(C)[C:2]([S:7]([OH:10])(=[O:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[CH3:12]O>>[C:5]1([CH3:12])[CH:6]=[CH:1][C:2]([S:7]([OH:10])(=[O:9])=[O:8])=[CH:3][CH:4]=1
Reactant: CO
Reactant: Cc1ccccc1S(=O)(=O)O
Product: Cc1ccc(S(=O)(=O)O)cc1

Procedure:
Compound C (250 mg, prepared in analogous fashion to the process described in Example 12 above) was dissolved in methanol (10 mL). Toluenesulphonic acid (110 mg) was added to the solution. The methanol was removed under reduced pressure and the remaining gum was re-dissolved in the minimum amount of hot ethyl acetate possible. The solution was seeded with previously prepared salt (prepared by slow evaporation of solvent from a small portion of a solution of title compound, prepared in analogous fashion to this procedure) and left in the fridge for several days to crystallise. The resulting crystals were collected by filtration and washed with a small amount of cold ethyl acetate (recovered 280 mg, 78%).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1.C(N(CC)C(C)C)(C)C.Cl[C:23]([C:25]1[CH:26]=[C:27]([CH2:31][NH:32][C:33]([CH2:35][CH2:36][N:37]2[CH2:42][CH2:41][CH:40]([O:43][C:44](=[O:58])[NH:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=3[C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[CH2:39][CH2:38]2)=[O:34])[CH:28]=[CH:29][CH:30]=1)=[O:24].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:23]([C:25]2[CH:26]=[C:27]([CH2:31][NH:32][C:33]([CH2:35][CH2:36][N:37]3[CH2:38][CH2:39][CH:40]([O:43][C:44](=[O:58])[NH:45][C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=4[C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)[CH2:41][CH2:42]3)=[O:34])[CH:28]=[CH:29][CH:30]=2)=[O:24])=[CH:8][CH:7]=1
Reactant: Nc1ccc(C2OCCO2)cc1
Reactant: O=C(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)NCc1cccc(C(=O)Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)NCc1cccc(C(=O)Nc2ccc(C3OCCO3)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a stirred solution of 4-(1,3-dioxolan-2-yl)phenylamine (0.0826 g, 0.500 mmol) and N,N-diisopropylethylamine (348 μL, 2.00 mmol) in DCM (2.0 mL) at room temperature was added a solution of biphenyl-2-ylcarbamic acid 1-{2-[(3-chlorocarbonylphenyl)methylcarbamoyl]ethyl}piperidin-4-yl ester (0.260 g, 0.500 mmol) in DCM (1.0 mL). The resulting mixture was stirred at room temperature for 1 h. LC-MS (Method 10-90) showed product was present (Rt 3.41 min; m/z 649.4 [M+H]+. Saturated aqueous sodium bicarbonate solution was added and the layers were separated. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (0-5% MeOH in DCM) to give the title compound (345 mg containing some solvent residue, ca. 100% yield) as a brown oil.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([CH2:10]Br)[C:7]([F:12])=[CH:6][C:3]=1[C:4]#[N:5].[Cl:13][C:14]1[CH:15]=[C:16]([OH:21])[CH:17]=[CH:18][C:19]=1[Cl:20].C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[Cl:13][C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][C:19]=1[Cl:20])[O:21][CH2:10][C:8]1[C:7]([F:12])=[CH:6][C:3]([C:4]#[N:5])=[C:2]([F:1])[CH:9]=1
Reactant: N#Cc1cc(F)c(CBr)cc1F
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: N#Cc1cc(F)c(COc2ccc(Cl)c(Cl)c2)cc1F
Temperature: 25 °C
Reaction time: 36 h
Yield: 21.2 %

Procedure:
To a stirred solution of 2,5-difluoro-4-(bromomethyl)benzonitrile (Preparation 22, 530 mg, 2.30 mmol) and 3,4-dichlorophenol (375 mg, 2.30 mmol) in acetone (12 mL) was added potassium carbonate (954 mg, 6.90 mmol). The mixture was stirred at room temperature for 36 hours. The reaction mixture was then poured into water (25 mL) and extracted with EtOAc (3×25 mL). The combined organics were dried over sodium sulphate and evaporated to yield the crude product as a yellow oil, which was purified by silica gel chromatography eluting with 50% heptanes in DCM to afford the title compound as a white solid (153 mg, 22%).
Reaction SMILES: [ClH:1].Cl.[Cl:3][C:4]1C(C2SC3C=CC=C(C(N)=O)C=3C=2)=NC(NCCC2CCN(C)CC2)=NC=1.[CH:32]1([NH:35][C:36]([C:38]2[C:46]3[CH:45]=[C:44]([C:47]4[C:52]([CH3:53])=[CH:51][N:50]=[C:49]([NH:54][CH2:55][CH2:56][CH2:57][CH:58]5[CH2:63][CH2:62][CH2:61][NH:60][CH2:59]5)[N:48]=4)[S:43][C:42]=3[CH:41]=[CH:40][CH:39]=2)=[O:37])[CH2:34][CH2:33]1>>[ClH:3].[ClH:1].[CH:32]1([NH:35][C:36]([C:38]2[C:46]3[CH:45]=[C:44]([C:47]4[C:52]([CH3:53])=[CH:51][N:50]=[C:49]([NH:54][CH2:55][CH2:56][CH2:57][CH:58]5[CH2:63][CH2:62][CH2:61][N:60]([CH3:4])[CH2:59]5)[N:48]=4)[S:43][C:42]=3[CH:41]=[CH:40][CH:39]=2)=[O:37])[CH2:34][CH2:33]1
Reactant: CN1CCC(CCNc2ncc(Cl)c(-c3cc4c(C(N)=O)cccc4s3)n2)CC1
Reactant: Cc1cnc(NCCCC2CCCNC2)nc1-c1cc2c(C(=O)NC3CC3)cccc2s1
Agent: Cl
Product: Cc1cnc(NCCCC2CCCN(C)C2)nc1-c1cc2c(C(=O)NC3CC3)cccc2s1

Procedure:
Using the method of 2-{5-chloro-2-[2-(1-methylpiperidin-4-yl)-ethylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid amide di-hydrochloride, the title compound is synthesized from racemic 2-[5-methyl-2-(3-piperidin-3-yl-propylamino)-pyrimidin-4-yl]-benzo[b]thiophene-4-carboxylic acid cyclopropylamide and isolated as a yellow solid. ES+(m/z) 464 [M(free base)+H].
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C@H:12]2[CH2:17][CH2:16][C@@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH:34]=[C:35]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[CH:36]=[CH:37][CH:38]=2)O1.O.C(=O)([O-])[O-].[Na+].[Na+].C(=O)(O)[O-].[Na+]>O.COCCOC.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>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([C@H:12]3[CH2:17][CH2:16][C@@H:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[CH2:14][CH2:13]3)[N:3]=[C:2]([C:33]3[CH:34]=[C:35]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:44])([CH3:43])[CH3:45])[CH:36]=[CH:37][CH:38]=3)[C:10]=12
Reactant: CC(C)(C)OC(=O)Nc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
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: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4cccc(NC(=O)OC(C)(C)C)c4)c4c(N)ncnc43)CC2)CC1
Temperature: 85 °C
Yield: 81.1 %

Procedure:
A mixture of cis-3-iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1.89 g, 4.28 mmol, 1 equiv), tert-butyl N-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (1.64 g, 5.14 mmol, 1.2 equiv), tetrakis(triphenylphosphine)palladium (0.271 g, 0.257 mmol, 0.06 equiv), and sodium carbonate monohydrate (1.28 g, 10.3 mmol, 2.4 equiv) in water (13 mL) and DME (18 mL) was heated at 85° C. for 14 h. The mixture was allowed to cool to ambient temperature. Saturated aqueous sodium bicarbonate solution (15 mL) was added and the aqueous portion was extracted with EtOAc (30 mL). The organic extract was dried over MgSO4, filtered, and concentrated to afford a pale yellow solid. Purification by column chromatography on silica gel (elution with 2 L of 95:4:1 CH2Cl2:Et3N:MeOH) afforded cis-tert-butyl N-(3-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)carbamate as a white solid (1.76 g, 3.47 mmol):
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:14](Cl)(=[O:16])=[O:15])[C:5]2[O:10][S:9](=[O:12])(=[O:11])[CH:8]=[CH:7][C:6]=2[CH:13]=1.[NH3:18].Cl>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([S:14](=[O:16])(=[O:15])[NH2:18])[C:5]2[O:10][S:9](=[O:12])(=[O:11])[CH:8]=[CH:7][C:6]=2[CH:13]=1
Reactant: N
Reactant: O=S1(=O)C=Cc2cc(Br)cc(S(=O)(=O)Cl)c2O1
Agent: Cl
Solvent: C1CCOC1
Product: NS(=O)(=O)c1cc(Br)cc2c1OS(=O)(=O)C=C2
Reaction time: 0.5 h

Procedure:
The crystalline product obtained in (c) is dissolved in as small an amount of tetrahydrofuran as possible and the solution is added dropwise to 20 ml of 25% aqueous ammonia solution. After the reaction mixture has been stirred for 30 minutes it is poured into a mixture of ice and 10% hydrochloric acid. Extraction with ether yields 0.3 g of 6-bromo-8-sulfamoyl-2,2-dioxo-1,2-benzoxathiine of m.p. 224°-228° C. (decomposition with black colouration).
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.ClC1C(=O)C2C(C(=O)C=1Cl)=CC=CC=2.[OH-].[Na+].C=O>C(O)C>[NH2:1][C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: O=C1c2ccccc2C(=O)c2c1cccc2[N+](=O)[O-]
Agent: C=O
Agent: O=C1C(Cl)=C(Cl)C(=O)c2ccccc21
Agent: [Na+]
Solvent: CCO
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O

Procedure:
76 parts of 1-nitroanthraquinone and 0.6 part of 2,3-dichloro-1,4-naphthoquinone in 300 parts by volume of ethanol and 150 parts by volume of 50% aqueous sodium hydroxide solution are heated to 78°-80° C. At this temperature, 37% aqueous formaldehyde solution is added dropwise to the solution in accordance with the consumption. The consumption of formaldehyde can be checked and the addition controlled by measuring the changes in the redox potential. The time taken for the addition is 11/2 to 2 hours. The 1-aminoanthraquinone so obtained is then completely precipitated by addition of water, and the precipitate is isolated by filtration, washed with water and dried in vacuo at 80° C. Yield: about 61 g (~91% of theory) of 1-aminoanthraquinone.
Reaction SMILES: O=[C:2]1[CH2:5][CH:4]([C:6]([O:8][CH3:9])=[O:7])[CH2:3]1.[CH3:10][NH:11][CH3:12].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>CCOC(C)=O>[CH3:10][N:11]([CH3:12])[CH:2]1[CH2:5][CH:4]([C:6]([O:8][CH3:9])=[O:7])[CH2:3]1
Reactant: COC(=O)C1CC(=O)C1
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: COC(=O)C1CC(N(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
A solution of methyl 3-oxocyclobutanecarboxylate (0.5 g, 3.90 mmol) in EtOAc (10 mL) was treated with dimethylamine (1M in THF, 11.71 mL, 11.71 mmol), stirred at RT for 1 h, treated portion-wise with sodium triacetoxyborohydride (1.158 g, 5.46 mmol) and stirred at RT overnight. The mixture was treated with 1N NaOH, extracted with EtOAc (3×) and the combined organics were washed with brine, dried over Na2SO4 and concentrated to dryness to afford methyl 3-(dimethylamino)cyclobutanecarboxylate (596 mg, 97%). 1H NMR (400 MHz, DMSO-d6): δ 3.57 (s, 3H), 3.33-3.26 (m, 1H), 2.75-2.74 (m, 1H), 2.19-2.18 (m, 2H), 1.97 (s, 6H), 1.88-1.85 (m, 2H).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[CH:17]=[C:16]([CH:18]3[CH2:22][CH2:21][CH2:20][N:19]3C(OC(C)(C)C)=O)[CH:15]=[CH:14][N:13]=2)=[N:3]1.[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33]>>[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33].[NH:19]1[CH2:20][CH2:21][CH2:22][CH:18]1[C:16]1[CH:15]=[CH:14][N:13]=[C:12]([C:4]2[S:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[C:2](=[O:1])[N:3]=2)[CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ccnc(-c2nc(=O)c3ccccc3s2)c1
Solvent: O=C(O)C(F)(F)F
Product: O=c1nc(-c2cc(C3CCCN3)ccn2)sc2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
tert-Butyl 2-[2-(4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]-1-pyrrolidinecarboxylate (0.35 g, 0.85 mmol) was dissolved in trifluoroacetic acid (5 ml), and the mixture was stirred at room temperature for 3 hrs. The solvent was evaporated, and the residue was recrystallized from diisopropyl ether-methanol to give the titled compound (0.31 g, 85%) as white crystals.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].O=C1CC[N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.CCCCCC>[CH2:4]=[C:3]1[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:1][CH2:2]1
Reactant: [Li]CCCC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 1 h
Yield: 58.8 %

Procedure:
To a solution of methyl triphenylphosphonium bromide (2.69 g, 7.5 mmol) in THF (20 mL) was n-butyllithium (1.8 M; 4.2 mL, 7.5 mmol) in hexane slowly added at −78° C. The mixture was stirred for 1 h. After this time, a solution of tert-butyl 4-oxopiperidine-1-carboxylate (1 g, 5.0 mmol) in THF (10 mL) was added dropwise to the mixture. The resultant mixture was stirred at room temperature overnight. The reaction mixture was quenched with water and extracted with isohexane (×3). The combined isohexane layers were evaporated and filtrated through a silica-plug. The crude product was purified using flash chromatography with DCM as eluent yielding 0.58 g (59%) of the title compound. HPLC purity 91%, RT=2.47 min (System A; 10-97% MeCN over 3 min); 86%, RT=2.43 min (System B; 10-97% MeCN over 3 min). 1H NMR (400 MHz, CDCl3) δ ppm 1.46 (s, 9H) 2.12-2.22 (m, 4H) 3.35-3.46 (m, 4H) 4.73 (s, 2H). MS (ESI+) for C11H19NO2 m/z 142 (M-C4H8)+. *Previously reported in J. Med. Chem. 2002, 45, 3143-3160.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH3:16])[CH:10]2[CH2:15][CH2:14]OCC2)=[CH:5][C:4]=1[N+:17]([O-])=O>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH3:16])[CH2:10][CH:15]2[CH2:14][CH2:1][O:2][CH2:3][CH2:4]2)=[CH:5][C:4]=1[NH2:17]
Reactant: COc1ccc(N(C)C2CCOCC2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COc1ccc(N(C)CC2CCOCC2)cc1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 102.6 %

Procedure:
To a stirred solution of 0.73 g (2.74 mmol) (4-methoxy-3-nitro-phenyl)-methyl-(tetrahydro-pyran-4-yl)-amine in 50 ml methanol was added 15 mg 10% palladium on charcoal and the mixture was then stirred for 18 hours at room temperature under an atmosphere of hydrogen. The mixture was then filtered and the filtrate concentrated in vacuo to afford 0.3520 g (54%) 4-methoxy-N1-methyl-N1-(tetrahydro-pyran-4-ylmethyl)-benzene-1,3-diamine as an off-white solid. Mp.: 97-99° C.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:8]=[C:7]([S:9]([CH3:12])(=[O:11])=[O:10])[S:6][C:5]=1[C:13]([O:15][CH3:16])=[O:14].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O.O>[CH2:17]([O:3][C:4]1[CH:8]=[C:7]([S:9]([CH3:12])(=[O:11])=[O:10])[S:6][C:5]=1[C:13]([O:15][CH3:16])=[O:14])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1sc(S(C)(=O)=O)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1sc(S(C)(=O)=O)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84 %

Procedure:
A mixture of NaH (3.18 g, 79.5 mmol) in dimethylformamide (DMF) is treated dropwise with a solution of methyl 3-hydroxy-5-(methylsulfonyl)-2-thiophenecarboxylate (15.0 g, 63.6 mmol) in DMF at 0° C., stirred for 10 minutes, treated with benzylbromide (8.30 ml, 70 mmol) at ice bath temperatures, allowed to warm to room temperature overnight and diluted with water. The resultant reaction mixture is filtered. The filtercake is washed with water, dried, stirred in a mixture of ethyl acetate/hexane (20 ml/130 ml), and filtered. The filtercake is washed with hexanes and dried in a Kugelrohr at 40° C. to give the title product as a white solid, 17. 4 g (84% yield), mp 125-126° C. identified by 1HNMR, 13CNMR, IR and mass spectral analyses.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Br:20])=[CH:4][N:3]=1.[CH3:21][N:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[CH:27]=O>>[Br:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:27]([C:23]3[N:22]([CH3:21])[CH:26]=[CH:25][CH:24]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: Cn1cccc1C=O
Product: Cn1cccc1-c1nc2c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)c(Br)cnc2[nH]1
Yield: 60.1 %

Procedure:
In a similar fashion to Compound LXXXVII, (1S,2S,3R,4R)-3-(2,3-Diamino-5-bromo-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (50 mg, 0.148 mmol) and 1-Methyl-1H-pyrrole-2-carbaldehyde (17.7 mg, 0.163 mmol) were reacted to produce 38 mg (60%) of the title compound. mp: 293-295° C., 1H NMR (300 MHz, DMSO-d6): 12.89 (s, 1H), 7.97 (s, 1H), 7.71 (s, 1H), 7.21 (s, 1H), 6.97 (s, 1H), 6.93 (br s, 2H), 6.35 (s, 1H), 6.28 (s, 1H), 6.14 (s, 1H), 5.26 (t, J=8 Hz, 1H), 4.05 (s, 3H), 3.32 (s, 1H), 3.29 (s, 1H), 2.85 (s, 1H), 2.73 (s, 1H), 2.59 (d, J=8 Hz, 1H), 2.26 (d, J=8 Hz, 1H), 1.40 (d, J=8 Hz, 1H). MS: 427, 429 (M+H), HPLC: 2.40 (G method).