Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][C:4]2([CH2:7][CH2:6][CH2:5]2)[CH2:3]1.OS(O)(=O)=O.[N+:20]([O-])([OH:22])=[O:21]>C(O)(=O)C>[N+:20]([C:12]1[CH:13]=[CH:14][C:9]2[O:8][C:4]3([CH2:7][CH2:6][CH2:5]3)[CH2:3][C:2](=[O:1])[C:10]=2[CH:11]=1)([O-:22])=[O:21]
Reactant: O=[N+]([O-])O
Reactant: O=C1CC2(CCC2)Oc2ccccc21
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: O=C1CC2(CCC2)Oc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3,4-Dihydro-4-oxo-spiro[2H-1-benzopyran-2,1′-cyclobutane] (Example 3) (10 mmol) in glacial acetic acid (2 ml), conc. H2SO4 (10 mmol) was added at 0° C. and the mixture was stirred for 10 min. A chilled nitrating mixture [prepared from HNO3 (9 mmol) and Conc. H2SO4 (10 mmol)] was then added very slowly and the reaction mixture was allowed to warm up to room temperature and stirred for 5 h. reaction mixture was then quenched with water and the compound was extracted in dichloromethane. Organic layer was separated, dried on anhydrous MgSO4 and concentrated under vacuum. The crude product was then purified by column chromatography to afford the desired compound as a yellow solid.
Reaction SMILES: [CH3:1][NH:2][CH3:3].C(N(CC)CC)C.Cl.[F:12][C:13]([F:47])([F:46])[C:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[N:17]=[C:16]([C:30]2[CH:35]=[CH:34][N:33]=[C:32]([C:36]3[CH:37]=[C:38]([S:42](Cl)(=[O:44])=[O:43])[CH:39]=[CH:40][CH:41]=3)[CH:31]=2)[N:15]=1>C1COCC1>[CH3:1][N:2]([CH3:3])[S:42]([C:38]1[CH:39]=[CH:40][CH:41]=[C:36]([C:32]2[CH:31]=[C:30]([C:16]3[N:15]=[C:14]([C:13]([F:12])([F:46])[F:47])[CH:19]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:22][CH:21]=4)[N:17]=3)[CH:35]=[CH:34][N:33]=2)[CH:37]=1)(=[O:43])=[O:44]
Reactant: O=S(=O)(Cl)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1
Reactant: CNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1
Temperature: 0 °C
Yield: 90.5 %

Procedure:
To a cooled (ice-water bath) and stirred mixture of dimethylamine solution (60% in water) (0.27 ml, 3.21 mmol), triethylamine (0.29 ml, 2.1 mmol) and THF (4 ml) was added drop wise a solution of 3-{4-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonyl chloride hydrochloride (example I.1) (0.58 g, 1.0 mmol) in THF (6 ml). The mixture was allowed to stir at room temperature for 16 h. Purification of the reaction mixture by flash chromatography on silica gel (ethyl acetate/heptane) and crystallization (dichloromethane/MeOH/hexane) yielded the title compound as a white solid (0.5 g, 97%). MS (ISP) 552.7 [(M+H)+]; mp 225° C.
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[CH:16]=[C:15]1[CH2:24][CH2:25][N:26]1[C:34](=[O:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]1=[O:36])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C.[CH2:44]([O:46][C:47](=[O:58])[C:48]1[CH:53]=[CH:52][C:51]([CH2:54][CH2:55][CH:56]=O)=[CH:50][CH:49]=1)[CH3:45].ClCC(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl.CO.O>[CH2:44]([O:46][C:47](=[O:58])[C:48]1[CH:53]=[CH:52][C:51]([CH2:54][CH2:55][CH2:56][C:16]2[C:17]3[C:22](=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=3)[N:14]([CH:1]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:15]=2[CH2:24][CH2:25][N:26]2[C:27](=[O:36])[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:34]2=[O:35])=[CH:50][CH:49]=1)[CH3:45]
Reactant: CCOC(=O)c1ccc(CCC=O)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCc1cc2cc(Cl)ccc2n1C(c1ccccc1)c1ccccc1
Agent: CC[SiH](CC)CC
Agent: O=C(O)CCl
Agent: O=C([O-])O
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)c1ccc(CCCc2c(CCN3C(=O)c4ccccc4C3=O)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Reaction time: 16 h
Yield: 89.8 %

Procedure:
4.91 g (10.0 mmol, 1 eq) 2-[2-(1-Benzhydryl-5-chloro-1H-indol-2-yl)-ethyl]-isoindole-1,3-dione made according to Example 3 was suspended in 50 mL CH2Cl2. 3.50 g (30.0 mmol, 3 eq) triethylsilane, 2.47 g (12 mmol, 1.2 eq) 4-(3-Oxo-propyl)-benzoic acid ethyl ester and chloro-acetic acid 7.56 g (80 mmol, 8 eq) were added in one portion. The mixture was heated to reflux for 92 h. LC showed less then 2% starting material at this end point. 15 mL sat. aq. NaHCO3 and 10 mL water was added to the reaction mixture, and stirring was continued over a period of 16 h. 10 mL MeOH was then added and the solid was collected by filtration. 9.4 g off-white solid was dried in the oven for 3 h at 60° C. to give 6.12 g 4-(3-{1-Benzhydryl-5-chloro-2-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-1H-indol-3-yl}-propyl)-benzoic acid ethyl ester (90% yield) with 74% purity.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:45])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH2:29][CH2:30][CH:31]=[CH2:32])[CH:19]=[C:15]3[N:14]=[C:13]([CH3:33])[C:12]=2[C@H:34]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:7][CH2:6]1)C=C.[BH4-].[Na+]>C(Cl)CCl.C1(C)C=C(C)C=C(C)C=1N1CCN(C2C(C)=CC(C)=CC=2C)C1=[Ru](Cl)(Cl)=CC1C=CC=CC=1OC(C)C>[C:41]([O:40][C@@H:34]([C:12]1[C:13]([CH3:33])=[N:14][C:15]2=[CH:19][C:18]3=[N:17][N:16]2[C:11]=1[N:8]1[CH2:9][CH2:10][C:5]([CH3:45])([O:4][CH2:1][CH2:32][CH2:31][CH2:30][CH2:29][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH2:22][O:21][CH2:20]3)[CH2:6][CH2:7]1)[C:35]([O:37][CH2:38][CH3:39])=[O:36])([CH3:44])([CH3:42])[CH3:43]
Reactant: C=CCCc1ccccc1COCc1cc2nc(C)c([C@H](OC(C)(C)C)C(=O)OCC)c(N3CCC(C)(OCC=C)CC3)n2n1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCCl
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc3nn2c1N1CCC(C)(CC1)OCCCCCc1ccccc1COC3
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.1 %

Procedure:
(S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(((2-(but-3-en-1-yl)benzyl)oxy)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (55 mg, 0.089 mmol) and (1,3-dimesitylimidazolidin-2-ylidene)(2-isopropoxybenzylidene)ruthenium(VI) chloride (5.57 mg, 8.89 μmol) in ClCH2CH2Cl (60 mL) was refluxed for 2 h. It was then concentrated and the residue was dissolved in MeOH (5 mL). Sodium borohydride (3.36 mg, 0.089 mmol) was added and the reaction was stirred at rt for 1 h. It was then quenched with water, extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated to obtain an oil, which was then purify by biotage to obtain ethyl (2S)-2-(tert-butoxy)-2-{4,25-dimethyl-11,24-dioxa-1,5,7,8-tetraazapentacyclo[23.2.2.16,9.02,7.013,18]triaconta-2,4,6(30),8,13(18),14,16-heptaen-3-yl}acetate (37 mg, 70.2%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.38-7.15 (m, 4H), 6.57 (s, 1H), 6.07 (s, 1H), 4.82-4.69 (m, 4H), 4.59 (t, J=11.2 Hz, 1H), 4.28-4.12 (m, 2H), 3.91 (t, J=10.9 Hz, 1H), 3.44 (d, J=7.3 Hz, 2H), 3.05 (d, J=11.3 Hz, 1H), 2.89 (dd, J=14.2, 6.4 Hz, 1H), 2.78 (dd, J=13.8, 8.3 Hz, 2H), 2.63 (s, 3H), 2.03-1.89 (m, 2H), 1.88-1.64 (m, 8H), 1.28 (s, 3H), 1.25 (s, 9H), 1.24-1.19 (m, 3H). LCMS (M+1)=593.4.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:14]=[C:13]([F:15])[C:12]([CH:16]([O:30][CH2:31][CH3:32])[C:17]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27](=[NH:29])[NH2:28])=[CH:23][CH:22]=3)=[O:18])=[C:11]([F:33])[CH:10]=2)=[CH:5][CH:4]=1.Cl.N[OH:36].C(N(CC)CC)C>CN(C=O)C>[NH2:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:14]=[C:13]([F:15])[C:12]([CH:16]([O:30][CH2:31][CH3:32])[C:17]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27](=[NH:28])[NH:29][OH:36])=[CH:23][CH:22]=3)=[O:18])=[C:11]([F:33])[CH:10]=2)=[CH:5][CH:4]=1
Reactant: NO
Reactant: CCOC(C(=O)NCc1ccc(C(=N)N)cc1)c1c(F)cc(-c2ccc(N)nc2)cc1F
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(C(=O)NCc1ccc(C(=N)NO)cc1)c1c(F)cc(-c2ccc(N)nc2)cc1F
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 99.3 %

Procedure:
To a solution of (RS)-(2-[4-(6-amino-pyridin-3-yl)-2,6-difluoro-phenyl]-N-(4-carbamimidoyl-benzyl)-2-ethoxy-acetamide hydrochloride (example 271, 60 mg) in DMF (1 ml) were added hydroxylamine hydrochloride (27 mg) and triethylamine (38 mg). The mixture was stirred at 50° C. for 2.5 h. After cooling to rt, the mixture was partitioned between EtOAc and ice water and extracted with EtOAc. The organic phase was washed with water, dried, filtered and concentrated to give (RS)2-[4-(6-amino-pyridin-3-yl)-2,6-difluoro-phenyl]-2-ethoxy-N-[4-(N-hydroxycarbamimidoyl)-benzyl]-acetamide (57 mg). Colorless solid. MS 456.0 ([M+H]+)
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[CH:9]=2)[N:4]([S:30]([C:33]2[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[CH:3]=1.[CH3:40][C:41]1[C:45](B2OC(C)(C)C(C)(C)O2)=[C:44]([CH3:55])[N:43]([CH2:56][C:57]2[CH:58]=[C:59]([CH:62]=[CH:63][CH:64]=2)[C:60]#[N:61])[N:42]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1(C)C=CC=CC=1.C(O)C.O>[C:60]([C:59]1[CH:58]=[C:57]([CH:64]=[CH:63][CH:62]=1)[CH2:56][N:43]1[C:44]([CH3:55])=[C:45]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:16]=[CH:15][C:14]([N:17]5[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]5)=[CH:13][CH:12]=4)[CH:9]=3)[N:4]([S:30]([C:33]3[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[CH:3]=2)[C:41]([CH3:40])=[N:42]1)#[N:61]
Reactant: Cc1nn(Cc2cccc(C#N)c2)c(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(C#N)c4)c3C)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Yield: 35.9 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, tert-butyl 4-(4-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate (intermediate 41) (200 mg, 0.3 mmol) was coupled with 3-((3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)benzonitrile (intermediate 55) (103 mg, 0.3 mmol) in sodium carbonate (98 mg, 0.9 mmol), PdCl2(dppf) (11 mg, 0.01 mmol), toluene/ethanol/water (2/2/1 ml) to give 80 mg (36% yield) of titled compound. 1H NMR (CD3OD, 400 MHz): δ8.44-8.43 (d, 1H), 7.85-7.84 (d, 1H), 7.55-7.49 (m, 5H), 7.38 (s, 1H), 7.09-7.07 (d, 2H), 6.60 (s, 1H), 5.41 (s, 2H), 3.27-3.24 (m, 4H), 3.11-3.09 (m, 4H), 2.21-2.17 (m, 6H). MS: m/z=488.1 (M+1), HPLC—92.75% (method-B).
Reaction SMILES: P(Br)(Br)[Br:2].[CH2:5]([O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19]O)=[CH:15][C:14]=1[Cl:21])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>ClCCl.C(OCC)C>[CH2:5]([O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][Br:2])=[CH:15][C:14]=1[Cl:21])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: OCc1ccc(OCc2ccccc2)c(Cl)c1
Reactant: BrP(Br)Br
Solvent: CCOCC
Solvent: ClCCl
Product: Clc1cc(CBr)ccc1OCc1ccccc1
Reaction time: 1 h

Procedure:
Phosphorous tribromide (2 mL) was added to a solution of (4-benzyloxy-3-chlorophenyl)-methanol (CAB02127, 3.40 g, 13.7 mmol) in dichloromethane (50 mL) at 0° C. The mixture was stirred at this temperature for 1 h, diluted with diethyl ether (100 mL), transferred into a separation funnel and washed with water (50 mL) and brine (50 mL). The organic layer was dried over magnesium sulphate and concentrated under reduced pressure to give a white, analytical pure solid. Yield: 4.27 g (100%).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([N:11]3[C:15]4=[N:16][CH:17]=[CH:18][CH:19]=[C:14]4[C:13]([C:20]([O:22]C)=[O:21])=[CH:12]3)[C:5]=2[CH:4]=[CH:3]1.O1CCCC1.[Li]>O>[CH3:1][N:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([N:11]3[C:15]4=[N:16][CH:17]=[CH:18][CH:19]=[C:14]4[C:13]([C:20]([OH:22])=[O:21])=[CH:12]3)[C:5]=2[CH:4]=[CH:3]1
Reactant: COC(=O)c1cn(-c2ncnc3c2ccn3C)c2ncccc12
Agent: [Li]
Solvent: C1CCOC1
Solvent: O
Product: Cn1ccc2c(-n3cc(C(=O)O)c4cccnc43)ncnc21
Temperature: 5 °C
Yield: 85.7 %

Procedure:
To 1.2 g (3.7 mmol) of methyl 1-(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylate were successively added 13.5 cm3 of tetrahydrofuran, 0.47 g (11.2 mmol) of lithium hydroxyde, monohydrate and 13.5 cm3 of distilled water. The reaction mixture was heated at reflux temperature for 4 hours and then concentrated to dryness in vacuo (2.7 kPa). The residue was dissolved into 72 cm3 of distilled water and the mixture was extracted with 35 cm3 of ethyl acetate. The aqueous phase was cooled to about 5° C. and 10 cm3 of 1N hydrochloric acid were added dropwise (pH ca. 3). The resulting precipitate was filtered, washed twice with 20 cm3 of distilled water and dried in vacuo at about 50° C. to yield 0.93 g of 1-(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid as off-white crystals. mp>260° C.; IR spectrum (KBr): 3461; 3152; 2951; 2571; 1678; 1590; 1544; 1452; 1263; 1204; 916; 808; 774; 746; 681 and 607 cm−1.
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:13][CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]([CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([N:27]([C:31]([NH:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=3)=[O:32])[CH2:28][CH:29]=[CH2:30])[CH2:23][CH2:22]2)[CH2:10]1)=O)(C)(C)C.[C:44]1([S:50](Cl)(=[O:52])=[O:51])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>>[C:44]1([S:50]([NH:8][CH:9]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]([CH2:20][N:21]3[CH2:22][CH2:23][CH:24]([N:27]([C:31]([NH:33][CH2:34][C:35]4[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=4)=[O:32])[CH2:28][CH:29]=[CH2:30])[CH2:25][CH2:26]3)[CH2:10]2)(=[O:52])=[O:51])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: C=CCN(C(=O)NCc1ccc([N+](=O)[O-])cc1)C1CCN(CC2CC(NC(=O)OC(C)(C)C)CC2c2ccccc2)CC1
Reactant: O=S(=O)(Cl)c1ccccc1
Product: C=CCN(C(=O)NCc1ccc([N+](=O)[O-])cc1)C1CCN(CC2CC(NS(=O)(=O)c3ccccc3)CC2c2ccccc2)CC1

Procedure:
Using essentially the same procedure as Example 16, Step A and B, 1-(RS)-((t-butoxycarbonyl)amino)-3-(SR)-((4-(N-(4-nitrobenzylaminocarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(SR)-phenylcyclopentane from Example 22, Step H (derived from the lower isomer from Example 20, Step E) was deblocked and acylated with phenylsulfonyl chloride to obtain the title compound.
Reaction SMILES: [P:1]([O-:7])([O:5][CH3:6])([O:3][CH3:4])=[O:2].[Na+].P(OC)(OC)(OC)=O.[I-].[Na+].[C:19](Cl)(=[O:21])[CH3:20]>O1CCCC1>[P:1]([O:7][C:19](=[O:21])[CH3:20])([O:5][CH3:6])([O:3][CH3:4])=[O:2]
Reactant: COP(=O)([O-])OC
Reactant: CC(=O)Cl
Agent: [I-]
Agent: [Na+]
Solvent: COP(=O)(OC)OC
Solvent: C1CCOC1
Product: COP(=O)(OC)OC(C)=O
Yield: 80 %

Procedure:
A suspension of sodium dimethyl phosphate (14.8 g, 0.1 mmol, from trimethyl phosphate and sodium iodide and acetyl chloride (7.8 g, 0.1 mmol) in dry tetrahydrofuran (80 mn) was stirred for two days at room temperature in a flask fitted with a drying tube. The reaction solution was filtered and the tetrahydrofuran was removed under reduced pressure. The resulting colorless liquid was Kugelrohr-distilled (Aldrich Kugelrohr apparatus, 55°-60° C. 0.30 torr) to give 14.2 g (80%) of dimethyl acetyl phosphate.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[C:9]=2[C:10]([OH:12])=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.S(Cl)(Cl)=O.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(C(C)C)CC)(C)C>C1COCC1>[N:1]1([CH2:7][C:8]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[C:9]=2[C:10]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:12])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: Nc1ccccc1
Reactant: O=C(O)c1c(CN2CCOCC2)cccc1[N+](=O)[O-]
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1)c1c(CN2CCOCC2)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of compound 6 (0.62 g, 2.3 mmol) in THF (50 mL) was treated with thionyl chloride (0.94 mL), stirred at room temperature for 4 h, and evaporated to dryness. The residue was dissolved in THF (50 mL) and treated with aniline (0.58 mL, 6.4 mmol) and diisopropylethylamine (1.12 mL, 6.4 mmol). The reaction mixture was stirred for 4 h, concentrated, dissolved in dichloromethane (50 mL), washed with saturated aqueous sodium bicarbonate (25 mL) and brine (25 mL), dried with sodium sulfate, and concentrated. The crude residue of compound 7 then was purified by flash chromatography (5% methanol in dichloromethane).
Reaction SMILES: [C:1]12([N:11]=[C:12]=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:14][NH:15][C:16]([C:18]1[CH:23]=[C:22]([O:24][C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=2)[CH:21]=[CH:20][N:19]=1)=[O:17].ClC1C=CC(NC(=O)N[C@H]2CC[C@H](OC3C=CC(C(O)=O)=CC=3)CC2)=CC=1C(F)(F)F>>[CH3:14][NH:15][C:16]([C:18]1[CH:23]=[C:22]([O:24][C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:12]([NH:11][C:1]34[CH2:10][CH:5]5[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]5)[CH2:2]3)[CH2:8]4)=[O:13])=[CH:27][CH:26]=2)[CH:21]=[CH:20][N:19]=1)=[O:17]
Reactant: CNC(=O)c1cc(Oc2ccc(N)cc2)ccn1
Reactant: O=C=NC12CC3CC(CC(C3)C1)C2
Agent: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)N[C@H]1CC[C@H](Oc2ccc(C(=O)O)cc2)CC1
Product: CNC(=O)c1cc(Oc2ccc(NC(=O)NC34CC5CC(CC(C5)C3)C4)cc2)ccn1
Yield: 60 %

Procedure:
Compound 2287 was prepared in 60% yield from adamantyl isocyanate and 4-(4-amino-phenoxy)-pyridine-2-carboxylic acid methylamide using the procedure detailed for compound 2221 in Example 4. 1H NMR (300 MHz, DMSO-d6) δ 8.73 (q, J=5 Hz, 1H), 8.48 (d, J=6 Hz, 1H), 8.39 (s, 1H), 7.49-7.42 (m, 2H), 7.36 (d, J=2 Hz, 1H), 7.13-7.03 (m, 3H), 5.89 (s, 1H), 2.78 (d, J=5 Hz, 3H), 2.09-2.01 (m, 3H), 1.98-1.92 (m, 6H), 1.68-1.60 (m, 61).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][O:25]4)=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:37][O:38][C:39]1[CH:44]=[CH:43][C:42]([S:45](Cl)(=[O:47])=[O:46])=[CH:41][CH:40]=1>C(Cl)Cl>[CH3:37][O:38][C:39]1[CH:40]=[CH:41][C:42]([S:45]([N:15]([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[CH:14][CH:13]=2)[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)=[CH:19][CH:18]=2)(=[O:47])=[O:46])=[CH:43][CH:44]=1
Reactant: c1cc(OC2CCCCO2)ccc1CNc1ccc(OCCN2CCCC2)cc1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)N(Cc2ccc(OC3CCCCO3)cc2)c2ccc(OCCN3CCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of [4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-[4-(tetrahydro-pyran-2-yloxy)-benzyl]-amine (1.40 g, 3.53 mmol) and triethylamine (1.48 mL, 10.59 mmol) in methylene chloride (35 mL) was added 4-methoxy-benzenesulfonyl chloride (1.46 g, 7.06 mmol) in three portions over 15 minutes. The reaction mixture was stirred at room temperature for 24 hr. The reaction mixture was quenched with saturated sodium bicarbonate and the aqueous solution was washed with methylene chloride. The combined organic solutions were dried (magnesium sulfate), filtered, and concentrated. Medium pressure chromatography using a solvent gradient (4% to 10% methanol/methylene chloride) afforded the title compound of Step A. MS 483.1 (M+1)+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([N+:19]([O-])=O)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1>C(O)C.C(O)(=O)C.[Fe]>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH2:19])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Temperature: 120 °C

Procedure:
A mixture of 34.5 g of N-(3-bromophenyl)-6-nitro-4-quinazolinamine and 16.8 g of iron powder in 150 ml of ethanol and 150 ml of glacial acetic acid was heated in an oil bath at 120° C. for 2 hours. After filtration of the solid, solid sodium carbonate was added to the filtrate giving a solid. This was filtered, and the solid was extracted with methanol. The extracts were treated with charcoal and evaporated to a solid. After washing the solid with ether 27.5 g of N-(3-bromophenyl)-4,6-quinazolindiamine was obtained: mass spectrum (m/e): 315.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1.[C:17]([NH2:20])(=[S:19])[CH3:18]>>[CH3:1][O:2][C:3]([C:4]1[N:20]=[C:17]([CH3:18])[S:19][C:5]=1[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)=[O:16]
Reactant: COC(=O)C(=O)C(Cl)c1ccc(OC)cc1
Reactant: CC(N)=S
Product: COC(=O)c1nc(C)sc1-c1ccc(OC)cc1

Procedure:
prepared by reaction of 3-chloro-3-(4-methoxy-phenyl)-2-oxo-propionic acid methyl ester with thioacetamide. LC-MS: tR=0.90 min; [M+H]+=263.93.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)=O.C(=O)(O)O.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH2:29])=[NH:28])=[CH:22][CH:21]=1>C(O)(C)C>[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([NH:26][C:27]2[N:29]=[C:5]([C:7]3[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=3)[CH:4]=[CH:3][N:28]=2)=[CH:24][CH:25]=1
Reactant: COc1ccc(NC(=N)N)cc1
Reactant: CN(C)C=CC(=O)c1cccnc1
Agent: O=C(O)O
Solvent: CC(C)O
Product: COc1ccc(Nc2nccc(-c3cccnc3)n2)cc1

Procedure:
A mixture of 14.4 g of 3-dimethylamino-1-(3-pyridinyl)-2-propen-1-one and 16.1 g of 4-methoxyphenyl guanidine carbonate in 200 ml of isopropanol was heated at reflux for 20 hours. The reaction mixture was cooled, the crude product was collected by filtration and washed with water. The material was recrystallized from isopropanol to give the desired product as light yellow crystals, mp 121°-122° C.
Reaction SMILES: C(O)(=O)C.[Cl:5][CH2:6][C:7]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:14]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:15]=1)=[O:8].[N+:28]([O-])([OH:30])=[O:29]>O>[Cl:5][CH2:6][C:7]([NH:9][C:10]1[C:11]([N+:28]([O-:30])=[O:29])=[CH:12][C:13]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:14]([NH:16][S:17]([CH3:20])(=[O:18])=[O:19])[CH:15]=1)=[O:8]
Reactant: CS(=O)(=O)Nc1cc(NC(=O)CCl)ccc1Oc1ccccc1
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Product: CS(=O)(=O)Nc1cc(NC(=O)CCl)c([N+](=O)[O-])cc1Oc1ccccc1
Temperature: 90 °C
Yield: 59 %

Procedure:
To 71 ml of an acetic acid solution containing 14.0 g of N-(5-chloroacetylamino-2-phenoxyphenyl)methanesulfonamide was added 4.4 g of 60% nitric acid with heating at 90° C. with stirring, followed by stirring for 20 minutes. Water was added to the reaction solution of which temperature was allowed to return to room temperature. The precipitate was collected by filtration and recrystallized from ethanol-n-hexane to give 9.3 g of N-(5-chloroacetylamino-4-nitro-2-phenoxyphenyl)methanesulfonamide as yellow needles.