Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:16][CH:15]3[CH:11]([CH2:12][NH:13][CH2:14]3)[CH2:10]2)[N:3]=1.[N:17]1[N:18]=[C:19]([C:22]2[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=2[C:24](O)=[O:25])[NH:20][CH:21]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(OCC)(=O)C.CN(C=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:16][CH:15]3[CH:11]([CH2:12][N:13]([C:24]([C:23]4[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=4[C:19]4[NH:18][N:17]=[CH:21][N:20]=4)=[O:25])[CH2:14]3)[CH2:10]2)[N:3]=1
Reactant: O=C(O)c1ccccc1-c1nnc[nH]1
Reactant: Cc1cc(C)nc(N2CC3CNCC3C2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)nc(N2CC3CN(C(=O)c4ccccc4-c4ncn[nH]4)CC3C2)n1
Yield: 55 %

Procedure:
A mixture of 2-(4,6-dimethyl-pyrimidin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole (60.0 mg, 0.28 mmol), 2-(4H-[1,2,4]triazol-3-yl)benzoic acid (57.2 mg, 0.30 mmol), HATU (156.8 mg, 0.41 mmol) and DIPEA (107.0 mg, 0.83 mmol) was stirred into DMF (5.0 mL) at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate (60.0 mL) and washed with water (2×100 mL). The organic phase was dried (Na2SO4), filtered and concentrated to dryness. The crude product was purified using Agilent HPLC (basic system) to yield pure title compound (60.0 mg, 56%). MS (ESI) mass calcd. for O21H23N7O, 389.46; m/z found 390.2 [M+H]+. 1H NMR (CDCl3): 8.12 (d, J=7.5, 1H), 8.05 (s, 1H), 7.53-7.39 (m, 2H), 7.37-7.31 (m, 1H), 6.28 (s, 1H), 3.95-3.77 (m, 2H), 3.76-3.55 (m, 3H), 3.48-3.33 (m, 2H), 3.19-3.03 (m, 1H), 3.02-2.95 (m, 1H), 2.91-2.82 (m, 1H), 2.36-2.19 (m, 6H).
Reaction SMILES: C1COCC1.Cl[C:7]1[NH:11][C:10]2[CH:12]=[C:13]([NH:27][C:28]([C:30]3[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=3[Cl:37])=[O:29])[CH:14]=[C:15]([C:16]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=3[CH3:26])=[O:17])[C:9]=2[N:8]=1.[NH2:38][CH2:39][C:40]([CH3:44])([CH3:43])[CH2:41][OH:42]>C(OCC)(=O)C>[Cl:25][C:21]1[C:20]([CH3:26])=[C:19]([NH:18][C:16]([C:15]2[C:9]3[N:8]=[C:7]([NH:38][CH2:39][C:40]([CH3:44])([CH3:43])[CH2:41][OH:42])[NH:11][C:10]=3[CH:12]=[C:13]([NH:27][C:28]([C:30]3[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=3[Cl:37])=[O:29])[CH:14]=2)=[O:17])[CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(CN)CO
Reactant: Cc1c(Cl)cccc1NC(=O)c1cc(NC(=O)c2cc(Cl)ccc2Cl)cc2[nH]c(Cl)nc12
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1c(Cl)cccc1NC(=O)c1cc(NC(=O)c2cc(Cl)ccc2Cl)cc2[nH]c(NCC(C)(C)CO)nc12
Yield: 88.4 %

Procedure:
THF (1 mL) was added to 2-chloro-N-(3-chloro-2-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-1H-benzimidazole-4-carboxamide (50 mg) and 3-amino-2,2-dimethyl-1-propanol (400 mg). The mixture was stirred at 150° C. in a sealed pressure-proof stainless steel container for 8 hours. The reaction mixture was diluted with ethyl acetate, washed with brine and concentrated under reduced pressure. The residue was purified on column chromatography to obtain N-(3-chloro-2-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-[(3-hydroxy-2,2-dimethylpropyl)amino]-1H-benzimidazole-4-carboxamide (50 mg) as pale yellow powder. This was dissolved in MeOH (1 mL), and 2N Hydrogen chloride/EtOH solution (1 Eq) was added, and it was stirred and concentrated. The residue was triturated in diethyl ether, and the precipitate was collected by filtration and dried to obtain the titled compound (40 mg) as white powder.
Reaction SMILES: [CH2:1]([N:4]=[C:5]=[S:6])[CH2:2][CH3:3].C(N(CC)CC)C.Br.[NH2:15][C:16]1[C:21]([C:22]([OH:24])=O)=[CH:20][C:19]([Br:25])=[CH:18][N:17]=1.C(O)C>CN(C)C=O>[Br:25][C:19]1[CH:18]=[N:17][C:16]2[NH:15][C:5](=[S:6])[N:4]([CH2:1][CH2:2][CH3:3])[C:22](=[O:24])[C:21]=2[CH:20]=1
Reactant: CCCN=C=S
Reactant: Nc1ncc(Br)cc1C(=O)O
Agent: Br
Solvent: CCO
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCn1c(=S)[nH]c2ncc(Br)cc2c1=O
Temperature: 25 °C

Procedure:
A mixture of n-propyl isothiocyanate (1.59 g, 1.62 mL), triethylamine (5.0 g, 13.8 mL), and 5.0 g of the tide compound of Step A was heated to 100-110° C. in 22 mL of dimethylformamide for 48 h. The reaction mixture was then allowed to cool to room temperature and treated with 10 mL of ethanol. The resulting precipitate was filtered, washed with ethanol followed by hexanes and dried to deliver 2.48 g of the title compound of Step B. 1H NMR (400 MHz, Me2SO-d6): δ 0.90 (t,3H), 1.60-1.78 (m,2H), 4.30 (t,2H), 8.41 (s,1H), 8.82 (s,1H), 13.55 (s,1H).
Reaction SMILES: C(OC(C1N=NC=CC=1)=O)C.[F:12][C:13]1[CH:18]=[C:17]([O:19][C:20]2[S:21][CH:22]=[CH:23][N:24]=2)[CH:16]=[CH:15][C:14]=1[NH2:25].[CH2:26]([O:28][C:29]([C:31]1[C:32]([CH3:57])=[C:33]2[C:38](NC3C=CC(SC4N(C)C=CN=4)=C(Cl)C=3)=[C:37]([C:54]#[N:55])[CH:36]=[N:35][N:34]2[CH:56]=1)=[O:30])[CH3:27]>>[CH2:26]([O:28][C:29]([C:31]1[C:32]([CH3:57])=[C:33]2[C:38]([NH:25][C:14]3[CH:15]=[CH:16][C:17]([O:19][C:20]4[S:21][CH:22]=[CH:23][N:24]=4)=[CH:18][C:13]=3[F:12])=[C:37]([C:54]#[N:55])[CH:36]=[N:35][N:34]2[CH:56]=1)=[O:30])[CH3:27]
Reactant: CCOC(=O)c1cn2ncc(C#N)c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c2c1C
Reactant: Nc1ccc(Oc2nccs2)cc1F
Agent: CCOC(=O)c1cccnn1
Product: CCOC(=O)c1cn2ncc(C#N)c(Nc3ccc(Oc4nccs4)cc3F)c2c1C
Yield: 83 %

Procedure:
Compound 427 (361 mg, 83%) was prepared from 4-chloro-3-cyano-5-methyl-pyrrolo]1,2-b]pyridazine-6-carboxylic acid ethyl ester (Example 1D) (264 mg, 1.0 mmol) and 427B (210 mg, 1.0 mmol) by a route analogous to that used for the preparation of compound 426. It is a dim yellow solid and has a retention time of 6.76 min (standard LC1 method, 8 min run). MS Found: (M+H)+=438.1
Reaction SMILES: Cl[CH2:2][O:3][C:4](=[O:26])[CH2:5][CH2:6][CH2:7][O:8][C:9](=[O:25])[C@H:10]([CH:22]([CH3:24])[CH3:23])[NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].[I-:27].[Na+]>C(#N)C>[I:27][CH2:2][O:3][C:4](=[O:26])[CH2:5][CH2:6][CH2:7][O:8][C:9](=[O:25])[C@H:10]([CH:22]([CH3:24])[CH3:23])[NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCCCC(=O)OCCl
Reactant: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCCCC(=O)OCI

Procedure:
4-(N-CBz-L-valyloxy) butyric acid chloromethyl ester (1.54 g, 4 mmole) was dissolved in acetonitrile (15 ml). Sodium iodide (840 mg, 5.6 mmole) was added to the solution. After reaction at 55° C. for 3 hr, the reaction mixture was filtered and the residue was dissolved in methylene chloride (20 ml) and refiltered. The solution was dried and gave the titled product. Yield 1.9 g.
Reaction SMILES: [CH2:1](C1C2C(=CC=CC=2)NC=1)[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.S(=O)(=O)(O)O>CO>[CH:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[N:4]=[C:3]3[CH:1]=[C:2]4[C:3](=[N:4][C:5]5[C:10]4=[CH:9][CH:8]=[CH:7][CH:6]=5)[CH:1]=[C:2]3[C:10]=12
Reactant: c1ccc2c(Cc3c[nH]c4ccccc34)c[nH]c2c1
Agent: O=S(=O)(O)O
Solvent: CO
Product: c1ccc2c(c1)N=c1cc3c(cc1-2)=Nc1ccccc1-3
Yield: 126.1 %

Procedure:
Under a nitrogen gas stream, about 250.69 g (i.e., about 205.8 mmol) of 3,3′-methylenediindole and about 30.55 g (i.e., about 206.1 mmol) of triethyl orthofomate are dissolved and mixed in methanol within a 3-neck flask. Thereafter, about 5.0 g (i.e., 51.5 mmol) of enriched sulfuric acid is slowly added little by little into the 3-neck flask and then the mixture within the 3-neck flask is refluxed during a single hour. The mixture within the 3-neck flask is frozen to be a normal temperature. Subsequently, about 33 g of indolo(3,2-b)carbazole corresponding to a compound of dark brown is obtained by filtering the frozen mixture.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18](I)=[CH:17][C:16]=3[F:24])=[O:11])=[CH:4][CH:3]=1.[CH3:25][CH:26]([OH:29])[C:27]#[CH:28].CCN(CC)CC>CN(C=O)C.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18]([C:28]#[C:27][CH:26]([OH:29])[CH3:25])=[CH:17][C:16]=3[F:24])=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(I)cc2c1O
Reactant: C#CC(C)O
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(O)C#Cc1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Temperature: 25 °C

Procedure:
A solution of the title compound of Example 5 (540.3 mg), 3-butyn-2-ol (0.13 mL), PdCl2 (PPh3)2 (21.1 mg), and 0.75 mL Et3N in 3 mL DMF is heated at 90° C. for 1 hr. The reaction mixture is cooled to room temperature and partitioned between EtOAc and H2O. The aqueous layer is washed with EtOAc (3×). The combined organic layers are dried over Na2SO4 and condensed to obtain a brown residue. The residue is diluted with MeOH, adsorbed onto silica, and chromatographed eluting with 2.5 % MeOH in CH2Cl2. Fractions homogenous by TLC are combined, condensed and recrystallized from EtOAc/hexanes to yield 0.207 g of the desired product as a creme-colored solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[CH:4][C:5]([OH:9])=[N:6][C:7]=1[CH3:8].FS([C:15]([F:20])([F:19])C(O)=O)(=O)=O.S([O-])([O-])(=O)=O.[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(#N)C>[Br:1][C:2]1[C:7]([CH3:8])=[N:6][C:5]([O:9][CH:15]([F:20])[F:19])=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(O)nc(C)c1Br
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1cc(OC(F)F)nc(C)c1Br

Procedure:
A mixture of 5-bromo-4,6-dimethylpyridin-2-ol obtained in Preparation Example 23(1) (500 mg), 2-(fluorosulfonyl)difluoroacetic acid (0.307 mL) and sodium sulfate (70.3 mg) was stirred in an acetonitrile solvent (10 mL) at room temperature for 3.5 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was then concentrated under reduced pressure. The residue was extracted with ethyl acetate, and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 0% to 10%) to give the title compound (68.6 mg).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11]C)=[O:10])=[C:6]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[N:5]=[C:4]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:3]=1.[OH-].[Na+]>CO>[CH3:1][C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([OH:11])=[O:10])=[C:6]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:23])[F:25])=[CH:18][CH:17]=2)[N:5]=[C:4]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:3]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1-c1ccc(C(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc(-c2ccccc2)nc1-c1ccc(C(F)(F)F)cc1
Yield: 98.6 %

Procedure:
This compound was prepared according to general method D from methyl 2-(4-methyl-2-phenyl-6-(4-(trifluoromethyl)phenyl)pyrimidin-5-yl)pentanoate (0.061 g; 0.142 mmol), sodium hydroxide 10N (0.200 mL; 2.0 mmol) in methanol (2 mL) to afford 0.058 g (98%) of the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[CH:7]([NH:16][C:17]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][N:20]=[C:19]([N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])[N:18]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:39][N:40]([CH3:44])[C:41](Cl)=[O:42]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6](=[O:31])[CH:7]([NH:16][C:17]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][N:20]=[C:19]([N:26]([CH2:27][CH3:28])[CH2:29][CH3:30])[N:18]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:41](=[O:42])[N:40]([CH3:44])[CH3:39])=[CH:11][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C(=O)Cl
Reactant: CCN(CC)c1ncc([N+](=O)[O-])c(NC(Cc2ccc(O)cc2)C(=O)OC(C)(C)C)n1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(CC)c1ncc([N+](=O)[O-])c(NC(Cc2ccc(OC(=O)N(C)C)cc2)C(=O)OC(C)(C)C)n1
Yield: 99.5 %

Procedure:
To a solution of 2-(2-diethylamino-5-nitropyrimidin-4-ylamino)-3-(4-hydroxy-phenyl)propionic acid t-butyl ester (31.80 g, 0.074 mol) in CH2Cl2 (600 mL) was added DMAP (9.00 g, 0.074 mol). After 5 minutes triethylamine (10.23 mL, 0.074 mol) was added dropwise. N,N-dimethylcarbamyl chloride (13.83 mL, 0.110 mol) was added dropwise, and the reaction was heated to reflux overnight. The reaction mixture was concentrated in vacuo and taken up in EtOAc (1 L). The organic phase was washed with 0.5 M citric acid (3×250 mL), sat. NaHCO3 (3×250 mL), brine (1×250 mL), dried (MgSO4), filtered, and concentrated in vacuo to yield 37.0 g (99%) the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[F:9].Cl[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=1>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:11]2[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:4][C:3]=1[F:9]
Reactant: Nc1ccc(Cl)c(F)c1
Reactant: O=[N+]([O-])c1cccnc1Cl
Product: O=[N+]([O-])c1cccnc1Nc1ccc(Cl)c(F)c1
Temperature: 180 °C
Reaction time: 0.17 h

Procedure:
4-Chloro-3-fluoroaniline (10.0 g, 68.7 mmol) was heated to 180° C. in an oil bath. 2-Chloro-3-nitropyridine (11.0 g, 69.4 mmol) was added, and the resulting mixture was stirred at 180° C. for 10 minutes. The reaction mixture was then cooled to 15° C. and washed with petroleum ether, providing the product as a salmon-pink solid. Yield: 15 g, 56 mmol, 82%. 1H NMR (400 MHz, CDCl3) δ 10.20 (br s, 1H), 8.57 (dd, J=8.3, 1.6 Hz, 1H), 8.54 (dd, J=4.6, 1.7 Hz, 1H), 7.90 (dd, J=11.3, 2.4 Hz, 1H), 7.38 (dd, J=8.5, 8.3 Hz, 1H), 7.23-7.28 (m, 1H, assumed; partially obscured by solvent peak), 6.94 (dd, J=8.3, 4.5 Hz, 1H).
Reaction SMILES: [CH2:1]1[O:44][C:4]2=[CH:5][C:6]3[C:19]4[N:18](C)[CH:17]([CH2:21][CH2:22][CH2:23][CH2:24][O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[C:16]5[C:11](=[CH:12][CH:13]=[C:14]([O:41][CH3:42])[C:15]=5[O:33][CH2:34][C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[C:10]=4[CH:9]=[CH:8][C:7]=3[CH:43]=[C:3]2[O:2]1>C1(C)C=CC=CC=1.CO.C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH2:1]1[O:44][C:4]2=[CH:5][C:6]3[C:19]4[C:10](=[C:11]5[C:16](=[C:17]([CH2:21][CH2:22][CH2:23][CH2:24][O:25][Si:26]([C:29]([CH3:31])([CH3:30])[CH3:32])([CH3:28])[CH3:27])[N:18]=4)[C:15]([O:33][CH2:34][C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)=[C:14]([O:41][CH3:42])[CH:13]=[CH:12]5)[CH:9]=[CH:8][C:7]=3[CH:43]=[C:3]2[O:2]1
Reactant: COc1ccc2c(c1OCc1ccccc1)C(CCCCO[Si](C)(C)C(C)(C)C)N(C)c1c-2ccc2cc3c(cc12)OCO3
Agent: [Mn+4]
Agent: [O-2]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1ccc2c(c(CCCCO[Si](C)(C)C(C)(C)C)nc3c4cc5c(cc4ccc23)OCO5)c1OCc1ccccc1
Temperature: 25 °C
Yield: 70.2 %

Procedure:
After 2,3-(methylenedioxy)-5-methyl-6-[4-(t-butyldimethylsiloxy)butyl]-7-benzyloxy-8-methoxy-5,6-dihydrobenzo[c]phenanthridine (300 mg, 0.49 mmol) was dissolved in toluene (8 mL), activated manganese dioxide (1.5 g) was added to the solution. The mixture was heated to reflux for an hour. After cooling to room temperature, the reaction mixture was diluted with a 10% methanol-methylene chloride solution (12 mL) followed by filtration. The filtrate was concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (eluted with methylene chloride) to provide 2,3-(methylenedioxy)-6-[4-(t-butyldimethylsiloxy)butyl]-7-benzyloxy-8-methoxy-benzo[c]phenanthridine (205 mg, yield 70%) as light brown crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[OH:9].[CH3:10][O:11][C:12](OC)([O:17]C)[C:13](OC)=O>CO>[F:8][C:4]1[C:3]2[O:9][C:13]([C:12]([O:11][CH3:10])=[O:17])=[N:1][C:2]=2[CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)C(OC)(OC)OC
Reactant: Nc1cccc(F)c1O
Solvent: CO
Product: COC(=O)c1nc2cccc(F)c2o1
Temperature: 25 °C
Yield: 53.3 %

Procedure:
A solution of 2-amino-6-fluorophenol (14) (254 mg, 2 mmol) and methyl 2,2,2-trimethoxyacetate (15) (328 mg, 2 mmol) in 3 ml MeOH was heated in micro wave reactor at 140° C. for 1 h. After cooling down to r.t. crystals formed. Filtration followed by washing with MeOH furnished 208 mg of methyl 7-fluorobenzoxazole-2-carboxylate (16) as brown needles. Yield: 53.3%. LC-MS: calculated M=195.15. observed M=195.96.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:34])[N:4]([C:19]2[CH:20]=[C:21]([C:26](=O)[CH2:27][C:28]([O:30]CC)=[O:29])[CH:22]=[CH:23][C:24]=2[CH3:25])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].C([N:37](CC)CC)C.Cl.NO.C([O-])(O)=O.[Na+]>CCO.C(Cl)Cl.[Cl-].[Na+].O>[Br:1][C:2]1[C:3](=[O:34])[N:4]([C:19]2[CH:20]=[C:21]([C:26]3[CH:27]=[C:28]([OH:30])[O:29][N:37]=3)[CH:22]=[CH:23][C:24]=2[CH3:25])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: CCOC(=O)CC(=O)c1ccc(C)c(-n2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Reactant: CCN(CC)CC
Agent: Cl
Agent: NO
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: Cc1ccc(-c2cc(O)on2)cc1-n1c(C)cc(OCc2ccc(F)cc2F)c(Br)c1=O
Reaction time: 2.5 h

Procedure:
A solution of ethyl 3-{3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylphenyl}-3-oxopropanoate (0.20 g, 0.37 mmol), triethylamine (0.06 mL, 0.41 mmol), and hydroxylamine hydrochloride (0.03 g, 0.41 mmol) in EtOH (3.00 mL) was heated overnight at 60° C. with a condenser. Additional triethylamine (0.06 mL) and hydroxylamine hydrochloride (0.03 g) were added. After 2.5 h, the additions of triethylamine and hydroxylamine hydrochloride were repeated. After 1 h, the reaction was concentrated and purified by preparatory HPLC. The product was isolated by freeze-drying and evaporation of the solvent to give a white solid. Dissolved solid in DCM. Upon addition of 5% NaHCO3, solution became a milky emulsion. Added additional DCM and some brine. Organic extracts were dried over Na2SO4, filtered, and concentrated to a pink solid, dried in vacuo (120 mg, 64%). 1H NMR (CD3OD/400 MHz) δ 7.66 (m, 2H), 7.44 (m, 2H), 7.04 (t, 2H, J=8.8 Hz), 6.64 (s, 1H), 5.36 (s, 2H), 2.04 (s, 3H), 2.01 (s, 3H). ES HRMS m/z 503.0415 and 505.0402 (M+H calculated for C23H18BrF2N2O4 requires 503.0413 and 505.0395).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:7]=1[N+:8]([O-:22])=[C:9]1[C:14](=[N+:15]2[O-:20])[C:13]([OH:21])=[CH:12][CH:11]=[CH:10]1.[CH2:23]([NH:25][CH2:26][CH3:27])[CH3:24].CS(C)=O>C(Cl)(Cl)Cl>[CH2:23]([N:25]([CH2:26][CH3:27])[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:7]=1[N+:8]([O-:22])=[C:9]1[C:14](=[N+:15]2[O-:20])[C:13]([OH:21])=[CH:12][CH:11]=[CH:10]1)[CH3:24]
Reactant: CCNCC
Reactant: [O-][n+]1c2cccc(OCCCCl)c2[n+]([O-])c2cccc(O)c21
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Product: CCN(CC)CCCOc1cccc2c1[n+]([O-])c1cccc(O)c1[n+]2[O-]
Temperature: 25 °C
Reaction time: 22 h

Procedure:
5.0 grams of 6-(3-chloropropoxy)-1-phenazinol 5,10-dioxide and 25ml of diethylamine were placed in a flask. To this was added 50ml of dimethylsulfoxide. The reaction mixture was stirred at room temperature for 22 hours. The reaction mixture was then diluted with 400ml CHCl3 and washed first with very dilute acetic acid and then with water until the water washes were neutral. The CHCl3 layer was extracted with 10 percent aqueous HCl. The combined HCl extracts were neutralized with sodium carbonate and extracted with ethyl acetate. The combined ethyl acetate extracts were washed with water, dried over sodium sulfate and concentrated in vacuo. The residue was slurried with ether/pentane (1:1) and filtered to yield red crystals of 6-(3-diethylaminopropoxy)-1-phenazinol 5,10-dioxide, m.p. 78°-80° (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.[C:16]([SiH2:20][O:21][C:22]([CH3:32])([CH3:31])[C:23]1[CH:28]=[C:27](Cl)[N:26]=[C:25]([Cl:30])[CH:24]=1)([CH3:19])([CH3:18])[CH3:17]>>[C:16]([SiH2:20][O:21][C:22]([CH3:32])([CH3:31])[C:23]1[CH:24]=[C:25]([Cl:30])[N:26]=[C:27]([NH:15][C:5]2[CH:6]=[CH:7][C:8]([N:9]3[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:28]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cc(Cl)nc(Cl)c1
Product: COc1cc(Nc2cc(C(C)(C)O[SiH2]C(C)(C)C)cc(Cl)n2)ccc1-n1cnc(C)c1

Procedure:
Prepared in analogy to example 62 from 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine and 4-(tert-butyl-dimethyl-silanyloxymethyl)-2,6-dichloro-pyridine. The title compound was obtained as a yellowish solid (Yield=31%). 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.64 (s, 1H), 7.36 (d, 1H), 7.17 (d, 1H), 6.95-6.85 (m, 2H), 6.75 (s, 1H), 6.73 (s, 1H), 6.68 (s broad, 1H), 4.65 (s, 2H), 3.86 (s, 3H), 2.30 (s, 3H), 0.94 (s, 9H), 0.11 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[CH3:9][NH2:10]>CO>[Cl:1][C:2]1[N:3]=[C:4]([NH:10][CH3:9])[CH:5]=[CH:6][N:7]=1
Reactant: CN
Reactant: Clc1ccnc(Cl)n1
Solvent: CO
Product: CNc1ccnc(Cl)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 27 %

Procedure:
2,4-Dichloropyrimidine (104, 500 mg, 3.30 mmol) was dissolved in methanol (5 mL) having 2.0 M monomethylamine dissolved therein, stirred at room temperature for 3 hours. Then, the methanol solvent was removed under reduced pressure and water was added to the reaction mixture. Organic compounds were extracted with ethyl acetate and evaporated after a treatment with sodium sulfate. Purification was performed by column chromatograph to give the target compound 2-chloro-4-(N-monomethylamino)pyrimidine (106b, 128 mg, 27%) as a yellow solid.
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:25]([O:27][C:28](=[O:44])[CH2:29][NH:30][C:31]([C:33]1[N:34]=[C:35]2[CH:40]=[CH:39][C:38](Cl)=[N:37][N:36]2[C:42]=1[Cl:43])=[O:32])[CH3:26].C(N(C(C)C)C(C)C)C>CN1CCCC1=O>[CH2:25]([O:27][C:28](=[O:44])[CH2:29][NH:30][C:31]([C:33]1[N:34]=[C:35]2[CH:40]=[CH:39][C:38]([NH:18][CH2:17][CH2:16][CH2:15][N:12]3[CH2:13][CH2:14][CH:9]([O:8][CH:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:10][CH2:11]3)=[N:37][N:36]2[C:42]=1[Cl:43])=[O:32])[CH3:26]
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Reactant: CCOC(=O)CNC(=O)c1nc2ccc(Cl)nn2c1Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CNC(=O)c1nc2ccc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn2c1Cl
Temperature: 95 °C
Reaction time: 24 h
Yield: 70.3 %

Procedure:
0.649 g of 4-(diphenylmethoxy)-1-piperidinepropanamine and 0.53 g of N-(3,6-dichloroimidazo[1,2-b]pyridazine-2-carbonyl)glycine ethyl ester were dissolved in 7 ml of 1-methyl-2-pyrrolidone; 0.345 ml of N-ethyldiisopropylamine was added, followed by stirring in an oil bath (90-100° C.) for 24 hours. After cooling, ice water was added, followed by extraction with ethyl acetate; the extract was washed with saline and dried with magnesium sulfate. The dry product was concentrated under reduced pressure; the residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol:triethylamine (185:15:2). The desired fraction was collected and recrystallized from ethyl acetate to yield 0.711 g of the title compound.
Reaction SMILES: [O:1]1[C:9]2[CH2:8][CH2:7][N:6]([S:10]([C:13]3[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=3)(=[O:12])=[O:11])[CH2:5][C:4]=2[CH:3]=[CH:2]1.[Cl-].[NH4+]>O1CCCC1.C1([Mg]Br)C=CC=CC=1>[O:1]1[C:9]2[CH2:8][CH2:7][N:6]([S:10]([C:13]3[CH:20]=[CH:19][C:16]([CH:17]([C:13]4[CH:20]=[CH:19][CH:16]=[CH:15][CH:14]=4)[OH:18])=[CH:15][CH:14]=3)(=[O:12])=[O:11])[CH2:5][C:4]=2[CH:3]=[CH:2]1
Reactant: O=Cc1ccc(S(=O)(=O)N2CCc3occc3C2)cc1
Agent: Br[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(C(O)c2ccccc2)cc1)N1CCc2occc2C1

Procedure:
To a solution of 0.252 g (0.865 mmol) of 4-(6,7-dihydro-4H-furo[3,2-c]pyridin-5-ylsulfonyl)benzaldehyde in 30 ml of tetrahydrofuran, phenylmagnesium bromide in tetrahydrofuran (prepared from 2.0 g of bromobenzene and 0.31 g of magnesium in 30 ml of tetrahydrofuran) was added at room temperature until the starting material disappeared on TLC. To the reaction mixture, aqueous ammonium chloride was added, followed by stirring and 3 extractions with ethyl acetate. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=3/1 to 2/1) to yield the desired product.